2005.02.28. Dr. Pogány - WHO, Shanghai 1/62 Workshop on Quality Assurance and GMP of multisource HIV/AIDS…

2005.02.28. Dr. Pogány - WHO, Shanghai 1/62

Workshop on Quality Assurance and GMP of multisource HIV/AIDS medicines

János Pogány, pharmacist, PhD, consultant to WHO

Shanghai, 01 March 2005E-mail: [email protected]

WHO Prequalification Project Dossier Assessment

mailto:[email protected]


Abbreviations and notesAPI(s) Active pharmaceutical ingredient(s)ARV AntiretroviralEOI Expression of interestFPP(s) Finished pharmaceutical product(s)ICH International Conference on

HarmonizationMLEM Model List of Essential MedicinesPh.Eur. European PharmacopoeiaPh.Int. International PharmacopoeiaUSP United States PharmacopeiaText in green refers to WHO guidelines or requirementsText in yellow indicates an assessment issue


Subjects for discussion1. Which ARV FPPs are prequalified?2. Prequalification data and information

requirements for quality WHO manuals, guides, EOI requirements Prequalification guides

• Assessment of product dossiers• Change control

ICH guides

3. Closing remarks

Which ARV FPPs are prequalified?

13th MODEL LIST OF ESSENTIAL MEDICINES and EXPRESSION OF INTEREST

(January 2004)


Nucleoside Reverse Transcriptase Inhibitors (NRTI)

ABACAVIRDIDANOSINE (ddl) buffered chewable, dispersible tablets 25 mg, 50 mg, 100 mg,

150 mg, 200 mg buffered powder for oral solution 100 mg, 167 mg, 250 mg

packets unbuffered enteric coated capsule 125 mg, 200 mg, 250 mg,

400 mg LAMIVUDINE (3TC) tablet, 150mg, oral solution 50 mg/5ml


Nucleoside Reverse Transcriptase Inhibitors (NRTI)

STAVUDINE (d4T) capsule 15mg, 20mg, 30mg, 40mg powder for oral solution, 5mg/5mlTENOFOVIR ZIDOVUDINE (ZDV or AZT) tablet, 300mg capsule 100 mg, 250 mg oral solution or syrup, 50mg/5ml solution for IV infusion, injection 10 mg/ml in 20-ml vial


Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI)

EFAVIRENZ (EFV or EFZ) capsule, 50 mg, 100 mg, 200 mg oral solution, 150 mg/5ml

NEVIRAPINE (NVP) tablet 200 mg oral suspension 50 mg/5-ml


Protease inhibitors (PI)INDINAVIR (IDV) capsule, 200 mg, 333 mg, 400 mg (as sulfate)

LOPINAVIR + RITONAVIR (LPV/r) capsule, 133.3 mg + 33.3 mg oral solution, 400 mg + 100 mg/5ml

NELFINAVIR (NFV) tablet, 250mg (as mesilate) oral powder 50mg/g cont.


Protease inhibitors (PI)RITONAVIR (r) capsule, 100 mg oral solution 400 mg/5ml

SAQUINAVIR (SQV) capsule, 200mg

+ Antibacterial and antimycobacterial agents, antiprotozoal agents, antiviral agents, antifungal agents and anti-cancer drugs listed in EOI5.


Fixed-dose combinations (EOI) LAMIVUDINE + STAVUDINE LAMIVUDINE + ZIDOVUDINE LAMIVUDINE + STAVUDINE + EFAVIRENZ LAMIVUDINE + STAVUDINE + NEVIRAPINE LAMIVUDINE + ZIDOVUDINE + EFAVIRENZ LAMIVUDINE + ZIDOVUDINE + NEVIRAPINE


Pillars of regulatory QA

MANUFACTURING AUTHORIZATION

DESIGN

CONSTRUCTION

AUTHORIZED PERSON

OTHERS

GMP & INSPECTIONQUALITY ASSURANCE (QA)

CONTAMINATION, ISSUES

QUALIFICATION, VALIDATION

OTHERS

MARKETING AUTHORIZATION

ANALYTICAL METHODS

DEVELOPMENT PHARMACEUTICS

COMPOSITION OF PIVOTAL BATCHES

OTHERS


Regulatory quality assurance The former slide emphasizes an integrated

approach to QA based on scientific risk management of the: manufacturing authorization based on GMP design

and construction, marketing authorization (assessment of product

dossiers), and inspections,


http://mednet3.who.int/prequal/ GMP : main principles for

pharmaceutical products GMP: starting materials

Active pharmaceutical ingredients (bulk drug substances)

Pharmaceutical excipients

GMP: specific pharmaceutical products Sterile pharmaceutical products


WHO GMP - General considerations

Licensed pharmaceutical products (marketing authorization) should be manufactured only by licensed manufacturers (holders of a manufacturing authorization) whose activities are regularly inspected by competent national authorities, p.9.

