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Pharmaceutical Quality Information Form (PQIF) - API

Pharmaceutical Quality Information Form (PQIF) - API. Abbreviations. API A ctive P harmaceutical I ngredient ASMF A ctive S ubstance M aster F ile CHMP C ommittee for M edicinal P roducts for H uman Use CPMP C ommittee for P roprietary M edicinal P roducts

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Pharmaceutical Quality Information Form (PQIF) - API

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  1. Pharmaceutical Quality Information Form(PQIF) - API Dr. Birgit Schmauser, BfArM, Bonn

  2. Abbreviations • API Active Pharmaceutical Ingredient • ASMF Active Substance Master File • CHMP Committee for Medicinal Products for Human Use • CPMP Committee for Proprietary Medicinal Products • DMF Drug Master File • EDQM European Directorate for the Quality of Medicines • FPP Finished Pharmaceutical Product • ICH International Conference on Harmonization • OOS Out Of Specification • PQIF Pharmaceutical Quality Information Form • QWP Quality Working Party Dr. Birgit Schmauser, BfArM, Bonn

  3. 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 Active Substance Master File Procedure [CPMP/QWP/227/02Rev 1] • 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 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 Q2B Validation of Analytical Procedures: Methodology [CPMP/ICH/281/95] Dr. Birgit Schmauser, BfArM, Bonn

  4. 2. Active Pharmaceutical Ingredient(s) [API(s)] • Presentation of information on the API • Full details as required according to Section 2 of the: • 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] • Full details according to the Drug Master File (Active Substance Master File) Procedure • Guideline on Active Substance Master File Procedure [CPMP/QWP/227/02 Rev 1] • With or without certification (EDQM) • (applicable only to Ph. Eur. - APIs) Dr. Birgit Schmauser, BfArM, Bonn

  5. 2. Active Pharmaceutical Ingredient(s) [API(s)] II • Advantages of the use of a DMF (ASMF) • Full details of chemistry, manufacturing process, quality controls during manufacture process validation, quality controls at batch release and stability • Once the DMF (ASMF) is prequalified, reference may be made to it in subsequent applications • Conditions for the reference • Information on regular updates must be provided • Version number and date must be assigned Dr. Birgit Schmauser, BfArM, Bonn

  6. Deficiencies from prequalification • DMF (ASMF) • No version number and no date assigned • Deficiency letters from WHO/prequalification are not addressed • Instead an update without reference to the deficiency list is submitted • No tabular overview is provided to WHO outlining the nature and the extent of the changes (updates) compared to the previous version • Updates are not properly justified/explained • Change in the route of synthesis • Change in the last step of purificaton/crystallization • No transparency with the use of DMFs Dr. Birgit Schmauser, BfArM, Bonn

  7. 2.2 Properties of API(s) • Categories of APIs • 2.2.1 API not described in BP, PhInt, PhEur or USP • Considered new, used for the first time in a FPP • Risk estimation high • Full information necessary • 2.2.2 API described in BP, 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 Dr. Birgit Schmauser, BfArM, Bonn

  8. 2.2 Properties of API(s) II • Categories of Antimalarials • APIs with existing monographs in major international pharmacopoeias • Amodiaquine, Chloroquine (-phospate, -sulfate), Dapsone, Quinine (-sulfate, -phosphate), Mefloquine, Sulfadoxine/Pyrimethamine, Trimethoprim • APIs with existing monographs in major international pharmacopoeias (recently) • Arthemether, Artemisinine, Artemotil, Artenimol (Dihydroartemisinine), Artesunate, • APIs without existing monographs in major international pharmacopoeias • Chlorproguanil, Lumefantrine, Naphthoquine, Piperaquine, Pyronaridine Dr. Birgit Schmauser, BfArM, Bonn

  9. 2.2 Properties of API(s) III • 2.2.1 APIs not described in BP, PhInt, PhEur or USP • a) evidence of chemical structure • spectral data • interpretation of data (narrative) • b) evidence of chemical structure • Isomerism • Stereochemistry • discussion of potential isomeric forms Dr. Birgit Schmauser, BfArM, Bonn

  10. 2.2 Properties of API(s) III cont. • 2.2.1 APIs not described in BP, PhInt, PhEur or USP • Properties relevant/critical for the performance of the API • c) potential polymorphic forms • physicochemical and physical characteristics (solubility, hardness, compressibility, density, melting point, etc.) may differ • polymorphism must be controlled • d) particle size distribution • requirement for low solubility drugs (dissolution, bioequivalence) • e) additional characteristics • critical characteristics to be controlled to ensure consistent performance of the API (e.g. hygroscopicity) Dr. Birgit Schmauser, BfArM, Bonn

