Updates On PIC/S GMP Standard

Updates on PIC/S GMP Standard
including Site Master File guidance

Good Manufacturing Practice for Medicinal Products Manufacturers
including Site Master File guidance
Presented by:
Boon Meow Hoe, Dy Director / Senior GMP Auditor,
Overseas Audit Unit(OAU),
Audit Branch (AB)
Audit & Licensing Division (ALD)
Health Product Regulatory Group (HPRG)
Health Sciences Authority )HSA)
1
Topics Topics
(A) An update on PIC/S memberships
(B) PIC/S publications
(C) An update on proposed revision to
PIC/S GMP Guide in the pipeline
in the PIC/S pipeline in the PIC/S pipeline
In the EMA (EU) pipeline
(D) Site Master File
(E) Q&A. Discussion
2
An Update on PIC/S Membership An Update on PIC/S Membership An Update on PIC/S Membership An Update on PIC/S Membership
3
PIC/S Membership PIC/S Membership
Slovenia / Agency for Medicinal Products and Medical Devices
(JAZMP)
Submitted & accepted Membership Accession Application on 28 Oct
2008
At last PIC/S COMMITTEE OF OFFICIALS MEETING held on 7 & 8
November 2011 at South Africa/Cape Town, PIC/S accepted Slovenia November 2011 at South Africa/Cape Town, PIC/S accepted Slovenia
/ JAZMP to join the PIC/S Scheme with effect from 1 January 2012.
40 YEARS ANNIVERSARY AND 40
th
MEMBERS WITH THE
ACCESSION OF SLOVENIA / JAZMP
4
To-date: PIC/S has 40 participating authorities (38 Countries)
Austria
Belgium
Cyprus
Czech Republic
Denmark
Estonia
Latvia
Lithuania
Malta
Netherlands
Poland
Portugal
Switzerland
Ukraine
Norway
Liechtenstein
Iceland
South Africa
Israel
Estonia
Finland
France
Germany
Greece
Hungary
Ireland
Italy
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Argentina
Canada
USA
Australia
Singapore
Malaysia
5
SINGAPORE
CANADA
40 PIC/S Members January 2012
USA
Slovenia
AUSTRALIA
ARGENTINA
SOUTH AFRICA
MALAYSIA
ISRAEL
UKRAINE
6
PIC/S Publications PIC/S Publications
7
Documents for industry
PIC/S GMP Guide
Site Master Files
Documents for inspectorates
Inspectorates
Documents for inspectors
Q&A Documents
Aide-Memoires
Current PIC/S Publications Current PIC/S Publications
Aide-Memoires
Guidance documents
Documents for the public
Information documents
Press Release
PIC/S Seminars
Miscelleneous
8
Documents for industry
PIC/S GMP Guide
PE 009-9 ZIP-File
PIC/S GMP GUIDE 2009-09-01
PE 009-9 (Intro)
PIC/S GMP GUIDE (INTRODUCTION) 2009-09-01
PE 009-9 (Part I)
PIC/S GMP GUIDE (PART I: BASIC REQUIREMENTS FOR MEDICINAL PRODUCTS) 2009-09-01
Current PIC/S Publications (Conti.) Current PIC/S Publications (Conti.)
PE 009-9 (Part II)
PIC/S GMP GUIDE (PART II: BASIC REQUIREMENTS FOR ACTIVE PHARMACEUTICAL INGREDIENTS) 2009-09-01
PE 009-9 (Annexes)PIC/S GMP GUIDE (ANNEXES) 2009-09-01
Site Master Files
PE 008-4
EXPLANATORY NOTES FOR INDUSTRY ON THE PREPARATION OF A SITE MASTER FILE 2011-02-15
PI 019-3
SITE MASTER FILE FOR SOURCE PLASMA ESTABLISHMENTS 2007-09-26
PI 020-3
SITE MASTER FILE FOR PLASMA WAREHOUSES 2007-09-25
9
Documents for inspectorates
Inspectorates
PICS 1/95 (Rev 5)
PIC/S SCHEME 2012-01-12
PS/INF 21/2002 (Rev 13)
PARTICIPATING AUTHORITIES & PARTNERS 2012-01-13
PIC Convention
PIC CONVENTION 2006-12-07
PI 002-3
QUALITY SYSTEM REQUIREMENTS FOR PHARMACEUTICAL INSPECTORATES 2007-09-25
QUALITY SYSTEM REQUIREMENTS FOR PHARMACEUTICAL INSPECTORATES 2007-09-25
PI 010-4
PROCEDURE FOR HANDLING RAPID ALERTS AND RECALLS ARISING FROM
QUALITY DEFECTS 2010-12-21
PI 013-3
STANDARD OPERATING PROCEDURE PIC/S INSPECTION REPORT FORMAT 2007-09-25
PI 031-1
STANDARD OPERATING PROCEDURE TEAM INSPECTIONS 2012-01-13
PI 037-1
PIC/S RECOMMENDATION ON RISK-BASED INSPECTION PLANNING 2012-01-16
10
Documents for inspectors
Q&A Documents
PS INF 20 2011 QA DISTRIBUTION ACTIVITIES FOR APIs - MAY 2010 2011-04-06
Aide-Memoires
PI 009-3 AIDE-MEMOIRE INSPECTION OF UTILITIES 2007-09-25
PI 021-2 AIDE MEMOIRE ON GMP PARTICULARITIES FOR CLINICAL TRIAL PRODUCTS 2007-09-26
PI 023-2 AIDE MEMOIRE ON INSPECTION OF QUALITY CONTROL LABORATORIES 2007-09-25
PI 024-2 AIDE MEMOIRE ON INSPECTION OF BIOTECH 2007-09-25
PI 025-2 AIDE-MEMOIRE ON MEDICINAL GASES 2007-09-25
PI 028-1 AIDE-MEMOIRE ON PACKAGING (Entry into force on 1 March 2009) 2009-01-21
PI 030-1 AIDE-MEMOIRE ON THE INSPECTION OF APIS 2009-01-21
Guidance documents Technical guides
PE 005-3 PIC/S GMP GUIDE FOR BLOOD ESTABLISHMENTS 2007-09-27
PE 010-3 GUIDE TO GOOD PRACTICES FOR THE PREPARATION OF MEDICINAL
PRODUCTS IN HEALTHCARE ESTABLISHMENTS (PE 010-3) 2008-10-01
PI 005-3 GUIDANCE ON PARAMETRIC RELEASE 2007-09-27
PI 006-3 VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION
NON-STERILE PROCESS VALIDATION CLEANING VALIDATION 2007-09-25
PI 007-6 VALIDATION OF ASEPTIC PROCESSES 2010-12-21
PI 008-3 PIC/S GUIDE TO INSPECTIONS OF SOURCE PLASMA ESTABLISHMENTS AND
PLASMA WAREHOUSES (INSPECTION GUIDE) 2007-09-25
PI 011-3 GOOD PRACTICES FOR COMPUTERISED SYSTEMS IN REGULATED GXP ENVIRONMENTS 2007-09-25
PI 012-3 RECOMMENDATION ON STERILITY TESTING 2007-09-25
PI 014-3 ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING 2007-09-25
PI 032-2 TECHNICAL INTERPRETATION OF REVISED ANNEX 1 TO PIC/S GMP GUIDE 2010-01-08
11
Information Documents
PIC/S BROCHURE MAY 2011 EDITION 2011-06-09
PS W 8 2005 PIC/S BLUEPRINT 2006-05-02
Press Releases (e.g.)
PR Nov 2011 PRESS RELEASE NOVEMBER 2011 2011-11-18
PR 02 Jun 2011 PRESS RELEASE NO 2 JUNE 2011 2011-06-09
PR 01 Jun 2011 PRESS RELEASE NO 1 JUNE 2011 2011-06-09
Annual Reports
Annual Reports
12
PIC/S Seminars
B 028 THE INTERFACE BETWEEN GOOD CLINICAL PRACTICES AND MANUFACTURING PRACTICES 2004-10-
27 (Montebello, Canada, October 2002)
SB 029 THE INSPECTION OF QUALITY CONTROL LABORATORIES 2004-10-27 (Bratislava, Slovak Republic, June 2003)
SB 030 THE INSPECTION OF API MANUFACTURERS 2007-01-17 (El Vendrell, Spain, June 2004)
SB 031 PRIMARY PACKAGING MATERIAL, LABELLING & PREVENTION OF MIX-UPS 2007-01-17 (Bucharest, Romania,
September 2005)
SB 032 QUALITY RISK MANAGEMENT AND RELATED ICH TOPICS 2007-01-17 (Dsseldorf, Germany, 31 May - 2 June 2006)
SB 033 INSPECTION OF MANUFACTURERS OF SOLID DOSAGE FORMS 2008-01-30 (Singapore, November 2007)
SB 034 GOOD DISTRIBUTION PRACTICES 2008-10-15 (Krakow, Poland, May 2008)
SB 035 ASEPTIC & STERILE MANUFACTURING FROM API TO FINISHED DOSAGE FORMS 2010-09-06 (Uppsala, Sweden,
November 2009)
SB 036 GMP INSPECTION OF MANUFACTURERS OF TRADITIONAL / HERBAL MEDICINAL PRODUCTS 2011-02-28 Kuala
Lumpur, Malaysia, November 2010
Lumpur, Malaysia, November 2010
SB 037 GOOD PHARMACEUTICAL INSPECTION PRACTICES 2011-12-27 Cape Town, South Africa, November 2011
Miscelleneous
PS/INF 1/2010 EXAMPLE OF QUALITY RISK MANAGEMENT IMPLEMENTATION 2010-01-08 An informal Working Group within PIC/S has
developed an example of methodology for the implementation of Quality Risk Management (QRM) in industry.
This example of methodology is not intended to be issued by PIC/S as a recommendation or as a guideline for industry and / or for GMP
inspectors but it could be used by PIC/S for training purposes.
Whether this example is used by industry for other purposes is of no concern to PIC/S and will not influence the outcome of PIC/S
inspections.
PIC/S-PDA&ISPE
JOINT WORKSHOP 2009-01-29 PIC/S co-organised a joint workshop with PDA and ISPE on the Manufacture of Sterile Medicinal Products
(EU-PIC/S GMP revised Annex 1) which took place in Geneva on 13-14 November 2008 (read press release).
13
PIC/S GMP Guide = Introduction + Part I + Part II + 20 Annexes
Part I of the PIC/S GMP Guide
Originally, the PIC/S GMP Guide (PIC Basic Standards of 1972) derives
from the WHO GMP Guide and was further developed subsequently.
In 1989, the EU adopted its own GMP Guide, which in terms of GMP
requirements was equivalent to the PIC/S GMP Guide. Since that time,
the EU and the PIC/S GMP Guides have been developed in parallel and
History of PIC/S GMP Guide History of PIC/S GMP Guide
the EU and the PIC/S GMP Guides have been developed in parallel and
whenever a change has been made to one, the other has been amended
so that both Guides are practically identical.
Part II of the PIC/S GMP Guide
On 22 May 2001, PIC/S adopted the GMP Guide for API (ICH Q7A) as a stand-alone guide
(PE 007).
On 29-30 May 2006, PIC/S made it Part II of the current Guide.
14
Part I of the PIC/S GMP Guide
Revisions History of PIC/S GMP Guide Revisions History of PIC/S GMP Guide
Date Version Number Reasons for revision
21 December 2000 PH 1/97 (Rev.)
Revision of Annex 14
Renumbering of all annexes
Change in the editors address and insertion of copyright
statement
Inclusion of revision history
10 August 2001 PH 1/97 (Rev. 2)
Amendment of para. 42 of Annex 1
Revision of Annex 6
New Annex 15
New Annex 17
Amendment to the glossary
15 January 2002 PH 1/97 (Rev. 3)
New Annex 4
New Annex 5
Reference to Annex 18 of EC GMP Guide
1 September 2003 PE 009-1
Amendment of Annex 1 (mainly section 3)
1 July 2004 PE 009-2
Revision of Annex 13
Change in the Editors co-ordinates
15
Revisions History of PIC/S GMP Guide (Conti.) Revisions History of PIC/S GMP Guide (Conti.)
Date Version
Number
Reasons for revision
1 January 2006
1 June 2006
1 August 2006
PE 009-3
Revision of Chapter 1 (Add PQR)
PE 009-4
o Revision of Chapter 6 (Add On-Going stability Programme)
PE 009-5
Corrections to revision of Chapter 6
Revision of Chapter 8 (add requirements on counterfeit products)
Reorganisation of the PIC/S GMP Guide in Part I, Part II and Annexes
5 April 2007 PE 009-6
Reorganisation of the PIC/S GMP Guide in Part I, Part II and Annexes
(EU level came into operation in Oct 2005)
Incorporation of PE 007 (APIs guide) as Part II
New Annex 19 (EU level came into operation on 1 Jun 2006)
Revision of the Introduction
Change in the Editors co-ordinates
Revision of General Introduction (History) and Introduction to Part
II
Deletion of footnotes in Chapter 6 (Part I) and Annex 13
15 January 2009 PE 009-8
Revision of Chapter 1 (Part I) (Add QRM)
Revision of Annex 1
New Annex 20 (QRM) (EU level came into operation in Mar 2006)
Revision of Annex 3 Manufacture of Radiopharmaceuticals (EU level
came into operation on 1 Mar 2009)
16
Changes Changes
An update on revision to PIC/S GMP
Guide
Adopted by PIC/S
In the PIC/S pipeline (i.e. adopted by EMA but not
PIC/S)
In the EMA (EU) pipeline (i.e. not adopted by both
EMA and PIC/S)
17
No change since last HPRG Regulatory Workshop 2011
conducted on 20 January 2011
PIC/S has not published / released any new changes
Changes to PIC/S Guide Changes to PIC/S Guide
PIC/S has not published / released any new changes
since last revision -- Version: PE-009-9 released on 1 Sept
2009
18
A new consultation procedure between PIC/S and the
European Medicines Agency (EMA) had been discussed in
Harmonisation of guidance documents Harmonisation of guidance documents
EMA Consultation Consultation PIC/S
European Medicines Agency (EMA) had been discussed in
order to ensure further improvements in the
harmonisation between the EU and the PIC/S GMP
Guides and related documents. This new procedure aims
at informing each party of ongoing revisions of current
documents and endorsement of new documents, including
the sharing of early drafts in order to facilitate appropriate
involvement in the adoption process.
19
Adopted by PIC/S Adopted by PIC/S
PIC/S Recommendation for Risk-based Inspection
Planning in the GMP Environment
Status:
Adopted and entered into force on 1
st
January 2012.
20
In the In the PIC/S PIC/S pipeline pipeline (i.e. adopted by EMA but not PIC/S) (i.e. adopted by EMA but not PIC/S)
Part I , Part II &
Annexes
EU/EMA PIC/S
Annex 6 (Manufacture of medicinal
gases)
Adopted and has come into
operation on 31
st
July 2010.
TBA
Annex 7 (Manufacture of herbal
medicinal products)
operation on 1
st
September 2009.
TBA
Annex 11 (Computerised systems) Adopted and has come into
operation on 30
th
June 2011.
TBA
operation on 30
th
June 2011.
Annex 13 (Manufacture of
investigational medicinal products)
operation on 31
st
July 2010
TBA
Annex 14 (Manufacture of products
derived from human blood or
human plasma)
operation on 30
th
November 2011.
TPA
Part I -- Chapter 4 (Documentation) Adopted and has come into
operation on 30
th
June 2011.
TBA
Part II (API) introduction of QM
principles
operation on 31
st
July 2010.
TBA
21
In the In the PIC/S PIC/S pipeline pipeline (i.e. adopted by EMA but not PIC/S) (i.e. adopted by EMA but not PIC/S)
Part I , Part II &
Annexes
EU/EMA PIC/S
Part III of the GMP guide
Part III of GMP Guide was
created and include:
Site Master File;
ICH Q9; and
ICH Q10
TBA
Site Master File: Formal
integration into EU system
PIC/S version of Site Master File
approved and published by EC.
The revised document
entered into force on 1
January 2011. On 15 Feb
integration into EU system
January 2011. On 15 Feb
2011, the PIC/S Secretariat
added a footnote into the
revised SMF without formally
amending the document. The
footnote indicates that a
D-U-N-S reference is required
for Site Master Files
submitted to EU/EEA
authorities for manufacturing
sites located outside of the
EU/EEA.
22
REVISION OF ANNEX 6 MANUFACTURE OF MEDICINAL GASES
Status:
At EU level, this revised Annex 6 has come into operation on 31
st
July 2010.
PIC/S level: Not adopted yet, it is likely to be adopted at next PIC/S CoO
meeting (Switzerland/Geneva ) in May 2012
The proposed revised Annex 6 was initiated as a consequence of the restructuring
of the GMP Guide and the need to modify the requirements of Part II of the Guide
for applicability to medicinal gases. There was also a need to define more clearly
Revisions to the GMP Guide in the Revisions to the GMP Guide in the PIC/S PIC/S pipeline pipeline
for applicability to medicinal gases. There was also a need to define more clearly
what should be considered as a starting material as opposed to a bulk
pharmaceutical product. The opportunity has also been taken to update the annex
in general.
On 1 Feb 2012, we received the following progress update:
(i) Australia/TGA had underlined that a number of terms were unclear or needed to be
better defined, e.g. paragraph 29 required traceability without specifying to which
extent (i.e. per individual cylinder, batch or customer?). It was proposed the best
way to address this issue was for PIC/S to adopt a Question & Answer document.
(ii) Canada/HPFBI suggested to amend paragraphs 35 and 36 dealing with the sealing
of cylinders and mobile cryogenic vessels to authorise devices in addition to seals
