Singapore Guideline 2011

Effective 1 April 2011
GUIDANCE ON MEDICINAL PRODUCT

REGISTRATION IN SINGAPORE
Please visit HSAs website at http://www.hsa.gov.sg for the latest

update
GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE APRIL 2011
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HEALTH SCIENCES AUTHORITY HEALTH PRODUCTS REGULATION GROUP Page 2 of 102

TABLE OF CONTENTS
CHAPTER A GENERAL OVERVIEW ............................................................................... 9 SEPTEMBER
1 FOREWORD .................................................................................................................. 9
1.1 Scope of this guidance document ..................................................................... 9
1.2 Medicinal product registration ..........................................................................10
2 APPLICANT RESPONSIBILITIES .................................................................................11
3 DATA PROTECTION ....................................................................................................12
4 PATENT LINKAGE........................................................................................................13
CHAPTER B REGISTRATION PROCESS ......................................................................14

5 PRE-SUBMISSION PREPARATION .............................................................................14
5.1 Application types ..............................................................................................14
5.2 Evaluation routes .............................................................................................16
5.3 Pre-Submission consultation ............................................................................16
5.3.1 Pre-submission inquiry ........................................................................16
5.3.2 Pre-submission meeting ......................................................................16
6 APPLICATION SUBMISSION .......................................................................................17
6.1 PRISM application form ...................................................................................17
6.2 Registration dossier .........................................................................................17
6.2.1 Softcopy and Hardcopy requirements ..................................................18
6.2.2 Language ............................................................................................19
6.2.3 Certifying non-original documents........................................................20
7 APPLICATION SCREENING.........................................................................................20
8 APPLICATION EVALUATION .......................................................................................21
9 REGULATORY DECISION ...........................................................................................23
10 POST-APPROVAL CHANGES......................................................................................24
11 FEES............. ................................................................................................................24
11.1 Screening fee...................................................................................................24
11.2 Evaluation fee ..................................................................................................24
11.2.1 Change in evaluation fees ...................................................................25
11.2.1.1 Change of Application within the Same Application Type...... 25
11.2.1.2 Change of Application between Different Application Types . 25
CHAPTER C NEW DRUG APPLICATION SUBMISSION ...............................................26

12 APPLICATION TYPES ..................................................................................................26
13 EVALUATION ROUTES ................................................................................................26
13.1 Full evaluation route.........................................................................................27
13.2 Abridged evaluation route ................................................................................27
13.2.1 Priority review ......................................................................................27
13.2.2 Applications for non-prescription medicines .........................................27
13.3 Verification evaluation route .............................................................................28
13.3.1 NDA-3 applications ..............................................................................29
14 DOCUMENTARY REQUIREMENTS .............................................................................29
14.1 Administrative documents ................................................................................29
14.2 CTD overview and summaries .........................................................................35
14.3 Quality documents ...........................................................................................36
14.3.1 Body of Data Drug Substance...........................................................36
14.3.2 Body of Data Drug Product ...............................................................39
14.4 Non-clinical documents ....................................................................................41
14.5 Clinical documents ...........................................................................................41
14.6 Specific documentary requirements for each evaluation route .........................42
14.6.1 Full evaluation route ............................................................................42
14.6.2 Abridged evaluation route ....................................................................42
14.6.3 Verification evaluation route.................................................................42

CHAPTER D GENERIC DRUG APPLICATION SUBMISSION ..........................................45

15.1 Generic product ...............................................................................................45 SEPTEMBER
15.2 Singapore reference product ............................................................................45
16.1 Abridged evaluation route ................................................................................46
16.2 Verification evaluation route .............................................................................46
17.2 CTD overview and summaries .........................................................................52
17.3.1 Body of Data Drug Substance...........................................................53
17.3.2 Body of Data Drug Product ...............................................................56
17.4 Non-clinical and clinical documents..................................................................59
17.5 Specific documentary requirements for each evaluation route .........................59
CHAPTER E BIOSIMILAR PRODUCT APPLICATION SUBMISSION ...........................62

18.1 Biosimilar product ............................................................................................62
18.2 Reference product ...........................................................................................63
20.2 CTD overviews and summaries .......................................................................64
20.4 Non-clinical and clinical documents..................................................................64
CHAPTER F POST-APPROVAL PROCESS ..................................................................65

21 VARIATION APPLICATION PROCESS ........................................................................66
21.1 Pre-Submission preparation .............................................................................66
21.1.1 Pre-submission inquiry ........................................................................67
21.1.2 Pre-submission meeting ......................................................................67
21.2 Application submission.....................................................................................67
21.2.1 PRISM application form .......................................................................67
21.2.2 Variation application dataset ................................................................67
21.2.2.1 Language ............................................................................. 68
21.2.2.2 Certifying non-original documents......................................... 69
21.3 Application screening .......................................................................................69
21.4 Application evaluation and Regulatory decision ...............................................69
21.5 Fees.................................................................................................................70
21.5.1 Screening fee ......................................................................................70
21.5.2 Evaluation fee ......................................................................................70
CHAPTER G MAJOR VARIATION (MAV) SUBMISSION ...............................................72

22 MAV-1 SUBMISSIONS..................................................................................................72
22.1 Evaluation routes .............................................................................................72
22.1.1 Full evaluation route ............................................................................72
22.1.2.1 Applications for non-prescription medicines .......................... 73
22.2 Documentary requirements ..............................................................................73
22.2.1 Administrative documents ....................................................................74
22.2.2 CTD overviews and summaries ...........................................................75
22.2.3 Quality documents ...............................................................................75

22.2.4
Non-clinical and clinical documents .....................................................75
22.2.5
Specific documentary requirements for each evaluation route .............75
22.2.5.1 Full evaluation route ............................................................. 75 SEPTEMBER
22.2.5.2 Abridged evaluation route ..................................................... 75
22.2.5.3 Verification evaluation route.................................................. 75
23 MAV-2 SUBMISSIONS..................................................................................................76
23.1 Eligibility criteria ...............................................................................................76
23.1.1 Me-too reclassification .......................................................................77
23.2 Documentary requirements ..............................................................................77
23.2.1 Me-too reclassification .......................................................................78
CHAPTER H MINOR VARIATION (MIV) SUBMISSION ..................................................79

24 MIV SUBMISSIONS ......................................................................................................79
CHAPTER J SUBMISSION OF A PRISM APPLICATION FORM ...................................80

25 SUBMITTING A PRODUCT APPLICATION ..................................................................80
25.1 Sections of a PRISM Application ......................................................................81
25.1.1 Section 1 Company Particulars .........................................................81
25.1.2 Section 2 Applicant Particulars .........................................................81
25.1.3 Section 3 Application Details.............................................................82
25.1.3.1 Section 3.1 Type of Application.......................................... 83
25.1.3.2 Section 3.2 Type of Product ............................................... 83
25.1.3.3 Section 3.3 Reference Product .......................................... 83
25.1.3.4 Section 3.4 Type of Dossier ............................................... 83
25.1.3.5 Section 3.5 Type of Format ................................................ 84
25.1.4 Section 4 Product Information ...........................................................84
25.1.4.1 Section 4.1 Product Name ................................................. 84
25.1.4.2 Section 4.2 Product Formula.............................................. 85
25.1.4.3 Section 4.3 Ingredients Derived From Human Blood/Animal
Sources .............................................................................. 90
25.1.4.4 Section 4.4 Pharmacotherapeutic Group ........................... 91
25.1.4.5 Section 4.5 Dosage Form .................................................. 91
25.1.4.6 Section 4.6 Route of Administration ................................... 92
25.1.4.7 Section 4.7 Packaging, Shelf Life and Storage Conditions . 92
25.1.4.8 Section 4.8 Forensic Classification .................................... 94
25.1.4.9 Section 4.9 Registration Status in Other Countries ............ 94
25.1.4.10 Section 4.10 Product Owner Information ........................... 96
25.1.5 Section 5 Manufacturer Particulars ...................................................96
25.1.5.1 Active Substance Manufacturer ............................................ 97
25.1.5.2 Finished Product Manufacturer ............................................. 98
25.1.6 Section 6 Information on Company Responsible for Batch Release100
25.1.7 Section 7 Supporting Attachments ..................................................102

LIST OF APPENDICES
APPENDIX 1 Target Processing Timelines SEPTEMBER
APPENDIX 2A Application Checklist (ICH CTD NDA and GDA)
APPENDIX 2B Application Checklist (ICH CTD MAV)
APPENDIX 3A Application Checklist (ASEAN CTD NDA and GDA)
APPENDIX 3B Application Checklist (ASEAN CTD MAV)
APPENDIX 4 Flowchart for Translation of Non-English Documents
APPENDIX 5 Guideline on Submission for Non-Prescription Medicinal Products
APPENDIX 6 Points to Consider for Singapore Labelling
APPENDIX 7 Patent Declaration Form
APPENDIX 8 Singapore Quality Overall Summary for Chemical Drugs
APPENDIX 9 Singapore Quality Overall Summary for Biologics
APPENDIX 10 Guideline on the Registration of Human Plasma-derived Medicinal

Products
APPENDIX 11 Guideline on the Registration of Human Medicinal Products Containing

Materials of Animal Origin
APPENDIX 12 Product Interchangeability and Biowaiver Request for Chemical

Generic Drug Applications
APPENDIX 12A Quick Reference on Acceptability of Bioequivalence Study
APPENDIX 13 Guideline on Submission for Indian Generic Products Under the CECA
Scheme
APPENDIX 14 MIV Filing and Submission Inquiry Form
APPENDIX 15 Guideline on Minor Variation Applications (MIV-1 & MIV-2) for

Chemical Drugs
APPENDIX 16 Guideline on Minor Variation Applications (MIV-1 & MIV-2) for Biologics
APPENDIX 17 Guidance on Registration of Similar Biological Products in Singapore

ABBREVIATIONS AND ACRONYMS

ACPM Advisory Committee on Prescription Medicines SEPTEMBER
ACRA Accounting and Corporate Regulatory Authority
ACTD ASEAN Common Technical Document
ACTR ASEAN Common Technical Requirements
ALD Audit and Licensing Division
ASEAN Association of Southeast Asian Nations
ATC Anatomical Therapeutic Chemical
BA Bioavailability
BE Bioequivalence
BP British Pharmacopoeia
BSE Bovine Spongiform Encephalopathy
BWP Blood Working Party
CECA Comprehensive Economic Cooperation Agreement
CEP Certificate of Suitability (Ph Eur monograph)
CHMP Committee for Medicinal Products for Human Use (formerly Committee for
Proprietary Medicinal Products) (EU)
CMC Chemistry, Manufacturing and Controls
CMS Concerned Member State
COA Certificate of Analysis
COO Country of Origin (Finished product manufacturer)
CPP Certificate of Pharmaceutical Product
CPMP Committee for Proprietary Medicinal Products
CTD Common Technical Document
CVMP Committee for Medicinal Products for Veterinary Use
DMF Drug Master File
EDQM European Directorate for the Quality of Medicines
EMA European Medicines Agency (EU)
FDA Food and Drug Administration (US)
FTA Free Trade Agreement
GDA Generic Drug Application
GSL General Sale List medicine
GMP Good Manufacturing Practice
HIV Human Immunodeficiency Virus
HPRG Health Products Regulation Group
HSA Health Sciences Authority (Singapore)
ICH International Conference on Harmonisation (of Technical Requirements for
Registration of Pharmaceuticals for Human use)
INN International Non-proprietary Names
JP Japanese Pharmacopoeia
MAV Major Variation
MHRA Medicines and Healthcare Products Regulatory Agency (UK)
MIV Minor Variation
NDA New Drug Application
NfG Note for Guidance
OTC Over-The-Counter
P Pharmacy only medicine
PD Pharmacodynamics
PDF Portable document format
Ph. Eur. European Pharmacopoeia
PI Package Insert (Singapore), Product Information
PIC/S Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-
operation Scheme
PIL Patient Information Leaflet
PK Pharmacokinetics

PMF Plasma Master File

POM Prescription Only Medicine
PRISM Pharmaceutical Regulatory and Information System SEPTEMBER
QOS Quality Overall Summary
RMS Reference Member State
SPC Summary of Product Characteristics
SOP Standard Operating Procedure
SQOS Singapore Quality Overall Summary
TGA Therapeutic Goods Administration (Australia)
TSE Transmissible Spongiform Encephalopathy
URL Uniform Resource Location
USP United States Pharmacopeia
WHO World Health Organisation
WTO World Trade Organisation

CHAPTER A GENERAL OVERVIEW
1 FOREWORD SEPTEMBER
This guidance document is intended to provide assistance in the submission of

applications relating to medicinal products in Singapore, including applications for a new
Product Licence for a medicinal product (i.e. drug registration) and applications to make
variations to an existing Product Licence.
This document should be read in conjunction with the current laws governing
pharmaceutical products in Singapore, which include the following:
Medicines Act (Chapter 176)

Poisons Act (Chapter 234)
Misuse of Drugs Regulations subsidiary legislation under the Misuse of Drugs Act
(Chapter 185)
Sale of Drugs Act (Chapter 282)
Medicines (Advertisement and Sale) Act (Chapter 177)
If there is any contradiction between this document and any written law, the latter shall
take precedence.
As the licensing authority under the Medicines Act, the Chief Executive of the Health
Sciences Authority (HSA) and the officers in HSAs Health Products Regulation Group
(HPRG) have the authority to grant, renew, vary, suspend and revoke licences and
certificates under the Medicines Act. Applicants are strongly encouraged to familiarise
themselves with the contents of this guidance document before submitting their
applications.
1.1 Scope of this guidance document
This guidance document describes the procedures and requirements for submitting an
application to obtain a new Product Licence or to make variations to an existing
registered medicinal product.
Applicants are expected to comply with the procedures and requirements laid out in this
guidance. However, alternative approaches to the specified procedures and requirements
may be accepted, provided there is adequate scientific evidence and justification. Any
alternative approach should be discussed with HSA and agreed upon in advance in order
to avoid rejection of the application. Conversely, HSA may request for information or
specify conditions not described in this document that is deemed necessary to adequately
assess the safety, efficacy and quality of the product under evaluation.
Take note that, within this document, the term quality may be used to describe chemical,
pharmaceutical and biological data while the term non-clinical may be used to describe
preclinical, pharmacological and toxicological data.
Applicants are advised to check HSAs website1 for the latest version of this guidance
document and other related medicinal product registration guidelines.
1
http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/western_medicines/guidelines.html

1.2 Medicinal product registration
Under the Medicines Act, a medicinal product refers to any substance or article (not SEPTEMBER
being an instrument, apparatus or appliance) which is manufactured, sold, supplied,
imported or exported for use wholly or mainly in the following ways:
use by being administered to one or more human beings for a medicinal purpose;
and/or,
use as an ingredient in the preparation of a substance or article which is to be
administered to one or more human beings for a medicinal purpose.
A medicinal purpose means any one or more of the following purposes:

treating or preventing disease;
diagnosing disease or ascertaining the existence, degree or extent of a
physiological condition;
contraception;
inducing anaesthesia; and/or,
otherwise preventing or interfering with the normal operation of a physiological
function, whether permanently or temporarily, and whether by way of terminating,
reducing or postponing, or increasing or accelerating, the operation of that function
or in any other way.
A Product Licence is required before a medicinal product can be sold or supplied in

Singapore (Medicines Act, section 5), unless otherwise exempted under the law. Each
Product Licence is specific to a product:
of a particular name;
with a particular formulation;
in a particular dosage form (i.e. physical presentation) and strength; and
with a particular set of approved indications and directions for use.
Any changes to the above parameters may result in the need to submit an application to
vary the existing Product Licence or possibly obtain a new Product Licence altogether.
Forensic classification
Medicinal products approved for registration in Singapore are classified under three
forensic classes:
Prescription Only Medicine (POM);
Pharmacy only medicine (P); or
General Sale List medicine (GSL).
Prescription Only Medicines (POM) control is required in the following situations:

a) The product poses a direct2 or indirect3 danger to human health, even when used
correctly, if used without medical supervision;
b) The product is frequently and widely used incorrectly and, as a result, is likely to
present a direct or indirect danger to human health;
c) The product requires further investigation into its activity and/or side effects; or,
d) The product is normally prescribed by a doctor or dentist to be administered
parenterally.
The following also needs to be taken into consideration when deciding whether a product
should be classified as a POM:
2
Direct danger: Adverse reactions for which there is no preventive action or which are serious, severe or of
high frequency
3
Indirect danger: Masking of an underlying condition that requires medical attention e.g. cancer, heart
disease

i. Whether the product contains a substance which is listed in either the Narcotic Drug
Convention or the Psychotropic Substances Convention;
ii. Whether the product is likely to lead to medicinal abuse or addiction if used incorrectly SEPTEMBER
or to be used for illegal purposes;
iii. Whether the product contains a substance which, by reason of its novelty or
properties, has the potential to fall within point (ii) above;
iv. Whether the product, by reason of its pharmaceutical characteristics, is reserved for
treatments which can only be instituted in a hospital;
v. Whether the product is used in the treatment of conditions which must be diagnosed
in a hospital or in an institution with special diagnostic facilities; or,
vi. Whether the product is intended for outpatients but may produce serious side effects,
which would require medical supervision throughout the treatment.
Pharmacy Only Medicines (P) control is required for products that possess characteristics
which are not sufficiently critical to warrant POM control but for which the following apply:
a) Consultation with a pharmacist is necessary to confirm the appropriate choice of
therapy;
b) The contraindications, drug interactions, precautions or warnings need reinforcement
by a pharmacist or are not easily recognised by the purchaser; or,
c) Special precaution is needed in the storage and handling of the product.
General Sales List Medicines (GSL) control is sufficient in the following situations:
a) The product is reasonably safe and can be sold or supplied without the need for
supervision by a registered doctor, dentist or pharmacist;
b) The contraindications, drug interactions, precautions and warnings are easily
recognised by the consumer; and,
c) The hazard to health, the risk of misuse, the risk of misdiagnosis, or the need to take
special precaution in the storage and handling the product is small.
As healthcare products are becoming increasingly complex e.g. combinations of a

medicinal product and medical device the regulation of such products will be based on
how they are classified. Thus, if there is doubt about the products classification, it is
recommended that the applicant seek clarification via email to
HSA_MedProd_Enquiry@hsa.gov.sg.
2 APPLICANT RESPONSIBILITIES
Applicants should note that they are responsible for the medicinal products quality,
efficacy and safety throughout its life cycle. What this means is that the applicants
responsibilities start with the registration of the medicinal product and end when the
product licence expires or is cancelled. Since the products quality, efficacy and safety
can change at any time during the course of its life cycle, it is the applicants responsibility
to inform HSA when these changes occur as per the current guidelines.
The applicants responsibilities include:
i. To ensure that all of the information given in the application form and supporting
documents are true and valid, and that all current data, reports and information
relevant to the benefit/risk assessment of the medicinal product have been supplied
at the time of the application submission;
ii. To ensure that all information and material included in the application dossier on
paper exactly matches the information and material included in the electronic
submission dossier. No information has been added, removed, or changed;

iii. To declare at the time of submission to HSA that the application submitted to HSA
has not been rejected, withdrawn, approved via appeal process or pending deferral
by any drug regulatory agency or HSA reference regulatory agencies, with reasons SEPTEMBER
in each case if applicable;
iv. To notify HSA of any change in the information submitted in the application and of
any new significant safety information during the course of evaluation and
throughout the products life cycle in the Singapore market;
v. To notify HSA if the application submitted to HSA has been rejected, withdrawn or
deferred by any drug regulatory agency or HSA reference regulatory agencies, with
reasons in each case if applicable, throughout the products life cycle in the
Singapore market;
vi. To respond to HSAs queries or requests for more data for review, within the
timelines stipulated by HSA;
vii. To ensure that the product will be sold, supplied and recommended for use in
accordance with the approved PI/PIL and in compliance with all licence conditions,
applicable legislation and guidelines;
viii. To ensure that all post-approval licensing conditions attached to the product licence
and post-approval commitments are fulfilled within the stipulated timelines;
ix. To notify HSA of any changes to the products quality, efficacy or safety throughout
the products life cycle in the Singapore market;
x. To notify HSA if the products marketing authorisation is withdrawn by any drug

regulatory agency or the product is no longer registered in any country, with the
reasons in each case, throughout the products life cycle in the Singapore market;
and,
xi. To ensure that all information provided to HSA is true and correct to the best of
his/her knowledge and that he/she has not wilfully suppressed any material fact.
The applicant is aware that if he/she makes any false statement, representation or
declaration in connection with an application submitted to HSA, he/she shall be
guilty of an offence under the Medicines Act (Chapter 176).
3 DATA PROTECTION
Sections 19A and 19B were included in the Medicines Act in 1998 to enable Singapore to
comply with its obligations under Article 39 of the WTO TRIPS Agreement. Article 39
requires countries to protect the test data of a pharmaceutical product against disclosure
and unfair commercial use.
Section 19D was introduced in July 2004, in order for Singapore to fulfil its obligations
under Article 16.8.1 of the US-Singapore Free Trade Agreement (FTA), stating that the
licensing authority may not grant marketing approval for a product on the basis of the
grant of an earlier approval for a period of 5 years from the date of the earlier approval,
unless with the consent of the holder of the earlier approval.

4 PATENT LINKAGE
Provisions for linkage between patent and marketing approval were introduced in July SEPTEMBER
2004, under Section 12A of the Medicines Act, in order for Singapore to fulfil its
obligations under Article 16.8.4(c) of the US-Singapore FTA.
The Medicines Act provides for a system of patent declaration by the applicant of a
product licence and power for the licensing authority to revoke a product licence in
relation to patent infringement and patent declaration. Relevant parts include sections
12A, 16 and 20 of the Act, and paragraph 5B of the Medicines (Licensing, Standard
Provisions and Fees) Regulations.
All applications for new product licences shall be accompanied by patent declarations
required under Section 12A of the Medicines Act. The applicant is required to furnish the
patent declaration using the form set out in Part I of the Sixth Schedule of the Medicines
(Licensing, Standard Provisions and Fees) (Amendment) Regulations 2004 at the time of
application submission, and at any other such time as HSA may require. As a general
guidance, a confirmatory declaration will be requested when an approvable regulatory
decision is issued. The applicant is required to furnish the confirmatory declaration within
the timeframe stipulated by HSA.
All declarations required under Section 12A of the Medicines Act should be submitted in
hard copies on original letterhead, signed by the person authorised to make the
declaration on behalf of the applicant. The authorised person is ordinarily an officer of the
company such as a director, the company secretary as registered with ACRA, or
equivalent. Evidence of such authorisation by the applicant of that person to make the
declaration on its behalf shall be submitted together with the declaration. Examples of
evidence of authorisation include a resolution of board of directors, a resolution of a
general meeting of the company, or an extract of the relevant portion of the companys
articles of association. Declaration forms must bear the original signatures of the
authorised person and the company stamp of the applicant.
Under Section 12A (3) of the Medicines Act, the licensing authority may, if the applicant
has declared that in his opinion and to the best of his belief the patent is invalid or will not
be infringed by the performing of the act for which the licence is sought (i.e. Category B
patent declaration), or if the licensing authority considers it appropriate in any particular
case, require the applicant to serve a notice to the proprietor of the patent in the form
prescribed in Part II of the Sixth Schedule of the Medicines (Licensing, Standard
Provisions and Fees) (Amendment) Regulations 2004.
If (i) there is a patent in force in respect of the medicinal product to which the application
relates, (ii) the applicant is not the proprietor of the patent, (iii) the proprietor has not
consented to nor acquiesced in the grant of the product licence, and (iv) the applicant is
requesting for grant of product licence after the expiry of the patent (i.e. Category A3
patent declaration), then such an application may not be made earlier than 18 months
before the expiry of the patent.
Applicants should take note that the information contained in this section is for the
purpose of guiding applicants in their patent declarations. Applicants requiring legal
advice should seek the assistance of their own legal counsel.

CHAPTER B REGISTRATION PROCESS

One part of a products life cycle is the pre-marketing activities, namely registration of a
product prior to market entry. The registration process involves a series of steps as seen
in Figure 1 below:
PRE-SUBMISSION
PREPARATION
APPLICATION
NON-ACCEPTANCE / SUBMISSION
WITHDRAWAL
APPLICATION
SCREENING
ACCEPTANCE
APPLICATION
EVALUATION
NON-APPROVAL /
WITHDRAWAL
REGULATORY
DECISION
APPROVAL
POST-APPROVAL
CHANGES
Figure 1. Registration Process for a Medicinal Product
For information on the registration processing time, refer to Appendix 1 of this guidance
document.
5 PRE-SUBMISSION PREPARATION
The first step in the registration process is one of the most important because it involves
i. Knowing which application to apply for;
ii. Knowing which evaluation route to choose; and,
iii. Arranging for a pre-submission consultation with HSA for advice, if required.
5.1 Application types
In applying for a new Product Licence for a medicinal product in Singapore, there are two
categories of applications: a new drug application (NDA) and a generic drug application
(GDA):


NDA-1: For the first strength of a product containing a new* chemical or biological entity.
NDA-2: i) For the first strength of a new drug product SEPTEMBER
containing a new* combination of registered chemical or biological entities;
containing registered chemical or biological entity(ies) in a new dosage
form;
containing registered chemical or biological entity(ies) for use by a new
route of administration; or,
containing registered chemical or biological entity(ies) for new indication(s),
dosage recommendation(s) and/or patient population(s).
ii) For new drug products that do not fall under the requirements for NDA-1,
NDA-3 or GDA.
NDA-3: For subsequent strength(s) of a new drug product that has been registered or has
been submitted as an NDA-1 or NDA-2. The product name, pharmaceutical
dosage form, indication, dosing regimen and patient population shall be the
same as that for the NDA-1 or NDA-2.
* Has not been registered before in Singapore

GDA-1: For the first strength of a generic chemical product.
GDA-2: For subsequent strength(s) of the generic chemical product that has been
registered or has been submitted as a GDA-1. The product name and
pharmaceutical dosage form shall be the same as that for the GDA-1.
A generic product is essentially similar to a currently registered product in Singapore

(known as the Singapore reference product) but excludes biologics. Essentially similar4
is defined as having the same qualitative and quantitative composition in terms of active
substances, having the same pharmaceutical form and being bioequivalent. By extension,
the concept of essentially similarity also applies to different conventional immediate
release oral dosage forms (i.e. tablets and capsules) which contain the same active
ingredient(s).
A schematic diagram to illustrate the various types of applications is seen in Figure 2

below:
YES
NO Essentially similar NO Contains new NDA 1

IS PRODUCT to a currently chemical or
REGISTERED? registered product? biological entity?
NDA 2
YES YES NO NDA 3
YES
GDA 1
Post-Approval First strength of
Process, Chapter F product?
GDA 2
NO
Figure 2. Schematic diagram of application routes for drug registration.
4
Note for Guidance on the Investigation of Bioavailability and Bioequivalence. CPMP/EWP/QWP/1401/98.

5.2 Evaluation routes
There are three types of evaluation routes for registration of a new product: SEPTEMBER
Full dossier: Applies to any product that has not been approved by any drug
regulatory agency at the time of submission.
Abridged dossier: Applies to any product that has been evaluated and approved by
at least one drug regulatory agency.
Verification dossier: Applies to any product that has been evaluated and approved by
HSAs reference drug regulatory agencies, which include EMA*,
US FDA, Health Canada, TGA and UK MHRA#.
* For products approved via the Centralised Procedure
# For products approved via the national procedure or where MHRA acted as the RMS for the MRP or
Decentralised Procedures in Europe
Applicants should be familiar with the eligibility criteria for each evaluation route for the
application type to be submitted because the documentary requirements for the full,
abridged and verification routes for an NDA and GDA are different.
Applicants should refer to Chapters C, D and E for detailed information about the
selection of appropriate evaluation routes for NDA, GDA and biosimilar product
applications, respectively.
NOTE: Refer to Section E for more information on the application types and
evaluation routes available for biosimilar products.
5.3 Pre-submission consultation
Applicants are encouraged to contact HSA prior to submission of an application if

questions arise or clarification is required. There are two methods to contact HSA:
i. Pre-submission Inquiry via email

ii. Pre-submission Meeting
Applicants are to note that all advice given by HSA will be based on knowledge that is
current at the time of the consultation. Such advice is not binding and does not have a
direct bearing on the eventual outcome of the application concerned.
5.3.1 Pre-submission inquiry
The applicant may submit a pre-submission inquiry via e-mail if any clarification on
medicinal product registration is needed prior to submission. The e-mail address is:
HSA_MedProd_Registration@hsa.gov.sg. The subject of the e-mail should state, Pre-
submission inquiry, in order for the e-mail to be sent to the relevant officer.
Once the inquiry has been received, an officer will look into the matter and a response will
be sent back to the applicant.
5.3.2 Pre-submission meeting
For complex issues relating to an impending submission, applicants are advised to

consult with HSA in a pre-submission meeting. The request for a consultation should be

made in writing, with the purpose, agenda and proposed date & time for the meeting, via
email to HSA_MedProd_Registration@hsa.gov.sg.
SEPTEMBER
For a submission under the full evaluation route, the applicant is required to notify HSA
via a pre-submission meeting two months prior to the intended submission date of the
application dossier.
6 APPLICATION SUBMISSION
Application submission comprises of two parts: the PRISM application form and the
registration dossier.
6.1 PRISM application form
All applications must be made on-line via PRISM. Refer to Chapter J for guidance notes
for submitting a PRISM application.
6.2 Registration dossier
The registration dossier contains the documents to support the evaluation of the
submitted application.
The complete dossier should be submitted within 2 working days after the PRISM
application submission to prevent delays in processing of the application. The date of
submission will be defined as the date when HSA receives the complete dataset for
the application.
Registration dossiers should be in a CTD format. The CTD provides a common format for
the preparation of a well-structured submission dossier. It uses a modular framework
described in ICH Topic M4 5 or the ASEAN guidelines on the Common Technical
Document for Registration of Pharmaceuticals for Human use: Organisation of the
Dossier6. This guidance document should be read in conjunction with the most recent
version of the ICH CTD and the ASEAN CTD (ACTD) guidance documents.
Thus, the dossier will be in one of the two formats, either the ICH CTD or the ACTD
format. According to the chosen format, the documents will be grouped into five Modules
(ICH CTD) or four Parts (ACTD). The main differences between these two formats are the
numbering and naming of the sections, as seen in Table 1:
Table 1. Format of the ICH CTD and ACTD.

Documents Location in
ICH CTD ACTD
Administrative Documents and Product Module 1 Part I
Information
Common Technical Document Overview Module 2 Incorporated in Parts II, III and
and Summaries IV
Quality documents Module 3 Part II
Non-clinical documents Module 4 Part III
Clinical documents Module 5 Part IV
5
http://www.ich.org/
6

NOTE: It is important to note that the implementation and use of the CTD
represents a work in progress. It is expected that future refinements to this SEPTEMBER
guidance document will continue to be necessary as a result of experience gained.
The CTD format cannot be changed once the application is submitted. Any subsequent
variation applications for the product should follow the same format.
6.2.1 Softcopy and Hardcopy requirements
In moving towards a greener environment, submission of the complete registration

dossier i.e. Modules 1 to 5 of the ICH CTD or Parts I to IV of the ACTD should be in
electronic format. But there is one exception: documents which require proof of
authenticity (e.g. CPPs, approval letters not available online, authorisation letters, GMP
certificate, patent declaration, declaration letters, etc) should be submitted in electronic
and hard copy format.
Applicants should ensure that all soft copies e.g. scanned documents of the dossier
are legible as illegible soft copies will cause unnecessary delays in the registration
process.
Table 2 and 3 outline the softcopy requirements for NDAs and GDAs submitted via the
full, abridged or verification evaluation route in either ICH or ACTD, respectively:
Table 2. Soft and Hard Copy Requirements for ICH CTD dossiers.
#
CTD Requirement
ICH CTD NDA (F) NDA (A) NDA (V) GDA (A + V)
Softcopy Hardcopy Softcopy Hardcopy Softcopy Hardcopy Softcopy Hardcopy
+ + + +
Module 1 PRISM 1 set PRISM 1 set PRISM 1 set PRISM 1 set
Module 2 PRISM/CD PRISM/CD PRISM/CD
PRISM/CD N/A N/A N/A N/A
Module 4 N/A N/A N/A
#
F: full route; A: abridged route; V: verification route; N/A: not applicable
+:
Only documents which require proof of authenticity are required to be submitted in hardcopy for Module 1
(e.g. CPPs, approval letters not available online, authorisation letters, GMP certificate, patent declaration,
declaration letters, etc)
Table 3. Soft and Hard Copy Requirements for ACTD dossiers.

#
CTD Requirement
ACTD NDA (F) NDA (A) NDA (V) GDA (A + V)
Softcopy Hardcopy Softcopy Hardcopy Softcopy Hardcopy Softcopy Hardcopy
+ + + +
Part I PRISM 1 set PRISM 1 set PRISM 1 set PRISM 1 set
Part II PRISM/CD PRISM/CD PRISM/CD
Overview Overview
Part III PRISM/CD N/A Only: N/A Only: N/A N/A N/A
PRISM/CD PRISM/CD
Part IV PRISM/CD PRISM/CD PRISM/CD
#
F: full route; A: abridged route; V: verification route; N/A: not applicable
+:

While Module 1/ Part I must be submitted in softcopy, it must also be submitted in

hardcopy, notably for documents that require proof of authenticity, such as Letters of
Authorisation, GMP certificates, CPPs, patent declaration forms and so forth. Official SEPTEMBER
documents issued by other drug regulatory agencies, declaration letters and patent
declaration form should also be submitted as the original copy; if these documents cannot
be submitted as originals, then refer to section 6.2.3 for more information on certifying
non-original documents. Applicants should also ensure that submitted electronic copies
are identical to the hardcopy documents.
For Modules 2 to 5/Parts II to IV, applicants can opt to attach the documents either in full
into PRISM section 7 (Supporting Attachments) or submit the softcopies (e.g. PDF
format) in a CD/DVD. However, applicants are advised not to combine PRISM
attachments with a CD/DVD submission i.e. all supporting documents must be attached
in PRISM or all supporting documents submitted in a CD/DVD.
In order to ensure that the dossier is complete, application checklists for both ICH CTD
and ACTD dossiers are provided in Appendix 2A and 3A, respectively. Each checklist
states the required documents for each dossier type and application type. Refer to the
specific Appendices for more details.
When submitting a CD/DVD, applicants are encouraged to organise the dossier via the
CTD format with folders and subfolders and to include bookmarks to facilitate
screening/reading of the reports.
Applicants must ensure that access to the CD/DVD is not restricted. If so, the applicant
must provide the password(s) to access the CD/DVD contents.
Upon acceptance of the application for evaluation, applicants will be notified if additional
copies of clinical documents (in CD/DVD) will be required.
6.2.2 Language
Information and documents supporting an application, such as certificates, approval

letters and approved product labels, must be in English and authenticated. If documents
are not originally in English, applicants should refer to Appendix 4 for the flow chart for
the translation of non-English documents.
Authentication of foreign documents for use in Singapore is required when the

authenticity of the documents cannot be determined.
If the foreign document is an original and bears the seal and signature of a recognised
government agency, the document does not require notarisation. Any other type of
document, such as declarations, translations, photocopies, documents lacking an original
signature, etc., must be notarised by a notary public in the country where the document
was issued before the document can be authenticated. The notary public will sign the
document and affix their seal. Notarisation is generally not required for documents
executed in Singapore for use in Singapore.
As an example, for notarisation, the information included on the document could be:
The name of the notary;
A statement that the notary is duly admitted to practice in the place of issue of the
certificate;
The names of the signatories and the capacity in which they have executed the
document, whether on their own behalf or in an official or representative capacity;

A statement authenticating the signatures of the parties and, where appropriate,

indicating that evidence has been produced to the notary proving the capacity in
which they have executed the document; SEPTEMBER
The place and date of issue of the notarial certificate; and
The signature and seal of the notary.
Authentication, also known as legalisation or consularisation, refers to the process

whereby the origin of a document is attested. Authentication of documents in support of
applications made to HSA can be done by:
The Ministry of Foreign Affairs of the country in which the document was issued; or,
The Singapore Embassy/Consulate in the country where the document was issued.
Applicants are advised to consult the Singapore Embassy/Consulate in the country where
the document originated on local requirements for document legalisation, as these may
deviate from the process as outlined in the preceding paragraph.
Certificates and documents issued in English by drug regulatory agencies do not require
authentication.
Apostille
By international agreement, an apostille can be issued for documents that are to be used
in another country that is party to the Hague convention. When an apostille stamp is
attached to a document, it is exempted from all forms of confirmation i.e. no further
legalisation from a foreign embassy is normally required. Although Singapore at present
is not a party of the Hague Convention, an apostille is acceptable for the authentication of
documents that are submitted to HSA as part of the application dossier.
6.2.3 Certifying non-original documents
A certified true copy certifies that the photocopy presented is a true and accurate copy of
the original document. Acceptable certification of documents to support product
applications to HSA can be done by the Company Director or Company Secretary as
registered with ACRA or above, or by an independent authority such as a lawyer, notary
public, Commissioner for Oaths/Declarations/Affidavits, Justice of Peace, the original
issuer of the document or Embassy/Consulate. A notarised copy is the same as a
certified true copy.
A certified true copy of approval letters requires certification by the drug regulatory
agency that issued the approval letter, a notary public or the Singapore
Embassy/Consulate in the country where the approval letter was issued. Certification of
approval letters is not required in the event the approval letter is available on the drug
regulatory agencys website. In this instance, applicants can provide the internet address
(URL) for validation by HSA.
7 APPLICATION SCREENING
After PRISM and dossier submission, the application will be screened to ensure that the
correct application type has been chosen and that there are no deficiencies that would
delay the registration process.
If the application type needs to be re-categorized, for example from NDA-2 to NDA-3 or
GDA-1 to NDA-2, the applicant will be notified and subsequently, the PRISM application
will be amended as described in section 11.2.1.

If any deficiencies are identified, a screening query letter via Input Request will be issued
to the applicant. The stop-clock starts whenever HSA requests for clarification or
additional information. The stop-clock ends when HSA receives a complete and SEPTEMBER
satisfactory response to the query.
The applicant will be required to submit all of the requested information and documents
within 30 calendar days from the date of the screening query letter. Any deficiencies
noted must be addressed before the dossier can be accepted for evaluation.
When the response to the screening query letter has been received, the requested
information and documents will be screened for completeness. The dossier will be
accepted when all requested information, and hence, the registration dossier, is found to
be adequate.
An acceptance notice will be issued to the applicant via email upon acceptance of an
application. The date of acceptance of the application will be considered as the start of
the evaluation timeline.
If the applicant fails to provide the requested information, or the submitted information is
incomplete or contains unsolicited information, the application will not be accepted for
evaluation. A non-acceptance letter will be issued by HSA and the documents will be
returned. If the applicant wishes to resubmit the dossier at a future time, it will be
processed as a new application.
Applicants are advised to ensure that the dossier is compiled according to the required
format. Failure to arrange the submission dossier accordingly will lead to non-acceptance
of the dossier without screening.
NOTE: The screening process only determines the completeness of the registration
dossier for evaluation. Acceptance of the dossier for evaluation does not constitute
acceptability of the data provided. Acceptability of the data can only be determined
during evaluation of the application.
8 APPLICATION EVALUATION
Upon acceptance of an application, evaluation by HSA is based on the data set submitted
by the applicant. A query letter will be issued to the applicant if clarification or additional
information is required.
The stop-clock starts whenever HSA issues a query letter and ends when HSA receives a
complete and satisfactory response from the applicant.
If the applicant anticipates difficulty in responding in full or within the specified timeframe,
then HSA should be contacted to discuss the request for information as soon as possible
after receipt of HSAs query letter. An application will be considered withdrawn if the stop-
clock time exceeds the deadline agreed upon by HSA and the applicant.
Additional supporting data submitted after acceptance of the application will not be
considered, unless requested by HSA or mutually agreed upon by HSA and the applicant
prior to acceptance.

For applications submitted in PRISM on or after 15 April 2009, applicants can check on
the progress of the evaluation for certain application types and evaluation routes. Table 4
describes the applicable product applications and the stages to the evaluation process: SEPTEMBER
Table 4. Product Applications Applicable for Notification of Stages During Evaluation
Stages of Notification to st nd rd th
1 Stage 2 Stage 3 Stage 4 Stage
Applicant
Evaluation Status
Application Dossier
Type type Accepted for Active Midway in Evaluation
Evaluation Evaluation Evaluation Completed
Application is Evaluation is
approximately completed for the
NDA-1 midway through application
Full or
NDA-2 the evaluation
Abridged Application is (provided that Application is now
NDA-3
accepted for When active there were no undergoing the
evaluation evaluation is in prior stop-clocks regulatory decision
progress for which may affect phase, after which
This marks the the application the evaluation a regulatory
start of the progress) decision letter*
evaluation would be issued.
GDA-1 Abridged or timeline Applicants could
GDA-2 Verification expect to receive Applicants could
the first set of still expect further
queries from HSA queries from HSA
during this stage during this stage
* The issuance of a regulatory decision letter would mark the end of the evaluation timeline for a product
application.
Applicants may view the evaluation stage via track@PRISM. Screenshots on viewing the
change in stages of a pending application are as follows:
Choose these options from

the drop-down lists
Enter PRISM application to

view stage of evaluation

SEPTEMBER
Active Evaluation
The evaluation stage

is seen here.
Applicants would also be notified via system-generated emails whenever an evaluation

stage change occurs.
During the evaluation process, HSA may determine that the application is more suitably
evaluated via an alternate route. Any re-routing of the application will be discussed with
the applicant.
HSA may engage external evaluators, experts and advisory committees in the evaluation
process, when necessary. These experts include scientists and clinicians from both local
and overseas institutions. All external evaluators and experts are bound by agreement to
protect the information made available to them. The identity of the external evaluators is
kept confidential.
9 REGULATORY DECISION
A regulatory decision is made based on the outcome of HSAs evaluation of the submitted
data package. Applicants will be notified by letter of one of the following outcomes:
Approval the application has satisfied the registration requirements for quality,
safety and efficacy;
Approvable when the application has minor deficiencies;
Non-approvable when the application has major deficiencies; or
Rejection when the response provided by the applicant fails to address the major
deficiencies highlighted in HSAs non-approvable decision.
Approval and rejection are final decisions issued by HSA.
If an approvable regulatory decision has been reached, the conditions for approval will
be stated in writing and the applicant will be required to fulfill these conditions within the
stipulated timeframe.
If a non-approvable regulatory decision has been reached, the applicant will be informed
of the non-approvable issues in writing. If the applicant wishes to address the non-
approvable concerns raised by HSA, a reply should be made within the specified
timeframe. The reply should be based on the original data set as submitted to HSA;
additional data which require evaluation will not be accepted. No extension of timeline will
be considered, unless mutually agreed between HSA and the applicant.
Applicants should note that issuance of a regulatory decision letter signals the end of the
evaluation timeline. Appendix 1 contains information on the application timelines.
An application will be considered withdrawn if the applicant fails to reply within the
stipulated timeframe subsequent to an approvable or a non-approvable decision. Once an

application is withdrawn, the applicant may submit a new application according to

prevailing submission requirements.
SEPTEMBER
Upon an approval regulatory decision, a Product Licence will be issued.
HSA may issue a product licence on the condition that certain documents/information
shall be submitted after the licence has been issued. Under such circumstances, an
official letter of commitment is required before the licence can be issued. The letter of
commitment should be specific, i.e. it addresses the particular issues of concern and
should provide details on how and when the post-approval licensing commitments will be
fulfilled. Failure to comply with these commitments may result in the suspension or
revocation of the Product Licence.
Applicants are expected to view the licensing conditions on-line in order to be reminded of
all post-approval commitments associated with the Product Licence.
10 POST-APPROVAL CHANGES
Upon issuance of a product licence, applicants will be responsible to maintain the

products quality, efficacy and safety to the end of its life cycle. Any aspect of the product
may change throughout its life cycle for example, there can be a change in
manufacturer or manufacturing process, change in indication or dosage regimen or
change in safety profile.
HSA must be notified of any changes to the products quality, efficacy and safety as per
Chapter F in this Guidance.
11 FEES
The fee structure and quanta are subject to on-going review. For updated information on
fees, please visit the HSA website7.
11.1 Screening fee
The screening fee per application is payable at the time of PRISM submission. The
screening fees are non-refundable once the application has been successfully submitted
via PRISM.
Applicants are advised to ensure that the dossier is compiled according to the required
of the dossier without screening. In these instances, the screening fees will be forfeited.
11.2 Evaluation fee
Evaluation fees are payable upon acceptance of the dossier for evaluation. The
evaluation fees are non-refundable once the application is accepted, regardless of the
final decision by HSA.
With effect from 15 April 2009, the progressive payment scheme was implemented to
allow payment of evaluation fees by instalments. This is an optional opt-in payment
scheme catered for companies who are under the GIRO payment scheme and only
applicable to applications types as listed in Table 5 on the next page:
7
http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/western_medicines/licences/
fees.html

Table 5. Product Applications Applicable for Progressive Payment Scheme
Percentage of Evaluation Fee Payable at Each Stage SEPTEMBER

Evaluation Status
Application Evaluation
Type Route Accepted for Active Midway in Evaluation
NDA-1
Full or
NDA-2
Abridged
NDA-3 30% 40% 20% 10%
GDA-1 Abridged or
GDA-2 Verification*
* Progressive payment scheme for the verification evaluation route for GDAs will be in effect from 1 Jan 2011
NOTE: To apply for the progressive payment for applications under the full
evaluation route, the applicant must contact HSA via
HSA_Medprod_Registration@hsa.gov.sg to request for a hardcopy progressive
payment application form prior to the submission in PRISM.
For applicants that had chosen the progressive payment scheme, in the event of an
application withdrawal at any point in time during the evaluation stage, any fees that had
been charged, but not yet collected, would still have to be paid; all evaluation fees that
had been paid are non-refundable.
11.2.1 Change in evaluation fees
Changes in the evaluation fees may occur if there are changes to the application type.
11.2.1.1 Change of Application within the Same Application Type
Re-categorisation of the application within the same application type (e.g. from NDA-2 to
NDA-3, or GDA-1 to GDA-2) would be carried out by the HSA officer during screening
prior to acceptance of the application. As there are differences in evaluation fees for
different application types, the change in application type would be communicated to the
applicant during the screening process. Applicants may opt to withdraw the application if
they do not agree to the change in application type; applicants are to note that in these
instances, the screening fee is non-refundable.
If there are no objections communicated to HSA, the application would be accepted with
the new application type and the new evaluation fee would be charged accordingly.
11.2.1.2 Change of Application between Different Application Types
Re-categorisation of GDA to NDA or vice versa requires withdrawal of the original

application before acceptance and resubmission of the application according to the
correct application type.
The screening fees for the original application are non-refundable. As such, applicants
are advised to consult HSA on the correct application category when in doubt.
NOTE: Non-GIRO paying applicants may need to make an additional payment to

top-up any differences in fees. Similarly, any excess in evaluation fees collected
would be refunded to the applicant upon acceptance.

CHAPTER C NEW DRUG APPLICATION SUBMISSION

This chapter applies to new drug applications for products containing new chemical and
biological entities. For new drug applications for biosimilar products, please refer to
Chapter E.
12 APPLICATION TYPES
There are 3 application types for a new drug application:

NDA-1: For the first strength of a product containing a new* chemical or biological entity.
NDA-2: i) For the first strength of a new drug product
containing a new* combination of registered chemical or biological entities;
containing registered chemical or biological entity(ies) in a new dosage
form;
containing registered chemical or biological entity(ies) for use by a new
route of administration; or,
containing registered chemical or biological entity(ies) for new indication(s),
dosage recommendation(s) and/or patient population(s).
ii) For new drug products that do not fall under the requirements for NDA-1,
NDA-3 or GDA.
NDA-3: For subsequent strength(s) of a new drug product that has been registered or has
been submitted as an NDA-1 or NDA-2. The product name, pharmaceutical
dosage form, indication, dosing regimen and patient population shall be the
same as that for the NDA-1 or NDA-2.
* Has not been registered before in Singapore
13 EVALUATION ROUTES
There are three evaluation routes for an NDA: full, abridged and verification evaluation.
The eligibility criteria are different for each evaluation route. Applicants should be familiar
with the criteria for each evaluation route because each route will have different
documentary requirements.
Figure 3 below is a schematic diagram to illustrate the evaluation routes for NDAs:
NO
NDA 1 Is the product FULL ROUTE
registered with NO
any drug ABRIDGED
regulatory ROUTE
NDA 2 agency?
Approved by
NDA 3 HSAs reference
YES
agencies and VERIFICATION
met verification
criteria? YES ROUTE
Figure 3. Schematic diagram of evaluation routes for NDAs.

13.1 Full evaluation route
Full evaluation will apply to a product that has not been approved by any drug regulatory SEPTEMBER
agency at the time of submission.
13.2 Abridged evaluation route
Abridged evaluation will apply to a product that has been approved by at least one drug
13.2.1 Priority review
For NDAs submitted via the abridged evaluation route, the applicant may request for
priority review for a life-saving drug if there are unmet medical needs. The following
states the criteria that will be considered for priority review:
a) The drug is intended for treatment of a serious life-threatening condition and

demonstrates the potential to address local unmet medical needs, as defined by:
the absence of a treatment option; or,
the lack of safe and effective alternative treatment and the drug would be a
significant improvement compared to available marketed products, as
demonstrated by
i. evidence of increased effectiveness in treatment, prevention, or diagnosis;
or
ii. elimination or substantial reduction of a treatment-limiting drug reaction.
b) Disease conditions that are of local public health concerns will be given primary
consideration for priority review. Currently these include:
cancer; and,
infectious diseases: dengue, tuberculosis, hepatitis and malaria.
The request for priority review should be made at the point of application submission and
accompanied by justification which warrants a priority review and how the product is
expected to benefit patients, as substantiated by the following evidence:
The seriousness of the disease condition, local and worldwide mortality rates,
anticipated morbidity and debilitation as a consequence of the disease;
Local epidemiology data and/or volume of requests through the exemption route on
a named-patient basis;
The unmet needs, current available treatment options and standard therapies, and
the inadequacy of current therapies;
The extent to which the product is expected to have a major impact on medical
practice, its major benefit, and how it addresses the unmet needs;
Clinical evidence supporting the claims of significant improvement compared to
available treatments.
HSA reserves the right to deny a request for priority review if it is deemed appropriate.
The decision for the granting of priority review would be conveyed to the applicant at the
point of acceptance of the application for evaluation.
13.2.2 Applications for non-prescription medicines
If the NDA is for a non-prescription medicine and is submitted via the abridged evaluation
route, the applicant may submit a written request for a waiver of clinical data submission.
Eligibility for waiver is subject to the criteria defined in Appendix 5 Guideline on
Submission Requirements for Non-Prescription Medicines. However, HSA reserves the
right to request for the complete clinical data set if it is deemed appropriate.

13.3 Verification evaluation route
Medicinal products with similar indication(s), dosing regimen(s), patient group(s), and/or SEPTEMBER
direction(s) for use that have been approved by at least two of the following HSAs
reference drug regulatory agencies may be submitted via the verification evaluation route.
HSAs reference drug regulatory agencies are:
Australia Therapeutic Goods Administration (TGA);

Health Canada (HC);
US Food and Drug Administration (FDA);
the European Medicines Agency (EMA) via the Centralised Procedure;
UK Medicines and Healthcare Products Regulatory Agency (UK MHRA) via
- the national procedure, or,
- as the Reference Member State (RMS) via the Mutual Recognition Procedure or
Decentralised Procedure.
However, approval by these reference regulatory agencies does not obligate HSA to
approve the application. HSA may also re-categorise applications to other evaluation
routes if deemed appropriate.
One of the reference drug regulatory agencies must be declared as the primary reference
agency. The chosen primary reference agency is defined as the reference agency for
which the qualifying supporting documents (as outlined in this guidance) will be
submitted.
Additional eligibility criteria for the verification route include:

The application must be submitted within three years from the approval date by the
chosen primary reference agency;
All aspects of the drug products quality, including but not limited to the formulation,
manufacturing site(s), release and shelf life specifications and primary packaging,
must be identical as that currently approved by the chosen primary reference
agency;
The product does not need a more stringent assessment as a result of differences
in local disease patterns and/or medical practices (e.g. some anti-infectives).
The product and its intended use i.e. indication(s), dosing regimen(s) and patient
group(s) has not been rejected, withdrawn, approved via appeal process or
pending deferral by a drug regulatory agency for safety and/or efficacy reasons;
and,
The product is not a biological product.
The proposed indication(s), dosing regimen(s), patient group(s) and/or direction(s) for use
should be the most stringent amongst those approved by the reference regulatory
agencies. In the event that the chosen primary reference agency does not bear the most
stringent indication(s), dosing regimen(s), patient group(s) and/or direction(s) of use, the
clinical assessment report from the other reference agency that met such requirements
should be submitted. The clinical assessment report from the other reference agency to
be submitted may be obtained from the public domain. The proposed PI/PIL should be
identical to that approved by this reference agency (with the exception of country-specific
information).
For a product with a proposed indication that has been designated as an Orphan Drug by
at least one reference agency or a product that has been approved by at least one
reference agency via an accelerated/fast-track approval, approval under exceptional
circumstances or equivalent approval process, the applicant should consult HSA on the
eligibility of such a product through the verification route prior to submission.

13.3.1 NDA-3 applications
For the NDA-3 application type, the verification evaluation route may be applied to the SEPTEMBER
registration of subsequent strengths of a currently-registered product in Singapore. To
qualify for the verification evaluation route for an NDA-3 application, if the product has
been evaluated and approved
by at least one of HSAs reference drug regulatory agencies, then the NDA-3 must
be submitted within two years from the date of approval by that reference agency;
OR,
by at least two of HSAs reference drug regulatory agencies, then the NDA-3 must
be submitted within three years from the date of approval by the chosen primary
reference agency.
All other eligibility criteria for the verification evaluation route as stated above in section
13.1.3 will apply except the following:
The proposed indication(s), dosing regimen(s), patient group(s), and/or direction(s)
for use must be identical to the corresponding approved NDA-1 and/or NDA-2
product(s); and,
The proposed PI/PIL should also be consistent with that currently approved for the
corresponding NDA-1 and/or NDA-2 product(s).
14 DOCUMENTARY REQUIREMENTS
Table 6 outlines the CTD Modules/Parts required for NDAs submitted under each
evaluation route:
Table 6. Dossier Submission Requirements for an NDA.

