Dossier Requirements for Generic Medicines
and Quality Guidelines
Sultan Ghani
WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E.
Focus of Presentation
 Part A: Organization and principal of assessment
 Part B: Organization of data and regulatory dossier
 Part C: Introduction to PQP Guidelines
 Part D: Other Relevant Documents and Guidelines
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
PART A:
Organization and principal of
assessment
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
Introduction
 WHO Procedure of assessment is based on the following
principles:
 Reliance of the information supplied by DRA
 Understanding of production and quality control of
the manufacturer
 Assessment of data and information on safety,
efficacy and quality
 GMP compliance of sites for APIs and FPPs
 GCP / GLP compliance
 Random sampling and testing
 Distribution recalls and complaints
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
Steps of the Procedure
EPO
SUBMISSION OF
DOSSIER
SOD
Multisource generic
product
N.S.D.
Expression of Interest
Submission of Dossiers
S.D.
- Detail of the Product
(See Presentation)
Screening
Dossier
Assessment
Site Inspection
Report and
Outcome of
Evaluation
Assessment
Results
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
Standard Dossier submitted to DRA –
Innovator Product
- WHO-type Certificate of Pharmaceutical
Product
- Assessment Report
- WHO-type Batch Certificate
- Different packaging requires stability data
Testing of Samples
 Random Sampling
 In case of failure investigation
 WHO will provide written report and recommendation
for action
 Relevant DRA will be invited to participate in inspection
or investigation
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
Other Issues
 Cost recovery
 Confidentiality and undertaking (inspectors and
evaluators)
 Conflict of interest
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
PART B:
Organization of data and regulatory
dossier
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
CTD FORMAT – ICH Requirements
 The CTD is not a “Global Dossier” !
 It is an agreed-upon common format for the “modular”
presentation of summaries, reports and data
 Incorporates relevant ICH guidelines
 It is organized into five sections:
 All “modules” harmonized except Module 1 –
regional specific
 Raw data per regional requirements
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
Result was the CTD Triangle
Module 1
Not Part of
CTD
Regional
Administrative
Information
Module 2
Quality
Overall
Summary
Nonclinical
Overview
Clinical
Overview
Nonclinical
Summaries
NDS
Clinical
Summary
CTD
Module 3
Module 4
Module 5
Quality
Nonclinical
Study Reports
Clinical
Study Reports
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
CTD Structure
 Full dossier contains 5 “Modules” - - Only Modules 2-5 are “CTD”
 Module 1 – region-specific but always included in
complete CTD structure
 Module 2- All summaries / overviews
 Module 3 – CMC (“Quality”)
 Module 4 – Preclinical
 Module 5 - Clinical
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
Module 2 - CTD Summaries
 2.1 Overall CTD ToC
 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
 2.7 Clinical Summary
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
2.2 CTD Introduction
 General introduction to the pharmaceutical, including
 Pharmacologic class
 Mode of action
 Proposed clinical use
 Typically 1 page
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
2.3 Quality Overall Summary - Content
 A Summary that follows the scope and outline of the
Body of Data in Module 3
 Emphasize and discuss critical key parameters of the
product
 Discuss key issues to integrate information from Module
3 and other modules
 Typically 40 pages, excluding tables, figures
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
2.3 Quality Overall Summary - Format
 2.3
Introduction
 2.3.S
Drug Substance
 2.3.P
Drug Product
 2.3.A
Appendices
 2.3.R
Regional Information
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
Submission of CMC Information in CTD Format
3.2.S
DRUG SUBSTANCE
3.2.S.1
General Information
3.2.S.2
Manufacture
3.2.S.3
Characterization
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
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
Submission of CMC Information in CTD Format
(cont’d)
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
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
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
Submission of CMC Information in CTD Format
(cont’d)
3.2.A
APPENDICES
3.2.A.1
Facilities and Equipment
3.2.A.2
Adventitious Agents Safety Evaluation
3.2.A.3
Excipients
3.2.R
REGIONAL INFORMATION
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
Submission of CMC Information in CTD Format
 The CTD Quality Module is unique in that it is a
combination of historical development and future
commitments that apply to the commercial, postapproval production period.
