Regulatory Requirements with Relevance for Quality of API

1. Regulatory Requirements with Relevance for Quality of API Beijing, March 2010 Jean-Louis ROBERT National Health Laboratory L – 1011 LUXEMBOURG CHMP co-opted member Chair CHMP/CVMP QWP

2. Topics addressed • General considerations – CTD-Q • Manufacturing: API starting materials • Impurities • Related substances • Residual solvents • Genotoxic impurities • Residual metal catalysts/reagents • Stability • EU Assessment Policy: known active substance • Conclusion • Back-up: References relevant guidelines • Application file CTD-Q structure • Decision tree identification/qualification impurities • Example of structure of genotoxic impurities

3. S.1 General Information • S.1.1 Nomenclature • S.1.2 Structure • S.1.3 General Properties • Physicochemical properties • Properties affecting pharmacological efficacy • …………..

4. S.2 Manufacture (1) • S.2.1 Manufacturer(s) • S.2.2 Description of Manufacturing Process and Process Controls • Flowchart • Sequential procedural narrative • Scale, range, yield…….. • S.2.3 Control of Materials • API starting material • Information on all materials of biological origin, incl. viral safety

5. S.2.3 Manufacture: API starting material (2) • API starting material incorporated as a significant structural fragment into the structure of the AS • Proposal and justification by the applicant • Full characterisation • Description of a one step synthesis not acceptable, unless described in the European Pharmacopoeia (CEP or compliance with EP monograph to be demonstrated) • Name of supplier has to be submitted • Detailed description of the synthesis and GMP compliance (ICH Q7) should go together.

6. S.2.3 Manufacture: API starting material only flow chart detailed description AS SM3 AS SM AS n AS SM

7. Example: Ibuprofen • N-Butyl-Ibuprofen as an impurity of Ibuprofen (n-butylbenzene present in starting material isobutylbenzene) Isobutyl-benzol Ibuprofen

8. Résolution test

10. S.2 Manufacture (2) • S.2.4 Controls for Critical Steps and Intermediates • Tests and acceptance criteria to be provided • S.2.5 Process Validation and/or Evaluation • Sterilisation process • S.2.6 Manufacturing Process Development • Changes in manufacturing occurring during development (pre-clinical, clinical, commercial) • Development of e.g. a design space, real time release testing

11. S.3 Characterisation • S.3.1 Elucidation of Structure and other Characteristics • Full elucidation or with reference to a pharmacopoeial standard • S.3.2 Impurities • Classification of Impurities • Organic impurities, Inorganic impurities, Residual solvents • Drug substance impurities: • Process (synthetic) and drug related impurities (degradation); • Drug product impurities: • Degradation products

12. Impurities: General Considerations • The ICH guidelines Q3A (R), [Q3B (R)], Q3C are the general basis for the control of impurities in active substances and medicinal products • Consideration of chemistry and safety aspects • Glossary • Initial scope: new active substances and corresponding products. • Extension to existing active substances and corresponding medicinal products. • European Pharmacopoeia: general monographs (e.g. Substances for Pharmaceutical Use) and chapters • New synthesis can generate new impurities (imp. profile) • Not necessarily qualified • In addition EU guidelines • Genotoxic Impurities Testing • Residual metal catalysts/ metal reagents

13. Q3A/B(R) and Q6A are complementary • Q3A-B: address the chemistry aspects and the safety aspects of impurities and defines different thresholds • reporting, • identification, • qualification. • Q6A: addresses the setting and justification of acceptance criteria and the selection of test procedures

14. Listing of 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

15. Thresholds (active substance) MDD < 2g MDD>2g Reporting T > 0.05% > 0.03% Identificat. T > 0.10% or > 0.05% 1.0 mg per day intake, whichever is lower • Qualificat. T > 0.15% > 0.05% • 1.0 mg per day intake, • whichever is lower

16. Active substances outside of the scope of the ICH guideline • For active substances outside of the scope of ICH guideline: • The applicant should justify adequate thresholds taking into account the nature of the active substance, the maximal daily dose, the duration of therapy, the ability of the analytical methods (current scientific status). • European Pharmacopoeia: • Organic impurities in peptides obtained by chemical synthesis: Reporting threshold: > 0.1% Identification threshold: > 0.5% Qualification threshold: > 1.0%

17. Scientific Discussion on Impurities • Summary of actual and potential impurities (sound scientific appraisal). Potential impurity: an impurity that can arise during manufacture or storage. It may or may not appear in the new drug substance. • Risk based approach (see also ICH Q9) • Thorough discussion by the applicant based on synthesis, reagents used, stability,... • Summary of laboratory studies conducted to detect impurities • Negative results can be helpful ! • Discussion on the impurity profiles found in preclinical and clinical trials: impurities above the qualification threshold have to be qualified.

