1. Slide 1 WHO Prequalification Programme: Training workshop March 2010, Beijing Requirements on documentation of API and FPP quality and evaluation process Presenter: Hua YIN Prequalification of Medicines Programme QSM / EMP / HSS

2. Slide 2 WHO Prequalification Programme: Training workshop March 2010, Beijing Glossary APIActive Pharmaceutical Ingredient APIMFActive Pharmaceutical Ingredient Master File ARVAntiretroviral CoSCertificate of Suitability EDQMEuropean Directorate for Quality of Medicines and HealthCare EoIExpression of Interest FPPFinished Pharmaceutical Product GMPGood Manufacturing Practices ICHInternational Conference on Harmonization Int. Ph. International Pharmacopoeia PILPatient Information Leaflet PQPrequalification PQIFPharmaceutical Quality Information form RHReproductive Health SPC Summary of Product Characteristics TBTuberculosis

3. Slide 3 WHO Prequalification Programme: Training workshop March 2010, Beijing WHO Reference text for Multisource (Generic) products / Definitions Active Pharmaceutical Ingredient (API) A substance or 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.

4. Slide 4 WHO Prequalification Programme: Training workshop March 2010, Beijing Guidelines for Product dossier /Quality Main Generic guide Guideline on Submission of Documentation for Prequalification of Multisource (Generic) Finished Pharmaceutical Products (FPPs) Used in the Treatment of HIV/AIDS, Malaria and Tuberculosis [under revision] Annex 1Annex 1 - Model Certificate of a Pharmaceutical Product Annex 2Annex 2 - Model Batch Certificate of Pharmaceutical Product Annex 3Annex 3 - Model Stability Report of Active Pharmaceutical Ingredient (API) Annex 4Annex 4 - Model Stability Report of Capsules/Tablets Annex 5Annex 5 - Suggested Structure of the Summary of Product Characteristics (SmPC) Annex 6Annex 6 - Suggested Structure of the Package Information Leaflet (PIL) Annex 7Annex 7 - Presentation of Bioequivalence Trial Information (BTIF) Annex 8Annex 8 - Presentation of Pharmaceutical Quality Information (PQIF) Supplement 1 : Dissolution testing Supplement 2 : Extension of the WHO list of stable APIs (not easily degradable)

5. Slide 5 WHO Prequalification Programme: Training workshop March 2010, Beijing Guidelines for Product dossier /Quality Guidelines for registration of fixed-dose combination medicinal products Guideline on Active Pharmaceutical Ingredient Master File (APIMF) Procedure Guidance on variations to a prequalified dossier Guide on Submission of Documentation for Prequalification of innovator Finished Pharmaceutical Products (FPPs) used in the treatment of HIV/AIDS, malaria and tuberculosis and approved by Drug Regulatory Authorities (DRAs) in the International Conference on Harmonization (ICH) region and associated countries, including among others the EU, Japan and USA Prequalification of Generic products approved by Stringent Regulatory Authorities (SRAs) NEW Requalification NEW Alternative procedure for accepting 2nd line TB Product dossiers New http://www.who.int/prequalhttp://www.who.int/prequal Chinese version available

6. Slide 6 WHO Prequalification Programme: Training workshop March 2010, Beijing Guidelines for Product dossier /Quality ICH notes for guidance (When WHO or PQ guidelines silent) for instance: –Q2(R1): Validation of Analytical Procedures –Q3A(R2). Impurities in new drug substances –Q3B(R2). Impurities in new drug products –Q3C(R3). Impurities: Guideline for residual solvents –Q6A. Specifications: Other agencies' requirements can be referenced. such as EU limits of genotoxic impurities, permitted colorants, EDQM limit of TEA 320ppm.

