Impurity Profiles in Active Pharmaceutical Ingredients

Transcription

1 Impurity Profiles in Active Pharmaceutical Ingredients EU/Swissmedic GMP Workshop Beijing University, Sept , 2006 Dr. Susanne Keitel Federal Institute for Drugs and Medical Devices (BfArM), Germany

2 Structure I. General principles II. III. IV. Dossier Requirements: NCE vs. Existing Substances, ASMF vs. CEP Specification of Impurities in the API Residual Solvents V. Metal Catalysts and Genotoxic Impurities VI. Need more Information?

3 Definition Impurity (1) Any component of the new drug substance which is not the chemical entity defined as the new drug substance. (2) Any component of the drug product which is not the chemical entity defined as the drug substance or an excipient in the drug product. ( ICH Q6A: Specifications) International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use

4 Classification of Impurities I Organic impurities (process- and drug-related) Inorganic impurities Residual solvents Polymorphic forms Enantiomeric impurities

5 Classification of Impurities II Organic impurities can arise during the manufacturing process and/or storage of the API. They can be identified or unidentified, volatile or non volatile e.g.: Starting materials By-products Intermediates Degradation products Reagents, ligands and catalysts

6 Classification of Impurities III Inorganic impurities can result from the manufacturing process, they are normally known and identified and include e.g.: Reagents, ligands, catalysts Heavy metals or other residual metals Inorganic salts Other materials, e.g. filter aids, charcoal.

7 Structure I. General principles II. III. IV. Dossier Requirements: NCE vs. Existing Substances, ASMF vs. CEP Specification of Impurities in the API Residual Solvents V. Metal Catalysts and Genotoxic Impurities VI. Need more Information?

8 API Documentation in the Licensing Process I S Drug Substance S.1 General Information: Nomenclature Structure General Properties S.2 Manufacture Manufacturer(s) Description of Manufacturing Process and Process Controls Control of Materials Controls of Critical Steps and Intermediates Process Validation and/or Evaluation Manufacturing Process Development

9 API Documentation in the Licensing Process II S.3 Characterisation Elucidation of Structure and Other Characteristics Impurities S.4 Control of Drug Substance Specification Analytical Procedures Validation of Analytical Procedures Batch Analyses S.5 Reference Standards or Materials S.6 Container Closure System S.7 Stability

10 Classification of APIs New chemical entities (NCE), used for the first time in a medicinal product for human or veterinary use Existing substances, not covered by a monograph in the European Pharmacopoeia or the national pharmacopoeia of an EU Member State Existing substances covered by a monograph in one of above pharmacopoeia

11 API Documentation in the Application File Bundesinstitut für Arzneimittel Complete part 3.2. S Active Substance Master File (ASMF) for new and existing APIs, not for biotech or biologicals! Certificate of Suitability of the European Directorate for the Quality of Medicines EDQM - (CEP; only for APIs covered by a Ph. Eur. monograph and for demonstration of TSE-safety)

12 New Chemical Entities I 3.2. S 3.2: Information on impurities Discussion of potential impurities arising from the synthesis, indication of their origin Statement whether actual samples of such impurities have been synthesized for test purposes. Structural analysis data and information which of the analytical methods described have been used to detect that impurity Discussion of possible routes of degradation Analytical methods (LOD and LOQ) used to detect likely impurities or other related impurities

13 New Chemical Entities II Copies of relevant chromatograms Summary on the nature and levels of actual impurities detected in the batch samples Justification for selecting the limits based on safety and toxicity data as well as on the methods used to control impurities?

14 New Chemical Entities III 3.2. S 7.3: Stability Data Forced degradation studies as integral part of the dossier. Aim: to generate degradation products and elucidate degradation pathways, e.g. hydrolysis, photolysis, thermal stress, oxidation. Information on the analytical methods and their validation

15 Existing Substances - ASMF vs. CEP Identical requirements on the documentation, i.e. pharmacopoeial monograph is able to detect all impurities resulting from the specific synthesis used Assessment: Competent Authority ASMF EDQM CEP

16 ASMF Open (applicant s) part, closed (confidential) part, letter of access Intended to keep trade secrets/know-how of API manufacturer confidential Submission only possibly in connection with a marketing authorisation application or variation!