What data and information needs to be submitted in a dossier for the assessment

of a generic product?

MULTISOURCE (GENERIC) FPPs


EOI criteria for quality assessment Valid manufacturer’s license for production Product registered or licensed in accordance

with national requirements Products manufactured in compliance with

GMP as certified by the national regulatory authority and/or certified GMP inspectors


EOI criteria for quality assessment Certificate of Pharmaceutical Product exist in

accordance with the WHO certification scheme on the quality of pharmaceutical products moving in international commerce

Product dossiers of acceptable quality are to be submitted and assessed with regard to the pre-qualification requirements and approved

Outcome of the GMP inspection performed by or on behalf of WHO, UNICEF, UNAIDS and UNFPA


http://mednet3.who.int/prequal/

Marketing Authorization of Pharmaceutical Products with Special Reference to Multisource (Generic) Products: A Manual for a Drug Regulatory Authority (The so-called blue book)

Regulatory Support Series, No. 5 WHO, Geneva, 1999


Initial decisions on options for premarket evaluation by a NDRA

Blue book, p. 21: Prepare its own reports; Rely on evaluation reports prepared by

other national authorities; Rely on decisions made by other national

authorities; Use some permutation of these approaches.


Domestically manufactured products If the FPP has been locally developed and

manufactured, the national drug regulatory authority (NDRA) must evaluate the data set itself (Blue book, p. 23).

If an evaluation report —critical summary and interpretation of the data, with conclusions— is not available, it is not possible to seek a WHO-type certificate (Blue book, p. 23).


Blue book, Annex 7: Detailed Advice on Evaluation of Data by the Drug Regulatory Authority

Example: Specifications for the finished product, p.153Provide a list of tests and limits for results for the finished product, including sufficient detail of test methods for them to be replicated by another laboratory. If the product is tested on the basis of a monograph in a pharmacopoeia, it is sufficient to provide a copy of the monograph together with any test methods referenced but not duplicated in the monograph. Provide details of any specifications additional to those in the pharmacopoeia. Provide both release and expiry limits for results. Provide the results of validation of the assay method for this formulation. For pharmacopoeial methods, provide data which demonstrate that the method is applicable to this formulation.


http://mednet3.who.int/prequal/1. Guideline on Submission of Documentation for Prequalification

of Multi-source (Generic) Finished Pharmaceutical Products (FPPs) Used in the Treatment of HIV/AIDS, Malaria and Tuberculosis

2. Guide on Requirements for Documentation of Quality pharmaceutical products manufactured in and approved by stringent drug regulatory authorities including inter alia EU, Japan and USA (not discussed in this presentation)

3. Other WHO guides4. International Conference on Harmonization (ICH) guidelines

Guideline on Submission of Documentation for Prequalification of Multi-source (Generic)

Finished Pharmaceutical Products (FPPs)Used in the Treatment of HIV/AIDS, Malaria and

Tuberculosis

Assessors’ Guide – Generic FPPs


Section 1. CHARACTERISTICS OF THE FPP

1.1 Details of the product1.1.1 Name, dosage form and strength of the product1.1.2 Approved generic name(s) [use International Non-

proprietary Name (INN), if any] 1.1.3 Visual description of the FPP1.1.4 Visual description of the packaging 1.2 Sample1.3 Regulatory situation in other countries

Section 2. Active Pharmaceutical Ingredients

Separate presentation on Tuesday, 1 March 2005

Just one point ...


Tablet Manufacturing Starts with the Purification/Crystallization of API

Isolation and purification

of API

Physical processing and packaging of

APIGranulation Compression


Tablet Manufacturing Starts with the Purification/Crystallization of API

Attributes with potential impact on processability: existence/absence of polymorphs and

water/solvent of crystallization/solvatation particle size bulk density (tapped and untapped) flowability (flowing properties) hygroscopicity

Section 3. Finished Pharmaceutical Products

ILLUSTRATIVE EXAMPLES OF

REQUIREMENTS


Section 3. FPP(s)3.1 Manufacturing and marketing

authorization3.2 Pharmaceutical development3.2.1 Company research and development3.2.2 Information from literature3.3 Formulation3.4 Sites of manufacture


Pharmaceutical developmentThis section should contain information on the development studies conducted to establish that the dosage form, the formulation, manufacturing process, container closure system, microbiological attributes and usage instructions are appropriate for the purpose specified in the application. The studies described here are distinguished from routine control tests conducted according to specifications.


