slide 1 who prequalification programme: training workshop march 2010, beijing requirements on...

WHO Prequalification Programme: Training workshop March 2010, Beijing

Requirements on documentation of API and FPP

quality and evaluation process

•Presenter: Hua YIN

Prequalification of Medicines ProgrammeQSM / EMP / HSS


GlossaryGlossary

API Active Pharmaceutical Ingredient

APIMF Active Pharmaceutical Ingredient Master File

ARV Antiretroviral

CoS Certificate of Suitability

EDQM European Directorate for Quality of Medicines and HealthCare

EoI Expression of Interest

FPP Finished Pharmaceutical Product

GMP Good Manufacturing Practices

ICH International Conference on Harmonization

Int. Ph. International Pharmacopoeia

PIL Patient Information Leaflet

PQ Prequalification

PQIF Pharmaceutical Quality Information form

RH Reproductive Health

SPC Summary of Product Characteristics

TB Tuberculosis


WHO Reference text for Multisource (Generic) products / Definitions

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.


Guidelines for Product dossier /QualityGuidelines 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)

• 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

• Guide on Submission of Documentation for Prequalification of innovator Finished Pharmaceutical Products (FPPs) used in the treatment of HIV/AIDS, malaria and tuberculosis and approved by Drug Regulatory Authorities (DRAs) in the International Conference on Harmonization (ICH) region and associated countries, including among others the EU, Japan and USA

• Prequalification of Generic products approved by Stringent Regulatory Authorities (SRAs) NEW

• Requalification NEW

• Alternative procedure for accepting 2nd line TB Product dossiers New

http://www.who.int/prequal Chinese version available



• ICH notes for guidance (When WHO or PQ guidelines silent)

for instance:

– Q2(R1): Validation of Analytical Procedures – Q3A(R2). Impurities in new drug substances– Q3B(R2). Impurities in new drug products– Q3C(R3). Impurities: Guideline for residual solvents– Q6A. Specifications:

• Other agencies' requirements can be referenced. such as EU limits of genotoxic impurities, permitted colorants, EDQM limit of TEA 320ppm.


Assessment Process - QualityAssessment Process - QualitySubmission of application

PQIF, Dossier

Screening (Internal)

Acceptance for evaluation PQ reference No.

Pre – Assessment

Assessment

Additional data

Prequalification

Requalification


Documentation to be submitted to the WHO PQ team

Documentation to be submitted to the WHO PQ team

- Covering letter

Clearly indicate the information submitted is true and correct

- Product dossier . Section 1: Characteristics of the FPP. Section 2: Active Pharmaceutical Ingredients (APIs) When more than one API used, use separate Section 2 . Section 3: Finished Pharmaceutical Products (FPPs). Section 4: Interchangeability

- PQIF: =Quality overall summary. filled out in WinWord format, See mock-up PQIF on www.who.int/prequal/ under training material and workshops, Hanoi, Vietnam, January 2006

- Sample


Quality dossier/ Section 1 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


Quality dossier / Section 2

Active Pharmaceutical Ingredient (API)


Quality dossier / Section 2Active 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, www.edqm.eu

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




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




CTDPQIF section 2S.1 General Information - Nomenclature- Structure

- General Properties

2.1 Nomenclature

2.2 Properties of API (s)

- General Properties pharmacopoieal

-Eluciation of structure non-pharmacopieal

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

2.3 Site(s) of Manufacture

2.4 Route(s) of synthesis- manufacturing process

-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

2.6 Container Closure System

2.7 Stability testing




Generic Guideline is under revision.

The PQIF format to be consistent with the CTD format

Focus on CTD format S.1 General Information

S.2 Manufacture

S.3 Characterisation

S.4 Control of Drug Substance

S.5 Reference Standards or Materials

S.6 Container Closure System

S.7 Stability testing


S.1 General InformationS.1 General Information

S.1.1 Nomenclature

International non-proprietary name (INN), chemical name, Chemical abstarct service (CAS) No., other names such as BAN, USAN…

S.1.2 Structure– Chemical structure, sterochemistry , molecular formula and relatively molecular mass


S.1 General InformationS.1 General Information

S.1.3 General properties– Physical description– Solubility in water (effect of pH), and organic solvents– Solid state/crystallography (eg polymorphism, including solvation/hydration, amorphous

character)– Hygroscopicity– Particle size, etc

Such information which relevant to formulating, processing and performance of the FPP


S.2 ManufactureS.2 Manufacture

Information on the manufacturer

A flow diagram of the process

A description of the manufacturing process (including, for example, starting materials, reagents, solvents, catalysts ， critical steps, and reprocessing) and the controls intended to result in the routine and consistent production of API.

A description of the Source and Starting Material and raw materials used in the manufacture of the API; When the synthetic route consists limited number of steps (e.g. One to three), information of starting material should be provided (e.g route of synthesis/specification)


S.2 ManufactureS.2 Manufacture

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.


