Slide 1 of 72D.K. Mubangizi, Dar Es Salaam Sept. 2007 Training Workshop for Evaluators from National Medicines Regulatory Authorities in East African Community.

Slide 1 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007

Training Workshop for Evaluators from National

Medicines Regulatory Authorities in East African

Community

Dar Es Salaam, Tanzania

Date: 10 to 14 September 2007

Evaluation of Quality and Interchangeability of Medicinal Products





Overview of Dossier Requirements and Guidelines

Presenter: Deus K. Mubangizi, pharmacist, MSc(Pharm.)

[email protected], [email protected]

Chief Inspector of Drugs, National Drug Authority

WHO expert

mailto:[email protected]

mailto:[email protected]




Outline of presentation

Objectives of presentation

Structure of dossier of medicinal products, information on the CTD format

Guideline on Submission of documentation for multisource FPPs

Supplement 1: (dissolution testing)

Supplement 2: (Extension of WHO list of stable compounds)

Products registered in ICH Region and related countries

Fixed-dose combinations

ICH guidelines

Variations




Objective of the presentation:

– To give an overview of the dossier requirements and Guidelines used or referenced during the evaluation of dossiers under the WHO Prequalification Program

– To demonstrate how the requirements and guidelines can be applied or used as reference during dossier evaluation


What is the product?

Is the quality presented acceptable on grounds of safety and efficacy?

Is the quality presented reproducible?

How long can the quality be maintained?

Quality must ensure consistency of safety and efficacy during the shelf life of all batches produced.

Data in the dossier should enable us to answer the

following questions:


Overview of Dossier Requirements and Guidelines (1)


Common Technical Document

(CTD)

An initiative under the ICH: Europe, Japan and USA.

http://www.ich.org

http://www.ich.org/


Structure of dossier of medicinal products, information on the CTD format (1)

Structure of dossier of medicinal products, information on the CTD format (1)

A common format for the technical documentation:– significantly reduces the time and resources needed to compile

applications for registration of human pharmaceuticals– eases the preparation of electronic submissions– Facilitates regulatory reviews and communication with the

applicant by a standard document of common elements– Simplifies exchange of regulatory information between

Regulatory Authorities

This guideline is not intended to indicate what studies are required. It merely indicates an appropriate format for the data that have been acquired.


CTD format (2)CTD format (2)

GENERAL PRINCIPLES – Text and tables should be prepared using margins that allow the document

to be printed on A4 paper.– The left-hand margin should be sufficiently large that information is not

obscured by the method of binding.– Font sizes for text and tables should be easily legible, even after

photocopying. Times New Roman, 12-point font, is recommended for narrative text.

– Every page should be numbered.– Acronyms and abbreviations should be defined the first time they are used

in each module.– References should be cited in accordance with the current edition of the

Uniform Requirements for Manuscripts Submitted to Biomedical Journals, International Committee of Medical Journal Editors (ICMJE)1.



The CTD is organized into five modules:– Module 1 is region specific.– Modules 2, 3, 4, and 5 are intended to be common for all

regions.

Module 1. Administrative Information and Prescribing Information

– Should contain documents specific to each region; e.g. application forms or the proposed label for use in the region. The content and format of this module can be specified by the relevant regulatory authorities.

Module 1: Administrative Information and Prescribing Information

– 1.1 Table of Contents of the Submission Including Module 1

– 1.2 Documents Specific to Each Region (for example, application forms, prescribing information)



Module 2. Common Technical Document Summaries – Should begin with a general introduction to the

pharmaceutical, including its pharmacological class, mode of action, and proposed clinical use. In general, the Introduction should not exceed one page.

– Should contain 7 sections in the following order : 2.1 Common Technical Document Table of Contents (Modules 2-5) 2.2 CTD Introduction 2.3 Quality Overall Summary 2.4 Non-clinical Overview 2.5 Clinical Overview 2.6 Non-clinical Written and Tabulated Summaries

Pharmacology Pharmacokinetics Toxicology

2.7 Clinical Summary Biopharmaceutical Studies and Associated Analytical Methods Clinical Pharmacology Studies Clinical Efficacy Clinical Safety Literature References Synopses of Individual Studies



Module 3. Quality – Information on Quality should be presented in the structured

format described in Guideline M4Q.