(e.g. Cylinders and mobile cryogenic vessels should be fitted with tamper-evident
seals or devices). 23
REVISION OF ANNEX 7 - Manufacture of Herbal Medicinal Products
Status:
st
Sept 2009.
The proposal is based on the revision of Annex 7 to the EU GMP Guide. Annex 7 has been
revised to also apply to active substances used as starting materials for the manufacture of
herbal medicinal products following the adoption of ICH Q7A as Part II of the EU GMP Guide.
herbal medicinal products following the adoption of ICH Q7A as Part II of the EU GMP Guide.
Good Agricultural and Collection Practice (GACP) requirement was introduced.
Paragraph 7 of EU Annex 7 reads as follows:
Herbal medicinal product manufacturers must ensure that they use only herbal starting
materials manufactured in accordance with GMP and the Marketing Authorisation dossier.
Comprehensive documentation on audits of the herbal starting material suppliers carried out
by, or on behalf of the herbal medicinal product manufacturer should be made available. Audit
trails for the active substance are fundamental to the quality of the starting material. The
manufacturer should ensure that the suppliers of the herbal substance / preparation are in
compliance with Good Agricultural and Collection Practice.
24
REVISION OF ANNEX 7 - Manufacture of Herbal Medicinal Products (Conti.)
Revised paragraph 7 regarding GACP requirement
Australia / TGA has expressed its concerns on the compulsory requirement for
GACP-compliance. TGA has thus counter proposed:
The manufacturer should verify, where appropriate, whether the
suppliers of the herbal substance / preparation are in compliance with Good
Agricultural and Collection Practice (or equivalent) and if not apply appropriate
Ensure that
Agricultural and Collection Practice (or equivalent) and if not apply appropriate
controls in line with QRM.
Italy / AIFA is in favour of the original EU version. AIFA has also counter
proposed:
The manufacturer should ensure that the suppliers of the herbal substance /
preparation are in compliance with Good Agricultural and Collection Practice
(published by the European Medicines Agency or by WHO) in order to perform
appropriate controls in line with QRM.
25
REVISION OF ANNEX 7 - Manufacture of Herbal Medicinal Products (Conti.)
The final proposal: Revised paragraph 7 regarding GACP requirement
Taking into both proposals made by Australia / TGA and Italy / AIFA into consideration:
.The manufacturer should verify, where appropriate, whether the suppliers of the
herbal substance / preparation are in compliance with Good Agricultural and
Collection Practice* and if not apply appropriate controls in line with QRM.
* EMA, WHO or equivalent
(This reference to the EMA or WHO take the form of a footnote and the words or
equivalent would be added).
26
Proposed Revision of ANNEX 11 (Computerised Systems) and
Chapter 4
Status:
th
Jun 2011.
Key proposed changes:
Revised in parallel with Chapter 4
27
REVISION OF ANNEX 13 MANUFACTURE OF INVESTIGATIONAL
MEDICINAL PRODUCTS
Status:
st
July 2010.
meeting (Switzerland/Geneva ) in May 2012.
Key Changes
Key Changes
The revision was initiated in order to reinforce the principle of independence between
production and quality control functions in cases where the number of personnel
involved is small. Changes have been made to sections 36 and 37 in order to
supplement, for investigational medicinal products, the guidance for reference and
retention samples given in Annex 19. A few editorial changes have been made in
the interest of consistency with terminology used throughout the GMP Guide.
28
On 1 Feb 2012, we received the following progress update:
(i) Australia/TGA highlighted the following issue: the proposed text (in particular paragraph
26b and Table 1, entry b) allows that for closed 'blinded' trials, the labelling does not include
any information regarding name/identifier and strength / potency of the clinical trial
material. This may lead to confusions in hospital pharmacies and can easily be avoided by
including a requirement (within clause 26b and Table 1 entry b) to include in the labelling a
statement of both the 'verum' and the placebo, for example: "acetylsalicylic acid 300mg or
placebo tablets". Such a labelling requirement would still leave the blinded character of the
trial intact while avoiding confusion in case of emergency.
trial intact while avoiding confusion in case of emergency.
(ii) Israel/ISCP commented that there was no mention of required labels for cytotoxic products
or articles requiring special storage conditions (e.g. "store at 2C-8C"). In addition, the
term "immediate container", which was outmoded in the revised Annex 13, still appeared in
paragraph 30.
It was proposed to integrate the above comments as footnotes in the revised Annex 13
of the PIC/S GMP Guide.
29
Proposed Revision of ANNEX 14 (Medicinal Products Derived from
Human Blood or Plasma)
Status:
st
July 2010.
Key changes:
- Plasma for fractionation from 3
rd
countries
- Demarcation between GMP and Blood legislation
30
CHAPTER 4 of the GMP Guide (Documentation)
Status:
At EU level, this revised Chapter 4 (Documentation)has come into operation
on 30
th
June 2011. (Same as Annex 11 on Computerized systems)
Key changes:
Revised in parallel with Annex 11
Revised section on Principle
Revised section on Required GMP documentation (by type)
inclusion of Site Master File,
Instructions (directions, or requirements) type
Specifications;
Manufacturing formulae, Processing, Packaging and Testing Instructions;
Procedures (SOPs);
Protocols; and
Technical agreements.
31
CHAPTER 4 of the GMP Guide (Documentation) (Conti)
Records/Report type-
Records;
Certificates of Analysis;
Reports
Revised section on Generation and control of documentation
All types of document should be defined and adhered to. The requirements apply equally to all forms of document media types.
Complex systems need to be understood, well documented, validated, and adequate controls should be in place. Many documents
(instructions and/or records) may exist in hybrid forms, i.e. some elements as electronic and others as paper based. Relationships and
control measures for master documents, official copies, data handling and records need to be stated for both hybrid and homogenous
systems. Appropriate controls for electronic documents such as templates, forms, and master documents should be implemented.
Appropriate controls should be in place to ensure the integrity of the record throughout the retention period.
Revised section on Retention of documents
Revised section on Retention of documents
It should be clearly defined which record is related to each manufacturing activity and where this record is located.
Secure controls must be in place to ensure the integrity of the record throughout the retention period and validated
where appropriate.
Specific requirements apply to batch documentation which must be kept for one year after expiry of the batch to
which it relates or at least five years after certification of the batch by the Qualified Person, whichever is the longer.
For investigational medicinal products, the batch documentation must be kept for at least five years after the
completion or formal discontinuation of the last clinical trial in which the batch was used. Other requirements for
retention of documentation may be described in legislation in relation to specific types of product (e.g. Advanced
Therapy Medicinal Products) and specify that longer retention periods be applied to certain documents.
For other types of documentation, the retention period will depend on the business activity which the documentation
supports. Critical documentation, including raw data (for example relating to validation or stability), which supports
information in the Marketing Authorisation should be retained whilst the authorization remains in force. It may be
considered acceptable to retire certain documentation (e.g. raw data supporting validation reports or stability
reports) where the data has been superseded by a full set of new data. Justification for this should be documented
and should take into account the requirements for retention of batch documentation; for example, in the case of
process validation data, the accompanying raw data should be retained for a period at least as long as the records for
all batches whose release has been supported on the basis of that validation exercise.
32
CHAPTER 4 of the GMP Guide (Documentation) (Conti)
Revised section on Other E.g.
4.29 There should be written policies, procedures, protocols, reports and the associated
records of actions taken or conclusions reached, where appropriate, for the following
examples:
- Validation and qualification of processes, equipment and systems;
- Equipment assembly and calibration;
- Technology transfer;
- Maintenance, cleaning and sanitation;
- Personnel matters including signature lists, training in GMP and technical matters, clothing and
- Personnel matters including signature lists, training in GMP and technical matters, clothing and
hygiene and verification of the effectiveness of training.
- Environmental monitoring;
- Pest control;
- Complaints;
- Recalls;
- Returns;
- Change control;
- Investigations into deviations and non-conformances;
- Internal quality/GMP compliance audits;
- Summaries of records where appropriate (e.g. product quality review);
- Supplier audits.
33
REVISION OF Part II (Basic Requirements for Active Substances used as Starting Materials)
Status:
At EU level: this revised Part II has come into operation on 31 July 2010.
Changes:
Changes:
The proposed revised Part II was initiated in order to incorporate
principles of QRM corresponding to similar changes made to Part I,
Chapter 1 of the Guide. A new section on QRM was introduced as section
2.2. The remaining sections of chapter 2 are renumbered. No other
changes have been made.
34
Proposed new Part III of the GMP guide
Status:
EU Level :Both revision to SMF explanatory notes and Part III
concept - adopted and published at EU level.
PIC/S Level : Revision to SMF explanatory notes adopted with effect
from 1 Jan 2011; Part III concept -- Not adopted by
from 1 Jan 2011; Part III concept -- Not adopted by
PIC/S yet
SMF has also become a standard expectation of EU authorities.
It is proposed to create a new informational Part III of the EU GMP Guide
for collection of GMP related documents which are not themselves GMP
guidelines and have no statutory force (i.e. non-binding documents) but
which complement the GMP guidelines and related regulatory procedures
such as inspections. It is expected that in the future, further documents
will be added to the new Part III [E.g. introductory part of GMP Guide,
ICH documents (Q9 and Q10) are proposed to be included in Part III].
35
Proposed Revisions to the EU GMP Guide Proposed Revisions to the EU GMP Guide -- -- In the EU (EMA) In the EU (EMA)
pipeline pipeline (i.e. Not adopted yet) (i.e. Not adopted yet)
Part I , Part II &
Annexes
EU/EMA PIC/S
Part I Chapter 1 and 2
New texts of chapter 1 proposed
during last EMAs GMP/GDP IWG
meeting. Revision of chapter 2 will
be done after consolidation of
chapter 1.
Participating Authorities
requested to send their
feedback on proposed
revisions by 15 Feb 2012.
Part I Chapters 3 and 5
(Dedicated Facilities)
EMAs Safety Working Party has
published Concept Paper on
development of toxicological tools.
Participating Authorities are
invited to comment on
proposed Concept Paper
Part I Chapters 5 (API
Slight changes proposed during last New draft is invited for
Part I Chapters 5 (API
pedigree)
Slight changes proposed during last
EMAs GMP/GDP IWG meeting.
New draft is invited for
comments till 15
th
Feb 2012.
Part I Chapters 5 (control
of starting materials)
Q&A was prepared, awaiting
approval.
Q&A is invited for comments
till 15
th
February 2012.
Part I Chapter 6 (Quality
Control)
Work on text has been started; first
draft will be available for next EMAs
GMP/GDP IWG meeting.
After first draft will be shared
with PIC/S.
Part I Chapter 7 (Contract
Manufacturer and Analysis)
Last draft sent for publication by
EC.
will be shared with PIC/S.
Part I Chapter 8
(notification of product
shortage)
First draft should be available for
next EMAs GMP/GDP IWG meeting.
First draft will be shared with
PIC/S once it is available.
36
Proposed Revisions to the EU GMP Guide Proposed Revisions to the EU GMP Guide -- -- In the EU (EMA) In the EU (EMA)
pipeline pipeline (i.e. Not adopted yet) (i.e. Not adopted yet)
Part I , Part II &
Annexes
EU/EMA PIC/S
Annex 2 (Biologicals)
Final draft prepared and was shared
with PIC/S. Adopted and sent to EC
for publication.
Will be tabled for adoption at
next PIC/S CoO
(Switzerland/Geneva) in may
2012.
Annex 16 (update of text)
Proposed overall revision of annex Concept paper from EMA will
Annex 16 (update of text)
Proposed overall revision of annex
16 Concept paper will be ready for
Concept paper from EMA will
be shared with PIC/S once
available.
GDP Guide
GDP Guideline approved for public
consultation. The work should be
coordinated with PIC/S working
group.
Format of GDP licence approved for
pilot phase till end of 2011.
Ongoing work of PIC/S
working group. Proposed EU
GDP guide are to be sent to
PIC/S PA for their comments
and local public consultation.
(this has to be confirmed by
chair of PIC/S working group
as discussed at last PIC/S
committee meeting).
37
Part I Proposed Revision of CHAPTER 1 (Quality Management ) &
CHAPTER 2 (Personnel)
Status:
EU/EMA: New texts of chapter 1 proposed during last EMAs GMP/GDP IWG meeting.
Revision of chapter 2 will be done after consolidation of chapter 1.
PIC/S: Participating Authorities requested to send their feedback on proposed revisions
by 15 Feb 2012.
Revisions to the GMP Guide in the Revisions to the GMP Guide in the EMA(EU) EMA(EU) pipeline pipeline
Proposed changes made to Chapter 1 is to harmonise with ICH Q10 (Part
III) A pharmaceutical quality system designed for the entire product lifecycle.
The following key changes are recommended to be added to Chapter 1:
- Quality Management System
Achieve Product Realisation
Establish and Maintain a State of Control
Facilitate Continual Improvement
38
Part I Proposed Revision of CHAPTER 1 (Quality Management ) &
CHAPTER 2 (Personnel) Continue
Quality Manual (or equivalent)
