EU requirements for quality of APIs in Marketing

EU requirements for quality of APIs in Marketing Authorisation Application Latest developments Maryam MEHMANDOUST, Ph. D ANSM, France Current Challenges in Global Regulatory Compliance – Quality of Pharmaceutical Ingredients 28 - 29 September 2012, Mumbai, INDIA

Glossary ALARP As low as reasonably practicable u API Active pharmaceutical ingredient API = active substance (AS) = drug substance u CEP Certificate of European Pharmacopoeia u CPP Critical process parameters u CQA Critical quality attribute u CTD Common technical documentation u DP Drug product u DS Design space u GMP Good manufacturing practices u GTI Genotoxic impurity u IPC In process control u MA Marketing autorisation u mfg Manufacturing u nfg Note for guidance u PDE Permitted daily exposure u Ph. European Pharmacopoeia u ppm Part per million u Q Quality u QP Qualified person u QWP Quality working group u RT Retention time u SM Starting material u SWP Safety working party u TTC Threshold of toxicological concern u Agence nationale de sécurité du médicament et des produits de santé 1

Topics addressed u EU Different options for submission of information on APIs u CTD quality part: Drug substance 3. 2. S. l Manufacture S. 2. v Manufacturers GMP status v Manufacture of mixtures v API Starting material (EU requirements, examples, ICH Q 11) v Manufacture: validation & mfg process development l Impurities S. 3. 2. l Control of API S. 4. v Specifications for highly toxic impurities: genotox, class 1 metal catalysts and solvents v Specifications for related impurities in antibiotics l Stability l Conclusion Agence nationale de sécurité du médicament et des produits de santé 2

Submission of data on APIs: Module 3 EU nfg Summary of requirements for AS in the Q part of the dossier, CHMP/QWP/297/97 Rev 1 corr u Full documentation on the API provided in the MA dossier Certificate European Pharmacopoeia (CEP) EDQM Certification procedure in order to confirm compliance with the Ph. Eur. monographs u u Active Substance Master File (ASMF) l New developments u For a pharmacopoeial substance demonstration of compliance with the monograph Option no more used Agence nationale de sécurité du médicament et des produits de santé 3

Active substance master File (ASMF) New developments (CHMP/QWP/227/02 Rev 3) u ASMF Working Party established (CMDh, CMDv, CHMP, CVMP) u Mandate: to find solutions for a worksharing system of ASMF assessments between EU Members States u ASMFs involved in EU procedures (CP, DCP and MRP) u Development of a database to host ASMF assessment reports l Creation of the EU ASMF number u Revision of the ASMF nfg regarding annexes (now 4 annexes) coming into force from October 1, 2012 u Paper on the rules of worksharing between MSs under preparation Agence nationale de sécurité du médicament et des produits de santé 4

Active substance master File (ASMF) New developments (CHMP/QWP/227/02 Rev 3) u Annex 2, Letter of access amended to inform ASMF holders about share of ASMF assessment reports between all EU MSs & EDQM u Annex 3, Submission letter & administrative details u Annex 4, Withdrawal of letter of access (when the ASMF holder does not wish anymore to use the ASMF submitted in support of a specific DP) u Guidance for new annexes developped and soon available for ASMF holders u Much insistance to have the latest version of the ASMF in different concerned MSs Agence nationale de sécurité du médicament et des produits de santé 5

CTD quality part: Drug substance 3. 2. S. u S. 1 General Information (Nomenclature, Structure, General Properties) u S. 2 Manufacture l S. 2. 1 Manufacturer(s) l S. 2. 2 Description of Manufacturing Process and Process Controls l S. 2. 3 Control of Materials l S. 2. 4 Controls for Critical Steps and Intermediates l S. 2. 5 Process Validation and/or Evaluation l S. 2. 6 Manufacturing Process Development S. 3 Characterisation l S. 3. 1 Elucidation of Structure and other Characteristics l S. 3. 2 Impurities S. 4 Control of Drug Substances S. 5 Reference Standards of Materials S. 6 Container Closure System S. 7 Stability u u u Agence nationale de sécurité du médicament et des produits de santé 6