Module 3: Quality – 3.1 Table of Contents of Module 3

– 3.2 Body of Data

– 3.3 Literature References



Module 4. Non-clinical Study Reports – The non-clinical study reports should be presented in the order

described in Guideline M4S.

Module 4: Non-clinical Study Reports – 4.1 Table of Contents of Module 4

– 4.2 Study Reports




Module 5. Clinical Study Reports – The human study reports and related information should be

presented in the order described in Guideline M4E.

Module 5: Clinical Study Reports – 5.1 Table of Contents of Module 5

– 5.2 Tabular Listing of All Clinical Studies

– 5.3 Clinical Study Reports



CTD format: Overall Table of Contents (ToC)

1.1ToC of Module 1or overall ToC,

including Module 12.1ToC of the CTD(Mod 2,3,4,5)

Module 1

Module 3 Module 4 Module 5

2.1

2.2

2.3

2.4 2.5

2.6 2.7

Module 2

3.1ToC for Module 3

4.1ToC for Module 4

5.1ToC for Module 5


CTD format: Numbering System

1.0 Regional Administrative Information

1.1 ToC of Module 1 or overall ToC,including Module 1

2.1 ToC of the CTD (Mod 2,3,4,5)

2.2 Introduction

2.3 Quality Overall Summary

2.4 Non-clinical Overview

2.5 Clinical Overview

2.7 Clinical Summary

2.6 Non-clinical Written and Tabulated Summaries

Module 1

Module 3 Module 4 Module 5

2.1

2.2

2.3

2.4 2.5

2.6 2.7

1.0

QualityNonclinical

Study ReportsClinical

Study Reports

Module 2


CTD format: Numbering System: Module 2

Module 2

2.1 OVERALL CTD TABLE OF CONTENTS OF MODULES 2, 3, 4, AND 5

2.2 INTRODUCTION

2.3 QUALITY OVERALL SUMMARY

2.3.S DRUG SUBSTANCE

2.3.S.1 General Information

2.3.S.2 Manufacture

2.3.S.3 Characterization

2.3.S.4 Control of Drug Substance

2.3.S.5 Reference Standards or Materials

2.3.S.6 Container Closure System

2.3.S.7 Stability

2.3.P DRUG PRODUCT

2.3.P.1 Description and Composition of the Drug Product

2.3.P.2 Pharmaceutical Development

2.3.P.3 Manufacture

2.3.P.4 Control of Excipients

2.3.P.5 Control of Drug Product

2.3.P.6 Reference Standards or Materials

2.3.P.7 Container Closure System

2.3.P.8 Stability



Module 2 (Cont.)

2.3.A APPENDICES

2.3.A.1 Facilities and Equipment

2.3.A.2 Adventitious Agents Safety Evaluation

2.3.A.3 Novel Excipients

2.3.R REGIONAL INFORMATION

2.4 NONCLINICAL OVERVIEW

2.4.1 Overview of the Nonclinical Testing Strategy

2.4.2 Pharmacology

2.4.3 Pharmacokinetics

2.4.4 Toxicology

2.4.5 Integrated Overview and Conclusions

2.4.6 List of Literature Citations

2.5 CLINICAL OVERVIEW

2.5.1 Product Development Rationale

2.5.2 Overview of Biopharmaceutics

2.5.3 Overview of Clinical Pharmacology

2.5.4 Overview of Efficacy

2.5.5 Overview of Safety

2.5.6 Benefits and Risks Conclusions

2.5.7 References

Module 2 (Cont.)