7. Slide 7 WHO Prequalification Programme: Training workshop March 2010, Beijing Assessment Process - Quality Submission of application PQIF, Dossier Screening (Internal) Acceptance for evaluation PQ reference No. Pre – Assessment Assessment Additional data Prequalification Requalification

8. Slide 8 WHO Prequalification Programme: Training workshop March 2010, Beijing Documentation to be submitted to the WHO PQ team -Covering letter Clearly indicate the information submitted is true and correct - Product dossier. Section 1: Characteristics of the FPP. Section 2: Active Pharmaceutical Ingredients (APIs) When more than one API used, use separate Section 2. Section 3: Finished Pharmaceutical Products (FPPs). Section 4: Interchangeability -PQIF: =Quality overall summary. filled out in WinWord format, See mock-up PQIF on www.who.int/prequal/ under training material and workshops, Hanoi, Vietnam, January 2006www.who.int/prequal/ -Sample

9. Slide 9 WHO Prequalification Programme: Training workshop March 2010, Beijing Quality dossier/ Section 1 Information on the FPP 1.1. Details of the Product - Name, dosage form and strength of the product - Approved generic name (INN) - Visual description of the FPP - Visual description of the packaging 1.2. Samples to be provided (for visual examination of assessors and comparison with the SPC and PIL) 1.3. Regulatory situation in Member States / list countries - Countries where a MA has been issued - Countries where a MA has been withdrawn - Countries where a Marketing Application has been rejected, deferred

10. Slide 10 WHO Prequalification Programme: Training workshop March 2010, Beijing Quality dossier / Section 2 Active Pharmaceutical Ingredient (API)

11. Slide 11 WHO Prequalification Programme: Training workshop March 2010, Beijing Quality dossier / Section 2 Active Pharmaceutical Ingredient (API) Scientific data on the API can be submitted using following ways and order of preference A valid Certificate of Suitability (CoS) or CEP, latest version, with all its annexes issued by EDQM, www.edqm.eu www.edqm.eu An APIMF (Active Pharmaceutical Ingredient Master File) ， submitted by the API manufacturer, containing the whole information requested in section 2 and presented in CTD format (see APIMF guideline) Complete submission of data requested in Section 2

12. Slide 12 WHO Prequalification Programme: Training workshop March 2010, Beijing Quality dossier / Section 2 Active Pharmaceutical Ingredient (API) 2.1.Nomenclature 2.2.Properties of the API 2.3.Site(s) of manufacture 2.4.Route(s) of synthesis 2.5.Specifications 2.6.Container- closure system 2.7.Stability testing

13. Slide 13 WHO Prequalification Programme: Training workshop March 2010, Beijing Quality dossier / Section 2 Active Pharmaceutical Ingredient (API) PQIF section 2CTD 2.1 Nomenclature 2.2 Properties of API (s) - General Properties pharmacopoieal -Eluciation of structure non-pharmacopieal S.1 General Information - Nomenclature - Structure - General Properties 2.3 Site(s) of Manufacture 2.4 Route(s) of synthesis - manufacturing process -Impurities S.2 Manufacture - Manufacturer - Description of manufacturing process - Control of materials - Control of critical steps and intermediates - Process validation - Manufacturing process development S.3 Characterisation - Elucidation of structure - Impurities 2.5 SpecificationsS.4 Control of Drug Substance S.5 Reference Standards or Materials 2.6 Container Closure System 2.7 Stability testing S.6 Container Closure System S.7 Stability testing

14. Slide 14 WHO Prequalification Programme: Training workshop March 2010, Beijing Quality dossier / Section 2 Active Pharmaceutical Ingredient (API) Generic Guideline is under revision. The PQIF format to be consistent with the CTD format Focus on CTD format S.1 General Information S.2 Manufacture S.3 Characterisation S.4 Control of Drug Substance S.5 Reference Standards or Materials S.6 Container Closure System S.7 Stability testing

15. Slide 15 WHO Prequalification Programme: Training workshop March 2010, Beijing S.1 General Information S.1.1 Nomenclature International non-proprietary name (INN), chemical name, Chemical abstarct service (CAS) No., other names such as BAN, USAN… S.1.2 Structure –Chemical structure, sterochemistry, molecular formula and relatively molecular mass