Documents Location in Module/Part required for
ICH CTD ACTD Full Abridged NDA Verification NDA
NDA
Administrative Module 1 Part I Yes Yes Yes
Documents
Common Technical Module 2 Incorporated Yes Yes Yes
Document Overview in Parts II, III
and Summaries and IV
Quality documents Module 3 Part II Yes Yes Yes
Non-clinical Module 4 Part III Yes ICH: No ICH: No
documents ACTD: Overview ACTD: Overview
only only
Clinical documents Module 5 Part IV Yes Study report(s) of Study report (s) of
pivotal studies and pivotal studies and
synopses of all synopses of all
studies (phase I-IV) studies (phase I-IV)
relevant to requested relevant to requested
indication, dosing indication, dosing
and/or patient group and/or patient group

Non-clinical overview included in Module 2 of the ICH CTD.
Applicants should use Appendix 2A and 3A as a guide to ensure that the dossier is
complete.
14.1 Administrative documents
The administrative documents relate to Module 1 of the ICH CTD or Part I of the ACTD
and are applicable to all evaluation routes for NDAs. The following sections are to be
submitted:

Comprehensive Table of Contents (section 1.1)
The comprehensive table of contents is a complete list of all documents provided in the SEPTEMBER
application dossier by Module/Part. The location of each document should be identified
by the Module/Part number. If a hardcopy registration dossier is submitted, then the
location of each document should be identified by the volume number and tab identifier
(name of the document or section heading according to the ACTD or ICH CTD format).
Introduction (section 1.2)
Applicants should give a concise summary of the application and justify the need for the
application for example, whether the product presents an advantage to patient groups
in terms of improved quality, safety and efficacy compared to available alternatives.
Applicants should also justify the lack of certain documents within the dossier and any
deviation from the guidelines.
Application Form (section 1.3)
A printout of the PRISM application form is to be included in the dossier.
Labelling, Package Insert and Patient Information Leaflet (section 1.4)
Applicants are required to provide the artwork/drafts of the proposed Singapore product
labels, PI and/or PIL for the product. Submission of the proposed PI or PIL is dependent
upon the forensic classification of the product to be registered, as described in the table
below:
Forensic Classification in Singapore

POM P GSL
Package Insert (PI), also known as prescribing Required Optional Optional
information, SPC, or product monograph
Patient Information Leaflet (PIL), also known as Optional, unless Required Required
consumer medicine information (CMI) warranted
All artwork and drafts should be legible. Any handwritten information is not acceptable.
Separate labels must be submitted for each different pack size of the drug product.
The product labels, PI and/or PIL must be in English. If non-English text is included in the
labelling, applicants must provide an official statement to declare that the non-English text
is complete, accurate and unbiased information and is consistent with the English text.
Appendix 6 contains specific details on product labelling requirements for Singapore.
Approved SPC/PI/PIL (section 1.5)
In this section, the applicant shall submit the following:

i. the approved SPC, PI and/or PIL from the drug regulatory agency that issued the
proof of approval; and,
ii. the approved SPC, PI and/or PIL from all of HSAs reference drug regulatory
agencies, where applicable.
Assessment Report from Reference Agencies (section 1.6)
This section refers only to applications submitted under the verification evaluation route.
Assessment reports and supporting documents issued by the primary reference agency

and inserted into this section must be unredacted and unedited. Applicants should refer to
section 14.6.3 for specific details on the required documents.
SEPTEMBER
Description of Batch Numbering System (section 1.7)
Detailed information on the system of assigning unique codes to different production

batches of the product should be provided to allow for batch identification. Where
applicable, examples of the batch numbering system should be included to illustrate how
the batch number enables identification.
Proof of Approval (section 1.8, 1.9)
Proof of approval is not required for NDAs undergoing a full evaluation.
For an abridged evaluation of an NDA product, proof of approval by any drug regulatory
agency is required. Proof of approval must come in the form of:
an official approval letter, or equivalent document (e.g. Certificate of Pharmaceutical
Product), which certifies the registration status of the drug product; and
the SPC, PI and/or PIL approved by the drug regulatory agency that issued the
approval letter.
If the SPC is in a non-English language, applicants should refer section 6.2.2 for more
information.
Note that all aspects of the products quality and intended direction(s) for use in
Singapore should be the same as approved by the drug regulatory agency that issued the
approval letter.
Approval letters should be either an original copy or a certified true copy and in English.
Applicants should refer to section 6.2.2 and 6.2.3 for more details.
HSA reserves the right to request for a Certificate of Pharmaceutical Product (CPP), if
deemed appropriate.
If the brand name (trade name) of the product as registered in the country which issued
the proof of approval is different from that proposed in Singapore, the applicant is
required to submit a declaration letter from the product owner to declare that both
products marketed under the different brand names are identical in all aspects of quality,
safety and efficacy except for the brand name.
Authorisation Letters (section 1.10)
All submitted authorisation letters shall be hardcopy originals on the authorising

companys (i.e. Product Owners) letterhead, dated and signed by the designated
authorised person in the company.
If the Product Owner is not the local Applicant Firm, Manufacturer and/or Batch Releaser,
then the following authorisation letter(s) must be submitted:
i. from Product Owner to the Applicant Firm (1.10.1) this letter authorises the local
applicant firm to apply for and be the Product Licence Holder for a specific
medicinal product.
ii. from Product Owner to Manufacturer (1.10.2) this letter authorises the specified
manufacturer to produce, pack and/or label the drug product intended for
Singapore. If there are multiple drug product manufacturers, then the applicant may
opt to submit one authorisation letter which clearly states all of the manufacturers

(names and addresses) and their responsibilities related to the drug product. For
biologic drug products, an additional authorisation letter from the Product Owner to
the Drug Substance Manufacturer is required. SEPTEMBER
iii. from Product Owner to Batch Releaser (1.10.3) this letter authorises the specified
company to batch release the drug product. If there are multiple sites responsible
for batch release of the product, then the applicant may opt to submit one
authorisation letter which clearly states all of the batch releasers (names and
addresses) and their responsibilities.
Applicants are to ensure that all names and addresses in the authorisation letters must be
consistent with the information provided in PRISM and the dossier. For Manufacturers
and Batch Releasers, the actual site address of the named company should be stated in
the letter(s) i.e. do not state the office address. Any discrepancy found will delay the
registration process.
All authorisation letters should also state specific product details, including the product
name, dosage form and strength.
Applicants also have the option to combine authorisation letters as stated above into one
document, provided that all names, addresses and responsibilities are clearly stated.
NOTE: if an applicant company has engaged a consultant to submit applications, an

additional Letter of Authorisation must be submitted from the company that
authorises the named consultant to register product(s) on their behalf.
GMP Certification/Proof of GMP Compliance (section 1.11)
Documentary evidence must be provided to certify that the manufacturer(s) complies with
current applicable GMP standards. Applicants must submit a GMP certificate issued by a
drug regulatory agency for all drug product manufacturing sites including, but not limited
to, bulk product manufacturers, primary packagers and secondary packagers. A CPP
may be submitted in lieu of a GMP certificate provided that the manufacturers name(s)
and address(es) is(are) stated on the CPP. Applicants should note that the names and
addresses of all manufacturers should be consistent throughout the application i.e.
GMP certificate, Letter of Authorisation, CTD section S2.1 and P3.1 and PRISM.
Proof of GMP compliance must not expire within six (6) months from the time of
submission to HSA and must be in hardcopy, in English and either an original or certified
true copy. Applicants should refer to section 6.2.2 and 6.2.3 for more details.
It should be noted that diluents used for reconstituting the drug product and are packaged
together with the drug product will be considered as part of the final drug product. Thus,
manufacturer(s) of the supplied diluent(s) will follow the same requirements applicable to
the drug product e.g. proof of GMP compliance.
For biologic NDA applications, proof of GMP compliance for the drug substance must be
submitted in addition to the aforementioned GMP requirements.
For products manufactured in the USA, if the applicant is unable to obtain any proof of
GMP compliance (in the form of CPP or GMP certificate) from either US FDA or other
drug regulatory agencies, the applicant is required to submit the latest Establishment
Inspection Report (EIR) issued by US FDA and any other relevant supporting document*
for proof of GMP compliance. The applicant is also required to provide the following
information if an EIR does not contain such information:

the last date of audit by US FDA;

the approved dosage forms;
any licensing conditions or restrictions; SEPTEMBER
the scope of the inspection; and/or,
objective evidence and the date of a satisfactory close-out of the latest inspection
conducted by US FDA.
* any other supporting document which declares GMP compliance of the manufacturing site in the US
and signed by an official of the US FDA.
All new overseas drug product manufacturing sites not previously registered with HSA
before 1st April 2004 and who intend to register their Western medicinal products in
Singapore will be subjected to a GMP Conformity Assessment by HSA. Thus, when
applicable, applicants must also submit a GMP Conformity Assessment application form8
with the required documents as stipulated in the Guidance Notes on GMP Conformity
Assessment of an Overseas Manufacturer9.
HSA reserves the right to request for additional or updated documents as evidence of
GMP compliance during the course of the registration process for example, an updated
GMP certificate in support of the product application or of a GMP Documentary Evidence
Evaluation Application. HSA also reserves the right to conduct an audit of any overseas
manufacturer irrespective of the documentary GMP evidence that is cleared by HSA, if
deemed appropriate.
Patent declaration (section 1.12)
The Patent Declaration form is required for each NDA. An original, signed and dated
hardcopy patent declaration form should be submitted for each application. Applicants
should refer to section 4 on information on patent linkage and Appendix 7 for a copy of
the Patent Declaration Form.
Here are some points to note when filling the Patent Declaration form:
i. Section 1 Applicant Particulars - state the name and address of the local
company.
ii. Section 2 Product Particulars - state the product name, name and strength of
active ingredient and dosage form. It should be consistent with that stated in
PRISM, all product labelling and all other relevant documents in the dossier.
iii. Section 3 Application Category - declare the patent category that your product
falls under (with respect to a Singapore Patent as registered with IPOS).
iv. Section 4 Information for Category A1 Applications - applicable if category A1 is
selected in Section 3.
v. Section 5 Information for Category A2 Applications - applicable if category A2 is
selected in Section 3. Check the box which is relevant and provide details of the
patent in force.
vi. Section 6 Information for Category A3 Applications - applicable if category A3 is
selected in Section 3. Provide details of the patent in force.
vii. Section 7 Information for Category B Applications - applicable if category B is
patent in force.
viii. Section 8 Declaration - the patent declaration must be signed by the person
authorised to make the declaration on behalf of the company named in Section 1.
8
http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/GMP/audit_icensing_
manufacturers/conformity_assessment/eServices_Forms.html
9
http://www.hsa.gov.sg/publish/etc/medialib/hsa_library/health_products_regulation/gmp/files_1.Par.60707.
File.dat/GUIDE-MQA-020-007.pdf

The authorised person is ordinarily an officer of the company such as Company

Director or Company Secretary as registered with ACRA, or equivalent. Evidence of
such authorisation is to be submitted together with the declaration. SEPTEMBER
Evidence of authorisation for Section 8 of the form could be in the form of:
An ACRA printout (BizFile) listing the Company Directors/Secretary;
Resolution of board of directors;
Resolution of a general meeting of the company; or,
Extract of the relevant portion of the companys articles of association.
Declaration forms must bear the original signatures of the authorised person and the
company stamp of the Applicant.
The patent declaration form needs to be submitted twice: at the time of dossier
submission and prior to issuance of the Product Licence (upon request by HSA), if the
evaluation was deemed satisfactory with respect to the products safety, efficacy and
quality aspects.
NOTE: the applicant should ensure that the information provided in the patent
declaration form and the evidence of authorisation is current at the point of
submission.
Declaration on rejection, withdrawal and deferral (section 1.13)
The document required for this section is a declaration letter that states that the
application as submitted to HSA or similar direction of use including indication(s), dosing
regimen(s) and patient population(s)
has not been rejected or withdrawn,
has not been approved via an appeal process, or,
is not pending deferral
by any drug regulatory agency. If any of the conditions apply to the application, details
and reasons must be provided to HSA.
Declaration for NDA verification (section 1.14)
This section applies only to the verification evaluation route.
A declaration must be provided to state that all aspects of the products quality are
identical to that currently approved by the chosen primary reference regulatory agency.
Quality aspects include, but are not limited to, formulation, manufacture site(s), release
and shelf life specifications and primary packaging.
If a Drug Master File is submitted, then a second declaration must also be provided to
state that the DMF submitted to HSA is identical to that submitted to the primary
reference regulatory agency.
Registration status in other countries (section 1.15)
The registration status of the product in other countries should be entered into PRISM
section 4.9 refer to section 25.1.4.9 of this document for further details.
In the event that the PRISM text space does not allow input of the full details of the
indication(s) and/or reason(s), a brief description may be entered. The full details should
then be attached in softcopy (PDF) in PRISM section 7 (Supporting Attachments) and

submitted in hardcopy in this section of the CTD dossier. The document should be in the
format as seen in Table 7 below:
SEPTEMBER
Table 7. Table of Information on Registration Status in Other Countries for CTD section 1.15.
Country Application Status Date Approved application Approved
status indication/dosing regimen details* forensic

classification
Country 1 Approved 12 Jan 2005 Adjuvant treatment of colorectal cancer POM
stage III (Dukes C) following complete
resection of primary tumour.
Country 2 Approved 2 Feb 2006 Adjuvant treatment of colorectal cancer POM
following surgery
Country 3 Withdrawn 14 Apr 2002 Indication submitted Adjuvant POM
by applicant treatment of colorectal cancer.
Withdrawn due to insufficient long-term
efficacy data (only phase II data
submitted).
Re-submitted on 16 June 2005 with
completed phase III data for Adjuvant
treatment of colorectal cancer following
surgery.
Country 4 Approved 21 Nov 2004 Adjuvant treatment of colorectal cancer POM
stage III (Dukes C) following complete
removal of primary tumour.
Notice of Compliance with Conditions

issued on 16 April 2003 based on
promising efficacy results with
condition to furnish confirmatory
efficacy data.
Country 5 Pending Submitted: Adjuvant treatment of colorectal cancer POM
15 Jun 2005 stage III (Dukes C) following surgery.
* Applicable to information on reference agencies, Country of Origin, and all rejections/withdrawals/deferrals

Applicable to information on reference agencies and Country of Origin.
14.2 CTD overview and summaries
The overview and summary documents are to be inserted into Module 2 of the ICH CTD
or into the relevant sections in Part II, III and IV of the ACTD.
A completed Singapore Quality Overall Summary (SQOS) must also be inserted into
Module 2, section 2.3 of the ICH CTD or Part II, section B of the ACTD, irrespective of
whether an ICH or ACTD QOS has been included in the application dossier. Take note
that the SQOS must be named and dated by the applicant prior to submission. The
electronic copy of the Singapore QOS should be in Microsoft Word format.
NOTE: the SQOS is only a summary of the technical information in the dossier.
Pages from the SQOS should not be used to replace documents required for the
application.
Here are some points to note when filling out and submitting the SQOS with the
application:
i. The information in the SQOS should be based on the documents located in each of
the CTD dossier sections provided by the drug product manufacturer;

ii. All of the tables in all of the SQOS sections should be filled out if there is missing
information, an Input Request will be sent to request to complete the SQOS; and,
iii. During screening of the application, all of the information in the relevant SQOS SEPTEMBER
sections should be updated when additional or updated documents are submitted in
response to an Input Request.
The SQOS template for chemical drug products is given in Appendix 8. The SQOS
template for biologic drug products, including biosimilar products, is given in Appendix 9.
14.3 Quality documents
The quality documents relate to Module 3 of the ICH CTD or Part II of the ACTD. In
addition to the ICH or ACTD technical content requirements, the following explanatory
notes pertain to requirements specific to Singapore:
14.3.1 Body of Data Drug Substance
The ICH M4Q technical guideline and ASEAN Common Technical Requirements (ACTR)
provide details on the information to be included in the drug substance sections of an
NOTE: if a drug product contains more than one drug substance, the information
within Module 3.2.S (ICH CTD) or Part II.S (ACTD) must be provided in its
entirety for each drug substance.
All of the drug substance sections of the CTD i.e. S1 to S7 should be submitted in the
application. If these sections are incomplete, then the dossier should make reference to a
Drug Master File (DMF), Plasma Master File (PMF) or Certificate of Suitability of
Monographs of the European Pharmacopoeia (CEP).
Because the drug product manufacturer is responsible for quality control of the drug
substance that is used in the drug product, applicants should note that the complete S
section of the CTD dossier should be provided by the drug product manufacturer
regardless of whether a DMF or CEP has been submitted in support of a product
application.
Drug Master File (DMF)
A Drug Master File is a reference that provides information about specific processes or
components used in the manufacturing, processing, and packaging of a drug. The DMF
contains information of a proprietary nature that is not available to the drug product
manufacturer or to the applicant of a product registration submission.
If a drug substance is sourced from a manufacturer that is different from the drug product
manufacturer, data on the manufacture, quality control and stability of the drug substance
may be submitted in the form of a DMF. If the drug substance and drug product are
manufactured by the same manufacturer, then either a DMF or complete S section can
be submitted.
The DMF is divided into two parts: an open (or applicants) part and a closed (or
restricted) part. The open part contains most of the information in Module 3.2.S (ICH
CTD) or Part II.C.S (ACTD) i.e. S1, S2.1 and S3 to S7 sections. The closed part
contains the confidential information in section 3.2.S.2.

The documentary requirements for an application making reference to a DMF are as

follows:
SEPTEMBER
From the Applicant:
the open part of the DMF, as part of the submitted dossier; and,
a copy of the Letter of Access.
From the Drug Substance Manufacturer (also referred to as DMF Holder):

the complete DMF i.e. both the open and closed parts; and,
the original Letter of Access.
The Letter of Access authorises HSA to refer to the DMF in support of the application for
a drug product. Thus, the Letter of Access must state the following:
the name of the drug product(s) (product name, dosage form and product strength)
to be registered;
the local applicant (name and address) responsible for product registration; and,
a declaration that the local applicant and HSA will be notified of any change in the
drug substance specification or in the manufacturing process that will likely affect
the products quality or safety.
If the Letter of Access does not fulfill these requirements, HSA reserves the right to return
the DMF to the DMF holder.
The DMF holder may submit the DMF directly to HSA to maintain confidentiality of the
contents. The information contained in the closed part of the DMF will be regarded as
confidential and will only be evaluated in support of the application(s) mentioned in the
Letter of Access. The confidential information will not be disclosed to any third party
without a written authorisation from the Drug Master File holder.
Upon receipt of the DMF, HSA will assign a DMF number. For future correspondence, the
applicant and the DMF holder should make a reference to the assigned DMF number. If
there are deficiencies within the closed part of the DMF, HSA will raise queries directly
with the DMF holder.
NOTE: Assignment of a DMF number does not constitute approval of the DMF it
is not approved or rejected. It is a separate document that is submitted in support
of an application. A DMF must always be linked to a product application.
If a product application makes reference to a currently-registered DMF, the original Letter

of Access specific to the product application is to be provided by the DMF Holder and a
copy of the Letter of Access is to be submitted by the applicant as part of the registration
dossier.
Applicants are responsible to maintain and update the DMF. If there are changes to the
DMF that will result in a post-approval variation to the drug product, applicants must file a
post-approval variation refer to Section F of this guidance for more information on the
post-approval process.
Plasma Master File (PMF)
A Plasma Master File is required whenever a human plasma-derived product is used

either as a drug substance or as an excipient as the PMF contains information on the
collection and control of source materials. The PMF may be submitted either as a stand-

alone document or as part of the registration dossier. Appendix 10 describes the PMF
data requirements for submission.
SEPTEMBER
If the PMF is a stand-alone document, then it should be filed separately from the
application dossier for pre-marketing evaluation. The applicant may cross-reference a
currently registered PMF of HSA where applicable.
Certificates of Suitability (CEP)
A Certificate of Suitability is a document issued by European Directorate for the Quality of

Medicines and Healthcare (EDQM) that certifies the quality of a drug substance in
compliance to the Ph. Eur. A CEP may be submitted in lieu of the CTD S Section or a
DMF.
If reference is made to a CEP, the applicant should submit a copy of the duly authorised,
valid CEP, including all annexes. A duly authorised CEP should contain the following
information in the Declaration of Access section of the CEP:
name of the Product Owner or local applicant;
name of the product to be registered it is recommended that the dosage form and
strength(s) also be stated;
signature and company stamp of the CEP holder; and,
date of authorisation.
The following additional documents must accompany the CEP and inserted into the
relevant CTD S sections:
i. batch analysis results (S4.4) from the drug substance manufacturer demonstrating
compliance with the Ph. Eur. monograph, including any additional tests/limits listed
on the CEP; and,
ii. if applicable, additional data to address any relevant parameter(s) not addressed in
the CEP, such as physico-chemical characteristics (e.g. particle size,
polymorphism, etc) and, if a re-test period is not stated on the CEP, container
closure system (S6) and stability data (S7).
NOTE: HSA reserves the right to request for any additional information about the
CEP-certified drug substance if it is seemed appropriate.
If there is a CEP for animal-derived material used in the drug product, the applicant may
submit the CEP in lieu of the documents stipulated in Appendix 11 Guideline on the
Registration of Human Medicinal Products Containing Materials of Animal Origin.
It is the applicants responsibility to submit the latest CEP updates, with annexes, as soon
as it is available from EDQM.
Control of Drug Substance (3.2.S.4)
Batch analysis data should be provided by the drug substance and drug product
manufacturers on the same drug substance batches, if available. While it is not required
to submit data on three batches for CTD section S4.4, the data should be for a
production-sized drug substance batch, if available.
Stability Data of Drug Substance (3.2.S.7)
At the time of submission, the minimum stability data required are as follows:

At least 12 months of real time data and 6 months of accelerated data on at least
three primary batches of the drug substance;
The batches should be at least pilot scale-sized and manufactured by a method SEPTEMBER
that simulates the final commercial process.
If the drug substance is sourced from multiple sites, stability data from each site should
be provided.
HSA may request for additional stability data if deemed necessary for the evaluation of
the application.
14.3.2 Body of Data Drug Product
The ICH M4Q and ACTR also provide details on the information to be included in the
drug product sections of an application dossier.
Pharmaceutical Development (3.2.P.2)
Detailed descriptions and discussions, with relevant data, which relates to the
development, and hence quality, of the drug product should be provided in the relevant
dossier sections. Examples include, but are not limited to:
polymorphism, solubility or particle size of the drug substance and its effect on the
products quality;
a description and the results of the formulation development;
the rationale for the choice of dissolution method and a discussion of its
discriminatory nature, with data;
compatibility of the container closure system for the product or preservative efficacy
test results; and,
optimisation of the manufacturing process, with data.
Process Validation (3.2.P.3.5)
The description, documentation and complete results of the validation studies on the
manufacturing process should be provided in the dossier. Particular care should be taken
to ensure that the documents include critical processes for the manufacturing process: for
example, blend uniformity validation for oral dosage forms and terminal sterilisation or
aseptic filling for sterile products.
Applicants should refer to the ASEAN Guidelines on Submission of Manufacturing

Process Validation Data for Drug Registration10 and the accompanying Q&A on ASEAN
Guideline on Process Validation for the minimum data requirements on process
validation. Other relevant international guidelines may also be referred to as appropriate.
Where ranges of batch sizes are proposed, it should be demonstrated that variations in
batch size would not adversely alter the characteristics of the finished product.
Control of Excipients (3.2.P.4)
This section refers to all excipients used in the drug product formulation, including
ingredients used in capsule shells and film coatings. The specifications and analytical
method(s) for each excipient should be described, with validation of any in-house test
method(s) if applicable.
10

Information on proprietary ingredients such as flavourings, colourants, perfumes and/or

printing inks should be as detailed as possible. Applicants are advised not to use internal
codes but rather give commercial names for such ingredients. SEPTEMBER
A CoA for an excipient may be submitted in lieu of the excipients specifications.
For excipients derived from human plasma, applicants should refer to the Appendix 10 for
more information on the data requirements.
For excipients derived from animal sources, applicants should refer to Appendix 11,
which is the guideline on the registration of human medicinal products containing
materials of animal origin. The checklist in Annex 1 in Appendix 11 may serve as a guide
to the documentary requirements for submission. Applicants should note that the
completed checklist in Annex 1 is to be submitted in CTD section 3.2.P.4.5 with the
supporting documents submitted in ICH CTD section 3.2.A.2 or ACTD section Q.A.2.
But for milk and certain milk derivatives, such as lactose, because these excipients are
generally considered non-infectious, a declaration from the supplier of the excipient
stating that the milk is from healthy cows fit for human consumption and no other
potentially infectious ruminant-derived materials were used in the manufacturing process
would be sufficient. This declaration is to be submitted in CTD section 3.2.P.4.5.
Control of Drug Product (3.2.P.5)
The drug products release and shelf-life specifications should be declared in section
P.5.1.
Descriptions of all test methods with complete validation results of all in-house methods
should be submitted in sections P.5.2 and P.5.3.
Descriptions (including size, origin and use) and test results of all relevant batches (e.g.
pre-clinical, clinical, pilot and production batches) used to establish the specification and
evaluate the consistency in manufacturing should be provided.
Batch analysis data and/or CoAs on three batches of the drug product should be
provided in section P.5.4.
Justification of the specifications (section P.5.6) should be based on scientific knowledge

and data collected during product development.
Container Closure System (3.2.P.7)
Technical information about each component of the container closure system(s) used for
the drug product should be included in the dossier. The technical information to be
included in the dossier includes, but is not limited to, schematic diagrams, descriptions,
specifications, analytical methods, CoAs and declarations of compliance to international
standards.
Stability Data of Drug Product (3.2.P.8)
HSA has adopted the ASEAN Guideline on Stability of Drug Product11 for guidance on the
conduct of stability studies for the ASEAN region. Applicants should familiarise
themselves with this guideline prior to submission. Applicants are also reminded that the
ASEAN stability requirements have been implemented since 1st January 2009.
11

At least 12 months of real time data and 6 months of accelerated data on primary
batches of the drug product, as per the ASEAN guideline; SEPTEMBER
The primary batches should be manufactured by the same method(s) and
packaged in the same container closure system as that proposed for Singapore.
All submitted stability data must be site specific to the product proposed for Singapore.
For example, if the drug substance is sourced from two different sites (e.g. site A and B),
stability data for the drug product must include one set of minimum requirements for the
drug product with drug substance from site A and one set for the drug product with drug
substance from site B i.e. a total of six batches at real time conditions and 6 batches at
accelerated conditions.
Blank Production Batch Records
For new product licence applications, one set of Blank Production Batch Records from
the intended site of manufacture may be requested.
14.4 Non-clinical documents
The non-clinical documents relate to Module 4 of the ICH CTD or Part III of the ACTD.
Applicants should refer to the ICH CTD Guidelines M4S12 (Safety) technical guidelines or
the ACTD Part III: Nonclinical13 guidelines for detailed information on the contents of non-
clinical documents for the application dossier.
14.5 Clinical documents
The clinical documents relate to Module 5 of the ICH CTD or Part IV of the ACTD.
Guidance on how to complete this Module/Part is provided in the ICH CTD Guideline
M4E 14 (Efficacy) technical guidelines, in particular the ICH E3 guidance document on
Structure and Contents of Clinical Study Reports, or the ACTD Part IV: Clinical 15
guidelines.
Clinical studies should generally be conducted using the drug product formulation
submitted in the application and in the appropriate patient population for the indication(s)
and/or dosing regimen(s) as requested in the NDA. Biopharmaceutic study reports are
required if the commercial formulation for the Singapore market differ from the clinical trial
formulation used in the pivotal studies.
Risk management plans (RMP) submitted to EMA, risk evaluation and mitigation
strategies (REMS) submitted to US FDA, and/or other relevant documents pertaining to
such purposes should be included, where available. The need to implement a risk
management plan in Singapore would be assessed on a case-by-case basis during the
review process.
12
http://www.ich.org/cache/compo/276-254-1.html
13
14
http://www.ich.org/cache/compo/276-254-1.html
15

14.6 Specific documentary requirements for each evaluation route
14.6.1 Full evaluation route SEPTEMBER
Full information on chemical/biological development, pharmaceutical/genetic

development, toxicological, pharmacological and clinical data needs to be submitted in
support of the application.
The technical documents required include:

complete quality documents for both drug substance and drug product;
complete pharmaco-toxicological or non-clinical documents; and,
complete clinical documents relevant to requested indication, dosing and/or patient
group; i.e. all study reports from phase I to phase III, including tables and
appendices.
14.6.2 Abridged evaluation route
All aspects of the products quality and direction(s) for use [including dosing regimen(s),
indication(s) and patient group(s)] should be the same as that approved by the drug
regulatory agency that issued the proof of approval.

a non-clinical overview; and,
a clinical overview, summaries of clinical efficacy and clinical safety, synopses of
relevant studies, a tabular listing of the clinical development programme and study
reports of the pivotal studies relevant to requested indication, dosing and/or patient
group (the tables and appendices to the pivotal study reports may be submitted
upon request by HSA).
14.6.3 Verification evaluation route
The complete assessment report and other relevant supporting documents from the
chosen primary reference agency must be submitted, as tabulated below. The
assessment reports from the primary reference agency must be unredacted or unedited.
Reports from the primary reference agency that are obtained from the public domain are
deemed unacceptable.
Primary reference Documentary requirements

agency
Health Canada Complete Clinical and Quality# assessment reports, including
and MHRA assessment on the Question & Answer documents between the
Sponsor & Agency and all annexes
Assessment reports and/or documents pertaining to post-
approval variations, if applicable
US FDA Complete Clinical and Quality# assessment reports, including
assessment on the Question & Answer documents between the
Sponsor & Agency and all annexes*


agency
EMA Complete CHMP Assessment Report#, including the following: SEPTEMBER
- Rapporteurs and Co-Rapporteurs Day 80 Assessment
Reports (non-clinical, clinical, quality, overview and List of
Questions)
- CHMP Day 120 List of Questions
- Rapporteurs Day 150 Assessment Report (non-clinical,
clinical, quality and overview)
- Day 180 List of Outstanding Issues
- All other annexes and appendices
Summary of CHMP Opinion
TGA Complete Clinical Assessment Reports, including assessment on
the Question & Answer documents between the Sponsor &
Agency and all annexes
Complete Chemistry and Quality Control Assessment Report#,
including assessment on the Question & Answer documents
between the Sponsor & Agency and all annexes
Delegates overview
Pre-ACPM response
ACPM minutes
* If theres difficulty in obtaining the unredacted reports, the FDA Sponsors Authorization signed by the
products Sponsor in the US can be submitted and HSA will help to facilitate the retrieval of the reports.
The time taken for HSA to retrieve the reports will be considered as the applicants stop-clock time. If
HSA is unable to obtained the reports within 3 months, the application will be routed to the abridged
evaluation route.
#
if the drug substance section is submitted to the primary reference agency as a Drug Master File, the
complete assessment report of the DMF, including assessment on the Question & Answer documents
between the DMF Holder & Agency and all annexes should be provided. Assessment reports, approval
letters and/or documents pertaining to post-approval DMF updates should also be submitted, if
applicable.
Administrative documents specific to the verification evaluation route that are required at
the time of submission include:
i. 1.9 Official approval letters, or equivalent documents, from the relevant reference
regulatory agencies that certify the registration status of the drug product;
ii. 1.13 Official letter declaring that the application submitted to HSA or similar
direction(s) of use, indication(s), dosing regimen(s) and/or patient group(s) have not
been rejected, withdrawn, approved via appeal process16, or pending deferral17 by
any drug regulatory agency, with reasons in each case if applicable;
iii. 1.14 Official letter declaring that the Drug Master File provided is the same as that
submitted to the primary reference agency, if applicable; and,
iv. 1.14 Official letter declaring that all aspects of the products quality intended for
sale in Singapore are identical as that currently approved by the primary reference
regulatory agency. This includes, but is not limited to, the formulation, site(s) of
manufacture, release and shelf life specifications and primary packaging.
16
Approval via appeal process includes, but is not limited to, the following: approval following negative
opinion, approval following rejection, approval following non-approvable etc.
17
Deferral includes, but is not limited to, the following: non-approvable, approvable, conditional approval,
conditional marketing authorisation, notice of compliance with conditions etc.


complete quality documents for both drug substance and drug product, which SEPTEMBER
includes:
i. Module 3 dossier as initially submitted to the chosen primary reference agency;
ii. From Sponsor:
- Question and Answers between the primary reference agency and sponsor
the Answers should include supporting documents used in response to the
Questions;
- All post-approval variations approved by the primary reference agency up to
the time of submission to HSA, including the application letter for the variation,
supporting documents for the variation, questions and answers between the
primary reference agency and sponsor and the approval letter for the variation
from the primary reference agency (if applicable); and,
- Relevant documents required by HSA which have not been submitted to the
primary reference agency, e.g. stability studies in accordance to ASEAN
Stability Guidelines, Singapore Quality Overall Summary, etc;
iii. From DMF Holder, if applicable:
- The initial open and closed parts of the DMF submitted to the primary
reference agency from the DMF Holder should be provided to HSA, together
with an original Letter of Access;
- Question and Answers between the primary reference agency and DMF
Holder the Answers should include supporting documents used in response
to the Questions; and,
- All post-approval DMF updates approved by the primary reference agency up
to the time of submission to HSA, including the application letter for the DMF
update, supporting documents for the DMF update, questions and answers
between the primary reference agency and sponsor and the approval letter for
the DMF update from the primary reference agency;
a non-clinical overview; and,
All of the data submitted to HSA must be the same as the data package submitted to the
reference regulatory agencies. Differences between the dossier submitted to HSA and
data reviewed by the reference regulatory agencies will not only delay the processing of
the application, but may also lead to re-routing of the dossier to the abridged evaluation
route if significant undisclosed differences have been discovered.
In the event that the chosen primary reference agency does not bear the most stringent
indication(s), dosing regimen(s), patient group(s) and/or direction(s) of use amongst those
approved by the reference regulatory agencies, a supplemental clinical assessment
report from the reference agency that approved the most stringent indication(s), dosing
regimen(s), patient group(s) and/or direction(s) of use is required. Reports from the public
domain are acceptable. The proposed PI/PIL should be identical to that approved by this
reference agency (with the exception of country-specific information).

CHAPTER D GENERIC DRUG APPLICATION SUBMISSION

This chapter applies to generic drug applications for products containing currently
registered chemical entities.
There are 2 application types for a generic drug application:

GDA-1: For the first strength of a generic chemical product.
GDA-2: For subsequent strength(s) of the generic chemical product that has been
registered or has been submitted as a GDA-1. The product name and
pharmaceutical dosage form shall be the same as that for the GDA-1.
15.1 Generic product

(known as the Singapore reference product) but excludes biologics. Essentially similar is
defined as having the same qualitative and quantitative composition in terms of active
substances, having the same pharmaceutical form and being bioequivalent. By extension,
the concept of essentially similarity also applies to different conventional immediate
release oral dosage forms (i.e. tablets and capsules) which contain the same active
ingredient(s).
The generic product must fulfil the following criteria:

i. the generic product is the same pharmaceutical dosage form as the Singapore
reference product;
ii. the route of administration of the generic product is the same as the Singapore
reference product;
iii. the conditions of use for the generic product fall within the directions for use
[including indication(s), dosing regimen(s) and patient group(s)] for the Singapore
reference product; and,
iv. the generic product is bioequivalent with the Singapore reference product.
15.2 Singapore reference product
The Singapore reference product must be a currently registered product that has been
granted market authorisation based on the evaluation of the products quality, efficacy
and safety i.e. a dossier with chemical, pharmaceutical, pharmacological-toxicological
and clinical data. If such a reference product is not registered in Singapore, then an
alternate registered comparator product may be used if adequately justified by the
applicant and agreed upon by HSA.
The generic product should contain the same active substance(s) and strength(s) and be
the same pharmaceutical dosage form as the Singapore reference product.
For generic products containing a different salt or ester form of the active substance
compared to the Singapore reference product, applicants are required to submit data to
demonstrate that the different salt/ester form does not affect the pharmacokinetic,
pharmacodynamic, efficacy or toxicity profile of the active substance in the reference
product.

Applicants are advised to search HSAs online database 18 to identify the Singapore
reference product. Applicants submitting GDAs should also refer to Appendix 12 for
further details on product interchangeability and biowaiver request. SEPTEMBER
Applicants are encouraged to contact HSA to discuss the acceptability of a GDA if the
generic product does not have a registered Singapore reference product of the same
strength. In these instances, applicants shall provide scientific justification for HSAs
consideration. However, a generic drug application for a higher strength than the
Singapore reference product will not be accepted.
There are two evaluation routes for a GDA: abridged and verification evaluation. The
eligibility criteria are different for each evaluation route. Applicants should be familiar with
the criteria for each evaluation route because each route will have different documentary
requirements.
Figure 4 below is a schematic diagram to illustrate the evaluation routes for GDAs:
NO
Approved by at least ABRIDGED
GDA 1 ROUTE
one of HSAs
reference agencies
and met verification
GDA 2 criteria? VERIFICATION
YES ROUTE
Figure 4. Schematic diagram of evaluation routes for GDAs.
16.1 Abridged evaluation route
Abridged evaluation will apply to a product that has been approved by at least one drug
16.2 Verification evaluation route
The verification evaluation route applies to a medicinal product that has been evaluated
and approved by at least one of the following HSAs reference drug regulatory agencies:
Australia Therapeutic Goods Administration;

Health Canada;
US Food and Drug Administration;
the European Medicines Agency via the Centralised Procedure;
UK Medicines and Healthcare Products Regulatory Agency via
- as the Reference Member State (RMS) via the Mutual Recognition Procedure or
Decentralised Procedure.
However, approval by these reference regulatory agencies does not obligate HSA to
approve the application.
18
http://eservice.hsa.gov.sg/prism/common/enquirepublic/SearchDRBProduct.do?action=load

Additional eligibility criteria include:

i. The registration dossier must be submitted within two years from the approval date
by a chosen reference agency; SEPTEMBER
ii. All aspects of the products quality, including but not limited to formulation,
manufacturing site(s), specifications and primary packaging, must be identical as
that currently approved by the chosen reference agency;
iii. The product is not a biologic product;
iv. The product and its intended use i.e. indication(s), dosing regimen(s) and patient
group(s) has not been rejected, withdrawn, approved by appeal or pending
deferral by a drug regulatory agency for efficacy and/or safety reasons; and,
v. The product has not been approved by the chosen reference agency via an
accelerated/fast-track approval, approval under exceptional circumstances or an
equivalent process.
The chosen reference agency is defined as the reference agency for which the qualifying
supporting documents (as outlined in this guidance) will be submitted.
Table 8 outlines the CTD Modules/Parts required for GDAs submitted under each
evaluation route:
Table 8. Dossier Submission Requirements for a GDA.

ICH CTD ACTD Abridged GDA Verification GDA
Administrative Module 1 Part I Yes Yes
Documents and (Refer to section 17.5.2)
Product Information
Common Technical Module 2 Incorporated SQOS + QOS SQOS + QOS
Document Overview into Parts II,
and Summaries III and IV
Quality documents Module 3 Part II Yes Yes
(Refer to section 17.5.2)
Non-clinical Module 4 Part III No No
documents
Clinical documents Module 5 Part IV BE studies or biowaiver Yes
justification may be (same dataset as that
inserted in this section submitted to RA)
Applicants should use Appendix 2A and 3A as a guide to ensure that the dossier is
complete.
The administrative documents relate to Module 1 of the ICH CTD or Part I of the ACTD
and are applicable to the evaluation routes for GDAs. The following sections are to be
submitted:
Comprehensive Table of Contents (section 1.1)
The comprehensive table of contents is a complete list of all documents provided in the
application dossier by Module/Part. If a hardcopy registration dossier is submitted, then
the location of each document should be identified by the volume number and tab
identifier (name of the document or section heading according to the ACTD or ICH CTD
format).

Introduction (section 1.2)
Applicants should give a concise summary of the application and justify the need for the SEPTEMBER
application for example, whether the product presents an advantage to patient groups
in terms of improved quality, safety and efficacy compared to available alternatives.
Applicants should also justify the lack of certain documents within the dossier and any
deviation from the guidelines.
Application Form (section 1.3)
A printout of the PRISM application form is to be included in the dossier.
Labelling, Package Insert and Patient Information Leaflet (section 1.4)
Applicants are required to provide the artwork/drafts of the proposed Singapore product
labels, PI and/or PIL for the product. Submission of the proposed PI or PIL is dependent
upon the forensic classification of the product to be registered, as described in the table
below:
Forensic Classification in Singapore

POM P GSL
Package Insert (PI), also known as prescribing Required Optional Optional
information, SPC, or product monograph
Patient Information Leaflet (PIL), also known as Optional, unless Required Required
consumer medicine information (CMI) warranted
All artwork and drafts should be legible. Any handwritten information is not acceptable.
Separate labels must be submitted for each different pack size of the drug product.
Appendix 6 of this guidance contains specific details on product labelling requirements for
Singapore.
The clinical information in the proposed PI/PIL should be consistent with that currently
approved for the Singapore reference product.
Approved SPC/PI/PIL (section 1.5)
In this section, the applicant shall submit the approved SPC, PI and/or PIL from the drug
regulatory agency that issued the proof of approval.
Assessment Report from Reference Agencies (section 1.6)
This section refers only to applications submitted under the verification evaluation route.
Assessment reports and supporting documents issued by the chosen reference agency
and inserted into this section must be unredacted and unedited. Applicants should refer to
section 17.5.2 for specific details on the required documents.
Description of Batch Numbering System (section 1.7)
Detailed information on the system of assigning unique codes to different production

batches of the product should be provided to allow for batch identification. Where

applicable, examples of the batch numbering system should be included to illustrate how
the batch number enables identification.
SEPTEMBER
Proof of Approval (section 1.8, 1.9)
Proof of approval is not required for GDAs undergoing abridged evaluation for finished
products manufactured (up to primary packaging) in Singapore.
For an abridged evaluation of an imported GDA product, proof of approval by any drug
regulatory agency is required. Proof of approval must come in the form of:
an official approval letter, or equivalent document (e.g. Certificate of Pharmaceutical
Product), which certifies the registration status of the drug product; and
the SPC, PI and/or PIL approved by the drug regulatory agency that issued the
approval letter.
If the SPC is in a non-English language, applicants should refer section 6.2.2 of this
guidance document for more information.
Note that all aspects of the products quality, should be the same as approved by the drug
regulatory agency that issued the approval letter.
Approval letters should be either an original copy or a certified true copy and in English.
Applicants should refer to section 6.2.2 and 6.2.3 for more details.
HSA reserves the right to request for a Certificate of Pharmaceutical Product (CPP), if
deemed appropriate.
If the brand name (trade name) of the product as registered in the country which issued
the proof of approval is different from that proposed in Singapore, the applicant is
required to submit a declaration letter from the product owner to declare that both
products marketed under the different brand names are identical in all aspects of quality,
safety and efficacy except for the brand name.
Authorisation Letters (section 1.10)
All submitted authorisation letter(s) shall be hardcopy originals on the authorising

authorised person in the company.
If the Product Owner is not the local Applicant Firm, Manufacturer and/or Batch Releaser,
then the following authorisation letter(s) must be submitted:
i. from Product Owner to the Applicant Firm (1.10.1) this letter authorises the local
applicant firm to apply for and be the Product Licence Holder for a specific
medicinal product.
ii. from Product Owner to Manufacturer (1.10.2) this letter authorises the specified
manufacturer to produce, pack and/or label the drug product intended for
Singapore. If there are multiple drug product manufacturers, then the applicant may
opt to submit one authorisation letter which clearly states all of the manufacturers
(names and addresses) and their responsibilities related to the drug product.
iii. from Product Owner to Batch Releaser (1.10.3) this letter authorises the specified
company to batch release the drug product. If there are multiple sites responsible
for batch release of the product, then the applicant may opt to submit one
authorisation letter which clearly states all of the batch releasers (names and
addresses) and their responsibilities.

Applicants are to ensure that all names and addresses in the authorisation letter(s) must
be consistent with the information provided in PRISM and the dossier. For Manufacturers SEPTEMBER
and Batch Releasers, the actual site address of the named company should be stated in
the letter(s) i.e. do not state the office address. Any discrepancy found will delay the
registration process.
All authorisation letters should also state specific product details, including the product
name, dosage form and strength.
Applicants also have the option to combine authorisation letters as stated above into one
document, provided that all names, addresses and responsibilities are clearly stated.
NOTE: if an applicant company has engaged a consultant to submit applications,

an additional Letter of Authorisation must be submitted from the company that
authorises the named consultant to register product(s) on their behalf.
GMP Certification/Proof of GMP Compliance (section 1.11)
Documentary evidence must be provided to certify that the manufacturer(s) complies with
current applicable GMP standards. Applicants must submit a GMP certificate issued by a
drug regulatory agency for all drug product manufacturing sites including, but not limited
to, bulk product manufacturer(s), primary packer(s) and secondary packer(s). A CPP may
be submitted in lieu of a GMP certificate provided that the manufacturers name(s) and
address(es) is(are) stated on the CPP. Applicants should note that the names and
addresses of all manufacturers should be consistent throughout the application i.e.
GMP certificate, Letter of Authorisation, CTD section S2.1 and P3.1 and PRISM.
Proof of GMP compliance must not expire within six (6) months from the time of
submission to HSA and must be in hardcopy, in English and either an original or certified
true copy. Applicants should refer to section 6.2.2 and 6.2.3 for more details.
It should be noted that diluents used for reconstituting the drug product and are packaged
together with the drug product will be considered as part of the final drug product. Thus,
manufacturer(s) of the supplied diluent(s) will follow the same requirements applicable to
the drug product e.g. proof of GMP compliance.
For products manufactured in the USA, if the applicant is unable to obtain any proof of
GMP compliance (in the form of CPP or GMP certificate) from either US FDA or other
drug regulatory agencies, the applicant is required to submit the latest Establishment
Inspection Report (EIR) issued by US FDA and any other relevant supporting document*
for proof of GMP compliance. The applicant is also required to provide the following
information if an EIR does not contain:
the last audited date by US FDA;

the approved dosage forms ;
any licensing conditions/restriction;
the scope of inspection; and/or,
objective evidence and the date of a satisfactory close-out of the latest inspection
conducted by US FDA.
* any other supporting document which declares GMP compliance of the manufacturing site in the US
and signed by an official of the US FDA.

All new overseas drug product manufacturing sites not previously registered with HSA
before 1st April 2004, and who intend to register their Western medicinal products in
Singapore will be subjected to a GMP Conformity Assessment by HSA. Thus, when SEPTEMBER
applicable, applicants must also submit a GMP Conformity Assessment application form 19
with the required documents as stipulated in the Guidance Notes on GMP Conformity
Assessment of an Overseas Manufacturer20.
HSA reserves the right to request for additional or updated documents as evidence of
GMP compliance during the course of the registration process for example, an updated
GMP certificate in support of the product application or of a GMP Documentary Evidence
Evaluation Application. HSA also reserves the right to conduct an audit of any overseas
manufacturer irrespective of the documentary GMP evidence that is cleared by HSA, if
deemed appropriate.
Patent declaration (1.12)
The Patent Declaration form is required for each GDA. An original, signed and dated
hardcopy patent declaration form should be submitted for each application. Applicants
should refer to section 4 on information on Patent Linkage and Appendix 7 for a copy of
the Patent Declaration Form.
Here are some points to note when filling the Patent Declaration form:
i. Section 1 Applicant Particulars - state the name and address of the local
company.
ii. Section 2 Product Particulars - state the product name, name and strength of
active ingredient and dosage form. It should be consistent with that stated in
PRISM, all product labelling and all other relevant documents in the dossier.
iii. Section 3 Application Category - declare the patent category that your product
falls under (with respect to a Singapore Patent as registered with IPOS).
iv. Section 4 Information for Category A1 Applications - applicable if category A1 is
selected in Section 3.
v. Section 5 Information for Category A2 Applications - applicable if category A2 is
patent in force.
vi. Section 6 Information for Category A3 Applications - applicable if category A3 is
selected in Section 3. Provide details of the patent in force.
vii. Section 7 Information for Category B Applications - applicable if category B is
patent in force.
viii. Section 8 Declaration - the patent declaration must be signed by the person
authorised to make the declaration on behalf of the company named in Section 1.
The authorised person is ordinarily an officer of the company such as Company
Director or Company Secretary as registered with ACRA, or equivalent. Evidence of
such authorisation is to be submitted together with the declaration.
Evidence of authorisation for Section 8 could be in the form of:

An ACRA printout (BizFile) listing the Company Directors/Secretary;
Resolution of board of directors;
Resolution of a general meeting of the company; or,
Extract of the relevant portion of the companys articles of association.
19
http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/GMP/audit_icensing_
manufacturers/conformity_assessment/eServices_Forms.html
20
http://www.hsa.gov.sg/publish/etc/medialib/hsa_library/health_products_regulation/gmp/files_1.Par.60707.
File.dat/GUIDE-MQA-020-007.pdf

Declaration forms must bear the original signatures of the authorised person and the
company stamp of the Applicant.
SEPTEMBER
The patent declaration form needs to be submitted twice: at the time of dossier
submission and prior to issuance of the Product Licence (upon request by HSA), if the
evaluation was deemed satisfactory with respect to the products safety, efficacy and
quality aspects.
NOTE: the applicant should ensure that the information provided in the patent
declaration form and the evidence of authorization is current at the point of
submission.
Declaration on rejection, withdrawal and deferral (section 1.13)
The document required for this section is a declaration letter that states that the
application as submitted to HSA or similar direction of use including indication(s), dosing
regimen(s) and patient population(s)
has not been rejected,
has not been withdrawn,
has not been approved via an appeal process, or,
is not pending deferral
by any drug regulatory agency. If any of the conditions apply to the application, details
and reasons must be provided to HSA.
Declaration for GDA verification (section 1.14)
This section applies only to the verification evaluation route.
A declaration must be provided to state that all aspects of the products quality are
identical to that currently approved by the chosen reference regulatory agency. Quality
aspects include, but are not limited to, formulation, manufacture site(s), release and shelf
life specifications and primary packaging.
If a Drug Master File is submitted, then a second declaration must also be provided to
state that the DMF submitted to HSA is identical to that submitted to the primary
reference regulatory agency.
Registration status in other countries (1.15)
The registration status of the product in other countries should be entered into PRISM
section 4.9 refer to section 25.1.4.9 of this document for further details.
In the event that the PRISM text space does not allow input of the full details of the
indication(s) and/or reason(s), a brief description may be entered. The full details should
then be attached in softcopy (PDF) in PRISM section 7 (Supporting Attachments) and
submitted in hardcopy in section 1.15 of the CTD dossier. The document should be in the
format as seen in Table 7 on page 35 of this guidance document.
17.2 CTD overview and summaries
The overview and summary documents are to be inserted into Module 2 of the ICH CTD
or into the relevant sections in Part II, III and IV of the ACTD.

A completed Singapore Quality Overall Summary (SQOS) must also be inserted into
Module 2, section 2.3 of the ICH CTD or Part II, section B of the ACTD, irrespective of
whether an ICH or ACTD QOS has been included in the application dossier. Take note SEPTEMBER
that the SQOS must be named and dated by the applicant prior to submission. The
electronic copy of the Singapore QOS should be in Microsoft Word format.
NOTE: the SQOS is only a summary of the technical information in the dossier.
Pages from the SQOS should not be used to replace documents required for the
application.
Here are some points to note when filling out and submitting the SQOS with the
application:
i. The information in the SQOS should be based on the documents located in each of
the CTD dossier sections provided by the drug product manufacturer;
ii. All of the tables in all of the SQOS sections should be filled out if there is missing
information, an Input Request will be sent to request to complete the SQOS; and,
iii. During screening of the application, all of the information in the relevant SQOS
sections should be updated when additional or updated documents are submitted in
response to an Input Request.
The SQOS template for chemical drug products is given in Appendix 8.
The quality documents relate to Module 3 of the ICH CTD or Part II of the ACTD. In
addition to the ICH or ACTD technical content requirements, the following explanatory
notes pertain to requirements specific to Singapore:
17.3.1 Body of Data Drug Substance
The ICH M4Q technical guideline and ASEAN Common Technical Requirements (ACTR)
provide details on the information to be included in the drug substance sections of an
NOTE: if a drug product contains more than one drug substance, the information
within Module 3.2.S (ICH CTD) or Part 2.S (ACTD) must be provided in its entirety
for each drug substance.
All of the drug substance sections of the CTD i.e. S1 to S7 should be submitted in the
application. If these sections are incomplete, then the dossier should make reference to a
Drug Master File (DMF) or Certificate of Suitability of Monographs of the European
Pharmacopoeia (CEP).
Because the drug product manufacturer is responsible for quality control of the drug
substance that is used in the drug product, applicants should note that the complete S
section of the CTD dossier should be provided by the drug product manufacturer
regardless of whether a DMF or CEP has been submitted in support of a product
application.

