Transcript Overview of dossier requirements and guidelines

Evaluation of Quality and Interchangeability
of Medicinal Products
Training Workshop for Evaluators
from National Medicines Regulatory
Authorities in East African
Community
Dar Es Salaam, Tanzania
Date: 10 to 14 September 2007
Slide 1 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 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
Slide 2 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Overview of Dossier Requirements and
Guidelines
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
Slide 3 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Overview of Dossier Requirements and
Guidelines
 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
Slide 4 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Data in the dossier should enable us to answer the
following questions:
 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.
Slide 5 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Overview of Dossier Requirements and
Guidelines (1)
Common Technical Document
(CTD)
An initiative under the ICH: Europe, Japan and
USA.
http://www.ich.org
Slide 6 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
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.
Slide 7 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
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.
Slide 8 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
CTD format (3)
 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)
Slide 9 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
CTD format (4)
 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






Slide 10 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
CTD format (5)
 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
Slide 11 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
CTD format (5)
 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
– 4.3 Literature References
Slide 12 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
CTD format (6)
 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
– 5.4 Literature References
Slide 13 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
CTD format: Overall Table of Contents (ToC)
2.1
ToC of the CTD
(Mod 2,3,4,5)
1.1
ToC of Module 1
or overall ToC,
including Module 1
Module 1
2.1
2.2
Module 2
2.4
2.5
2.3
2.6
Module 3
Module 4
3.1
4.1
ToC
for
Module
4
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2.7
Module 5
5.1
ToC for Module 5
CTD format: Numbering System
Module 1
Module 2
1.0 Regional Administrative Information
1.1 ToC of Module 1 or overall ToC,
including Module 1
1.0
2.1 ToC of the CTD (Mod 2,3,4,5)
2.1
2.2 Introduction
2.3 Quality Overall Summary
2.2
2.4 Non-clinical Overview
2.4
2.5
2.3
2.6
Module 3
Quality
Module 4
2.5 Clinical Overview
2.7
2.6 Non-clinical Written and
Tabulated Summaries
Module 5
2.7 Clinical Summary
Clinical
Nonclinical
Reports
Study
Reports
Slide
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D.K. Mubangizi,Study
Dar Es Salaam
Sept. 2007
CTD format: Numbering System: Module 2
Module 2
2.1
2.2
2.3
2.3.S
2.3.S.1
2.3.S.2
2.3.S.3
2.3.S.4
2.3.S.5
2.3.S.6
OVERALL CTD TABLE OF CONTENTS OF MODULES 2, 3, 4, AND 5
INTRODUCTION
QUALITY OVERALL SUMMARY
DRUG SUBSTANCE
General Information
Manufacture
Characterization
Control of Drug Substance
Reference Standards or Materials
Container Closure System
2.3.S.7
2.3.P
2.3.P.1
2.3.P.2
2.3.P.3
2.3.P.4
2.3.P.5
2.3.P.6
2.3.P.7
2.3.P.8
Stability
DRUG PRODUCT
Description and Composition of the Drug Product
Pharmaceutical Development
Manufacture
Control of Excipients
Control of Drug Product
Reference Standards or Materials
Container Closure System
Stability
Slide 16 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
CTD format: Numbering System: Module 2
Module 2 (Cont.)
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
2.4.6
2.5
2.5.1
2.5.2
2.5.3
2.5.4
2.5.5
2.5.6
2.5.7
2.6
2.6.1
2.6.2
2.6.3
2.6.4
2.6.5
2.6.6
2.6.7
2.7
2.7.1
CONTENT OF NONCLINICAL WRITTEN AND
TABULATED SUMMARIES
Introduction
Pharmacology Written Summary
Pharmacology Tabulated Summary
(Appendix B)
Pharmacokinetics Written Summary
Pharmacokinetics Tabulated Summary
(Appendix B)
Toxicology Written Summary
Toxicology Tabulated Summary (Appendix B)
CLINICAL SUMMARY
Summary of Biopharmaceutics and
Associated Analytical Methods
Summary of Clinical Pharmacology Studies
Summary of Clinical Efficacy
Summary of Clinical Safety
References
Synopses of Individual Studies
Integrated Overview and Conclusions
List of Literature Citations
CLINICAL OVERVIEW
Product Development Rationale
2.7.2
Overview of Biopharmaceutics
2.7.3
Overview of Clinical Pharmacology
2.7.4
Overview of Efficacy
2.7.5
Overview of Safety
2.7.6
Benefits and Risks Conclusions
References Slide 17 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
CTD format: Numbering System: Module 3
Module 3
3.1
3.2
3.2.S
3.2.S.1
3.2.S.2
3.2.S.3
3.2.S.4
3.2.S.5
3.2.S.6
3.2.S.7
3.2.P
3.2.P.1
3.2.P.2
3.2.P.3
3.2.P.4
3.2.P.5
3.2.P.6
3.2.P.7
3.2.P.8
MODULE 3 TABLE OF CONTENTS
BODY OF DATA
DRUG SUBSTANCE
General Information
Module 3 (Cont.)
Manufacture
3.2.A
APPENDICES
Characterisation
Control of Drug Substance
3.2.A.1 Facilities and Equipment
Reference Standards or Materials
3.2.A.2 Adventitious Agents Safety Evaluation
Container Closure System
3.2.A.3 Novel Excipients
Stability
3.2.R REGIONAL INFORMATION
DRUG PRODUCT
3.3
LITERATURE REFERENCES
Description and Composition of the Drug
Product
Pharmaceutical Development
Manufacture
Control of Excipients
Control of Drug Product
Reference Standards or Materials
Container Closure System
Slide 18 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Stability
CTD format: Numbering System: Module 4
4.1
4.2
4.2.1
4.2.2
4.2.3
4.3
Module 4
MODULE 4 TABLE OF CONTENTS
STUDY REPORTS
Pharmacology
Pharmacokinetics
Toxicology
LITERATURE REFERENCES
Slide 19 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
CTD format: Numbering System: Module 5
Module 5
MODULE 5 TABLE OF CONTENTS
5.1
TABULAR LISTINGS OF ALL CLINICAL STUDIES
5.2
CLINICAL STUDY REPORTS
5.3
Reports of Biopharmaceutic Studies
5.3.1
5.3.2
Reports of Studies Pertinent to Pharmacokinetics
using Human Biomaterials
Reports of Human Pharmacokinetic (PK) Studies
5.3.3
Reports of Human Pharmacodynamic (PD) Studies
5.3.4
Reports of Efficacy and Safety Studies
5.3.5
Reports of Post-Marketing Experience
5.3.6
Case Report Forms and Individual Patient Listings
5.3.7
LITERATURE REFERENCES
5.4
Slide 20 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Overview of Dossier Requirements and
Guidelines (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
http://mednet3.who.int/prequal
Slide 21 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Generic 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.
Slide 22 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Multisource (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
Slide 23 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Quality 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))
Same Safety –
Same efficacy
Equal quality with the
comparator or a quality shown and
assessed to be as acceptable
Demonstration of pharmaceutical equivalence of the
FPP including that of the API
Slide 24 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Generic 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