16. Slide 16 WHO Prequalification Programme: Training workshop March 2010, Beijing S.1 General Information S.1.3 General properties –Physical description –Solubility in water (effect of pH), and organic solvents –Solid state/crystallography (eg polymorphism, including solvation/hydration, amorphous character) –Hygroscopicity –Particle size, etc Such information which relevant to formulating, processing and performance of the FPP

17. Slide 17 WHO Prequalification Programme: Training workshop March 2010, Beijing S.2 Manufacture Information on the manufacturer A flow diagram of the process A description of the manufacturing process (including, for example, starting materials, reagents, solvents, catalysts ， critical steps, and reprocessing) and the controls intended to result in the routine and consistent production of API. A description of the Source and Starting Material and raw materials used in the manufacture of the API; When the synthetic route consists limited number of steps (e.g. One to three), information of starting material should be provided (e.g route of synthesis/specification)

18. Slide 18 WHO Prequalification Programme: Training workshop March 2010, Beijing S.2 Manufacture A discussion of the selection and justification of critical manufacturing steps, process controls, and acceptance criteria. Discuss critical process intermediates; A description of process validation and/or evaluation. A brief summary of major manufacturing changes made throughout development and conclusions from the assessment used to evaluate product consistency. The QOS should cross-refer to the non-clinical and clinical studies that used batches affected by these manufacturing changes.

19. Slide 19 WHO Prequalification Programme: Training workshop March 2010, Beijing 2.3.S.3 Characterisation A summary of the interpretation of evidence of structure and isomerism. For API described in a pharmacopoeia Confirm the structure by comparison with an official Reference Standard using a specific method e.g. IR

20. Slide 20 WHO Prequalification Programme: Training workshop March 2010, Beijing S.3 Characterisation 3.2 Impurities Identification of potential and actual impurities arising from synthesis, manufacture and/or degradation, with an indication of their origin:  Impruities contained in the starting material  Starting material unreacted  Intermediates unreacted  By-products (unwanted reaction products)  Degradants  Reagents,Catalysts,Residual solvents Summary of the levels of the actual impurities detected in the batch samples (e.g. non clinical, clinical, toxicological studies, stability) Justification for selecting the limits, based on safety and toxicity data when applicable. ICH Q3A

21. Slide 21 WHO Prequalification Programme: Training workshop March 2010, Beijing S.4 Control of Drug Substance A summary of the specification, analytical procedures and validation of the methods should be included. For Pharmacopoeial API The current monograph always applicable Additional critical specifications not included in monograph e.g. –particle size & polymorphic form –impurities, resulting from specific synthesis process –residual solvents (specific to process) Analytical procedures should be verified under actual condition of use, such as specificity, precision, and stability of the sample solution

22. Slide 22 WHO Prequalification Programme: Training workshop March 2010, Beijing S.5 Reference Standards or Materials For pharmacopoeial APIs: use an official Reference Standard (USP, Ph. Eur., Int. Ph.) as primary standard For non-pharmacopoeial APIs Description of how primary and/or a working standard has been established Provide Certificate of Analyses, including storage instuctions and duration of use

23. Slide 23 WHO Prequalification Programme: Training workshop March 2010, Beijing S.6 Container closure system Description of the packaging Identification of materials and components of the packaging Specifications of these materials Justification for choice of these materials, e.g. - protection against light, humidity - compatibility of the used materials with the API, interactions between the API and the closure such as sorption, leaching (mainly in case of a liquid API)

24. Slide 24 WHO Prequalification Programme: Training workshop March 2010, Beijing S.7 Stability Stress study –to know different degradation pathways of an API and degradation products formed –to demonstrate the intrinsic stability of the API –To demonstrate the stability indicating power of the analytical procedure used Reference can be done to the literature, if the above information is there available

