Presentation on theme: "Glossary ALARP As low as reasonably practicable"— Presentation transcript:
0 EU requirements for quality of APIs in Marketing Authorisation Application Latest developments Maryam MEHMANDOUST, PhD ANSM, FranceCurrent Challenges in Global Regulatory Compliance – Quality of Pharmaceutical IngredientsSeptember 2012, Mumbai, INDIA
1 Glossary ALARP As low as reasonably practicable API Active pharmaceutical ingredientAPI = active substance (AS) = drug substanceCEP Certificate of European PharmacopoeiaCPP Critical process parametersCQA Critical quality attributeCTD Common technical documentationDP Drug productDS Design spaceGMP Good manufacturing practicesGTI Genotoxic impurityIPC In process controlMA Marketing autorisationmfg Manufacturingnfg Note for guidancePDE Permitted daily exposurePh. Eur. European Pharmacopoeiappm Part per millionQ QualityQP Qualified personQWP Quality working groupRT Retention timeSM Starting materialSWP Safety working partyTTC Threshold of toxicological concern
2 Topics addressedEU Different options for submission of information on APIsCTD quality part: Drug substance 3.2.S.Manufacture S.2.Manufacturers GMP statusManufacture of mixturesAPI Starting material (EU requirements, examples, ICH Q11)Manufacture: validation & mfg process developmentImpurities S.3.2.Control of API S.4.Specifications for highly toxic impurities: genotox, class 1 metal catalysts and solventsSpecifications for related impurities in antibioticsStabilityConclusion
3 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 corrFull documentation on the API provided in the MA dossierCertificate European Pharmacopoeia (CEP)EDQM Certification procedure in order to confirm compliance with the Ph. Eur. monographsActive Substance Master File (ASMF)New developmentsFor a pharmacopoeial substance demonstration of compliance with the monograph Option no more used
4 Active substance master File (ASMF) New developments (CHMP/QWP/227/02 Rev 3) ASMF Working Party established (CMDh, CMDv, CHMP, CVMP)Mandate: to find solutions for a worksharing system of ASMF assessments between EU Members StatesASMFs involved in EU procedures (CP, DCP and MRP)Development of a database to host ASMF assessment reportsCreation of the EU ASMF numberRevision of the ASMF nfg regarding annexes (now 4 annexes) coming into force from October 1, 2012Paper on the rules of worksharing between MSs under preparation
5 Active substance master File (ASMF) New developments (CHMP/QWP/227/02 Rev 3) Annex 2, Letter of access amended to inform ASMF holders about share of ASMF assessment reports between all EU MSs & EDQMAnnex 3, Submission letter & administrative detailsAnnex 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)Guidance for new annexes developped and soon available for ASMF holdersMuch insistance to have the latest version of the ASMF in different concerned MSs
6 CTD quality part: Drug substance 3.2.S. S.1 General Information (Nomenclature, Structure, General Properties)S.2 ManufactureS.2.1 Manufacturer(s)S.2.2 Description of Manufacturing Process and Process ControlsS.2.3 Control of MaterialsS.2.4 Controls for Critical Steps and IntermediatesS.2.5 Process Validation and/or EvaluationS.2.6 Manufacturing Process DevelopmentS.3 CharacterisationS.3.1 Elucidation of Structure and other CharacteristicsS.3.2 ImpuritiesS.4 Control of Drug SubstancesS.5 Reference Standards of MaterialsS.6 Container Closure SystemS.7 Stability
7 S.2. Manufacture S.2.1. Manufacturers / GMP status of sites EU Directive 2001/83/ EC revised in October 2005, art 46f (50f in 2001/82/EC)Obligation of MA holders: Use as starting materials* only active substances manufactured in accordance with guidelines on GMP of starting materialsQP declaration: responsibility on QP in the site responsible for batch release of drug product to audit the API manufacturer and verify the above requirementManufacture of active substance begins from the use of the API starting material according to ICH Q7/ EU GMP Part IIQP 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
8 S.2. Manufacture S.2.1. Manufacturers / GMP status of sites For sterile API a QP declaration is not sufficient.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.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
9 S.2. Manufacture Mixture(s) of API(s) and excipients QWP Q&A Quality, Part 1 and 2 A mixture of an active substance with an excipient cannot be submitted through an ASMFBlending of AS and excipient considered as the 1st step in mfg of the medicinal productExceptions: 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 excipientsMixing of different active substances produced at different mfg sites cannot be considered as active substance manufacturemixing 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.
