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

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

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

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

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.

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

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

Résolution test

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

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

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

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

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

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

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%

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.

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

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.

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

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

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.

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).

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

Residual Solvents: some comments CHMP 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.

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”.

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.

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

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.

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

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

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.

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)

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)

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

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).

Synthesis Indinavir Sulfate

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

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

S.5 Reference Standards of Materials Full characterisation Pharmacopoeial standards

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

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

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.

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. Study Storage condition Minimum time period covered by data at submission Long term* 25°C ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH New AS. 1 year Exi. AS: 6 mo. (opt. a and b) Intermediate 6 months Accelerated 40°C ± 2°C/75% RH ± 5% RH

Stability: Storage conditions Refrigerator Freezer Study Storage condition Minimum time period covered by data at submission Long term 25°C ± 2°C/60% RH ± 5% RH or New AS. 1 year Exi. AS: 6 mo. (opt. a and b) Accelerated 25°C ± 2°C/60% RH ± 5% RH 6 months Study Storage condition Minimum time period covered by data at submission Long term -20°C ± 5°C New AS. 1 year Exi. AS: 6 mo. (opt. a and b)

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.

Declaration Storage Conditions (CPMP) Testing conditions where stability has been shown Required label Additional label, where relevant 25°C/60%RH alt. 30°C/65%RH 40°C/75%RH None Do not refrigerate or freeze 25°C/60%RH + 30°C/60%RH (interm) or 30°C/65%RH Do not store above 30°C Do not store above 25°C 5°C±3°C Store at 2-8°C Do not freeze Below 0°C Store in freezer

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 …..

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)

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.

EU Assessment Policy (known ASs) (3) Each active substance with regard to impurities has ultimately to be assessed on its own merits. If the impurity profile of the proposed product is different from that of the reference product, this fact is not a ground for rejection of the application if the impurities are considered qualified. In the development part of the application, it is expected to find a discussion whether the product is likely to have a different impurity profile as compared to the original product.

EU Assessment Policy (known ASs) (4) It is expected that the applicant of a generic product justifies why he considers the impurities in his product safe for the intended use and qualified, either by reference to expected similarity with the originator or by other means e.g. compliance with relevant (V)ICH guidelines. In the case where the impurity profile of a generic product differs qualitatively from the originator, or where higher amount of impurities are seen, the full qualification or other adequate information about the safety of these impurities will be requested.

Outlook Preparation of an ICH API (chemical and biotechnological origin) guideline (Q11) taking into account the concepts and principles described in Q8R (Pharmaceutical Development). enhanced/systematic development establishment of design space establishment of real time release testing New Paradigm: combination of enhanced process understanding, formal use risk management tools and establishment of an efficient quality system

Conclusion The pharmaceutical quality requirements for the API (AS) are very much guided by the harmonised ICH guidelines: Impurities, stability, analytical validation,……… From a pharmaceutical quality point of view there is no difference between new ASs and existing/known ASs. The section on impurities is one of the most important section in an application file. Thorough preparation and presentation of this section is most helpful for the assessor. During lifetime of the product, attention has to be paid to changes in the manufacturing process including change in suppliers of starting materials. Impurities profile depends very much on the route of synthesis.!!

Back-up slides

References - Relevant Guidelines (API) 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). CHMP NfG: Chemistry on new active substances CHMP NfG: Summary of requirements for Active Substances in the Quality Part of the Dossier Q3A (R2): Impurities Testing in new drug substances Q3C: Impurities: Guideline for Residual Solvents CHMP position paper class 1/class 2 solvents CHMP NfG: Testing on Genotoxic Impurities CHMP HfG: Specification limits for residues of metal catalysts or metal reagents

References - Relevant Guidelines (API) Q6A: Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products Q2R: Validation of analytical procedures Q1A (R2): Stability: new active substances……. CHMP NfG: Stability: existing active substances……. European Pharmacopoeia General monograph: Substances for pharmacopoeial use General chapter: Control of Impurities (5.10) Residual Solvents (5.4) EMEA Website: www.emea.europa.eu including Q&As

Application file: CTD-Q: Drug Substances 3.2.S S.1 General Information S.1.1 Nomenclature S.1.2 Structure S.1.3 General Properties S.2 Manufacture S.2.1 Manufacturer(s) S.2.2 Description of Manufacturing Process and Process Controls S.2.3 Control of Materials S.2.4 Controls for Critical Steps and Intermediates S.2.5 Process Validation and/or Evaluation S.2.6 Manufacturing Process Development

Applicatin file: CTD-Q: Drug Substances 3.2.S S.3 Characterisation S.3.1 Elucidation of Structure and other Characteristics S.3.2 Impurities S.4 Control of Drug Substances 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

Application file: CTD-Q: Drug Substances 3.2.S S.5 Reference Standards of Materials S.6 Container Closure System S.7 Stability S.7.1 Stability Summary and Conclusions S.7.2 Post-approval Stability Protocol and Stability Commitment S.7.3 Stability Data

Decision Tree for Identification and Qualification Is impurity greater than identification Threshold? No action Yes No Structure identified? Any known human relevant risks? Yes Reduce to save level Yes No further action No No Yes Reduce to not more than (≤) identification threshold Yes Reduce to not more than (≤) identification threshold Greater than qualification Threshold? No action Yes No No No Consider patient population and duration of use and consider conducting: Genotoxicity studies (point mutation, chromosomal aberration) General toxicity studies (one species, usually 14 to 90 days) Other specific toxicity endpoints, as appropriate Any clinically relevant adverse effects? Reduce to save level Qualified Yes No

Examples of Structure of Genotoxic Impurities