2.6 CONTENT OF NONCLINICAL WRITTEN AND TABULATED SUMMARIES

2.6.1 Introduction

2.6.2 Pharmacology Written Summary

2.6.3 Pharmacology Tabulated Summary (Appendix B)

2.6.4 Pharmacokinetics Written Summary

2.6.5 Pharmacokinetics Tabulated Summary (Appendix B)

2.6.6 Toxicology Written Summary

2.6.7 Toxicology Tabulated Summary (Appendix B)

2.7 CLINICAL SUMMARY

2.7.1 Summary of Biopharmaceutics and Associated Analytical Methods

2.7.2 Summary of Clinical Pharmacology Studies

2.7.3 Summary of Clinical Efficacy

2.7.4 Summary of Clinical Safety

2.7.5 References

2.7.6 Synopses of Individual Studies



Module 3

3.1 MODULE 3 TABLE OF CONTENTS

3.2 BODY OF DATA

3.2.S DRUG SUBSTANCE

3.2.S.1 General Information

3.2.S.2 Manufacture

3.2.S.3 Characterisation

3.2.S.4 Control of Drug Substance

3.2.S.5 Reference Standards or Materials

3.2.S.6 Container Closure System

3.2.S.7 Stability

3.2.P DRUG PRODUCT

3.2.P.1 Description and Composition of the Drug Product

3.2.P.2 Pharmaceutical Development

3.2.P.3 Manufacture

3.2.P.4 Control of Excipients 3.2.P.5 Control of Drug Product 3.2.P.6 Reference Standards or Materials 3.2.P.7 Container Closure System 3.2.P.8 Stability

Module 3 (Cont.)

3.2.A APPENDICES

3.2.A.1 Facilities and Equipment

3.2.A.2 Adventitious Agents Safety Evaluation

3.2.A.3 Novel Excipients

3.2.R REGIONAL INFORMATION

3.3 LITERATURE REFERENCES



Module 4


4.2 STUDY REPORTS

4.2.1 Pharmacology

4.2.2 Pharmacokinetics

4.2.3 Toxicology




Module 5


5.2 TABULAR LISTINGS OF ALL CLINICAL STUDIES

5.3 CLINICAL STUDY REPORTS

5.3.1 Reports of Biopharmaceutic Studies

5.3.2 Reports of Studies Pertinent to Pharmacokinetics using Human Biomaterials

5.3.3 Reports of Human Pharmacokinetic (PK) Studies

5.3.4 Reports of Human Pharmacodynamic (PD) Studies

5.3.5 Reports of Efficacy and Safety Studies

5.3.6 Reports of Post-Marketing Experience

5.3.7 Case Report Forms and Individual Patient Listings





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

http://mednet3.who.int/prequal

http://mednet3.who.int/prequal


Generic Guide: DefinitionsGeneric Guide: 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.


Multisource (Generic) productMultisource (Generic) product

Multisources are Pharmaceutically equivalent (WHO definition)

same amount of the same API

same dosage form

meet the same or comparable standards

intended to be administered by the same route

Multisources which are therapeutically equivalent are interchangeable


Quality of a Generic productQuality of a Generic product

Multisource products must be of good quality and at least as safe and efficacious as existing products (WHO Manual, Blue Book, P. 29, chapter H., Interchangeability))

Demonstration of pharmaceutical equivalence of the FPP including that of the API

Same Safety – Same efficacy

Equal quality with the comparator or a quality shown and

assessed to be as acceptable


Generic Guide: Documentation on Quality Part to be submitted to the WHO PQ teamGeneric Guide: Documentation on Quality Part to be submitted to the WHO PQ team

- Covering letter

- Product dossier on Quality part

- PQIF (annex 8 to the main generic guide): properly filled out in WinWord format, See mock-up PQIF on www.who.int/prequal/ under training material and workshops, Hanoi, Vietnam, January 2006

- Product dossier of Efficacy part

- BTIF (annex 7 to the main generic guide) properly filled out in WinWord format

http://www.who.int/prequal/


Generic Guide: Quality dossier / Section 1Generic Guide: Quality dossier / Section 1

Information on the Finished Pharmaceutical Product (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 (visual examination 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


Generic Guide:Generic Guide:

Quality dossier / Section 2

Active Pharmaceutical Ingredient (API)


Generic Guide: Quality/Section 2: APIGeneric Guide: Quality/Section 2: API

Scientific data on the API can be submitted in the following 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

Complete submission of data requested in Section 2


Generic Guide: Quality/Section 2: APIComplete submission option

Generic Guide: Quality/Section 2: APIComplete submission option

2.1. Nomenclature (INN, chemical name, CAS No.)

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

** The requirements may differ depending on if the API is pharmacopoeial or non-pharmacopoeial



TB drugs / 6th EoI

Rifampicin (rifampin) Ph. Eur., USP, BP, Ph. Int.

