1. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn Pharmaceutical Quality Information Form (PQIF) API

2. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn PQIF Summary of quality characteristicsSummary of quality characteristics –Focus on critical quality attributes Designed to facilitate prequalificationDesigned to facilitate prequalification –For assessors –For applicants

3. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn Abbreviations APIActive Pharmaceutical ngredientAPIActive Pharmaceutical Ingredient APIMFAPI Master FileAPIMFAPI Master File –DMFDrug Master File –ASMFActive Substance Master File CHMPCommittee for Medicinal Products for Human UseCHMPCommittee for Medicinal Products for Human Use CPMPCommittee for Proprietary Medicinal ProductsCPMPCommittee for Proprietary Medicinal Products FPPFinished Pharmaceutical ProductFPPFinished Pharmaceutical Product ICHInternational Conference on HarmonisationICHInternational Conference on Harmonisation OOSOut of SpecificationOOSOut of Specification QWPQuality Working PartyQWPQuality Working Party

4. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn Guidelines 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 [GuideGeneric]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 [GuideGeneric] Guidance on Variations to a prequalified Dossier [Variation Guide]Guidance on Variations to a prequalified Dossier [Variation Guide] Guideline on Active Substance Master File Procedure [CPMP/QWP/227/02 Rev1]Guideline on Active Substance Master File Procedure [CPMP/QWP/227/02 Rev1] –Guideline on Active Pharmaceutical Ingredient Master File (APIMF) Procedure [Draft] Guideline on Summary of Requirements for Active Substances in the Quality Part of the Dossier [CPMP/QWP/297/97 Rev 1 corr]Guideline on Summary of Requirements for Active Substances in the Quality Part of the Dossier [CPMP/QWP/297/97 Rev 1 corr] ICH Q3A [R] Impurities Testing Guideline: Impurities in New Drug Substances [CPMP/ICH/2737/99]ICH Q3A [R] Impurities Testing Guideline: Impurities in New Drug Substances [CPMP/ICH/2737/99] ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances [CPMP/ICH/367/96 corr]ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances [CPMP/ICH/367/96 corr] ICH Q2A Validation of Analytical Procedures: Definitions and Terminology [CPMP/ICH/381/95]ICH Q2A Validation of Analytical Procedures: Definitions and Terminology [CPMP/ICH/381/95] ICH Q2B Validation of Analytical Procedures: Methodology [CPMP/ICH/281/95]ICH Q2B Validation of Analytical Procedures: Methodology [CPMP/ICH/281/95]

5. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn 2. Active Pharmaceutical Ingredient(s) [API(s)] Options for presentation of API-dataOptions for presentation of API-data –As integral part of the dossier according to Section 2 of: Guideline on Submission of Documentation for Prequalification of Multi-Source (Generic) Finished Pharmaceutical Products (FPPs) Used in the Treatment of HIV / AIDS, Malaria and TuberculosisGuideline on Submission of Documentation for Prequalification of Multi-Source (Generic) Finished Pharmaceutical Products (FPPs) Used in the Treatment of HIV / AIDS, Malaria and Tuberculosis –As independent part according to an API Master File Procedure Guideline on Active Substance Master File Procedure [CPMP/QWP/227/02 Rev 1]Guideline on Active Substance Master File Procedure [CPMP/QWP/227/02 Rev 1] Guideline on Active Pharmaceutical Ingredient Master File (APIMF) Procedure - DraftGuideline on Active Pharmaceutical Ingredient Master File (APIMF) Procedure - Draft

6. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn 2. Active Pharmaceutical Ingredient(s) [API(s)] II Essentials of an APIMFEssentials of an APIMF –Scientifically equivalent to Section 2 of: 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 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 –Presented in two different parts OP (open part)OP (open part) RP (restricted part)RP (restricted part) –Accompanied by essential references Letter of accessLetter of access Covering letterCovering letter

7. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn 2. Active Pharmaceutical Ingredient(s) [API(s)] III Advantages of an APIMF (DMF, ASMF)Advantages of an APIMF (DMF, ASMF) –Independent (Stand alone) evaluation procedure of the API –Reference to prequalified APIs Saving timeSaving time „Good APIMF Practice“„Good APIMF Practice“ –Clear identification Letter of accessLetter of access Covering letterCovering letter –Automatic information on Changes and Updates Covering letterCovering letter

8. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn Deficiencies from PQ No transparency with APIMFsNo transparency with APIMFs –No letter of access Version no.?Version no.? Version date?Version date? –No adequate presentation of updates and changes No covering letterNo covering letter –No tabulated summary, no „history“-overview, No proper justification of update/changeNo proper justification of update/change –Change of critical parameters

9. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn 2.2 Properties of API(s) Categories of APIsCategories of APIs –2.2.1 API not described in BP, PhInt, PhEur or USP Considered newConsidered new –(?) information on (adverse) drug reaction Risk estimation highRisk estimation high Profound information necessaryProfound information necessary –2.2.2 API described in BP, PhInt, PhEur or USP Considered in useConsidered in use –Information on (adverse) drug reaction (monitored) Risk estimation based on available dataRisk estimation based on available data Information necessary limited to data beyond the monographInformation necessary limited to data beyond the monograph –Essential control by the monograph

10. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn 2.2 Properties of API(s) II Categories of AntimalarialsCategories of Antimalarials –APIs described in monographs of major international pharmacopoeias (  1 decade) Amodiaquine, Chloroquine, Dapsone, Quinine, Mefloquine, Sulfadoxine/Pyrimethamine, TrimethoprimAmodiaquine, Chloroquine, Dapsone, Quinine, Mefloquine, Sulfadoxine/Pyrimethamine, Trimethoprim –APIs described in monographs of major international pharmacopoeias (recently) Arthemether, Artemisinin, Artemotil, Artenimol, ArtesunateArthemether, Artemisinin, Artemotil, Artenimol, Artesunate –APIs not described in monographs of major international pharmacopoeias Chlorproguanil, Lumefantrine, Naphthoquine, Piperaquine, PyronaridineChlorproguanil, Lumefantrine, Naphthoquine, Piperaquine, Pyronaridine

11. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn Properties of Antiinfectives Well established use (+)Well established use (+) –Widely used in a sufficiently large number of patients to permit assumption that efficacy and safety are well- known Well established use (-)Well established use (-) –Widely used in a large number of patients - mechanisms of resistance developed CombinationsCombinations –Artemisinines and well established APIs/new APIs Prevent/prolong new resistancePrevent/prolong new resistance Overcome established resistanceOvercome established resistance

12. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn 2.2 Properties of API(s) III 2.2.1 APIs not described in BP, PhInt, PhEur or USP2.2.1 APIs not described in BP, PhInt, PhEur or USP a) evidence of chemical structurea) evidence of chemical structure –spectral data –interpretation of data (narrative) b) evidence of chemical structureb) evidence of chemical structure –Isomerism –Stereochemistry –Discussion of potential isomeric forms

13. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn 2.2 Properties of API(s) III cont. Properties relevant/critical for the performance of the APIProperties relevant/critical for the performance of the API c) potential polymorphic formsc) potential polymorphic forms –Influence on physicochemical and physical characteristics (solubility, hardness, compressibility, density, melting point, etc.) »Must be controlled d) particle size distributiond) particle size distribution –requirement for low solubility drugs (dissolution, bioequivalence) e) additional characteristicse) additional characteristics –critical characteristics to be controlled to ensure consistent performance of the API (e.g. hygroscopicity)

14. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn 2.2 Properties of API(s) IV 2.2.1 APIs described in BP, PhInt, PhEur or USP2.2.1 APIs described in BP, PhInt, PhEur or USP –Evidence of chemical structure control of structure by suitable compendial identification testscontrol of structure by suitable compendial identification tests –Properties relevant/critical for the performance of the API (not necessarily covered by the monograph) a) potential polymorphic formsa) potential polymorphic forms –Influence on physicochemical and physical characteristics (solubility, hardness, compressibility, density, melting point, etc.) »Must be controlled b) particle size distributionb) particle size distribution –requirement for low solubility drugs (dissolution, bioequivalence) c) additional characteristicsc) additional characteristics –critical characteristics to be controlled to ensure consistent performance of the API (e.g. hygroscopicity)

15. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn Properties of Artemisinins Artemisinin (C 15 H 22 O 5 )Artemisinin (C 15 H 22 O 5 ) –7 centers of asymmetry –2 7 potential isomers –One isomer in biosynthesis –Chemical synthesis FeasableFeasable Economically unacceptableEconomically unacceptable Chemical derivatization at C-10 (carbonyl-moiety) converts C-10 into an additional stereoisomeric center:Chemical derivatization at C-10 (carbonyl-moiety) converts C-10 into an additional stereoisomeric center:  - and  -isomers are formed  - and  -isomers are formed 1 2 3 4 5 6 5a 8a 7 8 9 10 11 12 12a

16. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn Properties of Artemisinins II 3D-image Artemisinin3D-image Artemisinin www.chemexper.comwww.chemexper.com Endo- peroxide- bond Carbonyl- moiety 10 11 12a 1 1 2 2 33 44 55 5a 6 6 77 88 8a 99 12 13

17. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn Properties of Artemisinins Proposed by ManufacturersProposed by Manufacturers Diastereomers may differ in their melting point/specific optical rotationDiastereomers may differ in their melting point/specific optical rotation Melting range Specific optical rotation  -Artemether 100°C  -Artemether 84 - 86°C, 86 – 90°C +166°-+173°, +168°-+173° 20mg/ml C 2 H 5 OH  -Artesunate 144°C, 143°C, 142- 146°C 132-135°C, 131-134°C +2.5°-+3.5°, +4.5°-+6.5°, +11°-+14° 10mg/ml CH 2 Cl 2 +11°-+14°, 40mg/ml CH 3 Cl, +10°-+14° (CH 3 Cl)  -Artesunate 132-135°C+2.5°-+3.5°  ~  ~Artenimol (in solution) +146° (15°C) (?mg/ml MeOH)

18. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn Deficiencies from PQ Pharmacopoeial specifications are not met without justificationPharmacopoeial specifications are not met without justification Stereospecificity not adequately addressedStereospecificity not adequately addressed Pharmacopoeial methods are not being followed to generate respective data on propertiesPharmacopoeial methods are not being followed to generate respective data on properties Data on properties are simply not provided at all (without justification)Data on properties are simply not provided at all (without justification) IR-spectra are not compared to a primary reference spectrumIR-spectra are not compared to a primary reference spectrum

19. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn 2.3 Site(s) of manufacture Identification of each API-manufacturerIdentification of each API-manufacturer –Name –Street address –Phone, Fax, Email –If applicable Referenced DMFs (APIMFs)Referenced DMFs (APIMFs) Letters of accessLetters of access –Why is identification of API-manufacturers essential?

20. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn 2.3 Site(s) of manufacture II The quality of APIs is dependent onThe quality of APIs is dependent on –Manufacturing site Equipment, personal, technology…Equipment, personal, technology… –Route of synthesis, operational conditions, IPCs… Impurity profile, stability (API & FPP)Impurity profile, stability (API & FPP) The quality of an API may consequently impact the quality of a FPPThe quality of an API may consequently impact the quality of a FPP –Change in manufacturing site Alternate API-manufacturersAlternate API-manufacturers –Change in route of synthesis Alternate API-manufacturersAlternate API-manufacturers

21. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn Deficiencies from PQ Quality of alternate API-sourcesQuality of alternate API-sources –Site of manufacture –Description of the API-quality Before prequalificationBefore prequalification –Submission as part of the application After prequalificationAfter prequalification –Submission as variation application Guidance on variations to a prequalified dossierGuidance on variations to a prequalified dossier

22. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn 2.4 Route(s) of synthesis 2.4.1 API not described in BP, PhInt, PhEur or USP2.4.1 API not described in BP, PhInt, PhEur or USP –Controls of critical steps and intermediates Potential impact on the quality of the API and intermediatesPotential impact on the quality of the API and intermediates –Process conditions, test requirements and other relevant parameters to be controlled within predetermined limits Examples of potentially critical stepsExamples of potentially critical steps –Mixing of multiple components –Phase change and phase separation steps –Steps where control of pH and temperature are critical –Introduction of an essential structural element or major chemical transformation –Introduction/removal of significant impurities to the API –Final purification step –Steps with an impact on solid state properties/homogeneity of the API

23. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn 2.4 Route(s) of synthesis II 2.4.1 API not described in BP, PhInt, PhEur or USP2.4.1 API not described in BP, PhInt, PhEur or USP –Process Validation and/or Evaluation All steps that are identified as critical for the APIAll steps that are identified as critical for the API All steps covering aseptic processing or sterilizationAll steps covering aseptic processing or sterilization

24. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn 2.4 Route(s) of synthesis III 2.4.1 API not described in BP, PhInt, PhEur or USP2.4.1 API not described in BP, PhInt, PhEur or USP –Manufacturing process development Description and discussion of any change to the manufacturing process and/or manufacturing site in developmental order:Description and discussion of any change to the manufacturing process and/or manufacturing site in developmental order: –Clinical –Comparative –Stability –Scaleup –Pilot –Production

25. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn 2.4 Route(s) of synthesis IV 2.4.1 API not described in BP, PhInt, PhEur or USP2.4.1 API not described in BP, PhInt, PhEur or USP –Impurities Identification of potential and actual impurities arising from synthesis, manufacture and/or degradationIdentification of potential and actual impurities arising from synthesis, manufacture and/or degradation –Potential sources of origin in sequential order »impurities contained in the starting material »starting material unreacted »intermediates unreacted »by-products (unwanted reaction products) »reagents »catalysts »residual solvents »degradants –Elucidation of origin may help to minimize impurities

26. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn 2.4 Route(s) of synthesis V 2.4.1 API not described in BP, PhInt, PhEur or USP2.4.1 API not described in BP, PhInt, PhEur or USP –Setting the acceptance criteria for impurities Maximum daily dose (total daily intake)Maximum daily dose (total daily intake) ICH thresholds for drug-related impuritiesICH thresholds for drug-related impurities Concentration limits for process related impuritiesConcentration limits for process related impurities –Residual solvents –Heavy metals Available safety and toxicity dataAvailable safety and toxicity data –Documented impurity levels according to the scheme provided –Reference to the analytical procedures used Specificity, sensitivitySpecificity, sensitivity –Justification of proposed acceptance criteria

27. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn 2.4 Route(s) of synthesis VI 2.4.1 API not described in BP, PhInt, PhEur or USP2.4.1 API not described in BP, PhInt, PhEur or USP –Setting the acceptance criteria for impurities ICH thresholds for drug related impurities [ICH Q3A (R)]ICH thresholds for drug related impurities [ICH Q3A (R)] Maximum Daily Dose Reporting Threshold Identification Threshold Qualification Threshold ≤ 2g/day 0.05% 0.10% or 1mg per day intake ( whichever is lower) 0.15% or 1mg per day intake ( whichever is lower) ≥ 2g/day 0.03%0.05%0.05%

28. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn 2.4 Route(s) of synthesis VII 2.4.2 Specifications of raw materials and intermediates used in the synthesis2.4.2 Specifications of raw materials and intermediates used in the synthesis –Quality and controls of materials coming into the process Starting materialsStarting materials Raw materialsRaw materials IntermediatesIntermediates ReagentsReagents CatalystsCatalysts SolventsSolvents –Specifications

29. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn 2.4 Route(s) of synthesis VIII 2.4.2 Specifications of raw materials and intermediates used in the synthesis2.4.2 Specifications of raw materials and intermediates used in the synthesis –TSE-safety of all materials coming into the process CEPCEP Letter of attestationLetter of attestation

30. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn 2.4 Route(s) of synthesis IX 2.4.3 API described in BP, PhInt, PhEur or USP2.4.3 API described in BP, PhInt, PhEur or USP –Impurities that are not included in the monograph Process related impuritiesProcess related impurities –Key intermediates –Residual solvents –Potential organic impurities not covered by the monograph

31. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn Potential impurities of Artemisinins Starting material (extracted from herbal sources)Starting material (extracted from herbal sources) –GuideGeneric: Starting materials from vegetable origin should be fully characterized and a contaminant profile should be established and submitted.Starting materials from vegetable origin should be fully characterized and a contaminant profile should be established and submitted. – CPMP/QWP/297/97 Rev 1 corr: In the case of substances isolated form herbal sources, the potential for impurities arising from cultivation and/or preparation (e.g. pesticide residues, fumigants, mycotoxins) should be addressed.In the case of substances isolated form herbal sources, the potential for impurities arising from cultivation and/or preparation (e.g. pesticide residues, fumigants, mycotoxins) should be addressed.

32. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn Potential impurities of Artemisinins II Impurities contained in the „starting material“ ArtemisininImpurities contained in the „starting material“ Artemisinin –Biosynthetic by-products Arteannuin B, Artemisitene, Artemisinic acid,Arteannuin B, Artemisitene, Artemisinic acid, –Extraction from fresh leaves with CHCl 3 within 1 min > 97% » Localisation in subcuticular space of the glands on the surface of the leaves Thujone (?)Thujone (?) –Cultivation reagents Pesticide residues, fumigants, mycotoxinsPesticide residues, fumigants, mycotoxins –Solvents from the extraction process Hexane, benzene, acetonitril, ether, pentane, chloroforme…..(?) diesel, fuel (?) [ICH Q3A (R)]Hexane, benzene, acetonitril, ether, pentane, chloroforme…..(?) diesel, fuel (?) [ICH Q3A (R)]

33. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn Localisation of Artemisinin (isolation from fresh leaves) Picture of a glandular trichome on a leaf of Artemisia annua L. before (A and B) and after (C and D) chloroforme extraction (black bar = 10 µm)Picture of a glandular trichome on a leaf of Artemisia annua L. before (A and B) and after (C and D) chloroforme extraction (black bar = 10 µm) The cuticule is crumpled after chloroforme extractionThe cuticule is crumpled after chloroforme extraction The epidermal cells are unaffected by this treatmentThe epidermal cells are unaffected by this treatment From: F.C.W. Van Nieuverburgh et al., J Chromatogr. A 1118 (2006) 180-187From: F.C.W. Van Nieuverburgh et al., J Chromatogr. A 1118 (2006) 180-187

34. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn Potential impurities of Artemisinins III Unreacted starting materialUnreacted starting material –Artemisinin (starting material for derivatives) –Artemisinic acid (starting matrial for dihydroartemisinin) –Dihydroartemisinin (starting material for derivatives) –…. Unreacted intermediates, by-productsUnreacted intermediates, by-products –  -Arthemether,  -Artheether –  /  -Dihydroartemisinin –  -Artesunate –….

35. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn Potential impurities of Artemisinins III cont. Reagents, catalysts, residual solventsReagents, catalysts, residual solvents –Methanol, acetonitril, chloroforme, acetone … –NaBH 4, succinic acid/anhydride, triethylamine, dimethylaminopyridine DegradantsDegradants –Stability of ester-derivative (Artesunate)ester-derivative (Artesunate) ether-derivative (Artemether, Arteether)ether-derivative (Artemether, Arteether) lactone (Artemisinin)lactone (Artemisinin) –Stability of artenimol (oxidation) –Susceptibility of endoperoxide bond to reduction Deoxyartemisinine (loss of active principle  )Deoxyartemisinine (loss of active principle  ) –Zn / AcOH or FeBr 2 / THF

36. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn Deficiencies from PQ Description of synthesis only covers part of the synthesis routeDescription of synthesis only covers part of the synthesis route –Evaluation regarding impurities and degradants (?) Details on stereospecificity of reaction steps are not addressedDetails on stereospecificity of reaction steps are not addressed Flow chart of the synthetic route is too crypticFlow chart of the synthetic route is too cryptic –quantity of materials, IPCs, operational conditions, intermediates, purification steps Narrative of the synthetic process is not providedNarrative of the synthetic process is not provided –Final batch size Environmental impact statement missingEnvironmental impact statement missing

37. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn Deficiencies from PQ cont. Impurities, intermediates, by-products, degradantsImpurities, intermediates, by-products, degradants –Potential to be expected from synthesis is not discussed Side reactions at critical process stepsSide reactions at critical process steps –are not analysed –Methods to assess impurities are not sensitive enough Quantitation limit (1%) far above the identification and qualification threshold (0.05 – 0.15%)Quantitation limit (1%) far above the identification and qualification threshold (0.05 – 0.15%)

38. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn 2.5 Specifications 2.5.1 API not described in BP, PhInt, PhEur or USP2.5.1 API not described in BP, PhInt, PhEur or USP –Presentation of the API-specification Any test that is not performed on a batch to batch-basis must be indicated (periodic testing or skip testing)Any test that is not performed on a batch to batch-basis must be indicated (periodic testing or skip testing) Standard claimed (e.g. in-house, BP, PhInt, PhEur, USP Reference or version number Specific test parameter Analytical procedure used Acceptance criteria

39. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn 2.5 Specifications II 2.5.1 API not described in BP, PhInt, PhEur or USP2.5.1 API not described in BP, PhInt, PhEur or USP –Skip testing ICH Q6AICH Q6A –performance of specified tests at release on pre-selected batches and/or predetermined intervals, rather than on a batch- to-batch basis with the understanding that those batches not being tested must still meet all acceptance criteria established for that product. –As this represents less than full testing it should be justified. –Any failure to meet acceptance criteria established for the periodic test should be handled by proper notification (inform WHO immediately). If the data demonstrate a need to restore routine testing, batch-by-batch release testing should be reinstated.

40. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn 2.5 Specifications III 2.5.1 API not described in BP, PhInt, PhEur or USP2.5.1 API not described in BP, PhInt, PhEur or USP –Skip testing ICH Q6AICH Q6A –The concept may be applicable to, f.ex., residual solvents and microbiological testing, for solid oral dosage forms. –Since only limited data may be available at the time of submission, the concept should generally be implemented post- approval (  post prequalification) GuideGenericGuideGeneric –Where testing for possible impurities is omitted, particular attention must be given to its justification »f. ex. particular method of production »f.ex. impuritiy has never been detected

41. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn 2.5 Specifications IV 2.5.1 API not described in BP, PhInt, PhEur or USP2.5.1 API not described in BP, PhInt, PhEur or USP –Batch analyses Description of the batchesDescription of the batches Results of the batchesResults of the batches –Certificates of Analysis Discussion of the results with respect to the use of the batchDiscussion of the results with respect to the use of the batch –Clinical, Comparative etc. Batch number Batch size Date and site of production Use (e.g. clinical, comparative

42. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn 2.5 Specifications V 2.5.1 API not described in BP, PhInt, PhEur or USP2.5.1 API not described in BP, PhInt, PhEur or USP –Justification of Specifications Evolution of testsEvolution of tests Evolution of analytical proceduresEvolution of analytical procedures Evolution of acceptance criteriaEvolution of acceptance criteria Differences from compendial standardsDifferences from compendial standards –f.ex. assay and impurities, heavy metals, residue on ignition

43. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn 2.5. Specifications VI 2.5.1 API not described in BP, PhInt, PhEur or USP2.5.1 API not described in BP, PhInt, PhEur or USP –Justification of Specifications ICH Q6AICH Q6A –Justification for each procedure and each acceptance criterion with reference to »relevant development data »pharmacopoeial standards »Test data for batches used in toxicology and clinical studies »Results from accelerated and long term studies »Reasonable range of analytical and manufacturing variability »Alternate justified approaches –Actual results obtained should form the primary basis for any justification

44. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn Deficiencies from PQ Different versions of specifications at different places (DMF, batch analyses, specification, FPP)Different versions of specifications at different places (DMF, batch analyses, specification, FPP) Essential parameters missing in specificationsEssential parameters missing in specifications Test methods missingTest methods missing Impurities insufficiently specifiedImpurities insufficiently specified Limits to be tightened (impurities) according to real values)Limits to be tightened (impurities) according to real values) Residual solvents not specified (w/o justification)Residual solvents not specified (w/o justification) Microbial purity not part of specificationMicrobial purity not part of specification Less than 3 batch certificates submittedLess than 3 batch certificates submitted Batch sizes, manufacturing site and date missing on certificates of analysis (CoAs)Batch sizes, manufacturing site and date missing on certificates of analysis (CoAs)

45. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn 2.5 Specifications VII 2.5.1 API not described in BP, PhInt, PhEur or USP2.5.1 API not described in BP, PhInt, PhEur or USP –Reference standards or materials ICH Q2BICH Q2B –Reference standards/materials should be well characterized with documented purity SourceSource –Official pharmacopoeial standards –In-house standards Characterization and evaluation of non-official standardsCharacterization and evaluation of non-official standards –Method of manufacture –Elucidation of structure –Certificate of analysis –Calibration against an official standard (if available)

46. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn 2.5 Specifications VIII 2.5.1 API not described in BP, PhInt, PhEur or USP2.5.1 API not described in BP, PhInt, PhEur or USP –Reference standards or materials (in-house) Primary (absolute) standardPrimary (absolute) standard –Documented purity (with purification procedure) –Assay by two independent procedures, one of which must be specific –Mass balance must be achieved »Assay value and all impurities found must amount to 100% (relative to the analytical procedure) –All further impurities (residue on ignition/inorganic substances, loss on drying etc.) must be considered to determine the absolute assay value Secondary (working) standardSecondary (working) standard –Documented purity with reference to the primary (absolute) standard –Intervals of control of content and duration of use

47. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn Deficiencies from PQ The role of the primary standard is not adequately reflectedThe role of the primary standard is not adequately reflected –Working standards are calibrated against other working standards –Working standards are calibrated against unofficial reference standards The source of the primary standard is unclearThe source of the primary standard is unclear Identity of primary reference standard is established by comparison with IR-spectra of secondary standardIdentity of primary reference standard is established by comparison with IR-spectra of secondary standard Information on preparation and quality specification of primary (absolute) and secondary (working) standards is not providedInformation on preparation and quality specification of primary (absolute) and secondary (working) standards is not provided

48. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn 2.5 Specifications IX 2.5.1 API not described in BP, PhInt, PhEur or USP2.5.1 API not described in BP, PhInt, PhEur or USP –Validation of analytical procedures Any in-house analytical procedure needs to be validatedAny in-house analytical procedure needs to be validated –ICH Q2A, ICH Q2B –Assay and impurities Capability to detect impurities and degradants from synthesisCapability to detect impurities and degradants from synthesis Stability indicating potentialStability indicating potential

49. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn 2.5 Specifications X 2.5.1 API not described in BP, PhInt, PhEur or USP2.5.1 API not described in BP, PhInt, PhEur or USP –Stress testing provides degradants that may occur during storage Isolation of impurities and (stable) degradants in the development phaseIsolation of impurities and (stable) degradants in the development phase In situ generation of potential degradantsIn situ generation of potential degradants –Validation of analytical procedures for assay and impurities/degradants Spiking experiments with isolated degradants/impuritiesSpiking experiments with isolated degradants/impurities In situ use of stressed samplesIn situ use of stressed samples Peak purity analysis of API-peaksPeak purity analysis of API-peaks

50. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn Deficiencies from PQ Methods are in use before they are validatedMethods are in use before they are validated Validation is not considered at allValidation is not considered at all –Serious deficiency Results of batch analysis are not reliableResults of batch analysis are not reliable Stability studies are not evaluableStability studies are not evaluable

51. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn 2.5 Specifications XI 2.5.2 API described in BP, PhInt, PhEur or USP2.5.2 API described in BP, PhInt, PhEur or USP –Name the monograph Name any test methods referenced in the monograph but not appearing in itName any test methods referenced in the monograph but not appearing in it –List of tests beyond the scope of the monograph Residuals, particle size, polymorphs, loss on dryingResiduals, particle size, polymorphs, loss on drying –Generic guide: 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.

52. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn Specifications XII 2.5.2 API described in BP, PhInt, PhEur or USP2.5.2 API described in BP, PhInt, PhEur or USP –Additional requirements Generic guide:Generic guide: –The quality of the API should meet not only the requirements of specific monographs but also those described in the general monographs of a pharmacopoeia on APIs, excipients and other substance for pharmaceutical use. »f. ex. Substances for pharmaceutical use (PhEur) »f. ex. Control of impurities for substances for pharmaceutical use (PhEur)

53. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn 2.5 Specifications XIII 2.5.2 API described in BP, PhInt, PhEur or USP2.5.2 API described in BP, PhInt, PhEur or USP –Validation of analytical methods Pharmacopoeial methods are considered validated, however, there is common understanding that certain parameters need to be adapted:Pharmacopoeial methods are considered validated, however, there is common understanding that certain parameters need to be adapted: –New chapter USP Verification of analytical procedures »Pharmacopoeial Forum 31, No. 2, March/April 2005 –System suitability test –PhEur 2.2.46 –Insufficient Precision (RSD=  ) leads to OOS results »3 x  ≤ 2% (assay specification) –Validation with respect to the stability indicating nature of the methods For impurities/degradants not covered by the monographFor impurities/degradants not covered by the monograph If the pharmacopoeial method is modifiedIf the pharmacopoeial method is modified

54. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn Deficiencies from PQ Pharmacopoeial acceptance criteria are not considered for APIs described in the pharmacopoeiaPharmacopoeial acceptance criteria are not considered for APIs described in the pharmacopoeia –API cannot be adequately controlled by wider ranges Acceptance ranges of test parameters are much wider than actual test results.Acceptance ranges of test parameters are much wider than actual test results. –Acceptance ranges do not control the quality of the API The Reference standard in use simply represents API from a normal batch.The Reference standard in use simply represents API from a normal batch. –The reference is missing In-house absolute reference standards are not validated against available official standards.In-house absolute reference standards are not validated against available official standards. Pharmacopoeial methods are modified but impurity profile is not adapted.Pharmacopoeial methods are modified but impurity profile is not adapted. –f.ex. Impurity A (in-house method) is different from Impurity A (pharmacopoeial method)

55. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn 2.6 Container closure system Description of the container closure system (for storage and shipment of the API)Description of the container closure system (for storage and shipment of the API) –Primary packaging material Identity of materials of construction of each primary packaging componentIdentity of materials of construction of each primary packaging component Reference to specification for each packaging componentReference to specification for each packaging component –Description –Identification, ADEQUATELY TESTED –Drawings of critical dimensions –Secondary packaging material Non-functional (briefly)Non-functional (briefly) FunctionalFunctional

56. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn 2.6 Container closure system II Discussion of the suitability of the container closure systemDiscussion of the suitability of the container closure system –Choice of material –Function of material f.ex. protectionf.ex. protection –Moisture, light, oxygen –Safety of material Compatibility with APICompatibility with API SorptionSorption LeachingLeaching

57. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn 2.6 Container closure system III ArtemisininesArtemisinines –Storage conditions PhInt: Should be kept in a well closed container, protected from light and kept in a cool placeShould be kept in a well closed container, protected from light and kept in a cool place –Discussion of the suitability of the container closure system with respect to: Protection from lightProtection from light –f.ex. types/colour of inner and outer bags/drums Protection from oxygen and moisture (well-closed)Protection from oxygen and moisture (well-closed) –f.ex. type of inner/outer container (permeability) –f.ex. use of seals, joints, gaskets

58. Dar es Salaam, August, 21-25, 2006Dr. Birgit Schmauser, BfArM, Bonn THANKYOUFORYOURATTENTION