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Pharmaceutical Quality Information Form (PQIF)

Pharmaceutical Quality Information Form (PQIF). API. PQIF. Summary of quality characteristics Focus on critical quality attributes Designed to facilitate prequalification For assessors For applicants. Abbreviations. API A ctive P harmaceutical I ngredient APIMF API M aster F ile

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Pharmaceutical Quality Information Form (PQIF)

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

  2. PQIF • Summary of quality characteristics • Focus on critical quality attributes • Designed to facilitate prequalification • For assessors • For applicants Dr. Birgit Schmauser, BfArM, Bonn

  3. Abbreviations • APIActive Pharmaceutical Ingredient • APIMFAPIMaster File • DMFDrug Master File • ASMFActive Substance Master File • CHMP CommitteeforMedicinalProductsforHumanUse • CPMP CommitteeforProprietaryMedicinalProducts • FPP FinishedPharmaceuticalProduct • ICH InternationalConferenceonHarmonisation • OOS OutofSpecification • QWPQualityWorkingParty Dr. Birgit Schmauser, BfArM, Bonn

  4. 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] • Guidance on Variations to a prequalified Dossier [Variation Guide] • 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] • 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

  5. 2. Active Pharmaceutical Ingredient(s) [API(s)] • Options 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 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 Pharmaceutical Ingredient Master File (APIMF) Procedure - Draft Dr. Birgit Schmauser, BfArM, Bonn

  6. 2. Active Pharmaceutical Ingredient(s) [API(s)] II • Essentials 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 • Presented in two different parts • OP (open part) • RP (restricted part) • Accompanied by essential references • Letter of access • Covering letter Dr. Birgit Schmauser, BfArM, Bonn

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

  8. Deficiencies from PQ • No transparency with APIMFs • No letter of access • Version no.? • Version date? • No adequate presentation of updates and changes • No covering letter • No tabulated summary, no „history“-overview, • No proper justification of update/change • Change of critical parameters Dr. Birgit Schmauser, BfArM, Bonn

  9. 2.2 Properties of API(s) • Categories of APIs • 2.2.1 API not described in BP, PhInt, PhEur or USP • Considered new • (?) information on (adverse) drug reaction • Risk estimation high • Profound information necessary • 2.2.2 API described in BP, PhInt, PhEur or USP • Considered in use • Information on (adverse) drug reaction (monitored) • Risk estimation based on available data • Information necessary limited to data beyond the monograph • Essential control by the monograph Dr. Birgit Schmauser, BfArM, Bonn

  10. 2.2 Properties of API(s) II • Categories of Antimalarials • APIs described in monographs of major international pharmacopoeias ( 1 decade) • Amodiaquine, Chloroquine, Dapsone, Quinine, Mefloquine, Sulfadoxine/Pyrimethamine, Trimethoprim • APIs described in monographs of major international pharmacopoeias (recently) • Arthemether, Artemisinin, Artemotil, Artenimol, Artesunate • APIs not described in monographs of major international pharmacopoeias • Chlorproguanil, Lumefantrine, Naphthoquine, Piperaquine, Pyronaridine Dr. Birgit Schmauser, BfArM, Bonn

  11. Properties of Antiinfectives • 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 (-) • Widely used in a large number of patients - mechanisms of resistance developed • Combinations • Artemisinines and well established APIs/new APIs • Prevent/prolong new resistance • Overcome established resistance Dr. Birgit Schmauser, BfArM, Bonn

  12. 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

  13. 2.2 Properties of API(s) III cont. • Properties relevant/critical for the performance of the API • c) potential polymorphic forms • Influence on physicochemical and physical characteristics (solubility, hardness, compressibility, density, melting point, etc.) • 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

  14. 2.2 Properties of API(s) IV • 2.2.1 APIs described in BP, PhInt, PhEur or USP • Evidence of chemical structure • control 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 forms • Influence on physicochemical and physical characteristics (solubility, hardness, compressibility, density, melting point, etc.) • 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

  15. 8 9 7 8a 10 11 12a 6 12 5a 5 1 3 4 2 Properties of Artemisinins • Artemisinin (C15H22O5) • 7 centers of asymmetry • 27potential isomers • One isomer in biosynthesis • Chemical synthesis • Feasable • Economically unacceptable • Chemical derivatization at C-10 (carbonyl-moiety)converts C-10 into an additional stereoisomeric center: • a- and b-isomers are formed Dr. Birgit Schmauser, BfArM, Bonn

  16. Properties of Artemisinins II Endo-peroxide-bond • 3D-image Artemisinin • www.chemexper.com Carbonyl-moiety 2 2 3 3 11 10 13 11 10 13 12 4 4 12 1 1 9 9 12a 12a 8a 5 5 8a 5a 5a 8 8 6 6 7 7 Dr. Birgit Schmauser, BfArM, Bonn

  17. Properties of Artemisinins • Proposed by Manufacturers • Diastereomers may differ in their melting point/specific optical rotation Dr. Birgit Schmauser, BfArM, Bonn