10 S.2.2. Description of the manufacturing process and process controls EU nfg chemistry of new active substance, CPMP/ QWP/ 130/96 Rev 1Description of the process represents the applicant / manufacturer’s commitmentAny step of the process having an impact on the quality of the API and classified as « critical » to be identified and described in this sectionFlow diagramShould include molecualr formulae, weights, yield ranges, chemical structures of starting materials, intermediates, API reflecting stereochemistry
11 S.2.2. Description of the manufacturing process and process controls EU nfg chemistry of new active substance, CPMP/ QWP/ 130/96 Rev 1Sequential procedural narrative including operating conditions, quantities of materials used for a representative commercial scale batch, yieldsIPCs for each stepScale of manufactureReprocessingICH Q11Any 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 DSDesign space is proposed by the applicant and subject to regulatory assessment and approval
12 S.2.3. Control of materialsAPI Starting material (still important topic)Information on quality and controls of all other materials used in the process (appropriate specifications for their intended use)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)Biologically sourced materialsViral and TSE aspects to be addressed for all materials of biological origin
13 API Starting Material/ important topic, why? Current situation and issuesContext of globalisationFragmentation of the API manufacturing chainMore and more applicants/ manufacturers of API submit a very short synthesis (reduced nb of steps 1 or 2)Proposal for API SM with a structure very close to the final API where the API can be a complex moleculeLack of information OR poor information on potential impurities arising from the API SM synthesis and their carry over into the APIinsufficient information to ensure full control of the final APIManufacturers of the proposed API SM are often external suppliersDo manufacturers of the API, ASMF and CEP holders have sufficient control on them?
14 API Starting Material/ important topic, why? Current situation and issuesRegulatory changes in EU only applicable to manufacturer of API SM and its specificationsConcerns for GMP application: short syntheses may not include critical steps that normally should be performed under GMP. Difficulties for inspectors to verify these stepsICH Q11 now adopted: The time where it was possible to say “assessment needs and GMP inspectors needs should not be confused ” is over.More and more request of reviewers to re-define the API SM to simpler molecules
15 API Starting Material ICH Q7 / 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.ICH Q7 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.
16 API Starting material EU nfg chemistry of new active substance, CPMP/ QWP/130/96, Rev 1 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.Use of the API starting material marks the beginning of the detailed description of the process.This is also where GMP starts according to ICH Q7 and ICH Q11Description 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.
17 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 applicantIncorporated as “significant structural fragment”Name and address of suppliers (to be understood as mfg sites)Full characterisation, complete specifications including an impurity profile/ method validation if not pharmacopoeialInformation about the SM synthesis (not detailed, flow-chart) to enable assessors to judge of the suitability of the proposed specificationsDiscussion on impurities present in the API SM and possibility of their carry over or as derivatives into the final APIAcceptance criteria for API SM to be set based on evaluation of the fate of impurities when subject to the normal process/ synthesis
18 API Starting material EU nfg chemistry of new active substance, CPMP/QWP/130/96, Rev 1
19 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)
20 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 circumstancesIf API SM described in Ph.Eur. and covered by a CEP presented in S.2.3.If API SM authorised as an active substance in a MAIf proof of conformity with the monograph is provided (testing according to the monograph)Option no more acceptable ! the nfg should be amended for clarificationReagents, solvents
21 API Starting material Experience of EU assessors Clopidogrel 5-Sulfosalicylate: not acceptable
22 API Starting material Experience of EU assessors Methy prednisolone hemisuccinate: not acceptable
23 API Starting material Experience of EU assessors Donepezil hydrochloride hydrate: not acceptable
24 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
25 API Starting material Experience of EU assessors 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 assessmentGenerally 1 or 2 steps are not sufficient to provide assurance of final API quality and not acceptable unless justified by API structureSome APIs are of so simple structure that it is obvious a process in one step is acceptable e.g.: chloroxylenol pirfenidoneCommercial availability on its own is not a criterion of selection of the API SMcontrary to what can be concluded from ICH Q7, now ICH 11 applicableAPI SM prepared by custom synthesis should meet not only the requirements of the nfg but also GMP considerationPurification, salt formation, salt transformation or milling are not considered synthesis stepWhen API SM not acceptable, redefinition is requested however difference of view about application of this measure to already accepted ASMFs and MAs
26 API Starting material ICH Q11 adopted (applicable in EU in November 2012) Selection of API SM, section 5Principles to determine where the AS mfg process beginsAccent on control strategyMain 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 APIRelationship between risk and number of steps from the end of the mfg process to be considered for 2 aspectsPhysical properties of the drug substanceFormation, fate and purge of impurities
27 API Starting material ICH Q11 adopted (applicable in EU in November 2012) Selection of API SM, section 5Risk and number of steps from the end of the mfg process to be considered for 2 aspectsPhysical properties of the drug substancefinal crystallisation and subsequent operations, all occuring usually at final stages therefore always described in S.2.2. part of applicant commitment and subject to GMPFormation, fate and purge of impuritiesPrinciple: 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 processFate: whether the impurity reacts and changes its chemical structurePurge: whether the impurity is removed via crystallisation, extraction, etc
28 This will include typically description of multiple chemical API Starting material ICH Q11 adopted (applicable in EU in November 2012) Selection of API SM, section 5To 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 applicationTo understand how impurities are formed, what could be the impact of changes in the process on their formation, fate and purgeTo understand why the control strategy proposed is suitable for the API mfg processThis will include typically description of multiple chemicaltransformation steps.