Management responsibilities
CAPA
Revisions to the GMP Guide in the Revisions to the GMP Guide in the EMA(EU) EMA(EU) pipeline pipeline
Process Performance and Product Quality Monitoring
Management of Outsourced Activities and Purchased Materials
Management Review & monitoring of the QMS
formalised periodic review process
internal and external factors to be considered
output from review process (documentation, timely and effective
communication of results)
39
Part I Proposed revision of CHAPTER 3 (Premises and Equipment) &
CHAPTER 5 (Production)
Status:
EU: EMAs Safety Working Party has published Concept Paper on development of
toxicological tools.
PIC/S: Participating Authorities are invited to comment on proposed Concept Paper
Key Proposed Changes:
Dedicated and self-contained Facilities
Proposed Revisions to the EU GMP Guide in the Proposed Revisions to the EU GMP Guide in the EMA(EU) EMA(EU) pipeline pipeline
Dedicated and self-contained Facilities
CHAPTER 3 -- PREMISES AND EQUIPMENT (Existing)
3.6. In order to minimise the risk of a serious medical hazard due to cross-contamination,
dedicated and self-contained facilities must be available for the production of particular
medicinal products, such as highly sensitising materials (e.g. penicillins) or biological
preparations (e.g. from live micro-organisms). The production of certain additional
products, such as certain antibiotics, certain hormones, certain cytotoxics, certain highly
active drugs and non-medicinal products should not be conducted in the same facilities. For
those products, in exceptional cases, the principle of campaign working in the same facilities
can be accepted provided that specific precautions are taken and the necessary validations
are made. The manufacture of technical poisons, such as pesticides and herbicides, should
not be allowed in premises used for the manufacture of medicinal products.
40
CHAPTER 5 PRODUCTION (Existing) -- Prevention of cross-contamination in production
5.18. Contamination of a starting material or of a product by another material or product
must be avoided. This risk of accidental cross-contamination arises from the uncontrolled
release of dust, gases, vapours, sprays or organisms from materials and products in process,
from residues on equipment, and from operators' clothing. The significance of this risk
varies with the type of contaminant and of product being contaminated. Amongst the most
hazardous contaminants are highly sensitising materials, biological preparations containing
hazardous contaminants are highly sensitising materials, biological preparations containing
living organisms, certain hormones, cytotoxics, and other highly active materials. Products
in which contamination is likely to be most significant are those administered by injection,
those given in large doses and/or over a long time.
41
CHAPTER 5 PRODUCTION (Existing) -- Prevention of cross-contamination in production
5.19 Cross-contamination should be avoided by appropriate technical or organisational
measures, for example:
a) production in segregated areas (required for products such as penicillins, live vaccines, live bacterial
preparations and some other biologicals), or by campaign (separation in time) followed by appropriate
cleaning;
b) providing appropriate air-locks and air extraction;
b) providing appropriate air-locks and air extraction;
c) minimising the risk of contamination caused by recirculation or re-entry of untreated
or insufficiently treated air;
d) keeping protective clothing inside areas where products with special risk of cross contamination are
processed;
e) using cleaning and decontamination procedures of known effectiveness, as ineffective cleaning of
equipment is a common source of cross-contamination;
f) using closed systems of production;
g) testing for residues and use of cleaning status labels on equipment.
42
Chapter 3 3.6 & Chapter 5 5.18 & 5.19
Lack of clarity I existing GMP Guide w.r.t. when a medicinal product should be manufactured in
dedicated , self-contained facility.
Proposed amendment on 3.6 dedicated facilities to include ICH Q9 QRM principles
Risk assessment should include a toxicological evaluation of the product being manufactured
in a shared facility.
The need to develop a Toxicological tool to conduct toxicological assessment (absence of
guidance w.r.t. a method of deriving acceptable exposure limits for cross contamination
between products manufactured using shared facilities) Concept paper agreed by EMAs
Safety Working Group (SWG) and GMP/GDP IWF in Sept 2011. First draft to be discussed at
next meeting in Feb 2012.
43
Proposed amendment to CHAPTER 5 : Production (API pedigree)
Status:
EU: Slight changes proposed during last EMAs GMP/GDP IWG meeting.
PIC/S: New draft is invited for comments till 15
th
Feb 2012.
Key proposed changes
Qualification of Suppliers of Starting Materials
Supply chain traceability for starting materials
Proposed Revisions to the EU GMP Guide in the Proposed Revisions to the EU GMP Guide in the EMA (EU) EMA (EU) pipeline pipeline
Supply chain traceability for starting materials
Testing for starting materials
Control of contamination (Dedicated facilities)
44
Proposed amendment to CHAPTER 5 : Production (API pedigree)
What is Pedigree?
A pedigree is a family tree for an active pharmaceutical ingredient
(API) tracing its history or supply chain from critical raw
material(s) used in the manufacture of the API to the
manufacturer of the dosage form.
Proposed Revisions to the EU GMP Guide in the Proposed Revisions to the EU GMP Guide in the EMA (EU) EMA (EU) pipeline pipeline
The pedigree should be reviewed periodically to ensure that it is up
to date (Chapter 1 proposal)
GMP Guide revision (Chapter 5 proposal):Pedigree = Traceability
45
Proposed revision of CHAPTER 6 (Quality Control)
Status:
EU: Work on text has been started; first draft will be available for
PIC/S: After first draft will be shared with PIC/S.
Proposed Revisions to the GMP Guide in the Proposed Revisions to the GMP Guide in the EMA (EU) EMA (EU) pipeline pipeline
Analytical method transfer
46
Proposed Revision of CHAPTER 7 (Contract Manufacture and Analysis to
be renamed as Outsourced Activities)
Status:
EU : Last draft sent for publication by EC.
PIC/S : will be shared with PIC/S.
Harmonise with ICH Q10 guideline (Outsourced activities -ICH terminology)
Proposed revised Chapter 7 provides updated guidance on outsourced
GMP regulated activities beyond the current scope of contract
manufacture and analysis operations. The title of the Chapter has been
changed to reflect this.
47
Proposed Revision of CHAPTER 8 (Complaints and Product Recall)
Status:
EU: First draft should be available for next EMAs GMP/GDP IWG meeting.
PIC/S: To be shared with PIC/S once available
To consider a revision in the light of discussions at a meeting of Quality
To consider a revision in the light of discussions at a meeting of Quality
Defect contact points held at EMA on 7-8 October 2009 on product
shortage notifications and to introduce specific Quality Risk Management
concepts in the context of this chapter.
i.e. reporting where product shortage arises due to manufacturing issues
48
Proposed Revision of ANNEX 2 of the GMP Guide (Biological
Medicinal Products)
Status:
EU :Final draft prepared and was shared with PIC/S. Adopted and sent to EC for
publication. The European Commission will decide about the entry into force
of the revised EU Annex 2.
PIC/S :Consulting PIC/S Participating Authorities, in particular, non-EEA
PIC/S :Consulting PIC/S Participating Authorities, in particular, non-EEA
Participating Authorities, on some unresolved issues .
Key proposed changes
Annex 2 of the EU GMP Guide has been revised as a consequence of the restructuring
of the GMP Guide, new manufacturing technology and concepts, the increased
breadth of biological products to include several new product types such as
transgenic derived products and the Advanced Therapy Medicinal Products, (ATMPs)
together with associated new EU legislation. The GMP guidance drawn up for the
latter products is to meet the requirements of Article 5 of Regulation 1394/2007
and to align with details in Directive 2009/120/EC.
49
Good Distribution Practice (GDP) Guide
Status
EU: Public consultation ended on 31 Dec 2011, coordinated with PIC/S GDP
working group.
PIC/S: From a GDP Working Group, forming an Expert Circle on GDP 1
st
meeting
proposed to be conducted on 18-20 April 2012 in Helsinki/Finland with a view
to adopt EMAs revised Guidelines on Good Distribution Practice.
Other Revisions to the GDP Guide in the Other Revisions to the GDP Guide in the PIC/S PIC/S pipeline pipeline
Reasons for change: The content of the EMA Guidelines on Good Distribution
Practice published in 1994 is no longer adequate. It needs to be reviewed to take
into account advancements of practices for an appropriate storage and distribution
of medicinal products in the European Union. Moreover, it should take into account
the amendments to the Community Code which have been introduced with
Directive 2011/62/EU of the European Parliament and of the Council amending
Directive 2001/83/EC on the Community code relating to medicinal products for
human use, as regards the prevention of the entry into the legal supply chain of
falsified medicinal products.
50
PIC/S Explanatory Notes for
pharmaceutical manufacturers on the
preparation of a site master file
SMF SMF
preparation of a site master file
(SMF)
(PE 008-4 dated 1 January 2011)
Revision adopted on 1 January 2011
51
PIC/S Explanatory Notes PIC/S Explanatory Notes for pharmaceutical manufacturers on the for pharmaceutical manufacturers on the
preparation of a site master file (SMF) preparation of a site master file (SMF) (PE 008 (PE 008--4 dated 1 January 2011) 4 dated 1 January 2011)
Revision adopted on 1 January 2011 Revision adopted on 1 January 2011
Status:
At PIC/S level: this revised document has been adopted and has
come into operation on 1 January 2011 (First time in
history that a document is adopted by PIC/S before
EU level)
At its meeting in Kuala Lumpur (8-9 November 2010), the PIC/S Committee has
adopted the revision of the Explanatory Notes for Industry on the Preparation of a Site adopted the revision of the Explanatory Notes for Industry on the Preparation of a Site
Master File (PE 008-4).
The main objectives of the revision are the simplification of the document and the
implementation of requirements in relation with quality risk management.
On 15 February, the PIC/S Secretariat added a footnote into the revised SMF without
formally amending the document. The footnote indicates that a D-U-N-S reference is
required for SMFs submitted to EU/EEA authorities for manufacturing sites located
outside of the EU/EEA.
At EU level: this revised document has also been adopted
(Ref:Brussels, SANCO/C8/AM/sl/ares(2010)1064603).
52
PIC/S Explanatory Notes PIC/S Explanatory Notes for pharmaceutical manufacturers on the for pharmaceutical manufacturers on the
preparation of a site master file (SMF) preparation of a site master file (SMF) (PE 008 (PE 008--4 dated 1 January 2011) 4 dated 1 January 2011)
Revision adopted on 1 January 2011 Revision adopted on 1 January 2011
Both documents are
almost identical.
53
PIC/S new SMF Guide
Rev. 4 (PE 008-4)
1 Jan 2011
EU new SMF Guide
10 Feb 2011
1. Document History
2. Introduction
3. Purpose
4. Scope
SMF SMF (Table of Contents) )
5. Content of SMF
6. Revision History
7. Appendices for a Site Master File
54
Purpose of the Site Master File
A Site Master File is a dossier prepared by the manufacturer that
contains specific information about the Quality Management
systems, policies and activities of the Company, Manufacturing Site
and/or quality control of manufacturing operations carried out by
the Site.
This Explanatory Note is a guide to prepare a Site Master File that This Explanatory Note is a guide to prepare a Site Master File that
can be utilized in planning and conducting GMP inspections. A Site
Master File is essential for pharmaceutical companies as it
is the basis for the regulatory authority to prepare for a
GMP inspection.
The SMF has become compulsory in the EU/EEA as the revised
Chapter 4 of the EU GMP Guide has already come into operation on
30
th
June 2011(the SMF will be included in Part 3 of the EU/EEA
GMP Guide). The Commission has published the EU/EEA SMF on
its website. 56
Format of the Site Master File Format of the Site Master File
SMF should contain information on the Sites GMP related activities.
SMF is a detailed document but should not exceed 25-30 pages
plus Appendices.
Dossier should have an Edition Number, and effective and expiry
dates and should be updated and reviewed to ensure it is dates and should be updated and reviewed to ensure it is
representative of current Site activities.
Format and headings should follow the outlined guidance notes.
57
Scope of the Site Master File Scope of the Site Master File
These Explanatory Notes apply to the preparation and content of the SMF.
Manufacturers should refer to regional / national regulatory requirements
to establish whether it is mandatory for manufacturers of medicinal
products to prepare a SMF.
These Explanatory Notes apply for all kind of manufacturing operations such
as production, packaging and labelling, testing, relabelling and
repackaging of all types of medicinal products. The outlines of this guide repackaging of all types of medicinal products. The outlines of this guide
could also be used in the preparation of a SMF or corresponding document
by Blood and Tissue Establishments and manufacturers of Active
Pharmaceutical Ingredients.
58
Overview on changes Overview on changes
Several possibilities regarding the indication of the geographic
location of the site have been added
A listing of the GMP inspections conducted in the past 5 years
must be included in the Site Master File
Higher importance is attached to the topic "supplier qualification"
(the indication of the supply chain is now required)
Introduction of the PQR point Introduction of the PQR point
New requirement on the description of relevant utilities (steam,
compressed air, nitrogen, etc.)
Concrete information on the storage of documents outside the
premises is required
Description of the system which ensures appropriate
