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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

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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 patient matters

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

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

established standards of efficacy, safety & quality


GMP Good manufacturing practices

ICH International Conference onHarmonization

PhEurEuropean Pharmacopoeia

PhInt International Pharmacopoeia

PIL Patient information leaflet

PQIF Pharmaceutical quality information form

SmPC Summary of product characteristics

TB Tuberculosis

USP United States Pharmacopeia

API Active pharmaceutical ingredient

APIMF API master file

BCS Biopharmaceutics classification system

BE Bioequivalence

BP British Pharmacopoeia

CEP Certificate of suitability (Ph.Eur.)

CPP WHO-type Certificate of a Pharmaceutical Product

EOIExpression of interest

FDC Fixed-dose combination

FPP Finished pharmaceutical product


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
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 website http who int prequal
Prequalification Programme website

Focus quality aspects
Focus – Quality aspects

Multisource (generic) medicines

  • ForTuberculosis (TB)

  • Mainly first line TB medicines

    • Rifampicin, isoniazid, pyrazinamide & ethambutol hydrochloride

  • Mainly oral solid dosage forms

  • Emphasis on fixed-dose combinations (FDCs)

Important definitions
Important definitions

  • Current WHO definitions

  • Used throughout the presentations

Who technical report series 937 2006
WHO Technical Report Series 937 (2006)

  • Multisource (generic) pharmaceutical products

    • Pharmaceutically equivalentorpharmaceutically 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 20061
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
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)

  • Excipient

    A 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
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
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 guideline administrative part
Generic GuidelineAdministrative part

A: Covering letter by responsible person

  • Statement: information is true and correct

    B: Application (requirements for productdossier)

  • Four main sections (with subsections)

  • Keep to the sections/subsections as prescribed

  • Sections/subsections should be clearly marked

    • preferably with securely fixed tags

  • Number all pages (essential)

  • Table of contents

    • List sections, subsections – with page numbers

  • Include Annexes 7 & 8(hard copy and CD-ROM)

Generic guideline dossier requirements main sections
Generic guidelineDossier requirements – main sections

Section 1

Characteristics of the FPP(3/26)

Section 2

Active Pharmaceutical Ingredients (APIs) (4/26)

Section 3

Finished Pharmaceutical Products (FPPs) (10/26)

Section 4

Interchangeability (Bioequivalence) (25/26)

Generic guideline annexes 1 6
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 guideline annexes 7 8
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 dossier

    Submit with application / dossier the following:

  • Hard copy of BTIF and PQIF – original & duly signed

  • Electronic (Word) copy of each on CD-ROM

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

Pqif example 1
PQIF – example 1

Grey parts for

assessors only

ETH-400 Tablets

Applicant fills out white parts

Etambutol 400mg Tablets

Main guideline annex 8 pqif example 2
Main guidelineAnnex 8 (PQIF) – Example 2








Ethambutol hydrochloride









Maize starch

Example of mock up pqif
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)

Other guidelines on pq website 1 quality related
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
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

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
Closing remarks

  • The dossier submittedmust conform to the requirements set out in the current WHO guidelines, as posted on the Prequalification website

    • PQIF & BTIF (Word format)

    • APIMF procedure

  • 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

  • The quality assessment includes variations orchanges to already prequalified products

  • Quality is built in by design, not tested in