Sultan Ghani WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Experience of Pre-Qualification Program Overview of Common Quality Problems

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E.. Active Pharmaceutical Ingredient (API)

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E Route(s) of synthesis Detailed description of the manufacturing of API, operating conditions and materials used, typical batch size Materials used: solvents, reagents and catalysts used in the process and their specifications are not specified.

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E Route(s) of synthesis Specifications of starting key raw material and intermediates Specifications for starting key material and intermediates are either absent or not complete. When present, they include only appearance and an assay by a non specific method with no indication on related substances. Ideally, they should include as minimum key specifications: appearance, identification by a specific method, a related substances test and an assay by a performing test such as HPLC and even residual solvents (if applicable). A manufacturer may use different sources of starting key raw material. It is essential that the specifications presented take into account the quality of all sources. It is to be discussed as to whether impurities and residual solvents of the starting material from each source can or cannot be carried over into the final substance.

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E Route(s) of synthesis In-process controls, identification of critical steps and their validation are not sufficiently described.

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E Specifications (Pharmacopoeial substance) Specifications of the API (analytical procedures and associated limits) should comply with the requirements of a specific monograph + those of the general monograph (if applicable) + controls on residual solvents e.g. Ph. Eur. General monograph on substances for pharmaceutical use (2034)

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E Specifications (Pharmacopoeial substance) If the API is prepared by a different method of synthesis liable to leave impurities other than those mentioned in the monograh is not demonstrated. The suitability of the monograph to determine new impurities due to a new route of synthesis is not demonstrated Monographs of pharmacopoeia are prepared with collaboration of a certain number of manufacturers. Not all of them in the world. In case of under patent and pharmacopoeia of ICH regions, the monograph is usually prepared with only one manufacturer, usually the innovator. They do not necessarily cover all the possible impurities from new sources which may use new/exotic routes of synthesis.

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E Specifications Batch analyses for at least 2 batches manufactured on each site and from each route of synthesis should be provided. Results expressed as “conform” or “complies” are not acceptable.

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E Specifications Description on how the reference standard used in analytical procedures is prepared, how its identity, its purity and its assay have been set The above description is in general missing. It is not clear how the reference standard has been prepared and how it is characterised. In case official reference standards are available, identification and assay should be performed in comparison to that official material in order to set a working standard. In case of no official standard, the whole information on how the working standard has been prepared, characterised (identity, purity, strength) should be given in the dossier. Full structural analysis should be done on the working standard (in-house primary standard).

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E Container-closure system Identification of materials and components of the packaging is not specified (LDPE bags etc.). At least IR should be performed.

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E.. Finished Pharmaceutical Product (FPP)

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E Pharmaceutical development  Pharmaceutical development is absent or not complete.  Lack of information on physico-chemical characteristics of the API which may have an impact on the performance of the product.  Compatibility of the API with excipients and in case of FDCs compatibility between APIs are not studied or at least not shown in the dossier.  Rationale behind choice of manufacturing process, overages (if any), … not given.  Lack of comparative dissolution testing with the innovator.

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E Pharmaceutical development For solid dosage forms, it is a requirement of the Prequalification Programme to submit comparative dissolution data includng profile comparison and discussion, for the biobatch and innovator/comparator batch used in the bioequivalence. These data can be included in both part quality and bioequivalence study of the dossier. - Setting of dissolution specifications

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E Pharmaceutical development Comparative dissolution testing / conditions Apparatus (choice) Paddle, 50 (75) rpm or Basket, 100 rpm Dissolution media All three media for full comparison 1.Buffer pH 6.8 or simulated intestinal fluid without enzymes 2.Buffer pH M HCl or buffer pH 1.2 or simulated gastric fluid without enzymes Volume of media900 ml or less Temperature37°C ± 0.5°C Sampling points10, 15, 20, 30, 45, (60, 120) min. (typical) Units (individual)12 for “official” studies

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E Pharmaceutical development Comparative dissolution testing / principle Two conditions to determine if the dissolution profiles of two products/batches in a particular dissolution medium are similar 1. If both the test and reference product show more than 85% dissolution within 15 minutes, the profiles are considered to be similar No calculations are required 2. If this is not the case, apply point 2 Calculate the f2 value (similarity factor) If f2 ≥ 50, the profiles are normally regarded similar The dissolution properties of the 2 products can be regarded comparable/similar only when the profiles are similar in all 3 media.