18. Impurities to be specified - Rationale for the inclusion or exclusion of impurities • Scientific knowledge/understanding about the manufacturing process of the active substance • Knowledge about how an impurity is generated • Establishment of a control strategy • Specifications of AS starting materials • Control of impurities at intermediates rather than on final AS • Identification of critical process parameters influencing the impurity profile • Process controls • Purification steps: influence on the impurity profile of the final active substance • Knowledge about the degradation pathway

19. Reminder: Control Strategy (ICH Q10) • A planned set of controls, derived from current product and process understanding, that assures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control. • Consider each unit operation but also an overall control strategy.

20. Acceptance criteria for impurities • Acceptance criteria should be based on • Relevant development data • Test data for the active substance used in toxicological and clinical studies • Results from long term and accelerated stability data • Range of expected analytical and manufacturing variability • Actual results obtained should form the primary basis for establishing the acceptance criteria • They should not be higher than the qualification level

21. Reporting impurities content of batches • Results to be provided for batches used for clinical, safety and stability testing, as well as batches representative of the proposed commercial process. • To be reported: > Reporting threshold. • Batches: detailed information to be provided. • Identity / size • Date and site of manufacture • Manufacturing process • Impurities content, single, total • Use of batches • Reference to analytical procedure used

22. New Impurities • Decision Tree for Identification and Qualification (ICH-Q3A R2) • Description of considerations for the qualification and identification of impurities when thresholds are exceeded. • Recommendation what to do when new impurities appear during later stage of development or after authorisation.

23. Residual Solvents: Q3C • Residual Solvents: Q3C • Defines safety limits for solvents (class 1, 2, 3 and (4) solvents) • Option 1 based on concentration • Option 2 based on MDD and PDE • When the acceptance criteria are identical to the safety limits (as indicated in the NfG): no justification is needed (option 1).

24. Residual Solvents: Q3C • Class 1 solvents In all cases, the limit of a class 1 solvent in the final active substance should comply with the requirements of the NfG, even if initially not used as a solvent. e.g. benzene: - use as starting material (synthesis) - present as contaminant e.g. toluene - by-product from a chemical reaction

25. Residual Solvents: some commentsCHMP position paper • Class 2 solvents • As a principle: • Should be routinely controlled either in an intermediate or in the active substance; • Last step of the synthesis: • Routine control in the final active substance • Prior to the last step: • If <10% present in a suitable intermediate or in the active substance, need not be controlled routinely.

26. Genotoxic Impurities • Joint SWP-QWP “Guideline on the Limits of Genotoxic Impurities” • published 2006 • came into effect on 1 January 2007 • Basis: ICH Q3A/B guideline: “For impurities known to be unusually potent or to produce toxic or unexpected pharmacological effects, the quantification - detection limit of the analytical procedures should be commensurate with the level at which the impurities should be controlled”.

27. Genotoxic Impurities • Scope • New active substances • 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 GTIs are introduced as compared to products currently authorised in the EU containing the same active substance (idem variations) • No need for retrospectively application to authorised products, unless there is a specific cause for concern.

28. Genotoxic Impurities • Principles • Identifications guided by existing genotoxic data or the presence of structure alerts • Genotoxic compounds with sufficient evidence for a threshold-related mechanism • Genotoxic compounds without sufficient evidence for a threshold-related mechanism Threshold of Toxicological concern: TTC value: 1.5 µg/day

29. Genotoxic impurities • Pharmaceutical considerations • Try to avoid genotoxic reagents • Limitations (if possible) at an intermediate rather at the end active substance • Introduction of a specific purification step (destruction of genotoxic impurity) • Assessment from the applicant justifying the potential presence or non presence of the genotoxic impurity • Discussion/collaboration with safety experts important.