17 ASMF Section ASMF Section Name AP RP 3.2.S.1 General information 3.2.S.2 Manufacture 3.2.S.2.1 Manufacturer(s) 3.2.S.2.2 Description of manufacturing process and process controls 3.2.S.2.3 Control of materials 3.2.S.2.4 Control of critical steps and intermediates 3.2.S.2.5 Process validation and evaluation 3.2.S.2.6 Manufacturing process development 3.2.S.3 Characterisation 3.2.S.4 Control of Drug Substance 3.2.S.5 Reference standards or materials 3.2.S.6 Container closure system 3.2.S.7 Stability ( )

18 EDQM Certification Scheme API-manufacturer (or representative or broker) submits dossier to EDQM Dossier assessment based on the current pharmacopoeial monograph and ICH-/CHMP- guidelines done by experts nominated by national competent authorities, i.e.quality assessors of NCAs (rapporteur/ co-rapporteur) Deficiency letter sent to the applicant, where relevant, and submission of response document to clarify open issues/deficiencies Granting of a Certificate of Suitability (CEP) by EDQM. Inclusion of additional tests/specifications/test methods, where relevant Marketing authorisation applicant submits CEP issued to the API-manufacturer in the dossier to demonstrate API quality NO CARTE BLANCHE!

19 EDQM Certification Scheme Basis for Assessment: Knowledge of the syntheses which the monograph is based upon Current relevant ICH/ CHMP-guidelines, use of toxicological expertise, where relevant Revision of monographs may be initiated based on the information gained from the application for CEPs

20 Pharmacopoeial Substances without CEP or ASMF Bundesinstitut für Arzneimittel Demonstration that pharmacopoeial monograph is able to detect all impurities resulting from the specific synthesis used Literature data not sufficient Data to demonstrate that all impurities are detected and separated from the main peak

21 Specification of Impurities in the API Impurities Testing Guideline: Impurities in New Drug Substances (ICH Q3A (R2)) Specific pharmacopoeial monograph and general monograph Substances for pharmaceutical use

22 Use of Ph.Eur. Monographs for API Specific monograph, e.g. Gentamicine sulphate, Acetazolamide + General texts: e.g. residual solvents impurities in substances for pharmaceutical use + General monographs Products of fermentation Products with a risk of transfer of spongiform encephalopathies of animal origin Substances for pharmaceutical use

23 Structure I. General principles II. III. IV. Dossier Requirements: NCE vs. Existing Substances, ASMF vs. CEP Specification of Impurities in the API Residual Solvents V. Metal Catalysts and Genotoxic Impurities VI. Need more Information?

24 Definition of Impurities I Identified Impurity: An impurity for which a structural characterisation has been achieved Specified Impurity: An impurity that is individually listed and limited with a specific acceptance criterion in the specification. Can be either identified or unidentified Unidentified Impurity: An impurity for which a structural characterisation has not been achieved and that is defined solely by qualitative analytical properties (e.g. chromatographic retention time)

25 Definition of Impurities II Unspecified Impurity: An impurity that is limited by a general acceptance criterion, but not individually listed with its own specific acceptance criterion in the specification Qualification: Process of acquiring and evaluating data that establishes the biological safety of an individual impurity or a given impurity profile at the level(s) specified

26 Specification of Impurities Organic Impurities Each specified identified impurity Each specified unidentified impurity Any unspecified impurity with an acceptance criterion of not more than the identification threshold Total impurities Residual Solvents Inorganic Impurities

27 Thresholds for Impurities Thresholds Maximum Reporting Identification Qualification Daily Dose Threshold Threshold Threshold 2 g/day > 0.05 % > 0.10 % or 1.0 mg/day > 0.15 % or 1.0mg/day (whichever is lower) (whichever is lower) > 2 g/day > 0.03 % > 0.05 % > 0.05 % number of decimal digits: two below 1.0 %, one above 1.0 % application of conventional rounding rules total impurities > 0.05 %

28 Illustration of Reporting Impurity Results Action Raw Result Reported Identification Qualification (%) Result (%) (0.10 %) (0.15 %) It may be appropriate to re-measure the actual amount of the impurity present and re-evaluate against the qualification threshold if the response factor is determined to differ significantly from the original assumptions

29 Structure I. General principles II. III. IV. Dossier Requirements: NCE vs. Existing Substances, ASMF vs. CEP Specification of Impurities in the API Residual Solvents V. Metal Catalysts and Genotoxic Impurities VI. Need more Information?