S. 2. Manufacture S. 2. 1. Manufacturers / GMP status of sites u EU Directive 2001/83/ EC revised in October 2005, art 46 f (50 f in 2001/82/EC) l Obligation of MA holders: Use as starting materials* only active substances manufactured in accordance with guidelines on GMP of starting materials u QP declaration: responsibility on QP in the site responsible for batch release of drug product to audit the API manufacturer and verify the above requirement u Manufacture of active substance begins from the use of the API starting material according to ICH Q 7/ EU GMP Part II l QP declaration includes logically also mfg sites of intermediates (see selection and outcome of assessment of the SM API) * The term starting material clarified now in Directive 2011/62/EC Agence nationale de sécurité du médicament et des produits de santé 7

S. 2. Manufacture S. 2. 1. Manufacturers / GMP status of sites u For sterile API a QP declaration is not sufficient. l A GMP certificate or a valid mfg authorisation from an EEA Authority or from the Authority of countries having Mutual Recognition Agreement (MRA) with EU is to be submitted. l Data on sterilisation and validation to be submitted to the MA holder/ applicant for inclusion in the MA file (regardless of the option of submission of data: CEP, ASMF) See at EMA website, scientific guidelines, Q&A on quality part 1, active substance Agence nationale de sécurité du médicament et des produits de santé 8

S. 2. Manufacture Mixture(s) of API(s) and excipients QWP Q&A Quality, Part 1 and 2 u A mixture of an active substance with an excipient cannot be submitted through an ASMF l Blending of AS and excipient considered as the 1 st step in mfg of the medicinal product l Exceptions: where the active substance cannot exist on its own, e. g. , due to insufficient stability without a stabilising agent, or in the case of herbal dry extracts if it is not possible to produce a solid extract without excipients u Mixing of different active substances produced at different mfg sites cannot be considered as active substance manufacture l mixing of active substances that can exist and produced on their own should be considered as the first step of the manufacture of the finished product. GMP + dossier consequence: mixture of active substances OR active substance + excipient is subject to compliance with part I of the EU GMP Guide (GMP of finished products), to be described in P. 3. Agence nationale de sécurité du médicament et des produits de santé 9

S. 2. 2. Description of the manufacturing process and process controls EU nfg chemistry of new active substance, CPMP/ QWP/ 130/96 Rev 1 u Description of the process represents the applicant / manufacturer’s commitment u Any step of the process having an impact on the quality of the API and classified as « critical » to be identified and described in this section u Flow diagram l Should include molecualr formulae, weights, yield ranges, chemical structures of starting materials, intermediates, API reflecting stereochemistry Agence nationale de sécurité du médicament et des produits de santé 10

S. 2. 2. Description of the manufacturing process and process controls EU nfg chemistry of new active substance, CPMP/ QWP/ 130/96 Rev 1 u Sequential procedural narrative including operating conditions, quantities of materials used for a representative commercial scale batch, yields IPCs for each step u Scale of manufacture u Reprocessing u ICH Q 11 Ø Any design space in the mfg process should be included as part of the mfg process description i. e. under S. 2. 2. : description of CPPs and non CPPs, identification of stages/unit operations covered by DS Ø Design space is proposed by the applicant and subject to regulatory assessment and approval Agence nationale de sécurité du médicament et des produits de santé 11

S. 2. 3. Control of materials u API Starting material (still important topic) u Information on quality and controls of all other materials used in the process (appropriate specifications for their intended use) u If quality of a specific input material critical for the quality of final API, validation data for non compendial methods used for its control (consider implications for API starting material) u Biologically sourced materials l Viral and TSE aspects to be addressed for all materials of biological origin Agence nationale de sécurité du médicament et des produits de santé 12