Ethambutol 2HCl Ph. Eur., USP, BP, Ph. Int., JP

Pyrazinamide Ph. Eur., USP, BP, Ph. Int., JP

Isoniazid Ph. Eur., USP, BP, Ph. Int., JP

Streptomycin sulfate Ph. Eur., USP, BP, Ph. Int.

Amikacin Ph. Eur., USP, BP, Ph. Int., JP

Kanamycin Ph. Eur., USP, BP

Capreomycin USP, Ph. Int.

Cycloserine USP, JP

Ethionamide Ph. Eur., USP, BP, Ph. Int., JP

Ofloxacin Ph. Eur., USP, BP

Prothionamide Ph. Int., JP

p-Aminosalicylic acid (and sodium salt) Ph. Eur., USP



Artemisinin based antimalarial drugs / EoI May 2005

Artesunate Ph. Int.

Artemether Ph. Int.

Artemotil (arte-ether) Ph. Int.

Amodiaquine Ph. Int.

mefloquine

Sulphadoxine

Pyrimethamine

Lumefantrine Non-pharmacopoeial



Antiretrovirals

Abacavir Ph. Int.

Didanosine Ph. Int.

Efavirenz Ph. Int.

Indinavir Ph. Int., USP

Lamivudine Ph. Eur., USP, BP, Ph. Int.

Nelfinavir Ph. Int.

Nevirapine Ph. Int., USP, Ph. Int.

Stavudine Ph. Eur., USP, BP, Ph. Int.

Saquinavir Ph. Int., USP

Ritonavir Ph. Int., USP

Zidovudine Ph.Int., USP, Ph. Eur., BP

Tenofovir and Emtricitabine Non-pharmacopoeial


Generic Guide: Quality/Section 2: API, Certification of Suitability (CoS) / CEP Option

Generic Guide: Quality/Section 2: API, Certification of Suitability (CoS) / CEP Option Issued by EDQM for substances described in the Ph. Eur. www.edqm.eu

2 types of CEPs: quality CEP and TSE CEP

Information which can be found on a quality CEP CEP reference, CEP holder, site of manufacture of the substance, monograph according to which the dossier is evaluated, additional impurities and residual solvents not mentioned in the monograph, additional methods to those of the monograph are appended, re-test period with packaging system and storage condition (if applicable), date of validity of the CEP

A quality CEP certifies that the quality of the substance can be checked according to the Ph. Eur. by applying the analytical methods described in the Ph. Eur. monograph supplemented by those

appended to the CEP.

http://www.edqm.eu/


Generic Guide: Quality/Section 2: API, APIMF Option

Generic Guide: Quality/Section 2: API, APIMF Option

Procedure implemented since January 2007, www.who.int/prequal

To protect the "know-how" of the manufacturer of the API – While giving the whole information on manufacture of the API to the

WHO PQ team of assessors– While giving a part of the information to the applicant to

Prequalification/ manufacturer of the finished product

An APIMF is composed of: Applicant's /Open part + Restricted / Closed part

Manufacturer of the API should make available to the applicant to Prequalification the Applicant's part + Letter of access

http://www.who.int/prequal


Generic Guide: Quality/Section 2: API. APIMF Option

Generic Guide: Quality/Section 2: API. APIMF Option

Manufacturer of the API should submit on the other hand the Applicant's part + Restricted + Letter of access to WHO team An APIMF is to be submitted only in support of a FPP dossier

An APIMF is not an independent dossier of API

Scope open to pharmacopoeial and non-pharmacopoeial APIs

Scope of APIMF only open to APIs ≠ US and Canadian master file procedures

See annex 1 of the APIMF guide for the content of an APIMF

Content of APIMF corresponds to data required in section 2 of the prequalification quality dossier without difference between pharmacopoeial and non-pharmacopoeial APIs


