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Requirements on documentation of API and FPP quality and evaluation process

Presented by Rutendo Kuwana


Prequalification of Medicines Programme QSM / EMP / HSS

Jakarta, October 2009

WHO Reference text for Multisource (Generic) products / Definitions


Active Pharmaceutical Ingredient (API) A substance or compound that is intended to be used in the manufacture of a pharmaceutical product as a therapeutically active compound (ingredient) Pharmaceutical Product Any preparation for human or veterinary use that is intended to modify or explore physiological systems or pathological states for the benefit of the recipient. Finished Pharmaceutical Product (FPP) A product that has undergone all stages of production, including packaging in its final container and labelling.

Jakarta, October 2009

Reference texts Prequalification quality guidelines for dossier submission


Guideline on submission of documentation for prequalification of multisource (Generic) Finished Pharmaceutical Products (FPPs) used in treatment of HIV/AIDS, Malaria and Tuberculosis (Main Generic guide with 8 annexes) [under revision] Supplement 1 : Dissolution testing Supplement 2 : Extension of the WHO list of stable APIs (not easily degradable)

Guidelines for registration of fixed-dose combination medicinal products


Guideline on Active Pharmaceutical Ingredient Master File (APIMF) Procedure Guidance on variations to a prequalified dossier ICH notes for guidance (When WHO or PQ guidelines silent) Prequalification of Generic products approved by Stringent Regulatory Authorities (SRAs) NEW Requalification Draft not finalised and not yet adopted

Jakarta, October 2009

Guidelines for Product dossier /Quality Main Generic guide


Guideline on Submission of Documentation for Prequalification of Multisource (Generic) Finished Pharmaceutical Products (FPPs) Used in the Treatment of HIV/AIDS, Malaria and Tuberculosis [under revision] Annex 1 - Model Certificate of a Pharmaceutical Product Annex 2 - Model Batch Certificate of Pharmaceutical Product Annex 3 - Model Stability Report of Active Pharmaceutical Ingredient (API) Annex 4 - Model Stability Report of Capsules/Tablets Annex 5 - Suggested Structure of the Summary of Product Characteristics (SmPC) Annex 6 - Suggested Structure of the Package Information Leaflet (PIL) Annex 7 - Presentation of Bioequivalence Trial Information (BTIF) Annex 8 - Presentation of Pharmaceutical Quality Information (PQIF)

Jakarta, October 2009

Assessment Process - Quality


Submission of application

PQIF, Dossier, BTIF


Screening (Internal)

Acceptance

Pre Assessment Screening

Assessment Report
Additional data

Prequalification LoPQ Requalification


Jakarta, October 2009

Quality dossier / Section 1


Information on the FPP
1.1. Details of the Product - Name, dosage form and strength of the product - Approved generic name (INN) - Visual description of the FPP - Visual description of the packaging 1.2. Samples to be provided (for visual examination of assessors and comparison with the SPC and PIL) 1.3. Regulatory situation in Member States / list countries - Countries where a MA has been issued - Countries where a MA has been withdrawn - Countries where a Marketing Application has been rejected, deferred

Jakarta, October 2009

Quality dossier / Section 2

Active Pharmaceutical Ingredient (API)

Jakarta, October 2009

Quality dossier / Section 2 Active Pharmaceutical Ingredient (API)


Scientific data on the API can be submitted using following ways and order of preference
A valid Certificate of Suitability (CoS) or CEP, latest version, with all its annexes issued by EDQM An APIMF (Active Pharmaceutical Ingredient Master File) submitted by the API manufacturer, containing the whole information requested in section 2 and presented in CTD format (see APIMF guideline) Complete submission of data requested in Section 2

Jakarta, October 2009

Quality dossier / Section 2 of PQIF - Active Pharmaceutical Ingredient (API)


2.1. Nomenclature

2.2. Properties of the API


2.3. Site(s) of manufacture

2.4. Route(s) of synthesis


2.5. Specifications

2.6. Container- closure system


2.7. Stability testing

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CTD Structure of API Sections


2.3.S 2.3.S.1 2.3.S.2 DRUG SUBSTANCE General Information Manufacture

2.3.S.3
2.3.S.4

Characterisation
Control of Drug Substance

2.3.S.5
2.3.S.6 2.3.S.7
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Reference Standards or Materials


Container Closure System Stability

2.3.S DRUG SUBSTANCE 2.3.S.1 General Information


2.3.S.1.1 Nomenclature Include INN, compendial name, chemical name(s), company/laboratory code, other non-proprietary names eg USAN, JAN, BAN and Chemical Abstracts Service (CAS) registry number.