25. Slide 25 WHO Prequalification Programme: Training workshop March 2010, Beijing S.7 Stability Formal stability study – To establish a re-test period – To determine the storage / labelling statement Definition of the re-test period Period of time during which the API is expected to remain within its specifications and can be used in the manufacture of a given product (without control prior to manufacture of Drug Product) in condition that the API has been stored under defined storage conditions

26. Slide 26 WHO Prequalification Programme: Training workshop March 2010, Beijing S.7 Stability A summary of the studies undertaken –conditions, –batches, –packaging –Stability-indicating quality parameters –analytical procedures) A brief discussion of the results and conclusions The proposed storage conditions, retest date or shelf life. The post-approval stability protocol should be included

27. Slide 27 WHO Prequalification Programme: Training workshop March 2010, Beijing Quality dossier / Section 3 Finished Pharmaceutical Product (FPP)

28. Slide 28 WHO Prequalification Programme: Training workshop March 2010, Beijing Quality dossier / Section 3 Finished Pharmaceutical Product (FPP) 3.1.Manufacturing and marketing authorization 3.2.Pharmaceutical development 3.3.Formulation 3.4.Sites of manufacture 3.5.Manufacturing process 3.6. Manufacturing process controls of Critical steps and intermediates 3.7.Process validation and Evaluation 3.8. Specifications for excipients 3.9. Control of the FPP 3.10. Container/closure system (s) and other packaging 3.11. Stability testing

29. Slide 29 WHO Prequalification Programme: Training workshop March 2010, Beijing Quality dossier / Section 3 Finished Pharmaceutical Product (FPP) 3.12. Container labelling 3.13.Product information for health professionals (SmPC) 3.14.Patient information and package leaflet 3.15.Justification for any differences to the product in the country OR countries issuing the submitted WHO-type certificate(s) Same as CTD, only different in numbering. Product information listed at the end which are included in CTD module 1.

30. Slide 30 WHO Prequalification Programme: Training workshop March 2010, Beijing Quality dossier / Section 3 Finished Pharmaceutical Product (FPP) 3.1. Manufacturing and Marketing Authorization -Valid manufacturing authorization for pharmaceutical production including the pharmaceutical form applied for -Marketing authorization to demonstrate the product is registered / licensed in accordance with national requirements

31. Slide 31 WHO Prequalification Programme: Training workshop March 2010, Beijing 3.2. Pharmaceutical development The aim is to build a quality product by design. Empirical (minimal)- essential product development for all products Enhanced- Quality by Design Critical understanding of product and process Regulatory relief

32. Slide 32 WHO Prequalification Programme: Training workshop March 2010, Beijing 3.2. Pharmaceutical development Empirical product development –Select the product profile (FPP) based on S&E and quality –Investigate quality attributes of the formulation components such as API, excipients etc. –Establish critical quality attributes –Determine an appropriate manufacturing process and scale up (process optimization) –the container closure system –microbiological attributes –Documentation Develop a formulation similar to the innovator product. Reduce risk pertaining to compatibility, manufacturability, stability and bioavailability

33. Slide 33 WHO Prequalification Programme: Training workshop March 2010, Beijing 3.2. Pharmaceutical development 1.Physico-chemical characteristics of the APIs –solubility (composition) –water content (stability) –hygroscopicity (stability) –particle size (solubility, bioavailability, suspension properties, stability …) –polymorphism (solubility, bioavailability, stability) Data obtained from literature : Books, Journals, International Pharmaceutical Abstracts, Chemical Abstracts, Analytical Abstracts, Internet …… Experimental data (if necessary)

34. Slide 34 WHO Prequalification Programme: Training workshop March 2010, Beijing 3.2. Pharmaceutical development 2.For fixed-dose combination (FDC) products  Compatibility of APIs with each other  WHO Guidelines for registration of fixed-dose combination medicinal products  WHO TRS 929 (on WHO Prequalification website) 3.Choice of excipients, e.g.  Compatibility with API(s)  Intended functions and concentrations in product  Characteristics (flowability, density, water content, etc)  Safety aspects, e.g. TSE risk, to be addressed

