| Slide 1 of 33 April 2007 Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Protea Hotel Victoria Junction, Waterfront Cape Town, South Africa Date: 16 to 20 April 2007 Pharmaceutical Development

| Slide 2 of 33 April 2007 Pharmaceutical Development Applications for prequalification: Dossier requirements Presenter: János Pogány, pharmacist, PhD WHO expert

| Slide 3 of 33 April 2007 Pharmaceutical Development Outline and Objectives of presentation  Multisource (generic) products  Products from ICH regions  New products developed by generic manufacturers  Main points

| Slide 4 of 33 April 2007 Guideline on Assessment Procedure Guideline on Submission of Documentation for Prequalification of Multi-Source (Generic) Finished Pharmaceutical Products (FPPs) Used in the Treatment of HIV / AIDS, Malaria and Tuberculosis [Generic Guideline under revision] Pharmaceutical Quality Information Form „A properly filled out and signed original copy of the PQIF with all its annexes (including a copy on CD-ROM in Win- Word format ) must be submitted.”

| Slide 5 of 33 April 2007 INACTIVE INGREDIENTS ACTIVE INGREDIENTS PACKING MATERIALS FPP MANUFACTURE R Manufacturin g authorization Marketing authorization GMP standards Pharmacopeia standards NATIONAL DRA1 NATIONAL DRA2 Critical factors of FPP quality

| Slide 6 of 33 April 2007 High-risk APIs  FPP is not registered in the ICH region and associated countries  API is not official in the internationally used major pharmacopoeias and ICH guidelines should be used for evaluation  Reference standard/comparator is not available for: –Pharmaceutical equivalence studies –Bioequivalence studies  Require particular attention by national DRAs as regards assessment of applications for marketing authorization / prequalification

| Slide 7 of 33 April 2007 Low-risk APIs  Certificate of suitability (CEP) is submitted (DRA)  Active Pharmaceutical Ingredient Master File – Open part (APPLICANT) – Closed part (WHO or DRA)  Pharmacopoeia monograph – Literature evidence of stability – Synthesis impurities and degradants are controlled by monograph – Class1 solvents excluded; class2 / class 3 solvents controlled  FPP is registered in the ICH region (DRA)

| Slide 8 of 33 April 2007 Guideline on APIMF procedure  Full details of development chemistry, scale up, manufacturing process and process controls, validation, specifications at batch release and stability are available for assessment  Once the APIMF is prequalified, reference may be made to it in subsequent FPP applications  Conditions for reference –Version number and date must be assigned –Information on regular updates must be provided  Availability of APIMF is critical for API inspection

| Slide 9 of 33 April Properties of API(s)  API not described in PhInt, PhEur or USP –Considered new, used for the first time in a FPP –Risk estimation high –Full information necessary  API described in PhInt, PhEur or USP –In use for a certain period of time –Information on safety and efficacy available –Risk estimation low(er) –Control by the monograph, additional information beyond the scope of the monograph necessary

| Slide 10 of 33 April 2007 API not described in PhInt, PhEur or USP  Any in-house analytical procedure needs to be validated ICH Q2(R1)  Reference standards/materials should be well characterized with documented purity ICH Q2(R1)  Source –Official pharmacopoeial standards –In-house standards  Characterization and evaluation of non-official standards –Method of manufacture –Elucidation of structure –Certificate of analysis –Calibration against an official standard (if available)

| Slide 11 of 33 April 2007 PhInt - Reference substances  International Chemical Reference Substances are established on the advice of the WHO Expert Committee on Specifications for Pharmaceutical Preparations. ( The stability of the International Chemical Reference Substances kept at the Collaborating Centre is monitored by regular re-examination.)  International Infrared Reference Spectra  WHO Collaborating Centre for Chemical Reference Substances ( Apoteket AB, Centrallaboratoriet, ACL, Prismavägen 2, SE Kungens Kurva, Sweden; Fax: ; )