  11. 2.2 Properties of API(s) IV • 2.2.1 APIs described in BP, PhInt, PhEur or USP • chemical structure elucidated [a) – b)], control of structure by suitable identification tests • Properties relevant/critical for the performance of the API (not necessarily covered by the monograph) • a) potential polymorphic forms • physicochemical and physical characteristics (solubility, hardness, compressibility, density, melting point, etc.) may differ • polymorphism must be controlled • b) particle size distribution • requirement for low solubility drugs (dissolution, bioequivalence) • c) additional characteristics • critical characteristics to be controlled to ensure consistent performance of the API (e.g. hygroscopicity) Dr. Birgit Schmauser, BfArM, Bonn

  12. 2.3 Site(s) of manufacture • Each API-manufacturer to be listed • Information on the quality of the API must be clearly linked to the respective manufacturing site (synthesis, production) • Name • Street address • Phone, Fax, Email • If applicable • referenced DMFs • letters of access Dr. Birgit Schmauser, BfArM, Bonn

  13. Deficiencies from prequalification • Quality of API missing • Detailed quality description on the API provided by one manufacturer, alternative manufacturers are named without presentation of information on the API • API-manufacturer and quality of API missing • Alternative API-manufacturers are not listed, but are revealed from the FPP-part of the dossier Dr. Birgit Schmauser, BfArM, Bonn

  14. 2.4 Route(s) of synthesis • 2.4.1 API not described in BP, PhInt, PhEur or USP • Controls of critical steps and intermediates • Potential impact on the quality of the API and intermediates • Process conditions, test requirements and other relevant parameters to be controlled within predetermined limits • Examples 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 Dr. Birgit Schmauser, BfArM, Bonn

  15. 2.4 Route(s) of synthesis II • 2.4.1 API not described in BP, PhInt, PhEur or USP • Process Validation and/or Evaluation • All steps that are identified as critical for the API to be validated • All steps covering aseptic processing or sterilization to be validated Dr. Birgit Schmauser, BfArM, Bonn

  16. 2.4 Route(s) of synthesis III • 2.4.1 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: • Clinical • Comparative • Stability • Scaleup • Pilot • Production Dr. Birgit Schmauser, BfArM, Bonn

  17. 2.4 Route(s) of synthesis IV • 2.4.1 API not described in BP, PhInt, PhEur or USP • Impurities • Identification 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 Dr. Birgit Schmauser, BfArM, Bonn

  18. 2.4 Route(s) of synthesis V • Potential impurities of Artemisinines • Starting material (extracted from herbal sources) • GuideGeneric: • Starting materials from vegetable origin should be fully charcterized 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. Dr. Birgit Schmauser, BfArM, Bonn

  19. 2.4 Route(s) of synthesis VI • Potential impurities of Artemisinines • Subsequent chemical reactions • Application of the scheme provided in PQIF 2.4.1, a) Impurities • Critical process steps to be controlled • Stereochemistry of the hydration step - stereoselective control method? • Derivatisation/Ether-/Esterification (stereoselectivity?) • Artemether, Artesunate, Artemotil - stereoselective purification procedure? - stability of the - ether versus -ester • Transformation Artenimol>>>Artemisinine? Dr. Birgit Schmauser, BfArM, Bonn

  20. 2.4 Route(s) of synthesis VII • 2.4.1 API not described in BP, PhInt, PhEur or USP • Setting the acceptance criteria for impurities • Maximum daily dose (total daily intake) • ICH thresholds for drug-related impurities • Concentration limits for process related impurities • Residual solvents • Heavy metals • Available safety and toxicity data • Documented impurity levels according to the scheme provided • Reference to the analytical procedures used • Specificity, sensitivity • Justification of proposed acceptance criteria Dr. Birgit Schmauser, BfArM, Bonn

  21. 2.4 Route(s) of synthesis VIII • 2.4.1 API not described in BP, PhInt, PhEur or USP • Setting the acceptance criteria for impurities • ICH thresholds for drug related impurities [ICH Q3A (R)] Dr. Birgit Schmauser, BfArM, Bonn

  22. Deficiencies from prequalification • Methods to assess impurities are not sensitive enough to assess impurities • Quantitation limit (1%) far above the identification and qualification threshold(0.05 – 0.15%) • Listing of impurities limited to those actually detected • Potential impurities are not discussed • Impurity levels are far above the qualification limit without justification Dr. Birgit Schmauser, BfArM, Bonn

  23. 2.4 Route(s) of synthesis IX • 2.4.2 Specifications of raw materials and intermediates used in the synthesis • Quality and controls of materials coming into the process • Starting materials • Raw materials • Intermediates • Reagents • Catalysts • Solvents • Specifications Dr. Birgit Schmauser, BfArM, Bonn

  24. 2.4 Route(s) of synthesis X • 2.4.2 Specifications of raw materials and intermediates used in the synthesis • Particularly addressing the TSE-safety of all materials coming into the process • Proof of safety by relevant data • CEP • Letter of attestation Dr. Birgit Schmauser, BfArM, Bonn

  25. 2.4 Route(s) of synthesis XI • 2.4.3 API described in BP, PhInt, PhEur or USP • Impurities that are not included in the monograph • Process related impurities • Key intermediates • Residual solvents • Potential organic impurities not covered by the monograph Dr. Birgit Schmauser, BfArM, Bonn