environmental conditions during transportation
Measures taken against illegal infiltration in the supply chain
59
New Requirements New Requirements
Notes address supply chain with Risk Management and incorporate
ICH Q 8, 9 and 10
General Company Information
GPS details must be provided to ensure accurate location of the facility
Information on GMP inspections, dates, relevant authority and outcomes
Quality Management System of the Company
Information regarding relevant standards for the company (ISO, ICH etc)
Dates and approvals for accreditation's and certified activities
Description of validation and change control policies
Actual names of responsible person(s) and QP(s) ;additional detail on their role
Information on PAT and real time release
Included Company Risk Management policies, qualification and oversight of
suppliers
Compliance with TSE guidelines
60
1. GENERAL INFORMATION ON THE MANUFACTURER
1.1 Contact information on the manufacturer (also see 4.1)
4
th
bullet point - Identification number of the site as e.g. GPS details,
D-U-N-S (Data Universal Numbering System) Number (a unique
identification number provided by Dun & Bradstreet) of the site or any
other geographic location system
1
.
Why?
SMF (Changes) SMF (Changes)
Why?
This new requirement is to better identify the location of manufacturing
site(s). These additional data are GPS co-ordinates, and (if available) a
DUNS number.
The purpose is to provide more reliability of the site location. Experience
showed that the way the applicants express their address may be either
incomplete or inconsistent.
The GPS coordinates or DUNS number will allow NDRA to unambiguously
identify the location of a manufacturing site.
60
Identification number: DUNS (Data Universal Numbering System)
What?
An unique, separate and distinct nine-digit number assigned to each business
location developed and maintained solely by a private company known as
Duns & Bradstreet (D&B).
This D&B DUNS Number is used by industries and organizations around the
world as a global standard for business identification and tracking.
world as a global standard for business identification and tracking.
This number can be applied for through the company website
(http://www.dnb.com/).
Local contact: Dun & Bradstreet (Singapore) Pte Ltd
Tel: (65) 6513 8347, Fax : (65) 6778-4627
Address :20 Harbour Drive, PSA Vista #06-02, Singapore 117612
(There is a charge of SGD 37.45 (inclusive of 7% GST) per DUNS Number request).
Your D-U-N-S Number will be sent to you within 3 days from receipt of the request and
payment confirmation.
61
Identification number: GPS details,
GPS CO-ORDINATES (Global Positioning System)
Which system (or datum)?
Provide GPS co-ordinates as per the WGS 84 system (World Godetic System).
Which unit should be used for GPS coordinates?
Latitude (North or South) and longitude (East or West), preferably expressed in the
Latitude (North or South) and longitude (East or West), preferably expressed in the
format: DD MM SS,S (Degrees Minutes Seconds to 1 decimal place).
Alternatively the latitude and longitude may be expressed in Degrees to at least 5
decimal places or Degrees Minutes to at least 3 decimal places.
62
Identification number: GPS details,
Which location?
Co-ordinates should preferably identify the main entrance of the manufacturing site
involved in the production . If the location for which the co-ordinates are given is not
the main entrance, this should be specified clearly in the application form.
How to measure/obtain GPS coordinates?
How to measure/obtain GPS coordinates?
Preferably, use a GPS device, calibrated with the units and system mentioned above.
or
Use Google Earth to identify the site entrance and copy the co-ordinates displayed in
the lower part of the map, with the format of the units and system mentioned above.
63
Identification number: DUNS (Data Universal Numbering System)
GPS details,
Other geographic location system
PIC/S Foot note:
1
: A D-U-N-S reference is required for Site Master Files
submitted to EU/EEA authorities for manufacturing sites located outside of
the EU/EEA.
Notes: EDQM -- Since 15 April 2011, applicants for new certificates of
suitability (CEP) or revisions of CEPs are requested to provide information
in the application form to better identify the location of their
manufacturing site(s). These additional data are GPS co-ordinates, and
(if available) a DUNS number. (i.e. Providing the DUNS number is not
mandatory in the framework of the submission of a CEP dossier).
64
1.2 Authorised pharmaceutical manufacturing activities of the site.
- ..
-
-
- List of GMP inspections of the site within the last 5 years; including dates and
name/country of the Competent Authority having performed the inspection. A copy
of current GMP certificate (Appendix 3) or reference to the EudraGMP database
should be included, if available.
2. QUALITY MANAGEMENT SYSTEM OF THE COMPANY
2.1 Description of the quality management system of the company
Provide information on quality management systems, maintenance of
the systems and senior management responsibilities
Provide reference to the relevant standards (i.e. ISO, ICH)
Provide information of accredited and certified activities carried out by
the company
65
SMF (Changes)
2. QUALITY MANAGEMENT SYSTEM OF THE COMPANY (Conti)
2.2. Release procedure of finished products
- Detailed description of qualification requirements (education and work experience)
of the Authorised Person(s) / Qualified Person(s) responsible for batch certification
and releasing procedures;
- General description of batch certification and releasing procedure;
- Role of Authorised Person / Qualified Person in quarantine and release of finished
products and in assessment of compliance with the Marketing Authorisation;
- The arrangements between Authorised Persons / Qualified Persons when several
Authorised Persons / Qualified Persons are involved;
- Statement on whether the control strategy employs Process Analytical Technology
(PAT) and/or Real Time Release or Parametric Release.
66
2.3 Management of suppliers and contractors
- A brief summary of the establishment/knowledge of supply chain and the external
audit program;
- Brief description of the qualification system of contractors, manufacturers of active
pharmaceutical ingredients (API) and other critical materials suppliers;
- Measures taken to ensure that products manufactured are compliant with TSE
(Transmitting animal spongiform encephalopathy) guidelines.
- Measures adopted where counterfeit/falsified products, bulk products, active
pharmaceutical ingredients or excipients are identified;
pharmaceutical ingredients or excipients are identified;
- Use of outside scientific, analytical or other technical assistance in relation to
manufacture and analysis;
- List of contract manufacturers and laboratories including the addresses and contact
information and flow charts of supply-chains for outsourced manufacturing and
Quality Control activities; e.g. sterilisation of primary packaging material for aseptic
processes, testing of starting raw materials etc, should be presented in Appendix 4;
- Brief overview of the responsibility sharing between the contract giver and acceptor
with respect to compliance with the Marketing Authorisation (where not included
under 2.2).
67
2. QUALITY MANAGEMENT SYSTEM OF THE COMPANY (Conti)
2.4 Quality Risk Management (QRM)
- Brief description of QRM methodologies used by the manufacturer;
- Scope and focus of QRM including brief description of any activities which are
performed at corporate level, and those which are performed locally. Any
performed at corporate level, and those which are performed locally. Any
application of the QRM system to assess continuity of supply should be mentioned.
2.5 Product Quality Reviews
- Brief description of methodologies used
68
4. PREMISES AND EQUIPMENT
4.1 Premises
- Short description of plant; size of the site and list of buildings. If the production for
different markets, i.e. for local, EU, USA, etc. takes place in different buildings on
the site, the buildings should be listed with destined markets identified (if not
identified under 1.1);
- Simple plan or description of manufacturing areas with indication of scale
(architectural or engineering drawings are not required);
- Lay outs and flow charts of the production areas (in Appendix 6) showing the room
- Lay outs and flow charts of the production areas (in Appendix 6) showing the room
classification and pressure differentials between adjoining areas and indicating the
production activities (i.e. compounding, filling, storage, packaging, etc.) in the
rooms;
- Lay-outs of warehouses and storage areas, with special areas for the storage and
handling of highly toxic, hazardous and sensitising materials indicated, if
applicable;
- Brief description of specific storage conditions if applicable, but not indicated on the
lay-outs.
69
4.2.3 GMP critical computerised systems
- Description of GMP critical computerised systems (excluding equipment specific
Programmable Logic Controllers (PLCs).
5. DOCUMENTATION
- Description of documentation system (i.e. electronic, manual);
- When documents and records are stored or archived off-site (including
pharmacovigilance data, when applicable): List of types of
documents/records; Name and address of storage site and an estimate of
time required retrieving documents from the off-site archive.
70
6. PRODUCTION
6.1. Type of products
(references to Appendix 1 or 2 can be made):
- Type of products manufactured including
list of dosage forms of both human and veterinary products which are
manufactured on the site
list of dosage forms of investigational medicinal products (IMP)
manufactured for any clinical trials on the site, and when different from the
manufactured for any clinical trials on the site, and when different from the
commercial manufacturing, information of production areas and personnel
- Toxic or hazardous substances handled (e.g. with high pharmacological activity
and/or with sensitising properties);
- Product types manufactured in a dedicated facility or on a campaign basis, if
applicable;
- Process Analytical Technology (PAT) applications, if applicable: general statement of
the relevant technology, and associated computerised systems.
71
6.2 Process validation
- Brief description of general policy for process validation;
- Policy for reprocessing or reworking.
8. DISTRIBUTION, COMPLAINTS, PRODUCT DEFECTS AND RECALLS
8.1 Distribution (to the part under the responsibility of the
manufacturer)
- Types (wholesale licence holders, manufacturing licence holders, etc) and locations
- Types (wholesale licence holders, manufacturing licence holders, etc) and locations
(EU/EEA, USA, etc.) of the companies to which the products are shipped from the
site;
- Description of the system used to verify that each customer / recipient is legally
entitled to receive medicinal products from the manufacturer;
- Brief description of the system to ensure appropriate environmental conditions
during transit, e.g. temperature monitoring/ control;
- Arrangements for product distribution and methods by which product traceability is
maintained;
- Measures taken to prevent manufacturers products to fall in the illegal supply
chain.
72
Appendices of Site Master Files
Appendix 1 - Copy of valid manufacturing authorization
Appendix 2 - List of products (dosage forms and/or APIs)
manufactured including for dosage forms the INN-
names of APIs used
Appendix 3 - Copy of valid GMP Certificate
Appendix 4 - Organizational charts
Appendix 5 - Lay outs of production areas including process,
equipment, waste and personnel flows
Appendix 6 - Schematic drawings of water systems
Appendix 7 - List of major production and laboratory equipment
used indicating the frequency for re-qualification
Appendix 8 - List of contractors including the addresses and
contact information
73
Q & A Q & A
74
THANK YOU THANK YOU THANK YOU THANK YOU THANK YOU THANK YOU
Together we will meet the
challenges of the future
75
TOPIC: APPLICATION OF
QUALITY RISK MANAGEMENT
Good Manufacturing Practice for Medicinal Products Manufacturers Good Manufacturing Practice for Medicinal Products Manufacturers
QUALITY RISK MANAGEMENT
Presented by:
Lai Weng Fai
Acting Director / Senior GMP Auditor
Licensing & Certification Branch (LCB)
15 February 2012
1
OUTLINE OF PRESENTATION OUTLINE OF PRESENTATION
Quality Risk Management (QRM)
Brief Background
Implementing QRM Expectations
Areas of Application - Examples
Summary
2
QRM QRM Brief Background Brief Background tbc tbc
Risk management has been part of the pharmaceutical industry for
many years.
GMP requirements are designed to address risk.
o The holder of a manufacturing authorisation must ... ensure that
medicinal products ... are fit for their intended use ... and do not
place patients at risk due to inadequate safety, quality or efficacy. place patients at risk due to inadequate safety, quality or efficacy.
[Chp 1, Principle]
o The responsibilities placed on any one individual should not be so
extensive as to present any risk to quality. [Chp 2 , Clause 2.1]
o the specific GMP requirements for sterile products (PIC/S GMP
Guide, Annex 1) are designed to mitigate the risk of sterility
failure.
3
QRM QRM Brief Background Brief Background tbc tbc
GMP specifies a risk based approach.
o A risk assessment approach should be used to determine the
scope and extent of validation [Annex 15, Principle].
o A risk analysis of the sterility assurance system focused on an
evaluation of releasing non-sterilised products should be
performed [Chp 17, Clause 3.7] performed [Chp 17, Clause 3.7]
Specifications in pharmacopoeial monographs include tests for known
potential contaminants.
4
QRM QRM Brief Background Brief Background
PIC/S GMP Guide greater emphasis on formalising these processes and
using formal risk management tools.
From a GMP perspective, we are only concerned with risks associated with
product quality (Purity, Identity, Potency, Safety, etc.)
i.e., Quality Risk Management.
Manufacturer is responsible for assessing risks to the medicinal products Manufacturer is responsible for assessing risks to the medicinal products
and managing these risks to an acceptable level.
5
Implementing QRM Implementing QRM Expectations Expectations tbc tbc
In the PIC/S GMP Guide (since 15 Jan 2009):