2.3.S.1.2 Structure
Include structural formula with relative and absolute stereochemistry, molecular formula, and the relative molecular mass. 2.3.S.1.3 General Properties Physicochemical and other relevant properties of the API.
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2.3.S.2 Manufacture
Information on the manufacturer; A brief description of the manufacturing process (including, for example, starting materials, reagents, solvents, critical steps, and reprocessing) and the controls intended to result in the routine and consistent production of API. A flow diagram; A description of the Source and Starting Material and raw materials used in the manufacture of the API;
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2.3.S.2 Manufacture Contd


A discussion of the selection and justification of critical manufacturing steps, process controls, and acceptance criteria. Discuss critical process intermediates;
A description of process validation and/or evaluation. A brief summary of major manufacturing changes made throughout development and conclusions from the assessment used to evaluate product consistency. The QOS should cross-refer to the non-clinical and clinical studies that used batches affected by these manufacturing changes.
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2.3.S.3

Characterisation

A summary of the interpretation of evidence of structure and isomerism.


When an API is chiral, it should be specified whether specific stereoisomers or a mixture of stereoisomers have been used in the nonclinical and clinical studies, and information should be given as to the stereoisomer of the API that is to be used in the final product intended for marketing.

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2.3.S.3

Characterisation Contd: Impurities

Summary of the data on potential and actual impurities arising from the synthesis, manufacture and/or degradation, and should summarise the basis for setting the acceptance criteria for individual and total impurities.

Summary of the impurity levels in batches of the API used in the non-clinical studies, in the clinical trials, and in typical batches manufactured by the proposed commercial process. The QOS should state how the proposed impurity limits are qualified.
A tabulated summary, with graphical representation, where appropriate should be included.

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2.3.S.4

Control of Drug Substance

A summary of the specification(s), the analytical procedures, and validation should be included.
A tabulated summary of the batch analyses.

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2.3.S.5

Reference Standards or Materials

Information on primary and working standards of the API and specified impurities.

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2.3.S.6

Container Closure System

A brief description and discussion of the primary and secondary packaging components.

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2.3.S.7

Stability

This section should include a summary of the studies undertaken (conditions, batches, analytical procedures) and a brief discussion of the results and conclusions, the proposed storage conditions, retest date or shelf-life.
The post-approval stability protocol should be included.

Jakarta, October 2009

Quality dossier / Section 2 Active Pharmaceutical Ingredient (API)


CTD
S.1 General Information
- Nomenclature - Structure - General Properties

PQ dossier section 2
2.1 Nomenclature 2.2 Properties of API (s) 2.3 Site(s) of Manufacture 2.4 Route(s) of synthesis
- API not described in pharmacopoeia - Specifications of raw materials and intermediates used in synthesis - API described in a pharmacopoeia

S.2 Manufacture
- Manufacturer
- Description of manufacturing process - Control of materials - Control of critical steps and intermediates - Process validation - Manufacturing process development

S.3 Characterisation
- Elucidation of structure - Impurities

S.4 Control of Drug Substance S.5 Reference Standards or Materials

2.5 Specifications

S.6 Container Closure System


S.7 Stability testing
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2.6 Container Closure System


2.7 Stability testing

Quality dossier / Section 3

Finished Pharmaceutical Product (FPP)

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Quality dossier / Section 3 Finished Pharmaceutical Product (FPP)


3.1. Manufacturing and marketing authorization 3.2. Pharmaceutical development 3.3. Formulation 3.4. Sites of manufacture 3.5. Manufacturing process 3.6. Manufacturing process controls of Critical steps and intermediates 3.7. Process validation and Evaluation 3.8. Specifications for excipients 3.9. Control of the FPP 3.10. Container/closure system (s) and other packaging 3.11. Stability testing

Jakarta, October 2009

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP)

3.12. Container labelling 3.13. Product information for health professionals

3.14. Patient information and package leaflet


3.15. Justification for any differences to the product in the country OR countries issuing the submitted WHO-type certificate(s)

Jakarta, October 2009

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP)


3.1. Manufacturing and Marketing Authorization

Valid manufacturing authorization for pharmaceutical production including the pharmaceutical form applied for
Marketing authorization to demonstrate the product is registered / licensed in accordance with national requirements

3.2. Pharmaceutical development The aim is to build a quality product by design.

Jakarta, October 2009

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP)


3.2. Pharmaceutical development
The section should contain information on the development studies conducted to establish that the dosage form, the formulation, the manufacturing process, the container closure system, microbiological attributes and storage and usage instructions

are appropriate for the purpose specified in the dossier.


