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Preparation of WHO Dossier Preparation of WHO Dossier Prequalification for a National Prequalification for a National

CompanyCompany

“Pharmaceutical Industry in 21st century: Challenges and Threats”

3rd May, 2012. PCSIR Lahore, Pakistan. Lahore, Pakistan.

Presented By:Presented By:SYED NAEEM RAZZAQSYED NAEEM RAZZAQ

RESEARCH AND DEVELOPMENT MANAGERRESEARCH AND DEVELOPMENT MANAGERSCHAZOO ZAKA Pvt. LtdSCHAZOO ZAKA Pvt. Ltd..

Lahore, PakistanLahore, Pakistan

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Three Groups of Medicines1. HIV / AIDS.1. HIV / AIDS.2. Tuberculosis.2. Tuberculosis.3. Malaria.3. Malaria.AdvantagesFree of cost, no Auditor or evaluation fee, WHO cGMP acceptable in Free of cost, no Auditor or evaluation fee, WHO cGMP acceptable in

more than 150 countries around the worldmore than 150 countries around the worldAccess to new markets

Websites:Site Master File: h

ttp://healthtech.who.int/pq/info_applicants/info_for_applicants_sitemasterfile.htm

Dossier Annexes: http://mednet3.who.int/prequal/info_applicants/guidelines

WHO PrequalificationWHO Prequalification

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Site Master FileDetails of the Manufacturing Facility

Product Dossier (Common Technical Document CTD)Details of the Product Dossier on CTD Format

Product SamplesRepresentative Product Samples for Testing

Expression of Interest Voluntary Participation for Prequalification Procedure

Submission RequirementsSubmission Requirements

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1. General InformationName, Address, Licensed activities, Employees, Quality Management system etc. of manufacturing facility.

2. Personnel'sOrganization Chart, Key Personnel, Training, Health requirement etc.

3. Premises and EquipmentsPlan of Facility, Nature of Construction / Finishes, HVAC, Water Systems, Preventive Maintenance of Premises & Equipments, Type of Equipments, Validations, Qualifications, Calibrations and Cleaning etc.

4. DocumentationPreparation, Revision & Distribution of Necessary Documentation

5. ProductionProduction Operation Procedure in Flow Charts, Sampling, Quarantine, Storage and Release of Materials, Rejected Material Handling, Process Validations etc.

Site Master FileSite Master File

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6. Quality ControlQuality Control System and Activities

7. Contract Manufacture and AnalysisGMP Compliance of Contract acceptor

8. Distribution, Complaints and Product RecallsDistribution System, Complaint and Recall Procedures

9. Self InspectionDescription of Self Inspection System (Internal cGMP Audits etc.)

Photographs and Video CD can also be added to Site Master File

Site Master File Site Master File Cont….Cont….

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Product Dossier (CTD Format)Product Dossier (CTD Format)

Module1. Administrative and Prescribing Information

Module 2. CTD Summaries

Module 3. Quality

Module 4. Non Clinical Study Reports (NA for multisource

products)

Module 5. Clinical Study Reports (BE Studies)

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Module1. Administrative and Module1. Administrative and Prescribing InformationPrescribing Information

1. Cover Letter

2. Application Information

2.1 Copy of Expression of Interest

2.2 Manufacturing and Marketing Authorization (s)/Information

Registration Status and /or the WHO Certificate of Pharmaceutical

Product (CPP).

2.3 Copy of Certificate(s) of Suitability of the European Pharmacopoeia

(CEP)

2.4 Letters of Access for APIMFs

2.5 Good Manufacturing Practices (GMP) Information

2.6 Biowaiver Requests in Relation to Conducting a Comparative

Bioavailability Study

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Module1. Administrative and Module1. Administrative and Prescribing InformationPrescribing Information Cont….Cont….