Pharmaceutical developmentIllustrative examples: Compatibility of APIs with each other [fixed-dose

combinations (FDCs)] A [discriminating (in the case of FDCs)]

dissolution method should be developed and integrated in the quality control and stability programs

Packaging should be selected to ensure the quality of the FPP throughout its shelf life.


Part 3. FPP(s)3.5 Manufacturing process3.6 Manufacturing Process Controls of

Critical Steps and Intermediates3.7 Process Validation and Evaluation3.7.1 New generic FPPs3.7.2 Established generic FPPs


Validation - new generic FPPs The progress from pre-formulation →

formulation → pilot manufacture → industrial scale manufacture should be shown in the dossier submitted for prequalification to be logical, reasoned and continuous.

Full validation studies should be completed for each FPP at the production scale.


Validation - new generic FPPs Short description of the process with a

summary of the critical processing steps or critical parameters to be monitored during validation.

Interim in-process controls proposed with acceptance criteria.


Validation - new generic FPPs Additional testing, e.g., failure mode

analysis, intended to be carried out Sampling plan — where, when and how the

samples are taken. Details of methods for recording and

evaluation of results. Proposed timeframe.


Validation – established genericsAnnual quality review data and analysis to prove that the manufacturing processes —including equipment, buildings, personnel and materials— are capable of achieving the intended results on a consistent and continuous basis.


Part 3. FPP(s)3.8 Specifications for excipients3.8.1Excipients not described in Int.Ph., JP, BP, Ph.Eur., or USP3.8.2Excipients described in Int.Ph., JP, BP, Ph.Eur., or USP 3.9 Control of the FPP3.9.1 Specifications for the FPP 3.9.2 Analytical procedures3.9.3 Validation of analytical procedures3.9.4 Batch analysed3.10 Container/closure system(s) and other packaging


Specifications for the FPPIllustrative issues: The maximum acceptable deviation in the API

content of the FPP shall not exceed ±5% of the label claim at batch release.

Degradation products, synthesis impurities (typically not applicable) and residual solvents (rarely applicable).

Dissolution versus disintegration time. All analytical methods should be validated or

verified (system suitability).


Part 3. FPP(s)3.11 Stability testing3.11.1 Stability-indicating quality parameters3.11.2 Photostability Testing3.11.3 Selection of Batches 3.11.4 Container Closure System3.11.5 Testing Frequency3.11.6 Storage Conditions3.11.7 General case3.11.8 Finished products packaged in impermeable containers2.11.9 Finished products packaged in semi-permeable containers2.11.10 Evaluation2.11.11 Extrapolation of data2.11.12 Core Storage Statements


Stability of FPPs Characteristics studied should be those in the FPP

specification that are likely to be affected by storage and/or not monitored routinely at the time of manufacture.

Analytical procedures should be fully validated and stability indicating. Whether and to what extent replication should be performed will depend on the results of validation studies.

It may be appropriate to have justifiable differences between the shelf life and release acceptance criteria based on the stability evaluation and the changes observed on storage.


Stability of FPPs A systematic approach should be adopted in the

presentation and evaluation of the stability information, which should include, as appropriate, results from the physical, chemical, biological and microbiological tests, including particular attributes of the dosage form (for example, dissolution rate for solid oral dosage forms, hardness, LOD, etc.).

An API is considered as stable if it is within the defined/regulatory specifications when stored at 30 ± 2 oC / 60 ± 5 % RH (2 years) and 40 ± 2 oC / 75 ± 5 % RH (6 months).


Part 3. FPP(s)3.12 Container labelling3.12.1 Outer packaging or, where there is no outer

packaging, on the immediate packaging3.12.2 Blisters and strips3.13 Product information for health professionals3.14 Patient information and package leaflet3.15 Justification for any differences to the product

in the country or countries issuing the submitted WHO-type certificate(s).


Labelling - blisters and strips 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 uncoded form.


WHOPAR Propose a copy of the Summary of Product

Characteristics (SmPC) aimed at medical practitioners and other health professionals and approved by the competent authority at the time of licensing. The SmPC is an essential part of pre-qualification and it can only be changed with the consent of WHO.

Provide copies of all package inserts distributed to the patients. The package leaflet should be in conformity with the SmPC. It should be written in English, should be legible and comprehensible.

