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QUALITY MANAGEMENT OF ANTIMALARIAL MEDICINES

János Pogány, Ph.D., WHO consultant Bangkok, 19 October 2004 E-mail: pogany@axelero.hu. QUALITY MANAGEMENT OF ANTIMALARIAL MEDICINES. Experience in prequalification of antimalarial medicines (product dossier assessment). ABBREVIATIONS and NOTES. API Active pharmaceutical ingredient

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QUALITY MANAGEMENT OF ANTIMALARIAL MEDICINES

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  1. János Pogány, Ph.D., WHO consultant Bangkok, 19 October 2004 E-mail: pogany@axelero.hu QUALITY MANAGEMENT OF ANTIMALARIAL MEDICINES Experience in prequalification of antimalarial medicines (product dossier assessment) Dr. Pogány - WHO, Bangkok

  2. ABBREVIATIONS and NOTES API Active pharmaceutical ingredient BP British Pharmacopoeia EOI Expression of interest FDC(s) fixed-dose combination(s) FPP(s) Finished pharmaceutical product(s) Ph.Eur. European Pharmacopoeia Ph.Int. International Pharmacopoeia USP United States Pharmacopeia Text in green refers to WHO documents or requirements Text in light blue indicates a quality assessment issue Dr. Pogány - WHO, Bangkok

  3. SUBJECTS FOR DISCUSSION • Interchangeability of FPPs • Artemisinin-based antimalarials • Requirements for submission of pharmaceutical data • Main gaps observed in the evaluation of dossiers • Regulatory aspects • Correspondence with FPP manufacturers • A few conclusions Dr. Pogány - WHO, Bangkok

  4. INTERCHANGEABILITYOF FPPs Pharmaceutical equivalence

  5. INTERCHANGEABILITY (IC) INTERCHANGEABILITY OF MULTISOURCE FPPs (IC) = (ESSENTIAL SIMILARITY WITH INNOVATOR) = PHARMACEUTICAL EQUIVALENCE (PE) + BIOEQUIVALENCE (BE) IC = PE + BE Dr. Pogány - WHO, Bangkok

  6. PHARMACEUTICAL EQUIVALENCE • FPPs MEET SAME ORCOMPARABLESTANDARDS • SAME API (chemical and physical equivalence) • SAME DOSAGE FORM AND ROUTE OF ADMINISTRATION • SAMESTRENGTH • COMPARABLE LABELING • WHO-GMP (batch-to-batch uniformity of quality) • STABILITY EQUIVALENCE Dr. Pogány - WHO, Bangkok

  7. FACTORS INFLUENCING PE INACTIVE INGREDIENTS ACTIVE INGREDIENTS PACKING MATERIALS GMP standards Manufacturing authorization FPP MANUFACTURER Marketing authorization Pharmacopeiastandards NATIONAL DRA1 NATIONAL DRA2 Dr. Pogány - WHO, Bangkok

  8. ARTEMISININ-BASED FPPs EXPRESSION OF INTEREST(March 2003)

  9. ARTEMISININ-BASED FPPs • Artemether, oral preparations • Artemether, intramuscular preparations • Artemether +lumefantrine, oral preparations • Artemotil, injectable forms • Artenimol (dihydroartemisinin) tablets, capsules, paediatric granules, suppositories Dr. Pogány - WHO, Bangkok

  10. ARTEMISININ-BASED FPPs • Artesunate injection for IV and IM • Artesunate, oral preparations • Artesunate + amodiaquine,oral preparations • Artesunate + mefloquine,oral preparations • Artesunate + sulphadoxine/pyrimethamine (SP), oral preparations Dr. Pogány - WHO, Bangkok

  11. PREQUALIFICATION PROJECT OF WHO Requirements for submission of pharmaceutical data

  12. PREQUALIFICATION GUIDES • http://www.who.int/medicines/library/qsm/ manual-on-marketing/who-dmp-rgs-985.doc • http://www.who.int/medicines/organization/qsm/activities/qualityassurance/gmp/gmpcover.html • WHO/HTP/EDM/QSM/2001: Standard Operating Procedure: Assessing Product Files • International Conference on Harmonization (ICH) guidelines Dr. Pogány - WHO, Bangkok

  13. WHO-GMP General Considerations • Licensed pharmaceutical products (marketing authorization) should be manufactured only by licensed manufacturers (holders of a manufacturing authorization) whose activities are regularly inspected by competent national authorities. Dr. Pogány - WHO, Bangkok