API Starting Material/ important topic, why? Current situation and issues u Context of globalisation l Fragmentation of the API manufacturing chain u More and more applicants/ manufacturers of API submit a very short synthesis (reduced nb of steps 1 or 2) u Proposal for API SM with a structure very close to the final API where the API can be a complex molecule u Lack of information OR poor information on potential impurities arising from the API SM synthesis and their carry over into the API v insufficient information to ensure full control of the final API u Manufacturers of the proposed API SM are often external suppliers l Do manufacturers of the API, ASMF and CEP holders have sufficient control on them? Agence nationale de sécurité du médicament et des produits de santé 13

API Starting Material/ important topic, why? Current situation and issues u Regulatory changes in EU only applicable to manufacturer of API SM and its specifications u Concerns for GMP application: short syntheses may not include critical steps that normally should be performed under GMP. Difficulties for inspectors to verify these steps u ICH Q 11 now adopted: The time where it was possible to say “assessment needs and GMP inspectors needs should not be confused ” is over. u More and more request of reviewers to re-define the API SM to simpler molecules Agence nationale de sécurité du médicament et des produits de santé 14

API Starting Material ICH Q 7 / EU GMP part II definition A raw material, intermediate, or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API. An API Starting Material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement or purchased in-house. API starting materials are normally of defined chemical properties and structure. u ICH Q 7 does not intend to define registration requirements and do not affect the ability of the responsible competent authority to establish specific registration requirements regarding APIs within the context of MA. Agence nationale de sécurité du médicament et des produits de santé 15

API Starting material EU nfg chemistry of new active substance, CPMP/ QWP/130/96, Rev 1 u Description of the process and synthesis schematic should include all the steps proceeding from the API starting material to the isolated intermediates and ultimately to the final API. u Use of the API starting material marks the beginning of the detailed description of the process. l This is also where GMP starts according to ICH Q 7 and ICH Q 11 u Description of the process should cover all the synthetic steps critical for the safety (impurities) and the efficacy (structural part for the activity) of the API. Agence nationale de sécurité du médicament et des produits de santé 16

API Starting material EU nfg chemistry of new active substance, CPMP/QWP/130/96, Rev 1 API SM to be proposed and justified by the applicant l Incorporated as “significant structural fragment” l Name and address of suppliers (to be understood as mfg sites) l Full characterisation, complete specifications including an impurity profile/ method validation if not pharmacopoeial l Information about the SM synthesis (not detailed, flow-chart) to enable assessors to judge of the suitability of the proposed specifications l Discussion on impurities present in the API SM and possibility of their carry over or as derivatives into the final API l Acceptance criteria for API SM to be set based on evaluation of the fate of impurities when subject to the normal process/ synthesis Agence nationale de sécurité du médicament et des produits de santé 17

API Starting material EU nfg chemistry of new active substance, CPMP/QWP/130/96, Rev 1 Agence nationale de sécurité du médicament et des produits de santé 18

API Starting material EU nfg chemistry of new active substance, CPMP/QWP/130/96, Rev 1 § Relevant viral safety and TSE data to be provided if any animal derived material used the API mfg process (e. g. fermentation, enzymes, amino acids, etc) § API SM of vegetable origin: full characterisation including contaminant profile (microbial contamination, pesticides, mycotoxins, etc) . See risk assessment for mycotoxins/aflatoxins in Q&A on quality of herbal medicinal products, EMA/HMPC/41500/2010 Rev 1 Publication date Feb 2012 (Q 6 for routine or skip testing). Q&A of QWP on SM of herbal origin available on EMA website (scientific guidelines, Q&A on quality part 1, active substance, starting material of herbal origin) Agence nationale de sécurité du médicament et des produits de santé 19

API Starting material EU nfg chemistry of new active substance, CPMP/QWP/130/96, Rev 1 A route of synthesis of one step is not acceptable unless in certain circumstances If API SM described in Ph. Eur. and covered by a CEP presented in S. 2. 3. u If API SM authorised as an active substance in a MA u If proof of conformity with the monograph is provided (testing according to the monograph) Option no more acceptable ! the nfg should be amended for clarification u Reagents, solvents Agence nationale de sécurité du médicament et des produits de santé 20

