Pharmaceutical Quality Information Form PQIF API PowerPoint Presentation

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Guilin, January, 9 -13, 2006 Dr. Birgit Schmauser, BfArM, Bonn Pharmaceutical Quality Information Form (PQIF) - API

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Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn 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

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Guilin, January, 9 – 13, 2006 Dr. 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 Active Substance Master File Procedure [CPMP/QWP/227/02 Rev 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]

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Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn 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)

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Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn 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

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Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn 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

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Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn 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

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Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn 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

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Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn 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

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Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn 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)

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Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn 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)

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Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn 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

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Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn 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

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Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn 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

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Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn 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

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Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn 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

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Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn 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

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Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn 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.

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Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn 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?

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Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn 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

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Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn 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)]

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Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn 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

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Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn 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

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Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn 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

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Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn 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

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Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn 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)

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Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn 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.

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Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn 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

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Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn 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.

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Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn 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

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Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn 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

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Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn 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)

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Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn 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

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Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn 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

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Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn 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.

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Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn 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)

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Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn 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

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Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn 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)

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Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn 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

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Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn 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

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Guilin, January, 9 – 13, 2006 Dr. Birgit Schmauser, BfArM, Bonn 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