3. Product Information

3.1 Summary of Product Characteristics (SmPC)

3.2 Labelling (outer and inner labels)

3.3 Package Leaflet (patient information leaflet PIL)

4. Regional Summaries

4.1 Bioequivalence (BE) Trial Information (BTIF)

4.2 Quality Information Summary (QIS)

5. Electronic Review Documents (e.g., Product Information,

BTIF, QIS, QOS-PD)

6. Samples (e.g., FPP, device (s), Certificate of Analysis)

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Module 2. CTD SummariesModule 2. CTD Summaries

1.1. A General Introduction to the Pharmaceuticals, Including A General Introduction to the Pharmaceuticals, Including

its Pharmacological Class, Mode of Action and its Pharmacological Class, Mode of Action and

Proposed Clinical Use.Proposed Clinical Use.

2.2. Summary of Product Quality Information i.e., Quality Summary of Product Quality Information i.e., Quality

Overall Summary-Product Dossier (QOS-PD) Template. Overall Summary-Product Dossier (QOS-PD) Template.

(Details Described in ICH M4Q)(Details Described in ICH M4Q)

3.3. Summary of Product Efficacy Information. Detail Summary of Product Efficacy Information. Detail

Described in ICH M4E.Described in ICH M4E.

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Module 3. QualityModule 3. Quality3.2 S Drug Substance

1. General Information

(Name, Manufacturer, Nomenclature, Structure and General Properties etc.)

2. Manufacturer

(Name, Description of Manufacturing Process and Process Control, Control of Materials, Control of Critical Steps and Intermediates, Process Validation and/or Evaluation, Manufacturing Process Development etc.)

3. Characterization

(Elucidation of Structure and other Characteristics, Impurities etc.)

4. Control of Drug Substance

(Specifications, Analytical Procedures, Validation of Analytical Procedures, Batch Analysis, Justification of Specifications etc.)

5. Reference Standards or Materials

6. Container Closure System

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Module 3. Quality cont.

7. Stability (Stability Summary and Conclusion, Post-approval Stability Protocol

and Stability Commitment, Stability Data etc.)3.2 P Drug Product1. Description and Composition of the Drug Product2. Pharmaceutical Development (Components of Drug Product e.g., Drug Substance and Excipients,

Drug Product e.g., Formulation Development, Overage, Physicochemical and Biological Properties, Manufacturing Process Development, Container Closure System, Microbiological Attributes, Compatibility etc.)

3. Manufacturer (Name, Batch Formula, Description of Manufacturing Process and

Process Control, Control of Critical Steps and Intermediates, Process Validation and/or Evaluation etc.)

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Module 3. Quality cont.

4. Control of Excipients (Specifications, Analytical Procedures, Validation of Analytical

Procedure, Justification of Specifications, Excipients of Human or Animal Origin, Novel Excipients etc.)

5. Control of Drug Product (Specifications, Analytical Procedures, Validation of Analytical

Procedure, Batch Analysis, Characterization of Impurities Justification of Specifications etc.)

6. Reference Standards or Materials7. Container Closure System8. Stability (Stability Summary and Conclusion, Post approval Stability

Protocol and Stability Commitment, Stability Data etc.)

* Details of module 3 are described in ICH M4QDetails of module 3 are described in ICH M4Q

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Module 5. Clinical Study Reports Module 5. Clinical Study Reports Bioequivalence Trial Inform. (WHO Annex 7) Bioequivalence Trial Inform. (WHO Annex 7)

Component and quality standard Function

Strength (label claim)

XX mg XX mg

Quantity per unit % Quantity per unit %

2. Clinical Study Report

3. Ethics

4. Investigators and Study Administrative Structure

5. Study Objectives

6. Overall Study Design and Plan – Description

7. Selection of Study Population

8. Inclusion Criteria / Exclusion Criteria

9. Removal of Subjects From Trial

10. Number of Subjects Enrolled in the Study / Withdrawals / Health Verification

11. List Criteria Used and All Tests Performed in Order to Judge Health Status

Summary of Bioavailability/Bioequivalence Studies Performed

1. Tabulation of the Composition of the Formulation Proposed for Marketing andThose Used for Bioequivalence Studies.

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Module 5. Clinical Study Reports Module 5. Clinical Study Reports Bioequivalence Trial Inform. (WHO Annex 7) Bioequivalence Trial Inform. (WHO Annex 7)