Jakarta, October 2009

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP)


3.2. Pharmaceutical development (pre-formulation)
Physico-chemical characteristics of the APIs solubility (composition) water content (stability) hygroscopicity (stability) particle size (solubility, bioavailability, suspension properties, stability ) polymorphism (solubility, bioavailability, stability) Data obtained from literature : Books, Journals, International Pharmaceutical Abstracts, Chemical Abstracts, Analytical Abstracts, Internet Experimental data (if necessary)

Jakarta, October 2009

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP)


3.2. Pharmaceutical development (choice of excipients)
Intended function of each excipient Criteria
compatibility of excipients with API(s), characteristics of the excipients (water content, particle size, flowability, density, rheological behavior)

Particularly : other non active constituents (lowest acceptable concentration to be chosen e.g. concentration of parabens as preservatives)

Experimental data needed.

Jakarta, October 2009

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP)


3.2. Pharmaceutical development (choice of the manufacturing process)
Parameters : characteristics of the APIs, dosage form, composition. . Rational behind the choice (e.g. why a non over kill process as a sterilisation process instead of terminal sterilisation in final container) Justification of the overage (if any) Identification of the critical steps In Process Control (IPC) Selection and optimisation of manufacturing process

Jakarta, October 2009

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP)


3.2. Pharmaceutical development (dissolution testing)
To study dissolution operating conditions (media, pH, rotation, ) To develop a discriminatory dissolution method Comparative dissolution testing is a tool, mandatory in development pharmaceutics section of the dossier in PQ, See Supplement 1
Help in selection of the formulation - compare formulation(s) with innovator product, - a basic strategy in development to maximize the chances of bioequivalence Comparison of pivotal batches to commercial batches/ post-approval changes

Setting of dissolution specifications

Jakarta, October 2009

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP)


3.2. Pharmaceutical development (comparative dissolution testing)

1.

Three media - 900 ml or less - all at 37C


Buffer pH 1.2 or 0.1M HCl Buffer pH 4.5 Buffer pH 6.8

2. 3. 4.

Water may be used additionally (not instead of) Paddle at 50 or basket at 100 rpm Twelve units of each product in all 3 media Dissolution samples collected at short intervals, e.g.
10, 15, 20, 30, 45 and 60 minutes Analyse samples for all APIs, when applicable

5.

Calculate similarity factor f2

Jakarta, October 2009

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP)


3.2. Pharmaceutical development (details of batches studied)
Provide a summary of development of the FPP from preformulation to production scale. Provide a comparison of formulas (tabulated form) of: bio-batche(s) (clinical / bioequivalence), development batches, stability batches, batches for validation/production

Jakarta, October 2009

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP)


3.2. Pharmaceutical development (choice of formulation and compatibility)
Compatibility of APIs with the excipients Compatibility of APIs between each other in case of fixed dose combinations

Jakarta, October 2009

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP)


3.3. Formulation
Formula in tabulated form for :
Administration unit (e.g. one tablet), Typical batch - Precise any overage, - Precise quantity adjustment of the API, - Precise q.s. for excipient.

Excipients :
State function (e.g. lubricant, disintegrant), Precise technical grade (e.g. micronised, purified water), describe also those removed during process (e.g. water), Describe also those not always added (e.g. acid & alkali for pH adjustment, Capsule shells, inked imprints on dosage form, Also gas (inert atmosphere).