35. Slide 35 WHO Prequalification Programme: Training workshop March 2010, Beijing 3.2. Pharmaceutical development 4.Selection, optimisation of manufacturing process  Rational behind the choice (e.g. why a non over kill process as a sterilisation process instead of terminal sterilisation in final container)  Critical steps & In process controls  Overages (justification)  Unsatisfactory processes to be rectified

36. Slide 36 WHO Prequalification Programme: Training workshop March 2010, Beijing 3.2. Pharmaceutical development 5.Comparative dissolution testing –See Supplement 1  A tool in selection of the formulation and optimisation of the process –compare formulation(s) with innovator product –a basic strategy in development to maximize the chances of bioequivalence  Comparison of pivotal batches to commercial batches  post-approval changes  Setting of dissolution specifications- a discriminatory dissolution method

37. Slide 37 WHO Prequalification Programme: Training workshop March 2010, Beijing 3.2. Pharmaceutical development comparative dissolution testing (cont’d) 1.Three media - 900 ml or less - all at 37°C –Buffer pH 1.2 or 0.1M HCl –Buffer pH 4.5 –Buffer pH 6.8  Water may be used additionally (not instead of) 2.Paddle at 50 or basket at 100 rpm 3.Twelve units of each product in all 3 media 4.Dissolution samples collected at short intervals, e.g. –10, 15, 20, 30, 45 and 60 minutes –Analyse samples for all APIs, when applicable 5.Calculate similarity factor f2

38. Slide 38 WHO Prequalification Programme: Training workshop March 2010, Beijing 3.2. Pharmaceutical development 6. Details of batches studied Provide a summary of development of the FPP from pre- formulation to production scale. Provide a comparison of formulas (tabulated form) of: – bio-batche(s) (clinical / bioequivalence), – development batches, – stability batches, – batches for validation/production

39. Slide 39 WHO Prequalification Programme: Training workshop March 2010, Beijing 3.3. Formulation Formula in tabulated form for : – Administration unit (e.g. one tablet), – Typical batch - Precise any overage, - Precise quantity adjustment of the API, - Precise q.s. for excipient. Excipients : – State function (e.g. lubricant, disintegrant), – Precise technical grade (e.g. micronised, purified water), – describe also those removed during process (e.g. water), – Describe also those not always added (e.g. acid & alkali for pH adjustment, – Capsule shells, inked imprints on dosage form, – Also gas (inert atmosphere).

40. Slide 40 WHO Prequalification Programme: Training workshop March 2010, Beijing 3.4. Manufacturing sites Name and street address of each facility where any aspect of manufacture occurs including production, sterilisation, packaging and quality control. Indicate the Unit, block if any. Include any alternative manufacturers Certificate issued by the Competent DRA according to WHO Certification scheme for each site where a major step of manufacturing is performed Submit a valid GMP certificate

41. Slide 41 WHO Prequalification Programme: Training workshop March 2010, Beijing 3.5. Manufacturing process A flow diagram giving the steps of the process and where materials enter the process. The critical steps and points at which process controls, intermediate tests or final product controls are conducted should be identified. Description of manufacturing/packaging including –Steps of the process –Scale of production –Equipment by type (e.g. tumble blender) & working capacity –Process parameters for steps, (e.g. time, temperature, pH) –Environmental conditions, e.g. relative humidity for hygroscopic FPPs., area class for sterile FPPs – Alternative methods

42. Slide 42 WHO Prequalification Programme: Training workshop March 2010, Beijing 3.5. Manufacturing process Proposal for reprocessing – justified with data. Copy of master formula. Batch manufacturing record – real batch (Biobatch) Sterile products – sterilisation steps and/or aseptic procedures.