Drug Master File
A Drug Master File is a reference that provides information about specific processes or SEPTEMBER
components used in the manufacturing, processing, and packaging of a drug. The DMF
contains information of a proprietary nature that is not available to the drug product
manufacturer or to the applicant of a product registration submission.
If a drug substance is sourced from a manufacturer that is different from the drug product
manufacturer, data on the manufacture, quality control and stability of the drug substance
may be submitted in the form of a DMF. If the drug substance and drug product are
manufactured by the same manufacturer, then either a DMF or complete S section can
be submitted.
The DMF is divided into two parts: an open (or applicants) part and a closed (or
restricted) part. The open part contains most of the information in Module 3.2S (ICH CTD)
or Part II.C.S (ACTD) i.e. S1, S2.1 and S3 to S7 sections. The closed part contains the
confidential information in section 3.2.S.2.
The documentary requirements for an application making reference to a DMF are as

follows:
From the Applicant:

the open part of the DMF, as part of the submitted dossier; and,
a copy of the Letter of Access.
From the Drug Substance Manufacturer (also referred to as DMF Holder):

the complete DMF i.e. both the open and closed parts; and,
the original Letter of Access.
The Letter of Access authorises HSA to refer to the DMF in support of the application for
a drug product. Thus, the Letter of Access must state the following:
the name of the drug product (product name, dosage form and product strength) to
be registered;
the local applicant responsible for product registration; and,
a declaration that the local applicant and HSA will be notified of any change in the
drug substance specification or in the manufacturing process that will likely affect
the products quality or safety.
If the Letter of Access does not fulfill these requirements, HSA reserves the right to return
the DMF to the DMF holder.
The DMF holder may submit the DMF directly to HSA to maintain confidentiality of the
contents. The information contained in the closed part of the DMF will be regarded as
confidential and will only be evaluated in support of the application(s) mentioned in the
Letter of Access. The confidential information will not be disclosed to any third party
without a written authorisation from the Drug Master File holder.
Upon receipt of the DMF, HSA will assign a DMF number. For future correspondence, the
applicant and the DMF holder should make a reference to the assigned DMF number.
Should there be deficiencies within the closed part of the DMF, HSA will raise queries
directly with the DMF holder.
NOTE: assignment of a DMF number does not constitute approval of the DMF it
is not approved or rejected. It is a separate document that is submitted in support
of an application. A DMF must always be linked to a product application.

If a product application makes reference to a currently-registered DMF, the original Letter

of Access specific to the product application is to be provided by the DMF Holder and a
copy of the Letter of Access is to be submitted by the applicant as part of the registration SEPTEMBER
dossier.
Applicants are responsible to maintain and update the DMF. If there are changes to the
DMF that will result in a post-approval variation to the drug product, applicants must file a
post-approval variation refer to Section F of this guidance for more information on filing
variations.
Certificates of Suitability
A Certificate of Suitability is a document issued by European Directorate for the Quality of

Medicines and Healthcare (EDQM) that certifies the quality of a drug substance in
compliance to the Ph. Eur. A CEP may be submitted in lieu of the CTD S Section or a
DMF.
If reference is made to a CEP, the applicant should submit a copy of the duly authorised,
valid CEP, including all annexes. A duly authorised CEP should contain the following
information in the Declaration of Access section of the CEP:
name of the Product Owner or local applicant;
name of the product to be registered it is recommended that the dosage form and
strength(s) also be stated;
signature and company stamp of the CEP holder; and,
date of authorisation.
The following additional documents must accompany the CEP and inserted into the
relevant CTD S section:
i. batch analysis results (S4.4) from the drug substance manufacturer demonstrating
compliance with the Ph. Eur. monograph, including any additional tests/limits listed
on the CEP; and,
ii. if applicable, additional data to address any relevant parameter(s) not addressed in
the CEP, such as physico-chemical characteristics (e.g. particle size,
polymorphism, etc) and, if a re-test period is not stated on the CEP, container
closure system (S6) and stability data (S7).
NOTE: HSA reserves the right to request for any additional information about the
CEP-certified drug substance if it is deemed appropriate.
If there is a CEP for animal-derived material used in the drug product, the applicant may
submit the CEP in lieu of the documents stipulated in Appendix 11 Guideline on the
Registration of Human Medicinal Products Containing Materials of Animal Origin.
It is the applicants responsibility to submit the latest CEP updates, with annexes, as soon
as it is available from EDQM.
Control of Drug Substance (3.2.S.4)
Batch analysis data should be provided by the drug substance and drug product
manufacturers on the same drug substance batches, if available. While it is not required
to submit data on three batches for CTD section S4.4, the data should be for a
production-sized drug substance batch, if available.

Stability Data of Drug Substance (3.2.S.7)
At the time of submission, the minimum stability data required are as follows: SEPTEMBER
At least 12 months of real time data and 6 months of accelerated data on at least
three primary batches of the drug substance;
The batches should be at least pilot scale-sized and manufactured by a method
that simulates the final commercial process.
If the drug substance is sourced from multiple sites, stability data from each site should
be provided.
HSA may request for additional stability data if deemed necessary for the evaluation of
the application.
17.3.2 Body of Data Drug Product
The ICH M4Q and ACTR also provide details on the information to be included in the
drug product sections of an application dossier.
Pharmaceutical Development (3.2.P.2)
Detailed descriptions and discussions, with relevant data, which relates to the
development, and hence quality, of the drug product should be provided in the relevant
dossier section. Examples include, but are not limited to:
polymorphism, solubility or particle size of the drug substance and its effect on the
products quality;
a description and the results of the formulation development;
the rationale for the choice of dissolution method and a discussion of its
discriminatory nature, with data;
compatibility of the container closure system for the product or preservative efficacy
test results; and,
optimization of the manufacturing process, with data.
Process Validation (3.2.P.3.5)
The description, documentation and complete results of the validation studies on the
manufacturing process should be provided in the dossier. Particular care should be taken
to ensure that the documents include critical processes for the manufacturing process: for
example, blend uniformity validation for oral dosage forms and terminal sterilisation or
aseptic filling for sterile products.
Applicants should refer to the ASEAN Guidelines on Submission of Manufacturing

Process Validation Data for Drug Registration21 and the accompanying Q&A on ASEAN
Guideline on Process Validation for the minimum data requirements on process
validation. Other relevant international guidelines may also be referred to as appropriate.
Where ranges of batch sizes are proposed, it should be demonstrated that variations in
batch size would not adversely alter the characteristics of the finished product.
Control of Excipients (3.2.P.4)
This section refers to all excipients used in the drug product formulation, including
ingredients used in capsule shells and film coatings. The specifications and analytical
21

method(s) for each excipient should be described, with validation of any in-house test
method(s) if applicable.
SEPTEMBER
Information on proprietary ingredients such as flavourings, colourants, perfumes and/or
printing inks should be as detailed as possible. Applicants are advised not to use internal
codes but rather give commercial names for such ingredients.
A CoA for an excipient may be submitted in lieu of the excipients specifications.
For excipients derived from animal sources, applicants should refer to Appendix 11,
which is the guideline on the registration of human medicinal products containing
materials of animal origin. The checklist in Annex 1 in Appendix 11 may serve as a guide
to the documentary requirements for submission. Applicants should note that the
completed checklist in Annex 1 is to be submitted in CTD section 3.2.P.4.5 with the
supporting documents submitted in ICH CTD section 3.2.A.2 or ACTD section Q.A.2.
Control of Drug Product (3.2.P.5)
The drug products release and shelf-life specifications should be declared in section
P.5.1.
Descriptions of all test methods with complete validation results of all in-house methods
should be included in sections P.5.2 and P.5.3.
Batch analysis data and/or CoAs on three batches of the drug product should be
provided in section P.5.4.
Justification of the specifications (section P.5.6) should be based on scientific knowledge

and data collected during product development.
Container Closure System (3.2.P.7)
Technical information about each component of the container closure system(s) used for
the drug product should be included in the dossier. The technical information to be
included in the dossier includes, but is not limited to, schematic diagrams, descriptions,
specifications, analytical methods, CoAs and declarations of compliance to international
standards.
Stability Data of Drug Product (3.2.P.8)
HSA has adopted the ASEAN Guideline on Stability of Drug Product22 for guidance on the
conduct of stability studies for the ASEAN region. Applicants should familiarise
themselves with this guideline prior to submission. Applicants are also reminded that the
ASEAN stability requirements have been implemented since 1st January 2009.
At least 12 months of real time data and 6 months of accelerated data on primary
batches of the drug product, as per the ASEAN guideline;
22

The primary batches should be manufactured by the same method(s) and

packaged in the same container closure system as that proposed for Singapore.
SEPTEMBER
All submitted stability data must be site specific to the product proposed for Singapore.
For example, if the drug substance is sourced from two different sites (e.g. site A and B),
stability data for the drug product must include one set of minimum requirements for the
drug product with drug substance from site A and one set for the drug product with drug
substance from site B i.e. a total of six batches at real time conditions and 6 batches at
accelerated conditions.
Product Interchangeability (3.2.P.9)
Since 1st April 2004, in vivo BE data is required for Prescription Only Medicines (POM) in
oral solid dosage forms.
GDA-2 applications will also require BE data if the application is for a Prescription Only
Medicine (POM) in an oral solid dosage form, even if the first strength (GDA-1)
application was submitted to HSA before 1 April 2004.
Applicants should ensure that the submitted BE study is complete, including all
appendices and data, as per the relevant guidelines. Examples of information to be
included in the report are:
i. Signature of the Principal Investigator to attest the authenticity of the report;
ii. Audit certificate(s), including a BE site inspection report, if available;
iii. Approval letter(s) from the Institutional Review Board/Independent Ethics
Committee and the appropriate drug regulatory agency;
iv. Information about the reference and test products, such as the product name,
strength, dosage form, batch number, manufacturing site, batch size of the test
product, etc.;
v. Certificates of Analysis of the reference and test products used in the BE study,
including the batch size of the test product and manufacturing/expiry date of both
products (where applicable);
vi. Description of the assay methodology and validation; and,
vii. A signed statement confirming that the test product used in the BE study is the
same formulation and is manufactured by the same process as that submitted for
registration.
In instances when the reference product used in the BE study is not the Singapore
reference product, if the criteria listed in section 2 of Appendix 12 are fulfilled, then the
following additional documents must be submitted in support of the application:
i. A comparative table that lists the qualitative composition of both the BE and
Singapore reference products;
ii. Certificates of Analysis of both the reference product used in the BE study and
Singapore reference products, analysed under the proposed specifications for the
generic product;
iii. Comparative dissolution profiles between the BE and Singapore reference
products, as per guideline; and,
iv. Comparative dissolution profiles between the generic and Singapore reference
products, as per guideline.
In instances when biowaiver of submission of a BE study is justified, then comparative

dissolution profiles between the generic and Singapore reference products, as per
guideline, are required.
Applicants should be familiar with Appendix 12 on Product Interchangeability and

Biowaiver Request.

HSA reserves the right to request for any additional information required to determine the
product interchangeability of the generic product to the Singapore reference product.
SEPTEMBER
Blank Production Batch Records
For new product licence applications, one set of Blank Production Batch Records from
the intended site of manufacture may be requested.
17.4 Non-clinical and clinical documents
GDAs generally are not required to include non-clinical (animal) and clinical (human) data
to establish a drug products safety and efficacy. Instead, documents required must
demonstrate product interchangeability with the Singapore reference product e.g. in
vivo BE and comparative dissolution studies.
17.5 Specific documentary requirements for each evaluation route
All aspects of the products quality which includes, but is not limited to, the formulation,
site(s) of manufacture, release and shelf life specifications and primary packaging should
be the same as that approved by the drug regulatory agency that issued the proof of
approval.

BE studies or justification for biowaiver, where applicable.
chosen reference agency must be submitted, as tabulated on the next page. The
assessment reports must be unredacted or unedited. Reports from the chosen reference
agency that are obtained from the public domain are deemed unacceptable.

agency
Health Canada Complete Clinical and Quality# assessment reports, including
and MHRA assessment on the Question & Answer documents between the
Sponsor & Agency and all annexes
US FDA Complete Clinical and Quality# assessment reports, including
assessment on the Question & Answer documents between the
Sponsor & Agency and all annexes*


agency
EMA Complete CHMP Assessment Report#, including the following: SEPTEMBER
- Rapporteurs and Co-Rapporteurs Day 80 Assessment
Reports (non-clinical, clinical, quality, overview and List of
Questions)
- CHMP Day 120 List of Questions
- Rapporteurs Day 150 Assessment Report (non-clinical,
clinical, quality and overview)
- Day 180 List of Outstanding Issues
- All other annexes and appendices
Summary of CHMP Opinion
TGA Complete Clinical Assessment Reports, including assessment on
Complete Chemistry and Quality Control Assessment Report#,
including assessment on the Question & Answer documents
between the Sponsor & Agency and all annexes
evaluation route.
#
applicable.
Administrative documents specific to the verification evaluation route that are required at
the time of submission include:
i. 1.4.3 the proposed PI or PIL should be aligned to the currently-registered
Singapore reference product PI or PIL;
ii. 1.9 Official approval letter, or an equivalent document, from the chosen reference
regulatory agency that certify the registration status of the drug product;
iii. 1.13 Official letter declaring that the application submitted to HSA or similar
direction(s) of use, indication(s), dosing regimen(s) and/or patient group(s) have not
been rejected, withdrawn, approved via appeal process23, or pending deferral24 by
any drug regulatory agency, with reasons in each case if applicable;
iv. 1.14 Official letter declaring that the Drug Master File provided is the same as that
submitted to the chosen reference agency, if applicable; and,
v. 1.14 Official letter declaring that all aspects of the products quality intended for
sale in Singapore are identical as that currently approved by the chosen reference
regulatory agency. This includes, but is not limited to, the formulation, site(s) of
manufacture, release and shelf life specifications and primary packaging.
23
Approval via appeal process includes, but is not limited to, the following: approval following negative
opinion, approval following rejection, approval following non-approvable etc.
24
Deferral includes, but is not limited to, the following: non-approvable, approvable, conditional approval,
conditional marketing authorisation, notice of compliance with conditions etc.

complete quality documents for both drug substance and drug product, which
includes:
i. Module 3 dossier as initially submitted to the chosen reference agency; SEPTEMBER
ii. From Sponsor:
- Question and Answers between the chosen reference agency and sponsor
Questions;
- All post-approval variations approved by the chosen reference agency up to
the time of submission to HSA, including the application letter for the variation,
reference agency and sponsor and the approval letter for the variation from
the reference agency, if applicable; and,
- Relevant documents required by HSA which have not been submitted to the
chosen reference agency, e.g. stability studies in accordance to ASEAN
Stability Guidelines, Singapore Quality Overall Summary, comparative
dissolution studies, etc;
- The initial open and closed parts of the DMF submitted to the chosen
reference agency from the DMF Holder should be provided to HSA, together
with the original Letter of Access;
- Question and Answers between the chosen reference agency and DMF
Holder the Answers should include supporting documents used in response
to the Questions; and,
- All post-approval DMF updates approved by the chosen reference agency up
to the time of submission to HSA, including the application letter for the DMF
update, supporting documents for the DMF update, questions and answers
between the reference agency and sponsor and the approval letter for the
DMF update from the reference agency;
clinical documents, such as BE studies or justification for biowaiver, as initially
submitted to the chosen reference agency with all questions and answers, including
supporting documents, between the reference agency and sponsor; and,
any additional documents to demonstrate product interchangeability with the
Singapore reference product as described in section 17.3.2, where applicable.
Data submitted to HSA must be the same as the data package submitted to the reference
regulatory agencies. Differences between the dossier submitted to HSA and data
reviewed by the reference regulatory agencies will not only delay the processing of the
application, but may also lead to re-routing of the dossier to the abridged evaluation route
if significant undisclosed differences have been discovered.
Special Scheme for Registration of Indian Generic Products
Pursuant to Chapter 5 of the India-Singapore Comprehensive Economic Cooperation

Agreement (CECA), a special scheme (hereinafter referred to as CECA scheme) for the
registration of generic products manufactured in India was introduced to facilitate the
market authorization of these products in Singapore.
Registration of Indian generic products may be possible through the CECA scheme
provided that the application meets the eligibility and documentary requirements.
Applicants intending to submit applications via the CECA scheme should refer to
Appendix 13 for more information.

CHAPTER E BIOSIMILAR PRODUCT APPLICATION

SUBMISSION
This chapter applies to new drug applications for biosimilar products.
Applicants submitting applications to register biosimilar products must be familiar with the
responsibilities of managing these products throughout their life cycle. Thus, it is
recommended to refer to Appendix 17 or HSAs website25 for more information.
This chapter serves to provide additional guidance on submission of biosimilar products.
The product must have been approved by at least one of the following reference
agencies: EU EMA, Australia TGA, US FDA and Health Canada.
Biosimilar products are eligible for the NDA-2 and NDA-3 application types. When
selecting the Product Type in PRISM section 3.2, select Biological Drug.

NDA-1: Not applicable to biosimilar products.
NDA-2: For the first strength of a biosimilar product with the same dosage form and route
of administration as the reference biological product.
NDA-3: For subsequent strength(s) of a biosimilar product that has been registered or
has been submitted as an NDA-2. The product name, pharmaceutical dosage
form, indication, dosing regimen and patient population shall be the same as
that for the NDA-2.
18.1 Biosimilar product
A biosimilar product is intended to be similar in terms of quality, safety and efficacy to a

registered biological product (reference biological product) for which there is a substantial
evidence of safety and efficacy.
The development of a biosimilar product involves stepwise comparability exercises

starting with comparison of the quality characteristics of the biosimilar product and the
reference product. Demonstration of similarity in terms of quality is a prerequisite for the
reduction of the non-clinical and clinical dataset required for registration. If relevant
differences are found in the quality, non-clinical and/or clinical studies, the product will not
likely qualify as a biosimilar product and a more extensive non-clinical and clinical dataset
will likely be required to support registration.
The standard generic approach of bioequivalence demonstration with reference to a

chemical derived drug product is scientifically not appropriate for biosimilar applications
since biological drugs are much more complex in their structure and inherent properties
as compared to chemically-derived drugs. The biosimilar product approach, based on
comparability (demonstration of similarity), should be followed.
25
Guidance on Registration of Similar Biological Products in Singapore.

18.2 Reference product
Considerations for the choice of a biological reference product: SEPTEMBER

The reference product should be a biological medicinal product registered in
Singapore (hereinafter known as Singapore biological reference product). A
biosimilar product cannot be used as a reference product.
The reference product used in the comparability assessments for quality, safety and
efficacy should be
i. the same product throughout all of the studies;
ii. the same strength as that registered in Singapore; and,
iii. from the same manufacturing site as that registered in Singapore.
The active substance(s) of the biosimilar product and reference product should be
similar in molecular and biological terms;
The pharmaceutical form, strength and route of administration of the biosimilar
product should be the same as the Singapore biological reference product. Any
differences will require additional comparability assessment data and have to be
justified by appropriate studies on case-by-case basis;
The conditions of use for the biosimilar product must fall within the directions for use
including indication(s), dosing regimen(s) and patient group(s) for the Singapore
registered reference product.
A biological product with no suitable Singapore biological reference product will not
qualify for registration as a biosimilar product in Singapore.
A biosimilar product is eligible only for the abridged evaluation route.
Table 9 outlines the CTD Modules/Parts required for NDAs submitted for registration of a
biosimilar product:
Table 9. Dossier Submission Requirements for Biosimilar Products.

ICH CTD ACTD Biosimilar product
Administrative Documents Module 1 Part I Yes
Common Technical Module 2 Incorporated in Yes
Document Overview and Parts II, III and
Summaries IV
Quality documents Module 3 Part II Complete quality module including
comparability studies
Non-clinical documents Module 4 Part III Complete non-clinical module
including comparability studies
Clinical documents Module 5 Part IV Complete clinical module including
comparability studies

Non-clinical overview included in Module 2 of the ICH CTD.
Applicants are advised to refer to the Guidance on Registration of Similar Biological

Products in Singapore for detailed information on the complete requirements for
registration of a biosimilar product.

The administrative documents of the registration dossier for biosimilar products is the SEPTEMBER
same as that described in section 14.1 in Chapter C.
20.2 CTD overviews and summaries
The CTD overviews and summaries are the same as that described in section 14.2 in
Chapter C.
The full quality data (i.e. Module 3 of ICH CTD or Part II of ACTD) should be submitted.
Data submitted should include extensive drug substance and drug product
characterisation and quality comparability data between the biosimilar and the Singapore
biological reference products. The comparability exercise should encompass both drug
substance and drug product and should take into consideration of the following:
the complexity of the molecular structure;
the types of changes introduced in the manufacturing process during development;
and,
the impact on quality, safety and efficacy.
Non-clinical and clinical data generated with the biosimilar product is also required.
The amount of non-clinical and clinical data required for submission will depend on:
the product or class of products;
the extent of characterisation possible undertaken using state-of-the-art analytical
methods;
observed or potential differences between the biosimilar product and the reference
product; and,
the clinical experience with the product class.
A case-by-case approach is needed for each class of products.

CHAPTER F POST-APPROVAL PROCESS
Throughout the life cycle of a medicinal product, changes to a products efficacy, quality
and/or safety are likely to occur.
HSA must be notified of any changes to a products safety, efficacy or quality through an
application process i.e. the variation application. Figure 5 below is a schematic diagram
of the variation application routes:
Efficacy, Safety MAV-1

IS PRODUCT
REGISTERED? MAJOR VARIATION
YES MAV-2
Change in safety, MIV-1

efficacy or quality
aspect? MINOR VARIATION
Quality, Safety
MIV-2
Figure 5. Schematic diagram of variation application routes.
There are two types of variation applications: major variation application (MAV) and minor
variation application (MIV). The variations are described as follows:
MAV Major Variation application for an existing registered product.

MAV-1: Any variation to the approved indication(s), dosing regimen(s), patient group(s),
and/or inclusion of clinical information extending the usage of the product (e.g.
clinical trial information related to an unapproved indication, dosing regimen
and/or patient population; recommendation for concomitant administration of
vaccines; additional bacterial strains to expand the indication(s) for
antimicrobial products).
MAV-2: A change in current approved forensic classification, also known as
reclassification.
MIV Minor Variation application for an existing registered product

MIV-1: A minor variation, which requires regulatory approval.
MIV-2: A minor variation or an administrative change.
HSA reserves the right to re-categorise the application type if appropriate. Applicants are
to note that, in PRISM, the re-categorisation of an application (e.g. MIV to MAV-1, MIV-2
to MIV-1 or vice versa) may require withdrawal of the original application. The applicant
will be notified if it will be required to resubmit the application according to the correct
category.
All applications require HSAs approval before the change(s) can be implemented, with
the exception of MIV-2 applications, where the change(s) can be implemented if there is
no objection from HSA within the notification timeline (refer to Appendix 1 for notification
timeline).

21 VARIATION APPLICATION PROCESS
The steps to submit an MAV or MIV is similar to submitting an NDA or GDA, as seen in SEPTEMBER
Figure 6 on the next page:
PRE-SUBMISSION
PREPARATION
APPLICATION
NON-ACCEPTANCE / SUBMISSION
WITHDRAWAL
APPLICATION
SCREENING
a
ACCEPTANCE
APPLICATION
EVALUATION
NON-APPROVAL /
WITHDRAWAL
REGULATORY
DECISIONb
a
An acceptance notice will not be sent for MIV-2 applications.
b
A regulatory decision letter will not be sent for MIV-2 applications.
Figure 6. Schematic diagram of the variation application process.
However, each variation application has distinct differences and the applicant should be
familiar with the variation application process in order to facilitate the process.
21.1 Pre-submission preparation
Since submission of a variation application is the same as an NDA or GDA, applicants

are advised to ensure that all the requirements for the variation are met before submitting
the application.
Applicants are encouraged to contact HSA prior to submission of a variation application if

there are questions regarding the application. There are two methods to contact HSA:
i. Pre-submission Inquiry via email

ii. Pre-submission Consultation
Applicants are to note that all advice given by HSA will be based on knowledge that is
current at the time of the consultation. Such advice is not binding and does not have a
direct bearing on the eventual outcome of the application concerned.

21.1.1 Pre-submission inquiry
The applicant may submit a Pre-Submission Inquiry via e-mail if any clarification on SEPTEMBER
submitting an MAV application is needed prior to submission. The e-mail address is:
HSA_MedProd_Registration@hsa.gov.sg. The subject of the e-mail should state, Pre-
submission inquiry, in order for the e-mail to be sent to the relevant officer.
For issues relating to MIV submissions, the applicant should email a completed MIV Filing
and Submission Inquiry Form (Appendix 14) to HSA_MedProd_Registration@hsa.gov.sg.
Upon receipt of an MIV Inquiry Form, an officer will look into the inquiry and respond back
to the named applicant via email with an Inquiry Reference Number. If the MIV is
submitted, then a copy of the Inquiry Form, with the Inquiry Reference Number, should be
included in the submission. The applicant may also opt to fax the completed form to HSA,
but the use of email is strongly encouraged.
21.1.2 Pre-submission meeting
Applicants may also request for consultation with HSA. The request should be made in
writing, with the purpose, agenda and proposed date & time for the meeting, and emailed
to HSA_MedProd_Registration@hsa.gov.sg. An officer will respond and facilitate the
arrangement of the meeting.
For a submission under the full evaluation route, the applicant is required to notify HSA
via a pre-submission meeting two months prior to the intended submission date of the
21.2 Application submission
A variation application should comprise of both the submission of the PRISM application
form and the variation application dataset.
21.2.1 PRISM application form
Submitting the application through PRISM is similar to that of a NDA or GDA, although
some of the fields in the PRISM application form would not be editable for variation
applications.
Refer to Chapter J for guidance on submitting a PRISM application.
21.2.2 Variation application dataset
The submission of the complete dataset should take place within 2 working days after the
PRISM application submission to prevent delays in processing of the application. The
date of submission will be defined as the date when HSA receives the complete
dataset for the application.
The dataset should be using the CTD format that was selected for the original new
product application.
In moving towards a greener environment, submission of the variation application dataset

should be in electronic format. But there is one exception: documents which require proof
of authenticity (e.g. CPPs, approval letters not available online, authorisation letters, GMP
certificate, patent declaration, declaration letters, etc) should be submitted in electronic
and hard copy format.

Applicants are responsible to ensure that all soft copies e.g. scanned documents of
the dossier are legible.
SEPTEMBER
When submitting a CD/DVD, applicants are encouraged to organise the dossier via the
CTD format with folders and subfolders and to include bookmarks to facilitate
screening/reading of the reports.
Applicants must ensure that access to the CD/DVD is not restricted. If so, the applicant
must provide the password(s) to access the CD/DVD contents.
Upon acceptance of the application for evaluation, applicants will be notified if additional
copies of clinical documents (in CD/DVD) will be required.
21.2.2.1 Language
Information and documents supporting an application, such as certificates, approval

letters and approved product labels, must be in English and authenticated. If documents
are not originally in English, applicants should refer to Appendix 4 for the flow chart for
the translation of non-English documents.
Authentication of foreign documents for use in Singapore is required when the

authenticity of the documents cannot be determined.
If the foreign document is an original and bears the seal and signature of a recognised
government agency, the document does not require notarisation. Any other type of
document, such as declarations, translations, photocopies, documents lacking an original
signature, etc., must be notarised by a notary public in the country where the document
was issued before the document can be authenticated. The notary public will sign the
document and affix their seal. Notarisation is generally not required for documents
executed in Singapore for use in Singapore.
As an example, for notarisation the information included on the document could be:
The name of the notary;
A statement that the notary is duly admitted to practice in the place of issue of the
certificate;
The names of the signatories and the capacity in which they have executed the
document, whether on their own behalf or in an official or representative capacity;
A statement authenticating the signatures of the parties and, where appropriate,
indicating that evidence has been produced to the notary proving the capacity in
which they have executed the document;
The place and date of issue of the notarial certificate; and
The signature and seal of the notary.
Authentication, also known as legalisation or consularisation, refers to the process

whereby the origins of a document are attested. Authentication of documents in support
of applications made to HSA can be done by:
The Ministry of Foreign Affairs of the country in which the document was issued; or,
The Singapore Embassy/Consulate in the country where the document was issued.
Applicants are advised to consult the Singapore Embassy/Consulate in the country where
the document originated on local requirements for document legalisation, as these may
deviate from the process as outlined in the preceding paragraph.
Certificates and documents issued in English by drug regulatory agencies do not require
authentication.

Apostille
By international agreement, an apostille can be issued for documents that are to be used SEPTEMBER
in another country that is party to the Hague convention. When an apostille stamp is
attached to a document, it is exempted from all forms of confirmation; i.e. no further
legalisation from a foreign embassy is normally required. Although Singapore at present
is not a party of the Hague Convention, an apostille is acceptable for the authentication of
documents to be submitted to HSA as part of the application dossier.
21.2.2.2 Certifying non-original documents
A certified true copy certifies that the photocopy presented is a true and accurate copy of
the original document. Acceptable certification of documents to support drug product
applications to HSA can be done by the Company Director or Company Secretary as
registered with ACRA or above, or by an independent authority such as a lawyer, notary
public, Commissioner for Oaths/Declarations/Affidavits, Justice of Peace, the original
issuer of the document or Embassy/Consulate. A notarised copy is the same as a
certified true copy.
A certified true copy of approval letters requires certification by the drug regulatory
agency that issued the approval letter, notary public or Singapore Embassy/Consulate in
the country where the approval letter was issued. Certification of approval letters is not
required in the event the approval letter is available on the drug regulatory agencys
website. In this instance, applicants shall provide the internet address (URL) for validation
by HSA.
21.3 Application screening
The screening process is similar to that for an application for a new medicinal product a
query will be sent to the applicant to address any noted deficiencies in the submission
within a stipulated timeframe.
Upon acceptance of an application, an acceptance notice will be issued to the applicant

for MAV and MIV-1 applications. The date of acceptance of the application will be
considered as the start of the evaluation timeline.
21.4 Application evaluation and Regulatory decision
The evaluation process is similar to that for an application for a new medicinal product.
For applications submitted in PRISM on or after 15 April 2009, applicants can check on
the progress of the evaluation for certain application types and evaluation routes. Table
10 describes the applicable applications and the stages to the evaluation process for
post-approval changes:

Table 10. Variation Applications Applicable for Notification of Stages for Post-Approval Changes
st nd rd th
Stages of Notification to 1 Stage 2 Stage 3 Stage 4 Stage
Applicant SEPTEMBER
Evaluation Status
Application Dossier
Type type Accepted for Active Midway in Evaluation
Application is Evaluation is
approximately completed for the
midway through application
the evaluation
Application is (provided that Application is now
accepted for When active there were no undergoing the
evaluation evaluation is in prior stop-clocks regulatory decision
Full or progress for which may affect phase, after which
MAV-1 This marks the the application a regulatory
Abridged the evaluation
start of the progress) decision letter*
evaluation would be issued.
timeline Applicants could
expect to receive Applicants could
the first set of still expect further
queries from HSA queries from HSA
during this stage during this stage
* The issuance of a regulatory decision letter would mark the end of the evaluation timeline for a product
application.
Applicants may view the evaluation stage via track@PRISM. Applicants would also be
notified via a system-generated email whenever a status change occurs.
The regulatory decision process is also similar to that for an application for a new
medicinal product. However, a regulatory decision letter will not be issued for MIV-2
applications as these are notifiable changes.
21.5 Fees
The fee structure and quanta are subject to on-going review. For updated information on
fees, please visit the HSA website26.
21.5.1 Screening fee
The screening fee per application is payable at the time of PRISM submission. It is only
applicable for MAV-1 applications. The screening fees are non-refundable once the
application has been successfully submitted via PRISM.
Applicants are advised to ensure that the dataset is compiled according to the required
of the dossier without screening. In these instances, the screening fees will be forfeited.
21.5.2 Evaluation fee
There are two different evaluation fees for MAV-1 applications:

i. Evaluation fees for a single strength product or the first product in a series of
products of different strengths; and,
ii. Evaluation fees for each subsequent product in a series of products of different
strengths.
26
http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/western_medicines/licences/
fees.html

Evaluation fees for MAV-1 applications are payable upon acceptance of the MAV-1 for
evaluation.
SEPTEMBER
Evaluation fees for MIV-1 applications are payable upon submission of the application in
PRISM.
Evaluation fees are non-refundable once the application is accepted, regardless of the
final decision by HSA.
With effect from 15 Apr 2009*, the progressive payment scheme was implemented to
allow the payment of evaluation fees by instalments. This is an optional opt-in payment
scheme catered for companies who are under the GIRO payment scheme and only
applicable to the application type listed in the Table 11:
Table 11. Variation Applications Applicable for Progressive Payment Scheme

Percentage of Evaluation Fee Payable at Each Stage
Evaluation Status
Application Dossier
Type type Accepted for Active Evaluation Midway in Evaluation
Evaluation Evaluation Completed
Full or
MAV-1 30% 40% 20% 10%
Abridged
NOTE: To apply for the progressive payment for applications submitted via the full
evaluation route, the applicant must contact HSA via
HSA_MedProd_Registration@hsa.gov.sg to request for a hardcopy progressive
payment application form prior to the submission in PRISM.
For applicants that had chosen the progressive payment scheme, in the event of an
application withdrawal at any point in time during the evaluation stage, any fees that had
been charged, but not yet collected, would still have to be paid; all evaluation fees that
had been paid are non-refundable.

CHAPTER G MAJOR VARIATION (MAV) SUBMISSION

This chapter applies to major variation applications for currently registered products.
22 MAV-1 SUBMISSIONS
An MAV-1 application applies to any variation to the following:

i. approved indication(s);
ii. approved dosing regimen(s);
iii. approved patient group(s); and/or,
iv. inclusion of clinical information outside the approved usage of the product for
example, clinical trial information related to an unapproved indication, dosing
regimen and/or patient population; recommendation for concomitant administration
of vaccines; and additional bacterial strains to expand the indication(s) for
antimicrobial products.
22.1 Evaluation routes
There are three evaluation routes for an MAV-1:
Full dossier: Applies to any MAV-1 variation that has not been approved by
any drug regulatory agency at the time of submission.
Abridged dossier: Applies to any MAV-1 variation that has been evaluated and
approved by at least one drug regulatory agency. The proposed
variation (i.e. the proposed indication(s), dosing regimen(s),
patient group(s) and/or clinical information) should be the same
as that approved by the regulatory agency that issued the proof
of approval.
Verification dossier: Applies to any MAV-1 variation that has been evaluated and
approved by at least two of HSAs reference drug regulatory
agencies, which include EMA*, US FDA, Health Canada, TGA
and UK MHRA#.
* For products approved via the Centralised Procedure
# For products approved via the national procedure or where MHRA acted as the RMS for the MRP or
Decentralised Procedures in Europe
The eligibility criteria are different for each evaluation route. Applicants should be familiar
with the criteria for each evaluation route because each route will have different
documentary requirements.
22.1.1 Full evaluation route
Full evaluation will apply to a major variation that has not been approved by any drug
Abridged evaluation will apply to a major variation that has been evaluated and approved
by at least one drug regulatory agency. The proposed variation i.e. the proposed
indication(s), dosing regimen(s), patient group(s) and/or clinical information should be
the same as that approved by the regulatory agency that issued the proof of approval.

22.1.2.1 Applications for non-prescription medicines
If the MAV-1 is for a non-prescription medicine and is submitted via the abridged SEPTEMBER
evaluation route, the applicant may submit a written request for a waiver of clinical data
submission. Eligibility for waiver is subject to the criteria defined in Appendix 5 Guideline
on Submission Requirements for Non-Prescription Medicines. However, HSA reserves
the right to request for the complete clinical data set if it is deemed appropriate.
Similar to an NDA, at least two of HSAs reference drug regulatory agencies must have
evaluated and approved the major variation. However, approval by these reference
regulatory agencies does not obligate HSA to approve the application.
One of the reference drug regulatory agencies must be declared as the primary reference
agency. The chosen primary reference agency is defined as the reference agency for
which the qualifying supporting documents (as outlined in this guidance) will be submitted
and which approved the strictest indication(s), dosing regimen(s), patient groups(s)
and/or direction(s) for use among the two HSA reference drug regulatory agencies which
approved the variation.
Additional eligibility criteria for the verification route include:

The application must be submitted within three years from the approval date by the
chosen primary reference agency;
The product does not need a more stringent assessment as a result of differences
in local disease patterns and/or medical practices (e.g. some anti-infectives); and,
The product and its intended use i.e. indication(s), dosing regimen(s) and patient
group(s) have not been rejected, withdrawn, approved via appeal process or
pending deferral by a drug regulatory agency for safety and/or efficacy reasons.
The proposed indication(s), dosing regimen(s), patient group(s) and/or direction(s) for use
should be the most stringent amongst those approved by the reference regulatory
agencies.
For a product with a proposed indication that has been designated as an Orphan Drug by
at least one reference agency or a product that has been approved by at least one
reference agency via an accelerated/fast-track approval, approval under exceptional
circumstances or equivalent approval process, the applicant should consult HSA on the
eligibility of such a product through the verification route prior to submission.
22.2 Documentary requirements
Table 12 outlines the CTD Modules/Parts required for MAV-1s submitted under each
evaluation route:

Table 12. Dossier Submission Requirements for MAV-1.

Location in Module/Part required for
ICH CTD ACTD Full Abridged Verification SEPTEMBER
MAV-1 MAV-1 MAV-1
Administrative Module 1 Part I Yes Yes Yes
Documents and
Product Information
Common Technical Module 2 Incorporated Yes Yes Yes
Document Overview into Parts II,
and Summaries III and IV
Quality documents Module 3 Part II No No No
# #
Non-clinical Module 4 Part III No No No
documents
Clinical documents Module 5 Part IV Yes Study report(s) Study report(s)
of pivotal of pivotal
studies and studies and
synopses of all synopses of all
studies (phase studies (phase
I-IV) relevant I-IV) relevant
to requested to requested
indication, indication,
dosing and/or dosing and/or
patient group patient group
If the proposed MAV-1 is related to non-clinical data, non-clinical summary and non-clinical overview as well
as relevant study reports is required.
#
Non-clinical overview only, if applicable.
For MAV-1 applications, in order to ensure that the dossier is complete, application
checklists for both ICH CTD and ACTD dossiers are provided in Appendix 2B and 3B,
respectively. Each checklist states the required documents for each dossier type and
application type. Refer to the specific Appendices for more details.
22.2.1 Administrative documents
The three evaluation routes for an MAV-1 share the same documentary requirements for
CTD Module 1/Part I. The documents required are:
i. 1.1 Comprehensive Table of Contents;
ii. 1.2 Introduction including the Table of Amendment Details of PRISM section
0.5;
iii. 1.3 PRISM application form;
iv. 1.4 Labelling, Package Insert and Patient Information Leaflet both the proposed
and currently approved Singapore product labels and PI/PIL are required. For the
proposed labelling/PI/PIL, a pristine and an annotated version (which highlights the
changes made to the currently approved labelling) are required;
v. 1.5 Approved SPC/PI/PIL from the drug regulatory agency that issued the proof of
approval and from each of HSAs reference drug regulatory agencies (where
applicable);
vi. 1.6 Assessment Report from Reference Agencies only for verification route
(see section 22.2.5.3);
vii. 1.8, 1.9 Proof of Approval for an MAV-1, the official approval letter(s) must
contain information on the requested Singapore variation. For the verification
evaluation route, the approval letters issued by the relevant reference agencies
should be submitted;
viii. 1.13 Declaration on rejection, withdrawal and deferral; and,
ix. 1.15 Registration Status in Other Countries.

22.2.2 CTD overviews and summaries
The following documents are to be submitted: SEPTEMBER

a non-clinical overview, if applicable; and,
a clinical overview and summaries of clinical efficacy and clinical safety
22.2.3 Quality documents
Quality documents (Module 3/Part II) are not required for MAV-1 applications.
22.2.4 Non-clinical and clinical documents
Each evaluation route will have different non-clinical and clinical documentary
requirements. Refer to section 22.2.5 for more information.
Risk management plans (RMP) submitted to EMA, risk evaluation and mitigation
strategies (REMS) submitted to US FDA, and/or other relevant documents pertaining to
such purposes should be included, where available. The need to implement a risk
management plan in Singapore would be assessed on a case-by-case basis during the
review process.
22.2.5 Specific documentary requirements for each evaluation route
22.2.5.1 Full evaluation route

complete non-clinical documents, if applicable; and,
complete clinical documents; i.e. all study reports from phase I to phase III relevant
to requested indication, dosing and/or patient group, including tables and
appendices.
22.2.5.2 Abridged evaluation route

22.2.5.3 Verification evaluation route
chosen primary reference agency must be submitted, as tabulated below. The
assessment reports from the primary reference agency must be unredacted or unedited.
Reports obtained from the public domain are deemed unacceptable.

agency
Health Canada Clinical assessment reports, including assessment on the
and MHRA Question & Answer documents between the Sponsor & Agency
and all annexes


agency
US FDA Clinical assessment reports, including assessment on the SEPTEMBER
Question & Answer documents between the Sponsor & Agency
and all annexes*
EMA Summary of CHMP Opinion
European Assessment Reports (i.e. Rapporteur, Co-Rapporteur
and Joint Clinical assessment reports), including assessment on
TGA Clinical assessment reports, including assessment on the
Question & Answer documents between the Sponsor & Agency
and all annexes
Delegates overview
Pre-ACPM response
ACPM minutes
evaluation route.

All of the data submitted to HSA must be the same as the data package submitted to the
reference regulatory agencies. Differences between the dossier submitted to HSA and
data reviewed by the reference regulatory agencies will not only delay the processing of
the application, but may also lead to re-routing of the dossier to the abridged evaluation
route if significant undisclosed differences have been discovered.
23 MAV-2 SUBMISSIONS
An applicant seeking to change the forensic classification of a registered product should

submit an MAV-2 application, otherwise known as reclassification. Examples of
reclassification include from POM to P or from P to GSL. If an MAV-2 application is riding
on a previous reclassification of an analogous product, then the applicant may submit a
me-too reclassification.
Reclassification may also be undertaken when experience gained shows that there is a
need to supervise the use of a product i.e. from GSL to P or POM.
Only the abridged evaluation route applies for such applications.
23.1 Eligibility criteria
A change of forensic classification of a POM or P drug product may be considered if the

following criteria are met:
i. The use of the product has been sufficiently extensive;

ii. The product has been marketed for a period of time sufficient to establish a post-
marketing adverse event profile; and,
iii. The products safety profile gives no cause for concern during the marketing period. SEPTEMBER
Applicants who wish to submit a request for reclassification of a medicinal product shall
provide justification based on the following information:
i. The forensic classification and approved indication(s) and dosing regimen(s) of the
product in the UK, US, Canada and Australia;
ii. The period of product registration in Singapore, UK, US, Canada and Australia, with
specific information on its forensic classification (i.e. POM, P and/or GSL) and
duration of sale in that classification;
iii. The period of actual product sale in Singapore;
iv. The rationale for requesting a change in the forensic classification;
v. Patient exposure of the product and its safety profile based on worldwide
spontaneous adverse drug reaction reports, data from post-marketing surveillance
studies, clinical trials, published literature and locally reported adverse drug
reactions; and,
vi. Potential problems and hazards arising from the inappropriate use of the product.
23.1.1 Me-too reclassification
A me-too reclassification will be considered if an analogous product with the same active
ingredient and intended use has been reclassified to the requested forensic classification.
One set of documents, as outlined in the checklists in Appendix 2B or 3B, should be

submitted in softcopy. Applicants should be reminded that all administrative documents in
CTD Module 1/Part I required for the application must be in softcopy and hardcopy refer
to section 21.2.2.
The documentary requirements for an MAV-2 submission include:

ii. 1.2 Introduction including the justification for re-classification, as listed above,
and the Table of Amendment Details of PRISM section 0.5;
iii. 1.3 PRISM Application Form;
iv. 1.4 Product Labels the proposed product labels/PIL should also be submitted, if
applicable;
v. 1.5 Approved SPC/PI/PIL;
vi. 1.8 Proof of Approval proof of the approved indication(s) and dosing regimen(s)
for the reclassified product in the UK, US, Canada and/or Australia;
vii. 1.15 Registration Status in Other Countries; and,
viii. Module 2/Part IV Summary of Clinical Safety the summary should include the
following:
a) The forensic classification of the product in the UK, US, Canada and Australia,
with specific information on its forensic classification and duration of sale in that
classification;
b) The experience of patient exposure to the product e.g. sales volume, patient-
years;
c) A summary of the product safety profile based on worldwide and local
spontaneous adverse drug reaction reports, post-marketing surveillance data,
clinical trials and published literature;
d) A list of the potential problems arising from using the product without medical
supervision; and,

e) An analysis of the hazards arising from therapeutic misuse or drug abuse,

whether deliberate or accidental e.g. consequence of delay in seeking medical
attention. SEPTEMBER
23.2.1 Me-too reclassification
The documentary requirements for a me-too reclassification application include:

ii. 1.2 Introduction including the justification for re-classification , as listed above,
and the Table of Amendment Details of PRISM section 0.5;
iii. 1.3 PRISM Application Form;
iv. 1.4 Product Labels the proposed product labels/PIL should also be submitted, if
applicable; and,
v. 1.5 Approved SPC/PI/PIL, if applicable.
The Summary of Clinical Safety in Module 2/Part IV is not required.

CHAPTER H MINOR VARIATION (MIV) SUBMISSION

This chapter applies to minor variation applications for currently registered products.
24 MIV SUBMISSIONS
Applicants should be familiar with the guidelines before submitting minor variation
applications (MIVs). The guidelines and documentary requirements are described in
Appendix 15 (chemical) and 16 (biologics).
A minor variation application (MIV) is submitted via the Amendment to a Licence of

Western Drug Product form in PRISM:
Here are some points to consider when submitting an MIV:

If one MIV contains multiple changes that belong to both MIV-1 and MIV-2
categories, then the MIV should be categorised as an MIV-1; and,
If a proposed MIV-2 does not meet its specified conditions, then the MIV must be
categorised as an MIV-1 with supporting documents.
With effect from 1 July 2011, MIV-1 changes should be grouped together as one
application when these changes are consequential changes. A consequential change is
regarded as a change that is unavoidable and is a direct result of another change, not
simply a change that occurs at the same time. HSA reserves the right to split any MIV-1
application with non-consequential changes into separate MIV applications.
HSA also reserves the right to re-categorise the MIV if deemed appropriate.
NOTE: Applicants are encouraged to fax or email the MIV Filing and Submission
Inquiry Form in Appendix 14 for any issues regarding MIV filing.
Applicants should ensure that all conditions and documentary requirements for the MIV
have been fulfilled prior to submission. For an MIV with multiple variations, all of the
requirements for each individual variation must be met. Applicants are advised to refer to
Appendix 15 or 16 for information on whether to submit documents in hardcopy or
softcopy.
Any undisclosed variation(s) embedded in the submitted data, including any flow-on
changes, will not be considered. Evaluation will be based on the data relevant to the
proposed variation(s), unless HSA specifically requests for additional information.
It is the applicants responsibility to ensure the completeness of the application and

compliance with all specified requirements failure to do so may delay the MIV review
process.

CHAPTER J SUBMISSION OF A PRISM APPLICATION FORM

This chapter primarily describes the process for submitting NDA/GDA applications via
PRISM. However, the process for submitting MAV/MIV applications via PRISM is similar
except that some of the fields would not be editable for MAV/MIV applications.
25 SUBMITTING A PRODUCT APPLICATION
HSA only accepts applications on-line via PRISM. Applicants are advised to visit the
prism@hsa27 webpage for further details on PRISM.
NOTE: NEW applicants must have a CRIS account in order to register medicinal
products via PRISM. For information on setting up a CRIS account, refer to the
following weblink:
http://www.hsa.gov.sg/publish/hsaportal/en/services/cris.html
A separate Product Licence, and therefore a separate application, would be required for
each pharmaceutical dosage form and strength of the medicinal product. Separate
application forms are also required for the following (see Example 1):
Powders for injection containing different amounts of drug substance per container;
Concentrates for reconstitution labelled with the actual amount of drug substance
before reconstitution; and,
All single-use pre-filled syringes containing different amount of active ingredient in
each syringe.
Example 1. Injectable products which require separate licences:
Examples Labelled strength before Application type

reconstitution
Powder for Solution 25mg/vial Submit as 2 separate applications:
for Injection 50mg/vial One as NDA-1/GDA-1 and the other as
NDA-3/GDA-2
Solution for Injection 2mg/mL in a vial containing Submit as 2 separate applications:
1 mL of the solution One as NDA-1/GDA-1 and the other as
2mg/mL in a 1 mL pre-filled NDA-2/GDA-1
syringe
Concentrate 10mg/5mL Submit as 2 separate applications:
20mg/10mL One as NDA-1/GDA-1 and the other as
NDA-3/GDA-2
Single-use Pre-filled 100 iu/mL Submit as 2 separate applications:
Syringe containing One as NDA-1/GDA-1 and the other as
different amount of NDA-3/GDA-2
400 iu/4mL
active ingredient in
each syringe
Example 2 on the next page are examples of injectable products which are allowed to be
registered under one product licence (as pack sizes):
27
http://www.hsa.gov.sg/publish/hsaportal/en/services/prism.html

Example 2. Injectable products which are allowed to be registered under one product
licence (as pack sizes):
SEPTEMBER
Examples Labelled strength before Application type
reconstitution
Solution for Injection 2mg/mL in a vial containing Submit as one application with two pack
1 mL of the solution sizes (i.e., 1 mL and 2 mL)
2mg/mL in a vial containing
2 mL of the solution
Concentrate 2mg/mL: presented in 5 mL Submit as one application with two pack
vial and 10 mL vial sizes (i.e., 5 mL and 10 mL)
25.1 Sections of a PRISM Application
25.1.1 Section 1 Company Particulars
Each application for a Product Licence is company-specific. The company named in this
section must be based and registered in Singapore. The company must be authorised by
a responsible person in the company/organisation that owns the medicinal product before
it can apply for a Product Licence for a specific medicinal product in Singapore.
In this section, input the company telephone and fax numbers; the name, address and
Business Registration number (UEN) will be automatically populated. If there is a direct
telephone and/or fax number, input it into this section to ensure no communication delays
between HSA and the applicant.
The company bears full responsibility for ensuring that all available and relevant
information is submitted in support of an application. For every successful application for
registration of a medicinal product granted approval, a Product Licence will be issued in
the name of the company, which will be the product licence holder.
25.1.2 Section 2 Applicant Particulars
The person named in this section should be a permanent staff of the company and
residing in Singapore. If the applicant is an external party engaged by the applicant
company to submit the application on their behalf (i.e. consultant), an original letter of
authorisation from the applicant company must be submitted (refer to section 14.1
Administrative Documents Authorisation Letters).
In this section, input the particulars of the named person name, NRIC/FIN and
designation. For PRISM sections 2.4 and 2.5, the company address and contact details
(as in PRISM section 1) may be entered as an alternative, as seen in the screenshot on
the next page:

SEPTEMBER
Company address
may be entered
Direct telephone and fax numbers

of the company may be entered.
Take note that only company email
addresses should be entered.
Care should be taken to ensure that the contact details are entered correctly to ensure no
communication delays between HSA and the applicant. Applicants are advised to notify
HSA immediately via amend@PRISM28 (select Amend Applicants Details for licences
and applications) if there is any change to this PRISM section, especially to the contact
details.
From this point on, any mention of the word applicant in this guidance document will
refer to the person named within this PRISM section.
25.1.3 Section 3 Application Details
In this PRISM section, enter specific details of the application, such as the application
type, dossier type, format type and any reference product(s), if applicable. A screenshot
of PRISM section 3 is shown below:
28
http://www.hsa.gov.sg/publish/hsaportal/en/services/prism/drugs.html

25.1.3.1 Section 3.1 Type of Application
Input the type of application to be submitted to HSA. SEPTEMBER
Note:
After the application has been submitted, if the type of application is selected incorrectly
and it needs to be changed
within the same application type (e.g. from NDA-2 to NDA-3), then HSA will notify
the applicant and change the application form on behalf of the applicant at the point
of acceptance of the application; or,
to a different application type (e.g. NDA-1 to GDA-1), then the original PRISM
application must be withdrawn first before re-submission under the correct
application type.
HSA reserves the right to re-categorise the application type when appropriate.
25.1.3.2 Section 3.2 Type of Product
Input either Chemical Drug for chemical drug product or Biological Drug for biologic
drug products. Please note that once the product type is set, it cannot be changed
throughout the entire products life cycle.
A biological medicinal product (a biologic) refers to products derived from biological

systems, which include:
Whole cells or organisms, e.g. whole virus/bacterium used as a vaccine;
Part of organisms, e.g. sub-unit vaccines, blood/serum-derived products;
Macromolecules extracted from or produced by organisms, e.g. proteins, nucleic
acids, proteoglycans, cytokines and growth factors; and,
Biotechnology products, e.g. recombinant hormones, enzymes, antibodies;
but does not include:
Metabolites from micro-organisms, e.g. antibiotics; and,
Macromolecules produced by chemical synthesis, e.g. peptides/oligo-nucleotides
produced by chemical synthesisers.
Applicants are advised to contact HSA, via pre-submission inquiry or meeting, as stated
in section 5.3, when in doubt on whether the drug product is considered a chemical or
biologic product.
25.1.3.3 Section 3.3 Reference Product
This section applies only to GDA-1, GDA-2 or NDA-3 applications.
For all GDA applications, applicants need to specify the Singapore Reference Products
SIN number, which can be obtained by searching HSAs online database29. If a GDA-2
application is not submitted at the same time as a GDA-1 application, specify both the
Singapore Reference Products and the GDA-1 products SIN numbers.
For NDA-3 applications, if the application is not submitted at the same time as an NDA-1
or NDA-2 application, input the SIN number of the Singapore-registered NDA-1 or NDA-
2.
25.1.3.4 Section 3.4 Type of Dossier
This refers to the three evaluation routes as mentioned in section 5.2 of this guide.
29

Only one option can be selected from the drop-down menu full, abridged or verification.
For applications under the Special Scheme for registration of Indian generic products, SEPTEMBER
choose the Verification CECA option.
HSA reserves the right to re-categorise the dossier type when appropriate. The applicant
will be informed if re-categorisation is necessary.
25.1.3.5 Section 3.5 Type of Format
Indicate whether the dossier format is ICH CTD or ACTD. Once the format type has been
set in PRISM, it cannot be changed throughout the entire products life cycle.
Applicants are expected to organise the documents into the respective CTD sections
before submitting the dossier to HSA. Explanatory notes on the registration dossier
format can be found in section 6.2.
25.1.4 Section 4 Product Information
25.1.4.1 Section 4.1 Product Name
The Product Name is the products trade name that is shown on the product labelling.
From this point on, any mention of the term product labels or product labelling in this
guidance document will refer to the inner label, outer carton, package insert (PI) and/or
patient information leaflet (PIL) of the product.
Applicants should ensure that the product name:

does not suggest greater safety or efficacy than that supported by clinical data;
does not imply superiority over another similar product in Singapore;
does not imply the presence of substance(s) not present in the product; and
shall not be confused with another product.
If the proposed product name is not acceptable, the applicant will be informed of the
reasons, and will be asked to amend it.
The Product Name should be entered in the following format:
Pharmaceutical Product Standard

Brand Name Product Strength
Dosage Form (optional)
ABC Solution for Injection 300mg/ml USP
Applicants are advised to use the same format for the product labelling. However, the
International Non-proprietary Name (INN) or common name of the active substance(s)
may be used when referring to the active ingredient(s)s properties in the PI.
The product strength represents the amount of the active substance in the
pharmaceutical dosage form, which is stated as per unit dose or concentration.
Concentration can be stated as a unit of mass (e.g. mg/g), a unit of volume (e.g. mg/mL)
or as a percentage (e.g. %w/v or %w/w).