API Starting material Experience of EU assessors Clopidogrel 5 -Sulfosalicylate: not acceptable Agence nationale de sécurité du médicament et des produits de santé 21

API Starting material Experience of EU assessors Methy prednisolone hemisuccinate: not acceptable Agence nationale de sécurité du médicament et des produits de santé 22

API Starting material Experience of EU assessors Donepezil hydrochloride hydrate: not acceptable Agence nationale de sécurité du médicament et des produits de santé 23

API Starting material Experience of EU assessors Famciclovir: no more acceptable while absence of carry over of impurities of SM API was justified under S. 2. 3 Agence nationale de sécurité du médicament et des produits de santé 24

API Starting material Experience of EU assessors u Impossible to define an acceptable number of steps that may fit all the situations as it depends on nb of factors (complexity of the molecule, control strategy, etc): case by case assessment u Generally 1 or 2 steps are not sufficient to provide assurance of final API quality and not acceptable unless justified by API structure u Some APIs are of so simple structure that it is obvious a process in one step is acceptable e. g. : chloroxylenol pirfenidone u Commercial availability on its own is not a criterion of selection of the API SM contrary to what can be concluded from ICH Q 7, now ICH 11 applicable u API SM prepared by custom synthesis should meet not only the requirements of the nfg but also GMP consideration Purification, salt formation, salt transformation or milling are not considered synthesis step u When API SM not acceptable, redefinition is requested however difference of view about application of this measure to already accepted ASMFs and MAs u Agence nationale de sécurité du médicament et des produits de santé 25

API Starting material ICH Q 11 adopted (applicable in EU in November 2012) Selection of API SM, section 5 Principles to determine where the AS mfg process begins u Accent on control strategy u u Main principle: Changes in material attributes or in operating conditions occuring near the beginning of the mfg process have lower potential to impact the quality of final API u Relationship between risk and number of steps from the end of the mfg process to be considered for 2 aspects l Physical properties of the drug substance l Formation, fate and purge of impurities Agence nationale de sécurité du médicament et des produits de santé 26

API Starting material ICH Q 11 adopted (applicable in EU in November 2012) Selection of API SM, section 5 u Risk and number of steps from the end of the mfg process to be considered for 2 aspects l Physical properties of the drug substance v final crystallisation and subsequent operations, all occuring usually at final stages therefore always described in S. 2. 2. part of applicant commitment and subject to GMP l Formation, fate and purge of impurities v Principle: consider risk of carry over to the final API. More chance to remove impurities generated early in the mfg process in purification steps (washings, crystallisation of intermediates) than those generated late in the process l Fate: whether the impurity reacts and changes its chemical structure l Purge: whether the impurity is removed via crystallisation, extraction, etc Agence nationale de sécurité du médicament et des produits de santé 27

API Starting material ICH Q 11 adopted (applicable in EU in November 2012) Selection of API SM, section 5 u To perform assessment of suitability of mfg process and controls (including on impurities) in place, enough of the API mfg process is to be described in the application l To understand how impurities are formed, what could be the impact of changes in the process on their formation, fate and purge l To understand why the control strategy proposed is suitable for the API mfg process This will include typically description of multiple chemical transformation steps. Agence nationale de sécurité du médicament et des produits de santé 28

API Starting material ICH Q 11 adopted (applicable in EU in November 2012) Principles to be applied together in selction of SMs rather than applying them in isolation u Mfg steps that impact the impurity profile of the API should normally be included in the mfg process described in S. 2. 2. u Application of GMP provisions described in ICH Q 7 to each branch of a convergent synthesis beginning from the 1 st use of a starting material. A SM is of defined chemical property and structure u Non isolated intermediates are not appropriate SMs u SM incorporated as a significant structural fragment and in this context, different from raw materials u Agence nationale de sécurité du médicament et des produits de santé 29