  18. Deficiencies from PQ • Pharmacopoeial specifications are not met without justification • Stereospecificity not adequately addressed • Pharmacopoeial methods are not being followed to generate respective data on properties • Data on properties are simply not provided at all (without justification) • IR-spectra are not compared to a primaryreference spectrum Dr. Birgit Schmauser, BfArM, Bonn

  19. 2.3 Site(s) of manufacture • Identification of each API-manufacturer • Name • Street address • Phone, Fax, Email • If applicable • Referenced DMFs (APIMFs) • Letters of access • Why is identification of API-manufacturers essential? Dr. Birgit Schmauser, BfArM, Bonn

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

  21. Deficiencies from PQ • Quality of alternate API-sources • Site of manufacture • Description of the API-quality • Before prequalification • Submission as part of the application • After prequalification • Submission as variation application • Guidance on variations to a prequalified dossier Dr. Birgit Schmauser, BfArM, Bonn

  22. 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

  23. 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 • All steps covering aseptic processing or sterilization Dr. Birgit Schmauser, BfArM, Bonn

  24. 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

  25. 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

  26. 2.4 Route(s) of synthesis V • 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

  27. 2.4 Route(s) of synthesis VI • 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

  28. 2.4 Route(s) of synthesis VII • 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

  29. 2.4 Route(s) of synthesis VIII • 2.4.2 Specifications of raw materials and intermediates used in the synthesis • TSE-safety of all materials coming into the process • CEP • Letter of attestation Dr. Birgit Schmauser, BfArM, Bonn

  30. 2.4 Route(s) of synthesis IX • 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

  31. Potential impurities of Artemisinins • 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. • 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

  32. Potential impurities of Artemisinins II • Impurities contained in the „starting material“ Artemisinin • Biosynthetic by-products • Arteannuin B , Artemisitene, Artemisinic acid, • Extraction from fresh leaves with CHCl3 within 1 min > 97% • Localisation in subcuticular space of the glands on the surface of the leaves • Thujone (?) • Cultivation reagents • Pesticide residues, fumigants, mycotoxins • Solvents from the extraction process • Hexane, benzene, acetonitril, ether, pentane, chloroforme…..(?) diesel, fuel (?) [ICH Q3A (R)] Dr. Birgit Schmauser, BfArM, Bonn

  33. 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) • The cuticule is crumpled after chloroforme extraction • The epidermal cells are unaffected by this treatment • From: F.C.W. Van Nieuverburgh et al., J Chromatogr. A 1118 (2006) 180-187 Dr. Birgit Schmauser, BfArM, Bonn

  34. Potential impurities of Artemisinins III • Unreacted starting material • Artemisinin (starting material for derivatives) • Artemisinic acid (starting matrial for dihydroartemisinin) • Dihydroartemisinin (starting material for derivatives) • …. • Unreacted intermediates, by-products • a-Arthemether, a-Artheether • a/b-Dihydroartemisinin • b-Artesunate • …. Dr. Birgit Schmauser, BfArM, Bonn

  35. Potential impurities of Artemisinins III cont. • Reagents, catalysts, residual solvents • Methanol, acetonitril, chloroforme, acetone … • NaBH4, succinic acid/anhydride, triethylamine, dimethylaminopyridine • Degradants • Stability of • ester-derivative (Artesunate) • ether-derivative (Artemether, Arteether) • lactone (Artemisinin) • Stability of artenimol (oxidation) • Susceptibility of endoperoxide bond to reduction • Deoxyartemisinine (loss of active principle ) • Zn / AcOH or FeBr2 / THF Dr. Birgit Schmauser, BfArM, Bonn

  36. Deficiencies from PQ • Description of synthesis only covers part of the synthesis route • Evaluation regarding impurities and degradants (?) • Details on stereospecificity of reaction steps are not addressed • Flow chart of the synthetic route is too cryptic • quantity of materials, IPCs, operational conditions, intermediates, purification steps • Narrative of the synthetic process is not provided • Final batch size • Environmental impact statement missing Dr. Birgit Schmauser, BfArM, Bonn

  37. Deficiencies from PQ cont. • Impurities, intermediates, by-products, degradants • Potential to be expected from synthesis is not discussed • Side 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%) Dr. Birgit Schmauser, BfArM, Bonn

  38. 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

  39. 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

  40. 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

  41. 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

  42. 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

  43. 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

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

  45. 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

  46. 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

  47. Deficiencies from PQ • The 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 unclear • Identity 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 provided Dr. Birgit Schmauser, BfArM, Bonn

  48. 2.5 Specifications IX • 2.5.1 API not described in BP, PhInt, PhEur or USP • Validation of analytical procedures • Any in-house analytical procedure needs to be validated • ICH Q2A, ICH Q2B • Assay and impurities • Capability to detect impurities and degradants from synthesis • Stability indicating potential Dr. Birgit Schmauser, BfArM, Bonn

  49. 2.5 Specifications X • 2.5.1 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 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

  50. Deficiencies from PQ • Methods are in use before they are validated • Validation is not considered at all • Serious deficiency • Results of batch analysis are not reliable • Stability studies are not evaluable Dr. Birgit Schmauser, BfArM, Bonn

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