Chapter 1 Quality Management [Principle]
To achieve the quality objective reliably there must be a comprehensively
designed and correctly implemented system of Quality Assurance
incorporating Good Manufacturing Practice, Quality Control and Quality incorporating Good Manufacturing Practice, Quality Control and Quality
Risk Management. It should be fully documented and its effectiveness
monitored.
The basic concepts of Quality Assurance, Good Manufacturing Practice,
Quality Control and Quality Risk Management are inter-related.
6
In the PIC/S GMP Guide (since 15 Jan 2009):
Chapter 1 Quality Management
Quality Risk Management
1.5 Quality risk management is a systematic process for the assessment,
control, communication and review of risks to the quality of the
medicinal product. It can be applied both proactively and medicinal product. It can be applied both proactively and
retrospectively.
7
1.6 The quality risk management system should ensure that:
- the evaluation of the risk to quality is based on scientific
knowledge, experience with the process and ultimately links to
the protection of the patient;
- the level of effort, formality and documentation of the quality
risk management process is commensurate with the level of
risk.
Quality
Risk
Degree to which a set
of inherent properties
of a product, system or process
fulfills requirements
combination of the
probability of occurrence of harm and
8
probability of occurrence of harm and
the severity of that harm(to the patient)
Systematic process for the assessment,
control, communication and review
of risks to the quality of the
drug (medicinal) product
across the product lifecycle.
It can be applied both proactively and
retrospectively.
& Management
QRM
What do GMP auditors look out for?
Written Policy/Procedure
Various aspects of business operations where QRM will be applied.
General approach to both planned and unplanned risk assessment.
Methods to be used (commensurate with risk level). Methods to be used (commensurate with risk level).
Implementation of QRM within companys QMS
Relevant procedures updated & integrated with QMS.
Formal methods defined (where applied).
Training of staff involved in QRM activities.
Involvement of senior management in the identification &
implementation of QRM principles within the company.
9
Systematic Approach
Local SOPs guide user into performing and documenting risk analysis.
System of archival and on-going review of significant risk assessments
used to justify operational activities, validations, etc.
One-off risk assessments should be documented, approved and
retained. retained.
Evidence of proactive and retrospective risk assessments in place
where required.
10
Outcomes of assessment
Risk-based decisions are well informed, science-based and
comprehensible, and taken by decision makers with appropriate
competence & authority.
Ultimate linkage to patient safety.
Assumptions & supporting reasons properly documented. Assumptions & supporting reasons properly documented.
Justifiable assessments
Level of efforts/resources deployed in the QRM activity commensurate
with the criticality of the identified problem.
High potential risk more thorough evaluation & report.
Low potential risk may be a one line justification.
11
QRM Issues Commonly Observed
1. Failure to apply/consider QRM
2. Inappropriate/incorrect application of QRM
Inadequate or no assessment of impact on product quality/linkage to
patient safety. patient safety.
Lack of scientific evidence supporting decisions.
Lack of process understanding and/or regulatory requirements.
Review of assessments without systematic approach.
Risk management used to justify a preconceived outcome.
Invalid assumptions made to suit the preconceived outcome.
Variable tolerance of risk inconsistent decision-making.
12
QRM Issues Commonly Observed
In general, in a typical audit process:
Auditors will review the QRM processes as part of the QMS section of the
audit (e.g. product complaints, recalls, deviations, PQR, etc.).
Auditors will be pragmatic regarding the level of scrutiny and degree of Auditors will be pragmatic regarding the level of scrutiny and degree of
formality expected of the outcome of QRM exercise.
Auditors will be flexible and ready to debate/accept outcome based on
good science.
If necessary, auditors may request company to produce a formal
summary of the risk assessment, key decisions and conclusions, or take
copies of complex assessments for further evaluation outside of the
audit.
13
QRM Non-Conformities (NC)
NCs will be categorised dependent on the significance of the findings, the
activities undertaken by the manufacturer and the number of
observations relating to the incorrect application of QRM.
QRM-related NCs may be grouped with other QMS-related NCs (QRM is
expected to be an integral part of the QMS). expected to be an integral part of the QMS).
Major NC will generally be cited where the manufacturer is completely
lacking a QRM system.
Critical NCs may reference QRM where the risk assessments have
inappropriately supported release of products that pose a threat to
patient safety.
14
QRM Non-Conformities (NC)
If the manufacturer has not undertaken an appropriate approach to
implementing the new requirements, an NC will be reported and will
usually be cited as an minor' NC against the relevant part of the GMP
standard.
Wherever companies demonstrate they are meeting the minimum Wherever companies demonstrate they are meeting the minimum
expectations , no NC will be cited.
15
Areas of Application Areas of Application tbc tbc
Risk Assessment
Risk Analysis
Risk Identification
Initiate
Quality Risk Management Process
A General
QRM Process
Model
16
Team
approach
Risk Review
R
i
s
k
C
o
m
m
u
n
i
c
a
t
i
o
n
Risk Evaluation
unacceptable
Risk Control
Risk Reduction
Review Events
Risk Acceptance
Output / Result of the
Quality Risk Management Process
R
i
s
k
M
a
n
a
g
e
m
e
n
t
t
o
o
l
s
Core Principles of Quality Risk Management:
1) Compliance with applicable laws.
Risk assessment should be used to assess how to ensure compliance and
to determine the resulting prioritization for action not for a decision
regarding the need to fulfill applicable regulations or legal requirements.
2) Risk can only be effectively managed when it is identified, assessed, 2) Risk can only be effectively managed when it is identified, assessed,
considered for further mitigation, and communicated.
4 stages of effective QRM process (risk assessment, risk control, risk
communication & risk review).
3) All quality risk evaluations must be based on scientific and process-
specific knowledge and ultimately linked primarily to the protection of the
patient (Figure 1 next).
17
18
Figure 1 Quality risk evaluation pyramid
Core Principles of Quality Risk Management:
4) Effective risk management requires a sufficient understanding of the
business, the potential impact of the risk, and ownership of the results of
any risk-management assessment.
5) Risk assessment must take into account the probability of a negative event
in combination with the severity of that event. in combination with the severity of that event.
Definition of risk = Probability of occurrence of harmand
severity of that harm
6) It is not necessary or appropriate to always use a formal risk-management
process (e.g., standardized tools).
use of informal risk management process (e.g. empirical assessment) is
acceptable for less complex areas which have lower potential risk.
19
Risk assessment supporting tools:
Determine the appropriate risk assessment tool/methodology
A key early step in the execution of a risk analysis .
No single best choice of risk assessment tool/methodology
The selection based on:
o the depth of analysis required
o complexity of the subject risk of concern
o the familiarity with the assessment tool
Risk ranking and filtering and flowcharting
most popular tools used for basic risk-assessment activities.
20
Risk assessment supporting tools:
Failure Mode Effect Analysis (FMEA)
appeared to be the most frequently used methodology for more
advanced risk analysis.
Often a combination of various tools may be required to facilitate risk
assessment. assessment.
21
PIC/S GMP Guide Annex 20 on Quality Risk Management
Appendix 1 Risk Management Methods & Tools
Not an exhaustive list.
1) Basic Risk Management Facilitation Methods
2) Failure Mode effects Analysis (FMEA)
Areas of Application Areas of Application tbc
Common risk management tools Common risk management tools
22
2) Failure Mode effects Analysis (FMEA)
3) Failure Mode, Effects & criticality Analysis (FMECA)
4) Fault Tree Analysis (FTA)
5) Hazard Analysis & Critical Control Points (HACCP)
6) Hazard Operability Analysis (HAZOP)
7) Preliminary Hazard Analysis (PHA)
8) Risk Ranking & Filtering
9) Supporting Statistical Tools
Common risk management tools Common risk management tools
23
Severity categorization Severity categorization an e.g. an e.g.
24
Some Examples
25
Some Examples
[1] Equipment Replacements [1] Equipment Replacements
Functional Equivalence Functional Equivalence tbc
Background
Obligation to ensure that manufacturing equipment is properly designed,
installed, tested, operated, and maintained throughout their service
lifetimes.
Manufacturing equipment will likely require both preventive and
corrective maintenance activities that may involve the replacement of corrective maintenance activities that may involve the replacement of
parts within the systems.
Appropriate change controls to be applied to parts replacements
ensure that manufacturing equipment remains in a validated state.
If replacement parts are exactly identical to the original parts
little issue with change control considerations.
26
However, it is not uncommon for procuring and installing replacement
parts that are not identical to the original parts.
due to changes affected by parts suppliers (e.g., product re-designs,
discontinuations).
A risk-management approach used to assess
whether replacement parts are functionally equivalent (i.e., like-for- whether replacement parts are functionally equivalent (i.e., like-for-
like) with original parts
ensure proper change control while also preventing unnecessary
revalidation activities.
27
In this case study, a risk-management approach was taken by the
manufacturer to identify the following:
Risks associated with equipment parts changes that might adversely
impact the validated state of manufacturing equipment
Risks associated with the process of determining whether original and
replacement parts are functionally equivalent replacement parts are functionally equivalent
Proper roles and responsibilities of the team of SME involved
What are the outputs?
A generic, robust, and repeatable process for performing
functional-equivalence assessments.
Define organizational roles and responsibilities supporting the
process.
28
Risk Question & Risk Assessment Method
Risk question:
Who should be involved to assess whether replacement parts are
functionally equivalent with original parts?
Company chooses to develop one risk assessment model for overall Company chooses to develop one risk assessment model for overall
(generic) assessment of functional equivalence to achieve these aims:
Identify potential gaps, inconsistencies, and redundancies within the
process that had historically been used for replacement parts
functional equivalence determinations.
Identify new or improved activities.
29
The team examined the risk question and core activities involved in the
historical functional equivalence assessment process. Identified the
following observations:
Functional equivalence assessment process was historically dependent
upon human judgment, expertise, and experience. upon human judgment, expertise, and experience.
Process risks (e.g., potential breakdowns of the process) were
qualitative in nature and difficult to quantify with specificity.
Risk assessment team selected Fault Tree Analysis (FTA) as risk
assessment method.
FTA is well suited for analysis of qualitative fault conditions that may
be related to human performance factors.
30
Risk Identification, Analysis & Evaluation
The risk assessment process involved
a review and analysis of the change control system
to determine how equipment parts replacements could potentially
cause unwanted or undetected change to the equipment's validated
state. state.
The analysis was organized into the fault tree structure (Figure 1 next).
31
Figure 1 Fault Tree Analysis
[Equipment changes &
validation impact]
32
[Functional equivalence
assessment]
33
Risk Control
For each of the 2 areas of significant risk identified in the FTAs, associated risk
control plans were established, as follows:
Training curricula were created to define the training and qualification
criteria for personnel initiating functional equivalence assessments.
Roles and responsibilities for each functional area participating in Roles and responsibilities for each functional area participating in
functional equivalence assessments were elaborated in the form of
executable checklists .
thorough and consistent assessment to be done.
34
Risk Control
This approach resulted in:
Minimising both gaps and redundancies in the assessment efforts
Creating a common assessment record format to facilitate overall
review of the assessment package
Functional area checklist details unique areas of consideration for the Functional area checklist details unique areas of consideration for the
assessment and with assessment conclusions and signatures of the
assessor(s).
Example of a checklist from Engineering function at Table 1
(see next).
35
Table 1
Checklist
template
36
Risk Documentation & Communication
The outputs of this risk management effort comprise the documented
justification for revisions to the quality system documents:
Training and qualification curricula for personnel initiating change
controls where functional-equivalence will be assessed
Equipment change control standard operating procedures on the Equipment change control standard operating procedures on the
functional equivalence assessment process for parts replacements
Maintenance systems inventory process control flow.
Training is required to be performed on these updated documents and
training records are periodically audited for compliance.
37
Functional Equivalence Functional Equivalence
