1. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 1 |1 | Pharmaceutical Development Applications for Prequalification Applications for Prequalification Maintenance of Prequalification Maintenance of Prequalification –Dossier Requirements Presented by: Birgit Schmauser, pharmacist, PhD Presented by: Birgit Schmauser, pharmacist, PhD

2. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 2 |2 | Pharmaceutical Development Types of assessment procedures Types of assessment procedures –Products from ICH regions (& associated countries) Innovators Innovators Generics (exception)Generics (exception) –Multisource (generic) products –New products that are neither considered as Innovators nor Generics (not registered in ICH regions) Artemisinin-FPPs Artemisinin-FPPs Majority of FDC-FPPs (Bioequivalence testing possible) Majority of FDC-FPPs (Bioequivalence testing possible) –Variations post prequalification

3. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 3 |3 | Documentation for FPPs from ICH regions http://mednet3.who.int/prequal/info_applicants/Guidelines/GuideSubmittingDocFPPs_DRA_ICH_08_2005.pdf http://mednet3.who.int/prequal/info_applicants/Guidelines/GuideSubmittingDocFPPs_DRA_ICH_08_2005.pdf Documentation for FPPs from ICH regions http://mednet3.who.int/prequal/info_applicants/Guidelines/GuideSubmittingDocFPPs_DRA_ICH_08_2005.pdf http://mednet3.who.int/prequal/info_applicants/Guidelines/GuideSubmittingDocFPPs_DRA_ICH_08_2005.pdf 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.

4. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 4 |4 | Guidelines on Assessment Procedure for Multisource (Generic) Products Guideline on Submission of Documentation for Prequalification of Multisource (Generic) Finished Pharmaceutical Products (FPPs) Used in the Treatment of HIV/AIDS, Malaria and Tuberculosis [Generic Guideline, under revision] Guideline on Submission of Documentation for Prequalification of Multisource (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 with all its annexes (including a copy on CD-ROM in WinWord format) must be filled out] 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 WinWord format) must be filled out] Guide on Variations to a prequalified dossier

5. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 5 |5 | Critical factors of FPP quality M A N U F A C T U R E O F F P P Excipients API API Packaging materials G M P Pharmacopoeial standards Marketing Authorization Manufacturing Authorization Drug Regulatory Authority 1 Drug Regulatory Authority 2

6. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 6 |6 | High risk API FPPs not registered in ICH region & associated countries FPPs not registered in ICH region & associated countries API is not official in internationally used major pharmacopoeias API is not official in internationally used major pharmacopoeias –ICH guidelines as standards for evaluation No Reference Standard/Comparator is available for No Reference Standard/Comparator is available for –Pharmaceutical Equivalence –Bioequivalence Studies Assessments of applications for marketing authorization / prequalification should be done with thoroughness/care

7. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 7 |7 | Low risk API FPP is registered in the ICH region & associated countries FPP is registered in the ICH region & associated countries Pharmacopoeia monograph Pharmacopoeia monograph –Synthesis impurities (and degradants) are controlled by the monograph –Requirement on control of residual solvents Class 1 solvents to be excluded Class 1 solvents to be excluded Class 2/3 solvents to be limited Class 2/3 solvents to be limited –Literature evidence of stability and/or control by the degradants´ specification APIMF APIMF –Open part –Closed part Certificate of suitability (of the monograph) Certificate of suitability (of the monograph)

8. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 8 |8 | Guideline on APIMF procedure Presentation of full details for assessment Presentation of full details for assessment: –Development chemistry Scale up Manufacturing process and process controls Validation Specifications at batch release Stability Prequalification of the APIMF Prequalification of the APIMF –Reference to the APIMF in subsequent FPP applications may be made Conditions for Reference Conditions for Reference –Version number and version date must be assigned –Information on regular updates must be provided Availability of APIMF is critical for API inspection Availability of APIMF is critical for API inspection

9. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 9 |9 | 2.2 Properties of the APIs 2.2.1 API not described in PhInt, PhEur or USP 2.2.1 API not described in PhInt, PhEur or USP –Considered new, used for the first time in FPP –Risk estimation high –Must be supported by full information 2.2.2 API described in PhInt, PhEur or USP 2.2.2 API described in PhInt, PhEur or USP –In use for a certain period of time –Information on safety and efficacy available –Risk estimation lowered –Mainly controlled by application of the monograph, to be supported by additional information beyond the scope of the monograph

10. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 10 | API not described in PhInt, PhEur or USP Any in-house analytical method needs to be validated [ICH Q2(R1)] Any in-house analytical method needs to be validated [ICH Q2(R1)] Reference standards/materials should be well characterised with documented purity [ICH Q2(R1)] Reference standards/materials should be well characterised with documented purity [ICH Q2(R1)] Source Source –Official pharmacopoeial standards –In-house standards Characterisation and evaluation of non-official standards Characterisation and evaluation of non-official standards –Method of manufacture –Elucidation of structure –Certificate of analysis –Calibration against an official standard if available

11. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 11 | PhInt Reference substances International Chemical Reference substances (ICRS) are established on the advice of the WHO Expert Committee on Specifications for Pharmaceutical preparations International Chemical Reference substances (ICRS) are established on the advice of the WHO Expert Committee on Specifications for Pharmaceutical preparations –The stability of the ICRS kept at the Collaborating Centre is monitored by regular re-examination International Infrared Reference Spectra International Infrared Reference Spectra WHO Collaborating Centre for Chemical Reference Substances (Apoteket AB, Centrallaboratoriet, ACL Prismavägen 2, SE-141 75 Kungens Kurva, Sweden) WHO Collaborating Centre for Chemical Reference Substances (Apoteket AB, Centrallaboratoriet, ACL Prismavägen 2, SE-141 75 Kungens Kurva, Sweden) –Fax:(+) 46 8 740 60 40 –Email:who.apl@apoteket.se

12. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 12 | API described in PhInt, PhEur or USP Physicochemical and other relevant properties critical for the performance/processability of API Physicochemical and other relevant properties critical for the performance/processability of API –Potential polymorphic forms –Particle size distribution User requirement for low solubility drugs (dissolution/bioequivalence) User requirement for low solubility drugs (dissolution/bioequivalence) –Additional characteristics (e.g. hygroscopicity) Validation of manufacturing steps covering aseptic processing or sterilization Validation of manufacturing steps covering aseptic processing or sterilization Proof of TSE safety Proof of TSE safety –CEP –Letter of attestation

13. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 13 | Q3A (R2) Decision tree - Impurities

14. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 14 | Q6A Decision tree - Polymorphism

15. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 15 | Residual Solvent Impurities ICH Q3C ICH Q3C –Class I solvents in pharmaceutical products (solvents that should be avoided) SOLVENTCONCENTRATION LIMITCONCERN SOLVENTCONCENTRATION LIMITCONCERN Benzene2ppmcarcinogenic Benzene2ppmcarcinogenic CHCl 4 4ppm toxic and environ- mental hazard CHCl 4 4ppm toxic and environ- mental hazard C 2 H 4 Cl 2 5ppmtoxic C 2 H 4 Cl 2 5ppmtoxic C 2 H 2 Cl 2 (1,1)8ppmtoxic C 2 H 2 Cl 2 (1,1)8ppmtoxic C 2 H 3 Cl 3 (1,1,1)1500ppm environmental hazard C 2 H 3 Cl 3 (1,1,1)1500ppm environmental hazard

16. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 16 | 2.5.1 API described in PhInt, PhEur or USP Name the monograph Name the monograph Name any test methods referenced in the monograph but not appearing in it Name any test methods referenced in the monograph but not appearing in it List additional tests for critical variables of the API that are beyond the scope of the monograph List additional tests for critical variables of the API that are beyond the scope of the monograph residual solvents, particle size, polymorphs, loss on drying… 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 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

17. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 17 | Batch numbers of the FPP used in Oral solution Validation batch TA 10071 was used to produce stability batches TA 10071a and b Validation batch TA 10072 was used to produce stability batches TA 10072a and b Validation batch TA 10073 was used to produce stability batches TA 10073a and b TA 1007 Clinical (bioequivalence) studies TA 1007 Dissolution studies TA 10073a (2000 x 100ml) TA 10072a (2000 x 100ml) TA 10071a (2000 x 100ml) Stability studies pack size 100 ml TA 10073b (2000 x 250ml) TA 10072b (2000 x 250ml) TA 10071b (2000 x 250ml) Stability studies pack size 250 ml TA 10073 700 L TA 10072 700 L TA 10071 700 L Validation studies (approved batch size)

18. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 18 | Batch numbers of the FPP used in (new) TA 160001 Bioequivalence studies TA 160001 Dissolution profile studies Stability studies (primary batches) TA 160003c TA 160002c TA 160001c Packaging configuration I TA 160003b TA 160002b TA 160001b Packaging configuration II ……. Stability studies (production batches) TA 170003c TA 170002c TA 170001c Packaging configuration I TA 170003b TA 170002b TA 170001b Packaging configuration II …… TA 160003 TA 160002 TA 160001 Validation studies (primary batches) TA 170003 TA 170002 TA 170001 Validation studies (production batches) The batch manufacturing records and certificates of analysis of the above batches should include the manufacturing site, the batch size and any significant equipment differences (e.g. difference in design, operating principle, size etc. between the pilot and the production batches

19. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 19 | Composition of clinical, primary stability and production FPP batches ProductionPH200646StabilityPH200646ClinicalPH200613UnitIngredients %kg%kg%kg%mg 58.1437.5058.1437.5058.1437.5058.14250.00 (PhIntAPI ( 27.5617.77527.5617.77527.5617.77527.56118.50 Cellulose, microcrystalline PhEur 11.637.50011.637.50011.637.50011.6350.00 Pregelatinised starch PhEur 2.321.5002.321.5002.321.5002.3210.00 Sodium starch glycolate PhEur 0.350.2250.350.2250.350.2250.351.5 Magnesium stearate PhEur.s. q Purified water PhEur 64.5064.5064.50430.0TOTAL 150.000 Nos 1 No White / White size “0” capsule shell with X on cap and YZ on body

20. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 20 | 3.5 Manufacturing process A flow diagramm 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. A flow diagramm 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. 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. 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. For sterile products, details of sterilization processes and/or aseptic procedures used must be described.

21. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 21 | Flow diagram Flow diagram of a process Flow diagram of a process Breaking the process down into unit operations and steps (activities) Breaking the process down into unit operations and steps (activities) Decision on sampling and IPC results Decision on sampling and IPC results –e.g. homogeneity of blend (FDCs) no yes Start End Activity Decision Action

22. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 22 | Narrative of the manufacturing process 1) Sifting The API, lactose monohydrate and microcrystalline cellulose are sifted and collected in suitable containers Sodium starch glycolate, colloidal silicon dioxide and microcrystalline cellulose are sifted and collected in suitable containers Magnesium stearate is sifted and collected in suitable containers 2) Binder Preparation Povidone is dissolved in purified water under continuous stirring 3) Granulation The material of Step 1) is loaded in the Rapid Mixer Granulator and mixed for 10 minutes at a slow speed Binder solution is added slowly to the RMG while running the agitator at slow speed over a period of 3-5 minutes ….

23. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 23 | 3.7 Process validation report 3.7.1 New (for the generic manufacturer) FPPs Tabulated batch analytical and in-process control data Tabulated batch analytical and in-process control data Certificates of analysis Certificates of analysis Batch production records Batch production records Unusual findings, modifications or changes found necessary Unusual findings, modifications or changes found necessary Conclusions Conclusions

24. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 24 | 3.7 Process validation and evaluation 3.7.2 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 10-25 consecutive batches (or more), 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. Manufacturing as well as in-process and quality control testing data should be evaluated. All but NLT a total of 10-25 consecutive batches (or more), 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. Rejected batches should not be included in the analysis but must be reported together with the reports of failure investigations. –See Notes page

25. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 25 | Case summary of 25 batches Assay API II [%] Assay API I [%] Dissolution API II [%] Dissolution API I [%] Av. Wt. [mg] Statistics 99.2899.4597.9996.79752.6Mean 2.261.322.533.7016.50STD 8.55.49.915.251Range 95.996.992.389.3725Min 104.5102.3102.2104.5786Max 95 – 105% 80%, 45 min 750 mg ± 37.5 mg Accept. Crit.

26. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 26 | 3.9.1 Specifications for the FPP Standard claimed (e.g. In-house, BP, PhInt, USP) Specification Reference Number and/or Version Acceptance Criteria Analytical Procedure Version/Type/Number Test Shelf life Batch release

27. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 27 | 3.9.1 Specifications for the FPP Justification of the specifications Justification of the specifications –Evolution of tests, analytical procedures and acceptance critera, exclusion of certain tests, differences from compendial standard Acceptance criteria Acceptance criteria –for degradants in FDC-FPPs should be established with reference to the API they are derived from –for impurities/degradants that results from a chemical reaction between two or more APIs should be calculated with reference to the API with the smallest area under the curve (WORST CASE) –for impurities/degradants can always be calculated in relation to their reference standard, if available Dissolution testing specifications should include all active components of the finished dosage form and utilise relevant media Dissolution testing specifications should include all active components of the finished dosage form and utilise relevant media

28. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 28 | Labeling and product information 3.12.1Outer packaging or, where there is no outer packaging, on the immediate packaging 3.12.1 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 indicatedList 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 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.) 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 The structure of SmPC does not follow that recommended by WHO

29. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 29 | New products developed by generic manufacturers Marketing authorization in ICH regions Dossier assessment Quality standard Innovator methodology WHO and ICH guidelines Not available Generic methodology for FPPs with a single API Additional features for fixed-dose combinations Generic methodology Innovator FPPs with a single API (rarely FDCs) are registered Multisource FPPs are registered Official compendia or in-house specifications Official compendia and in-house specifications

30. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 30 | Quality risks Manufacture of APIs is not regulated Pharmaceutical exports are not regulated Marketing authorization 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

31. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 31 | New products developed by generic manufacturers Artemisinine type antimalarial FPPs 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 4-FDC antituberculotic FPPs and 3-FDC antiretroviral FPPs –Compatibility testing of APIs –Dissolution test development –Non-routine manufacturing process

32. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 32 | Solubility of Artesunate and stability of solutions Dissolved Artesunate (mg/ml) pH 1.91 1.55 3.56 10.27 12.28 Degradation (%) Time (h) Conditions 02H 2 O (pH 7) 7420.1 N HCl 10020.1 N NaOH

33. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 33 | Variations to a prequalified FPP Variations are subject to approval Variations are subject to approval –may impact the pharmaceutical quality Variations are classified into three categories according to their potential impact on pharmaceutical quality Variations are classified into three categories according to their potential impact on pharmaceutical quality –Notification (mainly administrative, some potential impact on quality) –Minor change (potential minor impact on quality) –Major change (potential major impact on quality) Variation Guide Variation Guide –Lists types of variations that are subject to notification or approval Annex 1 ( Annex 2 ) Annex 1 ( Annex 2 ) –Gives assistance in identifying the intended change and in documentation to be provided Annex 1 Annex 1

34. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 34 | Variations to a prequalified FPP Documentation to be supplied Conditions to be fulfilled 26Change in the qualitative and/or quantitative composition of the immediate packaging material 1, 2, 3, 4, 5 1, 2, 3, 4 a)Semisolid and liquid pharmaceutical forms N 1, 4, 5 1, 2, 3, 4 b)All other pharmaceutical forms 1, 2, 3, 4, 5 1, 3, 4 Conditions 1- The product concerned is not a sterile product 1- The product concerned is not a sterile product 2- The packaging type and material remain the same (e.g. a different blister, but same type) 2- The packaging type and material remain the same (e.g. a different blister, but same type) 3- The relevant properties of the proposed packaging material must be at least equivalent to those of the prequalified material 3- The relevant properties of the proposed packaging material must be at least equivalent to those of the prequalified material 4- Relevant stability studies with the relevant guidelines have been started with at least two pilot- scale or production scale batches, and at least three months´ stability data are at the disposal of the applicant. Assurance is given that these studies will be finalised and that the data will be provided immediately to WHO if outside specifications or potentiall outside specifications at the end of the prequalified shelf life (with proposed action.) 4- Relevant stability studies with the relevant guidelines have been started with at least two pilot- scale or production scale batches, and at least three months´ stability data are at the disposal of the applicant. Assurance is given that these studies will be finalised and that the data will be provided immediately to WHO if outside specifications or potentiall outside specifications at the end of the prequalified shelf life (with proposed action.)Documentation 1-…. 2-….. 3-… 4-….. 5-….. 1-…. 2-….. 3-… 4-….. 5-…..

35. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 35 | Variations to a prequalified FPP Scope of the change Scope of the change –Change in manufacturing site of the FPP Does not include : Does not include : – Change in batch size – Change in FPP specification If applicable, additional variation applications have to be filed If applicable, additional variation applications have to be filed

36. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 36 | 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 procedure New products developed by generic manufacturers deserve special attention by quality assessors Variations to prequalified FPPs are subject to approval

37. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 37 | THANK YOU