Jakarta, October 2009

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP)


3.4. Manufacturing sites Name and street address of each facility where any aspect of manufacture occurs including production, sterilisation, packaging and quality control include Units and/or Blocks Include any alternative manufacturers

Certificate issued by the Competent DRA according to WHO Certification scheme for each site where a major step of manufacturing is performed Submit a valid GMP certificate

Jakarta, October 2009

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP)


3.5. Manufacturing process (cont.)
Flow chart with indication of each step showing where materials enter the process. Indication of critical steps and in-process controls Description of manufacturing/packaging including
Scale Equipment by type (e.g. tumble blender) & working capacity Process parameters for steps, (e.g. time, temperature, pH) Environmental conditions, e.g. relative humidity for hygroscopic FPPs., area class for sterile FPPs Steps of the process Alternative methods

Jakarta, October 2009

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP)


3.5. Manufacturing process (cont.)
Proposal for reprocessing justified with data. Copy of master formula. Batch manufacturing record real batch. Sterile products sterilisation steps and/or aseptic procedures. Description of in-process tests including plan of sampling and acceptance limits. Data for 3 full scale batches to support achievement of predetermined specifications.

Jakarta, October 2009

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP)

3.6. Manufacturing Process Controls of Critical steps and Intermediates


Identification of critical steps with test methods and justified acceptance criteria

Information on quality of isolated intermediates, test methods and justified acceptance criteria to control them

Jakarta, October 2009

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP)


3.7. Process Validation and Evaluation
Validation mandatory for processes including a critical step

The aim is to show that critical steps are under control and lead continuously to the desirable quality
Examples of critical steps (list non exhaustive)
mixing, coating, granulation, emulsification, non-standard sterilisation

Jakarta, October 2009

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP)


3.7. Process Validation and Evaluation (details on 3 first production batches)
Batches
. batch number . batch size . place and date of manufacture . batch number of API(s) . yield . batch purpose (validation, stability, clinical trial )

Process
. equipment . process parameters . validation protocol.

Results
. critical steps . in process control . finished product

Jakarta, October 2009

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP)


3.7. Process Validation and Evaluation
OR Concurrent validation carried out during normal production on the first 3 production batches

For well-established processes process data, in-process controls and quality controls on a total of 10- 25 batches to present a statistically significant picture

Jakarta, October 2009

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP)


3.7. Process Validation and Evaluation
If validation data (on production scale batches) are not available submit
validation protocol, commitment that validation report will be submitted later for evaluation, commitment that data will be available in case of inspection,

commitment that WHO will be informed of any significant deviation.

Jakarta, October 2009

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP)


3.7. Process Validation and Evaluation
Validation protocol should include
brief description of the process with summary of critical steps and parameters to be followed during validation, specifications of the FPP at release, details of analytical procedures and limits, sampling plan, unifromity of dosage units essential for FDCs, proposed timeframe

Validation report when submitted should include results for each batch, certificates of analysis, batch production records, report on unusual findings, modifications, observations and conclusions

Jakarta, October 2009

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP)


3.8. Specifications for excipients
- Non pharmacopoeial substances - Details for manufacturing process, - Specifications (description of procedures and acceptance criteria) - Stability data - Cross-reference to non-clinical (toxicological)- clinical data for safety aspects - Certificates of analyses - Pharmacopoeial excipients Copy of the pharmacopoeial monograph used for control + certificates of analysis

- For excipients of animal, human, microbial origin


- TSE (Transmissible Spongiform Encephalopathy) risks and viral safety should be addressed - TSE CEP preferred

Permitted colorants are those allowed in UE, USA and Japan

Jakarta, October 2009

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP)


3.9. Control of the FPP
2 sets of specifications are possible: at release and at the end of shelf-life (list of attributes non exhaustive)
Description of the FPP /appearance Identification of API Assay of API: 5% of the label claim at release and 10% at the end of shelf-life Degradation products Pharmaceutical tests e.g. dissolution, disintegration (where applicable) Uniformity of dosage units (mass or content) Identification of colorants, identification and assay of anti-oxidants, chemical preservatives Microbial contamination, Sterility, bacterial endotoxins

Jakarta, October 2009

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP)


3.9. Control of the FPP (cont.)
Monographs of Ph. Int., USP, BP are acceptable for the FPP + complementary tests If non-pharmacopoeial FPP, note for guidance Q6A applicable Description of all analytical procedures in details if not described in a pharmacopoeial monograph Validation of analytical methods and/or demonstration of applicability for pharmacopoeial methods Batch analyses for 3 lots with details of each lot (batch no, size, date of manufacture, use of batch)