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E Pharmaceutical development Comparative dissolution testing / principle n = number of time points R(t) = mean % API dissolved of reference product at time point x T(t) = mean % API dissolved of test product at time point x Minimum of 3 time points (zero excluded) 12 units (each in own dissolution vessel) for each product (for “official” purposes) Only one measurement should be considered after both products have reached 85 % dissolution RSD at higher time points ≤ 10%

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E Pharmaceutical development Comparative dissolution testing/ deficiencies  12 units are not used in the study  The 3 media are not tested, only results in 1 or 2 media are given.  Figured results for assay of API are not presented, they are mentioned as "complies". Therefore, the assessor cannot calculate the f2 factor. The actual results are to be provided.

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E Process Validation and Evaluation If validation data (on production scale batches) are not available submit  validation protocol and different commitment should be submitted. The validation data /protocol and commitments are not submitted. If several manufacturing sites are claimed, this requirements apply to all of them.

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E Control of the FPP  Validation of analytical methods and/or demonstration of applicability for pharmacopoeial methods  The FPP is pharmacopoeial, the pharmacopoeial method is used but a minimum validation is not performed. The pharmacopoeial monograph cannot cover all the formulations for a FPP. As a minimum, the selectivity of the pharmacopoeial method towards a specific formulation should be demonstrated.

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E Stability testing  Lots included in the study: 1 production batch and 2 of pilot scale manufactured OR 3 pilot batches according to the process described in the dossier  Pilot scale batch for solid dosage forms is 10% of production scale or whichever is greater For new manufacturers, batches included in the stability study are not of sufficient size

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E Stability testing Specifications: widening of the acceptance criteria at the end of shelf-life is possible for some parameters with justification and unacceptable for some others, e.g. Limit for degradation products are widened in comparison to release but no justification on the acceptability of new limits is given. Dissolution testing cannot be widened as the specification at release has been set in relation to the dissolution characteristics of the biobatch for which the bioequivalence with the innovator has been established

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E Stability testing Compatibility testing is not provided For products which should be diluted or reconstituted according to their SPC, in-use stability testing is to be provided over the period of time which is considered as in-use shelf-life.

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E Stability testing 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 where 6 months accelerated and 6 months long term data may be sufficient at submission Even for stable APIs and related FPPs, the length of data presented are often too short (eg 3 months) to accord a re-test period and a shelf-life.

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E Stability testing Storage conditions for the study Unless otherwise justified, 30°C / 65% RH is the recommended storage condition for Prequalification The long term storage condition applied for the study is 25°C/ 60% RH without any justification. This condition cannot be accepted where batches of product are manufactured, stored and marketed in different climatic zones such as IVa and IVb.

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E Stability testing Definition of "significant change" same as ICH Q1A (R2) –A 5% change in assay of the API from its initial value; or failure to meet the acceptance criteria for potency when using biological or immunological procedures. –Any degradation product exceeding its acceptance criterion –Failure to meet the acceptance criteria for appearance, physical attributes, and functionality test (e.g., color, phase separation, hardness). And, as appropriate for the dosage form –Failure to meet the acceptance criterion for pH; or –Failure to meet the acceptance criteria for dissolution for 12 dosage units Case of aqueous based FPP packed in semi-permeable packaging – 5% water loss is a significant change

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E Stability testing Pitfall The assay of the API is still within the limits but the change during stability is more than 5.0% Example – Release limit assay for API: 95.0 – 105.0% – Stability assay limit of API is widened: 92.5 – 105.0% – Release assay result for a batch: 101.0% (within spec) – 24- month assay result for the same batch: 93% (within spec) BUT – Loss in potency: 8.0% This is a significant change

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E Stability testing  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 Most of the time, lack of commitment to continue the study and to communicate any OoS results  Long term stability should anyhow be followed to cover the whole shelf-life accorded After having being accorded a re-test period and a shelf-life, the study is often not continued. The study should be continued until the end of re-test period or the end of shelf-life.

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. THANK YOU FOR YOUR ATTENTION