WHO workshop on

Theo Dekker -- Jiaxing, China --September 20072 |

WHO workshop on

Quality, good manufacturing practice and bioequivalence with a focus on antituberculotics

Jiaxing, China

5 to 9 November 2007

Introduction to: Dossier requirements and guidelines for generics (quality part)

Theo Dekker, D.Sc.Research Institute for Industrial Pharmacy

North-West University, Potchefstroom, South Africa


The patient matters

The joint efforts of WHO, manufacturers, procurement agencies & other role players

should cover all activities aimed at ensuring thatthe patient receives a product that meets

established standards of efficacy, safety & quality


AbbreviationsAPI Active pharmaceutical ingredient

APIMF API master file

BCS Biopharmaceutics classificationsystem

BE Bioequivalence

BP British Pharmacopoeia

CEP Certificate of suitability (Ph.Eur.)

CPP WHO-type Certificate of a Pharmaceutical Product

EOI Expression of interest

FDC Fixed-dose combination

FPP Finished pharmaceutical product

GMP Good manufacturing practices

ICH International Conference onHarmonization

PhEur European Pharmacopoeia

PhInt International Pharmacopoeia

PILPatient information leaflet

PQIF Pharmaceutical quality informationform

SmPC Summary of product characteristics

TB Tuberculosis

USP United States Pharmacopeia


Objective

To give brief overview of – Guidelines used in Prequalification Programme

The guidelines are important for– Product development

• Safety, efficacy & quality– Preparation of submissions, for example

• Dossier• PQIF (Pharmaceutical Quality Information Form)• BTIF (Bioequivalence Trial Information Form)

– Good manufacturing practices (GMP)– Good laboratory practices (GLP of BE studies)


Where to find ?

All information on the Prequalification Program? e.g.

Guidelines

Other training material on prequalification– Very useful for

• applicants and regulators

Also– Current invitation for expression of interest– Assessment meeting dates


Prequalification Programme websitehttp://who.int/prequal/


Focus – Quality aspects

Multisource (generic) medicines– For Tuberculosis (TB)– Mainly first line TB medicines

• Rifampicin, isoniazid, pyrazinamide & ethambutol hydrochloride– Mainly oral solid dosage forms– Emphasis on fixed-dose combinations (FDCs)


Important definitions

Current WHO definitions

Used throughout the presentations


WHO Technical Report Series 937 (2006)Multisource (generic) pharmaceutical products

– Pharmaceutically equivalent or pharmaceutically alternative products

• that may or may not be therapeutically equivalent– Multisource pharmaceutical products that are therapeutically

equivalent are interchangeable

Pharmaceutical equivalent products– Contain the same API(s)

• in the same molar amount(s) • in the same dosage form

– Meet similar quality standards– Are intended for the same route of administration…– May or may not be therapeutically equivalent


WHO Technical Report Series 937 (2006)Pharmaceutical alternative products contain

– the same molar amount of the same active pharmaceutical moiety(s), but

• differ in dosage form (e.g. tablets versus capsules) and/or• differ in chemical form (e.g. different salts, different esters).

Pharmaceutical alternatives– deliver the same active moiety by the same route of

administration• but are otherwise not pharmaceutically equivalent• They may or may not be bioequivalent or therapeutically equivalent to the

comparator product.


Product ingredients

Active Pharmaceutical Ingredient (API)A substance or compound intended to be used in the manufacture of a pharmaceutical product as a therapeutically active compound (ingredient)

ExcipientA substance or compound, other than the API and packaging materials, that is intended or designated to be used in the manufacture of a pharmaceutical product


The product

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 pharmaceutical product that has undergone all stages of production, including packaging in its final container & labelling


Guideline on generics

Main generic guideline

Guideline on submission of documentation for prequalification of multi-source (Generic) Finished Pharmaceutical Products (FPPs) used in treatment of HIV/AIDS, Malaria and Tuberculosis

– with 8 annexes [under revision]

– Supplement 1: Dissolution testing– Supplement 2: Extension of the WHO list of stable APIs (not

easily degradable) [stability testing]


Generic GuidelineAdministrative part

A: Covering letter by responsible person– Statement: information is true and correct

B: Application (requirements for product dossier)1. Four main sections (with subsections)2. Keep to the sections/subsections as prescribed3. Sections/subsections should be clearly marked

• preferably with securely fixed tags4. Number all pages (essential)5. Table of contents

• List sections, subsections – with page numbers6. Include Annexes 7 & 8 (hard copy and CD-ROM)


Generic guidelineDossier requirements – main sections

Section 1 Characteristics of the FPP (3/26)

Section 2Active Pharmaceutical Ingredients (APIs) (4/26)

Section 3Finished Pharmaceutical Products (FPPs) (10/26)

Section 4Interchangeability (Bioequivalence) (25/26)


Generic guidelineAnnexes (1 - 6)

Annex 1: Model Certificate of a Pharmaceutical Product (CPP)

Annex 2: Model Batch Certificate of Pharmaceutical Product

Annex 3: Model Stability Report of API

Annex 4: Model Stability Report of Capsules/Tablets

Annex 5: Suggested Structure of the Summary of Product characteristics (SmPC)

Annex 6: Suggested structure of the Package Information Leaflet (PIL)


Generic guidelineAnnexes (7 & 8)

Annex 7: Presentation of Bioequivalence Trial Information (BTIF) (Zip Word file)

Annex 8: Presentation of Pharmaceutical Quality Information (PQIF) (Zip Word file)

Applicant must properly complete BTIF and PQIF– Provide detailed & accurate information, referenced to dossierSubmit with application / dossier the following:1. Hard copy of BTIF and PQIF – original & duly signed2. Electronic (Word) copy of each on CD-ROM

BTIF and PQIF are used for assessment reports (CD-ROM)


PQIF – example 1

Grey parts forassessors only

Applicant fills out white parts

ETH-400 TabletsEtambutol 400mg Tablets


Main guidelineAnnex 8 (PQIF) – Example 2

1001

1002 1003

Ethambutol hydrochlorideMaize starch

40020

1001

1002 10031001

80 80 804 4 4


Example of mock-up PQIF

On Prequalification website (by Dr. J. Pogány):

Training Workshop on Pharmaceutical Quality and Bioequivalence - Hanoi, Vietnam, 17 - 19 January 2006

– PQIF (API)– PQIF (FFP)

Example shows how PQIF is:– filled out by applicant (typed in black)– assessed by first assessor (typed in red)– assessed by second assessor (typed in blue)


Copy from mock-up PQIF


Other guidelines on PQ website (1)Quality related

Guideline on Active Pharmaceutical Ingredient Master File (APIMF) Procedure

– Implemented since January 2007

Guidance on variations to a prequalified 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 are subject to approval within the prequalification program

• Some variations are notifications


Other guidelines on PQ website (2)Quality related

Guidelines for registration of fixed-dose combination medicinal products (TRS 943)

Innovators 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


ICH guidelines

ICH guidelines are used when a quality aspect cannot be (fully) assessed by the WHO guidelines, for instance:– Q3A(R2). Impurities in new drug substances– Q3B(R2). Impurities in new drug products– Q3C(R3). 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)


Closing remarks

1. The dossier submitted must conform to the requirements set out in the current WHO guidelines, as posted on the Prequalification website– PQIF & BTIF (Word format)– APIMF procedure

2. The assessment of data is based on the current WHO guidelines– ICH guidelines are used when a quality aspect cannot be assessed

by the WHO guidelines

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

4. Quality is built in by design, not tested in


the patient matters

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