Risk Review
Routine internal audits and document reviews are performed throughout
each of the functions impacted by this risk assessment (i.e., training,
change control, and equipment maintenance).
Adverse findings or trends identified during these audits/reviews
provide indication whether the risk assessment needs to be revised or provide indication whether the risk assessment needs to be revised or
fine tuned.
38
[2] Process Deviation [2] Process Deviation
Empty Product Capsules Empty Product Capsules tbc
Background
A finished product manufacturer produces pain-free capsules, which are
indicated as an anti-epileptic and for treatment of neuropathic pain.
Multiple customer complaints of empty capsules were received.
Lot ABC was fully distributed in the market and no stock of the
affected batch remains within company control. affected batch remains within company control.
There is no evidence of product tampering.
Batch record review indicated that during processing, a loose dosator was
replaced on the encapsulation equipment.
Following replacement and prior to resuming encapsulation,:
perform acceptance testing of capsules (as per SOP) product met
requirements.
39
Background
Further investigation revealed that the loose dosator caused empty
capsules to be produced.
This empty capsule removal system includes a reservoir for holding empty
capsules rejected during the manufacturing process.
Loose dosator atypically high number of reject empty/low fill Loose dosator atypically high number of reject empty/low fill
capsules were produced overflowing of holding reservoir.
The reservoir was physically located over the acceptable capsule flow.
Holding reservoir overflowed potential for rejected capsules to fall
back into the acceptable capsule exit chute re-introduced to the lot.
40
Risk Question:
Do a small number of potential low fill or empty capsules in a single batch
of product pose an unacceptable risk to patients, and secondarily, to the
company?
In this case study, the risk factors are more qualitative than quantitative. In this case study, the risk factors are more qualitative than quantitative.
Failure Mode Effects Analysis (FMEA) is specifically designed to
systematically study processes for possible failure modes and then to
develop actions to mitigate these failure modes.
Need to consider additional element detectability of the defect.
Is it possible for the pharmacist or the patient to readily detect empty
capsules?
41
The FMEA technique is an optimal tool for this application as this standard
methodology includes all three risk components (i.e., probability, severity,
and detectability).
Hence, the risk methodology selected for the subject case study is: FMEA.
42
FMEA process involves the identification of potential risks that could be
caused by empty capsules in the market & possible consequences of each
risk.
sufficient data may not always be available
risk identification based on best available data, scientific knowledge risk identification based on best available data, scientific knowledge
and historical experience
Examples of potential risks:
patients may receive empty capsules,
product supply shortage
audit observation from internal auditor/regulatory authority
etc.
43
Numerical ratings for the FMA analysis are based on the following criteria:
1) Severity of the failure
2) Frequency of the failure
3) Ability to detect the parameter
A numerical ranking of 13 is applied to each evaluated hazard, as
demonstrated in the example FMEA risk-score ranking table using a three-
point ranking scale (Table 1 next).
44
Table 1
45
In the FMEA analysis, the company determined:
If risk evaluation score moderate or greater appropriate risk
mitigating actions required to lower the risk to an acceptable level.
if the score for an evaluated hazard > 9 corrective measures to the
reduce risk of failure will be taken. reduce risk of failure will be taken.
If after attempting risk mitigation, the score could not be lowered below 9,
the resulting risk would not be accepted.
For those items with a score below the defined threshold, risks will be
accepted. Conclusions are documented.
An example worksheet for calculating the Risk Evaluation Score for this
analysis is presented in Table 2 (next).
46
Table 2
47
Risk Control
Risk reduction and acceptance decisions focused on patient safety.
Despite the apparently low number of empty/low fill capsules that may be
present, there was no assurance that the numbers of empty capsules in
the market was low.
Capsule shell is opaque a pharmacist or patient unable to detect an Capsule shell is opaque a pharmacist or patient unable to detect an
empty or partially filled capsule readily.
48
Risk Control
Most importantly, the potential medical consequence for some patients
due to receiving and administering an empty or partially filled capsule was
severe.
As a result of the potentially high risk associated with some patients taking
empty/low-fill capsules, and the inability of the company to implement empty/low-fill capsules, and the inability of the company to implement
appropriate risk mitigating actions to lower this risk (i.e., severity and
ability to detect) to an acceptable level, the decision was taken to initiate
a product recall.
49
Site procedures require preparation and Quality division endorsement of a
deviation report.
The risk assessment output was incorporated into a number of existing
work processes and their associated documentation.
To prevent re-introduction of rejected product to the product, an To prevent re-introduction of rejected product to the product, an
automated sensor was incorporated into the empty capsule reject
reservoir. When activated, this sensor automatically shuts down the
encapsulation machine should rejected capsules in the reservoir reach the
sensor level, thereby preventing overflow.
The overflow sensor with automated equipment shutdown was applied to
all encapsulation machines at the firm.
50
Empty Product Capsules Empty Product Capsules
Additionally, the results of the FEMA analysis and recommendation for
product recall were presented at an internal management meeting :
Minutes of risk analysis and associated conclusions were documented.
Affected regulatory agencies were formally notified of the recall
decision. decision.
Risk Review & Conclusion
To gain additional understanding of the extent of the defect that reached
the market through:
Evaluation of product complaints.
Adverse event reports.
Further examination of product received from the product recall.
51
[3] [3] GMP Self GMP Self- -Inspection Inspection tbc
Background
Formal self-inspection - an integral part of an effective quality system in a
GMP-compliant pharmaceutical manufacturing facility.
Involved periodic internal audits of site operations (e.g., quality,
manufacturing, engineering, logistics) and associated systems with
potential GMP impact. potential GMP impact.
Overall administration of the internal audit program is the responsibility of
the quality control (QC) unit.
The QC unit is responsible to identify the focus, frequency and resources
to support the internal audits as well as to determine the effectiveness of
the conducted audits.
Internal audits are typically conducted according to a predetermined
schedule and on a regular basis.
52
Background
The manufacturing site is a diverse finished product facility.
Ideally, the site would be able to perform internal audits of all site
operations and systems within a given calendar year but not always easy
to do so.
One potential approach to administer an effective internal audit system is One potential approach to administer an effective internal audit system is
to determine audit frequency based upon the criticality of the various
operations.
The site maintains a list of current operations and also periodically reviews
and understands the performance of these operations and associated
systems.
The companys management recognizes that there are certain internal
systems that could benefit from additional attention.
53
Background
Site management wants to ensure that resources are applied to those
operations having the highest potential for GMP impact.
Use of quality risk management (QRM) as a tool to effectively prioritise a
and allocate resources for internal audits of various functional areas.
54
Risk Question:
What is the optimal internal audit schedule to ensure that those
operations and associated systems with the greatest potential impact on
product quality and, therefore, potentially the patient, are audited on a
more frequently than those determined to be less critical? more frequently than those determined to be less critical?
An internal audit is a diverse activity with more qualitative characteristics
than quantitative ones.
Therefore, the selected risk assessment tool will produce a qualitative
description of risk (e.g., high, medium, or low).
An additional objective of the selected tool assist in the organization of
data as the assessment moves to the next stage of the process.
55
The developed list of site operations and associated systems ensures
identification of the potential risks.
Hence, a complex risk assessment tool is not required. A simple tool that
allows for qualitative analysis and evaluation is sufficient.
Risk assessment methodology selected: Risk ranking and filtering. Risk assessment methodology selected: Risk ranking and filtering.
56
Risk Identification & Analysis
The site has prepared a master list identifying all operations and
associated systems which have potential impact on product quality
(Table 1 next).
57
Table 1
Risk evaluation
score
58
The risk analysis stage of the QRM process estimates the potential harm(s)
associated with each potential risks.
The analysis may be qualitative or quantitative in nature, or a combination
of the two.
The risk score will be determined by combining the probability/likelihood The risk score will be determined by combining the probability/likelihood
of a problem in a given site operation and the outcome.
The risk evaluation score is calculated as follows:
(Probability Score Outcome Score) = Risk Evaluation Score
Numerical value of 1, 2, or 3 is assigned to correspond with a low,
medium, or high risk analysis determination, respectively.
59
The probability and outcome scores and subsequent risk evaluation scores
for the selected operations are presented in Table I.
If desired, the evaluation could be further modified to include
consideration of the length of time since the last audit was performed.
Formula for determining the risk evaluation score can be modified to Formula for determining the risk evaluation score can be modified to
include the time since the last audit as follows:
(Probability Score x Outcome Score) + (Years since last audit) =
Risk Evaluation Score
With application of QRM, the site is now able to better prioritize resource
utilization to focus auditing efforts on those areas with the highest risk
scores.
60
Risk Control
Risk is reduced by identifying site operations above a specific threshold
score from the risk ranking, and scheduling internal audits for those
operations.
Inherent risk will be accepted for those site operations which are below
that threshold. that threshold.
For those operations, an internal audit will be deferred until audits have
been completed for those operations with a higher risk ranking.
61
Risk Review
During development of annual schedule review the risk assessment
process and assumptions made.
The site will confirm that included operations/systems are still in use,
remove those that are not and add any new operations/systems to the
process. process.
Examples of changes that may potentially impact risk of site operational
systems include:
changes to control systems
changes to equipment and processes
changes in suppliers/contractors
organizational restructuring
62
Communication of the utilized QRM process should include all key
stakeholders of the affected departments to ensure organizational buy-in
and support.
Documentation needed and endorsed by site Quality Unit:
Output of QRM process Output of QRM process
The audit schedule
Associated risk analysis justifying the approach
Effective communication to stakeholders.
63
Summary Summary tbc
The concept of QRM is not necessarily new to pharmaceutical
manufacturers and inspectors in GMP environments. But there is a greater
emphasis now on adopting more formalised approaches to QRM.
Effective QRM facilitates better and more informed decisions, and provide
regulators with greater assurance of a companys ability to deal with
potential risks. potential risks.
The degree of rigor and formality of QRM should reflect available
knowledge and be commensurate with the complexity and/or criticality of
the issue to be addressed.
When integrated in quality systems, QRM is intended to enable and
enhance compliance with regulatory requirements and science-based
decisions.
If QRM is done properly, there should be increased assurance of quality
(and possibly cost savings).
64
Summary Summary
The QRM process should not be used as an excuse to delay or avoid
compliance gaps/issues or complying with regulatory requirements.
There is no one size fits all risk management methods for all application
areas.
Manufacturer is responsible for identifying areas of application,
identifying risk to product quality and managing that risk. identifying risk to product quality and managing that risk.
QRM will be reviewed at each GMP audit.
Auditors will be flexible and ready to debate/accept outcome based on
good science.
65
Further Reading Further Reading
T. Frank et al., Pharm. Technol. 35 (7), (8), (10), (12) 2011
PIC/S Guide to GMP (PE 009-9) & Annex 20 (www.picscheme.org)
QRM Implementation of ICH Q9 in the pharmaceutical field, PS/INF
1/2010
Application of hazard analysis and critical control point (HACCP)
methodology to pharmaceuticals, Quality assurance of pharmaceuticals. methodology to pharmaceuticals, Quality assurance of pharmaceuticals.
A compendium of guidelines and related materials. Vol. 2, 2
nd
updated
edition. Good manufacturing practices and inspection. Geneva, WHO,
2007.
ICH Q9 Briefing Pack (www.ich.org)
ICH Q8/Q9/Q10 Training Material (www.ich.org)
www. tga.gov.au
www.mhra.gov.uk
66
Thank you for your attention! Thank you for your attention!
67