29 API Starting material ICH Q11 adopted (applicable in EU in November 2012) Principles to be applied together in selction of SMs rather than applying them in isolationMfg steps that impact the impurity profile of the API should normally be included in the mfg process described in S.2.2.Application of GMP provisions described in ICH Q7 to each branch of a convergent synthesis beginning from the 1st use of a starting material.A SM is of defined chemical property and structureNon isolated intermediates are not appropriate SMsSM incorporated as a significant structural fragment and in this context, different from raw materials
30 API Starting material ICH Q11 adopted (applicable in EU in November 2012) Principles to be applied together in selction of SMs rather than applying them in isolationJustification for appropriateness of selected API SMAbility of analytical methods to detect impurities in SMsFate and purge of these impurities and their derivatives in the processHow the specification of each SM will contribute to the control strategyNo need to justify use of commercially available SM howeverCommercially available chemical is one that is sold as a commodity in a NON Pharmaceutical marketChemicals prepared by custom synthesis are not considered as commercially availableSelection of a chemical prepared by custom synthesis is to be justified according to the general principles described in ICH Q11
31 API Starting material ICH Q11 adopted (applicable in EU in November 2012) Semi synthetic APIs: obtained by combination of chemical synthesis & fermentation or extraction from botanical materialPossible to describe the mfg process from one of the isolated intermediates (as SM API) in the synthetic processThe selected isolated intermediate should comply with the principles outlined before for selection of API SMAnalytical characterisation of the selected SM including its impurity profile, impact of fermentation or botanical material/extraction on the impurity profile of the APIIf not, description of the mfg process should be from the source material (microorganism producer or plant)
32 API Starting material ICH Q11 adopted (applicable in EU in November 2012) Assurance of quality of API: application of GMP to mfg process together with appropriate control strategyA control strategy can include but is not limited toControls on material attributes (raw materials, SM, intermediates, primary packaging, etc)Controls implicit in design of the mfg process (order of steps or addition of reagents)In-process controls (IPC tests and process parameters)Controls on drug substance (e.g. release testing)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.
33 API Starting material ICH Q11: example of application of principles of API SM selection together and not in isolationWhy D can be selected as API SM instead of A?1st step generation of chiral centre, control of undesired enantiomer in DStereocentre stable up to the endSteps 4,5 & 6 generation of impuritiesSteps 2 and 3 no impact on impurity profile
34 S.2. Manufacture S.2.5 Process Validation and/or Evaluation Sterilisation processFor non sterile API, validation should be carried out but not needed to provide in the file (see ICH Q11)S.2.6 Manufacturing Process DevelopmentChanges in manufacturing occurring during development (pre-clinical, clinical, scale up, commercial)Development of e.g. a design space, real time release testingRisk assessment & assignment of criticality: Identification of CQAs and CPPEstablishing a Design space: design of experiments & design space verificationDefining a control strategy
35 S.3. Characterisation S.3.2. Impurities Classification of impuritiesOrganic impurities ICH Q3 A (R)Residual solvents ICH Q3C and EU nfg CPMP/QWP/450/03Inorganic impuritiesMetal catalysts (EU nfg EMEA/CHMP/SWP/4446/2000)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 Q3A and Q3C by application of Ph. Eur. general monograph 2034)
36 S.3. 2. Impurities Related substances & thresholds to apply Each specified identified impurityEach specified unidentified impurity but identified at least by an analytical character e.g. RT in a chromatographic systemAny unspecified impurity with an acceptance criterion of not more than (<) the identification thresholdTotal impurities
37 S.3. 2. Impurities APIs outside the scope of ICH and EU guidelines Organic impurities in peptides obtained by chemical synthesis, Ph. Eur. general monograph 2034Reporting threshold > 0.1%Identification threshold > 0.5%Qualification threshold > 1.0%For other type of APIs, Justification to be provided for adequate thresholdsthe nature of the active substance,the maximal daily dose of drug product,the duration of therapy,the ability of the analytical methods (current scientific status)