43. Slide 43 WHO Prequalification Programme: Training workshop March 2010, Beijing 3.6. Manufacturing Process Controls of Critical steps and Intermediates Identification of critical steps with test methods and justified acceptance criteria Information on quality of isolated intermediates, test methods and justified acceptance criteria to control them

44. Slide 44 WHO Prequalification Programme: Training workshop March 2010, Beijing 3.7. Process Validation and Evaluation Each critical step of the manufacturing process must be validated Other steps in the process must be under control to maximize the probability that the finished product meets all quality and design specifications

45. Slide 45 WHO Prequalification Programme: Training workshop March 2010, Beijing 3.7. Process Validation and Evaluation To understand the sources of variation To detect the presence and degree of variation To understand the impact of variation on the process and ultimately on product attributes To control the variation in a manner commensurate with the risk it represents to the process and product

46. Slide 46 WHO Prequalification Programme: Training workshop March 2010, Beijing 3.7. Process Validation and Evaluation The following unit operations are generally accepted as critical for most pharmaceutical processes:  Blending operations  Encapsulation  Tablet compression  Sterilization procedures  Lyophilization

47. Slide 47 WHO Prequalification Programme: Training workshop March 2010, Beijing 3.7. Process Validation and Evaluation Validate the performance of manufacturing processes that may be responsible for causing variability in the product: Mixing homogeneity Tablet/capsule weight variation Disintegration time Dissolution rate and time pH of aqueous solutions

48. Slide 48 WHO Prequalification Programme: Training workshop March 2010, Beijing 3.7. Process Validation and Evaluation New Generic FPPs Information form product development studies and primary batches should be used in designing the validation protocol Differences in design, operating principles, size, etc. between pilot and production batches should be highlighted Protocol should be linked to the lot of FPP used in bioequivalency studies Comparative dissolution profiles of process validation batches against dissolution profile of the bio lot should be provided Commitment to undertake validation of three consecutive batches should be provided

49. Slide 49 WHO Prequalification Programme: Training workshop March 2010, Beijing 3.7. Process Validation and Evaluation Validation protocol should include  brief description of the process with summary of critical steps and parameters to be followed during validation,  specifications of the FPP at release, details of analytical methods.  In-process controls with acceptance criteria (cross reference)  Additional testing intended to be carried out  sampling plan,  unifromity of dosage units is essential for FDCs,  proposed timeframe Validation report when submitted should include results for each batch, certificates of analysis, batch production records, report on unusual findings, modifications, observations and conclusions

50. Slide 50 WHO Prequalification Programme: Training workshop March 2010, Beijing 3.7. Process Validation and Evaluation Established FPPs Details of the batches manufactured in the last several years, 10- 25 consecutive batches Formulation and description of method of manufacture, including in-process control test Specification and test methods Changes to formulation or process, if any, or compliance problems Comprehensive report using retrospective validation

51. Slide 51 WHO Prequalification Programme: Training workshop March 2010, Beijing 3.8. Specifications for excipients -Pharmacopoeial excipients Copy of the pharmacopoeial monograph used for control + certificates of analysis - Non pharmacopoeial substances –Details for manufacturing process, –Characterisation –Controls –Safety (non-clinical, clinical data ) –Certificates of analyses - For excipients of animal, human, microbial origin - TSE (Transmissible Spongiform Encephalopathy) risks and viral safety should be addressed - TSE CEP preferred Permitted colorants are those allowed in UE, USA and Japan

52. Slide 52 WHO Prequalification Programme: Training workshop March 2010, Beijing 3.9. Control of the FPP 2 sets of specifications are possible: at release and at shelf-life (list of attributes non exhaustive) Description of the FPP /appearance Identification of API Assay of API: ± 5% of the label claim at release and ±10% at the end of shelf- life Degradation products Pharmaceutical tests e.g. dissolution, disintegration (where applicable) Uniformity of dosage units (mass or content) Identification of colorants, identification and assay of anti-oxidants, chemical preservatives Microbial contamination, Sterility, bacterial endotoxins