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
Impact of the CTD
 The ICH CTD represents one of the most ambitious and
successful international harmonization activities
undertaken
 It will significantly reduce time and resources needed by
industry to compile applications for global registration
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
Benefits of the CTD
 More “reviewable” applications
 Complete, well-organized submissions
 More predictable format
 More consistent reviews
 Easier analysis across applications
 Easier exchange of information
 Facilitates electronic submissions
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
CTD FORMAT – WHO Documents Requirements
1. Characteristics of the Finished Pharmaceutical
Product (FPP)
1.1 Detail of the Product
- Names, Dosage Forms & Strength
- Description of Product & Packaging (Bottle, Blister,
Bulk)
1.2 Sample
- all proposed market presentations
1.3 Regulatory Situation in Other Countries
- CANADA, USFDA, PEPFAR, EU, etc.
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
CTD FORMAT – WHO Documents Requirements
(cont’d)
2. Active Pharmaceutical Ingredient(s) (APIs)
2.1 Nomenclature
- INN, Compendial Name, Chemical Name, Drug
Substance Code, USAN, CAS Number.
2.2 Properties of APIs
- API not described in Pharmacopoeia
- API described in Pharmacopoeia
- Structure Elucidation, Isomerism, Polymorphs,
Particle Size Distribution (PSD), Critical additional
characteristics (solubility, partition coefficient, etc.),
Literature references.
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
CTD FORMAT – WHO Documents Requirements
(cont’d)
2. Active Pharmaceutical Ingredient(s) (APIs)
2.3 Site(s) of Manufacture
- DMF(s), API-MF, GMP Certificate & Manufacturing
licence, - - Specify: if inspected by WHO or any
other Regulatory Agency.
2.4 Route(s) of API Synthesis
- Specifications of Raw Materials & Intermediates
- Controls of Critical Steps & Intermediates
- Process Validation or Evaluation.
- Impurities (organic, inorganic, catalysts, etc.).
- Residual Solvents.
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
CTD FORMAT – WHO Documents Requirements
(cont’d)
2. Active Pharmaceutical Ingredient(s) (APIs)
2.5 Specifications
- Complete specifications, signed & dated
- Batch analysis
- Summary of analytical results of relevant batches
used in clinical or comparative studies.
- Justification of specifications.
- Reference Standards or Materials.
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
CTD FORMAT – WHO Documents Requirements
(cont’d)
2. Active Pharmaceutical Ingredient(s) (APIs)
2.6 Container Closure System
- Specifications & Test Methods
- IR identification tests to be performed.
2.7 Stability Testing
- Stress testing, Accelerated testing, long-term
testing
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
CTD FORMAT – WHO Documents Requirements
(cont’d)
3. Finished Pharmaceutical Product (FPP)
3.1 Marketing & Manufacturing Authorization
3.2 Pharmaceutical Development
- API characterization studies
- Compatibility of API & Excipients
- Selection of excipients
- Formulation development
- Overages
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
CTD FORMAT – WHO Documents Requirements
(cont’d)
3. Finished Pharmaceutical Product (FPP)
3.3 Formulation
- Standard unit composition
- Clinical batch composition
- Proposed commercial batch
- Highlight differences (if any)
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
CTD FORMAT – WHO Documents Requirements
(cont’d)
3. Finished Pharmaceutical Product (FPP)
3.4 Site(s) of Manufacture
- Name & address of the facility
3.5 Manufacturing Process
- Flow chart of manufacturing process In-process control
- Identification of critical steps
- Target limits (if any)
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
CTD FORMAT – WHO Documents Requirements
(cont’d)
3. Finished Pharmaceutical Product (FPP)
3.6 Control of Critical Steps & Intermediates
- Tests (according to dosage form)
- Methods (compendial, In-house, etc.)
