Sultan Ghani

1. Dossier Requirements for Generic Medicines Content of Quality Dossier Sultan Ghani WHO Prequalification Programme of Priority Essential Medicines, 11-13 October 2010, Abu Dhabi, U.A.E.

2. Product Definitions • Active Pharmaceutical Ingredient (API) • A substance of compound that is intended to be used in the manufacture of a pharmaceutical product as a therapeutically active compound (ingredient) • 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 product that has undergone all stages of production, including packaging in its final container and labelling

3. Multisource (Generic) product • Multisources are pharmaceutically equivalent if • Same amount of the same API • Same dosage form • Meet the same or comparable standards • Intended to be administered by the same route

4. Quality dossier / Section 1 Information on the Finished Pharmaceutical Product (FPP) 1.1 Details of the Product - Name, dosage form and strength of the product - Approved generic name (INN) - Description of the FPP - Description of the packaging 1.2 Samples to be provided 1.3 Regulatory situation in Member countries / list countries

5. Quality dossier / Section 2Active Pharmaceutical Ingredient (API) • Scientific data on the API can be submitted in the following ways: • A valid Certificate of Suitability • An APIMF (Active Pharmaceutical Ingredient Master File) • Complete submission of data requested in Section 2

6. Quality dossier / Section 2Active Pharmaceutical Ingredient (API) 2.1 Nomenclature (INN, chemical name, CAS No.) 2.2 Properties of the API - Properties which are not described in a monograph such as solubility, polymorphs, particle size - Verification of structure by IR comparison to an official reference standard 2.3 Site(s) of manufacture - Name and address of facilities and the manufacturing authorization for production of API

7. Quality dossier / Section 2Active Pharmaceutical Ingredient (API) 2.4 Route(s) of synthesis Brief outline of manufacturing process - flow chart and description of the manufacturing of API - name of the solvents, reagents and catalysts - purification and crystalization Note: for non-pharmacopeial substance, more details are required, including impurity profile, information on reprocessing/reworking and TSE risk material

8. Quality dossier / Section 2Active Pharmaceutical Ingredient (API) 2.5 Specifications (Pharmacopeial Substance) - Copy of monograph plus any additional test - Impurities - Validation of analytical method if they are new - Existence of polymorphs - Solubility and particle size specification (if not covered in pharmacopeial monograph) Note: Batch analysis for at least two batches manufactured on each site

9. Quality dossier / Section 2Active Pharmaceutical Ingredient (API) 2.5 Specifications (Non-Pharmacopeial Substance) - Characterize all impurities, organic and inorganic, residual solvents, catalysts, etc. - Propose acceptable limits according to ICH Q3A and ICH Q3C - Appropriate analytical procedure suitable for intended use and correctly validated - Batch analysis for at least two batches manufactured - Reference standard (identity, purity and assay)

10. Quality dossier / Section 2Active Pharmaceutical Ingredient (API) 2.6 Container-closure system - Description - Identification of material and components - Specification - Justification for choice of these materials

11. Quality dossier / Section 2Active Pharmaceutical Ingredient (API) 2.7 Stability testing (a) Stress study (b) Formal stability study to establish re-test period - Three lots of API, at least two of pilot size - Parameter susceptible to change during storage - Frequency of testing (three months first year, six months second year, then annually) - Storage condition according to ICH Q1A (R2) Note: Unless otherwise justified, the long-term storage condition for pre-qualification is 30°C/65%RH

12. Quality dossier / Section 2Active Pharmaceutical Ingredient (API) 2.7 Stability testing (cont’d) (c) Data requirements - 12 months long-term ICH condition 25°C/60% RH - 12 months intermediate ICH condition 30°C/65% RH - 6 months accelerated ICH 40°C/75% RH Exception for NOT easily degradable APIs, see the list in Supplement 2 6 months long-term data at submission (either ICH condition 25°C/60% RH OR 30°C/65% RH) + 6 months accelerated ICH 40°C/75%RH A re-test period of 24 months can be accorded

13. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.1 Manufacturing and marketing authorization • Valid manufacturing authorization • Marketing authorization to demonstrate product registration 3.2 Pharmaceutical development • Build a quality product by design • Information on development studies conducted • Physico-chemical studies/compatibility studies

14. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.2 Pharmaceutical development (cont’d) • Experimental data • Justification of overage • Identification of critical processes • Optimization of manufacturing process • Comparative dissolution

15. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.3 Formulation • Tabulated form of the formula • Detail of excipients and their function 3.4 Sites of manufacture • Name and address of facility where manufacturing, processing, packaging and quality control is performed • GMP Certificate by competent DRA

16. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.5 Manufacturing process • Flow chart with indication of each step showing where material enters in the process • Indication of critical steps and in-process control • Type of equipment • If re-processing is used, justification of the data, copy of master formula, batch record • Sterilization processes for sterile products

17. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.6 Manufacturing process controls of Critical steps and intermediates • Identification of critical steps with test methods and justified acceptance criteria • Information on the quality of intermediates and test method

18. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.7 Process validation and evaluation • All aspects of operation and critical processes require to be validated (mixing, coating, granulation, etc.) • First reproduction batches require to be validated • Concurrent and retrospective validation may be accepted • Suitable validation protocol and commitment of validation report

19. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.8 Specifications for excipients • Non-pharmacopeial substances require manufacturing process, specification, stability data, clinical data for safety, and certificate of analysis • Pharmacopeial excipients, copy of pharmacopeial monograph and certificate of analysis • Animal and human origin TSC certificate

20. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.9 Control of the FPP • Two sets of specifications at release and at the end of shelf-life • Description, identification and assay • Degradation products • Dissolution/disintegration uniformity of dosage units • Identification of colour, anti-oxidants and preservatives • Microbial contamination • Use Q6A for non-pharmacopeial FPP • Batch analysis for three lots

21. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.10 Container/closure system(s) and other packaging • Discussion on choice of container • Detailed description of the container • Description of the second re-packaging

22. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.11 Stability testing • One production batch and two pilot batches manufactured according to the described process • Stability parameters such as assay, degradation products, preservative testing, dissolution testing and microbial contamination • Stability should be performed in commercial packaging (container closure system) • Storage condition according to ICH Q1A(R2)

23. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.11 Stability testing (cont’d) • Minimum stability data to be submitted at time of submission: 12 months long-term ICH 25°C/60% RH, 12 months intermediate ICH 30°C/65% RH and 6 months accelerated ICH 40°C/75% RH with exception according to Supplement 2 to the main generic guide • Unless otherwise justified, 30°C/65% RH is the recommended storage condition for prequalification • Case of products packed in semi-permeable containers foreseen (liquid dosage forms susceptible to loss of solvent or water low in low relative humidity conditions). Storage condition will be long-term ICH 25°C/40% RH and accelerated 40°C/25% RH

24. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.11 Stability testing (cont’d) • Extrapolation of data to accord a longer shelf-life possible according to ICH Q1E + Supplement 2 in condition of commitments • Supplement 2: tentative 2-year re-test period and/or shelf-life may be accorded to APIs and corresponding solid forms (tablets and capsules) listed in Supplement 2 based only on 6 months accelerated data and 6 months long-term data • Long-term stability should be followed to cover the whole shelf-life accorded

25. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.12 Container labelling (a) Outer packaging (where no outer packaging, on immediate packaging, e.g. HDPE bottle) • Labelling should include at least the following: • Name of the FPP • Method of administration • A list of APIs (using INNs if applicable) showing the amount of each present in a dosage unit, and a statement of the container, e.g. number of dosage units, weight or volume

26. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.12 Container labelling (cont’d) • List of excipients known to be a safety concern for some patients, e.g. lactose, gluten, metabisulfites, parabens, ethanol, or tartrazine • Instruction on use • Batch number assigned by manufacturer • Expiry date in uncoded form • Storage conditions or handling precautions that may be necessary

27. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.12 Container labelling (cont’d) • Directions for use and any warnings or precautions that may be necessary • Name and address of the manufacturer, company or person responsible for placing the product on the market

28. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.12 Container labelling (b) Blisters and strips should include, as a minimum, the following information • Name, strength and pharmaceutical form of the FPP • Name of the manufacturer, company or person responsible for placing the product on the market • Batch number assigned by the manufacturer • Expiry date in uncoded form

29. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.13 Product information for health professionals • Summary of product characteristics (SmPC) • Aimed at medical practitioners and health professionals • Changes to SmPC to be approved by WHO • See Annex 5 of the main generic guide

30. Quality dossier / Section 3Finished Pharmaceutical Product (FPP) 3.14 Patient information and package leaflet • Copy of the patient information leaflet (PIL) • In conformance with SmPC • See Annex 6 of the main generic guide 3.15 Justification for any differences to the product in the country or countries issuing the submitted WHO-type certificate(s)

31. Thank you