38 S.3. 2. Impurities Scientific discussion on impurities & rationale for setting acceptance criteria Summary of actual and potential impurities & discussion on their origin and generationDiscussion on impurity profiles found in preclinical and clinical batches for new APIsDiscussion on impurity profile found in development, pilot, commercial batches for existing APIsComparison to the pharmacopoeial monographImpurities above the qualification thresholds have to be qualified, acceptance criteria cannot be higher than qualified levelActual results obtained including stability data should be the basis for setting the acceptance criteria i.e. specifications have to reflect resultsDecision Tree for Identification and Qualification of new impurities in Q3ADemonstration of similarity with the reference product possible
39 S.3. 2. Impurities Residual solvents Safety limits for 3 classes of solventsClass 1 solvents highly toxic, to be avoided, suitable justification needed for their useClass 2 solvents to be limited with 2 optionsConcentration limit (ppm) and PDE (mg/day)NEW: cumene classified now in class 2option 1 limit of NMT 70 ppmoption 2 limit (PDE) of 0.7 mg/daySee rules of omission of testing in EU nfg CPMP/QWP/450/03 as annex to Q3C. These rules do not preclude that if the API is tested, it should anyhow meet the requirement of the ICH Q3C nfgClass 3 solvents, low toxic potentialTable 4, a non exhaustive list of solvents for which safety data are not available
40 S.3. 2. Impurities Residues of metal catalysts, metal reagents EU nfg EMEA/CHMP/SWP/4446/2000 objectivesTo recommend maximum acceptable concentration limits for residues of metal catalysts/reagents in pharmaceutical substances or in drug productsControl of residual metal with a suitable methodPharmacopoeial heavy metal test generally not acceptableImplementation 5 years for existing productsICH guideline for metal impurities ICH Q3D under preparation
41 S.3. 2. Impurities Residues of metal catalysts, metal reagents EU nfg EMEA/CHMP/SWP/4446/2000 objectivesClass 1 Metals: metals of high toxic potentialKnown carcinogens3 sub-classesClass 1B: not individual limit but total limit for whole classClass 2 Metals: metals with low toxic potentialNutritional trace metals, common in food and food additives: Cu, MnClass 3 Metals: metals with no significant toxicityUbiquitous in environment, plants and animals: Fe, ZnDifference is made between requirements for oral, parenteral and inhalation exposure
42 S.3. 2. Impurities Genotoxic impurities (GTIs) EU nfg CPMP/SWP/5199/02 and EMEA/CHMP/QWP/251344/2006Joint SWP-QWP “Guideline on the Limits of Genotoxic Impurities” with effect on 1 January 2007Basis: 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”.An ICH guideline is under preparation, genotoxic impurities M7
43 S.3. 2. Impurities Genotoxic impurities (GTIs) EU nfg CPMP/SWP/5199/02 and EMEA/CHMP/QWP/251344/2006ScopeNew active substancesNew 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
44 S.3. 2. Impurities Genotoxic impurities (GTIs) EU nfg CPMP/SWP/5199/02 and EMEA/CHMP/QWP/251344/2006PrinciplesIdentification guided by existing genotoxic data or the presence of alert structuresGenotoxic compounds with sufficient evidence for a threshold related mechanism e.g. data from long term carcinogenocity studies (PDE)Genotoxic compounds without sufficient evidence for a threshold related mechanism, ALARP principleIF data not availableApplication of a generally applicable approach as defined by the threshold of Toxicological Concern TTCThreshold of Toxicological concern: TTC value: 1.5 µg/dayTTC not applicable to high potency genotoxic carcinogens such as aflatoxins, N-nitroso and azoxy compounds
45 S.3. 2. Impurities Genotoxic impurities (GTIs) EU nfg CPMP/SWP/5199/02 and EMEA/CHMP/QWP/251344/2006Pharmaceutical considerationsTry to avoid genotoxic reagents or their generation (design of synthesis)Limitations (if possible) at an intermediate rather at the end active substanceIntroduce a specific purification step (destruction of genotoxic impurity)Assessment from the applicant justifying the potential presence or non presence of the genotoxic impurityIf not possible to avoid GTIs then go through relevant safety studiesSee decision trees in the EU nfg on GTIs
46 S.3. 2. Impurities Genotoxic impurities (GTIs) Joint SWP-QWP Q & A, EMA/ CHMP/ SWP/ / 2007 Rev . 3Revision 3 adopted in September 2010The aim of the Q&As, is to provide clarification and harmonisation of interpretation of the Guideline on the Limits of Genotoxic ImpuritiesAddresses several key areas including amongst othersAn explanation for cause of concern e.g. mesylate estersWhen ALARP should be appliedAmes test overruling alert structures but to be conducted to regulatory acceptable standardsHow to control GTIs in clinical trials and concept of staged TTCIn 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)