For products where it would be difficult to include the strength in the product name (e.g.
vaccines, total parental nutrition solution, haemofiltration solution, etc), the product
strength may be omitted from the product name. SEPTEMBER
For specific pharmaceutical dosage forms, there are additional points to take note of as
seen in the table below:
Product Format Example

Fixed-combination Strength of each active Multi-Tab Tablet
ingredient separated by a / 100mg/25mg
Single-dose preparation, State the amount of active Ingredient 300mg per vial
total use ingredient per unit dose
Multi-dose preparation State the concentration per mL, per puff, per drop,
per kg, per m2, etc.
Powder for reconstitution, State the concentration after Antibiotic 200mg/5mL
oral reconstitution
Powder for reconstitution, State the amount of active Ingredient 300mg per vial
injection or infusion ingredient before reconstitution
or dilution
Transdermal patches State the amount of active Trans-Patch 24mg/24 hrs
ingredient released in 24 hours
25.1.4.2 Section 4.2 Product Formula
The Product Formula is a list of all of the active substance(s) and excipients (including
water) that are present in the final pharmaceutical dosage form, as seen in the
screenshot below:
Choose either Active

Ingredient or Excipient
from the drop-down list
Proper or commercial names for ingredients, such as printing inks or colourants, are
permissible but internal abbreviations, acronyms or codes for any ingredient are not
acceptable. The grade for each ingredient should be specified e.g. in-house, BP, USP,
Ph. Eur., etc.
Full compositions of all ingredients (e.g. colourants, flavouring agents, etc.) used in the
product should be stated in the Product Formula, and their uses differentiated as stated
below.

Differentiating the use of excipients in the product
Ingredients relating to the pharmaceutical dosage form, such as tablet film coating or SEPTEMBER
capsule shell, should be indicated within parentheses before the ingredient name, as
shown in the following screenshot:
Film coating ingredient
Printing ink
If the product contains proprietary ingredients, relating to the dosage form (such as tablet
film coating or capsule shell), this information should be captured in PRISM as shown in
Example 3.
Example 3. Entry of proprietary ingredients relating to the dosage form for Product XYZ:
Name of Substance Type of Grade Strength Remarks

Substance
(Film coat) Ingredient H Excipient USP Qs Ingredient H is used in the film
coat, but it is not part of the Coat
Brand D
(Film coat, Coat Brand D) Excipient In- 3mg Coat Brand D is a proprietary film
Ingredient E house coat composing of 3mg of
Ingredient E
Ingredient F house coat composing of 1mg of
Ingredient F
Ingredient G house coat composing of 1mg of
Ingredient G
(Film coat) Coat Brand D Excipient In- 5mg There is no need to state the
house total amount of the proprietary
film coat, Coat Brand D.
The ingredients in the table above should be entered in PRISM as follows:

Product XYZ
SEPTEMBER
The 3 ingredients in Film

Coat Brand D are entered
3mg as follows.
1mg
There is no need to enter
1mg both Film Coat Brand D
and the total composition
of Film Coat Brand D into
PRISM.
If the product contains ingredients relating to a particular portion of the finished drug
product, such as powder (active substance) and solvent (solution for reconstitution) or a
multi-layered tablet, the portion of the drug product should be stated in parentheses
before the ingredient name of the excipients see Examples 4 and 5:
Example 4. A product with powder and solvent:
Excipient in powder
Excipient in solvent
Example 5. A multi-layered tablet:
Do NOT include layer

separation for active
ingredients
Excipients in Y layer
Excipients in Z layer
Entering the strength of ingredients
Quantities of each active substance and excipient must be expressed in international

units of measure, wherever appropriate. If an active substance is present in the form of a

salt, the quantity stated should reflect that stated on the product labelling, and should be
clearly written in the following format (see table below and Examples 6 to 8):
SEPTEMBER
Eg Description Product strength stated Format of product strength
on product label to be stated in PRISM
6 Strength on the label refers 30mg Active Substance Active Substance phosphate
to the base form of the 32mg eqv Active Substance
active substance.
7 Strength on the label refers 30mg Active Substance Active Substance 28mg eqv
to the salt form of the phosphate Active Substance phosphate
active substance.
8 Strength refers to neither 30mg Active Substance Active Substance 28mg eqv
the base nor salt form of sodium Active Substance phosphate
the active substance. 32mg eqv Active Substance
sodium
Example 6. Strength on label refers to base form of active substance:
Enter the strength of

the active substance
base here if the
strength stated on
the product labels
refers to the active
ingredient in its
base form.
Example 7. Strength on label refers to salt form of active substance:

salt here if the
strength stated on
the product labels
refers to the active
ingredient in its salt
form.

Example 8. Strength on label refers to neither base or salt form of active substance:
SEPTEMBER

as described on
the product label
here if the strength
stated on the
product labels refers
to neither the active
ingredient in its
base nor salt form.
Ingredients of residual amounts in the product
Information on substances which were removed during the manufacturing process, such
as water or ethanol which evaporates during drying, should be included in the Product
Formula, but with the strength stated as qs.
Information on residual amounts of materials of allergic potential (e.g. antibiotics and

preservatives) and biological origin (e.g. human serum albumin) added or present in the
drug product must be declared. Information to declare includes the following:
the materials name enter (Residual), followed by the materials name in the
Name of Substance field;
the materials grade, if applicable;
the materials limit in the product enter , followed by the limit in the Strength
field.
Example 9. Screenshot of product containing residual amounts of certain materials:
This strength will

actually be entered here

25.1.4.3 Section 4.3 Ingredients Derived From Human Blood/Animal Sources
SEPTEMBER
Section 4.3a Ingredients Derived From Human Blood
Human plasma-derived products used as an active substance, as an excipient or within

the manufacturing process, must be declared in this PRISM section.
If the answer is Yes, the following information must be inserted as per the format below:
the type of product derived from blood and its role in the drug product i.e. as an
active substance, excipient or within the manufacturing process; and,
the country of the source product.
A screenshot of a PRISM section 4.3(a) entry is given:
If constrained by PRISMs text limit, reference to a document uploaded into PRISM

section 7 e.g. Yes see file xyz.pdf attached in PRISM.
NOTE: additional information is required when human plasma-derived products are used.
Refer to Appendix 10 for details on the data requirements for submission.
Section 4.3b Ingredients Derived From Animal Sources
Animal-derived materials used either as an excipient or within the manufacturing process

must be declared in this PRISM section.
If the answer is Yes, the following information must be inserted as per the format below:
the source product and species the ingredient is derived from;
its role in the drug product (i.e. excipient or within the manufacturing process); and,
the country of the source product.

A screenshot of a PRISM section 4.3(b) entry is given:
SEPTEMBER
If constrained by PRISMs text limit, reference to a document uploaded into PRISM

section 7 e.g. Yes see file xyz.pdf attached in PRISM.
NOTE: refer to Appendix 11 for details on the data requirements for submission.
25.1.4.4 Section 4.4 Pharmacotherapeutic Group
Indicate the WHO ATC code for each distinct therapeutic indication proposed for a
product, if available. Applicants may refer to the WHO Collaborating Centre for Drug
Statistics Methodology30 for the ATC Code and more information.
25.1.4.5 Section 4.5 Dosage Form
A screenshot of PRISM section 4.5 is seen below:
The dosage form is the pharmaceutical dosage form of the drug product, e.g. tablet,
injection and cream. The dosage form should be as specific as possible because each
form is considered distinct e.g. effervescent powder, powder for reconstitution,
modified-release tablet and gastro-resistant capsule.
In certain cases, the dosage form may also include information about the container
closure system e.g. pre-filled syringe, spray pump and pressurised container.
30
http://www.whocc.no/

25.1.4.6 Section 4.6 Route of Administration
Screenshots of PRISM section 4.6 is given below: SEPTEMBER
Choose from the dropdown

list and Save before
adding another option
Include all routes of administration proposed for the product.
25.1.4.7 Section 4.7 Packaging, Shelf Life and Storage Conditions
Section 4.7.1 Container Closure System (CCS)
This section refers to the container immediately enclosing the dosage form. Information
should be specific, including the type of material(s) used, colour, size, etc. For example,
Type I 1mL amber glass vial and Transparent PVC/PVdC blister with Alu foil should be
entered instead of Amber glass vial and PVC/PVdC blister, respectively.
If a sample pack is to be registered, include (sample) at the end of the CCS description.

Section 4.7.2 Quantity per CCS
This section refers to the quantity/amount of the dosage form per container closure SEPTEMBER
system. For example, 10 tablets/blister, 5ml/vial and 15g/tube may be entered.
Section 4.7.3 Shelf Life
This section refers to the proposed shelf life of the drug product, which should be
supported by stability data. If there is more than one component in a drug product (e.g.
powder for injection and diluent as a composite pack) and each component has a
different shelf life, the shorter shelf life is to be used as the shelf life of the composite
pack. HSA reserves the right to amend the proposed shelf life after review of the stability
data submitted in the dossier.
Section 4.7.4 Storage Condition
This section refers to the proposed storage condition of the drug product for example,
store below 25C, do not freeze, keep away from light, etc which should be supported
by stability data. HSA reserves the right to amend the proposed storage condition after
review of the stability data submitted in the dossier.
Section 4.7.5 CCS per Pack Size
This section refers to the number of container closure systems in each commercial pack
of the product. For example, for a box of 50 tablets packed as 5 blister strips of 10 tablets
in each strip, the Pack Size should be entered as 5.
A screenshot with PRISM section 4.7 entries is shown below:
NOTE: Click
Save after
each complete
CCS entry.
Thereafter, to
enter a new
CCS, click
New first.
Furthermore, information on shelf life after the first opening of the product (e.g. eye drops)
and shelf life after reconstitution (e.g. lyophilised powder for reconstitution) should be
provided and supported by stability data. The information should be inserted in PRISM
sections 4.7.6 and 4.7.7, respectively:

25.1.4.8 Section 4.8 Forensic Classification
State the forensic classification proposed for the drug product in Singapore. SEPTEMBER
HSA reserves the right to approve the product under a different forensic classification, as
deemed appropriate.
25.1.4.9 Section 4.9 Registration Status in Other Countries
Applicants are required to provide information on the registration status of the application
in other countries at the time of submission. A screenshot of PRISM section 4.9 is given:
For each country, the applicant must state the application status, status date and forensic
classification (if applicable). For all HSAs reference agencies, the applicant must state
the application status, status date, application details and forensic classification. This is
described in Table 13 on the next page.

Table 13. Registration Status of Drug Product in Other Countries.

Country Application Status Status Date Application POM/P/GSL
Details
#
SEPTEMBER
For all countries APPROVAL State the approval POM/P/GSL
date
REJECTION or State the date of State the reason(s)
WITHDRAWAL rejection/withdrawal
DEFERRAL State the date of State the reason(s)
e.g. non-approvable, deferment
approvable,
conditional approval,
conditional marketing
authorization, etc.
For HSAs PENDING State the State the expected POM/P/GSL
reference EVALUATION submission date regulatory decision
agencies date, if applicable
(if applicable) PENDING State the expected POM/P/GSL
SUBMISSION submission date or
reason(s) for not
registering
#
For approved indication(s) and dosing regimen(s) for an approved application, you can make
reference to the approved PI of the reference agency instead of typing out the information under
Application Details.
For products approved via an appeal process, following either a negative

opinion/rejection/non-approvable decision or an approvable/conditional approvable
decision, the applicant must provide reasons for the initial regulatory decision along with
the subsequent approval.
The screenshot below displays some entries into PRISM section 4.9:
For applications submitted or approved by:

Individual countries:
i. Select the name of the country under 4.9.1 State Country; and,
ii. For approval in EU Countries via the national procedure, state National
procedure under 4.9.4 Application Details.
European Union:

i. Select European Union under 4.9.1 State Country and specify the type of
application submitted to the agencies (Centralised, Decentralised or Mutual
Recognition Procedure) under 4.9.4 Application Details; and/or, SEPTEMBER
ii. For applications approved via Decentralised or Mutual Recognition Procedure,
either state All EU countries or list the EU countries which participated in the
procedure under 4.9.4. Application Details; and,
iii. For applications approved via Decentralised or Mutual Recognition Procedure,
state the EU country which acted as the Reference Member State (RMS) and
Concerned Member State (CMS) under 4.9.4 Application Details.
The applicant is required to update HSA on the registration status of any pending
applications in other countries while pending evaluation by HSA. The applicant shall
inform HSA of any rejection, withdrawal or deferral of any application and provide details
of the reason(s) once it becomes known.
In the event that the PRISM text space does not allow input of full details of the
indication(s), dosing regimen(s), and/or reason(s), a brief description may be entered.
The full details should be attached in softcopy (PDF) in PRISM section 7 (Supporting
Attachments) and in hardcopy in section 1.15 of the CTD Module 1/Part I. The document
should be in the format as seen in Table 7 in this guidance.
25.1.4.10 Section 4.10 Product Owner Information
Input the full name and address of the legally registered owner of the product formulation,
i.e. the drug product.
25.1.5 Section 5 Manufacturer Particulars
Enter information on the various manufacturers involved in all aspects of producing the
final drug product. Information to be entered include:
Manufacturer type involved either in Active Substance or Finished Product
manufacture;
Manufacturers name;
Manufacturing operation involved in bulk production, packing, labelling or any
combination of the three; and,
Manufacturers address input both the manufacturing site and office (i.e.
headquarters) address.

SEPTEMBER
All manufacturers of the active substance(s), drug product (inclusive of diluent packed
and sold together with the drug product), and primary/secondary packaging sites must be
declared.
25.1.5.1 Active Substance Manufacturer
When entering the details of the Active Substance Manufacturer, select the active
substance(s) that is manufactured by that particular manufacturer from the drop-down list
in section 5.8 of the PRISM application form. After selecting the Active Substance, click
the Save Substance button; this may be repeated for other substances if the
Manufacturer produces multiple substances for the drug product. Once complete, click
the Save Manufacturer button to save the entire section for that Active Substance
Manufacturer:

SEPTEMBER
Save Substance button
Save Manufacturer button
25.1.5.2 Finished Product Manufacturer
Entries of finished product manufacturers would include not only manufacturers of the
finished product but also secondary packagers and manufacturers of diluents that are
packed and sold together with the drug product.
After entering the details of the Finished Product Manufacturer, click the Save
Manufacturer button to save the entire section for that Finished Product Manufacturer:

SEPTEMBER
Here are some additional points to note:

For products packed and sold together with the diluent that is used to reconstitute
the product, enter (Diluent) after the name of the diluent manufacturer; and,
For secondary packagers, enter (Secondary packager) after the name of the
manufacturer:
NOTE: ALL Manufacturers names and addresses should be consistent throughout all
of the documents submitted in the application, i.e. CPPs, GMP certificates, Letters of
Authorisation, Module 3/Part II of the CTD and so forth.

25.1.6 Section 6 Information on Company Responsible for Batch Release
Enter the name, site/plant address and office address of the company responsible for the SEPTEMBER
final batch release of the drug product in the exporting country. The Finished Product
Manufacturer(s), which the Batch Releaser is releasing the product from, must also be
specified.
This screenshot is an example of an entry into PRISM section 6.
Save Batch Releaser button
After selecting the Finished Product Manufacturer that this particular Batch Releaser is
releasing the products from (PRISM section 6.4), click the Save Manufacturer button to
save that manufacturer to that batch releaser.
Click the Save Batch Releaser button to save the entire section for that Batch Releaser.
It is also possible to have one Batch Releaser releasing products from two finished
product manufacturers as well as multiple Batch Releasers see Examples 11 and 12 on
the next page:
Example 11. One Batch Releaser responsible for multiple Finished Product
Manufacturers.
SEPTEMBER
2 manufacturers with the same

batch releaser
Example 12. Mulitple Batch Releasers responsible for batch release of the final product.
Two batch releasers for this product
25.1.7 Section 7 Supporting Attachments
Before completion of the on-line application, applicants must attach all documents relating SEPTEMBER
to Module 1/Part I of the CTD into this PRISM section. For the remaining Modules/Parts,
applicants can opt to either attach the documents in full into this PRISM section or submit
soft copies of the documents in a CD/DVD.
Here are some additional points to note:

Use Portable Document Format (PDF) whenever possible;
Do not combine documents if the content is unrelated for example, do not submit
a GMP certificate with Letters of Authorisation as a single PDF;
Ensure that the documents are appropriately named for easier recognition to
facilitate screening more detail in the file name will enhance recognition of its
contents;
Attaching a file for document 7.1 CD Submission would render the rest of the
online attachments non-mandatory in PRISM system. However, even if the
submission of the dossier set in CD-ROM is selected, the entire Module 1 would still
be required to be attached in PRISM;
During scanning of documents, applicants are advised not to break seals of
authenticated documents as this will render them invalid; and,
When attaching new documents in response to an Input Request, do not delete or
override the existing document in PRISM. Attach it as a new document.
NOTE: Acceptance of the dossier for evaluation does not constitute acceptability
of the data provided in the dossier. Acceptability of the data can only be
determined during evaluation of the application.
LIST OF APPENDICES
APPENDIX 1 Target Processing Timelines
APPENDIX 2A Application Checklist (ICH CTD NDA and GDA)
APPENDIX 2B Application Checklist (ICH CTD MAV)
APPENDIX 3A Application Checklist (ASEAN CTD NDA and GDA)
APPENDIX 3B Application Checklist (ASEAN CTD MAV)
APPENDIX 4 Flowchart for Translation of Non-English Documents
APPENDIX 5 Guideline on Submission for Non-Prescription Medicinal Products
APPENDIX 6 Points to Consider for Singapore Labelling
APPENDIX 7 Patent Declaration Form
APPENDIX 8 Singapore Quality Overall Summary for Chemical Drugs
APPENDIX 9 Singapore Quality Overall Summary for Biologics
APPENDIX 10 Guideline on the Registration of Human Plasma-derived Medicinal

Products
APPENDIX 11 Guideline on the Registration of Human Medicinal Products Containing

Materials of Animal Origin
APPENDIX 12 Product Interchangeability and Biowaiver Request for Chemical

Generic Drug Applications
APPENDIX 12A Quick Reference on Acceptability of Bioequivalence Study
APPENDIX 13 Guideline on Submission for Indian Generic Products Under the CECA
Scheme
APPENDIX 14 MIV Filing and Submission Inquiry Form
APPENDIX 15 Guideline on Minor Variation Applications (MIV-1 & MIV-2) for

Chemical Drugs
APPENDIX 16 Guideline on Minor Variation Applications (MIV-1 & MIV-2) for Biologics
APPENDIX 17 Guidance on Registration of Similar Biological Products in Singapore
HEALTH SCIENCES AUTHORITY HEALTH PRODUCTS REGULATION GROUP


TARGET PROCESSING TIMELINES
APPENDIX 1 TARGET PROCESSING TIMELINES
HSA shall endeavour to meet the target processing timelines for all submitted
applications. Applicants should ensure that the dossiers are complete before submission.
Incomplete dossiers and untimely responses to queries will cause unnecessary delays to
the registration process and thus, will have a negative impact on the target processing
timelines.
Recalling Figure 1 in Chapter B of the Guidance, a flowchart of the registration process

and processing timelines can be seen below:
Application submission date is

APPLICATION the date when the complete
SUBMISSION dataset is received.
NON-ACCEPTANCE /
WITHDRAWAL
Time to 1st communication for
APPLICATION NDA, GDA, MAV, MIV-1 is 25
SCREENING working days.
APPLICATION Acceptance date is the start

ACCEPTANCE of the evaluation timeline.
Processing timelines vary

APPLICATION between the different
application types refer to
EVALUATION section 2 for the timelines.
Evaluation is completed when

REGULATORY regulatory decision has been
DECISION reached and a letter issued to
the applicant.
1 SCREENING TIMELINE
The target processing timeline for screening of the dossiers (NDA, GDA, MAV-1, MAV-2,
MIV-1) is 25 working days before the first communication, in the form of an Input
Request or acceptance/non-acceptance notification, is issued. The target processing
timeline for screening of a dossier submitted under the CECA scheme is 14 working days
(refer to Appendix 13).
The screening timeline begins from the date of the dossier submission, which should be
within 2 working days after PRISM submission to prevent delays in processing of the
application. The date of submission will be defined as the date when HSA receives the
complete dataset for the application (including all hard copies of original signed
documents and CD/DVD- ROMs).
2 EVALUATION TIMELINE
The target processing timeline for evaluation of an application is the period from the date
of acceptance to issuance of a regulatory decision letter, excluding all stop-clocks. The
target timelines for the various evaluation routes are as follows:
HEALTH SCIENCES AUTHORITY HEALTH PRODUCTS REGULATION GROUP Appendix 1 - Page 1 of 2

TARGET PROCESSING TIMELINES
The timelines stated (in working days) are subject to change.
Dossier type NDA GDA MAV-1 MAV-2 MIV-1

Full 270 270
Abridged 180 240 180 180 120
Verification 60 120 60
Verification CECA 90
3 NOTIFICATION TIMELINE for MIV-2 APPLICATIONS
For MIV-2 applications, the applicant can implement the proposed change(s) if HSA does
not raise any objection within 40 working days from the date of submission of the
complete dataset for the application. The complete dataset includes the PRISM
application submission, all hard copies of original signed documents and the supporting
documents required for the proposed changes.
If queries are raised on the completeness of the dataset, a stop-clock time will apply. This
stop-clock time is to be excluded from the 40 working days timeline.
4 STOP-CLOCK
Stop-clocks can occur during the screening and evaluation stages of the application. The
stop-clock starts when HSA requests for clarification or additional information with regard
to a product application. The stop-clock period ends when HSA receives a complete and
satisfactory response to the query.
NOTE: the stated processing timelines are intended for reference only and do not
necessarily represent the actual processing timelines for the applications.
Applicants should refer to track@PRISM for updates on application status and
processing time.

APPLICATION CHECKLIST 2A (ICH CTD - NDA AND GDA)
APPENDIX 2A APPLICATION CHECKLIST (ICH CTD NDA and GDA)
This Application Checklist should be used to ensure submission of a complete dataset in the ICH Common Technical Dossier (ICH CTD) format
for NDA and GDA applications only.
To use this Checklist, check against the dossier and application type for your submission.
Note:
Cells with indicates that the document shown in the second column of the same row is mandatory for the selected application type and
evaluation route.
Cells with with an asterisk * indicates that the document shown in the second column of the same row may be optional depending on the
application type/product/change concerned.
Cells without indicates that the document shown in the second column of the same row is not required for the selected application type and
evaluation route.
Please refer to the Guidance on Medicinal Product Registration in Singapore and the ICH technical guidance for explanatory notes on the
preparation of documents for a submission in ICH CTD format.
HEALTH SCIENCES AUTHORITY HEALTH PRODUCTS REGULATION GROUP Appendix 2A - Page 1 of 21

Module 1 Administrative Documentation
Application Type & Evaluation Route
Section Documents
NDA GDA
Full Abridged Verification Abridged Verification
1.1 Comprehensive Table of Contents

Include a complete list of all documents provided in the application dossier by Module
The location of each document should be identified by the Module number
For any documents submitted in hardcopy, the location of each document should be
identified by the volume number and tab identifiers (name of document or section
heading according to ICH CTD format)
1.2 Introduction
Provide a concise and precise summary of the application
Justify the lack of certain documents and deviation(s) from guidelines
1.3 PRISM Application Form
1.3.1 Section 1: Company Particulars
Company shall be based and registered in Singapore
1.3.2 Section 2: Applicant particulars
Applicant must be a permanent staff of the company and is residing in
Singapore. If the person making the application / correspondence person is
an external party (consultant) engaged by the applicant company, an original
letter of authorization from the applicant company must be submitted.
Company address and contact details may be entered instead of personal
residential address and contact details of the applicant
1.3.3 Section 3: Application Details
3.1 Type of Application
3.2 Type of Product
3.3 Reference Product * * *

Section Documents
NDA GDA
All GDA applications Specify Singapore Reference Products SIN

number
If GDA-2 application not submitted at the same time as GDA-1
application Specify both the Singapore Reference Products and
the GDA-1 products SIN numbers
*: Applicable if NDA-3 applications not submitted at the same time
as NDA-1/2 application Specify the NDA-1/2s SIN number
3.4 Product intended for export
3.5 Type of Dossier
3.6 Type of Format
1.3.4 Section 4: Product Information
4.1 Product name
Refer to Guidance document, Chapter J, Section 25.1.4.1 for details
Enter in the following format:
Product Name - Dosage Form Product Strength
4.2 Product Formula
Refer to Guidance document, Chapter J Section 25.1.4.2 for details
Include the full composition of all active substances and excipients
(including water) that are present in the final pharmaceutical dosage
form
Use of excipients should be differentiated in the product formula
using parentheses before the ingredient name, e.g. (Film coating)
Ingredient Z.
For active ingredients presented in the form of salts and chelate, the
quantity should be clearly stated, e.g., XX phosphate 32 mg
(equivalent to XX) etc.

Section Documents
NDA GDA
Information on residual amounts of certain materials, such as

antibiotics, thiomersal and materials of biological origin (e.g. human
serum albumin), added or present in the drug product must be
declared.
4.3 Ingredients derived from human blood or animal sources
* * * * *
*: Applicable if product contains ingredient derived from human
blood or animal sources
Information to be provided in the following format: (Species &
product) (In manufacturing/drug substance/excipient) (Country)
The human plasma-derived product checklist (Annex 1 of Appendix
10) or TSE checklist (Annex 1 of Appendix 11) should be submitted
if applicable.
4.4 ATC Code
4.5 Dosage Form
4.6 Route of Administration
Include all routes of administration proposed for the product
4.7 Packaging, Shelf Life & Storage Condition
Where more than one drug component is included in a drug product
(e.g., powder for injection with solvent as composite pack) and each
component has a different shelf life, the shorter shelf life is to be
used as the shelf life of the composite pack
4.8 Forensic Classification
4.9 Registration Status in Other Countries
For each country - State the application status, status date and
forensic classification (if applicable)
For all HSAs reference agencies - State the application status,
status date, application details and forensic classification

Section Documents
NDA GDA
If an application is pending or not submitted to either of HSAs

reference agencies State that the application is pending (including
the submission and expected outcome dates), or not submitted
(date not required).
For products approved via an appeal process, following either a
negative opinion/rejection/non-approvable decision or an
approvable/conditional approvable decision Provide reasons for
the initial regulatory decision along with the subsequent approval
For applications submitted to the European Union agencies, the type
of application i.e. centralised, decentralised, mutual recognition or
national, should be identified; For decentralised and mutual
recognition applications, the reference member state should be
indicated
For applications approved by the UK MHRA Indicate whether
approval was granted through national procedure or whether MHRA
acted as RMS or CMS for decentralised and mutual recognition
procedures in European Union
For approved indication(s) and dosing regimen(s) for an approved
application, you can make reference to the approved PI of the
reference agency instead of typing out the information under
Application Details
In the event that the PRISM text space does not allow input of full
details of the indication(s), dosing regimen(s), and/or reason(s), a
brief description may be entered; The full details should be attached
in softcopy (PDF) in PRISM section 7 (Supporting Attachments)
4.10 Product Owner
1.3.5 Section 5: Manufacturers Particulars
All manufacturers of active substance(s), drug product and diluent used to
reconstitute the product (if packed and sold together with the drug product)
must be declared
manufacturer

Section Documents
NDA GDA
All manufacturers names and addresses should be consistent throughout all

of the documents submitted in the application, such as GMP certificates,
CPPs, Letters of authorisation, Module 3 of the CTD and so forth
1.3.6 Section 6: Batch Release Details
If there are multiple companies responsible for batch release, the applicant
must declare all of the sites
The finished product manufacturer(s) which the batch releaser is releasing the
product from must be specified
1.3.7 Supporting Documents
Attach all documents relating to Module 1 of the CTD
Other Modules Either attach in full in this PRISM section or submit soft
copies in CD
1.4 Labelling and PI/PIL proposed in Singapore.
Labelling must be in English. Highlight any non-English country-specific labelling
requirements on the artwork/drafts if the labelling is shared with other countries
*: If non-English text is included in the labelling, applicants must provide an official
statement to declare that the non-English text is complete, accurate and unbiased * * * * *
information and is consistent with the English text
1.4.1 Outer carton Labels
1.4.2 Inner/Blister Labels
1.4.3 Package Insert (PI)
1.4.4 Patient Information Leaflet (PIL)
1.5 Approved SmPC/PI/PIL
1.5.1 SmPC/PI/PIL approved by HSAs reference regulatory agencies
The approved SmPC / PI / PIL currently approved by each of HSAs reference
agencies should be submitted, where applicable

Section Documents
NDA GDA
1.5.2 SmPC/PI/PIL approved by Country of Origin/Country of Manufacture * * * *

1.5.3 PI / SmPC / PIL approved by other regulatory agency
The approved SmPC / PI / PIL from the drug regulatory agency that issued the *
proof of approval, if different from the Country of Origin
If applicable: declaration that the translation of the SmPC/PI/PIL conforms to the
1.5.4 * * * *
SmPC/PI/PIL currently approved
Assessment report issued by HSAs reference regulatory
1.6
agency: (Please specify)
1.7 Description of batch numbering system
1.8 Proof of Approval from:
Country of Origin Reference Agency Others: *
__________________________________________________
Declaration letter should be provided if the trade name of the product registered in the
country which issued the proof of approval is different from that proposed in Singapore
*: Proof of approval is not required for GDAs undergoing abridged evaluation for
finished product manufactured (up to primary packaging) in Singapore
1.9 Proof of Approval from HSAs reference regulatory agencies
(NDA: 2 reference regulatory agencies, GDA: 1 reference regulatory agency)
Please specify issuing agencies:
__________________________________________________
1.10 Authorisation Letters

authorised person in the company
The names and addresses stated in the letters should be consistent with the
information provided in application form and dossier
1.10.1 Authorisation Letter from Product Owner to the Applicant firm

Section Documents
NDA GDA
This letter authorises the local applicant firm to apply for and be the Product
Licence Holder for a specific medicinal product
1.10.2 Authorisation Letter from Product Owner to the Manufacturer(s)
This letter authorises the specified manufacturer to produce, pack and/or label
the drug product intended for Singapore
If there are multiple drug product manufacturers, the applicant may opt to
submit one authorisation letter which clearly states all of the manufacturers
(names and addresses) and their responsibilities related to the drug product
For biologic drug products, an additional authorisation letter from the Product
Owner to the Drug Substance Manufacturer is required
1.10.3 Authorisation Letter from Product Owner to the Batch Releaser
This letter authorises the specified company to test and batch release the drug
product
GMP certification/proof of GMP compliance for each finished product manufacturer
1.11
inclusive of secondary packer(s)
For biologics: GMP certification/proof of GMP compliance for each drug substance
manufacturer must be provided
For GDA Verification CECA: GMP certificate/ proof of GMP compliance and the latest
inspection report as issued by the reference agency should be submitted
Proof of GMP compliance must not expire within 6 months from the time of submission
to HSA
Diluents used for reconstituting the drug product and are packaged together with the
drug product will be considered as part of the final drug product; Manufacturer(s) of the
supplied diluent(s) will follow the same requirements applicable to the drug product
e.g. proof of GMP compliance
The names and addresses of manufacturer(s) / repacker(s) should be consistent with
information provided in application form
If applicable, application for GMP Conformity Assessment should be submitted together
with the product application
1.12 Patent declaration form

Section Documents
NDA GDA
The Patent Declaration form is required for each NDA and GDA
Under Applicant Particulars, name & address of the local applicant firm to be stated
Under Product Particulars, the product name is stated and it should be consistent with
that stated in PRISM, the application form, all product labelling and all other relevant
documents in the dossier
Under Declaration, the patent declaration must be signed by the Company Director,
Company Secretary as registered with ACRA, or equivalent.
Evidence of authorisation (e.g. ACRA printout) should be submitted together with the
declaration.
1.13 Declaration on rejection, withdrawal and deferral
Declaration that all aspects of the Singapore products quality are identical to that
1.14
currently approved by the chosen primary reference regulatory agency.
Official letter declaring that the Drug Master File provided is the same as that submitted
to the primary reference agency, if applicable.
Registration Status in Other Countries as separate attachment in PRISM under [7]
1.15
Supporting Attachments
For NDA & GDA, registration status should be entered into PRISM section 4.9; In the
event that the PRISM text space does not allow input of the full details of the
indication(s) and/or reason(s), a brief description may be entered; The full details
should then be attached in softcopy (PDF) in this PRISM section (supporting
attachments)

Module 2 Common Technical Document Summaries
Section Documents
NDA GDA
2.1 Overall CTD Table of Contents of Modules 2, 3, 4 and 5

2.2 Introduction
2.3 Singapore Quality Overall Summary (QOS) & QOS in other format, if available
2.4 Non-clinical Overview
2.5 Clinical Overview
2.6 Non-clinical Summary
2.6.1 Introduction
2.6.2 Pharmacology Written Summary
2.6.3 Pharmacology Tabulated Summary
2.6.4 Pharmacokinetics Written Summary
2.6.5 Pharmacokinetics Tabulated Summary
2.6.6 Toxicology Written Summary
2.6.7 Toxicology Tabulated Summary
2.7 Clinical Summary
2.7.1 Summary of Biopharmaceutics and Associated Analytical Methods
2.7.2 Summary of Clinical Pharmacology Studies
2.7.3 Summary of Clinical Efficacy
2.7.4 Summary of Clinical Safety
2.7.5 Synopses of Individual Studies

Module 3 Quality
Section Document
NDA GDA
For verification dossier The submission should include Module 3 dossier as originally
submitted to the reference agency, and any documentations submitted to the same reference
agency in subsequent variations to the quality aspects of the product.
3.1 Module 3 Table of Contents
3.2 Body of Data
3.2.S Drug Substance (Active Substance)
If DMF is submitted, refer to main Guidance, sections 14.3.1 & 17.3.1
If CEP (Certificate of Suitability) is submitted, waiver of documents for this
section can be granted except for S4.1, S4.2 & S4.4.
The manufacturers info provided in the CEP is consistent with the
information provided in the application form.
Please note that information not included in the CEP would have to be
supported by substantial data (e.g. S6 & S7 is required if no retest period
and/or packaging is stated in the CoA).
To take note of the validity of the certificate.
3.2.S.1 General Information
3.2.S.1.1 Nomenclature
3.2.S.1.2 Structure
3.2.S.1.3 General Properties
3.2.S.2 Manufacture
3.2.S.2.1 Manufacturer(s)
Description of Manufacturing Process and Process
3.2.S.2.2
Controls

Section Document
NDA GDA
3.2.S.2.3 Control of Materials * * * * *

3.2.S.2.4 Controls of Critical Steps and Intermediates * * * * *
3.2.S.2.5 Process Validation and/or Evaluation
* * * * *
Must be submitted for sterile APIs and NBEs (in
accordance to the ICH M4Q guidelines)
3.2.S.2.6 Manufacturing Process Development * * * * *
*: For applications with DMF, sections S2.3, S2.4, S2.5 and S2.6 are
included in the closed part of DMF
3.2.S.3 Characterisation
3.2.S.3.1 Elucidation of Structure and other Characteristics
3.2.S.3.2 Impurities
3.2.S.4 Control of Drug Substance
3.2.S.4.1 Specification of Drug Substance
3.2.S.4.2 Analytical Procedures
3.2.S.4.3 Validation of Analytical Procedures
*: Can be waived for methods that reference to * * * * *
compendial methods
3.2.S.4.4 Batch Analyses
3.2.S.4.5 Justification of Specification
*: Justification is not required if compedial requirements is met (e.g. * * * * *
Limits are set according to USP standards)
3.2.S.5 Reference Standards or Materials

Section Document
NDA GDA
State if source of reference standard is in house, official with

reference to compendia standard
For in house, specification of reference standard are to be
submitted
Evidence of characterization for in-house / working standards (e.g.
tests of NMR, MS are documented in the CoA will suffice) is
required
3.2.S.6 Container Closure System
Complete technical information on type of container closure used
3.2.S.7 Stability
3.2.S.7.1 Stability Summary and Conclusions
Post-approval Stability Protocol and Stability
3.2.S.7.2
Commitment
3.2.S.7.3 Stability Data
NOTE: S6 & S7 would have to be submitted if the retest period is not
stated in the CEP
At point of submission, at least 12 months of real time data and 6
months of accelerated data on at least 3 primary batches of the DS
should be provided
The batches should be manufactured to a minimum of pilot scale
by the same synthetic route as, and using the method of
manufacture and procedure that simulates the final process to be
used for production batches
If the DS is sourced from 2 different sites, stability data from both
sites should be provided

Section Document
NDA GDA
Stability studies are conducted on DS stored in proposed

packaging
3.2.P Drug Product
3.2.P.1 Description and Composition of the Drug Product
3.2.P.2 Pharmaceutical Development
3.2.P.2.1 Components of the Drug Product
3.2.P.2.1.1 Drug Substance
3.2.P.2.1.2 Excipients
3.2.P.2.2 Drug Product
3.2.P.2.2.1 Formulation Development
3.2.P.2.2.2 Overages
3.2.P.2.2.3 Physicochemical and Biological Properties
3.2.P.2.3 Manufacturing Process Development
3.2.P.2.4 Container Closure System
3.2.P.2.5 Microbiological Attributes
3.2.P.2.6 Compatibility
3.2.P.3 Manufacture
3.2.P.3.1 Manufacturer(s)
3.2.P.3.2 Batch Formula
For multiple batch sizes, batch formula for each
batch sizes are to be provided

Section Document
NDA GDA
Description of Manufacturing Process And Process

3.2.P.3.3
Controls
Flow chart and IPC should be submitted
3.2.P.3.4 Controls of Critical Steps and Intermediates
3.2.P.3.5 Process Validation and/or Evaluation
Table of Contents for Process Validation
Documentation
For Option 1: 3 consecutive production batch
For Option 2: P2 + Validation report of 1 pilot batch
OR Validation protocol at time of submission but
batches required at time of evaluation
To highlight in dossier if Option 2 is selected
3.2.P.4 Control of Excipients
State if excipient used are compendial or non-compendial
Compendial: Reference made to compendial specifications will
suffice.
Non-compendia: P4.1-P4.5
3.2.P.4.1 Specifications
3.2.P.4.2 Analytical Procedures
3.2.P.4.3 Validation of Analytical Procedures
3.2.P.4.4 Justification of Specifications
3.2.P.4.5
Excipients of Human or Animal Origin * * * * *

Section Document
NDA GDA
For animal derived excipient, please indicate Yes

in PRISM section 4.3b and provide relevant
information
For lactose monohydrate, declaration on source of
milk is safe for human consumption will suffice
For other animal derived excipient, checklist in
Appendix 11 are to be submitted with relevant
information
3.2.P.4.6 Novel Excipients
Provide information provided as per full DS Section
and submit in section 3.2.A.3
3.2.P.5 Control of Drug Product
3.2.P.5.1 Specification(s) of Drug Product
3.2.P.5.2 Analytical Procedures
3.2.P.5.3 Validation of Analytical Procedures
3.2.P.5.4 Batch Analyses
3.2.P.5.5 Characterisation of Impurities
3.2.P.5.6 Justification of Specification(s)
Justifications for each of the specification
3.2.P.6 Reference Standards or Materials
State if source of reference standard is in house, official with
reference to compendia standard
For in house, specification of reference standard is required
Evidence of characterization for in-house / working standards (e.g.
tests of NMR, MS are documented in the CoA will suffice)

Section Document
NDA GDA
3.2.P.7 Container Closure System

3.2.P.8 Stability
Information provided is consistent with stability data provided.
Stability studies meet minimum ASEAN requirement
3.2.P.8.1 Stability Summary and Conclusions
Post-approval Stability Protocol and Stability
3.2.P.8.2
Commitment
3.2.P.8.3 Stability Data
At point of submission, at least 12 months of real
time data and 6 months of accelerated data on at
least 3 primary batches of the DP should be
provided
The primary batches should be of the same
formulation and packaged in the same container
closure system as proposed for marketing in
Singapore
Stability data should be site specific applicable to
the Singapore product
If the DS is sourced from 2 different sites, stability
data for the DP should include one set of minimum
requirements for the DP with DS from site A and
one set of minimum requirements for the DP with
DS from site B (i.e., total of 6 batches at real time
conditions and 6 batches at accelerated conditions)

Section Document
NDA GDA
3.2.A Appendices
3.2.A.1 Facilities and Equipment
3.2.A.2 Adventitious Agents Safety Evaluation * *
3.2.A.3 Novel Excipients * *
3.2.R Regional Information/Requirements
Checklist for Human Blood Product with required supporting
3.2.R.1
documents * * * * *
For human derived materials, please indicate Yes in PRISM
section 4.3a and complete with relevant information
3.2.R.2 TSE Checklist with required supporting documents
* * * * *
For animal derived materials, please indicate Yes in PRISM
section 4.3b and complete with relevant information
3.2.R.3 Product Interchangeability (Bioequivalence Study Reports)
* * *
Reference product used in Bioequivalence study is the Singapore
Reference Product and uses the same site of manufacturing.
If not, refer to Appendix 12 for the bridging data required
If BE study not required, justification for viowavier is required, with
supporting documents
3.2.R.4 Blank Production Batch Record * * * * *
3.3 List of Literature References

Module 4 Non-clinical Study Reports
Section Documents
NDA GDA

4.2 Study Reports
4.2.1 Pharmacology
4.2.1.1 Primary Pharmacodynamics
4.2.1.2 Secondary Pharmacodynamics
4.2.1.3 Safety Pharmacology
4.2.1.4 Pharmacodynamic Drug Interactions
4.2.2 Pharmacokinetics
4.2.2.1 Analytical Methods and Validation Reports
4.2.2.2 Absorption
4.2.2.3 Distribution
4.2.2.4 Metabolism
4.2.2.5 Excretion
4.2.2.6 Pharmacokinetic Drug Interactions (non-clinical)
4.2.2.7 Other Pharmacokinetic Studies
4.2.3 Toxicology
4.2.3.1 Single-Dose Toxicity
4.2.3.2 Repeat-Dose Toxicity
4.2.3.3 Genotoxicity
4.2.3.4 Carcinogenicity

Section Documents
NDA GDA
4.2.3.5 Reproductive and Developmental Toxicity

4.2.3.6 Local Tolerance
4.2.3.7 Other Toxicity Studies
4.3 List of Literature References

Module 5 Clinical Study Reports
Section Document
NDA GDA

5.2 Tabular Listings of All Clinical Studies
5.3 Clinical Study Reports
5.3.1 Reports of Biopharmaceutic Studies
* * * *
*: For Abridged and Verification Dossiers: only final study report(s) of
biopharmaceutic studies to establish bioequivalence between commercial
product formulation and clinical trial formulation used in pivotal studies
should be submitted, if applicable
5.3.2 Reports of Studies Pertinent to Pharmacokinetics using Human Biomaterials
5.3.3 Reports of Pharmacokinetic (PK) Studies
5.3.4 Reports of Pharmacodynamic (PD) Studies
5.3.5 Reports of Efficacy and Safety Studies
Study reports of ALL clinical trials, including the appendices & tables
Study reports of pivotal or relevant clinical trials (appendices & tables are
required upon request by HSA)
5.3.6 Reports of Post-marketing Experience * * *
Case Report Forms and Individual Patient Listings (required upon request by
5.3.7
HSA)
5.4 List of Key Literature References
5.5 Other Supporting Documents


APPLICATION CHECKLIST 2B (ICH CTD - MAV)
APPENDIX 2B APPLICATION CHECKLIST (ICH CTD MAV)
This Application Checklist should be used to ensure submission of a complete dataset in the ICH Common Technical Dossier (ICH CTD) format
for MAV applications only.
Note:
evaluation route.
evaluation route.
Please refer to the Guidance on Medicinal Product Registration in Singapore and the ICH technical guidance for explanatory notes on the
preparation of documents for a submission in ICH CTD format.
HEALTH SCIENCES AUTHORITY HEALTH PRODUCTS REGULATION GROUP Appendix 2B - Page 1 of 10

Module 1 Administrative Documentation
Section Documents
MAV-1 MAV-2
Full Abridged Verification Abridged

Include a complete list of all documents provided in the application dossier by Module
The location of each document should be identified by the Module number
For any documents submitted in hardcopy, the location of each document should be identified
by the volume number and tab identifiers (name of document or section heading according to
ICH CTD format)
1.2 Introduction
Applicant must be a permanent staff of the company and is residing in Singapore. If
the person making the application / correspondence person is an external party
(consultant) engaged by the applicant company, an original letter of authorization
from the applicant company must be submitted.
Company address and contact details may be entered instead of personal residential
address and contact details of the applicant
3.2 Type of Product
3.3 Reference Product

Section Documents
MAV-1 MAV-2

3.5 Type of Dossier
3.6 Type of Format
4.1 Product name
4.2 Product Formula
4.4 ATC Code
* * *
*: Applicable if the MAV is in relation to a change in ATC code
4.5 Dosage Form
*: Applicable if the MAV is in relation to a change in route of * * *
administration
As the PRISM fields are not amendable in a variation application,
the full details should be attached in softcopy (PDF) in PRISM
section 7 (Supporting Attachments)

Section Documents
MAV-1 MAV-2
If an application is pending or not submitted to to either of HSAs

reference agencies State that the application is pending (with
submission date), or not submitted (date not required).
indicated
4.10 Product Owner
Attach all documents relating to Module 1 of the CTD
Other Modules Either attach in full in this PRISM section or submit soft copies in CD
1.4 Labelling and PI/PIL proposed and currently approved in Singapore.
Labelling must be in English. Highlight any non-English country-specific labelling requirements
on the artwork/drafts if the labelling is shared with other countries
*: If non-English text is included in the labelling, applicants must provide an official statement to
declare that the non-English text is complete, accurate and unbiased information and is * * * *
consistent with the English text

Section Documents
MAV-1 MAV-2
1.4.1 Outer/Carton Labels * * * *

1.4.2 Inner/Blister Labels * * * *
1.5.2 SmPC/PI/PIL approved by Country of Origin/Country of Manufacture * * *
The approved SmPC / PI / PIL from the drug regulatory agency that issued the proof
of approval, if different from the Country of Origin
1.5.4
1.6 Assessment report issued by HSAs reference regulatory agency:
(Please specify)
__________________________________________________
Declaration letter should be provided if the trade name of the product registered in the country
which issued the proof of approval is different from that proposed in Singapore
*: Proof of approval for MAV-2 should be in the form of documentation which proves that that
product had been reclassified (for specific indication(s) or dosing regimen(s)) in the UK, US,
Canada and/or Australia. This is not required for me-too reclassification.

Section Documents
MAV-1 MAV-2
Proof of Approval from at least 2 of HSAs reference regulatory agencies

1.9 Please specify issuing agencies: __________________________________________________

GMP certification/proof of GMP compliance for each finished product manufacturer inclusive
1.11
secondary packer(s)
Declaration that all aspects of the Singapore products quality are identical to that currently
1.14
approved by the chosen primary reference regulatory agency.
Official letter declaring that the Drug Master File provided is the same as that submitted to the
primary reference agency, if applicable.
Registration Status in Other Countries as separate attachment in PRISM under [7] Supporting
1.15
Attachments
The full details should then be attached in softcopy (PDF) in this PRISM section (supporting
attachments)
For MAV-2 applications, the registration status should also include the forensic classification of
the product in the approved countries.

Module 2 Common Technical Document Summaries
Section Documents
MAV-1 MAV-2
2.1 Overall CTD Table of Contents of Modules 2, 3, 4 and 5

2.2 Introduction
2.3 Singapore Quality Overall Summary (QOS) & QOS in other format, if available
2.4 Non-clinical Overview * * *
2.5 Clinical Overview
2.6 Non-clinical Summary
2.6.1 Introduction *
2.6.2 Pharmacology Written Summary *
2.6.3 Pharmacology Tabulated Summary *
2.6.4 Pharmacokinetics Written Summary *
2.6.5 Pharmacokinetics Tabulated Summary *
2.6.6 Toxicology Written Summary *
2.6.7 Toxicology Tabulated Summary *
2.7 Clinical Summary
2.7.1 Summary of Biopharmaceutics and Associated Analytical Methods * * *
2.7.2 Summary of Clinical Pharmacology Studies * * *
2.7.3 Summary of Clinical Efficacy
2.7.4 Summary of Clinical Safety
*
*: Not required for me-too reclassification
2.7.5 Synopses of Individual Studies

Module 4 Non-clinical Study Reports
Section Documents
MAV-1 MAV-2
4.1 Module 4 Table of Contents *

4.2 Study Reports
4.2.1 Pharmacology
4.2.1.1 Primary Pharmacodynamics *
4.2.1.2 Secondary Pharmacodynamics *
4.2.1.3 Safety Pharmacology *
4.2.1.4 Pharmacodynamic Drug Interactions *
4.2.2 Pharmacokinetics
4.2.2.1 Analytical Methods and Validation Reports *
4.2.2.2 Absorption *
4.2.2.3 Distribution *
4.2.2.4 Metabolism *
4.2.2.5 Excretion *
4.2.2.6 Pharmacokinetic Drug Interactions (non-clinical) *
4.2.2.7 Other Pharmacokinetic Studies *
4.2.3 Toxicology
4.2.3.1 Single-Dose Toxicity *
4.2.3.2 Repeat-Dose Toxicity *

Section Documents
MAV-1 MAV-2
4.2.3.3 Genotoxicity *
4.2.3.4 Carcinogenicity *
4.2.3.5 Reproductive and Developmental Toxicity *
4.2.3.6 Local Tolerance *
4.2.3.7 Other Toxicity Studies *
4.3 List of Literature References *

Module 5 Clinical Study Reports
Section Document
MAV-1 MAV-2

5.2 Tabular Listings of All Clinical Studies
5.3 Clinical Study Reports
5.3.1 Reports of Biopharmaceutic Studies * * *
5.3.2 Reports of Studies Pertinent to Pharmacokinetics using Human Biomaterials *

5.3.3 Reports of Pharmacokinetic (PK) Studies *
5.3.4 Reports of Pharmacodynamic (PD) Studies *
5.3.5 Reports of Efficacy and Safety Studies
Study reports of pivotal or relevant clinical trials (appendices & tables are required
upon request by HSA)
5.3.6 Reports of Post-marketing Experience * * *
5.3.7 Case Report Forms and Individual Patient Listings (required upon request by HSA)
5.4 List of Key Literature References
5.5 Other Supporting Documents * * *

APPLICATION CHECKLIST 3A (ACTD - NDA AND GDA)
APPENDIX 3A APPLICATION CHECKLIST (ASEAN CTD NDA and GDA)
This Application Checklist should be used to ensure submission of a complete dataset in the ASEAN Common Technical Dossier (ACTD) format
for NDA and GDA applications only.
Note:
evaluation route.
evaluation route.
Please refer to the Guidance on Medicinal Product Registration in Singapore and the ASEAN Guidance on ACTD for explanatory notes on the
preparation of documents for a submission in ACTD format.

Part I Administrative Documentation
Section Documents
NDA GDA

Include a complete list of all documents provided in the application dossier by Part
The location of each document should be identified by the Part number
For any documents submitted in hardcopy, the location of each document should be
identified by the volume number and tab identifiers (name of document or section
heading according to ACTD format)
1.2 Introduction
Applicant must be a permanent staff of the company and is residing in
Singapore. If the person making the application / correspondence person is
an external party (consultant) engaged by the applicant company, an original
letter of authorization from the applicant company must be submitted.
Company address and contact details may be entered instead of personal
residential address and contact details of the applicant
3.2 Type of Product
3.3 Reference Product * * *

Section Documents
NDA GDA
All GDA applications Specify Singapore Reference Products SIN

number
If GDA-2 application not submitted at the same time as GDA-1
application Specify both the Singapore Reference Products and
the GDA-1 products SIN numbers
*: Applicable if NDA-3 applications not submitted at the same time
as NDA-1/2 application Specify the NDA-1/2s SIN number
3.5 Type of Dossier
3.6 Type of Format
4.1 Product name
Refer to Guidance document, Chapter J, Section 25.1.4.1 for details
Enter in the following format:
Product Name - Dosage Form Product Strength
4.2 Product Formula
Refer to Guidance document, Chapter J Section 25.1.4.2 for details
Include the full composition of all active substances and excipients
(including water) that are present in the final pharmaceutical dosage
form
Use of excipients should be differentiated in the product formula
using parentheses before the ingredient name, e.g. (Film coating)
Ingredient Z.
For active ingredients presented in the form of salts and chelate, the
quantity should be clearly stated, e.g., XX phosphate 32 mg
(equivalent to XX) etc.