Generic Guide:Generic Guide:

Quality dossier / Section 3

Finished Pharmaceutical Product

(FPP)


Generic Guide: Quality/Section 3: FPPGeneric Guide: Quality/Section 3: 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


Generic Guide: Quality/Section 3: FPPGeneric Guide: Quality/Section 3: 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)

Bioequivalence dossier (BE) requirements for the prequalification project


Generic Guide: BE Dossier requirements: general

Generic Guide: BE Dossier requirements: general

5. Interchangeability

5.1 Bioequivalence study

5.2 Summary of pharmacology, toxicology* and efficacy of the product (expert reports)

* not required anymore for artemisinines but for combinations


Generic Guide: BE Basic guidelinesGeneric Guide: BE Basic guidelines

In vivo Bioequivalence studies are clinical trials:

in accordance with the guidelines on

Good Clinical Practice

Good Manufacturing Practice

Good Laboratory Practice


Generic Guide: BE Basic guidelinesGeneric Guide: BE Basic guidelines

Additional guidance

WHO TRS No. 937, 2006, Annex 9

Guidelines for organizations performing in vivo bioequivalence studies. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Fortieth report. Geneva, World Health Organization


Generic Guide: BE study reportGeneric Guide: BE study report

The Bioequivalence study report should include information on:

Ethics, Investigators and administrative structure

Clinical phase of a study

Bioanalytical method of study

Pharmacokinetic and statistical analysis

Study protocol


Generic Guide: BE study reportGeneric Guide: BE study report

Complete structure is presented:

Table of Contents

Bioequivalence Trial Information Form (BTIF)


Generic Guide: BE dossier requirementsSPC and PIL

Generic Guide: BE dossier requirementsSPC and PIL

The “generic” SPC + PIL

=

innovator SPC + PIL




Main guideline: SupplementsSupplement 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

Dissolution Testing

for use from July 2005 (CPH25)


Supplement 1: Dissolution TestingDefinitions

Supplement 1: Dissolution TestingDefinitions

Immediate release:– means that 75% of the API is dissolved within 45

minutes.

Rapidly dissolving:– means that 85% of the API is dissolved within 30

minutes.

Very rapidly dissolving:– means that 85% of the API is dissolved within 15

minutes


Supplement 1: Dissolution TestingChoice of Dissolution Media

Supplement 1: Dissolution TestingChoice of Dissolution Media

Prescribes media to be considered for immediate release products during development studies:

– pH 6.8 buffer (or simulated intestinal fluid without enzymes) – pH 4.5 buffer – pH 1.2 buffer (or simulated gastric fluid without enzymes) or 0.1

M hydrochloric acid. – Water may be considered as an additional medium

Recommends testing intervals in the above media for purposes of generation of dissolution profiles:

– 10, 15, 20, 30 and 45 minutes.


Supplement 1: Dissolution TestingRole in Pharmaceutical Development

Supplement 1: Dissolution TestingRole in Pharmaceutical Development

Enables: – Selection of the formulation, by comparison of the dissolution profiles with that of the

innovator product. This is to maximize the chances of bioequivalence.

– Comparison of the release properties of the pivotal batches to demonstrate in vitro similarity, which is considered essential for retention of efficacy and safety. Note that bioequivalence studies are done normally only once on a pivotal batch during development – it must therefore be demonstrated that the product retains the release characteristics up to and during commercial production.

– The selection of the dissolution specifications (conditions and acceptance criteria) for product release and stability study purposes. A dissolution specification should be discriminating, implying that it should be able to detect inadequate release properties of the commercial batches.

– Post-approval amendment application. If the amendment is of a major nature and requires bioequivalence studies, in vitro data may be acceptable, provided that (1) the profiles of the amendment batch and the current batch are similar and (2) that the dissolution study design is acceptable (preferably the three media and short interval multipoint).


Supplement 1: Dissolution TestingScenarios

Supplement 1: Dissolution TestingScenarios

If both the test and reference product show more than 85% dissolution within 15 minutes, the profiles are considered similar (no calculations required).