HPRG JOINT REGULATORY WORKSHOP Year: 2012
Case Study Review of a Quality System Procedure

INTRODUCTION:
THE COMPANY PTE LTD is a local manufacturer of a range of western pharmaceutical products in various
finished dosage forms and is in the midst of conducting its routine self inspection. You are one of the
auditors in the inspection team and you are provided with a copy of the supplier qualification
procedure
1
for review. (Please refer to your workshop folder for the copy.)

TASK:
Review the SOP and
i) identify (by circling it) the possible non-conformities against the PIC/S GMP Guide and
ii) Identify areas for improvement (if any).
Please note that the associated documents and forms related to the SOP are not needed to complete
this case study.

OUTCOME OF SOP REVIEW:
The outcome of the review will be presented at the end of the case study.

1
The content of this document, including the name of the company and name of the signatories are
fictitious and is written for the purpose of this workshop. Any resemblance to actual names or scenario
should be deemed as mere coincidence.

THE COMPANY PTE LTD

Title: RAW MATERIAL SUPPLIER ASSESSMENT, APPROVAL AND
MONITORING

Document No.: QA-2043-03
Doc Type: SOP Dept: Quality Assurance (QA) Supersedes: QA-2043-02
Prepared by:
Ctrlalt Del

Written by:
Wolverin

Approved by:
Yearofdra Gon

Page Number: 1 of 5
Effective Date: 30/09/2010
Date:
Date:
Date:

1.0 PURPOSE
Procedure to approve suppliers of Raw Materials (including primary packaging material) for production use
in accordance with the current GMP requirements for finished pharmaceutical products.
Note: References to Raw Materials throughout this procedure include primary packaging materials.

2.0 RESPONSIBILITY
2.1 Quality Assurance (QA) is responsible for:
2.1.1 Implementation of the procedure.
2.1.2 Review of all supplier approval documentation to ensure it is in compliance with this
procedure, GMP requirements and that only supplier that are capable of supplying
materials which meet THE COMPANY PTE LTD requirements are approved.
2.1.3 Maintenance of regulatory filings and notifications as a result of new/changed suppliers.
2.1.4 Assessment of impact of changes to THE COMPANY PTE LTD products and notification
where deemed necessary.

2.2 Supply Chain (SC) is responsible for:
2.2.2 Maintaining the Approved Suppliers List.
2.2.3 Ensuring that materials are ordered from approved suppliers
2.2.4 Serve as primary contact and coordinator with suppliers.