2.3.S.3 Characterisation 2.3.S.3 Characterisation

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

For API described in a pharmacopoeia

Confirm the structure by comparison with an official Reference Standard using a specific method e.g. IR


S.3 CharacterisationS.3 Characterisation

3.2 Impurities

Identification of potential and actual impurities arising from synthesis, manufacture and/or degradation, with an indication of their origin:

Impruities contained in the starting material Starting material unreacted Intermediates unreacted By-products (unwanted reaction products) Degradants Reagents,Catalysts,Residual solvents

Summary of the levels of the actual impurities detected in the batch samples (e.g. non clinical, clinical, toxicological studies, stability)

Justification for selecting the limits, based on safety and toxicity data when applicable. ICH Q3A


S.4 Control of Drug SubstanceS.4 Control of Drug Substance

A summary of the specification, analytical procedures and validation of the methods should be included.

For Pharmacopoeial API

The current monograph always applicable

Additional critical specifications not included in monograph e.g.– particle size & polymorphic form– impurities, resulting from specific synthesis process– residual solvents (specific to process)

Analytical procedures should be verified under actual condition of use, such as specificity, precision, and stability of the sample solution


S.5 Reference Standards or MaterialsS.5 Reference Standards or Materials

For pharmacopoeial APIs:

use an official Reference Standard (USP, Ph. Eur., Int. Ph.) as primary standard

For non-pharmacopoeial APIs

Description of how primary and/or a working standard has been established

Provide Certificate of Analyses, including storage instuctions and duration of use


S.6 Container closure systemS.6 Container closure system

Description of the packaging

Identification of materials and components of the packaging

Specifications of these materials

Justification for choice of these materials, e.g.

- protection against light, humidity

- compatibility of the used materials with the API, interactions between the API and the closure such

as sorption, leaching (mainly in case of a liquid API)


S.7 StabilityS.7 Stability

Stress study– to know different degradation pathways of an API

and degradation products formed– to demonstrate the intrinsic stability of the API– To demonstrate the stability indicating power of the

analytical procedure used

Reference can be done to the literature, if the above information is there available



Formal stability study– To establish a re-test period – To determine the storage / labelling statement

Definition of the re-test period

Period of time during which the API is expected to remain within its specifications and can be used in the manufacture of a given product (without control prior to manufacture of Drug Product) in condition that the API has been stored under defined storage conditions



A summary of the studies undertaken –conditions, –batches, –packaging–Stability-indicating quality parameters–analytical procedures)

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


Quality dossier / Section 3

Finished Pharmaceutical Product

(FPP)


Quality dossier / Section 3Finished 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




3.12. Container labelling

3.13. Product information for health professionals (SmPC)

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)

Same as CTD, only different in numbering. Product information listed at the end which are included in CTD module 1.




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 development3.2. Pharmaceutical development

The aim is to build a quality product by design.

Empirical (minimal)- essential product development for all

products

Enhanced- Quality by Design

Critical understanding of product

and process

Regulatory relief



Empirical product development– Select the product profile (FPP) based on S&E and quality– Investigate quality attributes of the formulation components such as

API, excipients etc.– Establish critical quality attributes– Determine an appropriate manufacturing process and scale up

(process optimization)

– the container closure system

– microbiological attributes– DocumentationDevelop a formulation similar to the innovator product. Reduce risk

pertaining to compatibility, manufacturability, stability and bioavailability



1. 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)



2. For fixed-dose combination (FDC) products Compatibility of APIs with each other WHO Guidelines for registration of fixed-dose combination medicinal products

WHO TRS 929 (on WHO Prequalification website)

3. Choice of excipients, e.g. Compatibility with API(s) Intended functions and concentrations in product Characteristics (flowability, density, water content, etc) Safety aspects, e.g. TSE risk, to be addressed



4. Selection, optimisation of manufacturing process

Rational behind the choice (e.g. why a non over kill process as a sterilisation process instead of terminal sterilisation in final container)

Critical steps & In process controls Overages (justification) Unsatisfactory processes to be rectified



5. Comparative dissolution testing– See Supplement 1

A tool in selection of the formulation and optimisation of the process– 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- a discriminatory dissolution method



comparative dissolution testing (cont’d)

1. Three media - 900 ml or less - all at 37°C – Buffer pH 1.2 or 0.1M HCl– Buffer pH 4.5– Buffer pH 6.8

Water may be used additionally (not instead of)

2. Paddle at 50 or basket at 100 rpm

3. Twelve units of each product in all 3 media

4. Dissolution samples collected at short intervals, e.g.– 10, 15, 20, 30, 45 and 60 minutes– Analyse samples for all APIs, when applicable

Calculate similarity factor f2



6. Details of batches studied

Provide a summary of development of the FPP from pre-formulation to production scale.