Slide 25 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Generic 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
Slide 26 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Generic Guide:
Quality dossier / Section 2
Active Pharmaceutical Ingredient
(API)
Slide 27 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Generic 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
Slide 28 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Generic Guide: Quality/Section 2: API
Complete 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 nonpharmacopoeial
Slide 29 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Generic Guide: Quality/Section 2: API
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
Slide 30 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Generic Guide: Quality/Section 2: API
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
Slide 31 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Generic Guide: Quality/Section 2: API
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
Slide 32 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
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.
Slide 33 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
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
Slide 34 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
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
Slide 35 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Generic Guide:
Quality dossier / Section 3
Finished Pharmaceutical Product
(FPP)
Slide 36 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Generic 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
Slide 37 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Generic 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)
Slide 38 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Bioequivalence dossier
(BE) requirements for the
prequalification project
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
Slide 40 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Generic 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
Slide 41 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Generic 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
Slide 42 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Generic 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
Slide 43 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Generic Guide: BE study report
Complete structure is presented:
 Table of Contents
 Bioequivalence Trial Information Form (BTIF)
Slide 44 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Generic Guide: BE dossier requirements
SPC and PIL
The “generic” SPC + PIL
=
innovator SPC + PIL
Slide 45 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Overview of Dossier Requirements and
Guidelines (3)
Main guideline: Supplements
Supplement 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)
Slide 46 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Supplement 1: Dissolution Testing
Definitions
 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
Slide 47 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Supplement 1: Dissolution Testing
Choice 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.
Slide 48 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Supplement 1: Dissolution Testing
Role 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).
Slide 49 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Supplement 1: Dissolution Testing
Scenarios
 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.
Slide 50 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Supplement 1: Dissolution Testing
Setting 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.
Slide 51 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Overview of Dossier Requirements and
Guidelines (4)
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)
Slide 52 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Supplement 2: Stability Data for stable APIs
List of stable APIs
 Abacavir
 Mefloquine
 Amodiaquine
 Nevirapine
 Didanosine
 Efavirenz
 Ethambutol 2HCl
 Ethionamide
 Isoniazid
 Lamivudine
 Lumefantrine
 Prothionamide
 Pyrazinamide
 Pyrimethamine
 Stavudine
 Sulfadoxine
 Zidovudine
Slide 53 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Supplement 2: Stability Data for stable APIs
Evaluation 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.
Slide 54 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Supplement 2: Stability Data for stable APIs
Singe 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 shelflife 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.
Slide 55 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Supplement 2: Stability Data for stable APIs
FDC 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.
Slide 56 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Overview of Dossier Requirements and
Guidelines (5)
Guideline
FPPs 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
Slide 57 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
FPPs 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.
Slide 58 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Overview of Dossier Requirements and
Guidelines (6)
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
Slide 59 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Guidelines: FDCs
Definitions
 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.
Slide 60 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Guidelines: 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.
Slide 61 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Guidelines: FDCs
Registration 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.
Slide 62 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Guidelines: FDCs
Registration Requirements (2)
– 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).
Slide 63 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Guidelines: FDCs
Registration Requirements (3)
 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.
Slide 64 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Guidelines: FDCs
Registration Requirements (4)
 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.
Slide 65 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Guidelines: FDCs
Registration Requirements (5)
Bioequivalence for FDC-FPPs:
 Comparison with
– an existing combination
– separate active APIs (drug)
Slide 66 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Overview of Dossier Requirements and
Guidelines (7)
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)
Slide 67 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Overview of Dossier Requirements and
Guidelines (8)
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.
Slide 68 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Variation Guideline (2)

ANNEX I

ANNEX II

ANNEX III
– 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
– 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
– 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
Slide 69 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
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
Slide 70 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Closing 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
Slide 71 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007
THANK YOU
Slide 72 of 72 D.K. Mubangizi, Dar Es Salaam Sept. 2007