Section Documents
NDA GDA
Information on residual amounts of certain materials, such as

antibiotics, thiomersal and materials of biological origin (e.g. human
serum albumin), added or present in the drug product must be
declared.
* * * * *
*: Applicable if product contains ingredient derived from human
blood or animal sources
Information to be provided in the following format: (Species &
product) (In manufacturing/drug substance/excipient) (Country)
The human plasma-derived product checklist (Annex 1 of Appendix
10) or TSE checklist (Annex 1 of Appendix 11) should be submitted
if applicable.
4.4 ATC Code
4.5 Dosage Form
Include all routes of administration proposed for the product
Where more than one drug component is included in a drug product
(e.g., powder for injection with solvent as composite pack) and each
component has a different shelf life, the shorter shelf life is to be
used as the shelf life of the composite pack

Section Documents
NDA GDA
If an application is pending or not submitted to either of HSAs

reference agencies State that the application is pending (including
the submission and expected outcome dates), or not submitted
(date not required).
indicated
For approved indication(s) and dosing regimen(s) for an approved
application, you can make reference to the approved PI of the
reference agency instead of typing out the information under
Application Details
In the event that the PRISM text space does not allow input of full
details of the indication(s), dosing regimen(s), and/or reason(s), a
brief description may be entered; The full details should be attached
in softcopy (PDF) in PRISM section 7
4.10 Product Owner
All manufacturers of active substance(s), drug product and diluent used to
reconstitute the product (if packed and sold together with the drug product)
must be declared
manufacturer

Section Documents
NDA GDA
All manufacturers names and addresses should be consistent throughout all

of the documents submitted in the application, such as GMP certificates,
CPPs, Letters of authorisation, Part II of the CTD and so forth
If there are multiple companies responsible for batch release, the applicant
must declare all of the sites
The finished product manufacturer(s) which the batch releaser is releasing the
product from must be specified
Attach all documents relating to Part I of the CTD
Other Parts Either attach in full in this PRISM section or submit soft copies
in CD
1.4 Labelling and PI/PIL proposed in Singapore.
Labelling must be in English. Highlight any non-English country-specific labelling
requirements on the artwork/drafts if the labelling is shared with other countries
*: If non-English text is included in the labelling, applicants must provide an official
statement to declare that the non-English text is complete, accurate and unbiased * * * * *
information and is consistent with the English text
1.4.1 Outer/Carton Labels
1.4.2 Inner/Blister Labels

Section Documents
NDA GDA
1.5.2 SmPC/PI/PIL approved by Country of Origin/Country of Manufacture * * * *

The approved SmPC / PI / PIL from the drug regulatory agency that issued the *
proof of approval, if different from the Country of Origin
1.5.4 * * * *
Assessment report issued by HSAs reference regulatory
1.6
agency: (Please specify)
__________________________________________________
Declaration letter should be provided if the trade name of the product registered in the
country which issued the proof of approval is different from that proposed in Singapore
*: Proof of approval is not required for GDAs undergoing abridged evaluation for
finished product manufactured (up to primary packaging) in Singapore
1.9 Proof of Approval from HSAs reference regulatory agencies
(NDA: 2 reference regulatory agencies, GDA: 1 reference regulatory agency)
Please specify issuing agencies:
__________________________________________________

authorised person in the company
The names and addresses stated in the letters should be consistent with the
information provided in application form and dossier
1.10.1 Authorisation Letter from Product Owner to the Applicant firm

Section Documents
NDA GDA
This letter authorises the local applicant firm to apply for and be the Product
Licence Holder for a specific medicinal product
1.10.2 Authorisation Letter from Product Owner to the Manufacturer(s)
This letter authorises the specified manufacturer to produce, pack and/or label
the drug product intended for Singapore
If there are multiple drug product manufacturers, the applicant may opt to
submit one authorisation letter which clearly states all of the manufacturers
(names and addresses) and their responsibilities related to the drug product
For biologic drug products, an additional authorisation letter from the Product
Owner to the Drug Substance Manufacturer is required
1.10.3 Authorisation Letter from Product Owner to the Batch Releaser
This letter authorises the specified company to test and batch release the drug
product
GMP certification/proof of GMP compliance for each finished product manufacturer
1.11
inclusive of secondary packer(s)
For biologics: GMP certification/proof of GMP compliance for each drug substance
manufacturer must be provided
For GDA Verification CECA: GMP certificate/ proof of GMP compliance and the latest
inspection report as issued by the reference agency should be submitted
Proof of GMP compliance must not expire within 6 months from the time of submission
to HSA
Diluents used for reconstituting the drug product and are packaged together with the
drug product will be considered as part of the final drug product; Manufacturer(s) of the
supplied diluent(s) will follow the same requirements applicable to the drug product
e.g. proof of GMP compliance
The names and addresses of manufacturer(s) / repacker(s) should be consistent with
information provided in application form
If applicable, application for GMP Conformity Assessment should be submitted together
with the product application

Section Documents
NDA GDA
The Patent Declaration form is required for each NDA and GDA
Under Applicant Particulars, name & address of the local applicant firm to be stated
Under Product Particulars, the product name is stated and it should be consistent with
that stated in PRISM, the application form, all product labelling and all other relevant
documents in the dossier
Under Declaration, the patent declaration must be signed by the Company Director,
Company Secretary as registered with ACRA, or equivalent.
Evidence of authorisation (e.g. ACRA printout) should be submitted together with the
declaration.
Declaration that all aspects of the Singapore products quality are identical to that
1.14
currently approved by the chosen primary reference regulatory agency.
Official letter declaring that the Drug Master File provided is the same as that submitted
to the primary reference agency, if applicable.
Registration Status in Other Countries as separate attachment in PRISM under [7]
1.15
Supporting Attachments
For NDA & GDA, registration status should be entered into PRISM section 4.9; In the
event that the PRISM text space does not allow input of the full details of the
indication(s) and/or reason(s), a brief description may be entered; The full details
should then be attached in softcopy (PDF) in this PRISM section (supporting
attachments)

Part II Quality
Section Document
NDA GDA
For verification dossier The submission should include Part II of the dossier as originally
submitted to the reference agency, and any documentations submitted to the same reference
agency in subsequent variations to the quality aspects of the product.
A Table of Contents of Part II
B Singapore Quality Overall Summary (QOS) & QOS in other format, if available
C Body of Data
Drug Substance (Active Substance)
If DMF is submitted, refer to main Guidance, sections 14.3.1 & 17.3.1
If CEP (Certificate of Suitability) is submitted, waiver of documents for this section can
be granted except for S4.1, S4.2 & S4.4.
The manufacturers info provided in the CEP is consistent with the information
provided in the application form.
Please note that information not included in the CEP would have to be supported by
substantial data (e.g. S6 & S7 is required if no retest period and/or packaging is stated
in the CoA).
To take note of the validity of the certificate.
S1 General Information
S1.1 Nomenclature
S1.2 Structure
S1.3 General Properties
S2 Manufacture
S2.1 Manufacturer(s)
S2.2 Description of Manufacturing Process and Process Controls

Section Document
NDA GDA
S2.3 Control of Materials * * * * *

S2.4 Controls of Critical Steps and Intermediates * * * * *
S2.5 Process Validation and/or Evaluation
Must be submitted for sterile APIs and NBEs (in accordance to the * * * * *
ICH M4Q guidelines)
S2.6 Manufacturing Process Development
*: For applications with DMF, sections S2.3, S2.4, S2.5 and S2.6 are included in * * * * *
the closed part of DMF
S3 Characterisation
S.3.1 Elucidation of Structure and other Characteristics
S3.2 Impurities
S4 Control of Drug Substance
S4.1 Specification of Drug Substance
S4.2 Analytical Procedures
S4.3 Validation of Analytical Procedures
* * * * *
*: Can be waived for methods that reference to compendial methods
S4.4 Batch Analyses
S4.5 Justification of Specification * * * * *
*: Justification is not required if compedial requirements is met (e.g.
Limits are set according to USP standards)
S5 Reference Standards or Materials

Section Document
NDA GDA
State if source of reference standard is in house, official with reference to

compendia standard
For in house, specification of reference standard are to be submitted
Evidence of characterization for in-house / working standards (e.g. tests of
NMR, MS are documented in the CoA will suffice) is required
S6 Container Closure System
S7 Stability
S7.1 Stability Summary and Conclusions
S7.2 Post-approval Stability Protocol and Stability Commitment
S7.3 Stability Data
NOTE: S6 & S7 would have to be submitted if the retest period is not stated in
the CEP
At point of submission, at least 12 months of real time data and 6 months of
accelerated data on at least 3 primary batches of the DS should be provided
The batches should be manufactured to a minimum of pilot scale by the same
synthetic route as, and using the method of manufacture and procedure that
simulates the final process to be used for production batches
If the DS is sourced from 2 different sites, stability data from both sites should
be provided
Stability studies are conducted on DS stored in proposed packaging
Drug Product
P1 Description and Composition of the Drug Product
P2 Pharmaceutical Development

Section Document
NDA GDA
P2.1 Information on Development Studies

P2.2 Components of the Drug Product
P2.2.1 Active Ingredients
P.2.2.2 Excipients
P2.3 Finished Product
P2.3.1 Formulation Development
P2.3.2 Overages
P2.3.3 Physicochemical and Biological Properties
P2.4 Manufacturing Process Development
P2.5 Container Closure System
P2.6 Microbiological Attributes
P2.7 Compatibility
P3 Manufacture
P3.1 Batch Formula
For multiple batch sizes, batch formula for each batch sizes are to
be provided
P3.2 Description of Manufacturing Process And Process Controls
Flow chart and IPC should be submitted
P3.3 Controls of Critical Steps and Intermediates
P3.4 Process Validation and/or Evaluation

Section Document
NDA GDA
Table of Contents for Process Validation Documentation

For Option 1: 3 consecutive production batch
For Option 2: P2 + Validation report of 1 pilot batch OR
Validation protocol at time of submission but batches required at
time of evaluation
To highlight in dossier if Option 2 is selected
P4 Control of Excipients
State if excipient used are compendial or non-compendial
Compendial: Reference made to compendial specifications will suffice.
Non-compendia: P4.1-P4.5
P4.1 Specifications
P4.2 Analytical Procedures
P4.3 Excipients of Human or Animal Origin
* * * * *
For animal derived excipient, please indicate Yes in PRISM
section 4.3b and provide relevant information
For lactose monohydrate, declaration on source of milk is safe for
human consumption will suffice
For other animal derived excipient, checklist in Appendix 11 are to
be submitted with relevant information
P4.4 Novel Excipients
Provide information provided as per full DS Section and submit in
section Q4A.3
P5 Control of Drug Product (Finished Product)
P5.1 Specification(s) of Drug Product
P5.2 Analytical Procedures

Section Document
NDA GDA
P5.3 Validation of Analytical Procedures

P5.4 Batch Analyses
P5.5 Characterisation of Impurities
P5.6 Justification of Specification(s)
Justifications for each of the specification
P6 Reference Standards or Materials
State if source of reference standard is in house, official with reference to
compendia standard
For in house, specification of reference standard is required
Evidence of characterization for in-house / working standards (e.g. tests of
NMR, MS are documented in the CoA will suffice)
P7 Container Closure System
P8 Stability
Information provided is consistent with stability data provided.
Stability studies meet minimum ASEAN requirement
P8.1 Stability Summary and Conclusions
P8.2 Post-approval Stability Protocol and Stability Commitment
P8.3 Stability Data
At point of submission, at least 12 months of real time data and 6
months of accelerated data on at least 3 primary batches of the
DP should be provided

Section Document
NDA GDA
The primary batches should be of the same formulation and

packaged in the same container closure system as proposed for
marketing in Singapore
Stability data should be site specific applicable to the Singapore
product
If the DS is sourced from 2 different sites, stability data for the
DP should include one set of minimum requirements for the DP
with DS from site A and one set of minimum requirements for the
DP with DS from site B (i.e., total of 6 batches at real time
conditions and 6 batches at accelerated conditions)
P9 Product Interchangeability (Bioequivalence Study Reports)
* * *
Reference product used in Bioequivalence study is the Singapore Reference
Product and uses the same site of manufacturing.
If not, refer to Appendix 12 for the bridging data required
If BE study not required, justification for biowaiver is required, with supporting
documents
D Key Literature References
Q Country-specific Quality Requirements
Q1 Checklist for Human Blood Product with the required supporting documents
For human derived materials, please indicate Yes in PRISM section 4.3a * * * * *
and complete with relevant information
Q2 TSE Checklist with the required supporting documents
For animal derived materials, please indicate Yes in PRISM section 4.3b and * * * * *
complete with relevant information
Q3 Blank Production Batch Record * * * * *
Q4 Appendices

Section Document
NDA GDA
A.1 Facilities and Equipment

A.2 Adventitious Agents Safety Evaluation * *
A.3 Novel Excipients * *

Part III Non-clinical Data
Section Documents
NDA GDA
A Table of Contents of Part III

B Non-clinical Overview
B1 General Aspect
B2 Content and Structural Format
C Non-clinical Summary (Written and Tabulated)
C1 Non-clinical Written Summary
C1.1 Pharmacology
C1.2 Pharmacokinetics
C1.3 Toxicology
C2 Non-clinical Tabulated Summaries
D Non-clinical Study Report
D1 Table of Contents
D2 Pharmacology
D2.1 Primary Pharmacodynamics
D2.2 Secondary Pharmacodynamics
D2.3 Safety Pharmacology
D2.4 Pharmacodynamic Drug Interactions
D3 Pharmacokinetics
D3.1 Analytical Methods and Validation Reports
D3.2 Absorption

Section Documents
NDA GDA
D3.3 Distribution
D3.4 Metabolism
D3.5 Excretion
D3.6 Pharmacokinetic Drug Interactions (non-clinical)
D3.7 Other Pharmacokinetic Studies
D4 Toxicology
D4.1 Single-Dose Toxicity
D4.2 Multiple-Dose Toxicity
D4.3 Genotoxicity
D4.4 Carcinogenicity
D4.5 Reproductive and Developmental Toxicity
D4.6 Local Tolerance
D4.7 Other Toxicity Studies
E List of Key Literature References

Part IV Clinical Data
Section Document
NDA GDA
A Table of Contents of Part IV

B Clinical Overview
C Clinical Summary
C1 Summary of Biopharmaceutic Studies and Associated Analytical Methods
C2 Summary of Clinical Pharmacology Studies
C3 Summary of Clinical Efficacy
C4 Summary of Clinical Safety
C5 Synopses of Individual Studies
D Tabular Listing of All Clinical Studies
E Clinical Study Reports
E1 Reports of Biopharmaceutic Studies
* * * *
*: For Abridged and Verification Dossiers: only final study report(s) of
biopharmaceutic studies to establish bioequivalence between commercial
product formulation and clinical trial formulation used in pivotal studies
should be submitted, if applicable
For Full Dossier, all biopharmaceutic study reports are required
E2 Reports of Studies Pertinent to Pharmacokinetics using Human Biomaterials
E3 Reports of Human Pharmacokinetic (PK) Studies
E4 Reports of Human Pharmacodynamic (PD) Studies
E5 Reports of Clinical Efficacy and Safety Studies
Study reports of pivotal or relevant clinical trials (appendices & tables are
required upon request by HSA)

Section Document
NDA GDA
E6 Reports of Post-marketing Experience * * *

Case Report Forms and Individual Patient Listings (required upon request by
E7
HSA)
F List of Key Literature References
G Other Supporting Documents


APPLICATION CHECKLIST 3B (ACTD - MAV)
APPENDIX 3B APPLICATION CHECKLIST (ACTD MAV)
This Application Checklist should be used to ensure submission of a complete dataset in the ASEAN Common Technical Dossier (ACTD) format
for MAV applications only.
Note:
evaluation route.
evaluation route.
Please refer to the Guidance on Medicinal Product Registration in Singapore and the ASEAN Guidance on ACTD for explanatory notes on the
preparation of documents for a submission in ACTD format.

Part I Administrative Documentation
Section Documents
MAV-1 MAV-2

Include a complete list of all documents provided in the application dossier by Part
The location of each document should be identified by the Part number
For any documents submitted in hardcopy, the location of each document should be identified
by the volume number and tab identifiers (name of document or section heading according to
ACTD format)
1.2 Introduction
Applicant must be a permanent staff of the company and is residing in Singapore. If
the person making the application / correspondence person is an external party
(consultant) engaged by the applicant company, an original letter of authorization
from the applicant company must be submitted.
Company address and contact details may be entered instead of personal residential
address and contact details of the applicant
3.2 Type of Product
3.3 Reference Product

Section Documents
MAV-1 MAV-2

3.5 Type of Dossier
3.6 Type of Format
4.1 Product name
4.2 Product Formula
4.4 ATC Code
* * *
*: Applicable if the MAV is in relation to a change in ATC code
4.5 Dosage Form
*: Applicable if the MAV is in relation to a change in route of * * *
administration
As the PRISM fields are not amendable in a variation application,
the full details should be attached in softcopy (PDF) in PRISM
section 7 (Supporting Attachments)

Section Documents
MAV-1 MAV-2
If an application is pending or not submitted to the country of origin

and all HSA reference agencies State that the application is
pending (with submission date), or not submitted (date not
required).
indicated
4.10 Product Owner
Attach all documents relating to Part I of the CTD
Other Parts Either attach in full in this PRISM section or submit soft copies in CD
1.4 Labelling and PI/PIL proposed and currently approved in Singapore.
Labelling must be in English. Highlight any non-English country-specific labelling requirements
on the artwork/drafts if the labelling is shared with other countries
*: If non-English text is included in the labelling, applicants must provide an official statement to
declare that the non-English text is complete, accurate and unbiased information and is * * * *
consistent with the English text

Section Documents
MAV-1 MAV-2
1.4.1 Outer/Carton Labels * * * *

1.4.2 Inner/Blister Labels * * * *
1.5.2 SmPC/PI/PIL approved by Country of Origin/Country of Manufacture * * *
The approved SmPC / PI / PIL from the drug regulatory agency that issued the proof
of approval, if different from the Country of Origin
1.5.4
1.6 Assessment report issued by HSAs reference regulatory agency:
(Please specify)
__________________________________________________
Declaration letter should be provided if the trade name of the product registered in the country
which issued the proof of approval is different from that proposed in Singapore
*: Proof of approval for MAV-2 should be in the form of documentation which proves that that
product had been reclassified (for specific indication(s) or dosing regimen(s)) in the UK, US,
Canada and/or Australia. This is not required for me-too reclassification.

Section Documents
MAV-1 MAV-2
Proof of Approval from at least 2 of HSAs reference regulatory agencies

1.9 Please specify issuing agencies: __________________________________________________

GMP certification/proof of GMP compliance for each finished product manufacturer inclusive of
1.11
secondary packer(s)
Declaration that all aspects of the Singapore products quality are identical to that currently
1.14
approved by the chosen primary reference regulatory agency.
Official letter declaring that the Drug Master File provided is the same as that submitted to the
primary reference agency, if applicable.
Registration Status in Other Countries as separate attachment in PRISM under [7] Supporting
1.15
Attachments
The full details should then be attached in softcopy (PDF) in this PRISM section (supporting
attachments)
For MAV-2 applications, the registration status should also include the forensic classification of
the product in the approved countries.

Part III Non-clinical Data
Section Documents
MAV-1 MAV-2
A Table of Contents Part III *

B Non-clinical Overview * * *
B1 General Aspect * * *
B2 Content and Structural Format * * *
C Non-clinical Summary (Written and Tabulated)
C1 Non-clinical Written Summary
C1.1 Pharmacology
C1.2 Pharmacokinetics
C1.3 Toxicology
C2 Non-clinical Tabulated Summaries
D Non-clinical Study Report
D1 Table of Contents
D2 Pharmacology
D2.1 Primary Pharmacodynamics *
D2.2 Secondary Pharmacodynamics *
D2.3 Safety Pharmacology *
D2.4 Pharmacodynamic Drug Interactions *
D3 Pharmacokinetics
D3.1 Analytical Methods and Validation Reports *
D3.2 Absorption *

Section Documents
MAV-1 MAV-2
D3.3 Distribution *
D3.4 Metabolism *
D3.5 Excretion *
D3.6 Pharmacokinetic Drug Interactions (non-clinical) *
D3.7 Other Pharmacokinetic Studies *
D4 Toxicology
D4.1 Single-Dose Toxicity *
D4.2 Multiple-Dose Toxicity *
D4.3 Genotoxicity *
D4.4 Carcinogenicity *
D4.5 Reproductive and Developmental Toxicity *
D4.6 Local Tolerance *
D4.7 Other Toxicity Studies *
E List of Key Literature References *

Part IV Clinical Data
Section Document
MAV-1 MAV-2
A Table of Contents of Part IV

B Clinical Overview
C Clinical Summary
C1 Summary of Biopharmaceutic Studies and Associated Analytical Methods * * *
C2 Summary of Clinical Pharmacology Studies * * *
C3 Summary of Clinical Efficacy
C4 Summary of Clinical Safety
*
*: Not required for me-too reclassification
C5 Synopses of Individual Studies
D Tabular Listings of All Clinical Studies
E Clinical Study Reports
E1 Reports of Biopharmaceutic Studies * * *

*: For Abridged and Verification Dossiers: only final study report(s) of biopharmaceutic
studies to establish bioequivalence between commercial product formulation and
clinical trial formulation used in pivotal studies should be submitted, if applicable
For Full Dossier, all biopharmaceutic study reports are required
E2 Reports of Studies Pertinent to Pharmacokinetics using Human Biomaterials *
E3 Reports of Human Pharmacokinetic (PK) Studies *
E4 Reports of Human Pharmacodynamic (PD) Studies *
E5 Reports of Clinical Efficacy and Safety Studies

Section Document
MAV-1 MAV-2
Study reports of pivotal or relevant clinical trials (appendices & tables are required
upon request by HSA)
E6 Reports of Post-marketing Experience * * *
E7 Case Report Forms and Individual Patient Listings (required upon request by HSA)
F List of Key Literature References
G Other Supporting Documents * * *

FLOWCHART FOR TRANSLATION OF NON-ENGLISH DOCUMENTS
APPENDIX 4 FLOW CHART FOR TRANSLATION OF NON-ENGLISH

DOCUMENTS
Non-English original document issued by a national drug regulatory agency (original bears seal and
signature)
e.g. GMP certificate, approval letter, CPP, SmPC/PIL (Product Information) and other documents
In Malay (including Bahasa In languages other than Malay

Indonesian), Tamil or Chinese (including Bahasa Indonesian),
Tamil or Chinese
Document translated at Translated by non-

Supreme Court (or Subordinate official source (e.g.
Courts) in Singapore In-house translation)
Embassy of Country of Embassy of Country of

Origin is available in Origin is not available in
Singapore OR Singapore Singapore OR Singapore
Embassy is available in Embassy is not available in
Country of Origin Country of Origin
Translator to make
declaration in presence of a
Translation to be notary public
endorsed/certified by a
responsible officer of
either the Embassy of the
Country of Origin in
Singapore OR the Notary public to be
Singapore Embassy in the authenticated by the relevant
Country of Origin authority in the Country of
Origin
Applicable to product applications submitted to HSA:

1. Submit all original documents (including all translations, declarations & confirmations, where
applicable) to HSA; or
2. Submit certified true copy of all documents to HSA. Originals should be kept with the
applicant and should be provided upon request by HSA.


GUIDELINE ON SUBMISSION FOR NON-PRESCRIPTION MEDICINAL PRODUCTS
APPENDIX 5 GUIDELINE ON SUBMISSION FOR NON-PRESCRIPTION

MEDICINAL PRODUCTS
This document is intended to provide assistance in the submission of NDA or MAV-1

applications under the abridged evaluation route for non-prescription medicinal products.
It provides guidance on the eligibility criteria for a reduced dataset submission and
additional explanatory notes on documentary requirements for product registration.
1 ELIGIBILITY FOR WAIVER OF CLINICAL DOCUMENTS
As stated in sections 13.2.2 and 22.1.2.1 of the Guidance on Medicinal Product

Registration in Singapore, applicants may submit a written request for a waiver of
clinical data submission. The request may be made if the product fulfils the criteria below:
a) The active substance(s) must not be currently classified as a POM in Singapore.
b) The medicinal product should have been evaluated and approved as a non-
prescription medicine, as defined below, by at least one of the following reference
regulatory agencies:
Australia TGA non-prescription medicines refer to drugs substances listed in

Schedule 2 and 3 of SUSDP1.
Health Canada non-prescription medicines refer to medicinal products

classified under Schedule II, III or U.
US FDA non-prescription medicines. Products registered under the FDA OTC

Monograph (21 Code of Federal Regulations Chapter 1, Parts 300-499)2, which
are marketed without prior FDA clearance, are excluded.
UK MHRA non-prescription medicines refer to medicinal products classified as

P or GSL.
The approved classification by a reference regulatory agency does not obligate

HSA. HSA reserves the right to determine the products forensic classification
based on assessment of the products risk versus benefit profile as well as local
public health implications.
c) The use of each active substance contained in the product should be well-
documented in the following standard reference texts:
Martindale: The Complete Drug Reference. Sweetman SC (Ed.). Pharmaceutical

Press, UK.
Handbook of Non-prescription Drugs. American Pharmaceutical Association,

USA.
Remingtons Pharmaceutical Sciences. Gennaro AR (Ed.). American

Pharmaceutical Association, USA and Pharmaceutical Press, UK.
AHFS Drug Information. McEvoy GK (Ed.). American Society of Health System

Pharmacists, USA.
1
Standard for the Uniform Scheduling of Drugs and Poisons
2
http://www.access.gpo.gov/nara/cfr/waisidx_01/21cfrv5_01.html

GUIDELINE ON SUBMISSION FOR NON-PRESCRIPTION MEDICINAL PRODUCTS
Handbook of Pharmaceutical Excipients. Kibbe AH (Ed.). American

Pharmaceutical Association, USA and Pharmaceutical Press, UK.
Other well-established reference texts may be accepted if deemed appropriate by

HSA.
If adequate documentation is provided, submission of clinical efficacy and safety data of

the product may not be required. Any use outside of the documented indication(s),
dosage(s) and route(s) of administration will require evidence of efficacy and safety
unless otherwise justified. It should be noted that anecdotal or limited clinical reports of
efficacy alone (for example, in Martindale, xxx has also been used in) will not be
accepted as evidence of safety and efficacy.
The documentary requirements are described in section 14 in Chapter C for NDAs and
section 22.2 in Chapter G for MAV-1s, with following additional explanatory notes:
The administrative documents required are the same as that for the abridged evaluation
route.
Product Labelling (section 1.4) for non-prescription medicines should be provided in the
form of a Patient Information Leaflet (PIL). A PIL must be clear, simple and readable so
that consumers can understand information about the product, its benefits, its risks and
how the product should be used appropriately. For details on PIL labelling requirements,
please refer to the Appendix 6 Points to consider for Singapore labelling.
The Proof of Approval (section 1.8) by the drug regulatory agency should be an official
approval letter or equivalent document that also states the forensic classification of the
product. However, HSA may still request a CPP, if deemed appropriate.
The quality requirements for an NDA non-prescription medicine are the same as that of a
POM product. MAV-1 applications do not require submission of quality documents.
If the product fulfils the criteria as defined in section 1, then the clinical data set in support
of the application may be reduced.
The clinical part of the dossier should include a Clinical Overview and supporting
information from standard reference texts as listed in section 1(c) above. The supporting
documents should be inserted in section 2.5 of Module 2 (ICH CTD) or section B of Part
IV (ACTD).
HSA reserves all rights to request for the complete clinical data set if it is deemed
appropriate.

POINTS TO CONSIDER FOR SINGAPORE LABELLING
APPENDIX 6 POINTS TO CONSIDER FOR SINGAPORE LABELLING
Labelling refers to any printed or graphic information on the immediate container, outer
packaging and any other form of printed material supplied together with the product.
Information provided in the labels should be consistent with the information submitted in
the application dossier. Any deviation should be highlighted and brought to HSAs
attention.
1 OUTER CARTON AND INNER/BLISTER LABELS
The Outer Carton refers to the product packaging in which the immediate packaging is
placed, e.g. the carton box containing blister strips. The Inner Label refers to the label
that is fixed onto the primary container closure system, e.g. the label affixed to a bottle,
vial or ampoule. The Blister Label refers to the foil backing of a blister strip.
In addition to the legal labelling requirements, the following information shall be present
on the labelling of the product:
Outer Inner
Parameters Blister Label
Carton Label
1. Product Name
2. Dosage Form * NA
3. Name of Active Substance(s)
4. Strength of Active Substance(s)
5. Batch Number
6. Manufacturing Date * NA
7. Expiry Date
8. Route of Administration NA
9. Storage Condition * NA
Name/Logo of
Name & Address of Product Owner
10. * Manufacturer/
and/or Product Licence Holder
Product Owner
11. Name & Address of Manufacturer** * NA
12. Warnings (if applicable) * NA
13. Pack Sizes (unit/volume) NA
14. Special Labelling (if applicable) * NA
Name & Content of preservative(s) (if
15. * NA
applicable)
NA Not applicable
* Exempted for small labels such as an ampoule or vial with a nominal volume of 10 ml or less. Other
factors may be considered such as the amount of information which needs to appear on the label and the
font size necessary to achieve legibility of the information.
** The name and address of either the manufacturer or the batch releaser should be present.

If the product is supplied without an outer carton, the information that is required on the
outer carton should be stated on the inner label.
Any handwritten information on the specimens, mock-ups or text is not acceptable, with
the exception of statements such as batch number and expiry dates will be printed or
similar.
Email addresses and/or telephone numbers on the products labelling may be considered.
However, website addresses are generally not allowed unless adequately justified, for
example, in the case where the information is intended for the purpose of adverse drug
reaction reporting.
2 PACKAGE INSERT (PI)
Package inserts are required for products classified as Prescription Only Medicines.
The PI is regarded as a document that contains information that will ensure safe and
effective use of the drug product. It includes a scientific, objective account of the
medicines usefulness and limitations as shown by data submitted in the application.
Information in the PI shall be non-promotional in nature.
The following information is required for the PI:
i. Brand or Product Name as provided in the application.

ii. Name and Strength of Active Substance(s) the non-proprietary name of each
therapeutically active drug substance.
iii. Product Description a description of relevant physical and chemical
characteristics of the drug product and its formulation(s), including the list of
excipients contained in the product.
iv. Pharmacodynamics/Pharmacokinetics information to be mentioned in this section
include: (a) the ATC code, if available, (b) the pharmacokinetic and pharmacological
action(s), particularly in humans, of each drug substance, (c) clinical trial
information relating to clinical efficacy and safety, and (d) any relevant
pharmacogenetic information from clinical studies with any data showing a
difference in benefit or risk to a particular genotype or phenotype.
v. Indication the therapeutic indication(s) of the product.
vi. Recommended Dosage the information required include, as appropriate:
dosing regimen (dose and interval);
information on dose adjustments in special populations, e.g. elderly, children,
renal insufficiency, hepatic insufficiency and concomitant disease;
maximum recommended/tolerated daily dose and the maximum dose for an
entire course of therapy;
advice relevant for dosage adjustment from monitoring of clinical symptoms and
signs and/or laboratory investigations, when appropriate, with cross-reference to
other sections where appropriate;
other pertinent information such as relationship to meals and compatibility with
other drugs and fluids; and,
reference to a dosing regimen for an unregistered product or unapproved
indication is not acceptable.
vii. Mode/Route of Administration only standard abbreviations should be used. Non-
standard or complicated routes of administration should be carefully explained in full

to avoid confusion, particularly when the product is made available for self-
selection.
viii. Contraindications situations where patients should never or generally not be
treated with the medicine. In rare cases where the medicine should never be given,
this must be explicitly stated. Information on the presence of residual quantities of
potentially allergenic materials used in the manufacturing of the product should be
stated.
ix. Warnings and Precautions circumstances where caution is required to ensure
safe and efficacious use of the drug. Information on the presence of residual
quantities of potentially allergenic materials used in the manufacturing of the
product should be stated.
x. Interactions with Other Medicines and Other Forms of Interaction information on
clinically relevant interactions and other potentially serious interactions based on
the pharmacology of the medicine.
xi. Use during Pregnancy/Lactation
xii. Adverse Effects/Undesirable Effects provide an indication of severity, clinical
importance and frequency, whenever possible. Description of the adverse reaction
based on the MedDRA terminology is preferred.
xiii. Overdose and Treatment symptoms, signs and recommended treatment of
overdose or accidental poisoning.
xiv. Incompatibilities (for injections only)
xv. Storage Condition if it is included in the PI, the storage condition must be
consistent with the product label and/or outer carton.
xvi. Dosage Forms or Presentation this refers to the available dosage form(s),
formulation(s), strength(s) and/or pack size(s). The statement Not all presentations
may be available locally, or equivalent, must be stated if this section lists
unregistered presentations.
xvii. Name and Address of Manufacturer or Product Owner or Product Licence Holder
xviii. Date of Revision of Package Insert if a common PI is used for an internationally
marketed product, the date can follow the date of revision of the common PI.
However, if a Singapore-specific PI is used, the date of revision must reflect the
actual date that the local PI is revised.
3 PATIENT INFORMATION LEAFLET (PIL)
Patient Information Leaflets (PILs) are required for Pharmacy Only and General Sale List
medicinal products. The PIL must be easily understood and be consistent with the
product labels and/or PI, as appropriate. The following information is required in the PIL:
i. Name of Product
ii. Description of Product
iii. What is the medicine?
iv. Strength of the medicineWhat is this medicine used for?
v. How much and how often should you use this medicine?
vi. When should you not take this medicine?
vii. Undesirable effects/side effects

viii. What other medicine or food should be avoided whilst taking this medicine?
ix. What should you do if you miss a dose?
x. How should you keep this medicine?
xi. Signs & symptoms of overdose
xii. What to do when you have taken more than the recommended dosage?
xiii. Name/logo of manufacturer/importer/product licence holder
xiv. Care that should be taken when taking this medicine?
xv. When should you consult your doctor?
If the product is sold without a PIL, the information that is required in the PIL must be
stated on the outer carton.

PATENT DECLARATION FORM
SEPTEMBER
Appendix 7: Patent Declaration Form

(Version 28 June 2004: 2 pages)

PATENT DECLARATION FORM
SEPTEMBER

REPUBLIC OF SINGAPORE
HEALTH SCIENCES AUTHORITY
MEDICINES ACT
(CHAPTER 176)
DECLARATION ON PATENT RELATED INFORMATION FOR

APPLICATION FOR PRODUCT LICENCE
Application No (for HSA use only):
SECTION 1: APPLICANT PARTICULARS

Name
Address
SECTION 2: PRODUCT PARTICULARS

Proprietary Name
Active Substance(s) and Strength
Dosage Form
SECTION 3: APPLICATION CATEGORY

Application Category (check one box)*
Category A1 (Proceed to Section 4)
Refers to an application where no patent is in force in respect of the medicinal product to which the application
relates.
Refers to an application where a patent is in force in respect of the medicinal product to which the application
relates; and the applicant is either the proprietor of the patent or, if the applicant is not the proprietor of the
patent, the proprietor has consented to or acquiesced in the grant of the product licence.
relates, the applicant is not the proprietor of the patent, the proprietor has not consented to nor acquiesced in
the grant of the product licence; and the applicant is requesting for grant of product licence after the expiry of
the patent. Such an application may not be made earlier than 18 months before the expiry of the patent.
Category B (Proceed to Section 7)
relates, the applicant is not the proprietor of the patent, the proprietor has not consented to nor acquiesced in
the grant of the product licence; and in the opinion and to the best belief of the applicant, the patent is invalid
or will not be infringed by the doing of the act for which the licence is sought.
SECTION 4: INFORMATION FOR CATEGORY A1 APPLICATIONS

I, the applicant/the authorised agent of the applicant on behalf of the applicant, declare that
there is no patent under the Patents Act (Cap. 221) in force in respect of the product stated in Section 2 on
the date of this declaration.
* For categories A2, A3 and B, please submit a separate declaration for each patent that is in force in respect of
the medicinal product.
I, the applicant/the authorised agent of the applicant on behalf of the applicant, declare that (check one box)
a patent under the Patents Act is in force in respect of the product stated in Section 2 on the date of this
declaration. I am the proprietor of the patent. The Singapore Patent No. for the patent is .
declaration. I am not the proprietor of the patent but the proprietor has consented to or acquiesced in the
grant of the product licence for the product stated in Section 2 to me. The name and address of the proprietor
of the patent or his authorised agent are . The Singapore Patent No. for the patent is .

declaration. I am not the proprietor of the patent and the proprietor has not consented to nor acquiesced in
the grant of the product licence for the product stated in Section 2 to me. I am requesting for the grant of the
product licence after the expiry of the patent. I am making the application not earlier than 18 months before
the expiry of the patent.
The name and address of the proprietor of the patent or his authorised agent are .
The Singapore Patent No. for the patent is .
The patent will expire on (dd/mm/yyyy), which is months from the date of my product licence
application.
SECTION 7: INFORMATION FOR CATEGORY B APPLICATIONS

declaration. I am not the proprietor of the patent and the proprietor has not consented to nor acquiesced in
the grant of the product licence for the product stated in Section 2 to me. In my opinion and to my best belief,
the patent (check one box)
is invalid; or
will not be infringed by the doing of the act for which the licence is sought.
The name and address of the proprietor of the patent or his authorised agent are .
The Singapore Patent No. for the patent is .
The patent will expire on (dd/mm/yyyy).
SECTION 8: DECLARATION
I am duly authorised by the applicant to make this declaration on behalf of the applicant, and enclose herewith
#
evidence of such authorisation .
I, the applicant/the authorised agent of the applicant on behalf of the applicant, declare that all information furnished
in this form is true. I am aware that a false declaration is an offence under the Medicines Act (Cap. 176). I further
undertake to notify the Health Sciences Authority of any change in the information furnished in this form.
Name: Designation:
Signature and Date: Applicants Stamp:
_______________________________
#
Please enclose appropriate evidence of authorisation. Delete this statement if applicant is a natural
person making the application personally.
SINGAPORE QUALITY OVERALL SUMMARY FOR CHEMICAL DRUGS
APPENDIX 8 SINGAPORE QUALITY OVERALL SUMMARY

New Drug Applications and Generic Drug Applications (Chemicals)
The Quality Overall Summary (QOS) should be completed to summarize the Quality (i.e.,
Chemistry, Manufacturing and Controls) portion of a New Drug Application (NDA) or a Generic Drug
Application (GDA) for a chemical drug product. Both hard copy and electronic copy of the Singapore
QOS shall be submitted for review.
The applicant is responsible for completing all sections and fields. Sections and fields that are not
applicable should be indicated with NA. An explanatory note must immediately follow all NA
entries.
INTRODUCTION
Proprietary Name of Drug Product
INN Common Name of Drug

Substance
Product Owner Name
Licence Holder Name
Dosage Form
Strength(s)
Route of Administration
Proposed Indication(s)
Application Type E.g. NDA-1, NDA-2, NDA-3, GDA-1, GDA-2 etc
Other introductory information:

Description of the dosage form: E.g. white, scored, round tablet
Container Closure System:
Shelf Life:
Storage Condition:
Others:

S DRUG SUBSTANCE
S 1 GENERAL INFORMATION
Check appropriate box.

DMF (open) part is attached.
DMF (open and restricted) and Letter of Access to be submitted by DDMMYYYY (within
one month of PRISM submission),
OR
Letter of Access to the DMF filed with HSA (015:________) is provided.
* CEP (Certificate of Suitability from EDQM) for Drug Substance is attached.
CEP Number:
CEP (Certificate of Suitability from EDQM) for Raw materials and Excipients is attached.
Drug Substance meets the current USP/PhEur/BP/JP (delete as appropriate)
requirements.
Drug Substance meets other pharmacopoeia standards. Analytical methods and
appropriate analytical method validation data are included in the dossier.
Drug Substance meets in-house specifications. Analytical methods and appropriate
analytical method validation data are included in the dossier.
* If CEP is provided and Ph.Eur standard is claimed for drug substance, please fill in S1, S2.1, S4.1, S4.4, S6 # and S7#
If CEP is provided and other standards are claimed for drug substance, please fill in S1, S2.1, S4.1 to S4.5, S6# and S7#
(#To be provided if re-test period/shelf life is not stated on CEP)
S 1.1 Nomenclature
Hard Copy Location/Pages:

E-Copy Location/File Name:
Chemical Name:
Other names: (e.g. INN, BAN, USAN, common name)
Company or laboratory code:
Chemical Abstracts Service (CAS) registry number:
S 1.2 Structure

Structural formula (including stereochemistry): [insert structure]

Molecular formula:
Molecular Mass:

S 1.3 General Properties

Physical description (e.g., appearance, colour, physical state):

Physical form (e.g., polymorphic form, solvate, hydrate):
Solubilities (e.g., in common solvents, aqueous/non-aqueous
solubility profile):
pH and pKa values:
Other (e.g., partition coefficients, melting or boiling points,
optical rotation, refractive index (for a liquid), hygroscopicity,
UV absorption maxima and molar absorptivity):
S 2 MANUFACTURE
S 2.1 Manufacturer(s)
Name, address, and activity of each manufacturer, including contractors, and each proposed
production site or facility involved in manufacture and testing:
Activity Name and Address *GMP Compliance (Please

indicate Approving Agency)
Site of Manufacture
Site of Batch Release

* For information only.
S 2.2 Description of Manufacturing Process and Process Controls

Flow diagram of the synthetic process(es):
[insert diagram]
S 2.3 Control of Materials


S 2.4 Controls of Critical Steps and Intermediates

S 2.5 Process Validation and/or Evaluation

S 2.6 Manufacturing Process Development

S 3 CHARACTERISATION
S 3.1 Elucidation of Structure and other Characteristics

S 3.2 Impurities
Summary of potential and actual impurities arising from the synthesis, manufacture and/or degradation:
Chemical Origin/Type of Impurity Structure

Name/Laboratory Code
[insert structure]
Process-related impurities (e.g., residual solvents):
Compound Name Step in Process

Process-related impurities (e.g., residual solvents):
Compound Name Step in Process
S 4 CONTROL OF THE DRUG SUBSTANCE
S 4.1 Drug Product Manufacturers Specification
Standard Claimed for the Drug Substance (e.g., USP, BP,

etc.):
Test Method Source (e.g., Release Shelf Life

(e.g., HPLC) USP, in- Specification Specification (if
house) applicable)

S 4.1 Drug Substance Manufacturers Specification (if different from above)
Standard Claimed for the Drug Substance (e.g., USP,

BP, etc.):
Test Method Source (e.g., Release Shelf Life

(e.g., HPLC) USP, in- Specification Specification (if
house) applicable)

S 4.2 Analytical Procedures (Drug Product Manufacturer)
S 4.3 Validation of Analytical Procedures (Drug Product Manufacturer)
For each test, please indicate yes or no as appropriate
Precision
- Reproducibility
- Intermediate
- Repeatability
Precision
Limit of Quantitation
Test Name
Method Description
System Suitability
Limit of Detection
(Please specify)
(as per S4.1)
Robustness
Selectivity
Or Others
Accuracy
Linearity
Range
S 4.2 Analytical Procedures (Drug Substance Manufacturer, if different from above)
S 4.3 Validation of Analytical Procedures (Drug Substance Manufacturer, if different from

above)

Precision
- Reproducibility
- Intermediate
- Repeatability
Precision
Test Name
Method Description
System Suitability
Limit of Detection
(Please specify)
(as per S4.1)

Robustness
Selectivity
Or Others
Accuracy
Linearity
Range

S 4.4 Batch Analyses
Typical production batch size:
Batch Type Date of

Batch Number Batch Size Site of Production
(pilot/production) Production
S 4.5 Justification of Specification

Test Justification of Specifications
S 5 REFERENCE STANDARDS OR MATERIALS

Drug Substance Batch Number Source (e.g., USP, in-house)

Primary Reference Standard
Working Standard
Impurities Batch Number Source (e.g., USP, in-house)

Working Standard
S 6 CONTAINER CLOSURE SYSTEM

Description of the container closure system(s) for the storage of the drug substance:
S 7 STABILITY
S 7.1 Stability Summary and Conclusions
Summary and discussion of all stability study results:

Proposed Production Batch Size (kg):
Batch Number Batch Size Date of Site of Manufacture Container Closure

Manufacture System
Storage Conditions Batch Number Completed Test Intervals

(C, % RH, light)
E.g. 0, 3, 6, 9, 12, 18, 24, 36 months
Proposed storage conditions and re-test period (or shelf life, as appropriate):
Container Closure System Storage Conditions Re-test Period Shelf Life
If applicable If applicable
S 7.2 Post-approval Stability Protocol and Stability Commitment

Stability protocol for commitment batches (if applicable):
Protocol Parameter Description

Number of batches and batch sizes
Tests and acceptance criteria
Container closure system(s)
Testing frequency
Storage conditions (and tolerances) of samples
Other
S 7.3 Stability Data

P DRUG PRODUCT
P 1 DESCRIPTION AND COMPOSITION OF THE DRUG PRODUCT
(1) Description of the Dosage Form:
Presence of Score Line: Yes / No (delete as appropriate)
(2) Composition, i.e., list of all components of the dosage form, and their amounts on a per unit basis
(including overages, if any):
Strength (Label claim):
Components Quality Standard Quantity per unit % Function
Total

(3) Composition, i.e., qualitative list of all components of proprietary materials (e.g., capsule shells,
colouring blends, imprinting inks, etc.):
Proprietary Material Qualitative Composition Quantitative Composition
(4) Description of accompanying reconstitution diluent(s), if applicable:
P 2 PHARMACEUTICAL DEVELOPMENT
P 2.1 Components of the Drug Product

P 2.2 Drug Product
P 2.2.1 Formulation Development

P 2.2.2 Overages
P 2.2.3 Physicochemical and Biological Properties

P 2.3 Manufacturing Process Development
Discussion of the development of the manufacturing process of the drug product (e.g., optimization of
the process, selection of the method of sterilization, etc.):

P 2.4 Container Closure System
Discussion of the suitability of the container closure system (described in P 7) used for the storage,
transportation (shipping), and use of the drug product (e.g., physicochemical tests, biological reactivity
tests, leaching, etc.):
P 2.5 Microbiological Attributes
Discussion of microbiological attributes of the dosage form (e.g., preservative effectiveness studies):
P 2.6 Compatibility
Discussion of the compatibility of the drug product with reconstitution diluent(s) or dosage devices (e.g.,
precipitation of drug substance in solution, sorption on injection vessels, etc.):
P 3 MANUFACTURE
P 3.1 Manufacturer(s)
production site or facility involved in manufacture and testing of product intended for Singapore:
Activity Name and Address
Site of Fabrication, Manufacturing
Site of Primary Packaging
Site of Secondary Packaging
P 3.2 Batch Formula
List of all components of the dosage form to be used in the manufacturing process, and their amounts
on a per batch basis (including overages, if any):

Batch Size (Number of dosage units):

Please provide batch formula for all proposed production batch sizes. If
a batch range is proposed, the minimum and maximum batch formula
should be provided.
Component Quality Standard (or Grade) Quantity per batch
Total
P 3.3 Description of Manufacturing Process and Process Controls

Flow diagram of the manufacturing process(es):
[insert diagram]
P 3.4 Controls of Critical Steps and Intermediates

P 3.5 Process Validation and/or Evaluation

Please check appropriate boxes.

Development Pharmaceutics Report Starting page #:
Ending page#:
Validation Scheme Starting page #:
Ending page#:
____ (e.g. 2) Pilot batches were used in the Starting page #:
validation study Ending page#:

Please check appropriate boxes.

____ (e.g. 3) full production batches were used in Starting page #:
the validation study Ending page#:
Type of Validation
Retrospective
Prospective
Concurrent*
Others; please specify:
* Prior consultation with HSA is required.
Manufacturing site at which the validation is carried out:

Product formula of validation batches: Same as section P.3.2
Yes
No, please provide justification
Batch Type
Batch Number Date of Production Batch Size
(production/pilot/experimental)
Post-Approval Commitment
(1) Validation protocol for commitment batches:
Number of batches per strength
Batch Size
P 4 CONTROL OF EXCIPIENTS
P 4.1 Specifications
Specifications for non-compendial excipients and for compendial excipients which include
supplementary tests not required by the monograph(s) may be found in:
P 4.2 Analytical Procedures


P 4.3 Validation of Analytical Procedures

P 4.4 Justification of Specifications
Justification of the specifications (e.g., evolution of tests, analytical procedures, and acceptance criteria,
exclusion of certain tests, differences from compendial standard, etc.):
P 4.5 Excipients of Human or Animal Origin

P 4.6 Novel Excipients

P 5 CONTROL OF DRUG PRODUCT
P 5.1 Specification(s)
Standard Claimed for the Drug Product

(e.g., USP, Ph.Eur, BP, JP etc.):
Test Method (e.g., Source (e.g., Release Shelf Life

HPLC) USP, In-house) Specification Specification


(e.g., USP, Ph.Eur, BP, JP etc.):
Test Method (e.g., Source (e.g., Release Shelf Life

HPLC) USP, In-house) Specification Specification

Precision
- Reproducibility
- Intermediate
- Repeatability
Precision
Test Name
Method Description
System Suitability
Limit of Detection
(Please specify)
(as per P5.1)
Robustness
Selectivity
Or Others
Accuracy
Linearity
Range
P 5.4 Batch Analyses
Date of Site of Site of Batch

Batch Number Batch Size Batch Type*
Production Production Release
* describe purpose of batch e.g. developmental, pilot, production, clinical, validation, commercial
P 5.5 Characterisation of Impurities

Information on the characterization of impurities, not previously provided in S 3.2 (e.g., summary of
actual and potential degradation products, basis for setting the acceptance criteria, etc):
Chemical Name/Laboratory Origin/Type of Impurity

Code
P 5.6 Justification of Specification(s)

P 6 REFERENCE STANDARDS OR MATERIALS
If the reference standard is a secondary standard (in house /working standard), evidence that the
secondary standard has been standardised against an official standard should be provided. Data of
studies performed on working standard against primary standard should be included, together with
appropriate Certificate of Analysis.

Working Standard

Working Standard
P 7 CONTAINER CLOSURE SYSTEM
Description of the container closure systems:
Description of Container Closure Quantity Per Container Pack Size

Description of Container Closure Quantity Per Container Pack Size
P 8 STABILITY
P 8.1 Stability Summary and Conclusions

Proposed Commercial Batch Size (kg):
Product formula of Stability Batches Same as section P.3.2

Yes
Batch Batch Size Date of Site of Source of Active Container
Number Manufacture Manufacture Ingredient and Closure
Batch Number System

(C, % RH, light)
E.g. 0, 3, 6, 9, 12, 18, 24, 36 months
In-use stability testing (where applicable):
In-use Storage Conditions Length of Storage prior to Start Completed In-use Test Intervals
(C, % RH, light) of In-use Stability Testing (e.g. minutes/ hours/ days)

Proposed storage conditions and shelf life:
Container Closure System Storage Conditions (with In-use Shelf Life (with In-use Period,
Storage Conditions, if applicable) if applicable)
P 8.2 Post-Approval Stability Protocol and Stability Commitment

(1) Stability protocol for commitment batches:
Number of batches per strength and batch

sizes
Testing frequency
Other
(2) Stability protocol for continuing (i.e., ongoing) batches:
Number of batches per strength per year and

batch sizes
Testing frequency
Other
P 8.3 Stability Data


P 9 PRODUCT INTERCHANGEABILITY
P 9.1 Bioavailability / Bioequivalence Study
Generic Product Submitted to Current Registered

HSA for Registration Singapore Reference
Product
Product Name
Strength of Dosage Form
Site of Manufacture
Site of Batch Release N/A
Details of BA/BE Study:

Study Report Number
BA/BE Study Site (Name & Address)
Date of Inspection of Study
Name of Inspecting Agency/Authority
Availability of Inspection Report (Yes/No)
Generic Product Used Reference Product Used
in BA/BE Study in BA/BE Study
Product Name
Site of Manufacture
Site of Batch Release N/A
Country where the supply is
sourced for this study:
Batch No.
Batch size N/A
Product formula Same as section P.3.2 N/A
Yes
P 9.2 Comparative Dissolution Profile


State the Product Name & strength, batch number and either BE/SIN reference product or generic
product.
Product 1: =
Product 2: =
Study Report Number:

Profile of Product 1 Profile of Product 2
Product Name
Site of Manufacture
Country where the supply is
sourced for this study:
Description of Dissolution e.g. USP paddle 1, 900mL, 50rpm
Method Used
Dissolution Test Profile of Product 1 Profile of Product 2

Results *0min 15min 30min 45min 60min 0min 15min 30min 45min 60min
Medium 1
Range
Mean of 12 tablets
RSD
F2 Calculation
Medium 2
Range
Mean of 12 tablets
RSD
F2 Calculation
Medium 3
Range
Mean of 12 tablets
RSD
F2 Calculation
Location of
Dissolution Graphs
*Please revise the table accordingly to suit the number of testing time intervals used.

A APPENDICES
A 1 FACILITIES AND EQUIPMENT (NAME, MANUFACTURER)

A 2 ADVENTITIOUS AGENTS SAFETY EVALUATION (NAME, DOSAGE FORM, MANUFACTURER)

A 3 NOVEL EXCIPIENTS

Applicants Name: Date:

SINGAPORE QUALITY OVERALL SUMMARY FOR BIOLOGICS
APPENDIX 9 SINGAPORE QUALITY OVERALL SUMMARY

New Drug Applications (Biologics)
The Quality Overall Summary (QOS) should be completed to summarize the Quality (i.e.,
Chemistry, Manufacturing and Controls) portion of a New Drug Application (NDA) for a biologic
drug product. Both hard copy and electronic copy of the Singapore QOS shall be submitted for
review.
The applicant is responsible for completing all sections and fields. Sections and fields that are not
applicable should be indicated with NA. An explanatory note must accompany all NA entries.
INTRODUCTION
Proprietary Name of Drug Product
Non-Proprietary or Common Name of

Drug Substance
Product Owner Name
License Holder Name
Dosage Form
Strength(s)
Route of Administration
Proposed Indication(s)
Application Type E.g. NDA-1, NDA-2, NDA-3, GDA-1, GDA-2 etc
Other introductory information:

Description of the dosage form: E.g. white, scored, round tablet
Container Closure System:
Shelf Life:
Storage Condition:
Others:

S DRUG SUBSTANCE
S 1 GENERAL INFORMATION
Check appropriate box.