1212. Indicate when Tests were Performed.. Indicate when Tests were Performed.

13.13. Study Site Normal Values.Study Site Normal Values.

14.14. Report any Results That were Outside Normal Values.Report any Results That were Outside Normal Values.

15.15. Products Administered.Products Administered.

16.16. Test Product.Test Product.

17.17. Batch Number, Size and Date of Manufacture for the Test Product.Batch Number, Size and Date of Manufacture for the Test Product.

18.18. Reference Product.Reference Product.

19.19. Name and Manufacturer of the Reference Product.Name and Manufacturer of the Reference Product.

20.20. Batch Number and Expiry Date for the Reference Product.Batch Number and Expiry Date for the Reference Product.

21.21. Justification of Choice of Reference Product.Justification of Choice of Reference Product.

22.22. Selection of Doses in the Study.Selection of Doses in the Study.

23.23. State Dose Administered.State Dose Administered.

24.24. Blinding.Blinding.

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25.25.Drug Concentration Measurements.Drug Concentration Measurements.

26.26. Biological Fluid Sampled.Biological Fluid Sampled.

27.27. Sampling Protocol.Sampling Protocol.

28.28. Sample HandlingSample Handling

29.29. Trial SubjectsTrial Subjects

30.30. Protocol DeviationsProtocol Deviations

31.31. Safety EvaluationSafety Evaluation

32.32. Efficacy Evaluation.Efficacy Evaluation.

33.33. Discussion of ResultsDiscussion of Results

34.34. Analytical Study Report.Analytical Study Report.

35.35. Bioanalytical Method Validation Report.Bioanalytical Method Validation Report.

36.36. Quality Assurance.Quality Assurance.

Module 5. Clinical Study Reports Module 5. Clinical Study Reports Bioequivalence Trial Inform. (WHO Annex 7) Bioequivalence Trial Inform. (WHO Annex 7)

Major Issues Regarding PQPMajor Issues Regarding PQP1.1. Data Arrangement From API Supplier i.e. Drug Master File Data Arrangement From API Supplier i.e. Drug Master File

(DMF), API Stability data etc.(DMF), API Stability data etc.

2.2. Arrangement of WHO Approved Comparator Products Arrangement of WHO Approved Comparator Products (Reference Products) from ICH Countries for In-Vivo (Reference Products) from ICH Countries for In-Vivo BA/BE Studies.BA/BE Studies.

3.3. High Cost of In-Vivo BA/BE Studies. High Cost of In-Vivo BA/BE Studies.

4.4. Arrangement of Reference Standards of Impurities and Arrangement of Reference Standards of Impurities and Degradation ProductsDegradation Products. .

5.5. Complete Analytical Method Validations of even USP, EP and Complete Analytical Method Validations of even USP, EP and IP Official Monographs (Both API, FPP) for Assay, IP Official Monographs (Both API, FPP) for Assay, Dissolution and Related Substances. Dissolution and Related Substances.

6.6. FPP and API specifications should include tests from USP, IP FPP and API specifications should include tests from USP, IP and EP besides particle size and bulk density.and EP besides particle size and bulk density. 1717

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1. WHO Prequalification Procedure is free of cost of applying and cost of auditor.

2. It Covers all Aspects of International cGMPs Including FDA, UK, Canada, Europe and Japan.

3. Details of Submission Procedure and Guidelines of Submission are Available on Website.

4. Compliance Assists in Local Regulatory Inspections

5. Acceptance Opens Export Opportunity to the Whole World.

ConclusionConclusion

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Thank YouThank You