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
Theo Dekker -- Jiaxing, China --September 20073 |
The patient mattersThe 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
Theo Dekker -- Jiaxing, China --September 20074 |
AbbreviationsAbbreviations
API 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
PIL Patient information leaflet
PQIF Pharmaceutical quality information
form
SmPC Summary of product characteristics
TB Tuberculosis
USP United States Pharmacopeia
Theo Dekker -- Jiaxing, China --September 20075 |
ObjectiveObjective
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)
Theo Dekker -- Jiaxing, China --September 20076 |
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
Theo Dekker -- Jiaxing, China --September 20077 |
Prequalification Programme websitehttp://who.int/prequal/
Prequalification Programme websitehttp://who.int/prequal/
Theo Dekker -- Jiaxing, China --September 20078 |
Focus – Quality aspectsFocus – 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)
Theo Dekker -- Jiaxing, China --September 20079 |
Important definitionsImportant definitions
Current WHO definitions
Used throughout the presentations
Theo Dekker -- Jiaxing, China --September 200710 |
WHO Technical Report Series 937 (2006)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
Theo Dekker -- Jiaxing, China --September 200711 |
WHO Technical Report Series 937 (2006)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.
Theo Dekker -- Jiaxing, China --September 200712 |
Product ingredientsProduct 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
Theo Dekker -- Jiaxing, China --September 200713 |
The productThe 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
Theo Dekker -- Jiaxing, China --September 200714 |
Guideline on genericsGuideline 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]
Theo Dekker -- Jiaxing, China --September 200715 |
Generic GuidelineAdministrative partGeneric Guideline
Administrative 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 prescribed
3. Sections/subsections should be clearly marked• preferably with securely fixed tags
4. Number all pages (essential)
5. Table of contents• List sections, subsections – with page numbers
6. Include Annexes 7 & 8 (hard copy and CD-ROM)
Theo Dekker -- Jiaxing, China --September 200716 |
Generic guidelineDossier 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)
Theo Dekker -- Jiaxing, China --September 200717 |
Generic guidelineAnnexes (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)
Theo Dekker -- Jiaxing, China --September 200718 |
Generic guidelineAnnexes (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:
1. Hard copy of BTIF and PQIF – original & duly signed
2. Electronic (Word) copy of each on CD-ROM
BTIF and PQIF are used for assessment reports (CD-ROM)
Theo Dekker -- Jiaxing, China --September 200719 |
PQIF – example 1PQIF – example 1
Grey parts forassessors only
Applicant fills out white parts
ETH-400 Tablets
Etambutol 400mg Tablets
Theo Dekker -- Jiaxing, China --September 200720 |
Main guidelineAnnex 8 (PQIF) – Example 2
Main guidelineAnnex 8 (PQIF) – Example 2
1001
1002 1003
Ethambutol hydrochlorideMaize starch
40020
1001
1002 10031001
80 80 804 4 4
Theo Dekker -- Jiaxing, China --September 200721 |
Example of mock-up PQIFExample 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)
Theo Dekker -- Jiaxing, China --September 200722 |
Copy from mock-up PQIFCopy from mock-up PQIF
Theo Dekker -- Jiaxing, China --September 200723 |
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
Theo Dekker -- Jiaxing, China --September 200724 |
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
Theo Dekker -- Jiaxing, China --September 200725 |
ICH guidelinesICH 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)
Theo Dekker -- Jiaxing, China --September 200726 |
Closing remarksClosing 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
Theo Dekker -- Jiaxing, China --September 200727 |
the patient matters
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