  26. 2.5 Specifications • 2.5.1 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) Dr. Birgit Schmauser, BfArM, Bonn

  27. 2.5 Specifications II • 2.5.1 API not described in BP, PhInt, PhEur or USP • Skip testing • ICH 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. Dr. Birgit Schmauser, BfArM, Bonn

  28. 2.5 Specifications III • 2.5.1 API not described in BP, PhInt, PhEur or USP • Skip testing • ICH 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) • GuideGeneric • 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 Dr. Birgit Schmauser, BfArM, Bonn

  29. 2.5 Specifications IV • 2.5.1 API not described in BP, PhInt, PhEur or USP • Batch analyses • Description of the batches • Results of the batches • Certificates of Analysis • Discussion of the results with respect to the use of the batch • Clinical, Comparative etc. Dr. Birgit Schmauser, BfArM, Bonn

  30. 2.5 Specifications V • 2.5.1 API not described in BP, PhInt, PhEur or USP • Justification of Specifications • Evolution of tests • Evolution of analytical procedures • Evolution of acceptance criteria • Differences from compendial standards • f.ex. assay and impurities, heavy metals, residue on ignition Dr. Birgit Schmauser, BfArM, Bonn

  31. 2.5. Specifications VI • 2.5.1 API not described in BP, PhInt, PhEur or USP • Justification of Specifications • ICH 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 Dr. Birgit Schmauser, BfArM, Bonn

  32. 2.5 Specifications VII • 2.5.1 API not described in BP, PhInt, PhEur or USP • Reference standards or materials • ICH Q2B • Reference standards/materials should be well characterized with documented purity • 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) Dr. Birgit Schmauser, BfArM, Bonn

  33. 2.5 Specifications VIII • 2.5.1 API not described in BP, PhInt, PhEur or USP • Reference standards or materials (in-house) • Primary (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) standard • Documented purity with reference to the primary (absolute) standard • Intervals of control of content and duration of use Dr. Birgit Schmauser, BfArM, Bonn

  34. 2.5 Specifications IX • 2.5.1 API not described in BP, PhInt, PhEur or USP • Validation of analytical procedures • Stability indicating potential • Any in-house analytical procedure needs to be validated • ICH Q2A, ICH Q2B • Assay and impurities • Stress testing provides degradants that may occur during storage • Isolation of impurities and (stable) degradants in the development phase • In situ generation of potential degradants • Validation of analytical procedures for assay and impurities/degradants • Spiking experiments with isolated degradants/impurities • In situ use of stressed samples • Peak purity analysis of API-peaks Dr. Birgit Schmauser, BfArM, Bonn

  35. 2.5 Specifications X • 2.5.2 API described in BP, PhInt, PhEur or USP • Name the monograph • Name any test methods referenced in the monograph but not appearing in it • List of tests beyond the scope of the monograph • Residuals, 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. Dr. Birgit Schmauser, BfArM, Bonn

  36. Specifications XI • 2.5.2 API described in BP, PhInt, PhEur or USP • Additional requirements • 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) Dr. Birgit Schmauser, BfArM, Bonn

  37. 2.5 Specifications XII • 2.5.2 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: • New chapter USP <1226> Verification of analytical procedures • Pharmacopoeial Forum 31, No. 2, March/April 2005 • System suitability test • PhEur 2.2.46 • Insufficient Precision (RSD=s) leads to OOS results • 3 x s≤ 2% (assay specification) • Validation with respect to the stability indicating nature of the methods • For impurities/degradants not covered by the monograph • If the pharmacopoeial method is modified Dr. Birgit Schmauser, BfArM, Bonn

  38. Deficiencies from prequalification • Pharmacopoeial 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 do not control the quality of the API • Only one type of Reference standard is provided and simply represents API from a normal batch. • In-house absolute reference standards are not validated against available official standards. • Pharmacopoeial methods are modified but impurity profile is not adapted. • f.ex. Impurity A (in-house method) is different from Impurity A (pharmacopoeial method) Dr. Birgit Schmauser, BfArM, Bonn

  39. 2.6 Container closure system • 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 component • Reference to specification for each packaging component • Description • Identification • Drawings of critical dimensions • Secondary packaging material • Non-functional (briefly) • Functional Dr. Birgit Schmauser, BfArM, Bonn

  40. 2.6 Container closure system II • Discussion of the suitability of the container closure system • Choice of material • Function of material • f.ex. protection • Moisture, light, oxygen • Safety of material • Compatibility with API • Sorption • Leaching Dr. Birgit Schmauser, BfArM, Bonn

  41. 2.6 Container closure system III • Artemisinines • Storage conditions PhInt: • Should 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 light • f.ex. types/colour of inner and outer bags/drums • Protection from oxygen and moisture (well-closed) • f.ex. type of inner/outer container • f.ex. use of seals, joints, gaskets Dr. Birgit Schmauser, BfArM, Bonn

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