  14. 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 SOP 020/00 - Assessing Product Files 8.4 Addendum D – Product Assessment Report – Generic FPPs

  15. SCOPE OF THE GUIDELINE • This guideline applies only to APIs manufactured by chemical synthesis or semi-synthetic processes and to FPPs containing such APIs. • APIs manufactured by fermentation and cell culture processes should comply with the general requirements and specific monographs of the Ph.Eur..or the USP. Corresponding FPPs should be assessed by the monographs of the BP or the USP; for non-compendial APIs and FPPs,the ICH-Q6B guide “Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products” should be used. Dr. Pogány - WHO, Bangkok

  16. Section 1. CHARACTERISTICS OF THE FPP 1.1Details of the product 1.1.1 Name, dosage form and strength of the product 1.1.2 Approved generic name(s) [use International Non-proprietary Name (INN), if any] 1.1.3Visual description of the FPP 1.1.4Visual description of the packaging 1.2 Sample 1.3Regulatory situation in other countries Dr. Pogány - WHO, Bangkok

  17. Section 2. APIquality issues Illustrative examples of requirements

  18. APIs UNDER DISCUSSION NON-COMPENDIAL APIs Lumefantrine Sulfamethoxypyrazine INTERNATIONAL PHARMACOPOEIA Artemether Artemisinin Artemotil Artenimol Artesunate Mefloquine hydrochloride Proguanil HCl INTERNATIONALLY USED PHARMACOPOEIAE Amodiaquine HCl (USP) Pyrimethamine (Ph.Eur., USP) Proguanil HCl (BP) Sulfadoxine (Ph.Eur.) Dr. Pogány - WHO, Bangkok

  19. LOW-RISK APIs • CERTIFICATE OF SUITABILITY (DRA) • DRUG MASTER FILE • OPEN PART (APPLICANT) • CLOSED PART(DRA) • PHARMACOPEIA MONOGRAPH • LITERATURE EVIDENCE OF STABILITY • SYNTHESIS IMPURITIES ARE CONTROLLED BY MONOGRAPH (toxicology of additional impurities) • CLASS1 SOLVENTS EXCLUDED, CLASS2 SOLVENTS CONTROLLED • FPP IS REGISTERED IN THE ICH REGION Dr. Pogány - WHO, Bangkok

  20. HIGH-RISK, ARTEMISININ-BASED APIs • NO INNOVATOR API/FPP IN THE ICH REGION. • NO REFERENCE STANDARD/COMPARATOR IS AVAILABLE FOR: • PHARMACEUTICAL EQUIVALENCE STUDIES • BIOEQUIVALENCE STUDIES • THE APIs and FPPs ARE NOT OFFICIAL INTHE INTERNATIONALLY USED MAJOR PHARMACOPOEIAS • WHO GUIDES/SOPsAPPLY TO MULTISOURCE FPPs. ICH GUIDESSHOULD BE USED FOR EVALUATION. Dr. Pogány - WHO, Bangkok

  21. Section 2. APIs 2.1 Nomenclature 2.1.1International Nonproprietary Name (INN) 2.1.2 Compendial name if relevant 2.1.3 Chemical name(s) 2.1.4 Company or laboratory code, if applicable 2.1.5 Other non-proprietary name(s), e.g., national name, United States Adopted Name (USAN), Japanese Accepted Name (JAN); British Approved Name (BAN) 2.1.6 Chemical Abstracts Service (CAS) registry number Dr. Pogány - WHO, Bangkok

  22. CHEMICAL NAME(s) • ARTESUNATE (3R,5aS,6R,8aS,9R,10S,12R,12aR)-Decahydro-3,6,9-trimethyl-3,12-epoxy-12H-pyrano[4,3-j]1,2-benzodioxepin-10-ol,hydrogen succinate; therefore eight (8) stereogenic centres exist, or128 pairs of enantiomers and 256 diastereo-isomersare possible. Only one used in therapy. • CAS Reg. No: 88495-63-0 Dr. Pogány - WHO, Bangkok

  23. Section 2. APIs 2.2Properties of API(s) 2.2.1API not described in BP, Int.Ph., JP, Ph.Eur., or USP 2.2.2API described in BP, Int.Ph., JP, Ph.Eur., or USP 2.2.3 Information from literature. Dr. Pogány - WHO, Bangkok