30 Classification of Residual Solvents Class I Class II Class III solvents to be avoided Known human carcinogens, strongly suspected human carcinogens, and environmental hazards Non-genotoxic animal carcinogens or possible causative agents of other irreversible toxicity. Solvents suspected of other significant but reversible toxicities solvents to be limited solvents with low toxic potential Solvents with low toxic potential to man; no health-based exposure limit is needed

31 Classification of Residual Solvents Class I Class II Class III solvents to be avoided solvents to be limited Benzene, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethene, 1,1,1- trichloroethane solvents with low toxic potential Acetonitrile, chloroform, cyclohexane, dioxane, methanol, methylbutylketone, tetrahydrofurane, toluene,... Acetone, butanol, butyl acetate, DMSO, ethanol, ethyl acetate, ethyl ether, heptane, isopropanol, methylethyl ketone,...

32 Specification of Residual Solvents in the API Class 1 residual solvents to be avoided, BUT are they always avoidable? Bundesinstitut für Arzneimittel Starting material: e.g. benzene, 1,2-dichloroethane in early steps in synthesis By-products from chemical reaction: e.g. benzene as a Grignard-by-product Impurity in another residual solvents: e.g. benzene as an impurity in toluene NO Need for control!

33 Class 1 Solvents as Impurity Routine test on a suitable intermediate or the final API OR Control of the solvent impurity in the originator solvent: level below limit specified in guideline (volatility of both solvents in drying processes must be taken into account!) NMT 30% of the specified limit in a suitable intermediate of final API, supporting data on 6 consecutive pilot scale- or 3 production scale batches Specification for originator solvent includes routine test and limit for the class 1 solvent

34 Specification of Class 2 Solvents Use in the last step of synthesis need for routine control in the final API Use prior to the last step of synthesis exemption from need for routine test if demonstrated on a suitable intermediate of the final API that content of solvent is NMT 10 % of the acceptable concentration limit stated in the ICH guideline (e.g. acetonitrile 41 ppm). Supporting data on 6 consecutive pilot scale or 3 production scale batches required!

35 Specification of Residual Solvents in the API Changes to the manufacturing process of an API in which it has been demonstrated initially that a Class 1 or Class 2 solvent is below the defined threshold for routine testing: Bundesinstitut für Arzneimittel Need to consider impact of process changes on solvent levels and revalidation, as necessary!

36 Structure I. General principles II. III. IV. Dossier Requirements: NCE vs. Existing Substances, ASMF vs. CEP Specification of Impurities in the API Residual Solvents V. Metal Catalysts and Genotoxic Impurities VI. Need more Information?

37 Residues of Metal Catalysts Draft EU-guideline on the Specification Limits for Residues of Metal Catalysts, scope: Metal catalysts in API and excipients 14 different elements PDE - maximum patient exposure tabulation of recommendations on oral and parenteral PDEs, taking oral bioavailability into account Routine control, based on suitable validated method Exception: validated reduction method for a specific catalyst established

38 Genotoxic Impurities EU-Guideline on the Limits of Genotoxic Impurities, addition to ICH Q 3 A and B For impurities known to be unusually potent or to produce toxic or unexpected pharmacological effects, the quantitation/detection limit of the analytical methods should be commensurate with the level at which the impurities must be controlled.