Jakarta, October 2009

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP) 3.10. Container-closure system
Discussion on the choice of container
Choice of the material Protection against light and humidity compatibility/interaction of materials in contact with dosage form Safety of materials used

Detailed description of the container


Specifications of the container with dimensions and drawings Specifications of materials in contact with FPP Composition of these materials, compliance with pharmacopoeia Identification of components e.g. IR for plastic materials

Description of the secondary packaging

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Quality dossier / Section 3 Finished Pharmaceutical Product (FPP)


3.11. Stability testing
The purpose of stability testing is to provide evidence on how the quality of a FPP varies with time under the influence of a variety of environmental conditions such as temperature, humidity and light and to establish a shelf-life for the FPP, to determine the storage conditions and the in-use stability.

Jakarta, October 2009

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP)


3.11. Stability testing
Lots included in the study: 1 production batch and 2 of pilot scale manufactured according to the process described in the dossier 3 Pilot scale batches are acceptable (exception for 2nd line TB products: 2 pilot batches) Pilot scale batch for solid dosage forms is 10% of production scale or 100 000 whichever is greater Parameters susceptible to change over storage should be followed:

. Organoleptic properties

. Assay of each API: 10% of the label claim possible at the end of shelf-life . Assay of degradation products . Assay of antioxidants and chemical preservatives, check also for their efficacy . Dissolution testing (limits should remain unchanged to release) . Microbial contamination, sterility, bacterial endotoxins

In-use stability data (if applicable)

Jakarta, October 2009

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP)


3.11. Stability testing
Study should be performed in the claimed commercial packaging (container-closure) Storage conditions and frequency of testing according to WHO stability guideline in TRS 953

Minimum stability data to be submitted at time of submission: Long term 12 months or 6 months or 3 months (as appropriate according to Supplement 2 to the Main Generic guide and exception for TB 2nd line products) 6 months intermediate 30C/65% RH 6 months accelerated 40C/75% RH
Unless otherwise justified, 30C / 75% RH is the recommended storage condition for Prequalification Definition of "significant change" in WHO stability guide is the same as ICH Q1A (R2)

Jakarta, October 2009

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP)


3.11. Stability testing
Case of products packed in semi-permeable containers foreseen (liquid dosage forms susceptible to loss of solvent or water loss in low relative humidity condition). The storage condition will be long term ICH 25C / 40% RH OR 30C/35% RH and accelerated 40C/25% RH Extrapolation of data to accord a longer shelf-life possible according to ICH Q1E + Supplement 2 in condition of commitments Supplement 2: tentative 2 year re-test period and /or shelf-life may be accorded to APIs and corresponding solid forms (tablets and capsules) listed in Supplement 2 based only on 6 months accelerated data and 6 months long term data Long term stability should anyhow be followed to cover the whole shelf-life accorded

Jakarta, October 2009

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP)


3.12. Container labelling
Outer packaging : Where no outer packaging, on immediate packaging, e.g. HDPE bottle.
Labelling should include at least the following : The name of the FPP. Method of administration. A list of API(s) (using INNs if applicable) showing the amount of each present in a dosage unit, and a statement of the container, e.g. number of dosage units, weight or volume. List of excipients known to be a safety concern for some patients, e.g. lactose, gluten, metabisulfites, parabens, ethanol, or tartrazine. Instruction on use. The batch number assigned by the manufacturer. The expiry date in an uncoded form. Storage conditions or handling precautions that may be necessary. Directions for use, and any warnings or precautions that may be necessary. The name and address of the manufacturer, company or person responsible for placing the product on the market.

Jakarta, October 2009

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP)

3.12. Container labelling


Blisters and strips should include, as a minimum, the following information

Name, strength and pharmaceutical form of the FPP Name of the manufacturer, company or person responsible for placing the product on the market The batch number assigned by the manufacturer The expiry date in an un-coded form

Jakarta, October 2009

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP)

3.13. Product information for Health Professionals


Summary of product characteristics (SmPC)

Aimed at medical practitioners and health professionals Changes to SmPC to be approved by WHO See Annex 5 of the main generic guide

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Quality dossier / Section 3 Finished Pharmaceutical Product (FPP) 3.14. Patient information and package leaflet
Copy of the patient information leaflet (PIL) In conformance with SmPC See Annex 6 of the main Generic guide

Jakarta, October 2009

Thank you for your attention

Jakarta, October 2009