  24. NON-COMPENDIAL APIs No reference standard/spectrum. Documented evidence of structure and stereochemistry-such as clearly visible, quality assurance (QA)-certified copies of infrared, nuclear magnetic resonance (proton and C-13), ultraviolet and mass spectra- should be submittedtogether with professional interpretation of the relevant parts of spectra, X-ray diffractograms, thermograms, and so on. Dr. Pogány - WHO, Bangkok

  25. (NON)-COMPENDIAL API(s) No/insufficient information from pharmacopoeia and manuals. Physicochemical and other relevant properties of the API, such as solubility in water, other solvents and buffers of different pH; partition coefficient; existence/absence of polymorphs and water/solvent of crystallization; results of hygroscopicity testing; particle size and so on. Dr. Pogány - WHO, Bangkok

  26. Section 2. APIs 2.3Site(s) of manufacture 2.4 Route(s) of synthesis 2.4.1 API not described in BP, Int.Ph., JP, Ph.Eur., or USP 2.4.2 API described in BP, Int.Ph., JP, Ph.Eur., or USP 2.4.3 Specifications of starting materials and intermediates used in the synthesis Dr. Pogány - WHO, Bangkok

  27. COMPENDIAL API(s) The official monograph of an API in a pharmacopoeia does not necessarily control the quality of the API. Impurities, including residual solvents, depend on the synthesis route (steps, conditions, catalysts, by-products, batch size, process control, etc.) and this may differ from manufacturer to manufacturer. Dr. Pogány - WHO, Bangkok

  28. 2.4 ROUTE(S) OF SYNTHESIS • European certificate of suitability (CEP) together with annexes. • Flow diagram of the synthetic process(es) that includes batch size, molecular formulae, chemical structures;description of operating conditions, purification steps, catalysts and solvents. • Sequential procedural narrative of the manufacturing process with detailed description of purification and crystallization. Dr. Pogány - WHO, Bangkok

  29. ARTESUNATE SYNTHESIS – Step 1 Dr. Pogány - WHO, Bangkok

  30. ARTESUNATE SYNTHESIS – Step 2 Dihydroartemisinine Dr. Pogány - WHO, Bangkok

  31. Section 2. APIs 2.5 Specifications 2.5.1 API not described in BP, Int.Ph., JP, Ph.Eur., or USP 2.5.2 API described in BP, Int.Ph., JP, Ph.Eur., or USP 2.6 Container closure system Dr. Pogány - WHO, Bangkok

  32. CHEMICAL EQUIVALENCE • OFFICIAL COMPENDIA • BATCH-TO-BATCH UNIFORMITY • IMPURITY PROFILE • RESIDUAL SOLVENTS • ASSAY • PHYSICOCHEMICAL PROPERTIES • GMP and STABILITY EQUIVALENCE Dr. Pogány - WHO, Bangkok

  33. IMPURITIES Concept of impurities has changed with time and the development of analytical methods. • IDENTIFIED IMPURITY • UNIDENTIFIED IMPURITY • SPECIFIED IMPURITY • UNSPECIFIED IMPURITY Dr. Pogány - WHO, Bangkok

  34. IMPURITY EQUIVALENCE • NO NEW IMPURITYIS OBSERVED IN THE KEY INTERMEDIATEABOVE 0.1% • NO NEW IMPURITY IS OBSERVEDIN API ABOVE THE QUALIFICATION THRESHOLD • EACH EXISTING IMPURITY IS WITHIN ITS STATED LIMIT • TOTAL IMPURITIES ARE WITHIN THE STATED LIMIT Dr. Pogány - WHO, Bangkok

  35. POTENTIAL SYNTHESIS IMPURITIES OF ARTESUNATE STARTING MATERIALS and REACTANTS • Potential impurities of artemisinin (pesticides) • Unreacted artemisinin • Unreacted artenimol (dihydroartemisinin), mixture of α- and β-epimers • Unreacted succinic acid (POTENTIAL) BY-PRODUCTS • Deoxy-artemisin • Dimers of artesunate • β-Artesunate Dr. Pogány - WHO, Bangkok