API Starting material ICH Q 11 adopted (applicable in EU in November 2012) Principles to be applied together in selction of SMs rather than applying them in isolation u Justification for appropriateness of selected API SM l Ability of analytical methods to detect impurities in SMs l Fate and purge of these impurities and their derivatives in the process l How the specification of each SM will contribute to the control strategy u No need to justify use of commercially available SM however l Commercially available chemical is one that is sold as a commodity in a NON Pharmaceutical market l Chemicals prepared by custom synthesis are not considered as commercially available Selection of a chemical prepared by custom synthesis is to be justified according to the general principles described in ICH Q 11 Agence nationale de sécurité du médicament et des produits de santé 30

API Starting material ICH Q 11 adopted (applicable in EU in November 2012) u Semi synthetic APIs: obtained by combination of chemical synthesis & fermentation or extraction from botanical material u Possible to describe the mfg process from one of the isolated intermediates (as SM API) in the synthetic process u The selected isolated intermediate should comply with the principles outlined before for selection of API SM l Analytical characterisation of the selected SM including its impurity profile, impact of fermentation or botanical material/extraction on the impurity profile of the API u If not, description of the mfg process should be from the source material (microorganism producer or plant) Agence nationale de sécurité du médicament et des produits de santé 31

API Starting material ICH Q 11 adopted (applicable in EU in November 2012) Assurance of quality of API: application of GMP to mfg process together with appropriate control strategy A control strategy can include but is not limited to Controls on material attributes (raw materials, SM, intermediates, primary packaging, etc) Ø Controls implicit in design of the mfg process (order of steps or addition of reagents) Ø In-process controls (IPC tests and process parameters) Ø Controls on drug substance (e. g. release testing) Ø Definition of control strategy: A planned set of controls, derived from current product and process understanding, that assures process performance and product quality. Every API mfg process, whether developed through a traditional or enhanced approach (or some combination thereof), has an associated control strategy. Agence nationale de sécurité du médicament et des produits de santé 32

API Starting material ICH Q 11: example of application of principles of API SM selection together and not in isolation Why D can be selected as API SM instead of A? § 1 st step generation of chiral centre, control of undesired enantiomer in D § Stereocentre stable up to the end § Steps 4, 5 & 6 generation of impurities § Steps 2 and 3 no impact on impurity profile Agence nationale de sécurité du médicament et des produits de santé 33

S. 2. Manufacture u S. 2. 5 Process Validation and/or Evaluation l Sterilisation process l For non sterile API, validation should be carried out but not needed to provide in the file (see ICH Q 11) u S. 2. 6 Manufacturing Process Development l Changes in manufacturing occurring during development (pre-clinical, scale up, commercial) l Development of e. g. a design space, real time release testing v Risk assessment & assignment of criticality: Identification of CQAs and CPP v Establishing a Design space: design of experiments & design space verification v Defining a control strategy Agence nationale de sécurité du médicament et des produits de santé 34

S. 3. Characterisation S. 3. 2. Impurities u Classification of impurities l Organic impurities ICH Q 3 A (R) l Residual solvents ICH Q 3 C and EU nfg CPMP/QWP/450/03 l Inorganic impurities v Metal catalysts (EU nfg EMEA/CHMP/SWP/4446/2000) l Genotoxic impurities (EU nfg CPMP/SWP/5199/02) These texts are applicable in EU to new active substances (NAS = New chemical entities NCE) and also to existing active substances (ICH Q 3 A and Q 3 C by application of Ph. Eur. general monograph 2034) Agence nationale de sécurité du médicament et des produits de santé 35

S. 3. 2. Impurities Related substances & thresholds to apply Each specified identified impurity u Each specified unidentified impurity but identified at least by an analytical u character e. g. RT in a chromatographic system Any unspecified impurity with an acceptance criterion of not more than (<) the identification threshold u Total impurities u Agence nationale de sécurité du médicament et des produits de santé 36

S. 3. 2. Impurities APIs outside the scope of ICH and EU guidelines u Organic impurities in peptides obtained by chemical synthesis, Ph. Eur. general monograph 2034 Reporting threshold > 0. 1% Identification threshold > 0. 5% Qualification threshold > 1. 0% u For other type of APIs, Justification to be provided for adequate thresholds v the nature of the active substance, v the maximal daily dose of drug product, v the duration of therapy, v the ability of the analytical methods (current scientific status) Agence nationale de sécurité du médicament et des produits de santé 37