Calculate the f2 value. If f2 ≥ 50, the profiles are normally regarded similar. Note that only one measurement should be considered after 85% dissolution of both products has occurred and excluding point zero.

The evaluation of similarity is based on the conditions of – a minimum of three time points (zero excluded) – 12 individual values for every time point for each formulation – not more than one mean value of > 85% dissolved for each formulation – that the standard deviation of the mean of any product should be less than

10% from second to last time point.


Supplement 1: Dissolution TestingSetting specifications

Supplement 1: Dissolution TestingSetting specifications

The specifications for the in vitro dissolution of the product should be derived from the dissolution profile of the batch that was found to be bioequivalent to the reference product and would be expected to be similar to those of the reference product.

For immediate release products, if the dissolution profile of the test product is dissimilar compared to that of the reference product and the in vivo data remains acceptable, the dissolution test method should be re-evaluated and optimised. In case that no discriminatory test method can be developed which reflects in vivo bioequivalence, a different dissolution specification for the test product could be set.




Main guideline: Supplements

Supplement 2

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

Extension of the WHO List of Stable(not easily degradable ARV) APIs

(for stability testing)

for use from July 2005 (CPH25)


Supplement 2: Stability Data for stable APIsList of stable APIs

Supplement 2: Stability Data for stable APIsList of stable APIs

Abacavir

Amodiaquine

Didanosine

Efavirenz

Ethambutol 2HCl

Ethionamide

Isoniazid

Lamivudine

Lumefantrine

Mefloquine

Nevirapine

Prothionamide

Pyrazinamide

Pyrimethamine

Stavudine

Sulfadoxine

Zidovudine


Supplement 2: Stability Data for stable APIsEvaluation Criteria for APIs

Supplement 2: Stability Data for stable APIsEvaluation Criteria for APIs

A two (2) years’ re-test period may be accepted on the basis of six (6) months’ accelerated and six (6) months’ long-term stability studies, if:

– Both the accelerated and the long-term stability data show so little degradation and so little variability.

– The Applicant undertakes in writing to continue long-term testing of the API under evaluation for a period of time sufficient to cover the whole proposed retest date (NLT 24 months) and to report any out-of-specification results immediately to WHO.


Supplement 2: Stability Data for stable APIsSinge API-FPPs

Supplement 2: Stability Data for stable APIsSinge API-FPPs

A two (2) years’ shelf life may be accepted for the single-API FPPs on the basis of six (6) months’ accelerated and six (6) months’ long-term stability studies, if:

– The API is known to be stable (not easily degradable)– Supporting data indicates that similar formulations have been assigned a shelf-life of

24 months or more; – The manufacturer will continue to conduct real-time studies until the proposed shelf-

life has been covered, and the results obtained will be submitted to the registration authority.

Additional requirements:– The tentative shelf life applies only to hard capsules and tablets containing only one

of the above-listed APIs. – The applicant should provide evidence that the primary packing material protects the

FPP against humidity and light, when applicable.– Both the accelerated and the long-term stability data should show so little

degradation and so little variability– The Applicant undertakes in writing to continue long-term testing of the FPP under

evaluation for a period of time sufficient to cover the whole proposed retest date (NLT 24 months) and to report any out-of-specification results immediately to WHO.


Supplement 2: Stability Data for stable APIsFDC Capsules & Tablets

Supplement 2: Stability Data for stable APIsFDC Capsules & Tablets

A two (2) years’ shelf life for FDC FPPs may be accepted on the basis of six (6) months’ accelerated and six (6) months’ long-term stability studies, if:

– All conditions for Single API-FPPs are met– the compatibility of the APIs with each other is

demonstrated by stress testing. Any evaluation should take into account the assay and the degradation or reaction products. Supporting HPLC chromatograms should be submitted.




GuidelineFPPs approved by ICH & associated DRAs

Guide on Submission of Documentation for Prequalification of 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 inter alia the EU, Japan and USA


FPPs approved by ICH & associated DRAsFPPs approved by ICH & associated DRAs A covering letter with:

– An original or certified copy of WHO-type Certificate of a Pharmaceutical Product issued by one of the regulatory authorities in the ICH region and associated countries, together with the approved summary of product characteristics (SmPC), or an equivalent thereof.