  36. RESIDUAL SOLVENTS • EACH EXISTING RESIDUAL SOLVENT(methanol, methylene chloride and heptane) IS WITHIN ITS STATED LIMIT • NEW RESIDUAL SOLVENTS, IN EITHER AN INTERMEDIATE OR THE API, ARE AT OR BELOW THE LEVELS RECOMMENDED IN THE ICH GUIDE • SKIP TESTING IS PERMITTED IF DOCUMENTED EVIDENCE HAS BEEN PROVIDED ON ABSENCE OF NOT LESS THAN ??? BATCHES Dr. Pogány - WHO, Bangkok

  37. ASSAY BY TITRATION During stability studies, the assay was increasing. The hydrolysis may yield artenimol and succinic acid. The latter can justify the increase in assay. + Dr. Pogány - WHO, Bangkok

  38. Artesunate – identification, impurities and assay Dr. Pogány - WHO, Bangkok

  39. CRITICAL DEFICIENCIES • Synthesis impurities, including residual solvents, which may be present in API, have not beencharacterised and analysed. • Analytical validation information-including experimental data for the analytical procedures used for testing the API and impurities-have not been provided. • The preparation and quality specification of primary (absolute) and secondary (working) standards has not been described. Dr. Pogány - WHO, Bangkok

  40. Section 2. APIs 2.7 Stability testing 2.7.1 Stress testing (forced degradation) 2.7.2 Regulatory stability testing Dr. Pogány - WHO, Bangkok

  41. FORCED DEGRADATION STUDIES • Intrinsic stability of the molecule (sensitivity of the API to potential effects of the external environment – selection of containers) • Identification of likely degradants • Stability-indicating power of assay method • Stability studies of the FPP • No standard method, 10-30% degradation, stress factors, conditions and time • Solid state degradation (supporting information) Dr. Pogány - WHO, Bangkok

  42. REGULATORY STABILITY TESTING • It is not necessary to examine specifically for certain degradation products if it has been demonstrated that they are not formed at 50-60 oC under moderate stress conditions. • Photostability (ICH Q1B, non-compendialAPIs) • Stability protocol, report with professional evaluation of data is required. • A re-test period should be derived from the stability information, and the approved retest date should be displayed on the container label. Dr. Pogány - WHO, Bangkok

  43. DATA OF STABILITY BATCHES The batches should be representative of the manufacturing process and should be manufactured from different batches of key intermediates. Dr. Pogány - WHO, Bangkok

  44. TEST PARAMETERS • CHEMICAL CHARACTERISTICS (ASSAY AND IMPURITIES INCLUDING DEGRADANTS) • PHYSICAL CHARACTERISTICS (PHOTOSTABILITY, APPEARANCE AND WATER) • MICROBIOLOGICAL ATTRIBUTES (STERILE APIS AS A RULE) Dr. Pogány - WHO, Bangkok

  45. GENERAL CONDITIONS • REAL TIME 25± 2oC and 60 ±5 %RH, 12 months • INTERMEDIATE 30± 2oC 65±5%RH, 6-12 months • ACCELERATED 40o ± 2oC 75 ±5%RH, 3-6 months (There may be justified exceptions with grandfathered drugs.) Dr. Pogány - WHO, Bangkok

  46. OBJECTIVE: RETEST PERIOD Regulatory stability studies provide documented evidence that an API remains within specification during the re-test periodif stored in the original container under prescribed conditions. • An API is considered as stable if it is within the defined/regulatory specifications when stored at 30 ± 2 oC / 65 ± 5 % RH for 2 years and at 40 ± 2 oC / 75 ± 5 % RH for 6 months. Dr. Pogány - WHO, Bangkok

  47. STABILITY and LABELING NOTE FOR GUIDANCE ON DECLARATION OF STORAGE CONDITIONS IN THE PRODUCT PARTICULARS. (LABELING OF PRODUCTS SENSITIVE TO TEMPERATURE, LIGHT AND HUMIDITY). Dr. Pogány - WHO, Bangkok

  48. FPPquality issues Illustrative examples of requirements

  49. Part 3.FPP(s) 3.1 Manufacturing and marketing authorization 3.2 Pharmaceutical development 3.2.1 Company research and development 3.2.2 Information from literature 3.3 Formulation 3.4 Sites of manufacture Dr. Pogány - WHO, Bangkok

  50. MARKETING AUTHORIZATION • If the FPP has been locally developed and manufactured, the national drug regulatoryauthority (NDRA)must evaluate the data set itself (p. 23). • If an evaluation report—critical summary and interpretation of the data, with conclusions—is not available, it is not possible to seek a WHO-type certificate(p. 23). Dr. Pogány - WHO, Bangkok

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