S. 3. 2. Impurities Scientific discussion on impurities & rationale for setting acceptance criteria u Summary of actual and potential impurities & discussion on their origin and generation u Discussion on impurity profiles found in preclinical and clinical batches for new APIs u Discussion on impurity profile found in development, pilot, commercial batches for existing APIs l Comparison to the pharmacopoeial monograph u Impurities above the qualification thresholds have to be qualified, acceptance criteria cannot be higher than qualified level u Actual results obtained including stability data should be the basis for setting the acceptance criteria i. e. specifications have to reflect results Decision Tree for Identification and Qualification of new impurities in Q 3 A u Demonstration of similarity with the reference product possible u Agence nationale de sécurité du médicament et des produits de santé 38

S. 3. 2. Impurities Residual solvents Safety limits for 3 classes of solvents u Class 1 solvents highly toxic, to be avoided, suitable justification needed for their use u Class 2 solvents to be limited with 2 options l Concentration limit (ppm) and PDE (mg/day) l NEW: cumene classified now in class 2 § option 1 limit of NMT 70 ppm § option 2 limit (PDE) of 0. 7 mg/day l See rules of omission of testing in EU nfg CPMP/QWP/450/03 as annex to Q 3 C. These rules do not preclude that if the API is tested, it should anyhow meet the requirement of the ICH Q 3 C nfg Class 3 solvents, low toxic potential u Table 4, a non exhaustive list of solvents for which safety data are not available u Agence nationale de sécurité du médicament et des produits de santé 39

S. 3. 2. Impurities Residues of metal catalysts, metal reagents EU nfg EMEA/CHMP/SWP/4446/2000 objectives u To recommend maximum acceptable concentration limits for residues of metal catalysts/reagents in pharmaceutical substances or in drug products u Control of residual metal with a suitable method u Pharmacopoeial heavy metal test generally not acceptable u Implementation 5 years for existing products ICH guideline for metal impurities ICH Q 3 D under preparation Agence nationale de sécurité du médicament et des produits de santé 40

S. 3. 2. Impurities Residues of metal catalysts, metal reagents EU nfg EMEA/CHMP/SWP/4446/2000 objectives l Class 1 Metals: metals of high toxic potential v Known carcinogens v 3 sub-classes l Class 1 B: not individual limit but total limit for whole class l Class 2 Metals: metals with low toxic potential v Nutritional trace metals, common in food and food additives: Cu, Mn l Class 3 Metals: metals with no significant toxicity v Ubiquitous in environment, plants and animals: Fe, Zn Difference is made between requirements for oral, parenteral and inhalation exposure Agence nationale de sécurité du médicament et des produits de santé 41

S. 3. 2. Impurities Genotoxic impurities (GTIs) EU nfg CPMP/SWP/5199/02 and EMEA/CHMP/QWP/251344/2006 u Joint SWP-QWP “Guideline on the Limits of Genotoxic Impurities” with effect on 1 January 2007 Basis: ICH Q 3 A/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”. u Ø An ICH guideline is under preparation, genotoxic impurities M 7 Agence nationale de sécurité du médicament et des produits de santé 42

S. 3. 2. Impurities Genotoxic impurities (GTIs) EU nfg CPMP/SWP/5199/02 and EMEA/CHMP/QWP/251344/2006 u Scope l New active substances l 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) l No need for retrospectively application to authorised products, unless there is a specific cause for concern Agence nationale de sécurité du médicament et des produits de santé 43