53. Slide 53 WHO Prequalification Programme: Training workshop March 2010, Beijing 3.9. Control of the FPP  Monographs of Ph. Int., USP, BP are acceptable for the FPP + complementary tests  If non-pharmacopoeial FPP, note for guidance ICHQ6A applicable  Justification  Description of all analytical procedures in details if not described in a pharmacopoeial monograph  Validation of analytical methods and/or demonstration of applicability for pharmacopoeial methods  Batch analyses for 3 lots with details of each lot (batch no, size, date of manufacture, use of batch)

54. Slide 54 WHO Prequalification Programme: Training workshop March 2010, Beijing 3.10. Container-closure system  Discussion on the choice of container –Choice of the material –Protection against light and humidity –compatibility/interaction of materials in contact with dosage form –Safety of materials used  Detailed description of the container –Specifications of the container with dimensions and drawings –Specifications of materials in contact with FPP –Identification of components e.g. IR for plastic materials  Description of the secondary packaging

55. Slide 55 WHO Prequalification Programme: Training workshop March 2010, Beijing 3.11. Stability testing The purpose of stability testing is to provide evidence on how the quality of a FPP varies with time under the influence of a variety of environmental conditions such as temperature, humidity and light, to -establish a shelf-life for the FPP, -determine the storage conditions -determine the in-use stability. To know about length of the time and conditions where efficacy, safety and quality of the FPP are maintained

56. Slide 56 WHO Prequalification Programme: Training workshop March 2010, Beijing 3.11. Stability testing WHO stability Guideline in TRS 953  3 batches, at least pilot scale (10% of production scale or 100 000 whichever is greater)  (exception for 2 nd line TB products: 2 pilot batches at time of submission)  in the claimed commercial packaging (container-closure)  Storage conditions and frequency of testing according to WHO stability guideline in TRS 953  Unless otherwise justified, 30°C / 75% RH is the recommended storage condition for Prequalification

57. Slide 57 WHO Prequalification Programme: Training workshop March 2010, Beijing 3.11. Stability testing  Parameters susceptible to change over storage should be followed:. appearance. Assay. degradation products. Assay of antioxidants and chemical preservatives, check also for their efficacy. Dissolution testing (limits should remain unchanged to release). Microbial contamination, sterility, bacterial endotoxins  Minimum stability data to be submitted at time of submission:  Long term 12 months or 6 months or 3 months (as appropriate according to Supplement 2 to the Main Generic guide and exception for TB 2nd line products)  6 months intermediate 30°C/65% RH  6 months accelerated 40°C/75% RH  In-use stability data (if applicable)

58. Slide 58 WHO Prequalification Programme: Training workshop March 2010, Beijing 3.12. Container labelling Outer packaging : Where no outer packaging, on immediate packaging, e.g. HDPE bottle. Labelling should include at least the following : –The name of the FPP. –Method of administration. –A list of API(s) (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. –List of excipients known to be a safety concern for some patients, e.g. lactose, gluten, metabisulfites, parabens, ethanol, or tartrazine. –Instruction on use. –The batch number assigned by the manufacturer. –The expiry date in an uncoded form. –Storage conditions or handling precautions that may be necessary. –Directions for use, and any warnings or precautions that may be necessary. –The name and address of the manufacturer, company responsible for placing the product on the market.

59. Slide 59 WHO Prequalification Programme: Training workshop March 2010, Beijing 3.12. Container labelling Blisters and strips should include, as a minimum, the following information – Name, strength and pharmaceutical form of the FPP – Name of the manufacturer, company responsible for placing the product on the market – The batch number assigned by the manufacturer – The expiry date in an un-coded form

60. Slide 60 WHO Prequalification Programme: Training workshop March 2010, Beijing 3.13. Product information Summary of product characteristics (SmPC)- for Health Professionals – Aimed at medical practitioners and health professionals – Changes to SmPC to be approved by WHO patient information leaflet (PIL) – In conformance with SmPC http://www.who.int/prequal/WHOPAR/WHOPARGUIDE/WHOPARGuidApplApp3v2_0.pdf

61. Slide 61 WHO Prequalification Programme: Training workshop March 2010, Beijing Thank you for your attention