Provide a comparison of formulas (tabulated form) of:– bio-batche(s) (clinical / bioequivalence),– development batches,– stability batches,– batches for validation/production


3.3. Formulation3.3. 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).


3.4. Manufacturing sites3.4. Manufacturing sites

Name and street address of each facility where any aspect of manufacture occurs including production, sterilisation, packaging and quality control. Indicate the Unit, block if any.

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


3.5. Manufacturing process3.5. Manufacturing process

A flow diagram giving the steps of the process and where materials enter the process. The critical steps and points at which process controls, intermediate tests or final product controls are conducted should be identified.

Description of manufacturing/packaging including – Steps of the process– Scale of production– 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– Alternative methods


3.5. Manufacturing process3.5. Manufacturing process

Proposal for reprocessing – justified with data.

Copy of master formula.

Batch manufacturing record – real batch (Biobatch)

Sterile products – sterilisation steps and/or aseptic procedures.


3.6. Manufacturing Process Controls of Critical steps and Intermediates

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


3.7. Process Validation and Evaluation3.7. Process Validation and Evaluation

Each critical step of the manufacturing process must be validated

Other steps in the process must be under control to maximize the probability that the finished product meets all quality and design specifications



To understand the sources of variation

To detect the presence and degree of variation

To understand the impact of variation on the process and ultimately on product attributes

To control the variation in a manner commensurate with the risk it represents to the process and product



The following unit operations are generally accepted as critical for most pharmaceutical processes:

Blending operations

Encapsulation

Tablet compression

Sterilization procedures

Lyophilization



Validate the performance of manufacturing processes that may be responsible for causing variability in the product:

Mixing homogeneity

Tablet/capsule weight variation

Disintegration time

Dissolution rate and time

pH of aqueous solutions


3.7. Process Validation and EvaluationNew Generic FPPs

3.7. Process Validation and EvaluationNew Generic FPPs

Information form product development studies and primary batches should be used in designing the validation protocol

Differences in design, operating principles, size, etc. between pilot and production batches should be highlighted

Protocol should be linked to the lot of FPP used in bioequivalency studies

Comparative dissolution profiles of process validation batches against dissolution profile of the bio lot should be provided

Commitment to undertake validation of three consecutive batches should be provided



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 methods.

In-process controls with acceptance criteria (cross reference)

Additional testing intended to be carried out

sampling plan,

unifromity of dosage units is essential for FDCs,

proposed timeframe

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


3.7. Process Validation and Evaluation

Established FPPs3.7. Process Validation and Evaluation

Established FPPs

Details of the batches manufactured in the last several years, 10- 25 consecutive batches

Formulation and description of method of manufacture, including in-process control test

Specification and test methods

Changes to formulation or process, if any, or compliance problems

Comprehensive report using retrospective validation


3.8. Specifications for excipients3.8. Specifications for excipients

- Pharmacopoeial excipients

Copy of the pharmacopoeial monograph used for control + certificates of analysis

- Non pharmacopoeial substances– Details for manufacturing process,– Characterisation– Controls– Safety (non-clinical , clinical data )– Certificates of analyses

- 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


3.9. Control of the FPP3.9. Control of the FPP

2 sets of specifications are possible: at release and at 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


3.9. Control of the FPP3.9. Control of the FPP

Monographs of Ph. Int., USP, BP are acceptable for the FPP + complementary tests

If non-pharmacopoeial FPP, note for guidance ICHQ6A applicable

Justification

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)


3.10. Container-closure system3.10. 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– Identification of components e.g. IR for plastic materials

Description of the secondary packaging


3.11. Stability testing3.11. 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, to

- establish a shelf-life for the FPP, - determine the storage conditions - determine the in-use stability.

To know about length of the time and conditions where efficacy, safety and quality of the FPP are maintained



WHO stability Guideline in TRS 953

3 batches, at least pilot scale (10% of production scale or 100 000 whichever is greater)

(exception for 2nd line TB products: 2 pilot batches at time of submission)

in the claimed commercial packaging (container-closure)

Storage conditions and frequency of testing according to WHO stability guideline in TRS 953

Unless otherwise justified, 30°C / 75% RH is the recommended storage condition for Prequalification



Parameters susceptible to change over storage should be followed:

. appearance

. Assay

. 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

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 30°C/65% RH 6 months accelerated 40°C/75% RH

In-use stability data (if applicable)


3.12. Container labelling3.12. 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 responsible for placing the

product on the market.


3.12. Container labelling3.12. 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 responsible for

placing the product on the market– The batch number assigned by the manufacturer– The expiry date in an un-coded form


3.13. Product information3.13. Product information

Summary of product characteristics (SmPC)- for Health Professionals

– Aimed at medical practitioners and health professionals– Changes to SmPC to be approved by WHO

patient information leaflet (PIL)– In conformance with SmPC

http://www.who.int/prequal/WHOPAR/WHOPARGUIDE/WHOPARGuidApplApp3v2_0.pdf


Thank youfor your attention

slide 1 who prequalification programme: training workshop march 2010, beijing requirements on...

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prequalification programme

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