S. 3. 2. Impurities Genotoxic impurities (GTIs) EU nfg CPMP/SWP/5199/02 and EMEA/CHMP/QWP/251344/2006 u Principles l Identification guided by existing genotoxic data or the presence of alert structures l Genotoxic compounds with sufficient evidence for a threshold related mechanism e. g. data from long term carcinogenocity studies (PDE) l Genotoxic compounds without sufficient evidence for a threshold related mechanism, ALARP principle IF data not available l Application of a generally applicable approach as defined by the threshold of Toxicological Concern TTC Ø Threshold of Toxicological concern: TTC value: 1. 5 µg/day TTC not applicable to high potency genotoxic carcinogens such as aflatoxins, N-nitroso and azoxy compounds Agence nationale de sécurité du médicament et des produits de santé 44

S. 3. 2. Impurities Genotoxic impurities (GTIs) EU nfg CPMP/SWP/5199/02 and EMEA/CHMP/QWP/251344/2006 u Pharmaceutical considerations l Try to avoid genotoxic reagents or their generation (design of synthesis) l Limitations (if possible) at an intermediate rather at the end active l l substance Introduce a specific purification step (destruction of genotoxic impurity) Assessment from the applicant justifying the potential presence or non presence of the genotoxic impurity If not possible to avoid GTIs then go through relevant safety studies See decision trees in the EU nfg on GTIs Agence nationale de sécurité du médicament et des produits de santé 45

S. 3. 2. Impurities Genotoxic impurities (GTIs) Joint SWP-QWP Q & A, EMA/ CHMP/ SWP/ 431994/ 2007 Rev. 3 Revision 3 adopted in September 2010 Ø The aim of the Q&As, is to provide clarification and harmonisation of interpretation of the Guideline on the Limits of Genotoxic Impurities Ø Ø Addresses several key areas including amongst others § § § An explanation for cause of concern e. g. mesylate esters When ALARP should be applied Ames test overruling alert structures but to be conducted to regulatory acceptable standards How to control GTIs in clinical trials and concept of staged TTC In presence of several GTIs, TTC should be applicable individually if impurities are structurally unrelated and to the sum if they are structurally similar (e. g. group of mesylates) Agence nationale de sécurité du médicament et des produits de santé 46

S. 3. 2. Impurities Potentially genotoxic impurities with alert structures, Muller and al. Agence nationale de sécurité du médicament et des produits de santé 47

S. 4. Control of API Harmonisation of policies on setting specifications to highly toxic impurities QWP Q&A, part 1, June 2012, EMA website Same principles (3 scenarios/cases) apply to Ø Genotox impurities Ø Class 1 metal catalysts Ø Class 1 solvents Example is given in following slides for GTIs Target limit is the limit in the corresponding guideline Agence nationale de sécurité du médicament et des produits de santé 48

S. 4. Control of API Harmonisation of policies on setting specifications (GTI) QWP Q&A, part 1, June 2012, EMA website What is a reasonable policy for setting specifications for potentially GTI that are theoretical or actual impurities in the API mfg process u Case 1 – A potential genotoxic impurity l If a potential genotoxic impurity is just a theoretical impurity i. e. based on theoretical considerations but not found in practice at any key stage in the mfg process as demonstrated by studies during development of the manufacture, the impurity does not need to be included in the drug substance specification OR a specification of an intermediate. l This implies availability of a suitable method and testing to show absence of such impurity Agence nationale de sécurité du médicament et des produits de santé 49

S. 4. Control of API Harmonisation of policies on setting specifications (GTI) QWP Q&A, part 1, June 2012, EMA website u Case 2 – A (potentially) genotoxic impurity actually formed or introduced prior to the final step of the synthesis Possible not to include such impurity in the drug substance specification l Controlled by a suitable limit in a synthesis intermediate and demonstration by analysis results (use of spiking experiments) that it does not exceed 30 % of the limit, derived either from TTC or otherwise defined acceptable limit etc, in the drug substance. Agence nationale de sécurité du médicament et des produits de santé 50