3.7 Process Validation
- Types of validation
- Purpose
- Validation Protocol
- Batch Size
- Batch Number
- Commitment
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
CTD FORMAT – WHO Documents Requirements
(cont’d)
3. Finished Pharmaceutical Product (FPP)
3.8 Specifications of Excipients
- Pharmacopoeial Grade
- Non-Pharmacopoeial Grade
3.9 Control of FPP
- Specifications
- Justification of specifications
- Test Methods
3.10 Container Closure System
- Type of container closure system
- Blister, HDPE Bottle, Bulk
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
CTD FORMAT – WHO Documents Requirements
(cont’d)
3. Finished Pharmaceutical Product (FPP)
3.11 Stability Testing
- Stability protocol
- Stability specifications
- Selection of batches
- Long term conditions
- Accelerated conditions
- Proposed shelf-life pf FPP commitment
batches
- Stability studies
3.12 Container Labelling
- outer, inner labels
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
CTD FORMAT – WHO Documents Requirements
(cont’d)
3. Finished Pharmaceutical Product (FPP)
3.13 Product Information for Health Professionals
3.14 Patient Information & Package Insert
3.15 Differences in the product in various countries
issuing the submitted WHO-type certificate(s).
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
PART C:
Introduction to PQP Guidelines
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
Introduction to PQP Guidelines
 PQP Dossier Submission Requirements:
Prequalification website address
www.who.int/prequal/
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
Introduction to PQP Guidelines
 Covering letter
 Product Dossier
 Product Sample e.g. 1 x 100 tablets
 Site Master File
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
PART D:
Other Relevant Documents
and Guidelines
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
Relevant Documents and Guidelines
 Marketing Authorizations of Pharmaceutical Products with
Special Reference to Multi-source (Generic) products. A
Manual for Drug Regulatory Authority – Regulatory
support series No. 5 (WHO / DMP / RGS / 98.5)
 Quality Assurance of Pharmaceuticals. A compendium of
guidelines and related materials, Vol. 2, Good
Manufacturing Practices and Inspection, Geneva. World
Health Organization
 Guidance for Industry – Q7A Guidance for Good
Manufacturing Practices for Active Pharmaceutical
Ingredients, August 2001
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
Relevant Documents and Guidelines (cont’d)
 World Health Organization WHO Technical Report Series
No. 850 Annex 3, Guidelines for Good Clinical Trials on
Pharmaceutical Products
 World Health Organization WHO Technical Report Series
No. 902, 2002 Annex 3, Good Practices for National
Pharmaceutical Control Laboratories
 UNDP / World Bank / WHO Special Programme for
Research and Training in Tropical Diseases (TDR)
Handbook. Good Laboratory Practices (GLP)
 Pre-assessment of Product Files (new submission) multisource (generic) products, January 2007 (SOP)
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
Relevant Documents and Guidelines (cont’d)
 World Health Organization WHO Technical Report Series
No. 937, 2006, Annex 7, Multisource (generic)
pharmaceutical products: guidelines on registration
requirements to establish interchangeability
 Guidelines on Submission of Documentation for PreQualification of Multisourced generic finished product
used in the treatment of HIV / AIDS, malaria and
tuberculosis
 World Health Organization WHO Technical Report Series
No. 943, 2005, WHO Expert Committee on Specifications
for Pharmaceutical Preparations
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
Relevant Documents and Guidelines (cont’d)
 Procedure for Assessing the Acceptability, in principle, of
Active Pharmaceutical Ingredients for use in
Pharmaceutical Products (draft – under discussion)
 Pharmaceutical Development for Multisource (generic)
Pharmaceutical Products. Draft.
 Good Trade and Distribution Practices for Pharmaceutical
Ingredients. WHO Expert Committee on Specifications
for Pharmaceutical Preparations. Thirty-eight report.
Geneva, 2004. Technical Report series No. 917, Annex 2.
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
Relevant Documents and Guidelines (cont’d)
 WHO Pharmaceutical Active Ingredients Certification
Scheme (SMACS) Guideline on Implementation. In:
WHO Expert Committee on Specification for
Pharmaceutical Preparation. Thirty-eight report. WHO
2004. Technical Report Series N. 917, Annex. 3
 WHO Good Manufacturing Practices: Main Principles for
Pharmaceutical Products. In: WHO Expert Committee
on Specification of Pharmaceutical Preparations. Thirtyseventh Report. WHO 203. Technical Report Series No.
908. Annex 4
 ICH Quality Guidelines, e.g. Q1, Q6A, Q8, etc.
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
Thank you
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.
WHO Prequalification Programme of Priority Essential Medicines,
11-13 October 2010, Abu Dhabi, U.A.E.