30. Genotoxic impurities SWP – QWP Q&As • Revision 1 issued June 2008 • The aim of the Q&As document is to provide clarification and harmonisation of interpretation of the Guideline on the Limits of Genotoxic Impurities • Addresses 7 key areas

31. Genotoxic impurities • “Cause for concern”: • If a manufacturing procedure for API remains essentially unchanged, a re-evaluation with respect to the presence of potentially genotoxic impurities is generally not needed. However, new knowledge may indicate a previously unknown “cause for concern”. • e.g. mesylate salt

32. Metal Catalysts/Metal Reagents Recommendation of acceptable concentration limits for the residues of metal catalysts or metal reagents that may be present in pharmaceutical substances or in drug products.

33. Metal Catalysts/Metal Reagents • EMEA/145858/2006 • General considerations • Same principles as for Residual Solvents ICH Q3C • Conservative approach compared to food additives • 3 classes • Class limit for class 1B • Reporting similar to ICH Q3C • Implementation 5 years (for existing products)

34. Metal Catalysts/Metal Reagents • Concept • Class 1 Metals: metals of high toxic potential • Known carcinogens • Class 2 Metals: metals with low toxic potential • Nutritional trace metals, common in food and food additives • Class 3 Metals: metals with no significant toxicity • Ubiquitous in environment, plants and animals • No need for health based exposure limit • Difference is made between oral, parenteral and inhalation exposure (class 1)

35. Metal Catalysts/Metal Reagents • Expectation: • The relevant residual metal should be controlled with a suitable method • Pharmacopoeial heavy metal test generally not acceptable • Further discussion at international level ongoing both on the methodology and the limits

36. Setting Specifications – Considerations Control of Impurities • Drug substance: • Identification of process parameter(s) (CQP) in the synthesis influencing the generation of a specific impurity in the final product: introduction of a specific in-process control: tightening of pH range. • Introduction of a specific purification step e.g. to limit a potential genotoxic impurity below TTC (degradation of this impurity).

37. Synthesis Indinavir Sulfate

38. Setting specification: GTI(case centralised authorised product) Final AS Intermediate II + Compound III Compound IV comp. III < 10 ppm (detection limit) < TTC (target) suspected GT

39. S.4 Control of Drug Substance • S.4.1 Specification • S.4.2 Analytical Procedures • S.4.3 Validation of Analytical Procedures • S.4.4 Batch Analyses • S.4.5 Justification of Specification

40. S.5 Reference Standards of Materials • Full characterisation • Pharmacopoeial standards

41. S.6 Container Closure System • Brief description of bulk container closure system

42. S.7 Stability (1) • S.7.1 Stability summary and Conclusions • S.7.2 Post-approval Stability Protocol and Stability Commitment • S.7.3 Stability Data

43. S.7 Stability (2) • EU in climatic zone I/II • Storage conditions according to ICH • Guidelines: • ICH 1A (R2): new active substances • CHMP: existing active substances derived from ICH guideline • In principle no difference in requirements between new active substances and existing active substances.

44. Stability: Storage conditions • General case * It is up to the applicant to decide whether long term stability studies are performed at 25°C ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH. In the latter case, no additional data under intermediate conditions will have to be generated.

45. Stability: Storage conditions • Refrigerator • Freezer

46. Stability: Further Considerations • Retest period to be defined • Pharmacopoeial substances: monographs cover synthetic and degradation products: if no retest date, batch has to be controlled immediately prior to be manufactured in the medicinal product.

47. DeclarationStorage Conditions (CPMP)

48. Setting Specifications: future position paper • Harmonisation approach for residual solvents, heavy metals, genotoxic impurities • Last step of the synthesis • Prior to the last step of the synthesis • …..

49. EU Assessment Policy (known ASs) • From a pharmaceutical quality point of view no difference is made between new active substances and “existing or known” active substances (and their corresponding products). • This is also highlighted in the European Pharmacopoeia where relevant ICH or CHMP guidelines or the policy adopted have been adopted: • Impurities • Residual solvents • Genotoxic impurities (EP policy) • Residual metal catalysts/reagents (EP policy)

50. EU Assessment Policy (known ASs) (2) • Applications for a MA of medicinal products containing existing active substances are assessed according to their own merit (based on quality risk management). • A summary of impurities present in batches of the active substance(s) …………..(and decomposition products arising during storage) as proposed for use in the product to be marketed together with an evaluation of these impurities. • For existing/known active substances, the European Pharmacopoeia general monograph “Substances for pharmaceutical use” is applicable.