S. 4. Control of API Harmonisation of policies on setting specifications (GTI) QWP Q&A, part 1, June 2012, EMA website u Case 2 (cont. ) – A (potentially) genotoxic impurity actually formed or introduced prior to the final step of the synthesis Possible not to include such impurity in the drug substance specification l Skip testing possible if level of the impurity in a synthesis intermediate does not exceed 30% of the limit, either TTC or otherwise defined acceptable limit etc, in the intermediate. Data to be presented for at least 6 consecutive pilot scale or 3 consecutive production scale lots. l If this condition is not fulfilled, a routine test in the intermediate is needed. l If the impurity exceeds 30% of the limit, either TTC or otherwise defined acceptable limit etc. , in the drug substance the impurity to be included in the drug substance specification and routinely l No control of genotoxic impurity at the intermediate stage, then the scenario of example 3 applies. Agence nationale de sécurité du médicament et des produits de santé 51

S. 4. Control of API Harmonisation of policies on setting specifications (GTI) QWP Q&A, part 1, June 2012, EMA website u Case 3 – A (potentially) genotoxic impurity is formed or introduced in the last step of the synthesis Such impurity should be included in the drug substance specification Ø Possible to apply skip testing if the level of the impurity does not exceed 30 % of the limit, derived from either TTC or otherwise defined acceptable limit etc, in the drug substance. Ø Data should be presented for at least 6 consecutive pilot scale or 3 consecutive production scale batches if skip testing is applied. Ø If this condition is not fulfilled, a routine test in the drug substance specification is needed. Agence nationale de sécurité du médicament et des produits de santé 52

S. 4. Control of API Setting specifications for impurities in antibiotics NEW, EU nfg EMA/CHMP/CVMP/QWP/199250/2009, effective end June 2013 Applicable to new antibiotics and new sources of existing antibiotics Ø Not applicable to residues from fermentation process Ø u Active substances manufactured by semi-synthesis l Reporting threshold: 0. 05%/ 0. 03% l Identification threshold: 0. 10% / 0. 05% l Qualification threshold: 0. 15% / 0. 05% u Active substances manufactured by fermentation, single compound l Reporting threshold: 0. 10% l Identification and qualification threshold: 0. 15% u Active substances manufactured by fermentation, family of compounds l Reporting threshold: 0. 10% l Identification threshold: 0. 15% l Qualification threshold: 0. 50% / 0. 2% (structurally close related compounds versus other related compounds) Agence nationale de sécurité du médicament et des produits de santé 53

S. 7. Stability u EU located in climatic zone I/II u Storage conditions according to ICH u Guidelines: l ICH Q 1 A (R 2): new active substances l EU nfg for existing active substances, derived from ICH, CPMP/QWP/122/02, rev 1 u Same requirements between new active substances and existing active substances UNLESS for length of data at time of submission u Retest period to be defined u If no retest period, API should be tested against its specifications before use in production of DP u Declarations of storage conditions according to CPMP/QWP/609/96/Rev 1 (different from WHO rules) Agence nationale de sécurité du médicament et des produits de santé 54

Conclusion Ø From a pharmaceutical quality point of view, no difference is made between new active substances and existing or known active substances § Adoption of certain ICH texts in Ph. Eur. general monograph 2034 Ø Much emphasis on “Impurities”: each API should be assessed with regard to impurities on its own merits. Thorough discussion needed. Ø Justification from the applicant why impurities in the product are considered qualified and safe for the intended use Ø API starting material, very important topic § Justify selection in view of EU nfg chemistry of new active substances & ICH Q 11 § Critical steps of the synthesis should be GMP § Consider steps of generation and removal of impurities § Attention to change of suppliers of SM API impacting the impurity profile of final API Agence nationale de sécurité du médicament et des produits de santé 55

Thank you for your attention Agence nationale de sécurité du médicament et des produits de santé 56

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Avertissement • Lien d’intérêt : personnel salarié de l’ANSM (opérateur de l’Etat). • La présente intervention s’inscrit dans un strict respect d’indépendance et d’impartialité de l’ANSM vis-à-vis des autres intervenants. • Toute utilisation du matériel présenté, doit être soumise à l'approbation préalable de l’ANSM. Warning • Link of interest: employee of ANSM (State operator). • This speech is made under strict compliance with the independence and impartiality of ANSM as regards other speakers. • Any further use of this material must be submitted to ANSM prior approval.