| Slide 12 of 33 April 2007 API described in PhInt, PhEur or USP  Properties relevant/critical for the performance of the API –potential polymorphic forms –particle size distribution  User requirement for low solubility drugs (dissolution, bioequivalence) –additional characteristics (e.g. hygroscopicity)  All manufacturing steps covering aseptic processing or sterilization must be validated  Proof of TSE-safety –CEP –Letter of attestation

| Slide 13 of 33 April 2007 Q3A(R2) Decision tree – Impurities

| Slide 14 of 33 April 2007 Decision tree – Polymorphism

| Slide 15 of 33 April 2007 Residual solvent impurities

| Slide 16 of 33 April API described in PhInt, PhEur or USP  Name the monograph  Name any test methods referenced in the monograph but not appearing in it  List of tests beyond the scope of the monograph: residual solvents, particle size, polymorphs, loss on drying, etc.  Whenever an API has been prepared by a method liable to leave impurities not controlled in the pharmacopoeial monograph, these impurities (based on 3 to 10 batch analysis results) including residual organic solvents, as well as their maximum tolerance limits should be declared and controlled by a suitable test procedure. 2.6 Container closure system 2.7 API stability

| Slide 17 of 33 April 2007 Batch number(s) of the FPPs used in CH Clinical (bioequivalence) studies* CH Dissolution studies CH CH CH Stability studies* “ Mother ” batch CH A 400x30 tabs CH070102A 400x30 tabs CH070101A 400x30 tabs Child batch 1 (pack size: 30 tablets) CH B 53x60 tabs CH B 800x60 tabs CH B 800x60 tabs Child batch 2 (pack size: 60 tablets) CH /2006 CH /2006 CH /2006 Validation studies (approved batch size)

| Slide 18 of 33 April Manufacturing process  A flow diagram should be presented giving the steps of the process and showing 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. Stages of manufacture, at which sampling is carried out for in-process control tests, should be indicated.  A narrative description of the manufacturing process, including packaging, that represents the sequence of steps undertaken and the scale of production should also be provided. For sterile products, details of sterilization processes and/or aseptic procedures used must be described.

| Slide 19 of 33 April 2007 Flow diagram  Flow diagram of a process  Breaking the process down into unit operations and steps (activities)  Decision on sampling and IPC results Activity Start Decision End Action Activity No Yes

| Slide 20 of 33 April 2007 Narrative of manufacturing process 1.Mix Amodiaquine hydrochloride, lactose monohydrate and maize starch in a high-shear, high-speed granulator for approximately 8 minutes 2.Mix maize starch and purified water in the heater until complete dissolution at approx. 70°C. 3.Cool the mixture prepared in step 2 until the required temperature (NMT 60°C) is reached. 4.Granulate the mixture prepared in step 1 whilst adding the mixture prepared in step 3 and mix until granulation endpoint is reached. 5.Add silica colloidal anhydrous and if necessary add purified water to the mixture from step 4 and mix until the granulation endpoint is reached. 6.….

| Slide 21 of 33 April Process validation report New (for the generic manufacturer) FPPs  Tabulated batch analytical and in-process control data  Certificates of analysis  Batch production records  Unusual findings, modifications or changes found necessary  Conclusions

| Slide 22 of 33 April Process Validation and Evaluation Established (for the generic manufacturer) FPPs  Manufacturing as well as in-process and quality control testing data should be evaluated. All but NLT a total of consecutive batches, manufactured over the period of the last 12 months, should be used when reviewing the results, to provide a statistically significant picture. Trend analysis should be presented.  Rejected batches should not be included in the analysis but must be reported together with the reports of failure investigations. See Notes page

| Slide 23 of 33 April 2007 Case summary of 20 batches StatisticsAv. wt. mgDissolution %Assay % Mean347,699,698,2 Median346,9100,097,5 STD5, Range Minimum Maximum Conf. level, 95% Accept. Crit.350±5%75%, 40'90-110