2.3 Quality Control (QC) is responsible for:
2.3.2 Ensuring that analysis of samples is performed as per documented procedures and that
results are submitted for filing as per this procedure.
3.0 SCOPE
The procedure provides for approving of all suppliers of Raw Materials for THE COMPANY PTE LTD
manufacturing facility.

THE COMPANY PTE LTD

MONITORING

Supersedes: QA-2043-02
Doc Type: SOP Dept: Quality Assurance (QA)
Page Number: 2 of 5

4.0 DEFINITIONS

Approved supplier A supplier which is fully approved for the supply of Raw Materials for production
use.
Non manufacturing material A material or item that is not used in the manufacturing process but is used in some
ancillary capacity where there is no direct product contact e.g. boiler salt, battery
acid, sodium hypochlorite.
Critical raw material A raw material which is the active ingredient of a product or which has major impact
on formulation of the product as categorized by SC.
Primary Packaging Materials Packaging that is intended to be in direct contract with the product.

5.0 PROCEDURE RAW MATERIALS SUPPLIERS
5.1 The need for a new supplier and/or material is identified by the department using the material or SC. In
the case of new product development, process development, new product support or research and
development, material must be at a minimum provisionally qualified before it is going to be used in
manufacturing.

5.2 SC will identify potential suppliers and will initiate initial discussions regarding pricing, raw material and
service requirements. As part of this, SC will confirm the suppliers ability to provide material meeting
THE COMPANY PTE LTD requirements by either:
5.2.1 Forwarding a copy of the THE COMPANY PTE LTD specifications and requirements for the
material to the supplier for confirmation they can supply to those requirements and/or
5.2.2 Request copy of the suppliers specification for the material being evaluated, this will be
reviewed internally at THE COMPANY PTE LTD to confirm it meets requirements.

5.3 If the supplier is an existing approved supplier of other Raw Materials, SC & QA will determine and
document if existing questionnaires or scope of supply cover the new material and can be applied to
the new approval.

5.4 If deemed necessary above, SC submits questionnaire to the prospective supplier for completion area.

5.5 SC will request any samples of material required.
5.5.1 Non-Critical Raw Materials - Three samples from three different lots of material
(min 30g each).
5.5.2 Critical Raw Materials Three samples from three different lots of material (min 150g each).

THE COMPANY PTE LTD

MONITORING

Page Number: 3 of 5

NOTE: In exceptional circumstances, if the supplier cannot provide 3 samples from 3 different batches,
this will be assessed with QA and a risk assessment performed to develop a rationale for alternative
sample submission requirements. This must be reviewed and approved by Site Director and QA.

5.7 Samples received are submitted to QC for testing with the Supplier Approval Sheet with
section 1 completed.

5.8 QC Analysis of Raw Materials
5.8.1 Each sample is assigned the next sequential QC number and detail of the sample recorded in
the QC number register. The QC number of each sample and the corresponding suppliers lot
number must be recorded on the Supplier Approval Sheet.
5.8.2 Samples are analyzed as per the current version of the relevant monograph. If there is no
current monograph available, testing is performed per the suppliers specification/certificate of
analysis. The completed analysis requisition is reviewed by the QC supervisor.
5.8.3 On completion of QC testing, all critical Raw Materials must be Use-tested. For non-critical Raw
Materials, QC Management may decide that further analysis or Use testing is required.
5.8.4 Where Use testing is required, the sample will be submitted to the R&D Dept accompanied by
a Use Test Request Sheet (QAD-025).
5.8.5 The R&D Dept will submit the product formulated from the material to the QC Dept
accompanied by the completed Use Test Request sheet recommending material acceptance or
otherwise.
5.8.6 The completed analysis requisition and Use test sheet is reviewed by the QC department.
5.8.7 On completing QC analysis of the Use test, QC Management fills Section 2 of the Supplier
Approval Sheet.
5.9 An on-site audit is not mandatory, the need for an on-site audit will be determined based on risk
factors such as intended use of the material, criticality of the Raw Material and other risks as deemed
appropriate. This will be documented on the supplier approval form. Audit is normally carried out by
the Marketing Department.

5.10 For suppliers of critical Raw Materials, an on-site audit is always recommended.
5.10.1 If an audit is recommended but cannot be performed within the timeframe that the material is
required, the supplier may be approved once the audit has been added to the supplier audit
schedule subject to all other requirements for supplier approval have been completed and are
satisfactory. This will be justified and documented on the supplier approval form.

5.11 If the review of QC and Use testing is acceptable, then the supplier is approved.
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MONITORING

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5.12 If the review of QC and Use testing concludes that the supplier cannot be approved then a
determination will be made as to whether continue with this supplier and work with them to
determine the reason for the failure and correct it or to find another supplier.

5.14 If the supplier is deemed acceptable, the paperwork is completed and the Approved Suppliers List
updated by SC. Completed documentation is filed as per documentation section below. Orders may be
placed with the supplier for approved products. SC will issue an MSDS for new Raw Materials to
Safety (as necessary) who in turn will circulate it to all relevant functional areas.

NOTE: For non-manufacturing material which has no product contact, detailed testing and evaluation is
not required.

6.0 SUPPLIER MONITORING

6.1 Problems with suppliers subsequent to approval must immediately be brought to the attention of QA
and SC by raising the Material Feedback Sheet (QAD-188)

6.2 SC will communicate these to the supplier and will request a written response.

6.3 The response will be reviewed by QA and SC for acceptability. Further clarification/corrective action will
be requested if deemed necessary.

6.4 If the response remains unsatisfactory, the supplier maybe removed from the Approved Suppliers List

6.5 On an annual basis, suppliers of critical Raw Materials will be contacted to identify any changes to their
details which will have an impact on the goods they provide.
6.5.1 Audit or re-audit of existing suppliers may be performed if deemed warranted based on poor
performance during the year or as part of the investigation of a material issue.

7.0 REGULATORY REQUIREMENTS

7.1 Where the supplier/manufacturer of a Raw material is changed, QA must assess the impact of this
change on the quality of product manufactured. This assessment must be filed with the supplier
approval documentation.
7.1.1 Where applicable a regulatory submission may be necessary to comply with regulatory
requirements of the products registered.
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8.0 RELATED DOCUMENTS

Supplier Approval Sheet (QAD-135)
Supplier Assessment Questionnaire (QAD-162)
Use Test Request Sheet (QAD-025)
Service Supplier Qualification Sheet (QAD-194)
Service Supplier Assessment Questionnaire (QAD-193)
Approved Supplier List

Workshop 5 Workshop 5
Good Manufacturing Practice for Medicinal Products Manufacturers Good Manufacturing Practice for Medicinal Products Manufacturers
CASE STUDY REVIEW OF A QUALITY SYSTEM
PROCEDURE PROCEDURE
Presented by:
Ng Liong Thiam
Dy Dir (GMPL Unit)
Audit Branch (AB)
Introduction Introduction
A GMP case study on the review of a quality system procedure of a
pharmaceutical manufacturer.
Main purpose of case study is to encourage active participation and
information sharing on the application of GMP principles.
The quality system documents that we will be reviewing today is a
procedure on supplier qualification.
Give an overview on the aspect of supplier qualification
Overview of Supplier Qualification Overview of Supplier Qualification
Purchasing of starting material for production use
important function
involve staff with knowledge of the suppliers
Starting material should only be purchased from approved suppliers
named in the relevant specification.
All aspects of requirements of the starting material is to be discussed
with the suppliers:
Specification
Control and production aspects including handling
Labeling and packaging requirement
Approach taken for complaints and rejection
Supply requirement
Others
Changes in supply of raw materials should be subject to a formalized
change control process.
The purchase, handling and control of primary and printed packaging
material should be accorded attention similar to that given to starting
materials. materials.
Supplier qualification system and procedure(s) should be established
Gathering information and identify potential suppliers
Questionnaires
Supplier records (if any)
Others
Assessing of suppliers including the material to be supplied
QC testing
Use testing
Site inspections
Review of track records (if applicable)
Supplier qualification system and procedure(s) should be established (cont)
Approving of suppliers
review of assessment made e.g. testing report, audit report etc
supply agreement (if applicable)
formalize the approval/rejection process including
the updating of approved supplier list
Monitoring of suppliers
document all transaction including supply problem, quality
problem, and complaints
follow-up on CAPA and complaint (if any)
conduct periodic audit or re-audit (if necessary)
updating of changes by supplier
periodic review of qualification status
Case Study Exercise Case Study Exercise
Introduction
Mocked up and written for the purpose of this workshop
Local manufacturer in midst of conducting its self inspection and
you are one of the internal auditors
Task Task
Review the SOP
Identify possible non conformities against GMP Guide and
Identify area for improvement (if any)
SOP Review
Given some time to review the SOP and discuss
Associated documents and forms to the SOP are not required to
complete the case study
Outcome will be presented after the SOP review
Review of Case Study Review of Case Study
Approval section on page 1 inadequate there is no functional titles
for the signatory
Header section of page 1 - the effective date is earlier than the
approved date which means SOP is effective before approval
Paragraph 4 on Definition the term non-critical raw material was not
defined (to differentiate it from the critical raw material) which will
explain the rational for the difference in sampling requirement as
mentioned in paragraph 5.5 between the two groups of material
Paragraph 5.8 on QC Analysis is too detail for this procedure should
be parked under the QC procedure (and put under responsibility of QC)
Missing subsection: 5.6 and 5.13
Paragraph 5.9 Auditing by Marketing Department: In this case, the
Marketing Department should have the adequate GMP training in
order to assess effectively the supplier. As far as possible, QA should
take part in the audit. take part in the audit.
Paragraph 5.9 states that an audit is not mandatory and based on a
number of risk factors however it fall short of giving guidance on risk
factors when an on-site audit has to be performed
Paragraph 5.10.1 the use of material before audit when it has been
deemed necessary is an issue should be covered by applying risk
minimisation factors such as additional sampling
Paragraph 5.11 Supplier Approval reviewing only the QC report and
Use testing report for approval not adequate.
Should also include others like the questionnaire, the audit report, the
previous track records (if any) etc.
Any gap identified should be clarified and evaluated as to whether the
approval process can proceed. approval process can proceed.
Paragraph 5.14 & 6.4 states SC will update the supplier list such list
should also be approved by QA who is the owner of this SOP.
Supplier monitoring inadequate
Paragraph 6.1 to 6.4 suggest monitoring for acceptability is only on
problem area (if any) this should be more detailed to include
other key performance indicators e.g. Supply track records,
response to request etc
Paragraph 6.5 - Changes to the supplier of critical raw material
should be pre-notified by the supplier on their own accord in a
timely manner for review and approval (if necessary) not only
annually.
Paragraph 6.5.1 - A maximum time interval between two audits
should be determined for critical raw-material suppliers.
Paragraph 8 on related documents section is inadequate:
Approved Suppler List should be a controlled document with a
unique document number (i.e. QAD number)
Material Feedback Sheet (QAD-188) mentioned in paragraph 6.1 is
not referenced under this section not referenced under this section
Service supplier document (QAD-194 and QAD-193) not referred
to in this SOP was listed here
Missing reference essential to this SOP e.g. Change Control
procedure, guidance documents on how to perform on-site audits
Conclusion Conclusion
The list of possible non-conformities and areas for
improvement presented as the outcome of the case study in
the previous slides is not to be taken as exhaustive.
A copy of this presentation is available at the counter on your
way out after the workshop session. way out after the workshop session.
Thanks to the Steering Committee of the PIC/S Expert Circle on
API for sharing a model of the case study presented during the
4
th
Expert Circle Meeting on API held in Singapore in Oct 2011.
THANK YOU THANK YOU

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