39 Genotoxic Impurities Scope: NCEs new applications for existing active substances where assessment of the route of synthesis, process control and impurity profile does not provide reasonable assurance that no new or higher levels of genotoxic impurities are introduced known genotoxic activity - normally based on positive findings in in-vivo mammalian test(s), supplemented by respective finding from in-vitrotest(s)

40 Genotoxic Impurities Establishment of two classes I. genotoxic substances with sufficient evidence for a threshold-related mechanism e.g. topoisomerase inhibition, inhibition of DNA -synthesis, interaction with the spindle apparatus of cell division,... establishment of exposure levels without appreciable risk of genotoxicity according to the procedure for class 2 solvents. Calculation of a PDE, derived from the noobserved-effect-level (NOEL) or the lowest-observedeffect level LOEL

41 Genotoxic Impurities II. Genotoxic compounds without sufficient evidence for a threshold-related mechanism, e.g. alkylating agents ALARP principle as low as reasonably practicable Case-by-case decision a) pharmaceutical assessment b) toxicological assessment Overall Risk-Benefit Evaluation

42 Genotoxic Impurities TTC concept (threshold of toxicological concern) Definition of a common exposure level for any unstudied chemical that will not pose a risk or significant carcinogenicity or other toxic TTC estimated as 1.5 µg/person/day - Not applicable to highly potent genotoxic carcinogens: aflatoxin-like -, N-nitroso -, azoxy compounds. This group requires compound-specific toxicity data!! - Not applicable to carcinogens where adequate toxicity data (long-term studies) are available and allow for a compoundspecific risk assessment!

43 Structure I. General principles II. III. IV. Dossier Requirements: NCE vs. Existing Substances, ASMF vs. CEP Specification of Impurities in the API Residual Solvents V. Metal Catalysts and Genotoxic Impurities VI. Need more Information?

44 Need More Information? ICH Harmonised Tripartite Guideline Q3A(R): Impurities in New Drug Substances. (February 2002). CPMP/ICH/2737/99 ICH Harmonised Tripartite Guideline Q3C: Impurities: Residual Solvents. CPMP/ICH/283/95 ICH Harmonised Tripartite Guideline Q3C(M): Impurities: Residual Solvents (Maintenance) PDE for N-Methylpyrrolidone (NMP) and PDE for Tetrahydrofurane. CPMP/ICH/1940/00 corr. (Nov 2002) und CPMP/ICH/1507/02 (April 2002). Annexes to: CPMP/ICH/283/95 Impurities: Guideline for Residual Solvents... Annex 1: Specifications for class 1 and class 2 residual solvents in active substances. Annex 2: Residues of solvents used in the manufacture of finished products. CPMP/QWP/450/03 (July 2004)

45 Note for Guidance on specification limits for residues of metal catalysts (June 2002). CPMP/SWP/4446/00 - Draft Guideline on the limits of genotoxic impurities (June 2006). CPMP/SWP/5199/02 ICH Harmonised Tripartite Guideline Q6A: Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances. CPMP/ICH/367/96 Guideline on active substance master file procedure. CPMP/QWP/227/02 (January 2004) ICH Harmonised Tripartite Guideline Q1A(R2): Stability Testing of New Drug Substances and Products (February 2003) CPMP/ICH/2736/99 ICH Harmonised Tripartite Guideline Q1B: Photostability Testing. CPMP/ICH/279/95 ICH Harmonised Tripartite Guideline Q1C: Stability Testing for New Dosage Forms. CPMP/ICH/280/95 ICH Harmonised Tripartite Guideline Q1E: Evaluation of Stability Data. (February 2003) Bundesinstitut für Arzneimittel

46 Note for Guidance on stability testing: stability testing of existing active substances and related finished products. CPMP/QWP/122/02, corr. ICH Harmonised Tripartite Guideline Q2A: Text on Validations of Analytical Procedures. CPMP/ICH/381/95 ICH Harmonised Tripartite Guideline Q2B: Methodology. CPMP/ICH/281/95 Guideline on the chemistry of new active substances. CPMP/QWP/130/96, Rev.1 Note for Guidance: Investigation of Chiral Active Substances. EC Document III/3501/91-EN

47 Need for more information? dralex/homev2.htm

48 Abbreviations ALARP as low as reasonably practicable ASMF active substance master file CEP Certificate of Suitability CTD Common Technical Document EDQM European Directorate for the Quality of Medicines LOEL lowest-observed-effect level NCA national competent authority NCE new chemical entity NMT not more than ( ) NOEL no-observed-effect level PDE permitted daily exposure QWP Quality Working Party SWP Safety Working Party TTC Threshold of Toxicological Concern