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

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. 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

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. 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

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. 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

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Quality dossier / Section 2 Active 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

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Quality dossier / Section 2 Active 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

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Quality dossier / Section 2 Active 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

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Quality dossier / Section 2 Active 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

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Quality dossier / Section 2 Active 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)

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Quality dossier / Section 2 Active Pharmaceutical Ingredient (API) 2.6 Container-closure system -Description -Identification of material and components -Specification -Justification for choice of these materials

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Quality dossier / Section 2 Active 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

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Quality dossier / Section 2 Active 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

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Quality dossier / Section 3 Finished 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

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Quality dossier / Section 3 Finished Pharmaceutical Product (FPP) 3.2 Pharmaceutical development (cont’d) Experimental data Justification of overage Identification of critical processes Optimization of manufacturing process Comparative dissolution

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Quality dossier / Section 3 Finished 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

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Quality dossier / Section 3 Finished 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

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Quality dossier / Section 3 Finished 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

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Quality dossier / Section 3 Finished 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

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Quality dossier / Section 3 Finished 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

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Quality dossier / Section 3 Finished 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

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Quality dossier / Section 3 Finished 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

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Quality dossier / Section 3 Finished 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)

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Quality dossier / Section 3 Finished 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

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Quality dossier / Section 3 Finished 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

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Quality dossier / Section 3 Finished 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

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Quality dossier / Section 3 Finished 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

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Quality dossier / Section 3 Finished 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

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Quality dossier / Section 3 Finished 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

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Quality dossier / Section 3 Finished 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

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Quality dossier / Section 3 Finished 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)

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Thank you

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E.