– Assessment report(s) issued by a DRA in the ICH region and associated countries. European Public Assessment Report (EPAR) is also acceptable.

– If the composition/formulation, strength, specifications, etc. are different from the product for which the WHO-type Product Certificate(s) was issued, then arguments and/or data to support the applicability of the certificate(s) — demonstration of pharmaceutical equivalence and bioequivalence should be submitted.

– If the primary packaging material of the product is different from the one approved by the drug regulatory authorities of the ICH regions and associated countries, then stability testing data should be submitted.

– Provide a sample of the FPP(s) to enable visual inspection of the FPP(s). Attach certificate of analysis. Variations to the terms of prequalification of a FPP should be implemented by the applicant only after the proposed changes have been evaluated and approved by WHO.




Guidelines: Fixed-Dose Combinations (FDCs)

WHO Expert Committee on Specifications for Pharmaceutical Preparations. 2005

Thirty-ninth report (WHO Technical Report Series, No. 929), Annex 5: Guidelines for registration of fixed-dose

combination medicinal products


Guidelines: FDCsDefinitions

Guidelines: FDCsDefinitions

Fixed-dose combination (FDC)– A combination of two or more actives in a fixed ratio of doses.

This term is used generically to mean a particular combination of actives irrespective of the formulation or brand. It may be administered as single entity products given concurrently or as a finished pharmaceutical product.

Fixed-dose combination finished pharmaceutical product (FDC-FPP)

– A finished pharmaceutical product that contains two or more actives.


Guidelines: FDCsThe Four ScenariosGuidelines: FDCs

The Four Scenarios Scenario 1. The new FDC-FPP contains the same actives in the same doses as an

existing FDC-FPP; that is it is a “generic” of the existing FDC-FPP; they are “multisource” products. The quality, safety and efficacy of the existing product have been established.

Scenario 2. The new FDC-FPP contains the same actives in the same doses as an established regime of single entity products, and the dosage regimen is the same. Alternatively the established regime may involve combinations of single entities and FDCs, for example, a single entity FPP combined with an FDC-FPP that contains two actives. In all cases, the established regime has a well-characterized safety and efficacy profile, and all of the FPPs used in obtaining clinical evidence have been shown to be of good quality.

Scenario 3– The new FDC-FPP combines actives that are of established safety and

efficacy but have not previously been used in combination for this indication.– The new FDC-FPP comprises a combination for which safety and efficacy

have been established, but that will be used in a different dosage regimen.

Scenario 4. The new FDC-FPP contains one or more new chemical entities.


Guidelines: FDCsRegistration Requirements (1)


Data requirements for marketing authorization of FDC-FPPs depend broadly on the scenario into which the application falls.

Issues that are specific to the development of FDC-FPPs include:

– 6.3.2.1 Chemical and physicochemical compatibility of the APIs in an FDC with one another as well as with possible excipients.

– 6.3.2.2 The degradability of each API under stress conditions in the presence of the others.

– 6.3.2.3 Uniformity of content of each active prior to compression (tablets) or filling (for instance capsules, sachets and suspension dosage forms). This study determines whether mixing during manufacture is adequate.




– 6.3.2.4 Analytical procedures. Validation should be conducted for each active in the presence of the others and in the presence of related synthesis (process) impurities and potential degradation products. In the case of high-performance liquid chromatography (HPLC), possible interference by degradation products in the assay of the active can usually be controlled by peak purity testing.

– 6.3.2.5 The dissolution rate of each active in pilot formulations. Multipoint limits should normally be established for routine quality control of each active. For some FDC-FPPs, different dissolution media may be acceptable for the different actives.

– 6.3.2.6 Different assay procedures may be necessary for the different actives in the finished product, and for different purposes (e.g. dissolution testing may be needed rather than stability testing).




6.3.3 For solid dosage forms:– a test and limit for content uniformity should be

applied to any active that is present at a weight of ≤25mg or when the API comprises 25% or less of a dosage unit. when any one API is present at less than 25 mg or less than

25% of the weight of a dosage unit, all of the actives are subjected to content uniformity testing.