CEP (Certificate of Suitability from EDQM) for Raw materials and Excipients is
attached.
Plasma Master File (PMF)
Site Master File (SMF)
Drug Substance meets in-house specifications. Analytical methods and appropriate
analytical method validation data are included in the dossier.
S 1.1 Nomenclature

Substance Name:
Other names:
(e.g. INN, BAN, USAN, common name)
Company or laboratory code:
S 1.2 Structure

Schematic amino acid sequence indicating

glycosylation sites or other post-translational
modifications and relative molecular mass
should be provided, as appropriate:
S 1.3 General Properties

Physicochemical and other relevant properties of

the drug substance, including biological activity
S 2 MANUFACTURE
S 2.1 Manufacturer(s)

Name and address, of each production site or facility involved in different manufacture and testing
activities:
2.1.1 Drug Substance Manufacture
2.1.2 Process Intermediates Manufacture

(e.g. Master or Working Cell Bank)
2.1.3 Pilot/ Development Batches

Manufacture
2.1.4 Testing of Process Intermediates and
Drug Substance Release
2.1.5 Stability Study
2.1.6 Others (if applicable, please specify)
S 2.2 Description of Manufacturing Process and Process Controls

Flow diagram of the manufacturing process:
[insert diagram]
S 2.3 Control of Materials

S 2.4 Controls of Critical Steps and Intermediates

S 2.5 Process Validation and/or Evaluation


S 2.6 Manufacturing Process Development

S 3 CHARACTERISATION
S 3.1 Elucidation of Structure and other Characteristics

S 3.2 Impurities
(1) Product-Related Impurities:

Name Description Control Method* & Acceptance Level
* Please indicate if it is controlled by in-process control test, product release test, or by validated purification
method.
(2) Process-Related Impurities:

Human plasma derived materials
Name Origin / Point of Entry Control Method* & Acceptance Level
Animal derived materials

Other materials
* Please indicate if it is controlled by in-process control test, product release test, or by validated purification
method.

S 4 CONTROL OF THE DRUG SUBSTANCE
S 4.1 Specification
Standard Claimed for the Drug Substance (e.g., USP, BP,

etc.):
Test Method Source/Ref # Release Shelf Life

(e.g., HPLC) or SOP #) Specification Specification (if
applicable)
Copy of official Drug Substance Release Specifications


S 4.2 Analytical Procedures
S 4.3 Validation of Analytical Procedures

Test Name (as
Precision
- Reproducibility
- Intermediate
- Repeatability
Precision
Method Description
System Suitability
Limit of Detection
per S4.1)
(Please specify)
Quantification
Robustness
Selectivity
Or Others
Accuracy
Linearity
Limit of
Range

S 4.4 Batch Analyses
Typical production batch size:
Batch Type Date of

Batch Number Batch Size Site of Production
(pilot/production) Production
S 4.5 Justification of Specification

S 5 REFERENCE STANDARDS OR MATERIALS


Working Standard

Working Standard

S 6 CONTAINER CLOSURE SYSTEM

Description of the container closure system(s) for the storage of the drug substance:
S 7 STABILITY
S 7.1 Stability Summary and Conclusions
Summary and Discussion of All Stability Study Results:

Proposed Production Batch Size (kg):
Batch Number Batch Size Date of Site of Manufacture Container Closure

Manufacture System

(C, % RH, light)
E.g. 0, 3, 6, 9, 12, 18, 24, 36 months
Proposed storage conditions and re-test period (or shelf life, as appropriate):
Container Closure System Storage Conditions Re-test Period Shelf Life
If applicable If applicable

S 7.2 Post-approval Stability Protocol and Stability Commitment


Number of batches and batch sizes
Testing frequency
Other
S 7.3 Stability Data

P DRUG PRODUCT
P 1 DESCRIPTION AND COMPOSITION OF THE DRUG PRODUCT
(1) Description of the Dosage Form (Type of container closure system used for the dosage
form and accompanying reconstitution diluent, if applicable):
(2) Composition (i.e., list of all components of the dosage form, and their amounts on a per unit
basis including overages):
Component Quality Standard Quantity per unit Function
(incl. overages)
Drug Substance
Excipients (Human Plasma Derived)

Excipients (Animal Derived)
Excipients (Others)
Residuals
(note: all residual materials listed here must be stated in the PI. Refer to Appendix 6.)
Reconstitution Diluents
P 2 PHARMACEUTICAL DEVELOPMENT
P 2.1 Components of the Drug Product

P 2.2 Drug Product
P 2.2.1 Formulation Development

P 2.2.2 Overages
P 2.2.3 Physicochemical and Biological Properties


Active Substance Structure Comparability with Singapore Reference Product

(applicable only for Biosimilar products)
Active Substance Name: Singapore Reference Product Name:
Site of Manufacture: Site of Manufacture:
Batch Number Batch Number:

(pilot/production):
Types of experiments used for structure comparison:
Final Product Comparability

(applicable only to Biosimilar products)
Biosimilar Product Submitted to HSA for Singapore Reference Product Name:
Registration:
Site of Manufacture: Site of Manufacture:
Batch Number. Batch Number:

(pilot/production):
Types of Bioassays used for drug product comparability:
Batch(es) used for Final Product Comparability is the same batch used in Clinical Studies
Submitted
Yes, please provide batch number(s):
P 2.3 Manufacturing Process Development
Discussion of the development of the manufacturing process of the drug product

(e.g., optimization of the process, selection of the method of sterilization, etc.):

P 2.4 Container Closure System
Discussion of the suitability of the container closure system (described in P 7) used for the
storage, transportation (shipping), and use of the drug product and reconstitution diluent (e.g.,
physicochemical tests, biological reactivity tests, leaching, etc.):
P 2.5 Microbiological Attributes
Discussion of microbiological attributes of the dosage form where applicable (e.g., preservative
effectiveness studies):
P 2.6 Compatibility
Discussion of the compatibility of the drug product with reconstitution diluent(s) or dosage
devices (e.g., precipitation of drug substance in solution, sorption on injection vessels, etc.):
P 3 MANUFACTURE
P 3.1 Manufacturer(s)
3.1.1 Drug Product Manufacture
3.1.2 Process Intermediates (e.g. Drug

Product bulk) Manufacture (if different
from 3.1.1)
3.1.3 Pilot/ Development Batches
Manufacture (if different from 3.1.1)
3.1.4 Testing for Process Intermediates and

Drug Product Release (if different from
3.1.1)
3.1.5 Stability Study (if different from 3.1.1)

3.1.6 Others (if applicable, please specify)
P 3.2 Batch Formula
List of all components of the dosage form to be used in the manufacturing process, and their
amounts on a per batch basis (including overages, if any):
Batch/ Lot Size (Number of dosage units):

Please provide batch formula for all proposed production batch
sizes. If a batch range is proposed, the minimum and maximum
batch formula should be provided.
Component Quality Standard (or Grade) Quantity per batch
Total
P 3.3 Description of Manufacturing Process and Process Controls

Flow diagram of the manufacturing process(es):
[insert diagram]
P 3.4 Controls of Critical Steps and Intermediates


P 3.5 Process Validation and/or Evaluation

Manufacturing site at which the validation is carried out:

Product formula of validation batches: Same as section P.3.2
Yes
Batch Type
Batch Number Date of Production Batch Size
(production/pilot/experimental)
Post-Approval Commitment
(1) Validation protocol for commitment batches:
Number of batches per strength
Batch Size
P 4 CONTROL OF EXCIPIENTS
P 4.1 Specifications
supplementary tests not required by the monograph(s):



P 4.4 Justification of Specifications
Justification of the specifications (e.g., evolution of tests, analytical procedures, and

acceptance criteria, exclusion of certain tests, differences from compendial standard, etc.):
supplementary tests not required by the monograph(s).
P 4.5 Excipients of Human or Animal Origin
Information regarding adventitious agents for excipients of human or animal origin (e.g.,
sources, specifications, description of the testing performed, viral safety data):
P 4.6 Novel Excipients

P 5 CONTROL OF DRUG PRODUCT
P 5.1 Specification(s)

(e.g., USP, Ph.Eur, BP, JP, In-house etc.):
Test Method (e.g., Source/Ref # Release Shelf Life

HPLC) or SOP # Specification Specification


(e.g., USP, Ph.Eur, BP, JP, In-house etc.):
Test Method (e.g., Source/Ref # Release Shelf Life

HPLC) or SOP # Specification Specification
Copy of Official Drug Product Release Specifications:


For each test, please indicate yes or no as appropriate Precision
- Reproducibility
- Intermediate
- Repeatability
Precision
Test Name
Method Description
System Suitability
Limit of Detection
(Please specify)
(as per P5.1)
Robustness
Selectivity
Or Others
Accuracy
Linearity
Range
P 5.4 Batch Analyses
Date of Site of Site of Batch

Batch Number Batch Size Batch Type*
Production Production Release
* describe purpose of batch e.g. developmental, pilot, production, clinical, validation, commercial

P 5.5 Characterisation of Impurities
Information on the characterization of impurities, not previously provided in S 3.2 (e.g., summary
of actual and potential degradation products, basis for setting the acceptance criteria, etc):
P 5.6 Justification of Specification(s)

P 6 REFERENCE STANDARDS OR MATERIALS
If the reference standard is a secondary standard (in house /working standard), evidence that the
secondary standard has been standardised against an official standard should be provided. Data
of studies performed on working standard against primary standard should be included, together
with a Certificate of Analysis.

Working Standard

Working Standard
P 7 CONTAINER CLOSURE SYSTEM


Container Closure System Quantity per Container Pack Size
P 8 STABILITY
P 8.1 Stability Summary and Conclusions
(1) Summary and Conclusions:

(2) Stability Study Details:

Proposed Commercial Batch Size (e.g.
kg, litres) :
Product formula of Stability Batches Same as section P.3.2
Yes
Batch Batch Size Date of Site of Source of Drug Container

Number Manufacture Manufacture Substance and Closure
Batch number System

(C, % RH, light)
E.g. 0, 3, 6, 9, 12, 18, 24, 36 months

In-use stability testing (where applicable):
In-use Storage Conditions Length of Storage prior to Completed In-use Test Intervals
(C, % RH, light) Start of In-use Stability (e.g. minutes/ hours/ days)
Testing
(3) Proposed Storage Conditions and Shelf Life:
Container Closure System Storage Conditions (with In-use Shelf Life (with In-use
Storage Conditions, if applicable) Period, if applicable)
P 8.2 Post-Approval Stability Protocol and Stability Commitment

(1) Stability Protocol for Commitment Batches:
Number of batches per strength and batch sizes
Testing frequency
Other
(2) Stability Protocol for Continuing (i.e., ongoing) Batches:
Number of batches per strength per year and

batch sizes

Testing frequency
Other
P 8.3 Stability Data

A APPENDICES
A 1 FACILITIES AND EQUIPMENT (NAME, MANUFACTURER)

A 2 ADVENTITIOUS AGENTS SAFETY EVALUATION (NAME, DOSAGE FORM,

MANUFACTURER)

A 3 NOVEL EXCIPIENTS

Applicants Name: Date:

GUIDELINE ON THE REGISTRATION OF HUMAN PLASMA-DERIVED MEDICINAL PRODUCTS
APPENDIX 10 GUIDELINE ON THE REGISTRATION OF HUMAN PLASMA-

DERIVED MEDICINAL PRODUCTS
This guideline1 is applicable to all plasma-derived medicinal products containing an active

or inactive ingredient that is derived from human blood. Because such products carry the
risk of transmission of infectious agents, the safety of these products is assured through
the requirements as described in this Appendix along with the main guidance document.
Applications for human plasma-derived medicinal products will be evaluated on its quality,
safety and efficacy prior to marketing. This guideline outlines the requirements for the
Plasma Master File (PMF) and specific quality documentation to support registration of
these products.
Documents pertaining to the collection and control of source materials should be provided
as a standalone PMF. One set of the PMF and the checklist in Annex 1 of this Appendix
should be submitted together with the dossier application for registration of a human
plasma-derived product. Reference to the relevant PMF/s may be made in the following
sections of the dossier.
i. CTD section 3.2.S.2.3 if the PMF relates to a drug substance; or,

ii. CTD section 3.2.R.1 (ICH CTD) or 3.2.Q.1 (ACTD) if the PMF relates to an
excipient.
1.1 Body of Data Drug Substance
1.1.1 Plasma Master File
The plasma master file is a standalone document and it should be filed separately from
the application. When the information on plasma collection and control is available as part
of the CTD dossier, this section of the dossier should be filed as a separate standalone
document.
Once a plasma master file / a dossier section on plasma collection and control
information is received as a separate standalone document a PMF number will be
assigned to the document.
Note that for plasma collection and control information previously submitted as part of
3.2.S.2.3 section of the dossier, the following information covering the data requirements
as per the PMF Data Requirements section of this Appendix should be submitted as a
standalone document:
Plasma source and collection
Characteristics of donations
Epidemiological data on blood transmissible infections.
Selection / exclusion criteria
Plasma quality and safety
Conditions of storage and transport of plasma
A copy of the plasma specification and plasma pool batch analysis data.
1
Adapted from CPMP NfG on Plasma-derived Medicinal Products (CPMP/BWP/269/95 rev. 3) and US FDA
Guidance for Industry for the Submission of Chemistry, Manufacturing and Controls and Establishment
Description Information for Human Plasma-derived Biological Products, Animal Plasma and Serum-derived
Products

However, if the source of the plasma-derived ingredient(s) is from a third-party supplier,

then it is the applicants responsibility to procure the PMF from the PMF holder for
submission to HSA. The applicant may also cross-reference a currently registered PMF to
the application, where applicable. Reference to more than one PMF is possible and
should be clearly indicated in the dossier.
Applicants are responsible to maintain and update the PMF every two years.
PMF Data Requirements
The checklist in Annex 1 of this Appendix may serve as a guide to the documentary
requirements for registration of human plasma-derived medicinal products and should be
submitted with the PMF.
The data must conform to the requirements recommended by HSAs reference drug
regulatory agencies and in particular, the following documents and their subsequent
revisions:
Note for Guidance on Plasma-Derived Medicinal Products (CPMP/BWP/269/95 rev.
4);
Guideline on the Scientific Data Requirements for a Plasma Master File (PMF)
(CPMP/BWP/3794/03);
Annexes to Guideline on the Scientific Data Requirements for Plasma Master File
(PMF).
The PMF document requirements include:
a) Documents that verify each donor of source material has undergone a proper
screening procedure and has met all established health criteria (including viral risks
requirements). The criteria used must conform to the recommendations on suitability of
blood and plasma donors set out by the US FDA, the Council of Europe and the
Australian TGA. The following details need to be provided:
i Collection centres
Names and addresses of blood/plasma collection centres, including sub-
contractors and any separate site for testing of individual donations; and,
Audits:
- Internal audits (frequency and date of last audit); and,
- Audits by regulatory authority (frequency and date of last audit).
ii Data on epidemiology and blood-borne infections

Provide an assurance that there is a continuing evaluation of the epidemiology at
collection centres; and,
Data should be reported as:
- Incidence of confirmed seroconversion rates in regular donors (per number of
donors and number of donations); and,
- Prevalence of confirmed positives in new donors and known donors.
iii Selection/Exclusion criteria

Characteristics of donation:
- Indicate whether or not a plasma donor is remunerated;
- Clarify the nature of any compensation for donation; and,
- Outline the nature of the examination and interview of donors; and,
Exclusion criteria for donors:

- Confirm that centres do not collect blood/plasma from a population with a high
prevalence of infections transmitted by blood (HIV, HCV, HBV etc.);
- Confirm that there are measures taken to ensure viral safety for recipients
with respect to major pathogenic agents; and,
- Compliance with those exclusion criteria specified in appropriate documents
(Directives, Guidelines, Pharmacopoeial).
b) Documents that verify each unit of source material has been tested non-reactive for
Hepatitis B surface antigen, anti-HIV-1&2 by NAT, anti-HCV by NAT and other test
parameters as recommended by US FDA or an equivalent authority. There must be no
pooling of plasma for testing purposes. The following details need to be provided:
i Screening tests for markers of infection:

List of tests performed on individual donation;
Licence number for each test kit used;
Validation of these screening procedure methods; and,
Details of any inventory hold/ quarantine periods and procedures.
c) Documents that verify all steps in the processing of source material, including donor
examination, blood collection, plasmapheresis, laboratory testing, labelling, storage,
and issuing, are performed in centres that have been licensed by the US FDA or
equivalent authority for that purpose. The centres must conform to the requirements
for the collection of source materials as specified in The Collection, Fractionation,
Quality Control, And Uses of Blood and Blood Products published by the WHO. The
following details need to be provided:
i. System to trace the path of any donation:

Confirm that there is a system in place that ensures traceability from the
donation centre to finished product and vice versa; and,
Provide information on steps that would be taken if it is found retrospectively that
the donation(s) should have been excluded from processing.
d) Documents that verify all source materials are collected by aseptic techniques
designed to assure the integrity and minimise the risk of contamination of the source
material. The documents should also verify that the closure of the container used
maintains a hermetic seal. The following details need to be provided:
i. Blood bags
Information on the name of bag, manufacturer, anticoagulant solution,
composition and specification; and,
Indication on conformance to a particular standard (e.g. WHO, Ph. Eur.).
ii. Plasma quality

Information on storage conditions and maximum storage time with an indication
on how conditions are maintained from collection centre to the manufacturer;
and,
Confirmation of compliance with appropriate standard.
iii. Plasma specification

Information on specification(s) and confirm compliance to specification(s); and,
Information on in-process tests on the plasma pool, if any.
e) Documents that verify that the source materials do not contain an additive other than
citrate or acid citrate dextrose anticoagulant solution, unless it has been shown that
the processing method yields a final product free of the additive to such an extent that

the continued safety, purity, potency, and effectiveness of the final product is not
adversely affected.
f) Documents that verify the fractionator/manufacturer and donation centre(s)/

organisation responsible for collecting plasma complies with PIC/S GMP and
procedures.
g) Letter of commitment from the Manufacturer stating that:
i. All collection centres have signed the contract; and,

ii. The national authority will be notified in the event of a serious failure of a blood
collection centre.
1.1.2 Intermediates
An intermediate plasma fraction (intermediate) is partially fractionated starting material

which must undergo further manufacturing steps before it becomes a bulk product or final
product. Intermediates, commonly used for further processing into a final product, are
fractions recovered from the process for the production of clotting factors (e.g. cryopaste)
or from the production process of immunoglobulins or albumin (e.g. fractions II, III, IV, V),
and may be prepared and stored by the product manufacturer or obtained from another
supplier (e.g. a contract manufacturer).
The collection and control of starting materials for the production of an intermediate
plasma fraction are important factors in the assurance of its quality. Information up to and
including the production of the plasma pool should be provided in the Plasma Master File
or in part 3.2.S of the dossier. This information should be provided to the manufacturer of
the finished product. A contract should be established between the supplier of the
intermediate and the manufacturer of the finished product. This contract should address
information from the manufacturing process, traceability and specifications of the plasma
and the intermediate, and the storage and transport of the intermediate. The Marketing
Authorisation Holder/applicant has final responsibility for the quality and safety of the
medicinal product.
1.1.3 Manufacturing Process and Control
Data requirements for plasma derived medicinal product should be documented as

described under various sections of the guidance documents (latest versions) listed
below:
Collection, Processing & Control:
WHO Recommendations for the Production, Control and Regulation of Human
Plasma for Fractionation.
WHO Requirements for the collection, processing and quality control of blood, blood
components and plasma derivatives. WHO Technical Report Series No. 840, Annex
2
Revision of the Note for guidance on Plasma-Derived Medicinal Products.
Viral Inactivation:
WHO Guidelines on viral inactivation and removal procedures intended to assure
the viral safety of human blood plasma products. Technical Report Series (TRS)
No. 924, Annex 4 (Adopted by ECBS 2001)
Quality of Biotechnological Products: Viral safety Evaluation of Biotechnology
Products derived from Cell Lines of Human or Animal Origin.

Virus Validation Studies: The Design, Contribution and Interpretation of Studies

validating the Inactivation and Removal of Viruses.
The following data should be filed in various 3.2.S sections of the CTD :
a) Documents that verify all steps in the manufacture of the final product are conducted in
establishments licensed by the US FDA or equivalent authority for that purpose. All
handling and processing techniques employed should conform with current relevant
international GMP guidelines of the US FDA, the Australian TGA, the EMEA CHMP or
WHO.
b) Documents that verify each batch of source material intended for manufacture has
been tested for Hepatitis B surface antigen, antibody to HIV-1&2 and antibody to
Hepatitis C Virus by tests approved for such use by the US FDA or an equivalent
authority. Each batch of source material must also be tested for HCV RNA by genomic
amplification testing. The following details need to be provided:
i. Plasma pooling
Information on the number of individual plasma units pooled together;
List of tests performed on these plasma pools; and,
Licence number for each test kit used.
c) Documents that verify the processing method used does not affect the integrity of the
product and has been demonstrated to consistently yield a product that is safe for use
in humans. Processing methods used for the manufacture of intravenous products
should have been shown to consistently yield a product that is safe for intravenous
injection.
d) Documents that verify processing steps are conducted to minimise risk of

contamination from pyrogens, micro-organisms, or other impurities. Preservatives to
inhibit growth of micro-organisms should not be used or added to the product at any
stage of processing. The following details need to be provided:
i. Manufacturing process
A detailed description of the manufacturing process and controls to demonstrate
proper quality control or prevention of possible contamination with adventitious
agents:
- Starting materials: Information on raw materials, intermediate products,
reagents and auxiliary materials with specifications or statements of quality of
each;
- Flowchart: A complete visual representation of the manufacturing process
flow. This flow should show the production steps, equipment, and materials
used, along with a complete list of the in-process controls and tests performed
on the product at each step. This diagram should also include information on
the methods used to transfer the product between steps;
- Detailed description: A detailed description of the fractionation, formulation,
sterilisation, purification and aseptic processes. This should include a
rationale for the chosen methods, and the precautions taken to assure
containment and prevention of contamination or cross-contamination. In-
process bioburden and endotoxin limits should be specified where
appropriate. Any reprocessing or related method should be fully validated and
described. The allowable conditions for reprocessing of all or parts of any
batch should be described; and,
- Batch record: A complete batch record of the process of production of the
biologic product should be included.

ii. Process control

A description of the control checks performed at various stages of the
manufacture, processing and packaging of the product;
A description of the in-process and final controls, including analytical tests and
appropriate data to support the specifications; and,
Validation data:
- A description of the validation studies, which identify and establish acceptable
limits for critical parameters to be used as in-process controls, to assure the
success of routine production;
- Validation studies for the purification process: a description of the validation of
the purification process to demonstrate adequate removal of extraneous
substances such as chemicals used in purification, column contaminants,
endotoxin, antibiotics, residual plasma proteins, non-viable particulates and
viruses; and,
- Validation studies for all sterilisation and aseptic processes (e.g. formulation
through filling and sealing).
iii. Notes on process steps for inactivation and removal of viruses

Procedures specifically designed to inactivate or remove infectious viruses
should be clearly defined, justified and documented. In addition, recent
transmissions of both enveloped and non-enveloped viruses by certain plasma-
derived products have highlighted the need for a strategy to further increase the
assurance of viral safety of these products;
When necessary, a viral risk assessment should be performed via calculation of
the estimated risk per dose, as outlined in the Guideline on Assessing the Risk
for Virus Transmission New Chapter 6 of the Notes for Guidance on Plasma-
derived Medicinal Products (CHMP/BWP/5180/03). The risk assessment should
demonstrate that the virus inactivation/removal capacity clearly exceeds the
potential amount of virus that could enter the production process;
The following document, and its subsequent revisions, should also be referred:
- Note for Guidance on Virus Validation Studies: The Design, Contribution and
Interpretation of Studies Validating the Inactivation and Removal of Viruses
(CPMP/BWP/268/95); and,
The following notes are provided as a general guide:
- Albumin (Human Solution and Plasma Protein Fraction [Human] Solution)
the product must have undergone heat treatment or other established viral
inactivation procedures. Heat treatment should be conducted so that the
solution is heated continuously for not less than 10 or more than 11 hours at
an attained temperature of 60 0.5oC.
- Clotting Factor Concentrate, Intravenous Immunoglobulin and Intramuscular
Immunoglobulin the product must have undergone processing methods that
include established and validated specific viral inactivation capable of
inactivating at least 105 infectious particles of HIV per mL of solution (i.e. a 5
log10 reduction in concentration of viable virus), and not to transmit viral
hepatitis.
1.2 Body of Data Drug Product
The following data should also be filed in the various 3.2.P sections of the CTD (Module 3
of ICH CTD or Part 2 of ACTD).

The physical, chemical and pharmaceutical properties of the finished product must
comply with the relevant United States, British or European Pharmacopoeial
requirements. The following details need to be provided:
a) Product testing
i. Specifications and analytical methods used for release testing and expiration
dating to assure product identity, purity, strength, or potency and lot-to-lot
consistency;
ii. Validation protocol and results for non-compendial analytical systems to
demonstrate system suitability;
iii. Lot release protocols, including specification ranges of representative lots of the
product. Specifications may include, but not limited to, biochemical purity, safety,
appearance, pH, residual moisture, excipients, endotoxins, and sterility; and,
iv. Methods and standards of acceptance, including the sampling plan and the
accuracy and precision of the analytical methods in sufficient detail to permit
duplication and verification.
b) Container closure system/shipping containers

i. A description of the container and closure system with information on its
compatibility with the biological substance; and,
ii. Evidence of container and closure integrity.
c) Stability
i. Stability data for the product as packaged in the registered container closure
system;
ii. A description of the storage conditions, study protocols and results supporting the
stability of the product and any intermediates that are stored;
iii. An expiration date supported by the results of the stability study; and,
iv. When used as an excipient in medicinal products, the expiry date of the plasma-
derived product should not be earlier than that of the finished product. It is
recommended that the manufacturers have a system in place to maintain
traceability and notifications regarding post-collection information.
v. The package insert should include warning statements as per Note for Guidance
on the warning on transmissible agents in summary of product characteristics and
package leaflets for plasma derived medicinal products.
2 REGULATORY DECISION
When approved for registration, the product licence issued for a human plasma-derived
medicinal product will have the following post-approval conditions:
a) The import and sale of the product must be accompanied by a batch certification. The
batch certification and product movement records shall be maintained for 10 years
from the date of importation and be made available for inspection by HSA when
required.
b) The Product Licence Holder is responsible for ensuring that the product imported for
local sale and supply is identical, in all aspects, to that approved by HSA. The licence
holder should notify HSA of minor variations and obtain approval before
implementation as stipulated in Appendix 16 of the Guidance of Medicinal Product
Registration in Singapore.

3 PLASMA MASTER FILE LIFE CYCLE MANAGEMENT
Applicants are responsible for keeping the PMF updated. The updates are to be
submitted every two years. The biannual update does not require submission via PRISM
the update should be sent to the Generics & Biosimilar Branch of HSA with reference to
the assigned PMF number.
If a new Plasma Master File is submitted in support of a currently-registered drug product,

the inclusion should be filed as an MIV-1 application refer to Part D of Appendix 16 for
further details.
If a currently-registered PMF contains an update or amendment which affect the

properties of the drug product, then the update/amendment should be filed as an MIV-1
application refer to Part D of Appendix 16 for further details.
If a currently-registered PMF contains an update or amendment which does not affect the
properties of the drug product, but
i. the update/amendment is a significant change (e.g. significant changes to the
plasma processing), then the update should be submitted as soon as it is made
known; OR,
ii. the update/amendment is not a significant change (e.g. a change of collection
centres), then it can be submitted as part of the biannual update.
Please note that, in case of significant changes implemented before the next biannual
update, only the affected sections need to be submitted.

ANNEX 1 CHECKLIST FOR THE REGISTRATION OF HUMAN PLASMA-DERIVED

MEDICINAL PRODUCTS
Appendix Yes/No
Document
Section (Encl. #)
1.1.1 Plasma Master File
1.1.1 (a) Documents that verify each donor of source material has
undergone a proper screening procedure to ensure that all
established health criteria (including viral risks requirements) are
met.
1.1.1 (a) (i) Details on collection centers
1.1.1 (a) (ii) Data on epidemiology and blood-borne infections
1.1.1 (a) (iii) Selection/ Exclusion criteria
1.1.1 (b) Documents that verify each unit of source material has been tested
non-reactive for Hepatitis B surface antigen, Anti-HIV-1 & 2 and
Anti-HCV.
1.1.1 (b) (i) Details of screening tests for markers of infection
1.1.1 (c) Documents that verify all steps in the processing of source
materials are performed in licensed centres that conform to WHOs
requirements.
1.1.1 (c) (i) Look back system to trace the path of any donation
1.1.1 (d) Documents that verify all source materials are collected by aseptic
techniques designed to assure the integrity and to minimise the
risk of contamination of the source material and that the closure of
the container used maintains a hermetic seal.
1.1.1 (d) (i) Blood bags
1.1.1 (d) (ii) Plasma quality
1.1.1 (d) (iii) Plasma specification
1.1.1 (e) Documents that verify source materials do not contain any additive
other than citrate or acid citrate dextrose anticoagulant solution
unless it has been shown that the processing method yields a final
product free of the additive to such an extent that the continued
safety, purity, potency and effectiveness of the final product is not
adversely affected.
1.1.1 (f) Documents that verify fractionator/ manufacturer and donation
centre(s)/organisation responsible for collecting plasma complies
with PIC/S GMP and procedures.
1.1.1 (g) a) Manufacturers letter of commitment.
1.2.1 Manufacturing Process and Control
1.2.1 (a) Documents that verify all steps in the manufacture of the final
product are conducted in licensed establishments for that purpose.
All handling and processing techniques employed should conform
to current relevant international GMP guidelines.

Appendix Yes/No
Document
Section (Encl. #)
1.2.1 (b) Documents that verify each batch of source material intended for
manufacture has been tested for hepatitis B surface antigen,
antibody to HIV-1 & 2, antibody to Hepatitis C Virus, and HCV
RNA.
1.2.1 (b) (i) Details of plasma pooling
1.2.1 (c) Documents that verify the processing method used does not affect
the integrity of the product and has been demonstrated to
consistently yield a product. Processing methods used for the
manufacture of products intended for IV use should have been
shown to consistently yield a product that is safe for IV injection.
1.2.1 (d) Documents that verify processing steps are conducted to minimise
risk of contamination from pyrogens, microorganisms, or other
impurities. Preservatives to inhibit growth of microorganisms are
not used of added to the product at any stage of processing.
1.2.1 (d) (i) Details of the manufacturing process
1.2.1 (d) (ii) Details of process control
1.2.1 (d) (iii) Details of assessing the risk for viral transmission
1.2.2 Drug Product
1.2.2 Statement on whether the physical, chemical and pharmaceutical
properties of the finished products comply with the relevant United
States, British or European Pharmacopoeial requirements.
1.2.2 (a) Details of product testing
1.2.2 (b) Details of container closure system/shipping containers
1.2.2 (c) Stability data

GUIDELINE ON THE REGISTRATION OF HUMAN MEDICINAL PRODUCTS CONTAINING
MATERIALS OF ANIMAL ORIGIN
APPENDIX 11 GUIDELINE ON THE REGISTRATION OF HUMAN MEDICINAL

PRODUCTS CONTAINING MATERIALS OF ANIMAL ORIGIN
Medicinal products containing animal-derived components carry the potential risk of

Transmissible Spongiform Encephalophathy (TSE). The safety of these products is
assured through the requirements as described in this appendix along with the main
guidance document.
This guideline1 is applicable to all medicinal products containing an ingredient, whether

active or inactive, that is derived from animals. It applies to all materials of animal origin
that are used in the preparation of both active (e.g. insulin) and inactive ingredients (e.g.
gelatin, cell culture medium), and any other reagent that may come into contact with a
pharmaceutical product during its manufacturing process (e.g. cell culture serum and
enzymes).
Transmissible Spongiform Encephalopathy (TSE)
Transmissible Spongiform Encephalopathy (TSE) is a group of degenerative brain

diseases that includes scrapie in sheep and goats, Chronic Wasting Disease (CWD) in
deer and elk, Bovine Spongiform Encephalopathy (BSE) in cattle and Kuru Creutzfeldt-
Jakob Disease (CJD) and Variant Creutzldt-Jacob Disease in humans. Agents causing
these diseases replicate in infected individuals generally without evidence of infection
detectable by currently available diagnostic tests. There is evidence to show that these
agents may have incubation periods of up to several years before causing observable
disease (usually neurological disorder) and eventually death. There is currently no
treatment or vaccine for the disease.
BSE is a food borne infection characterised by the presence of prion proteins, abnormal
infectious proteins in nervous tissue. The subsequent spongy degeneration of the brain
results in severe and fatal neurological signs and symptoms. There is evidence
suggesting that the new variant of human Creutzfeldt-Jakob Disease (vCJD) may be
caused by the same agent that is responsible for BSE in cattle.
The discovery of vCJD has raised concerns that the BSE agent can be transmitted to
humans. Therefore caution is warranted if biological materials from animals known to be
affected by TSE are used in the manufacture of medicinal products.
Applications for medicinal products containing animal-derived materials will be evaluated

on its quality, safety and efficacy prior to marketing. Documents with detailed information
must be submitted to support the registration of all the medicinal products that contain
animal-derived ingredients.
The checklist in Annex 1 may serve as a guide to the documentary requirements, which
are further described below in sections 1.1 and 1.2. The completed checklist in Annex 1 is
to be submitted in CTD section 3.2.P.4.5 with the supporting documents submitted in ICH
CTD section 3.2.A.2 or ACTD section Q.A.2.
1
Adapted from CPMP-CVMP NfG on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy
Agents via Human and Veterinary Medicinal Products (EMEA/410/01 Rev. 2)

1.1 Products Containing Animal-Derived Materials WITH a valid TSE risk

evaluation Certificate of Suitability (CEP)
Preference is accorded to animal-derived materials that have been awarded Certificates

of Suitability by the European Directorate for the Quality of Medicines & Healthcare
(EDQM). Applicant may refer to the European Pharmacopoeia and the EDQM website2
for more information on TSE and the Certificate of Suitability.
Supporting documents to be submitted include:
a) A valid TSE Risk Evaluation Certificate of Suitability (CEP)
b) A brief description of the following:
i. Rationale for using animal-derived materials
When manufacturers choose to use animal-derived materials, the rationale for using
these materials instead of that from the non-animal origin should be given.
ii. Source of animals
A compulsory notification of BSE cases in the country of origin and a compulsory

clinical and laboratory verification of suspected cases are required for product
application.
The most satisfactory source of materials is from countries without any reported
case of BSE. The assessment of a countrys BSE status is based on the following:
Office International Des Episooties (OIE) classification3

Opinions of the Scientific Steering Committee of the European Commission4
As far as possible, animal-derived materials should be sourced from countries with

a negligible BSE risk in accordance to Terrestrial Animal Health Code (Chapter
2.3.13) of the World Organisation for Animal Health (OIE).
iii. Nature of animal tissue used and measures taken to minimise BSE risk
A declaration of the nature of the animal tissue used should be submitted.
In a TSE-infected animal, different organs and secretions have different levels

of infectivity. In accordance with the EMEA Note for Guidance, selected
ruminant tissues and fluids are classified into the three main categories as
follows:
Category A (High Infectivity): brain, spinal cord, retina, optic nerve, spinal
ganglia, trigeminal ganglia, pituitary gland and dura mater.
2
http://www.edqm.eu
3
http://www.oie.int/eng/info/en_esbmonde.htm
4
http://ec.europa.eu/food/fs/sc/ssc/outcome_en.html

Category B (Low Infectivity): peripheral nerves, enteric plexuses, lymph

nodes, nictitating membrane, thymus, oesophagus, forestomach,
stomach/abomasums, duodenum, jejunum, ileum, large intestine, lung, liver,
kidney, spleen, tonsil, placenta, cerebrospinal fluid, adrenal, pancreas, bone
marrow, blood vessels, olfactory mucosa, gingival tissue, salivary gland,
cornea, blood.
Category C (No detectable Infectivity): faeces, heart/pericardium, mammary

gland/udder, milk, semen, placenta fluids, ovary, saliva,
prostate/epididymis/seminal vesicle, skeletal muscle, testis, uterus (non-
gravid), foetus, embryos, tongue, tendon, trachea, adipose tissue, thyroid
gland, colostrum, cord blood, sweat, tears, nasal mucus, bone, skin, urine.
Examples of category C materials include:
a) Gelatin may be extracted from the skin and/or bones of cattle. Gelatin
extracted from skin has a lower risk than gelatin extracted from bones
especially bones from which skulls and vertebral columns have not been
carefully excluded because hide gelatin offers little opportunity for cross
contamination with potentially infective tissue (e.g. brain, spinal cord and
ganglia). Thus, it is recommended to collect bovine bones for processing
into gelatin only from BSE-free countries or from countries with a low
prevalence of BSE; it is preferable to exclude skull and vertebral columns
from bones used for gelatin. The use of bone gelatin produced by alkaline
hydrolysis (augmented, whenever possible, by additional approved
processes) rather than by acid treatment alone further reduces the risk of
contamination with TSE agents. Compliance with these precautions provides
assurance that gelatin used in the manufacture of medicinal products is
unlikely to be contaminated. Amino acids derived from gelatin are further
highly processed, so their risk may be even lower.
b) Materials derived from ruminant tallow, such as triglycerides, glycerol,

sorbitan esters and polysorbate, or amino acids of ruminant origin (even if
higher-risk tissues were not completely eliminated) are considered highly
unlikely to remain contaminated by the time the final reagent has been
produced, so long as they were prepared by processes of extraction and
purification at high temperatures and if good manufacturing practices (GMP)
were rigorously controlled.
c) Milk and certain milk derivatives, such as lactose, are generally considered
non-infectious, regardless of geographic origin, provided that the milk is from
healthy cows fit for human consumption and no other potentially infectious
ruminant-derived materials were used in the manufacturing process.
As a general rule, ruminant-derived raw materials that have been classified as

Category A and Category B tissues or fluids must be sourced from countries
with a negligible BSE risk.
In certain situations, there could be cross-contamination of tissues from

different categories of infectivity, e.g. direct contact between different materials,
or the use of penetrative brain stunning as a method of slaughtering the
animals.

Thus, in such cases, procedures used in collecting the intended animal

tissues/organs and the measures in place to avoid cross-contamination with a
higher risk material must also be described in detail.
iv. Nature and quantity of each animal-derived material used
Detailed information must be provided on the nature and quantity of each animal-
derived material used for the preparation of:
Drug substance;
Excipients and adjuvants;
Raw and starting materials and reagents used in production e.g. bovine
serum albumin, enzymes and culture media including those used to prepare
working cell banks or new master cell banks.
Materials that come into direct contact with the equipment used in the manufacture
of the medicinal product or that come in contact with the medicinal product and
therefore have the potential for contamination should also comply with these
guidelines. Likewise, materials used in the qualification of plant and equipment,
such as culture media used in media fill experiments to validate the aseptic filling
process shall be considered in compliance with these guidelines.
As far as possible, information on the residual amount of animal-derived materials

present in the drug product should be clearly stated as follows:
For example: Foetal bovine serum (residual) 0.350 mcg/mL
1.2 Products Containing Animal-Derived Materials WITHOUT a valid TSE risk

The use of animal-derived materials that have NOT been awarded Certificates of
Suitability by the European Directorate for the Quality of Medicines & Healthcare (EDQM)
may still be acceptable, subjected to the risk assessment of the TSE in the form of a
detailed assessment report.
Supporting documents to be submitted includes:
a) Detailed Assessment Report for the risk of TSE
i. The scope of this report should include section 1.1 (b) as well as the risk factors
associated with the route of administration and the maximum therapeutic dosage
(daily dosage and duration of treatment) of the product.
ii. Production process steps for inactivation of TSE agents
Controlled sourcing is the most important criterion in achieving acceptable safety of

the product due to the documented resistance of TSE agents to most inactivation
procedures. The production process, wherever possible, should be designed to take
into consideration all available information on methods that are thought to inactivate
or remove TSE agents.
If claims are made that inactivation of TSE agents occurs during the manufacturing
process, then relevant information on the process should be submitted for
evaluation.

b) Certificate of analysis for each animal-derived material used.
2 RESPONSIBILITY OF PRODUCT LICENSE HOLDER
The Product Licence holder is responsible for ensuring that the product imported for local
sale and supply is identical, in all aspects, to that approved by the licensing authority. The
licence holder should notify HSA of variations and obtain approval before implementing
the variation if necessary (for example, change of source materials for manufacturing).
3 CONCLUSION
The acceptability of a medicinal product containing animal-derived ingredients, or which

as a result of manufacture could contain these materials, will be influenced by a number
of factors, including:
Documented and recorded source of animals;

Nature of animal tissue used in the manufacture;
Production process;
Route of administration;
Quantity of tissue used in the medicinal products;
Maximum therapeutic dosage; and/or,
Intended use of the product.
The above guidelines only serve as guidance. Pharmaceutical manufacturers and owners
are required to observe international best practices at all times and to comply with the
requirements of the EMEA, USA, Australia, Canada, in particular, the requirements set
down in the given references and their subsequent revisions.
4 REFERENCES
a) CPMP & CVMPs Note for Guidance on Minimising the Risk of Transmitting Animal
Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products,
EMEA/410/01 Rev. 2 October 2003).
b) Guidance for Industry The Sourcing and Processing of Gelatin to Reduce the
Potential Risk Posed by Bovine Spongiform Encephalopathy (BSE) in FDA-Regulated
Products for Human Use, by US FDA.
c) Ph. Eur. general monograph on Product with risk of transmitting agents of animal
spongiform encephalopathies.
d) Guidelines on the Investigation of Manufacturing Processes for Plasma-Derived

Medicinal Products with regard to vCJD risk (EMEA/BWP/5136/03).
e) CPMP/BWP/337/02/Public/Final, Risk and regulatory assessment of lactose and other

products prepared using calf rennet.
f) CPMP/BWP/1793/02/Guidance on the use of Bovine Serum in the manufacture of

human biological medicinal products.
g) Terrestrial Animal Health Code, World Organisation for Animal Health (OIE).

h) Use of Materials Derived from Cattle in Medical Products Intended for Use in Humans
and Drugs Intended for Use in Ruminants; Proposed Rule by FDAs Department of
Health and Human Services.
i) TGA Supplementary requirements for Therapeutic Goods for Minimising the Risk of
Transmitting Spongiform Encephalopathies (TSEs).
j) WHO Guidelines on Transmissible Spongiform Encephalopathies in relation to

Biological and Pharmaceutical Products (WHO 2003).
k) Guidance for Industry Revised Preventive Measures to Reduce the Possible Risk of
Transmission of CreutzfeldtJakob Disease (CJD) and Variant Creutzfeldt-Jacob
Disease (vCJD) by Blood and Blood Products. U.S. FDA, Department of Health and
Human Services, Center for Biologics Evaluation adn Research, May 2010.

ANNEX 1 CHECKLIST FOR THE REGISTRATION OF HUMAN MEDICINAL

PRODUCTS CONTAINING MATERIALS OF ANIMAL ORIGIN
Appendix Document Yes/No

section (Encl. #)
1.1 Products Containing Animal-Derived Materials WITH a valid TSE risk

1.1 (a) TSE Risk Evaluation Certificate of suitability (CEP)

(Please put the number and date of certificate and attach
copy to this checklist).
Basic information providing a brief description of the following:
1.1 (b) (i) Rationale for using animal-derived materials
1.1 (b) (ii) Source of Animals
1.1 (b) (iii) Declaration of the nature of the animal tissue used.
1.1 (b) (iii) Description of the tissue/organ-collection procedures and

measures in place to avoid cross-contamination.
1.1 (b) (iv) Nature and quantity of each animal-derived material used:
As a drug substance.
As an excipient or adjuvant.
As a starting material used in the manufacture of a drug

substance
As a starting material used in the manufacture of excipient.
As a reagent or culture media component used in

manufacture.

establishing mastercell banks.

establishing working cell banks.
Others, give details.

Appendix Document Yes/No

section (Encl. #)
1.2 Products Containing Animal-Derived Materials WITHOUT a valid TSE

risk evaluation Certificate of Suitability (CEP)
Detailed Assessment Report for the risk of TSE.

The scope of this assessment report should include the following:
1.1 (b) (i) Rationale for using animal-derived materials
1.1 (b) (ii) Source of Animals
1.1 (b) (iii) Declaration of the nature of the animal tissue used.
1.1 (b) (iii) Description of the tissue/organ-collection procedures and

measures in place to avoid cross-contamination.
1.2 (a) Details of the risk factors associated with the route of
administration and maximum therapeutic dosage of the
product.
1.1 (b) (iv) Nature and quantity of each animal-derived material used:
As a drug substance.
As an excipient or adjuvant.
As a starting material used in the manufacture of a drug

substance
As a starting material used in the manufacture of

excipient.

manufacture.

establishing mastercell banks.

establishing working cell banks.
Others, give details.
1.2 (a) (ii) Relevant information to support the claim that the
manufacturing process is capable of inactivating TSE agents.
1.2 (b) Certificates of analysis for each animal-derived materials

used

PRODUCT INTERCHANGEABILITY AND BIOWAIVER REQUEST FOR CHEMICAL GENERIC DRUG
APPLICATIONS
APPENDIX 12 PRODUCT INTERCHANGEABILITY AND BIOWAIVER

REQUEST FOR CHEMICAL GENERIC DRUG
APPLICATIONS
Applicants are advised to be familiar with The ASEAN Guideline on the Conduct of
Bioavailability and Bioequivalence Studies1 on the conduct of bioavailability (BA) and
bioequivalence (BE) studies for the purposes of drug registration. Applicants are also
advised to consult the relevant international guidelines from EMA CHMP2, US FDA3 or
WHO for the conduct and analysis of bioavailability and bioequivalence studies.
From 1st April 2004, in vivo BE data is required for Prescription Only Medicines (POM) in
oral solid dosage forms. Also, GDA-2 applications will require bioequivalence data if the
application is for a Prescription Only Medicine (POM) in an oral solid dosage form, even if
the first strength (GDA-1) application was submitted to HSA before 1 April 2004.
HSA reserves the right to request for any additional information required to determine the
product interchangeability of the generic product to the Singapore reference product.
1 PRODUCT INTERCHANGEABILITY
A generic product is considered interchangeable with the Singapore reference product if it

demonstrates therapeutic and pharmaceutical equivalency. A BE study generally is the
most appropriate method for demonstrating therapeutic equivalence between products
that are pharmaceutically equivalent. However, there may be cases where there is a
similar extent of absorption but different rates of absorption; in such instances, applicants
are recommended to consult with HSA on the acceptability of the proposed documents to
demonstrate interchangeability prior to submission.
For generic products containing a different salt or ester form of the active substance
compared to the Singapore reference product, applicants are required to submit data to
demonstrate that the different salt/ester form does not affect the pharmacokinetic,
pharmacodynamic, efficacy or toxicity profile of the active substance in the reference
product.
The applicant is responsible for demonstrating product interchangeability between the

generic and Singapore reference products. The outcome of the evaluation will only be
determined based on the documents provided in the registration dossier. HSA reserves
the right to request for additional information, including in vivo BE data, if deemed
appropriate to determine product interchangeability.
2 BE STUDY
The report of a BE study should include the complete documentation of its protocol,
conduct and evaluation in compliance with GCP and related ICH E34 guideline.
Deviations, additions, or omissions from existing guidelines must be explained, either by
introductory remarks or within each relevant module/part of the submission, whichever is
more appropriate. Examples of information to be included in the report are:
1
2
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000043.jsp
&murl=menus/regulations/regulations.jsp&mid=WC0b01ac05800240cb&jsenabled=true
3
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm121568.htm
4
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000429.jsp
&murl=menus/regulations/regulations.jsp&mid=WC0b01ac0580029590

APPLICATIONS
i. Signature of the Principal Investigator to attest the authenticity of the report;

ii. Audit certificate(s), including a BE site inspection report, if available;
iii. Approval letter(s) from the Institutional Review Board/Independent Ethics
Committee and the appropriate drug regulatory agency;
iv. Information about the reference and test products, such as the product name,
strength, dosage form, batch number, manufacturing site, batch size of the test
product, etc.;
v. Certificates of Analysis of the reference and test products used in the BE study,
including the batch size of the test product and manufacturing/expiry date of both
products (where applicable);
vi. Description of the assay methodology and validation; and,
vii. A signed statement confirming that the test product used in the BE study is the
same formulation and is manufactured by the same process as that submitted for
registration.
The generic or test product used in the BE study must be the same as the Singapore
drug product submitted for registration. In other words, the test product must be
manufactured at the same drug substance and drug product manufacturing sites by the
same manufacturing processes as submitted in the GDA registration dossier. The test
product used in the BE study should also be from a batch of at least 100,000 units or 1/10
of production scale, whichever is greater.
It is highly recommended that the reference product used in the BE study be the same as
the Singapore reference product i.e. the BE reference product should be of the same
strength as the generic product and manufactured from the Singapore registered drug
product manufacturing site. Details of the manufacturing source of the Singapore
reference product can be found by searching HSAs online database5.
If the BE reference product was manufactured by a non-Singapore-registered

manufacturer, the following criteria must be fulfilled in order to accept the submitted BE
study:
a) The reference product is registered in, and obtained from, a country with a competent
regulatory system as defined by WHO;
b) It is documented that the reference product is marketed in the country of origin
i. by the same innovator company or corporate entity that markets the same drug
product (same dosage form and strength) in Singapore; or,
ii. through a licensing arrangement with the innovator company or corporate entity that
markets the same product in Singapore;
c) The reference product is a conventional, immediate-release oral dosage form (tablet,
capsule) or an enteric coated tablet or capsule formulation that releases the drug
substance promptly once the enteric coating has dissolved;
d) The ingredients in the BE reference product are qualitatively identical to those used in
the Singapore reference product, with exception of minor excipients that are unlikely
to affect the bioavailability of the product (e.g. colourants and inks);
e) The active ingredient has a well-described dose response curve and does not exhibit
the following:
i. a narrow therapeutic range or safety margin e.g. does not require careful dosage
titration or patient monitoring;
ii. a steep dose-response relationship;
iii. a risk of serious undesired effects; and/or,
5

APPLICATIONS
iv. complicated or variable pharmacokinetics (PK) e.g. non-linear PK, variable or

incomplete absorption, site-specific absorption and substantial first-pass
metabolism (>40%); and,
f) The BE reference product
i. contains the same nominal quantity of active ingredient as the innovator product
marketed in Singapore;
ii. is the same as the Singapore reference product with respect to size, weight and
type of coating (e.g. uncoated, film-coated or enteric-coated); and,
iii. exhibits individual and mean dissolution profiles comparable to the Singapore
reference product.
Applicants should ensure that the submitted BE study is complete, including all
appendices and data, as per the relevant guidelines.
A quick reference on the acceptability of a BE study is given in Appendix 12A. If the

acceptability of a BE study is still in doubt, applicants are advised to email HSA at
HSA_MedProd_Registration@hsa.gov.sg with the completed Appendix 12A. HSA will
respond to the applicants inquiry after review of the information provided.
3 COMPARATIVE DISSOLUTION
A dissolution test is used as a tool to identify formulation factors that may influence and
have a critical effect on the BA of the product. A dissolution test is also used in the quality
control to ensure batch-to-batch consistency of production batches and dissolution
profiles of production batches remain similar to the pivotal clinical trial batch(es).
Dissolution profiles should be determined in at least three dissolution media within the
physiological range (pH 1 to 7.5), such as 0.1 N HCl, a pH 4.5 buffer and a pH 6.8 buffer.
One of the dissolution media should be described in the BP or USP monograph, if one
exists.
For comparative in vitro dissolution studies, the following data should be submitted:
a) individual dissolution data in each of the media;
b) mean, range and RSD values of 12 units conducted in the three different media; and,
c) statistical comparison using a procedure described in relevant international guidelines
e.g. F2 calculations.
The results of in vitro dissolution tests obtained from the test and reference products used
in the BE study should be reported.
For more information on the conduct and reporting of comparative dissolution studies,
applicants are advised to refer to the ASEAN Guideline on the Conduct of Bioavailability
and Bioequivalence Studies and other relevant international guidelines, as appropriate.
4 BIOWAIVER REQUEST
Results from comparative bioavailability studies should be provided in support of the

safety and efficacy of each proposed product and proposed strength included in a GDA
submission. In the absence of such studies, a justification supporting a waiver of this
requirement should be provided for each product and strength.
In general, BE data or a justification for not providing such data are not required for the
following:

APPLICATIONS
a) Simple or complex solutions that do not contain any ingredient which can be regarded
as a pharmacologically active substance;
b) Haemodialysis and peritoneal dialysis solutions;
c) Simple aqueous solutions intended for intravenous injection or infusion containing the
same active substance(s) in the same concentration as currently registered products.
Simple solutions do not include complex solutions such as micellar or liposomal
solutions;
d) Solutions for injection that contain the same active ingredients and excipients in the
same concentrations as currently registered products and which are administered by
the same route(s);
e) Products that are powder for reconstitution as a solution and the solution meets either
criterion (c) or (d) above;
f) Oral immediate-release tablets, capsules and suspensions containing drug
substances with high solubility and high permeability and where the drug product has
a high dissolution rate, provided that the applicant submits an acceptable justification
for not submitting BE data in terms of the CHMP or FDA guidelines;
g) Oral solutions containing the same active ingredient(s) in the same concentration as a
currently registered oral solution and not containing excipients that may significantly
affect gastric passage or absorption of the active ingredient(s);
h) Products for topical use provided that the product is intended to act without systemic
absorption when applied locally;
i) Products containing substances which are not systemically or locally absorbed and do
not contribute to a therapeutic effect (e.g. barium sulphate enemas, powders in which
no ingredient is absorbed). If there is doubt as to whether absorption occurs, a study
or justification may be required;
j) Otic or ophthalmic products prepared as aqueous solutions and containing the same
drug substance(s) in the same concentration; and,
In all other cases, justification for biowaiver of BE studies is required.
For example, when a generic product is to be marketed in several strengths, if the

formulation of each of the strengths is dose-proportional, then the results of a single
comparative BE study may be extrapolated to all strengths in the series and the applicant
would need to provide scientific justification for biowaiver for the other strengths (other
than that used in the BE study).
In preparing a justification, the applicant should address the following issues, as

applicable:
the nature of the dosage form;
the solubility of the drug substance(s)/active ingredient(s);
the comparative dissolution profiles across the physiological pH range (1-7.5) of the
generic, BE reference and/or Singapore reference products;
the comparative dissolution profiles across the physiological pH range between
additional strengths of the generic products and the corresponding strengths of the
Singapore reference products;
the pharmacokinetic characteristics of the active ingredient(s), such as permeability
(or absolute bioavailability), linearity or otherwise, first pass effect (if any) and its
significance;

APPLICATIONS
the clinical consequences of any potential differences in bioavailabilities of the

products under consideration (for example, increased dose leading to toxicity or
decreased dose leading to lack of efficacy);
the width of the margin between the minimum effective and minimum toxic plasma
concentration; and/or,
the similarities of, or differences between, the formulations being considered.
If the justification is not considered adequate, the applicant will be required to provide
relevant biopharmaceutic data.
This document reflects the current thinking of HSA on the minimum data necessary for
assessment. HSA reserves the right to request additional information if deemed
appropriate.


GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE QUICK REFERENCE ON ACCEPTABILITY OF BIOEQUIVALENCE STUDY APRIL 2011
APPENDIX 12A QUICK REFERENCE ON ACCEPTABILITY OF BIOEQUIVALENCE STUDY

SEPTEMBER 2008
Generic Product submitted to HSA Singapore Reference Product
(include all proposed strengths in this application) (include all registered strengths)
Product Name Product Name
Proposed Registered
strength(s) strength(s)
Manufacturing site Manufacturing site
(name & address) (name & address)
Generic Product used in BE study Reference product used in BE study Reference Product used in BE study
Manufacturing Site Manufacturing Site Strength
Manufacturing site Generic Product used in BE Manufacturing site Reference Product in BE Strength of Reference Product used in BE
same as proposed site for Singapore GDA same as registered Singapore site same as registered Singapore strength
from different manufacturing site from different manufacturing site is not available in Singapore
(not acceptable, test product used in BE study
One RED tick box: BE study acceptable with bridging data (comparative dissolution)
must be from same manufacturing site as the
proposed Singapore product) More than one RED tick box BE study not acceptable; considered two steps

GUIDELINE ON SUBMISSION FOR INDIAN GENERIC PRODUCTS UNDER THE CECA SCHEME
APPENDIX 13 GUIDELINE ON SUBMISSION FOR INDIAN GENERIC

PRODUCTS UNDER THE CECA SCHEME
Pursuant to Chapter 5 of the India-Singapore Comprehensive Economic Cooperation

Agreement (CECA), a special scheme (hereinafter referred to as CECA scheme) for the
registration of generic products manufactured in India was introduced to facilitate the
market authorization of these products in Singapore.
Registration of Indian generic products may be possible through the CECA scheme
provided that the application meets the eligibility and documentary requirements. This
document is intended to provide assistance in the submission of applications under the
CECA scheme.

(known as the Singapore reference product). Essentially similar1 is defined as having the
same qualitative and quantitative composition in terms of active substances, having the
same pharmaceutical form and being bioequivalent. Thus, the generic product to be
registered should demonstrate pharmaceutical and bio-equivalency with the Singapore
reference product i.e. to demonstrate interchangeability with the Singapore reference
product.
1 ELIGIBILITY CRITERIA
For eligibility of registration under the CECA scheme, the following criteria must be
satisfied:
a) The generic product is manufactured by licensed manufacturer(s) located only in India;

b) The generic product has been evaluated and approved by at least one of the following
regulatory agencies:
Australia Therapeutic Goods Administration;
Health Canada;
US Food and Drug Administration;
the European Medicines Agency via the Centralised Procedure;
UK Medicines and Healthcare Products Regulatory Agency via
- as the Reference Member State (RMS) via the Mutual Recognition Procedure
or Decentralised Procedure.
c) The approval by the reference agency is within two (2) years from the date of
submission to HSA; and,
d) All aspects of the generic products quality, including the formulation, manufacturing
site(s), release and shelf life specifications and primary packaging, must be identical to
that currently approved by the reference agency.
Applicants should note that approval by these reference regulatory agencies does not
obligate HSA to approve the application.
Generic products excluded from this scheme include:
a) Products that infringe upon valid patents in Singapore,

b) Products that do not have a Singapore Reference Product,
c) Biological or biotechnological products;
1
Note for Guidance on the Investigation of Bioavailability and Bioequivalence. CPMP/EWP/QWP/1401/98.

d) Products that have been rejected, withdrawn from, approved via appeal process or
pending deferral by a national drug regulatory authority; and,
e) Products that have been approved by one of the reference agencies via an
accelerated/fast-track approval, approval under exceptional circumstances or an
equivalent approval process.
2 REGISTRATION PROCESS
Applications for registration of Indian generic products shall undergo the same process as
other medicinal products as described in the Guidance of Medicinal Product Registration
in Singapore (hereinafter referred to as Guidance). Figure 3 on page 12 of the Guidance
is a flowchart of the registration process.
It is highly recommended for applicants wishing to submit applications under the CECA
scheme to undergo a pre-submission consultation. This consultation is to determine the
eligibility of the dossier and suitability of the dataset for registration under this scheme. In
turn, this should facilitate the registration process as it may help to minimize/reduce
potential delays i.e. the need for Input Requests in the registration process.
Applicants who wish to arrange for a pre-submission consultation should request an

appointment, stating the purpose and proposed date(s) & time(s), via email to
HSA_MedProd_Registration@hsa.gov.sg.
Dossiers submitted under the CECA scheme must be in the ICH CTD or ACTD format.
Dossiers submitted should also be in electronic format, either as a CD/DVD or uploaded
into PRISM. See section 6.3.1 in the Guidance for more information.
2.1.1 Administrative documents (ICH CTD Module 1 or ACTD Part 1)
Administrative documents must be submitted in both hard copy and soft copy. All official
documents must be original or certified true copies.
The administrative documentary requirements for the CECA scheme are similar to the
GDA verification evaluation route. See section 17.1 in the Guidance for more information
on the specific administrative document required. However, applicants should note that
the requirements listed in table below are specific to the CECA scheme:
Administrative document CECA scheme

1.4.3 PI or PIL The PI/PIL should be aligned to the currently-registered
Singapore Reference Product.
1.5 SPC/PI/PIL The SPC/PI/PIL should be that approved by the
reference agency.
1.6 Assessment report The unedited assessment report# from the reference
agency shall include details of imposed licensing
conditions, final product labelling, chemistry review and
other relevant documents in relation to the products
approval. Refer to the table in section 17.5.2 in the
Guidance.
1.9 Approval letter from Approval letter issued by the reference agency.
reference agency

1.11 GMP certification Valid GMP certificate and latest inspection report as
issued by the reference agency.
1.14 Declaration Declaration letter stating that the Singapore product to
be registered and the information submitted are exactly
the same as those submitted to the reference agency.
#
applicable.
The assessment reports must be unredacted or unedited. Reports obtained from the
public domain are deemed unacceptable.
Applicants should note that, with effect from 1st April 2004, all overseas drug product
manufacturing sites previously not registered with HSA will be subjected to a GMP
Conformity Assessment by HSA. Refer to GUIDE-202 on the HSA website for more
information.
2.1.2 Summaries (ICH CTD Module 2 or ACTD Part 2/3/4)
The documentary requirements for the CECA scheme is the same as the GDA abridged
evaluation route, which includes the Singapore Quality Overall Summary and Quality
Overall Summary.
2.1.3 Quality documents (ICH CTD Module 3 or ACTD Part 2)
The CMC quality documents required for the CECA scheme is as follow:
i. Module 3 dossier as initially submitted to the chosen reference agency;

ii. From Sponsor:
- Question and Answers between the chosen reference agency and sponsor the
Answers should include supporting documents used in response to the Questions;
- All post-approval variations approved by the chosen reference agency up to the
time of submission to HSA, including the application letter for the variation,
reference agency and sponsor and the approval letter for the variation from the
reference agency, if applicable; and,
- Relevant documents required by HSA which have not been submitted to the chosen
reference agency, e.g. stability studies in accordance to ASEAN Stability
Guidelines, Singapore Quality Overall Summary, comparative dissolution studies,
etc;
- The initial open and closed parts of the DMF submitted to the chosen reference
agency from the DMF Holder should be provided to HSA, together with the original
Letter of Access;
- Question and Answers between the chosen reference agency and DMF Holder
Questions; and,
- All post-approval DMF updates approved by the chosen reference agency up to the
time of submission to HSA, including the application letter for the DMF update,
supporting documents for the DMF update, questions and answers between the
2
http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/GMP/guidelines.html

reference agency and sponsor and the approval letter for the DMF update from the
reference agency.
Applicants should refer to section 17.5.2 of the Guidance for more detailed information.
Data submitted to HSA must be the same as the data package submitted to the reference
regulatory agencies. Differences between the dossier submitted to HSA and data
reviewed by the reference regulatory agencies will not only delay the processing of the
application, but may also lead to re-routing of the dossier to the abridged evaluation route
if significant undisclosed differences have been discovered.
2.1.4 Non-clinical & clinical documents
Non-clinical documents (ICH CTD Module 4 or ACTD Part 3) are not required.
The clinical documents (ICH CTD Module 5 or ACTD Part 4) required for the CECA
scheme is as follow:
i. All clinical documents submitted to the reference agency that had approved the
generic product. Examples of clinical documents include bioequivalence (BE)
studies, justification for biowaiver of BE studies and other relevant documents; and,
ii. All Questions and Answers between the reference agency and Sponsor during the
evaluation which led to market authorization of the generic product the Answers
should include all supporting documents in response to the Questions.
Applicants are to note that generic products applied through the CECA scheme must also
demonstrate product interchangeability to the Singapore reference product. As such,
applicants should refer to Appendix 12 of the Guidance for more information.
2.2 Regulatory Decision
A regulatory decision is made based on the evaluation of the submitted data package.
Applicants should refer to section 9 of the Guidance for more information.
Upon issuance of a Product Licence, applicants are responsible fulfilling all post-approval
licensing conditions attached to the Licence. Applicants should view the licensing
conditions online for specific details.
2.3 Timeline
Because this scheme was established to facilitate market entry of Indian generic
products, the table below describes the target processing timeline, in working days and
excluding any stop-clocks:
CECA scheme GDA Abridged

Screening of the dossier before the 1st query 14 25
Evaluation of the dossier to regulatory decision 90 240
NOTE: the screening timeline begins from the date of submission of the complete dossier.
Applicants are advised to refer to Appendix 1 of the Guidance for more information. As
such, HSA reserves the right to amend the application date when all documents have been
submitted.

2.4 Fees
For information on the fees, please visit the HSA website.
The screening fee is payable at the time of PRISM submission. The evaluation fee is
payable upon acceptance of the dossier for evaluation. The screening and evaluation
fees are non-refundable, regardless of the final decision by HSA. Thus, applicants are
advised to ensure that the dossier is compiled according to the required format and
complete prior to submission.
The progressive payment scheme was implemented for applications under this route to
allow payment of evaluation fees by instalments. The evaluation fees of the CECA
scheme can be paid by instalments via the progressive payment scheme.


MIV FILING AND SUBMISSION INQUIRY FORM
APPENDIX 14 MIV FILING AND SUBMISSION INQUIRY FORM
EMAIL the completed form in MS WORD format to HSA_MedProd_Registration@hsa.gov.sg
Please be reminded that every section in this form MUST be filled up in order to facilitate the
process.
Name of applicant: Date:

Designation:
Company:
Tel: Fax:
Email:
Product name: License no:
Product type: Chemical (Appendix 15)

(Check appropriately) Biologic (Appendix 16)
Proposed change(s):
1.
2.
Proposed section(s) for submission, and provide justification as needed: (Must complete)
e.g. Appendix 15 - Section B3, MIV-2, cannot find appropriate section, etc...
1.
2.
Registration status and date of proposed change(s) in other agencies/countries; provide reason
if this is not applicable: (Must complete)
e.g. type of application, regulatory agency/country, date of submission or date of
approval/withdrawal/rejection
Additional comments/information:

MIV FILING AND SUBMISSION INQUIRY FORM
Below for Official Use Only
Inquiry reference number:

Inquiry response officer:
Difficulty of the inquiry? Easy - applicant kindly reminded to review guidance documents
Medium
Hard - proposed guidance update(s): section ____________
Recommended Course of Action for the Applicant: (Check all that apply)
Include a copy of this form in the submission, attach any relevant correspondence
Submit as a MIV-2 application
Submit as a MIV-1 application
Submit documents/sections as proposed
Submit the following documents/sections in support of the proposed changes
HSA reserves the right to re-route the application type, split unrelated changes or request for
additional information during the course of the screening/evaluation.

GUIDELINE ON MINOR VARIATION APPLICATIONS FOR CHEMICAL DRUGS
APPENDIX 15 GUIDELINE ON MINOR VARIATION APPLICATIONS FOR

CHEMICAL DRUGS
TABLE OF CONTENTS
PART A: INTRODUCTION ............................................................................................ 3
PART B: DOSSIER REQUIREMENTS FOR MIV-1 VARIATION ................................... 6
B1 Addition or Replacement of Manufacturing Site of Drug Substance .......................... 7

B2 Major Change of Manufacturing Process of Drug Substance ................................... 8
B3 Change of Specification of Drug Substance or Drug Product .................................... 9
B4 Addition or Change of Score/Break Line of Tablet .................................................. 10
B5 Major Change of Excipients ................................................................................... 10
B6 Addition or Replacement of Manufacturing Site of Drug Product ............................ 11
B7 Addition or Change of Primary Packaging Site ....................................................... 12
B8 Change of Batch Size of Drug Product ................................................................... 12
B9 Change of Manufacturing Process and/or In-Process Control of Drug Product ...... 13
B10 Addition, Replacement or Change of Test Procedure of Drug Product ................... 13
B11 Addition or Change of Container Closure System of Drug Product ......................... 14
B12 Change of Shelf Life or Storage Condition of Drug Product .................................... 14
B13 Change of Shelf Life After Reconstitution or First Opening ..................................... 14
B14 Change of Pack Size for Sterile Drug Product ........................................................ 15
B15 Change of Sterility Testing to Parametric Release.................................................. 15
B16 Change of Product Labelling .................................................................................. 16
PART C: DOSSIER REQUIREMENTS FOR MIV-2 VARIATION ................................. 17

C1 Change of Product Name ....................................................................................... 18
C2 Change of Product Owner ...................................................................................... 18
C3 Change of Batch Numbering System...................................................................... 19
C4 Withdrawal or Deletion of Manufacturer.................................................................. 19
C5 Renaming of Manufacturing Site of Drug Substance .............................................. 19
C6 Minor Change of Manufacturing Process of Drug Substance ................................. 19
C7 Change of Batch Size of Drug Substance .............................................................. 20
C8 Change to Comply with Accepted Pharmacopoeia for Drug Substance.................. 20
C9 Change of Test Procedure of Drug Substance ....................................................... 21
C10 Tightening of Specification or Addition of New Test Parameter and Limit of Drug
Substance .............................................................................................................. 21
C11 Extension of Retest Period or Shelf Life of Drug Substance ................................... 21
C12 Change of Imprints, Bossing or Other Markings on Tablet or Printing on Capsules 22
C13 Change of Dimensions of Tablet, Capsule, Suppository or Pessary ....................... 22
C14 Minor Change of Excipients .................................................................................... 23
C15 Change of Colouring System of Drug Product ........................................................ 24
C16 Change of Flavouring System of Drug Product ....................................................... 25
C17 Quantitative Change in Coating Weight of Tablet or Weight of Capsule Shell ........ 25

C18 Renaming of Manufacturing Site of Drug Product .................................................. 26

C19 Addition or Replacement of Secondary Packaging Site.......................................... 26
C20 Addition or Replacement of Site Responsible for Batch Release ........................... 26
C21 Change of Batch Size of Drug Product ................................................................... 27
C22 Change of In-Process Control of Drug Product ....................................................... 27
C23 Minor Change of Manufacturing Process of Drug Product ...................................... 28
C24 Change to Comply with Pharmacopoeia for Excipient ............................................ 28
C25 Change of Test Procedure for Excipient ................................................................. 29
C26 Tightening of Specification or Addition of New Test Parameter and Limit of
Excipient ................................................................................................................ 29
C27 Change of Test Procedure of Drug Product ............................................................ 29
C28 Tightening of Release and Shelf Life Specifications or Addition of New Test
Parameter and Limit of Drug Product ..................................................................... 30
C29 Minor Change of Container Closure System of Drug Product ................................. 30
C30 Change in Shape or Dimensions of Container Closure System .............................. 31
C31 Addition or Change of Pack Size for Drug Product ................................................ 31
C32 Deletion of Pack Size for Drug Product .................................................................. 32
C33 Addition or Replacement of Measuring Device for Oral Liquid and Other Dosage
Forms ..................................................................................................................... 32
C34 Change of Product Labelling due to Safety Updates .............................................. 32
C35 Change of Product Labelling Relating to: ............................................................... 32
C36 Change of Product Labelling of Language(s) Other Than English .......................... 33

PART A: INTRODUCTION
This document describes the requirements of a Minor Variation Application (MIV)

submitted for an existing registered chemical drug product in Singapore. Product licence
holders should be familiar with the contents of this document, the Guidance on Medicinal
Product Registration in Singapore and the governing legislation prior to submitting an MIV
to HSA.
Minor Variation Applications are divided into two sub-categories:
MIV-1: A minor variation which requires regulatory approval

MIV-2: A minor variation or an administrative change.

NOTE: Product licence holders are encouraged to email the MIV Filing and
Submission Inquiry Form in Appendix 14 for any issues regarding MIV filing, such
as the absence of a relevant checklist for a particular change.
An MIV is submitted via the Amendment to a Licence of Western Drug Product form in
PRISM.
Product licence holders should disclose all proposed changes in Section 0 Licence
Summary under Section 0.4 Amendment Summary, and in the Table of Amendment
Details, which can be downloaded via the link indicated in Section 0.5 Amendment
Details. Any undisclosed variation(s) embedded in the submitted data, or any follow-on
changes not specifically requested by HSA, will not be considered for evaluation.

Click here for the Table of

Amendment Details template
The following documents must be submitted with each MIV submission, as given in Table
A below:
Table A. MIV Application Hard Copy and Electronic Copy Requirements
Soft Copy Hard Copy

PRISM application form PRISM N/A
Table of Contents PRISM N/A
Checklist for MIV applications PRISM 1 set
Table of Amendment Details PRISM N/A
MIV-specific Supporting documents
+
- Administrative (Module 1/Part 1) PRISM 1 set
#
- Other supporting documents PRISM/CD N/A
Current and proposed product labelling (annotated and PRISM N/A
pristine copies), where applicable
+
# All supporting documents may be submitted via PRISM or CD-ROM do not combine PRISM
attachments with a CD submission
The checklists for MIV-1 and MIV-2 applications for chemical drug products are located in
Part B and C of this Appendix. These checklists will serve as a guide for submitting the
required documents relevant to each proposed MIV. When submitting the Checklist, the
following should be included:
A copy of the relevant checklist(s) to each proposed MIV(s) the boxes should be
checked to ensure that the required documents are included in the submission; and,
The Declaration for the MIV with the submission date and the product licence
holders name and signature.
The Table of Amendment Details should concisely describe the proposed MIV(s). The
following information must be stated in the Table:
Section(s) of the original dossier affected by the change(s);
Current and proposed condition(s);
Reason(s) for the change(s); and,
Registration status and date of the proposed change(s) in other countries/agencies
that had approved the variation(s), especially the country of origin and HSAs
reference agencies.

For an MIV application with multiple related or unrelated variations, all of the
supporting documents for each individual variation should be submitted. If the
required documents have not been submitted, justification must be provided.
NOTE: For unstable drug substances or critical dosage forms, whenever stability
data is required, a minimum of three batches (at least two pilot scale or larger) must
be submitted.
assessment. Product licence holders are responsible for ensuring that all necessary
validations were conducted to demonstrate that the change does not adversely affect the
quality, safety or efficacy of the product concerned. HSA reserves the right to request for
additional information if deemed appropriate.

PART B: DOSSIER REQUIREMENTS FOR MIV-1 VARIATION
Product licence holders should be familiar with the documentary requirements for MIV
submissions to facilitate the review process.
A below:
Soft Copy Hard Copy

+
#
+
When submitting the Checklist for Minor Variation Applications (MIV-1) for Chemical
Drugs, product licence holders must make the following declaration:
Declaration of the product licence holder for MIV-1

I hereby submit an application for the concerned product to be varied in accordance with
the proposals given above. I declare that
There are no other changes than those identified in Section 0.4 Amendment
Summary;
All Conditions for the change(s) concerned are fulfilled; and,
The required documents as specified for the change(s) have been submitted.
NOTE: When submitting the Checklist, please delete the MIV-1 checklist
category(ies) that do not relate to the MIV application being submitted.


the proposals given above. I declare that (please tick the appropriate declarations)
Summary;
____________________ ______________________ _______________

Name Signature Date
B1 Addition or Replacement of Manufacturing Site of Drug Substance

B1.1 where CEP for Drug Substance is not available
B1.2 where CEP for Drug Substance is available
Supporting Documents
B1.1 Where CEP for Drug Substance is not available:
1) (a) Complete CTD section S1-S7; OR,
(b) The open part of the DMF from the product licence holder and the open and
closed part of the DMF, with the Letter of Access, from the DMF holder;
2) Comparative table that highlights all of the differences of the manufacturing
process and controls of the drug substance between the currently-registered
information and the proposed manufacturer, where applicable;
3) Comparative batch analysis data (in a table) of at least two pilot batches of the
drug substance from the current and proposed manufacturing sites;
4) A letter of commitment to conduct real time stability study on the drug product
manufactured with the drug substance from the proposed manufacturing site
and report to HSA of any out-of-specification result (with proposed action) or
when requested.
B1.2 Where CEP for Drug Substance is available:
1) The latest version of the duly authorised, valid CEP, with all annexes;
2) Comparative batch analysis data (in a table) of at least two pilot batches of the
drug substance from the current and proposed manufacturing sites;
3) If the re-test period is not stated in the CEP, then stability data up to the re-test
period on two pilot batches of the drug substance manufactured from the
proposed manufacturing sites should be submitted;
4) A letter of commitment to conduct real time stability study on the drug product
manufactured with the drug substance from the proposed manufacturing site
when requested.

B2 Major Change of Manufacturing Process of Drug Substance

B2.1 where CEP for Drug Substance is not registered
B2.2 where CEP for Drug Substance is registered
For any changes not covered by MIV-2 C6 (e.g. alternative synthetic route)
B2.1 Where CEP for Drug Substance is not registered:
1) (a) Relevant CTD sections; OR,
(b) The relevant sections of the open part of the DMF from the product licence
holder and relevant sections of the open and closed parts from the DMF
holder, where applicable;
2) A comparative table of the current and proposed process, with the changes
clearly indicated (e.g. underscored, highlighted);
3) Validation scheme and data if the drug substance is sterile;
4) (a) A declaration from the product licence holder that the drug substance
specification has not changed; OR,
(b) If there is any change to the specification (i.e. tightening), a comparative
table of the texts of the current and proposed specifications should be
provided;
5) (a) A declaration from the product licence holder that no new impurities have
been introduced at or above the accepted threshold for qualification of
impurities; OR,
(b) If there is an increase in the level of impurities OR if there any potential new
impurities that are detectable at an acceptable limit of detection, appropriate
evidence must be provided;
6) Comparative batch analysis data (in a table) of at least two batches (minimum
pilot scale) of the drug substance manufactured according to both the currently
approved and proposed processes;
7) Results of real time and accelerated stability data of at least six months on two
pilot batches of the drug substance manufactured according to the proposed
process in accordance with the relevant guidelines;
8) A letter of commitment to conduct real time stability study for the drug product
manufactured with the drug substance from the new manufacturing process,
when requested.
B2.2 Where CEP for Drug Substance is registered:
1) The latest version of the duly authorised, valid CEP, with all annexes;
2) (a) A declaration from the product licence holder that the specification of the
drug substance has not changed; OR,
provided;
3) (a) A declaration from the product licence holder that no new impurities have
been introduced at or above the accepted threshold for qualification of
impurities; OR,
(b) If there is an increase in the level of impurities OR if there any potential new
impurities that are detectable at an acceptable limit of detection, appropriate
evidence must be provided;

pilot scale) of the drug substance manufactured according to both the currently
approved and proposed processes;
5) If retest period is not stated on the CEP, results of real time and accelerated
stability data of at least 6 months on two pilot batches of the drug substance
manufactured according to the proposed process in accordance with the
relevant guidelines should be provided;
6) A letter of commitment to conduct real time stability study for the drug product
manufactured with the drug substance from the new manufacturing process,
when requested.
B3 Change of Specification of Drug Substance or Drug Product

For any changes not covered by MIV-2 C10 or C28
1) Scientific and/or historical data used to support the change;
2) A comparative table of the currently-registered and proposed release and/or
shelf life specifications, with the changes clearly indicated (e.g. underscored,
highlighted);
3) Proposed release and/or shelf-life specifications of the drug substance or drug
product;
4) Description of any new analytical method and summary of the validation data, if
applicable;
5) Batch analysis of pilot or production scale batches of drug substance or drug
product for all tests in the proposed specification;
6) For any change of the stability-indicating parameters in the specification,
(a) results of at least six months real time stability studies of at least two
production batches of the drug substance or drug product; AND,
(b) a letter of undertaking to continue the stability studies to the retest period or
shelf life, where applicable, and to report to HSA of any out-of-specification
result (with proposed action) or when requested;
7) If there is a change in drug substance specification, a letter of commitment to
conduct real time stability study for the drug product manufactured with the
drug substance under the proposed specification, and report to HSA of any
out-of-specification result (with proposed action) or when requested.

B4 Addition or Change of Score/Break Line of Tablet

1) Detailed drawing and written description of the current and proposed tablet;
2) Justification to support the addition or change of the score/break line;
3) Data on uniformity of dosage unit of the subdivided parts using at least one
production batch of the proposed tablets;
4) Current and proposed release and shelf life specifications;
5) Certificate of Analysis (CoA) of at least one production batches of drug product;
6) Official letter of commitment from the product licence holder
(a) to inform users of the relevant changes; and,
(b) that the current product stock will be exhausted before the new product is
marketed.
B5 Major Change of Excipients

For any qualitative or quantitative change in one or more excipients in the formulation,
including addition of new or replacement/deletion of existing excipients. Also, for any
changes not covered by MIV-2 C14
For a change of the preservatives, refer to MIV-1 B3
For any changes affecting the release and/or shelf life specification, refer to MIV-1 B3
HSA reserves the right to re-categorise the application to NDA or GDA, if deemed
appropriate
1) A table of the current and revised product formulation with the changes clearly
indicated (e.g. underscored, highlighted) and the calculated percentage of
changes;
2) Revised product formulation;
3) Justification for the change must be given by appropriate development
pharmaceutics (including stability aspect and antimicrobial preservation where
appropriate);
4) A table of the current and proposed manufacturing batch formula with the
changes clearly indicated;
5) Amended relevant CTD P sections;
6) Specifications of the new excipient;
7) For excipients susceptible to a TSE risk, if applicable,
(a) a CEP for the excipient should be provided; and/or,
(b) documentary evidence that the TSE risk of the excipient has been
assessed should be provided;
8) Release and shelf life specifications of the drug product;
9) A declaration from the product licence holder that the change of excipient does
not interfere with the drug product release and shelf life specification test
methods;
10) Comparative batch analysis data (in a table) of at least two pilot batches of
drug product with the current and proposed formulations;
11) Results of real time and accelerated stability studies on at least 6 months of
two pilot/production batches of drug product manufactured according to the

proposed product formulation with a letter of undertaking to continue the on-

going real time stability studies and report to HSA of any out-of-specification
result (with proposed action).
12) A bioequivalence study or justification for biowaiver;
13) Comparative dissolution data between the current formulation (production
scale) and the proposed formulation (at least pilot scale) in accordance with the
relevant guidelines, where applicable.
B6 Addition or Replacement of Manufacturing Site of Drug Product

1) Official letter declaring that the drug substance source & specification, product
formulation, product manufacturing process, analytical test methods, and
release and shelf life specifications have not changed;
2) Proof that the proposed site is appropriately authorised for the pharmaceutical
form concerned: a GMP certificate;
3) Official letter from the Product Owner to authorise the proposed site to
manufacture and batch release (if applicable) the product;
4) Batch numbering system for the proposed site;
5) Drug substance specification;
6) Product formula;
8) If the proposed manufacturing site and the primary packaging site are different,
conditions of transport and bulk storage should be specified and relevant
validation or stability data should be provided;
9) Validation scheme and data of the manufacturing process and sterilization
process at the proposed site using a minimum of three consecutive production
batches of the drug product;
11) Comparative batch analysis data (in a table) of the last three production
batches from the current site and a minimum of two production batches (or one
production batch and two pilot batches) from the proposed site simulating the
production process;
12) A letter of commitment to provide upon request batch analysis data on the next
two full production batches or to report to HSA of any out-of-specification
release or shelf-life result (with proposed action);
13) Results of real time stability data of at least 6 months of two pilot/production
batches of the drug product manufactured from the proposed manufacturing
site with a letter of undertaking to continue the on-going real time stability
studies and report to HSA of any out-of-specification result (with proposed
action) or when requested;
14) Comparative dissolution data between the current site (production scale) and
proposed manufacturing site (at least pilot scale) in accordance with the
relevant guidelines, where applicable.

B7 Addition or Change of Primary Packaging Site

For any changes affecting the container closure system or packaging materials, refer to
MIV-1 B11 or MIV-2 C29
1) Proof that the proposed site is appropriately authorised for the packaging
activity concerned: GMP certificate;
2) Official letter from the Product Owner to authorise the proposed site to package
the product and to state the types of activity performed by the packager;
3) Amended CTD P3.1 section;
4) As the manufacturing site and the proposed primary packaging site are
different, conditions of transport and bulk storage should be specified and
relevant validation or stability data should be provided;
5) Validation data on the manufacturing process for suspensions and emulsions;
6) Results of real time stability data of at least 6 months of two pilot/production
batches of the drug product from the proposed packaging site with a letter of
undertaking to continue the on-going real time stability studies and report to
HSA of any out-of-specification result (with proposed action) or when
requested.
B8 Change of Batch Size of Drug Product

For any change in the batch size of the current registered manufacturing process at any
stage during manufacture drug product not covered by MIV-2 C21
1) Amended relevant CTD P3 sections;
2) Validation scheme and data using a minimum three consecutive drug product
batches of the proposed batch size at the respective manufacturing site;
4) Comparative batch analysis data (in a table) of at least two batches
manufactured according to the currently-registered and proposed batch sizes;
5) Results of real time stability data of at least 6 months on two batches of the
proposed batch size with a letter of undertaking to continue the on-going
stability studies and report to HSA of any out-of-specification result (with
proposed action) or when requested;
6) Comparative dissolution data between the currently-registered and proposed
batch sizes in accordance with the relevant guidelines, where applicable.

B9 Change of Manufacturing Process and/or In-Process Control of Drug Product

For any changes in the procedure of the currently-registered manufacturing process at
any stage during the manufacture of the drug product not covered by MIV-2 C22 or C23
For a change only in the in-process control of drug product, supporting document 3), 7),
8) and 9) may not be applicable but scientific justification should be provided.
2) A table of the current and proposed process and/or in-process control with the
changes clearly indicated (e.g. underscored, highlighted) and scientific
justification for the change;
3) Validation scheme and data of the proposed manufacturing process using a
minimum of three consecutive production batches of the drug product;
4) A description of the analytical methodology and summary of validation data
must be provided for all new analytical methods, where applicable;
6) Comparative batch analysis data of at least two production batches (or one
production batch and two pilot batches) manufactured according to currently-
registered and proposed processes and/or in-process control;
7) Results of real time and accelerated stability data of at least 6 months on two
pilot/production batches of the drug product manufactured according to the
proposed manufacturing process with a letter of undertaking to continue the
on-going real time stability studies and report to HSA of any out-of-specification
9) For solid oral dosage form, comparative dissolution data between the currently
registered process (production scale) and the proposed process (at least pilot
scale) in accordance with the relevant guidelines.
B10 Addition, Replacement or Change of Test Procedure of Drug Product

For any changes not covered by the MIV-2 C27
1) Justification for the proposed change;
2) A table of the current and proposed test procedure with the changes clearly
indicated (e.g. underscored, highlighted);
3) Description of the proposed test procedure;
4) Comparative validation data between the current and proposed test
procedures;
6) Batch analysis data of at least two production batches (or one production batch
and two pilot batches) of the drug product tested according to the current and
proposed test procedure;
7) A letter of commitment to report to HSA of any out-of-specification shelf-life
result (with proposed action) from on-going stability studies using the proposed
test procedure or when requested.

B11 Addition or Change of Container Closure System of Drug Product

For any change relating to the qualitative and/or quantitative composition of the
container closure system
For any change to the type of container closure system used
For any changes not covered by MIV-2 C29
1) Compatibility data and/or scientific evidence to show that there is no interaction
between the product and the packaging material, if applicable;
2) Amended relevant CTD P3 sections, if applicable;
3) For sterile products, validation data of the relevant manufacturing and
sterilization process;
4) A declaration from the product licence holder that the release and shelf life
specifications of the drug product are not affected;
5) Amended CTD P7 section, including technical information of the proposed
packaging material;
6) Comparative table of the current and proposed immediate packaging
specifications, if applicable;
7) Results of real time and accelerated stability data of at least 6 months on two
pilot/production batches of the drug product in the proposed container closure
system with a letter of undertaking to continue the on-going real time stability
studies and report to HSA of any out-of-specification result (with proposed
action) or when requested.
B12 Change of Shelf Life or Storage Condition of Drug Product

2) Results of real time stability studies of at least two pilot/production batches of
the drug product in the registered container closure system covering the
duration of the proposed/approved shelf life under the proposed/approved
storage condition.
B13 Change of Shelf Life After Reconstitution or First Opening

2) Results of appropriate in-use stability studies of at least two production
batches of the product after reconstitution or first opening in the registered
container closure system covering the duration of the proposed shelf life after
reconstitution or first opening in accordance with the relevant guidelines;
3) Results of appropriate microbiological testing, if applicable.

B14 Change of Pack Size for Sterile Drug Product

For any changes including changes to the fill weight or volume of a sterile drug product
1) Justification that the proposed pack size is consistent with the dosage regimen
and duration of use as is approved in the package insert or Patient Information
Leaflet;
2) Validation data of the manufacturing process, sterilization and container
closure system (where applicable);
3) Results of the real time stability study for at least 6 months on 2
pilot/production batches of drug product in the proposed pack size with a letter
of undertaking to continue the stability studies up to the proposed shelf life and
to report to HSA should any results fall outside shelf life specification (with
specifications of the drug product are not affected if applicable.
B15 Change of Sterility Testing to Parametric Release

Consult HSA prior submission
HSA reserve the right to request for more supporting documents if deemed necessary
1) Risk assessment: prior knowledge, consistency of performance of sterilizer,
historical batch analysis data, risk of loading pattern/container/contamination
from the environment to product sterility, re-processing plan and etc.
2) Process validation of sterilizer: type/design/cycle parameter, container closure
system integrity, heat distribution study for 3 consecutive runs, heat penetration
studies for 3 consecutive runs for each loading pattern and container size,
effectiveness of the load monitor used for each routine run, bioburden, sterility
assurance level of 10-6 or better should be demonstrated, re-processing (if
applicable) and etc.
3) Control Strategy: Tabulation of all validated critical process parameter and
loading pattern, describes the process and requirement for releasing/rejection
of a batch, bioburden monitoring and control program, segregation of sterile
from non-sterile product, routine maintenance/re-validation program for
sterilizer and etc.
4) Approval letter for parametric release from regulatory agency of any PIC/s or
Japan
5) Revision of the certificates of analysis that parametric release is now the
method used to provide assurance of the requirement of sterility

B16 Change of Product Labelling

For safety-related changes of the product labels, refer to MIV-2 C34
Conditions
- The change is not a major variation (MAV)
1) Justification and clinical documents to support the proposed changes.

PART C: DOSSIER REQUIREMENTS FOR MIV-2 VARIATION
An MIV-2 application is a variation for which only a notification is required to be submitted

to HSA. Each MIV-2 notification shall be submitted at least 40 working days before
implementation of the variation.
submitted as an MIV-1 with supporting documents. HSA reserves the right to re-
categorise the MIV if deemed appropriate.
A below:
Soft Copy Hard Copy

+
#
+
When submitting the Checklist for Minor Variation Applications (MIV-2) for Chemical
Drugs, product licence holders must make the following declaration:

Summary;
The change(s) will not adversely affect the quality, efficacy and safety of the
product;


Summary;
product;
All Conditions for the notification(s) concerned are fulfilled; and,
The required documents for the notification(s) have been submitted.
____________________ ______________________ _______________

Name Signature Date
C1 Change of Product Name

Conditions
- There is no change to the product (formulation, release and shelf life specifications,
manufacturing source and process) except the product name change
- There is no confusion with another drug product either when spoken or written
- The new name does not imply (a) greater safety or efficacy than supported by clinical
data, (b) superiority over a similar product in Singapore, (c) imply a therapeutic use for
the product, or (d) the presence of substance(s) not present in the product
1) Official letter authorising the change of product name;
2) A declaration from the product licence holder that there is no change to the
product except name;
3) Official letter to inform users of the relevant changes, and that the current
product stocks will be exhausted before the product labelled with the new
name is marketed;
C2 Change of Product Owner

Conditions
- The product licence holder remains the same
1) Official letter from the previous Product Owner indicating the transfer of
ownership to the new Product Owner;
2) Official letter from the new Product Owner declaring the change, and
authorising the local product licence holder to be responsible for the product
licence in Singapore;
3) If the new Product Owner is not the manufacturer and/or batch releaser of the
drug product, an official letter by the new Product Owner authorising the
manufacturer and/or batch releaser to manufacture and/or batch release the
drug product on its behalf.

C3 Change of Batch Numbering System

1) Description of the batch numbering system;
2) Official letter stating the commencement date of the change.
C4 Withdrawal or Deletion of Manufacturer

For Drug Substance, Drug Product, Packager and/or Batch Releaser
1) Reason for withdrawal or deletion.
C5 Renaming of Manufacturing Site of Drug Substance

Conditions
- The manufacturing site of the drug substance remains at the same physical location
1) A declaration from the product licence holder that manufacturing site remains
the same and that the renaming does not involve changes to the manufacturing
process and/or quality of the product;
2) Updated information of the manufacturer of the drug substance.
C6 Minor Change of Manufacturing Process of Drug Substance

Conditions
- The synthetic route remains the same
- There is no adverse change in the physical properties
- The specification and re-test period/shelf life of the drug substance remains the same
- There is no new impurity or change in level of impurities which would require further
qualification via toxicological safety studies
1) Amended relevant CTD S sections;
3) (a) A declaration from the product licence holder that the specification of the
drug substance has not changed; OR,
provided;
4) A declaration from the product licence holder that no new impurities have been
introduced at or above the accepted threshold for qualification of impurities OR
that there is no increase in the level of impurities that would require further
safety studies;
pilot scale) manufactured according to the currently approved and proposed
process; and,
6) A declaration that

(a) the stability studies on at least two batches of drug substance (pilot or
production scale) have been started and will continue to the registered re-test
period/shelf-life; AND,
(b) to provide the data to HSA if there are any out-of-specification results (with
proposed action) or when requested.
C7 Change of Batch Size of Drug Substance

Conditions
- The change does not affect the reproducibility of the process
1) Amended relevant CTD S sections;
2) Specification of the drug substance;
3) Comparative batch analysis data (in a table) on a minimum of one batch
manufactured to according to the currently-registered and proposed batch
sizes;
4) A letter of commitment
(a) to provide upon request batch analysis data on the next 2 batches at the
proposed batch size; AND,
(b) to report of any out-of-specification results (with proposed action).
C8 Change to Comply with Accepted Pharmacopoeia for Drug Substance

Pharmacopoeias accepted by HSA are Ph. Eur., USP, BP, and JP
Conditions
- The change is made exclusively to comply with an update of the relevant
pharmacopoeial monograph
- The change excludes a change from one accepted pharmacopoeia to another
1) A comparative table of the current and revised specifications, with changes
2) Revised specification of the drug substance;
3) Batch analysis of the drug substance for all tests under the proposed
specification;
4) The latest version of the duly authorised, valid CEP for the drug substance,
with all annexes, where applicable.

C9 Change of Test Procedure of Drug Substance

Conditions
- Results of the method validation show the new test procedure to be at least equivalent
to the former procedure
1) Specification of the drug substance;
2) Description of the analytical methodology, a summary of validation data and
comparative analytical results between the current and proposed test method,
if appropriate;
3) A declaration from the product licence holder that the specification of the drug
substance has not changed.

Drug Substance
Conditions
- New test method does not concern a novel non-standard technique or a standard
technique used in a novel way
1) A comparative table of the current and revised specification of drug substance,
with the changes clearly indicated (e.g. underscored, highlighted);
2) Revised specification of the drug substance;
3) Description of any new analytical method and summary of the validation data,
where applicable;
4) Batch analysis of the drug substance for all tests under the new specification;
5) Justification of the specification or change.
C11 Extension of Retest Period or Shelf Life of Drug Substance

Condition
- The studies must show compliance with the registered specification
1) Shelf-life specification of the drug substance;
2) Stability data of the drug substance of at least two batches (pilot or production
scale) to the proposed retest period or shelf life.

C12 Change of Imprints, Bossing or Other Markings on Tablet or Printing on

Capsules
For changes affecting tablets and capsules
For changes including the addition or change of the inks used for product marking
Conditions
- The new markings do not cause confusion with other tablets or capsules
- The inks have not been rejected for pharmaceutical use
- The release and shelf life specifications of the drug product have not changed except
for appearance
- For changes involving the score/break line, refer to MIV-1 B4
1) Detailed drawing and written description of the current and proposed imprint,
bossing, markings and/or inks;
2) Details of the proposed new inks, if applicable;
specifications of the drug product have not changed (except for appearance);
(a) to inform users of the relevant changes; AND,
marketed.
C13 Change of Dimensions of Tablet, Capsule, Suppository or Pessary

C13.1 Conventional dosage form, suppository and pessary
C13.2 Critical dosage form and scored tablet
Conditions
- There is no change in the qualitative and quantitative composition and mean mass of
the drug product
- There is no change in the dissolution profile
- The release and shelf life specifications of the drug product have not changed except
for dimensions
C13.1 Conventional dosage form, suppository and pessary
1) Detailed drawing and written description of the current and proposed
appearance;
2) Revised drafts of the package insert and labelling incorporating the proposed
variation, where applicable;
3) Release and shelf life specifications of the drug product.
C13.2 Critical dosage form and scored tablet
4) C13.1 documents (1), (2) and (3);
5) Comparative dissolution data on at least one pilot/production batch of the
current and proposed dimensions in accordance with HSAs drug registration
guidelines;
6) Justification for not submitting a new bioequivalence study;
7) For a scored tablet, data on the test for uniformity of content of the subdivided
parts of the tablet at release should be submitted.

C14 Minor Change of Excipients

For changes relating to qualitative and/or quantitative changes to the excipient
composition of a drug product
Conditions
- The total quantitative change is within 5% (w/w), inclusive of the following:
Disintegrant: Starch ( 3%), other ( 1%)
Binder ( 0.5%)
Lubricant: Ca or Mg Stearate ( 0.25%), other ( 1%)
Glidant: Talc ( 1%), other ( 0.1%), and/or,
Film Coat ( 1%)
- A single excipient is replaced with a comparable excipient at a similar level
- There is no change in functional characteristics of the pharmaceutical form, e.g.
disintegration time, dissolution profile
- Any minor adjustment to the formulation to maintain the total weight should be made by
an excipient which currently makes up a major part of the finished product formulation, if
applicable
- The release and shelf life specifications of the drug product have not changed,
excluding deletion of identification test (if applicable)
- For new proposed novel excipients, refer to MIV-1 B5
- For a change of the preservatives, refer to MIV-1 B3
- For changes affecting the release and shelf life specification of the drug product, refer to
MIV-1 B3
1) A comparative table of the current and revised product formulation with the
changes clearly indicated (e.g. underscored, highlighted);
3) Justification for the change of excipients must be given by appropriate
development pharmaceutics (including stability aspect and antimicrobial
preservation where appropriate);
4) Specifications of the new excipient, if applicable;
previously assessed should be provided;
6) Release and shelf-life specification of the drug product;

7) A declaration from the product licence holder that
(a) the release and shelf life specifications of the drug product have not
changed; AND,
(b) the new excipient does not interfere with the drug product release and shelf
life specifications test method, where applicable;
8) Batch analysis data of the new drug product;

(a) the stability studies on at least two batches (pilot or production scale) of
drug product have been started and will continue to the registered shelf-life;
AND,
11) Comparative dissolution data between the current formulation (production
scale) and the proposed formulation (at least pilot scale) in accordance with the
relevant guidelines.
C15 Change of Colouring System of Drug Product

For changes relating to an addition, deletion or replacement of a colouring system
Conditions
- The colouring systems have the same functional characteristics
- There is no change in dissolution profile for solid oral dosage forms
- The colouring system must not have been rejected for pharmaceutical use
- The release and shelf life specifications of the drug product have not changed, except
for the change in appearance/colour
1) A comparative table of the current and proposed product formulation, including
the qualitative and quantitative information of the colouring system;
(a) the release and shelf life specifications have not changed, except for
appearance; AND,
(b) the change in the colouring system does not interfere with the drug product
release and shelf life specifications test methods;
(a) the stability studies on at least two batches of drug product(pilot or
production scale) have been started and will continue to the registered shelf-
life; AND,
(a) to inform users of the relevant changes; and,
marketed.

C16 Change of Flavouring System of Drug Product

For changes relating to an addition, deletion or replacement of a flavouring system
Conditions
- The proposed flavour must not have been rejected for pharmaceutical use
for the change in flavour
1) A comparative table of the current and proposed product formulation, including
the qualitative and quantitative information of the flavouring system;
(a) the release and shelf life specifications have not changed, except for the
flavour; AND,
(b) the change in the flavouring system does not interfere with the drug product
release and shelf life specifications test methods;
(a) the stability studies on at least two batches of drug product(pilot or
production scale) have been started and will continue to the registered shelf-
life; AND,
marketed.
C17 Quantitative Change in Coating Weight of Tablet or Weight of Capsule Shell

Conditions
- The product release and shelf life specifications have only been updated with respect to
the weight and dimensions, if applicable
1) Revised manufacturing batch formula;
2) Revised release and shelf life specifications of the drug product;
(a) the release and shelf life specifications have not changed, except for the
average weight and/or dimensions; AND,
(b) the change does not interfere with the drug product release and shelf life
specifications test methods;
5) Comparative dissolution data between the currently-registered drug product
(production scale) and the proposed drug product (at least pilot scale) in
accordance with the relevant guidelines (for modified release products, in vitro
data which has been correlated with in vivo data should be provided).

C18 Renaming of Manufacturing Site of Drug Product

Conditions
- The manufacturing site for the drug product remains at the same physical location
1) Official letter from the Product Owner authorising the manufacturer with the
new name/address to manufacture the drug product, where applicable;
2) A CPP or GMP certificate with the new name or address;
3) A declaration from the product licence holder that the manufacturing site
remains the same and that the renaming does not involve changes to the
manufacturing process and/or quality of the product.
C19 Addition or Replacement of Secondary Packaging Site

1) Official letter from the Product Owner authorising the proposed manufacturer to
perform secondary packaging;
2) Evidence (i.e. GMP certificate) demonstrating that the proposed site is
appropriately authorised for the packaging activity concerned.
C20 Addition or Replacement of Site Responsible for Batch Release

Conditions
- The manufacturer and primary packager of the drug product remains the same
1) Official letter from the Product Owner authorising the proposed site to be
responsible for batch release;
2) GMP certificate of the proposed site, where applicable.

C21 Change of Batch Size of Drug Product

Conditions
- The change does not affect the consistency of production
- The change only applies to standard immediate release oral dosage forms and to non-
sterile liquid forms, otherwise refer to MIV-1 B8
- The change involves up to a 10-fold change when compared to the batch size currently
registered with HSA
- Validation scheme is available or validation of the manufacture has been successfully
carried out according to protocol with at least three consecutive batches at the
proposed new batch size in accordance with the relevant guidelines
2) (a) Validation scheme and data; OR,
(b) Scientific justification if validation data is not submitted;
4) Comparative batch analysis data (in a table) on a minimum of one production
batch manufactured to both the currently approved and the proposed batch
sizes;
5) A letter of commitment to provide upon request batch analysis data on the next
two batches and to report to HSA of any out-of-specification release and shelf-
life result (with proposed action);
6) A letter of commitment to put the product manufactured according to the
proposed batch size under stability studies in accordance with the relevant
stability guidelines.
C22 Change of In-Process Control of Drug Product

Conditions
- In-process control limits are tightened or new tests are added
- For major changes in the in-process control of the drug product, refer to MIV-1 B9
1) A comparative table of the current and proposed in-process controls with the
changes clearly indicated (e.g. underscored, highlighted);
2) A description of the analytical methodology and summary of validation data
must be provided for all new analytical methods, where applicable;
3) Batch analysis data of one production batch of the drug product for all tests in
the proposed specification, if applicable.

C23 Minor Change of Manufacturing Process of Drug Product

Conditions
- The release and shelf life specifications of the drug product are not adversely affected
- The new process must lead to an identical or better product regarding all aspects of
quality, safety and efficacy
- The product is not a sterile drug product
- For major changes in the manufacturing process such as from wet granulation to direct
compression of dry powder, refer to MIV-1 B9
2) A comparative table of the current and proposed process with changes
3) Provide scientific justification for the change;
4) Process validation data should be submitted, unless justified;
5) (a) Release and shelf life specifications of the drug product; and/or,
(b) If there is any change of the specification (i.e. tightening), a comparative
provided;
6) Comparative batch analysis data (in a table) of at least one production batch
manufactured according to the currently-registered and proposed process;
(a) the stability studies on the drug product have been started and will
continue to the registered shelf-life; AND,
(b) to provide the data to HSA if there are any out-of-specification results
(with proposed action) or when requested;
9) Comparative dissolution data of one production batch from the current and
proposed process in accordance to the relevant guidelines.
C24 Change to Comply with Pharmacopoeia for Excipient

Pharmacopoeia accepted by HSA include Ph. Eur., USP, BP, and JP
Conditions
- The change is made exclusively to comply with an update of the relevant monograph of
the Pharmacopoeia
1) A comparative table of the current and revised specifications of the excipient
with the changes clearly indicated (e.g. underscored, highlighted);
2) Specifications of the excipient;
3) Batch analysis of the excipient for all tests in the new specification;
4) Official letter to declare that the quality of the drug product is not adversely
affected.

C25 Change of Test Procedure for Excipient

Conditions
- Appropriate validation studies have been performed in accordance with the relevant
guidelines
- Results of the method validation show that the new test method is at least equivalent to
the former method
- The new test method does not concern a novel non-standard technique or a standard
1) Description of the proposed analytical method and a summary of the
validation data;
2) Comparative validation results showing that the current test and the proposed
one are equivalent;
3) Revised specification for the impurities, if applicable.

Excipient
Conditions
1) A comparative table of the current and revised specification of the excipient
with changes clearly indicated (e.g. underscored, highlighted);
2) Revised specification of the excipient;
if applicable.
C27 Change of Test Procedure of Drug Product

Conditions
- Results of the method validation show that the new test procedure is at least equivalent
to the former method
1) Description of the proposed analytical method and appropriate validation
data;
2) Comparative validation results between the current and the proposed
analytical method;
3) Comparative release and shelf life specifications of the drug product, if
applicable.

C28 Tightening of Release and Shelf Life Specifications or Addition of New Test
Parameter and Limit of Drug Product
Conditions
1) A comparative table of the current and revised release and shelf life
specifications of the drug product with the changes clearly indicated (e.g.
underscored, highlighted);
2) Revised release and shelf life specifications of the drug product;
3) Batch analysis of the drug product for all tests in the new specification;
4) Descriptions of any new analytical method and a summary of validation data,
if applicable.
C29 Minor Change of Container Closure System of Drug Product

Conditions
- The change relates to the same container closure system (for example blister to blister)
- The proposed packaging material must be at least equivalent or better than the
currently-registered material in respect of its relevant properties
- For changes relating to sterile products, refer to MIV-1 B11
1) Justification for the change of, with appropriate scientific studies on, the new
packaging material;
2) For semisolid and liquid dosage forms, scientific evidence that there is no
interaction between the product and the packaging material (e.g. no migration
of components of the proposed material into the product, no loss of
components of the product into the material);
3) A declaration from the product licence holder that the product will meet the
release and shelf life specifications;
4) Specifications of the immediate packaging material;
(a) the stability studies on at least two batches (at least pilot scale) of the drug
product have been started and will continue to the registered shelf-life; AND,

C30 Change in Shape or Dimensions of Container Closure System

Conditions
- There is no change in the qualitative and quantitative composition of the container and
stability of the product in the container
- The change does not concern a fundamental component of the packaging material
which affects the delivery or use of the product
- The change does not relate to sterile preparations
specifications of the drug product have not changed;
2) Detailed description and drawing of the new container shape;
3) A declaration from the product licence holder that the specifications of the
container (except for shape) have not changed;
(a) the stability studies on at least two batches (at least pilot scale) of the drug
product in the proposed container (for changes in headspace or
surface/volume ratio) have been started and will continue to the registered
shelf-life; AND,
C31 Addition or Change of Pack Size for Drug Product

Conditions
- The change does not apply to sterile preparations unless the change relates to the
number of units in the secondary packaging, otherwise refer to MIV-1 B14
- The change does not apply to sterile products unless the change relates to the number
of containers, sachets, tablets, etc. in the secondary packaging, otherwise refer to MIV-
1 B14
- There is no change to the release and shelf life specifications of the drug product
- The new pack size is consistent with the dosage regimen and duration of use as
approved in the PI
- The packaging material remains the same
1) Justification that the new pack size is consistent with the dosage regimen and
duration of use as is approved in the PI;
specifications of the drug product are not affected, the container and closure
composition is unchanged;
(a) the stability studies on at least two production batches of the drug product
where stability parameters could be affected have been started and will
continue to the registered shelf-life; AND,
(with proposed action) or when requested.