47 S.3. 2. Impurities Potentially genotoxic impurities with alert structures, Muller and al.
48 S.4. Control of API Harmonisation of policies on setting specifications to highly toxic impurities QWP Q&A, part 1, June 2012, EMA websiteSame principles (3 scenarios/cases) apply toGenotox impuritiesClass 1 metal catalystsClass 1 solventsExample is given in following slides for GTIsTarget limit is the limit in the corresponding guideline
49 S.4. Control of API Harmonisation of policies on setting specifications (GTI) QWP Q&A, part 1, June 2012, EMA websiteWhat is a reasonable policy for setting specifications for potentially GTI that are theoretical or actual impurities in the API mfg processCase 1 – A potential genotoxic impurityIf 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.This implies availability of a suitable method and testing to show absence of such impurity
50 S.4. Control of API Harmonisation of policies on setting specifications (GTI) QWP Q&A, part 1, June 2012, EMA websiteCase 2 – A (potentially) genotoxic impurity actually formed or introduced prior to the final step of the synthesisPossible not to include such impurity in the drug substance specificationControlled 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.
51 S.4. Control of API Harmonisation of policies on setting specifications (GTI) QWP Q&A, part 1, June 2012, EMA websiteCase 2 (cont.) – A (potentially) genotoxic impurity actually formed or introduced prior to the final step of the synthesisPossible not to include such impurity in the drug substance specificationSkip 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.If this condition is not fulfilled, a routine test in the intermediate is needed.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 routinelyNo control of genotoxic impurity at the intermediate stage, then the scenario of example 3 applies.
52 S.4. Control of API Harmonisation of policies on setting specifications (GTI) QWP Q&A, part 1, June 2012, EMA websiteCase 3 – A (potentially) genotoxic impurity is formed or introduced in the last step of the synthesisSuch impurity should be included in the drug substance specificationPossible 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.Data should be presented for at least 6 consecutive pilot scale or 3 consecutive production scale batches if skip testing is applied.If this condition is not fulfilled, a routine test in the drug substance specification is needed.
53 S.4. Control of API Setting specifications for impurities in antibiotics NEW, EU nfg EMA/CHMP/CVMP/QWP/199250/2009, effective end June 2013Applicable to new antibiotics and new sources of existing antibioticsNot applicable to residues from fermentation processActive substances manufactured by semi-synthesisReporting threshold: 0.05%/ 0.03%Identification threshold: 0.10% / 0.05%Qualification threshold: 0.15% / 0.05%Active substances manufactured by fermentation, single compoundReporting threshold: 0.10%Identification and qualification threshold: 0.15%Active substances manufactured by fermentation, family of compoundsIdentification threshold: 0.15%Qualification threshold: 0.50% / 0.2%(structurally close related compounds versus other related compounds)
54 S.7. Stability EU located in climatic zone I/II Storage conditions according to ICHGuidelines:ICH Q1A (R2): new active substancesEU nfg for existing active substances, derived from ICH, CPMP/QWP/122/02, rev 1Same requirements between new active substances and existing active substances UNLESS for length of data at time of submissionRetest period to be definedIf no retest period, API should be tested against its specifications before use in production of DPDeclarations of storage conditions according to CPMP/QWP/609/96/Rev 1 (different from WHO rules)
55 ConclusionFrom a pharmaceutical quality point of view, no difference is made between new active substances and existing or known active substancesAdoption of certain ICH texts in Ph. Eur. general monograph 2034Much emphasis on “Impurities”: each API should be assessed with regard to impurities on its own merits. Thorough discussion needed.Justification from the applicant why impurities in the product are considered qualified and safe for the intended useAPI starting material, very important topicJustify selection in view of EU nfg chemistry of new active substances & ICH Q11Critical steps of the synthesis should be GMPConsider steps of generation and removal of impuritiesAttention to change of suppliers of SM API impacting the impurity profile of final API