– a test and limit for mass variation should be applied if all of the actives are present in a solid dosage form at a weight of greater than 25mg and greater than 25% of the weight of a dosage unit.




6.3.4 Acceptance criteria for impurities in FDC-FPPs should be expressed with reference to the parent API (and not with reference to the total content of APIs).

– If an impurity results from reaction between two APIs, its acceptance limits should be expressed in terms of the API that represents the worst case.

– If available, a reference standard should be used to quantify the degradation product in percentage mass/mass with respect to the parent API.

– Note: there should be an approximate mass balance. Together with the remaining active, degradants expressed with reference to the parent compound should sum to approximately 100% of initial strength.

6.3.5 The specifications and defining characteristics of the product should be based on the most vulnerable active. For example expiry dates should be based on the stability of the least stable active.




Bioequivalence for FDC-FPPs:

Comparison with– an existing combination

– separate active APIs (drug)




ICH guidelines

ICH guidelines are used when a quality aspect cannot be (fully) assessed by the WHO guidelines, for instance:– Q3A(R). Impurities in new drug substances– Q3B(R). Impurities in new drug products– Q3C. Impurities: Guideline for residual solvents– Q6A. Specifications: Test procedures and acceptance criteria

for new drug substances and new drug products: chemical substances (with decision trees)




GUIDANCE ON VARIATIONS TO A PREQUALIFIED PRODUCT DOSSIER

The prequalification process is dynamic, taking into account that changes to the original dossier may become necessary during the lifetime of the product

Any changes or variations may involve administrative and/or more substantial changes and are subject to approval within the prequalification program

Where a variation requires consequential revision of the Summary of Product Characteristics (SmPC), labelling and package leaflet/insert, this is considered as part of the variation.

Whenever FPPs have been prequalified on the basis of approval by a drug regulatory authority of the ICH region and associated countries (Innovator Products or Generic Products) subsequent variation applications are also to be approved by these drug regulatory authorities and WHO should be notified about the approval of the changes.


Variation Guideline (2)Variation Guideline (2) ANNEX I

– List of minor changes The conditions which must apply are stipulated The relevant part of the dossier to be resubmitted or updated, with the documentation required,

is listed

ANNEX II– Lists major changes in general: Major changes exceed the scope of minor

changes as listed in Annex I, e.g. they exceed/do not comply with the conditions to be fulfilled along with the change: Change in the manufacturing process of the API Change in the composition of the finished product Change of immediate packaging of the product

ANNEX III– Lists types of changes which may require a new application:

Changes to the API (±type, quantity) Changes to the pharmaceutical form/dosage form Changes in the route of administration


Variation Guideline (3)Variation Guideline (3)

Approval of changes– Applications for minor changes that are classified notifications (N) must provide

evidence to fulfil the conditions and documentation requirements as listed. Within a period of three months these notifications will be evaluated by WHO and can be considered approved if no correspondence by WHO with the applicant has been initiated within that time.

– For all other change applications that are not considered as notifications, prior approval by WHO is always necessary before the changes can be implemented.

Certain changes are so fundamental that they alter the terms of the prequalified dossier and consequently cannot be considered as a change. For these cases a new dossier must be submitted (Annex III).

All parts of the dossier that are affected by a variation are to be resubmitted according to the structure of the Pharmaceutical Quality Information Form (PQIF)1


Closing remarksClosing remarks

1. The dossier submitted must conform to the requirements set out in the current WHO guidelines, as posted on web

2. The assessment of quality and safety/efficacy data presented is based on the current WHO guidelines

3. ICH guidelines are used when a quality aspect cannot be assessed by the WHO guidelines

4. The quality assessment includes variations or changes to already prequalified products


THANK YOUTHANK YOU

Slide 1 of 72D.K. Mubangizi, Dar Es Salaam Sept. 2007 Training Workshop for Evaluators from National Medicines Regulatory Authorities in East African Community.

Documents

dossier evaluation slide

expert slide

evaluation of quality

common format

guidelines presenter

guidelines objective

ctd format guideline

common technical document