C32 Deletion of Pack Size for Drug Product

1) Reason for deletion.
C33 Addition or Replacement of Measuring Device for Oral Liquid and Other
Dosage Forms
Conditions
- The size and the accuracy of the proposed measuring device (if applicable) must be
compatible with the approved posology stated in the currently-registered PI
- The new device is compatible with the drug product
1) Detailed description and drawing of the device;
2) The composition of the device material;
3) Scientific justification and evidence that shows that size and accuracy of the
device are adequate for the approved posology stated in the product
labelling.
C34 Change of Product Labelling due to Safety Updates

Conditions
- The change relates to tightening of the products target-patient population
- The change is an addition of warnings, precautions, contraindications or adverse
events/effects to the approved product labels
1) Official letter stating:
(a) the reasons for the notification, AND,
(b) the status of the proposed changes in other countries;
2) A declaration from the product licence holder that no other changes have
been made to the labelling and that the changes are supported by data.
C35 Change of Product Labelling Relating to:

Addition/deletion/change of bar code
Replacement of distributor details
Layout or editorial change
Deletion of indication (Note: Re-inclusion of the deleted indication in the future
should be submitted as MAV-1 according to the prevailing requirement)
Addition/deletion/replacement of logos, pictures or diagrams that do not
imply an unapproved indication
Conditions
- There is no change to the text or meaning of the wordings
- The change is not an MAV and does not contain promotional information
been made to the labelling.

C36 Change of Product Labelling of Language(s) Other Than English

Conditions
- There is no change to the text or meaning of the English wording
- The change is not an MAV and does not contain promotional information
1) A declaration from the product licence holder that the information in the non-
English language(s) provides complete, accurate and unbiased information
on the product and is consistent with the English information.


GUIDELINE ON MINOR VARIATION APPLICATIONS FOR BIOLOGICS
APPENDIX 16 GUIDELINE ON MINOR VARIATION APPLICATIONS FOR

BIOLOGIC DRUGS
TABLE OF CONTENTS
PART A: INTRODUCTION .................................................................................................. 3
PART B: DOSSIER REQUIREMENTS FOR MIV-1 VARIATION ........................................ 6
B1 Change of Manufacturing Site ....................................................................................... 7

B2 Change of Testing Laboratory ....................................................................................... 8
B3 Change of Manufacturing Process ................................................................................ 8
B4 Replacement of a Master Cell/Seed Bank ..................................................................... 9
B5 Change of Excipient ...................................................................................................... 9
B6 Change of Specifications............................................................................................. 10
B7 Change of Test Procedure .......................................................................................... 11
B8 Change of Container Closure System ......................................................................... 11
B9 Change of Pack Size of Drug Product ....................................................................... 111
B10 Change of Shelf Life and/or Storage Condition ........................................................... 12
B11 Change of Product Label............................................................................................. 12
B12 Seasonal Variation of Influenza Strains for Vaccine .................................................... 12
PART C: DOSSIER REQUIREMENTS FOR MIV-2 VARIATION ...................................... 14
C1 Change of Product Name ............................................................................................ 15

C2 Change of Product Owner ........................................................................................... 15
C3 Change of Batch Numbering System .......................................................................... 16
C4 Withdrawal of Manufacturing Site ................................................................................ 16
C5 Renaming of Manufacturing Site ................................................................................. 16
C6 Addition or Replacement of Secondary Packaging Site............................................... 16
C7 Change of Batch Releaser Site ................................................................................... 16
C8 Minor Changes in Manufacturing Process ................................................................... 17
C9 Replacement or Change of Working Cell/Seed Bank .................................................. 18
C10 Change in Colouring and/or Flavouring System of Product Including Addition, Deletion
or Replacement of Colourant(s) and/or Flavourant(s). ................................................ 18
C11 Change to Comply with Pharmacopoeia for Excipient ................................................. 19
C12 Tightening of Specification or Addition of New Test Parameter and Limit of Excipient 19
C13 Minor Change of Container Closure System .............................................................. 20
C14 Change of Secondary Packaging ................................................................................ 20
C15 Change of Pack Size for Drug Product ........................................................................ 21

C16 Deletion of Pack Size for Drug Product ..................................................................... 21

C17 Change of Product Labelling due to Safety Updates ................................................. 21
C18 Change of Product Labelling Relating to: .................................................................. 22
C19 Change of Product Labelling of Language(s) other than English ............................... 22
PART D: DOSSIER REQUIREMENTS FOR VARIATION OF A PLASMA MASTER FILE. . 23
D1 Inclusion of New/Updated/Amended PMF ................................................................... 24

PART A: INTRODUCTION
This document describes the requirements of a Minor Variation Application (MIV) submitted
for an existing registered biologic drug product in Singapore. Product licence holders
should be familiar with the contents of this document, the Guidance on Medicinal Product
Registration in Singapore and the governing legislation prior to submitting an MIV to HSA.
Minor Variation Applications are divided into two sub-categories:

MIV-1: A minor variation which requires regulatory approval
MIV-2: A minor variation or an administrative change

NOTE: Product licence holders are encouraged to email the MIV Filing and
Submission Inquiry Form in Appendix 14 for any issues regarding MIV filing, such as
relevant checklist could not be found.
A minor variation application (MIV) is submitted via the Amendment to a Licence of

Western Drug Product form in PRISM.
Product licence holders should disclose all proposed change(s) in Section 0 Licence
Summary under Section 0.4 Amendment Summary and in the Table of Amendment
Details, which can be downloaded via the link indicated in Section 0.5 Amendment Details.
Any undisclosed variation(s) embedded in the submitted data, or any flow-on changes not
specifically requested by HSA, will not be considered for evaluation.

Click here for the Table of

Amendment Details template
The following documents must be submitted with each MIV submission, as given in Table A
below:
Soft Copy Hard Copy

+
#
Relevant CTD section(s) of the currently registered version PRISM N/A
with the proposed change(s) clearly annotated
+
The Checklist for Minor Variation Applications for Biologic Drugs is located in Part B, C and
D of this guidance document. These checklist serves as a guide for submitting the required
documents relevant to each proposed MIV. When submitting the Checklist, the following
should be included:
A copy of the relevant checklist(s) to each proposed MIV(s) the boxes should be
checked to ensure that the required documents are included in the submission; and,
The Declaration for the MIV with the submission date and the local product licence
holders name and signature.
The Table of Amendment Details concisely describes the proposed MIV(s). The following
information must be stated in the Table:
Section of the original dossier affected by the change(s);
Current and proposed condition(s);
Reason for the change(s); and,

Registration status and date of the proposed change(s) in other countries/agencies

that had approved the variation(s), especially the country of origin and the reference
agencies.
For an MIV application with multiple related or unrelated variations, all of the
supporting documents for each individual variation should be submitted. If the
required documents have not been submitted, justification must be provided.
assessment. Product licence holders are responsible for ensuring that all necessary
validations were conducted to demonstrate that the change does not adversely affect the
quality, safety or efficacy of the product concerned. HSA reserves the right to request
additional information if deemed appropriate.

PART B: DOSSIER REQUIREMENTS FOR MIV-1 VARIATIONS
A below:
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When submitting the Checklist for Minor Variation Applications (MIV-1) for Biologics,
product licence holders must make the following declaration:

Summary;


Summary;
____________________ _________________________ _____________

Name Signature Date
B1 Change of Manufacturing Site

For any change, including addition to or replacement, of currently registered
manufacturing site(s) of drug substance, drug product, process intermediates, and/or
primary packager
If there are any changes in the manufacturing process, include documents listed
under MIV-1 B3
1) Proof that the proposed site is appropriately authorised for the
pharmaceutical form concerned: a GMP certificate;
perform the related activity;
3) Batch numbering system for the proposed site;
4) Comparative table that highlights all of the differences of the manufacturing
process and controls of the drug substance between the currently-registered
information and the proposed manufacturer, where applicable;
5) Amended relevant CTD Sections;
6) For the change of manufacturing site for drug substance or drug substance
intermediates, comparability of approved and proposed drug substance or
any intermediate of the drug substance (where applicable) with respect to
physico-chemical characterization, biological activity and impurity profile;
7) Validation study reports and/or summaries of the manufacturing process at
the proposed manufacturing site;
8) Release and/or shelf life specifications;
9) Comparative batch analysis data (in a table) of at least three batches
manufactured at the currently registered and proposed site;
10) (a) Results of appropriate stability studies of at least three batches produced
at the proposed manufacturing site in accordance with the relevant stability
guidelines; AND,
(b) a letter of undertaking to continue the stability studies to the retest period
or shelf life, where applicable, and to report to HSA of any out-of-specification

B2 Change of Testing Laboratory

For any addition or replacement of the current registered laboratories for stability tests
or any quality control (QC) tests
perform the related activity;
2) Release specification;
3) Validation study reports and/or summaries at the proposed site;
4) Analytical assays at the proposed site;
5) Comparative batch analysis data (in a table) of at least two batches tested at
the currently registered and proposed site.
B3 Change of Manufacturing Process

For any change in the procedure and/or scale of the current registered manufacturing
process at any stage during manufacture of drug substance, process intermediates
and/or drug product.
For any changes not covered by MIV-2 C8.
2) Amendment of the relevant section(s) of the dossier;
3) For the change of manufacturing process for drug substance or drug
substance intermediates, comparability of approved and proposed drug
substance or any intermediate of the drug substance (where applicable) with
respect to physico-chemical characterization, biological activity and impurity
profile;
4) Validation study reports and summaries of the proposed manufacturing
process;
5) Release and/or shelf life specifications;
manufactured according to the currently registered and proposed process;
with the proposed manufacturing process in accordance with the relevant
stability guidelines; AND,
(a) there is no change in qualitative and quantitative impurity profile or in
physico-chemical properties;
(b) the change does not adversely affect the reproducibility of the process;
(c) it is not the result of unexpected events arising during manufacture or
because of stability concerns; AND,
(d) the specifications of the drug substance and/or drug product remain
unchanged.

B4 Replacement of a Master Cell/Seed Bank

For the generation a new master cell/seed bank derived from the original or pre-
approved master cell/seed bank or working cell/seed bank by subcloning
This does not relate to any change in host cell line
HSA reserves the right to re-categorise the application to NDA, if deemed appropriate
1) Source, history and passage number of the new master cell/seed with
documentation of all raw material of human or animal origin used for the
entire culture history;
2) Result of all identity testing, including cytogenetic characteristics that could be
used to identify the cells;
3) Results of all available adventitious agent testing on the donor and the new
master cells;
4) Growth and expression characteristic if the cell substrate is used to produce a
recombinant protein. This includes evaluating the copy number and stability of
introduced nucleic acids and the quantity and quality of express protein up to
a passage level beyond the anticipated production cycle time;
5) Validated cell stability under the freezing and storage conditions using cell
recovery or viability data;
6) For viral master seed, document all manipulation of the viral phenotype such
as attenuation of virulence or genetic re-assortment or recombinant. This
includes the determination of the nucleic acid sequences and sourcing of the
biological starting material;
7) Sterility tests, mycoplasmas and adventitious viruses test data if appropriate;
8) Comparability of approved and proposed drug substance with respect to
physico-chemical characterization, biological activity and impurity profile;
9) Comparative batch analysis data (in a table) of at least three batches of drug
substance derived from the current and new cell/seed bank;
with the new cell/seed bank in accordance with the relevant stability
guidelines; AND,
B5 Change of Excipient
For any change of the qualitative or quantitative formulation of the excipients of drug
substance and/or drug product.
HSA reserves the right to re-categorise the application to NDA, if deemed appropriate.
1) A table of the current and revised product formulation with the changes
clearly indicated (e.g. underscored, highlighted) and the calculated
percentage of changes;

3) Justification for the change must be given by appropriate development

pharmaceutics (including stability aspect and antimicrobial preservation
where appropriate);
4) Information demonstrating comparability in term of physico-chemical
characterization and impurity profile of the proposed excipient with the
approved excipient (if applicable).
5) A table of the current and proposed manufacturing batch formula with the
changes clearly indicated;
6) Amended relevant CTD P4 section;
assessed should be provided;
8) A declaration that the change of excipient does not interfere with the drug
product release and shelf life specification test methods;
9) Release and shelf life specifications;
manufactured according to the currently registered and proposed formulation;
11) (a) Results of appropriate stability studies of at least three batches with the
proposed formulation in accordance with the relevant stability guidelines;
AND,
result (with proposed action) or when requested.
B6 Change of Specifications
For any change of release and/or shelf life specifications of drug substance, drug
product, in-process tests, product release tests, and/or stability tests
1) Scientific and/or historical data with justification to support the change;
2) Currently registered version of the release and/or shelf life specifications with
the proposed change(s) clearly highlighted, underscored, or otherwise
indicated;
3) Proposed release and/or shelf life specification;
4) Batch analysis for all tests in the proposed specification;
5) For any change of the stabilityindicating parameters in the specification,
(a) results of appropriate stability studies of at least three production batches
tested according to the proposed specification in accordance with the relevant

B7 Change of Test Procedure

For any change of test procedure of drug substance, drug product, in-process tests,
excipients, product release tests, and/or stability tests
1) Release and/or shelf life specification;
2) Description of the proposed analytical method
3) Validation study reports and summaries of the proposed test procedure;
4) Comparative test results between the current and proposed test procedure.
B8 Change of Container Closure System

For any change, including type of container closure, qualitative and/or quantitative
composition, shape and dimension of the container closure system that is in
immediate contact with the drug substance, drug product, process intermediates,
and/or diluent used for reconstitution
For any changes not covered by MIV-2 C13 & C14
1) Information on construction materials and design features of the proposed
container closure system;
2) Study reports and/or summaries on compatibility, leaching materials, leak
tests, etc. for demonstrating the suitability of using the proposed container
closure system;
3) Validation study reports and/or summaries of the manufacturing process for
any packaged in the proposed container closure system (if applicable);
with the proposed container closure system in accordance with the relevant
B9 Change of Pack Size of Drug Product

1) Justification that the proposed pack size is consistent with the dosage
regimen and duration of use as is approved in the Package Insert or Patient
Information Leaflet;
2) Validation data of the manufacturing process, sterilization and container
closure system (where applicable);
3) A declaration that the release and shelf life specifications of the drug product
are not affected;


with the proposed pack size in accordance with the relevant stability
guidelines; AND,
(b) a letter of undertaking to continue the stability studies to the shelf life and
to report to HSA of any out-of-specification result (with proposed action) or
when requested.
B10 Change of Shelf Life and/or Storage Condition

For any change of shelf life and/or storage condition of drug substance, drug product,
and/or process intermediates after initial opening or after reconstitution
2) Results of appropriate stability studies of at least three batches covering the
duration of the proposed shelf life under the proposed storage conditions in
accordance with the relevant stability guidelines.
B11 Change of Product Label

For any change of product labelling of the package insert (PI), patient information
leaflet (PIL), unit carton label, inner label, and/or blister strips which cannot be
classified as an MAV or an MIV-2 e.g. update concomitant use of Vaccine A with
Vaccine B and addition of clinical studies which are not relevant to the approved
indication are considered an MAV
1) Justification for the proposed change(s) and supporting clinical documents,
where applicable;
2) Currently registered product label with the proposed change(s) clearly
highlighted, underscored, or otherwise indicated;
3) Proposed product label with all change(s) incorporated;
B12 Seasonal Variation of Influenza Strains for Vaccine

For a change of only influenza strains for the formulation of an influenza vaccine
according to WHO Recommendations for Influenza Vaccine Composition may be
expedited (Note: additional changes other than strain changes will require additional
supporting documents, which may delay the evaluation timeline)
1) Currently registered product label with the proposed change(s) clearly
highlighted, underscored, or otherwise indicated;
2) Proposed product label with all change(s) incorporated;
3) CTD Module 2 - Section 2.3 Quality Overall Summary;
4) Identification of working seed stock as per the pharmacopoeial requirements;
5) Validation study reports and/or summaries of the critical manufacturing
process for drug substances (new strain), e.g. inactivation, splitting efficiency;
6) Release and/or shelf life specification for the drug substances;
7) Validation study reports and summaries of the test method for new strain;
8) Batch analyses data for drug substances;

9) Composition of the vaccine;
10) Actual formula(e) of the vaccine used for clinical trial studies and commercial
purpose (in a table);
11) Release and/or shelf life specification for the vaccine;
12) Comparative batch analyses data (in a table) of the vaccines manufactured
using the currently registered and proposed strains;
13) CTD Module 3 Section 3.2.P 8 Stability (Summary & Conclusion) of at least
6 months of the vaccine from the preceding year or season; and,
14) A letter of undertaking to perform stability studies up to the proposed shelf-
life of the product and to report to HSA of any out-of-specification result (with

PART C: DOSSIER REQUIREMENTS FOR MIV-2 VARIATIONS
An MIV-2 application is a variation for which only a notification is required to be submitted

to HSA. Each MIV-2 notification shall be submitted at least 40 working days before
implementation of the variation.
submitted as an MIV-1 with supporting documents. HSA reserves the right to re-
categorise the MIV if deemed appropriate.
Product licence holder should be familiar with the documentary requirements for MIV
A below:
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Summary;
product;


Summary;
product;
____________________ ______________________ _______________

Name Signature Date
C1 Change of Product Name

Conditions
- There is no change to the product (formulation, release and shelf life specifications,
manufacturing source and process) except the product name change
- There is no confusion with another drug product either when spoken or written
- The new name does not imply (a) greater safety or efficacy than supported by clinical
data, (b) superiority over a similar product in Singapore, (c) imply a therapeutic use for
the product, or (d) the presence of substance(s) not present in the product
1) Official letter authorising the change of product name;
2) A declaration from the product licence holder that there is no change to the
product except name;
3) Official letter of commitment to inform users of the relevant changes, and that
the current product stocks will be exhausted before the product labelled with
the new name is marketed.
C2 Change of Product Owner

Conditions
- The product licence holder remains the same
1) Official letter from previous Product Owner indicating the transfer of
ownership to the new Product Owner;
2) Official letter from the new Product Owner declaring the change, and
authorising the local product licence holder to be responsible for the product
licence in Singapore;
3) If the new Product Owner is not the manufacturer and/or batch releaser of the
drug product, an official letter by the new Product Owner authorising the
manufacturer and/or batch releaser to manufacture and/or batch release the
drug product on its behalf.

C3 Change of Batch Numbering System

1) Description of batch numbering system;
2) Official letter stating the commencement date of the change.
C4 Withdrawal of Manufacturing Site

1) Official letter stating the withdrawal or deletion of the manufacturing site to
perform the related activity.
C5 Renaming of Manufacturing Site

Conditions
- The current manufacturing site(s) of drug substance, drug product, process
intermediates, and/or batch release remains unchanged and at the same physical
location
1) Updated information of the manufacturing site(s);
2) A declaration from the product licence holder that the manufacturing site
remains the same and that the renaming does not involve changes to the
manufacturing process and/or quality of the product;
3) A CPP or GMP certificate with new name or address.
C6 Addition or Replacement of Secondary Packaging Site

perform secondary packaging;
2) Evidence (i.e. GMP certificate) demonstrating that the proposed site is
appropriately authorised for the packaging activity concerned.
C7 Change of Batch Releaser Site

Conditions
- Batch release procedure is equivalent between the current and new site
1) Official letter from the Product Owner authorising the proposed site to be
responsible for batch release;
2) A GMP certificate of the proposed site, where applicable.

C8 Minor Changes in Manufacturing Process

For any minor change in the procedure and/or scale of the current registered
manufacturing process at any stage during manufacture of drug substance and/or
drug product
Relates to a non-critical change in the process, such as change in harvesting and/or
pooling procedures without change in the method of manufacturing, recovery, storage
conditions or production scale; duplication of a fermentation train; addition of identical
or similar/comparable bioreactors;
Increase in aseptic manufacturing scale for drug product without change in equipment,
e.g. changes in the number of vials filled.
Conditions:
- No change in the principle of sterilization procedures
- No change in the specifications outside of the approved ranges
- No change in the impurity profile of the drug substance outside of the approved limits
- The change is not caused by recurring events arising during manufacture or because
of stability concerns
2) Amendment of the relevant section(s) of the dossier;
3) Summary of process changes in relation to approved protocol in a table
format;
4) Appropriate justification and validation of the change (where applicable);
5) For the change of manufacturing process for drug substance or drug
substance intermediates, comparability of approved and proposed drug
substance or any intermediate of the drug substance (where applicable) with
respect to physico-chemical characterization, biological activity and impurity
profile;
have not been changed;
manufactured according to currently approved and proposed process;
8) Official letter of commitment to
(a) conduct appropriate stability studies on at least three batches of drug
product (pilot or production scale) in accordance with the relevant stability
guideline; AND,

C9 Replacement or Change of Working Cell/Seed Bank

Conditions
- Establishing a new working cell/seed bank derived from a previously approved master
cell/seed bank according to SOPs on file in the approved license application
1) Comparative summary of the current and new working cell/seed bank cell
number, viability and sterility and functional assay data for the new working
cell/virus bank;
2) Comparative batch analysis data (in a table) of at least three batches of drug
substance derived from the current and new cell/seed bank;
have not been changed;
guideline; AND,
C10 Change in Colouring and/or Flavouring System of Product Including

Addition, Deletion or Replacement of Colourant(s) and/or Flavourant(s).
For changes relating to an addition, deletion or replacement of a colouring or
flavouring system
Conditions
- The colouring systems have the same functional characteristics
- The colouring system must not have been rejected for pharmaceutical use
for the change in appearance/colour/flavour
1) A comparative table of the current and proposed product formulation,
including the qualitative and quantitative information of the colouring and/or
flavouring system;
(a) the release and shelf life specifications of the drug product have not
changed, except for appearance, colour and/or flavour; AND,
(b) the change in the colouring/flavouring system does not interfere with the
drug product release and shelf life specifications test methods;
guideline; AND,
(with proposed action) or when requested; and,


marketed.
C11 Change to Comply with Pharmacopoeia for Excipient

Pharmacopoeia accepted by HSA include Ph. Eur., USP, BP, and JP
Conditions
- The change is made exclusively to comply with an update of the relevant monograph
of the Pharmacopoeia
1) A comparative table of the current and revised specifications of the
excipient(s) with the changes clearly indicated (e.g. underscored, highlighted);
2) Specifications of the excipient;
4) Declaration that the quality of the drug product is not adversely affected.

Excipient
Conditions
1) A comparative table of the current and revised specification of the excipient
with changes clearly indicated (e.g. underscored, highlighted);
2) Revised specification of the excipient;
if applicable.

C13 Minor Change of Container Closure System

For minor change of the container closure system that is in immediate contact with the
drug substance, drug product, process intermediates, and/or diluents used for
reconstitution
The change is made only to improve quality of the container and does not modify the
product-contact material (e.g. increase thickness of the glass vial without changing
interior dimension)
Conditions
- The proposed packaging material must be at least equivalent or better than the
currently-registered material in respect of its relevant properties
- The change does not concern a sterile substance or product
1) Justification for the change of, with appropriate scientific studies on, the new
packaging material;
2) A declaration that the product will meet the release and shelf life
specifications;
3) Information on construction materials and design features of the proposed
container closure system;
(a) conduct appropriate stability studies on at least three batches (at least
pilot scale) of the drug product have been started and will continue to the
registered shelf-life in accordance with the relevant guidelines; AND,
C14 Change of Secondary Packaging

Conditions
- Conformance to current drug product release and shelf life specifications
- The change is consistent with the dosage regimen and duration of use as approved in
the PI
1) Official letter stating that release and shelf life specifications, the container
and closure system compositions have not been changed;
2) Justification that the change is consistent with the dosage regimen and
duration of use as approved in the PI.

C15 Change of Pack Size for Drug Product

For any change only concerns the number of units or containers in a pack; otherwise
refer to MIV-1
Conditions
- There is no change to the release and shelf life specifications of the drug product
- The new pack size is consistent with the dosage regimen and duration of use as
approved in the PI
- The packaging material remains the same
1) Official letter stating that release and shelf life specifications, the container
and closure system compositions have not been changed;
2) Justification that the new pack size is consistent with the dosage regimen and
duration of use as is approved in the PI.
(a) conduct appropriate stability studies on at least three production batches
of the drug product where stability parameters could be affected have been
started and will continue to the registered shelf-life in accordance with the
relevant guidelines; AND,
C16 Deletion of Pack Size for Drug Product

1) Reason for deletion.
C17 Change of Product Labelling due to Safety Updates

Note: Changes to safety information on product labels and package insert may be
allowed without prior approval from HSA provided the changes fulfil the conditions
stipulated below. Companies that need to disseminate safety information urgently can
continue to do so through Dear Healthcare Professionals Letters, in consultation with
HSA. Thereafter, product labelling should be updated in accordance with the labelling
safety-related update notification system.
Conditions
- The change is an addition of warnings, precautions, contraindications or adverse
events/effects to the current product labelling
- The change relates to tightening of the target-patient population
been made to the labelling and that the change is supported by data.

C18 Change of Product Labelling Relating to:

Addition/Deletion/Change of Bar Code
Replacement of Distributor Details
Layout or editorial change
Deletion of Indication (Note: Re-inclusion of the deleted indication in the future
should be submitted as MAV-1 according to the prevailing requirement)
Addition/Deletion/Replacement of Logos, Pictures or Diagrams that do not
Imply an Unapproved Indication
Conditions
- There is no change to the text or meaning of the wordings
- There is no unapproved indications, usages, dosage regimens or promotional
information
been made to the labelling.
C19 Change of Product Labelling of Language(s) other than English

Conditions
- There is no change to the text or meaning of the English wordings
- There is no unapproved indications, usages, dosage regimens or promotional
information
1) A declaration from the product licence holder that the information in other
language(s) provides complete, accurate and unbiased information on the
product and is consistent with the English version.

PART D: DOSSIER REQUIREMENTS FOR THE VARIATIONS OF A PLASMA

MASTER FILE (PMF)
Variations submitted for Plasma Master Files are categorized as a MIV-1 application.
NOTE: If a D1 variation results in consequential changes to the manufacturing

process/control of the plasma-derived drug substance, drug product and/or
excipients, then the relevant variations specified under Part B or Part C should be
filed.
A below:
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Summary;


Summary;
____________________ ______________________ _______________

Name Signature Date
D1 Inclusion of New/Updated/Amended PMF

Conditions
- Variation filed for currently-registered plasma-derived medicinal product
- Variation has potential impact on the quality and safety of the product
1) A GMP certificate for newly included plasma collection and processing facility
and/or GMP Compliance declaration letter for the exiting plasma collection
and processing facility in case of updated/amended plasma source;
2) Updated 3.2.S.2.2 for drug substance and/or 3.2.P.3.3 for drug product,
where applicable;
3) Release and/or shelf life specifications for drug substance;
4) Release and/or shelf life specifications for drug product;
5) Comparative batch analyses data (in a table) of at least three batches
manufacturing using the previous and new/amended plasma sources;
6) Results of appropriate stability studies of at least three batches produced
with the new PMF source and/or amended plasma source, in accordance
with the relevant stability guidelines;
7) Adventitious Agents Safety Evaluation Report, if applicable;
8) An expert statement outlining all changes introduced with the new/updated
PMF or 3.2.S.2.3 section with evaluation of the potential impact on the drug
product, including specific risk assessments;
9) For new/amended PMF, the additional documents required include:
i. New/updated version of the PMF;
ii. A copy of the plasma specification and plasma pool batch analysis data;
iii. EMA annual recertification letter and, if available, recertification
assessment report;
iv. Letter of Access issued by the PMF Holder to the Product Owner; and,

10) For new/updated 3.2.S.2.3 section, the additional documents required

include:
i. New/updated 3.2.S.2.3 section of the dossier, which should include the
following information:
Plasma source and collection;
Characteristics of donations;
Epidemiological data on blood transmissible infections;
Selection/exclusion criteria;
Plasma quality and safety;
Conditions of storage and transport of plasma;
ii. A copy of the plasma specification and plasma pool batch analysis data.
Note: For plasma collection and control information previously submitted as
part of S.3.2.S.2.3 section of the dossier the above information covering the
data requirements as per Appendix 10, PMF Data Requirements should be
submitted as a standalone document.


- GUIDANCE ON REGISTRATION OF SIMILAR BIOLOGICAL PRODUCTS IN SINGAPORE
APPENDIX 17 GUIDANCE ON REGISTRATION OF SIMILAR BIOLOGICAL

PRODUCTS IN SINGAPORE
TABLE OF CONTENTS
1 INTRODUCTION ............................................................................................................. 3
1.1 Scope.................................................................................................................. 3
1.2 Purpose .............................................................................................................. 3
1.3 Definition ............................................................................................................ 3
2 BASIC PRINCIPLES....................................................................................................... 4
2.1 Biosimilar Product Approach ........................................................................... 4
2.2 Choice of Reference Product ............................................................................ 5
3 SUBMISSION PROCEDURE .......................................................................................... 5
4 DOCUMENTARY REQUIREMENTS .............................................................................. 6
4.1 Quality Documentation...................................................................................... 6
4.2 Non-Clinical Documentation ............................................................................. 7
4.3 Clinical Documentation ..................................................................................... 7
5 INTERCHANGEABILITY & SUBSTITUTABILITY .......................................................... 9
6 PHARMACOVIGILANCE REQUIREMENTS .................................................................. 9
7 POST-APPROVAL BATCH RELEASE REQUIREMENTS ........................................... 10

ABBREVIATIONS AND ACRONYMS

ACTD ASEAN Common Technical Document
ADR Adverse Drug Reaction
CHMP Committee for Medicinal Products for Human Use (formerly Committee for
Proprietary Medicinal Products) (EU)
cGMP Current Good Manufacturing Practice
CTD Common Technical Documents
DNA Deoxyribonucleic Acid
EMEA European Medicines Agency (formerly the European Agency for the
Evaluation of Medicinal Products) (EU)
FDA Food and Drug Administration (US)
GLP Good Laboratory Practice
HSA Health Sciences Authority (Singapore)
ICH International Conference on Harmonisation (of Technical Requirements for
Registration of Pharmaceuticals for Human Use)
PD Pharmacodynamics
PK Pharmacokinetics
PSUR Periodic Safety Update Report
QOS Quality Overall Summary
TGA Therapeutics Goods Administration (Australia)
UK United Kingdom
US United States

1 INTRODUCTION
Biological medicines are produced using a living system or organism. They are different from
traditional chemical medicines in many ways. The manufacturing process of a biological
medicine is highly complex and is a determining factor in the development of a biological
medicine. The definition of process includes the type or identity of the source material and
the individual process steps in cell fermentation, protein purification, sterile filling and drug
product formulation. Even very small process changes can result in significant differences in
the clinical properties of the biological medicines.
The expiration of the patents on many biological products has prompted the development of
these products as similar biological products. A similar biological product would have an
abbreviated non-clinical and clinical development programme leveraging on the existing
information of the original product and focusing on demonstration of similarity with the
original product. While the launch of such similar biological products would provide patients
with potentially cheaper alternatives, it is also prudent to ensure that the quality, safety and
efficacy of such products are not compromised.
1.1 SCOPE
This guidance document describes the basic principles of a similar biological product, as well
as the procedures and requirements for registration of a similar biological product.
Applicants are expected to comply with the procedures and requirements laid out in this
guidance. However, alternative approaches to the specified procedures and requirements
may be accepted, provided there is adequate scientific evidence and justification. Any
alternative approach should be discussed with HSA and agreed upon in advance in order to
avoid rejection of the application. Conversely, HSA may request for information or specify
conditions not described in this document but deemed necessary to adequately assess the
safety, efficacy and quality of the product under evaluation.
1.2 PURPOSE
This guidance document is intended to:

Introduce the concept of similar biological products
Outline the basic principles to be applied for similar biological products
Describe the procedure and documentary requirements for submitting an application for
a similar biological product
Describe the pharmacovigilance requirements for similar biological products
Describe the post-approval batch release requirements for similar biological products
This guidance document is adapted mainly from the EMEA guidelines on similar biological
products1,2, with consideration of Singapores local regulatory environment.
1.3 DEFINITION
A similar biological (biosimilar) product is a biological medicinal product referring to an

existing registered product, submitted for medicinal product registration by an independent
1
http://www.emea.europa.eu/htms/human/humanguidelines/multidiscipline.htm
2
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000330.jsp&murl=me
nus/regulations/regulations.jsp&mid=WC0b01ac058002956b

applicant, and is subject to all applicable data protection periods and/or intellectual property
rights for the original product.
Applicants are advised to refer to sections 11 & 12 in the Guidance on Medicinal Product
Registration in Singapore3 for details on Data Protection, Data Exclusivity and Patent
Linkage.
2 BASIC PRINCIPLES
2.1 BIOSIMILAR PRODUCT APPROACH
In principle, the concept of a similar biological medicinal product is applicable to any

biological medicinal product. However, in practice, the success of such a development
approach will depend on the ability to characterise the product and therefore to demonstrate
the similar nature of the concerned products.
Biological medicinal products are usually more difficult to characterise than chemically
derived medicinal products. In addition, there is a spectrum of molecular complexity among
the various products (recombinant DNA, blood or plasma-derived, immunologicals, gene and
cell-therapy, etc.). Moreover, parameters such as the three-dimensional structure, the
amount of acido-basic variants or post-translational modifications such as the glycosylation
profile can be significantly altered by changes, which may initially be considered to be minor
in the manufacturing process. Thus, the safety/efficacy profile of these products is highly
dependent on the robustness and the monitoring of quality aspects.
The standard generic approach (demonstration of bioequivalence with a reference medicinal

product by appropriate bioavailability studies) is normally applied to chemically derived
medicinal products. Due to the complexity of biological/biotechnology-derived products, the
generic approach is scientifically not appropriate for these products. The biosimilar product
approach, based on a comparability exercise (demonstration of similarity), will then have to
be followed.
Current technologies, such as peptide mapping, protein sequencing, and mass spectroscopy
enable manufacturers to determine, with certainty, the amino acid sequence of a
recombinant protein. However, the amino acid sequence is the most rudimentary
characteristic of a protein. Conclusive analysis of other aspects of a protein's structure
requires much more sophisticated technologies and is fraught with uncertainties that are
proportional to the size and complexity of the protein itself. Therefore, the ability to predict
the clinical comparability of two products depends on our understanding of the relationship
between the structural characteristics of the protein and its function, as well as on our ability
to demonstrate structural similarity between the biosimilar product and the reference
product. Although this may be currently possible for some relatively simple protein products,
technology is not yet sufficiently advanced to allow this type of comparison for more complex
protein products. Similarity will therefore need to be confirmed via non-clinical and clinical
studies.
Comparability exercises to demonstrate similarity are more likely to be applied to highly

purified products, which can be thoroughly characterised (such as some biotechnology-
derived medicinal products).
The biosimilar product approach is more difficult to apply to other types of biological
medicinal products, which by their nature are more difficult to characterise, or which have
little clinical and regulatory experience in their evaluation. Whether a medicinal product
3

would be acceptable using the biosimilar product approach depends on the state of the art of
analytical procedures, the manufacturing processes employed, as well as clinical and
regulatory experience.
Vaccines, blood or plasma-derived products & their recombinant alternatives, and other
types of biological medicinal products, such as gene or cell products used for advanced
therapy, and human tissues or cells intended for human application, are of a complex nature
and applications for biosimilar products for such products will not be considered at the
present moment.
Products employing clearly different approaches to manufacture than the reference product
(e.g., use of transgenic organisms versus cell culture, or use of eukaryotic versus prokaryotic
host cell), or any use of a non-analogous host cell line or change to the culture conditions
(e.g. cell monolayer versus suspension), would require a strong rationale in order to be
considered eligible as a biosimilar product.
2.2 CHOICE OF REFERENCE PRODUCT
The chosen reference medicinal product must be a medicinal product registered in

Singapore. A biosimilar product cannot be used as a reference product. Data generated from
comparability studies with medicinal products registered in other countries may only provide
supportive information.
The same chosen reference product should be used throughout the comparability
assessment for quality, safety and efficacy studies during the development of a biosimilar
product in order to allow the generation of coherent data and conclusions. The chosen
reference product used should be of the corresponding strength and from the Singapore
registered drug product manufacturing source.
The active substance of a similar biological medicinal product must be similar, in molecular
and biological terms, to the active substance of the reference medicinal product.
The pharmaceutical form, strength, and route of administration of the similar biological
medicinal product should be the same as that of the reference medicinal product. When the
pharmaceutical form, the strength or the route of administration is not the same, additional
data in the context of the comparability exercise should be provided. Any differences
between the similar biological medicinal product and the reference medicinal product will
have to be justified by appropriate studies on a case-by-case basis.
3 SUBMISSION PROCEDURE
Applicants are encouraged to discuss the submission and documentary requirements in a
pre-submission consultation prior to submission of a biosimilar product. The request for a
consultation should be made in writing, with the purpose and agenda for the consult stated,
via email to HSA_MedProd_Registration@hsa.gov.sg.
Application for a biosimilar product is to be submitted as a new drug application (NDA) via
the abridged dossier evaluation route. The timelines and fees applicable for a NDA via the
abridged evaluation route apply. The administrative requirements are as per required for a
NDA via the abridged dossier evaluation route.

Applicants are advised to refer to the Guidance on Medicinal Product Registration in

Singapore4 for details on the general procedures and requirements for submitting a NDA.
The biosimilar product is to be evaluated and approved by at least one of HSAs reference
agencies namely, Australia TGA, Health Canada, EMEA and US FDA. If not, the submission
is to be submitted with the complete dataset as per required for a new biological product.
Application for a biosimilar product would not qualify for evaluation via the verification
evaluation route as with all biological products.
4.1 QUALITY DOCUMENTATION
The quality documentation requirements are adapted from the CHMP Guideline on Similar
Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active
Substance: Quality Issues (CHMP/49348/05)5, and CHMP Guideline on Comparability of
Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Quality
Issues (CHMP/BWP/3207/00 Rev. 1)6.
The complete quality dossier as required for a new biological product submitted via the
abridged dossier evaluation route is to be submitted, including the Singapore Quality Overall
Summary (QOS).
The biosimilar product shall, with regards to the quality data, fulfill all technical content
requirements for Module 3 of the ICH CTD or Part 2 of the ACTD, and satisfy the technical
requirements of the monographs of pharmacopoeia and any additional requirements, such
as defined by HSA and ICH guidelines. Complete information on the development,
manufacture and control of both the active drug substance and the drug product should be
provided.
Comparability data between the biosimilar product and the reference product (in terms of
quality) must be submitted in the quality dossier. The extent of the comparability studies and
the assessment criteria depends on the complexity of the product and the capability of the
methods used to demonstrate comparability. The comparability exercise should entail
evaluation of both drug substance and drug product. Comparability study must take into
consideration:
the complexity of the molecular structure,
the type of changes introduced in the manufacturing process during development, and
their impact on quality, safety and efficacy.
For the purposes of clarity, any comparability exercise(s) for process changes introduced
during development should be clearly identified and addressed separately from the
comparability exercise versus the reference product.
Comparability is essential to establish an overall development package for biosimilars. The

manufacturer must carefully design the comparability exercise based upon full knowledge of
the molecular structure and its relevance to the mode of action. The result is a series of
physicochemical tests, along or in combination with such biological tests as in vitro and in
vivo bioassays, and receptor binding studies. These tests are applied to the biosimilar and
4
5
http://www.emea.europa.eu/pdfs/human/biosimilar/4934805en.pdf
6
http://www.emea.europa.eu/pdfs/human/bwp/320700en.pdf

the selected reference product to demonstrate similarities and differences between the two
products. Where comparability testing cannot establish similarity or where differences arise,
the outstanding issues must be addressed through supporting preclinical and/or clinical
work.
4.2 NON-CLINICAL DOCUMENTATION
The non-clinical documentation requirements are adopted from the CHMP Guideline on
Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active
Substance: Non-clinical and Clinical Issues (CHMP/42832/05)7.
Before initiating clinical development, non-clinical studies should be performed. These

studies should be comparative in nature and should be designed to detect differences in
response between the similar biological product and the reference medicinal product and not
just the response per se. Relevant international guidelines should be referred to in the
design of an appropriate non-clinical study programme.
The requirements for the non-clinical documentation would include:

In vitro studies: Assays like receptor-binding studies or cell-based assays should
normally be undertaken in order to establish comparability in reactivity and the likely
causative factor(s) if comparability cannot be established.
Animal studies should be performed to investigate pharmacodynamic effect/activity
relevant to the clinical application, non-clinical toxicity as determined in at least one
repeat dose toxicity study, including toxicokinetic measurements, and specific safety
concerns.
Normally other routine toxicological studies such as safety pharmacology, reproduction

toxicology, mutagenicity and carcinogenicity studies are not required for biosimilar products,
unless indicated by the results of repeat dose studies.
4.3 CLINICAL DOCUMENTATION
The clinical documentation requirements are adopted from the CHMP Guideline on Similar
Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active
Substance: Non-clinical and Clinical Issues (CHMP/42832/05)8.
The requirements depend on the existing knowledge about the reference medicinal product
and the claimed therapeutic indication(s). Available product/disease specific guidelines
should be followed when appropriate. Relevant international guidelines should be referred to
in the design of an appropriate clinical study programme for biosimilar products.
The required clinical data for the comparability study should be generated with the test
product produced with the final manufacturing process and therefore representing the quality
profile of the batches to be commercialised. Any deviation from this is to be justified and
supported by adequate additional data.
The clinical comparability exercise should begin with pharmacokinetic (PK) and
pharmacodynamic (PD) studies followed by clinical efficacy and safety studies.
7
8

Comparative PK studies designed to demonstrate clinical comparability between the

biosimilar product and the reference product with regard to key PK parameters are required.
Pharmacodynamic studies to demonstrate therapeutic efficacy of the product is required.
Normally comparative clinical studies are required for the demonstration of clinical
comparability. In certain cases however, comparative PK/PD studies between the biosimilar
product and the reference product may be sufficient to demonstrate clinical comparability,
provided that all the following conditions are met:
The PK of the reference product are well characterised.
There is sufficient knowledge of the PD properties of the reference product, including
binding to its target receptor(s) and intrinsic activity. Sometimes, the mechanism of
action of the biological product will be disease-specific.
The relationship between dose/exposure and response/efficacy of the reference product
is sufficiently characterised.
At least one PD marker is accepted as a surrogate marker for efficacy, and the
relationship between dose/exposure to the product and this surrogate marker is well
known.
For comparative clinical studies to demonstrate clinical comparability between the biosimilar
product and the reference product, clinical comparability margins should be pre-specified
and justified, primarily on clinical grounds.
The conditions of use for the biosimilar product must fall within the directions for use
including indication(s), dosing regimen(s) and patient group(s) for the Singapore reference
product.
In case the reference medicinal product has more than one indication, the efficacy and
safety of the biosimilar product has to be justified or, if necessary, demonstrated separately
for each of the claimed indications. In certain cases it may be possible to extrapolate
therapeutic similarity shown in one indication to other indications of the reference medicinal
product. Justification will depend on e.g., clinical experience, available literature data,
whether or not the same mechanisms of action or the same receptor(s) are involved in all
indications. Possible safety issues in different subpopulations should also be addressed.
Immunogenicity
The ability to predict immunogenicity of a protein product, particularly the more complex
proteins, is extremely limited. Animal studies may not be able to predict how a protein is
likely to behave in humans as immunogenic response is species dependent. Development of
antibodies in some instances is a benign effect causing few, if any, undesirable symptoms in
patients receiving therapy. In other instances, induction of antibodies is associated with
undesirable consequences, which manifest themselves as mild to severe anaphylactoid
reactions. The efficacy may be diminished by induction of neutralising antibodies.
The immunogenicity of a biosimilar product must always be investigated. The extent of

independent testing needed will again depend on a variety of scientific factors such as the
indication, whether the product is to be administered chronically, the overall assessment of
the product's immunogenic potential, and whether there is the possibility of generating a
cross-reaction with an important endogenous molecule.
The assessment of immunogenicity requires an optimal antibody testing strategy,

characterisation of the observed immune response, as well as evaluation of the correlation
between antibodies and pharmacokinetics or pharmacodynamics, relevant for clinical safety

and efficacy in all aspects. It is important to consider the risk of immunogenicity in different
therapeutic indications separately.
Reference is to be made to the CHMP Guideline on Immunogenicity Assessment of

Biotechnology-Derived Therapeutic Proteins (CHMP/BMWP/14327/06)9.
5 INTERCHANGEABILITY & SUBSTITUTABILITY

A product is interchangeable with another if both products are approved for the same
indication, and can be used for the said indication. Two products are substitutable with each
other if they can both be used in lieu of the other during the same treatment period. For
interchangeable products, one or the other can be used (prescribed) but these products
cannot be substituted with one another during a treatment period. Interchangeability does
not imply substitutability.
Unlike generic chemical drugs, whereby the chemical structure is identical to that of the
reference chemical product, a biosimilar product does not usually have an identical structure
to the reference biological product. Therefore, even though a biosimilar product may be
approved to be similar in terms of quality, safety and efficacy to the reference product,
immunogenicity may preclude switching between products.
A warning statement on the risks associated with switching of products during treatment, and
against product substitution, is to be included in the package insert of the biosimilar product.
6 PHARMACOVIGILANCE REQUIREMENTS
At the time of market approval for a medicinal product, information on the safety of the
product is relatively limited. There are some potential risks which may not have been
identified at the time of market authorization due to several factors like small numbers of
subjects in clinical trials, small study population with specific inclusion criteria and short
duration of exposure. However, when the medicinal product is used more widely in the
postmarket setting, new and unidentified risks associated with the product may emerge. In
addition to the above concerns with medicinal products on the whole, biosimilars may induce
unwanted immune response in treated patients.
This potential immunological response is partly a reflection of the complexities of

manufacturing, and safety and efficacy controls of biosimilars when compared to their small-
molecule generic chemical counterparts. With manufacturing protocols being proprietary
knowledge of the originator company, it is impossible for a biosimilar's manufacturer to
duplicate the process. This invariably leads to structural differences in the final products,
resulting in differences in efficacy and adverse events such as triggering of patient's immune
responses, which could have serious consequences.
The current systems of detecting safety issues relating to medicinal products are applicable
for biosimilar products. In view of the inherent potential of biologics to provoke immunologic
reactions, special care on reporting and assessing of adverse reactions should be taken for
biosimilar products.
The following activities are required in addition to current pharmacovigilance activities for
medicinal products:
9
http://www.emea.europa.eu/pdfs/human/biosimilar/1432706enfin.pdf

(i) Adverse drug reaction (ADR) reporting by product licence holders
In the current framework for medicinal products, the product licence holder has to report
suspected serious ADRs occurring in Singapore to the Pharmacovigilance Branch no later
than 15 days from the first receipt of the reports. For biosimilar products, this reporting by
product licence holder will extend to include the reporting of non-serious adverse reactions
that do not appear in the product label occurring in Singapore as well. This is to enable the
Pharmacovigilance Branch to capture cluster effects of both serious and non-serious ADRs.
(ii) Reviewing of periodic safety update reports (PSURs) for biosimilar products
The product licence holder is required to submit the global PSURs to HSA every 6 monthly
for the first 2 years, followed by yearly for the following 3 years for a biosimilar product that is
newly registered in Singapore. In addition, the product licence holder will be required to
submit the line listings of all the serious and non-serious adverse events in Microsoft Excel
format to the Pharmacovigilance Branch to aid in assessments and reviews, when
requested.
(iii) Risk management plans for biosimilar products
For all biosimilar products, additional monitoring activities need to be in place to address the
safety concerns which these products may bring about, on top of routine pharmacovigilance
activities. The product licence holder is required to submit a risk management plan for the
biosimilar product at the time of application for product licensure. The plan must be with the
intention to mitigate potential risks associated to the biosimilar product.
(iv) Educational materials
The product licence holder should provide additional educational materials to the physicians
to provide them with information on the specific risks of the biosimilar product and measures
on how to reduce them.
Patients information leaflets should be prepared by the product licence holder to provide
patients with relevant information on what are the potential risks of the product and what are
the signs and symptoms which they should alert their healthcare providers on.
(v) Product Sales Data
The product licence holder is required to supply the Pharmacovigilance Branch with the
sales data, in terms of number of units of product sold and the buyer categories (e.g.
restructured hospitals, private hospitals, specialist clinics, general practitioner clinics) of their
biosimilar product on a quarterly basis. These data will be used for an estimation of the
number of local exposures to the product. When requested by HSA, the product licence
holder will be required to provide buyer list of their biosimilar product.
7 POST-APPROVAL BATCH RELEASE REQUIREMENTS

Biosimilar products are subjected to a risk-based post-approval batch release programme.
The product licence holder is to submit the following documents prior to import and sale of
each batch of the biosimilar product:
Manufacturers batch release data and certificate of analysis

A letter of commitment to provide yearly stability data on annual stability batch
HSA may choose to request for the following additional documents:

Batch release certification from one of HSAs reference agencies namely, Australia TGA,
Health Canada, EMEA, UK Medicines and Healthcare Products Regulatory Agency
(MHRA) and US FDA
Certificates of analysis from a laboratory in one of HSAs reference agencies or other
accredited biologics testing laboratory10
HSA may also choose to carry out independent batch testing of selected batches based on
the following factors:
No batch release certificate from one of HSAs reference agencies
Unsatisfactory result(s) in the certificate of analysis from a laboratory in one of HSAs
reference agencies or other accredited biologics testing laboratory11
Unsatisfactory inspection history
Unsatisfactory testing history
Unsatisfactory stability data
Post-marketing experience e.g., adverse drug reaction
10
Laboratory in compliance with the latest recommendations from the US FDA, ICH, CHMP and all assays
performed under full compliance with GLP and cGMP standards
11
Laboratory in compliance with the latest recommendations from the US FDA, ICH, CHMP and all assays
performed under full compliance with GLP and cGMP standards



Pharmaceuticals & Biologics Branch / Generics & Biosimilars Branch
Pre-Marketing Division
Health Products Regulation Group
Health Sciences Authority
11 Biopolis Way, #11-01 Helios

Singapore 138667
www.hsa.gov.sg
Tel: 68663400
Fax: 64789032
Email: HSA_MedProd_Registration@HSA.gov.sg

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Effective 1 April 2011

GUIDANCE ON MEDICINAL PRODUCT

Please visit HSAs website at http://www.hsa.gov.sg for the latest

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CHAPTER B REGISTRATION PROCESS ......................................................................14

CHAPTER C NEW DRUG APPLICATION SUBMISSION ...............................................26

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CHAPTER D GENERIC DRUG APPLICATION SUBMISSION ..........................................45

CHAPTER E BIOSIMILAR PRODUCT APPLICATION SUBMISSION ...........................62

CHAPTER F POST-APPROVAL PROCESS ..................................................................65

CHAPTER G MAJOR VARIATION (MAV) SUBMISSION ...............................................72

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CHAPTER H MINOR VARIATION (MIV) SUBMISSION ..................................................79

CHAPTER J SUBMISSION OF A PRISM APPLICATION FORM ...................................80

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APPENDIX 2A Application Checklist (ICH CTD NDA and GDA)

APPENDIX 2B Application Checklist (ICH CTD MAV)

APPENDIX 3A Application Checklist (ASEAN CTD NDA and GDA)

APPENDIX 3B Application Checklist (ASEAN CTD MAV)

APPENDIX 4 Flowchart for Translation of Non-English Documents

APPENDIX 5 Guideline on Submission for Non-Prescription Medicinal Products

APPENDIX 6 Points to Consider for Singapore Labelling

APPENDIX 7 Patent Declaration Form

APPENDIX 8 Singapore Quality Overall Summary for Chemical Drugs

APPENDIX 9 Singapore Quality Overall Summary for Biologics

APPENDIX 10 Guideline on the Registration of Human Plasma-derived Medicinal

APPENDIX 11 Guideline on the Registration of Human Medicinal Products Containing

APPENDIX 12 Product Interchangeability and Biowaiver Request for Chemical

APPENDIX 12A Quick Reference on Acceptability of Bioequivalence Study

APPENDIX 14 MIV Filing and Submission Inquiry Form

APPENDIX 15 Guideline on Minor Variation Applications (MIV-1 & MIV-2) for

APPENDIX 17 Guidance on Registration of Similar Biological Products in Singapore

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ABBREVIATIONS AND ACRONYMS

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PMF Plasma Master File

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CHAPTER A GENERAL OVERVIEW

This guidance document is intended to provide assistance in the submission of

Medicines Act (Chapter 176)

1.1 Scope of this guidance document

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1.2 Medicinal product registration

A medicinal purpose means any one or more of the following purposes:

A Product Licence is required before a medicinal product can be sold or supplied in

Prescription Only Medicines (POM) control is required in the following situations:

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As healthcare products are becoming increasingly complex e.g. combinations of a

The applicants responsibilities include:

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x. To notify HSA if the products marketing authorisation is withdrawn by any drug

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CHAPTER B REGISTRATION PROCESS

Figure 1. Registration Process for a Medicinal Product

5.1 Application types

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NDA New Drug Application

GDA Generic Drug Application

A generic product is essentially similar to a currently registered product in Singapore

A schematic diagram to illustrate the various types of applications is seen in Figure 2

NO Essentially similar NO Contains new NDA 1

Figure 2. Schematic diagram of application routes for drug registration.