Other WHO guides on quality of FPPs

AN ILLUSTRATIVE EXAMPLE


Animal Spongiform Encephalopathy Agents

Products with risk of transmitting agents of animal spongiform encephalopathies are those derived from tissues or secretions of animals susceptible to transmissible spongiform encephalopathies. This definition applies to all substances or preparations obtained from such animals and to all substances or preparations where products obtained from such animals are included as active substances or excipients or have been used during production, e.g. as raw or source materials, starting materials or reagents.

WHO Technical Report Series, No. 908, 2003

International Conference on Harmonization guides

AN ILLUSTRATIVE EXAMPLE


Impurities in New Drug Products -Q3B(R)

Illustrative excerpts: This guideline addresses only those impurities in new drug

products classified as degradation products of the API or reaction products of the API with an excipient and/or immediate container.

Generally, impurities present in the API need not be monitored or specified in the FPP unless they are also degradation products.

The specification for a FPP should include a list of degradation products expected to occur during manufacture of the commercial product and under recommended storage conditions.

Guidance on variations in a dossier submitted within the

prequalification program

GENERAL OVERVIEW


Minor changes

MINOR CHANGE is a change concerning an amendment to the contents of the documents such as they existed at the time when the product was listed as prequalified.

PRIOR EVALUATION of the submitted documentation amended as a result of the variation is required for minor changes.

41 minor changes are listed in the document.


Example of minor change: Replacement or addition of a manufacturing site for part or all of the manufacturing

process of the FPP – cont.

Conditions Site appropriately authorised by the relevant competent authority for

the packaging or manufacturing of the pharmaceutical form and product concerned.

New site must be approved by WHO as complying with WHO GMP, a satisfactory inspection of the manufacturing site has been performed in the last three years by WHO or a competent authority of a ICH region country.

Product concerned is not a sterile product. Validation scheme is available or validation of the manufacture at

the new site has been successfully carried out according to the current protocol with at least three production scale batches.




Documentation Proof that the proposed site is authorised by the relevant

competent authority as complying with WHO GMP within the prequalification project for the packaging or manufacturing of the pharmaceutical form and product concerned.

The batch numbers of not less than 3 batches used in the validation study should be indicated and related validation protocol (scheme) to be submitted.

The variation application should clearly outline the “present” and “proposed” finished product manufacturers.




Documentation Copy of approved release and end-of-shelf life

specifications. Batch analysis data on three production batches and

comparative data on the last three batches from the previous site.

For semisolid and liquid formulations in which the API is present in non-dissolved form, appropriate validation data including microscopic imaging of particle size distribution and morphology.



process of the FPP

Documentation For solid dosage forms a comparative dissolution test data

on the last 3 batches from the previous site and the 3 first batches for the new site including not less than 6 time points should be provided.

Statement as when the change will be effective should be submitted.

Submit updated section 3.4 of the product dossier.


Major changeA MAJOR CHANGE is a change to the documentation which can neither be deemed to be a minor variation within the meaning of preceding definition (therefore exceeding the frame of a minor change) nor to be a change for which the submission of a new application would be necessary.


Major changes Change in the manufacturing process of the

API Change in the composition of the finished

product Change of immediate packaging of the FPP


New dossierCertain changes are so major that they are considered to fundamentally alter the terms of a prequalification and consequently cannot be considered as a change. For these changes a new dossier must be submitted.


New dossierChanges to the API (self-evident examples): Change of the API to a different API Inclusion of an additional API to a multi-

component product Removal of one API from a multi-

component product Change in the dose of one or more APIs


New dossierChanges to the pharmaceutical dosage form: Change from an immediate release product

to a slow- or delayed-release dosage form and vice versa

Change from a liquid to a powder for reconstitution, or vice versa

Changes in the route of administration


Additional stability studiesIn all cases of changes the supplier of the dossier has to investigate whether or not the intended change will have an impact or not on the quality of the API and the FPP and consequently on their stability.For all changes that require the generation of stability data, the first three production scale batches manufactured following notification/approval of the change should be placed on long term stability testing using the same stability testing protocols as described in the assessment guide. The results of the stability studies when available should be submitted within the prequalification program.


Main points again1. Only ARV FPPs included in MLEM and EOI are

prequalified.2. WHO manuals and guides were prepared with

well-established, compendial, multisource FPPs in mind but ARV FPPs rarely meet these criteria.

3. Prequalification guides permit the assessment of non-compendial, multisource FPPs, as well.

4. ICH guidelines are used, when a quality issue cannot assessed by WHO guides.

5. Changes to prequalified FPPs are also controlled in the evaluation process.


THANK YOU

谢谢 !

Documents

2005.02.28. Dr. Pogány - WHO, Shanghai 1/62 Workshop on Quality Assurance and GMP of multisource HIV/AIDS…