| Slide 24 of 33 April Specifications for the FPP Standard Claimed (e.g., In-house, BP, PhEur, PhInt, USP) Specification Reference Number and/or Version Test Analytical Procedure (Type/Source/Version ) Acceptance Criteria Batch release Shelf life

| Slide 25 of 33 April Specifications for the FPP  Justification of the specifications (e.g., evolution of tests, analytical procedures, and acceptance criteria, exclusion of certain tests, differences from compendial standard):  Acceptance criteria for degradants in FDC-FPPs should be established with reference to the API they are derived from. If an impurity results from a chemical reaction between two or more APIs, then its acceptance limits should be calculated with reference to the worst case (API with the smallest area under the curve). Alternatively, the content of such impurities could be calculated in relation to their reference standards.  Dissolution testing specifications should include all active components of the finished dosage form and utilize relevant media.

| Slide 26 of 33 April 2007 Labeling and product information  Outer packaging or, where there is no outer packaging, on the immediate packaging. Typical deficiencies: –List of excipients known to be a safety concern for some patients –e.g. lactose, gluten, metabisulfites, parabens, ethanol, or tartrazine– are not indicated. –Storage instructions do not reflect stability conditions.  Summary of Product Characteristics (SmPC) is frequently not approved by the national DRA. (Particular problem with artemisinin-derivative FPPs.)  The structure of SmPC does not follow that recommended by WHO.

| Slide 27 of 33 April 2007 Documentation for FPPs from ICH regions  An original or certified copy of WHO-type Certificate of a Pharmaceutical Product (CPP)  Assessment report(s) issued by a DRA in the ICH regions  If the composition, strength, specifications, materials, etc. are different from the product for which the CPP was issued, then pharmaceutical equivalence and bioequivalence should be demonstrated.  If the primary packaging material of the product is different from the one approved by the DRA of the ICH regions, then stability testing data should be submitted.  A sample should be provided.  Change control: approved variations to the MA should be notified.

| Slide 28 of 33 April 2007 New products developed by generic manufacturers Market authorization in ICH regions Dossier assessment Quality standard Not available Innovator methodology WHO and ICH guidelines Innovator FPPs with a single API (rarely also FDCs) are registered Generic methodology for FPPs with a single API or in-house specifications Official compendia or in-house specifications Additional features for fixed-dose combinations Multisource FPPs are registered Generic methodology and in-house specifications Official compendia and in-house specifications

| Slide 29 of 33 April 2007 Quality risks  Manufacture of APIs is not regulated  Pharmaceutical exports are not regulated  Marketing Authorization (MA) is issued without evaluation by the NDRA  Clinical studies are not required for generic MA  Stability studies are not required for generic MA  National GMP do not comply with WHO-GMP

| Slide 30 of 33 April 2007 New products developed by generic manufacturers Artemisinine-type antimalarial FPPs  Artesunate 60mg powder for injection is a life-saving FPP  Clinical studies on efficacy and safety should be evaluated  High risk API (at the start of the PQ project)  All issues described with non-compendial APIs and FPPs apply  The FPP manufacturing process and its validation is complex  It takes time to get into compliance 4-FDC antituberculotic FPPs and 3-FDC antiretroviral FPPs:  Compatibility testing of APIs  Dissolution test development  Non-routine manufacturing process

| Slide 31 of 33 April 2007 Solubility of Artesunate and stability of solutions pHDissolved material (mg/ml) 11,9 51,5 63,5 710,2 812,2 ConditionsTime (h)Degradation (%) Water20 0.1N HCl N NaOH 2100

| Slide 32 of 33 April 2007 Main points  Generic guideline is used for the assessment of dossiers submitted for prequalification  An electronic version of the PQIF facilitates evaluation  APIMF is the preferred form of presenting data and information on APIs  Innovator FPPs are prequalified by a simple procedures  New products developed by generic manufacturers deserve special attention by quality assessors

| Slide 33 of 33 April 2007 THANK YOU