Glossary ALARP As low as reasonably practicable

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

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

Topics addressed EU Different options for submission of information on APIs CTD quality part: Drug substance 3.2.S. Manufacture S.2. Manufacturers GMP status Manufacture of mixtures API Starting material (EU requirements, examples, ICH Q11) Manufacture: validation & mfg process development Impurities S.3.2. Control of API S.4. Specifications for highly toxic impurities: genotox, class 1 metal catalysts and solvents Specifications for related impurities in antibiotics Stability Conclusion

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 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 Active Substance Master File (ASMF) New developments For a pharmacopoeial substance demonstration of compliance with the monograph Option no more used

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 States ASMFs involved in EU procedures (CP, DCP and MRP) Development of a database to host ASMF assessment reports Creation of the EU ASMF number Revision of the ASMF nfg regarding annexes (now 4 annexes) coming into force from October 1, 2012 Paper on the rules of worksharing between MSs under preparation

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 & EDQM Annex 3, Submission letter & administrative details 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) Guidance for new annexes developped and soon available for ASMF holders Much insistance to have the latest version of the ASMF in different concerned MSs

CTD quality part: Drug substance 3.2.S.
S.1 General Information (Nomenclature, Structure, 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 S.3 Characterisation S.3.1 Elucidation of Structure and other Characteristics S.3.2 Impurities S.4 Control of Drug Substances S.5 Reference Standards of Materials S.6 Container Closure System S.7 Stability

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 materials 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 Manufacture of active substance begins from the use of the API starting material according to ICH Q7/ EU GMP Part II 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

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

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 ASMF Blending of AS and excipient considered as the 1st step in mfg of the medicinal product 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 Mixing of different active substances produced at different mfg sites cannot be considered as active substance manufacture 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.

S.2.2. Description of the manufacturing process and process controls
EU nfg chemistry of new active substance, CPMP/ QWP/ 130/96 Rev 1 Description of the process represents the applicant / manufacturer’s commitment 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 Flow diagram Should include molecualr formulae, weights, yield ranges, chemical structures of starting materials, intermediates, API reflecting stereochemistry

S.2.2. Description of the manufacturing process and process controls
EU nfg chemistry of new active substance, CPMP/ QWP/ 130/96 Rev 1 Sequential procedural narrative including operating conditions, quantities of materials used for a representative commercial scale batch, yields IPCs for each step Scale of manufacture Reprocessing ICH Q11 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 Design space is proposed by the applicant and subject to regulatory assessment and approval

S.2.3. Control of materials API 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 materials Viral and TSE aspects to be addressed for all materials of biological origin

API Starting Material/ important topic, why?
Current situation and issues Context of globalisation Fragmentation of the API manufacturing chain More 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 molecule Lack of information OR poor information on potential impurities arising from the API SM synthesis and their carry over into the API insufficient information to ensure full control of the final API Manufacturers of the proposed API SM are often external suppliers Do manufacturers of the API, ASMF and CEP holders have sufficient control on them?

API Starting Material/ important topic, why?
Current situation and issues Regulatory changes in EU only applicable to manufacturer of API SM and its specifications 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 ICH 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

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.

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 Q11 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.

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 Incorporated 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 pharmacopoeial Information about the SM synthesis (not detailed, flow-chart) to enable assessors to judge of the suitability of the proposed specifications Discussion on impurities present in the API SM and possibility of their carry over or as derivatives into the final API Acceptance criteria for API SM to be set based on evaluation of the fate of impurities when subject to the normal process/ synthesis

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)

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. If API SM authorised as an active substance in a MA 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 Reagents, solvents

API Starting material Experience of EU assessors
Clopidogrel 5-Sulfosalicylate: not acceptable

Methy prednisolone hemisuccinate: not acceptable

Donepezil hydrochloride hydrate: not acceptable

Famciclovir: no more acceptable while absence of carry over of impurities of SM API was justified under S.2.3

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 Generally 1 or 2 steps are not sufficient to provide assurance of final API quality and not acceptable unless justified by API structure Some APIs are of so simple structure that it is obvious a process in one step is acceptable e.g.: chloroxylenol pirfenidone Commercial availability on its own is not a criterion of selection of the API SM contrary to what can be concluded from ICH Q7, now ICH 11 applicable 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 When API SM not acceptable, redefinition is requested however difference of view about application of this measure to already accepted ASMFs and MAs

API Starting material ICH Q11 adopted (applicable in EU in November 2012) Selection of API SM, section 5 Principles to determine where the AS mfg process begins Accent on control strategy 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 Relationship between risk and number of steps from the end of the mfg process to be considered for 2 aspects Physical properties of the drug substance Formation, fate and purge of impurities

API Starting material ICH Q11 adopted (applicable in EU in November 2012) Selection of API SM, section 5 Risk and number of steps from the end of the mfg process to be considered for 2 aspects Physical properties of the drug substance 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 Formation, fate and purge of impurities 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 Fate: whether the impurity reacts and changes its chemical structure Purge: whether the impurity is removed via crystallisation, extraction, etc

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 5 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 To understand how impurities are formed, what could be the impact of changes in the process on their formation, fate and purge To understand why the control strategy proposed is suitable for the API mfg process This will include typically description of multiple chemical transformation steps.

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 isolation Mfg 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 structure Non isolated intermediates are not appropriate SMs SM incorporated as a significant structural fragment and in this context, different from raw materials

Principles to be applied together in selction of SMs rather than applying them in isolation Justification for appropriateness of selected API SM Ability of analytical methods to detect impurities in SMs Fate and purge of these impurities and their derivatives in the process How the specification of each SM will contribute to the control strategy No need to justify use of commercially available SM however Commercially available chemical is one that is sold as a commodity in a NON Pharmaceutical market 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 Q11

Semi synthetic APIs: obtained by combination of chemical synthesis & fermentation or extraction from botanical material Possible to describe the mfg process from one of the isolated intermediates (as SM API) in the synthetic process The selected isolated intermediate should comply with the principles outlined before for selection of API SM Analytical characterisation of the selected SM including its impurity profile, impact of fermentation or botanical material/extraction on the impurity profile of the API If not, description of the mfg process should be from the source material (microorganism producer or plant)

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) 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.

API Starting material ICH Q11: 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? 1st 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

S.2. Manufacture S.2.5 Process Validation and/or Evaluation
Sterilisation process For non sterile API, validation should be carried out but not needed to provide in the file (see ICH Q11) S.2.6 Manufacturing Process Development Changes in manufacturing occurring during development (pre-clinical, clinical, scale up, commercial) Development of e.g. a design space, real time release testing Risk assessment & assignment of criticality: Identification of CQAs and CPP Establishing a Design space: design of experiments & design space verification Defining a control strategy

S.3. Characterisation S.3.2. Impurities
Classification of impurities Organic impurities ICH Q3 A (R) Residual solvents ICH Q3C and EU nfg CPMP/QWP/450/03 Inorganic impurities Metal 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)

S.3. 2. Impurities Related substances & thresholds to apply
Each specified identified impurity Each specified unidentified impurity but identified at least by an analytical character e.g. RT in a chromatographic system Any unspecified impurity with an acceptance criterion of not more than (<) the identification threshold Total impurities

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 2034 Reporting threshold > 0.1% Identification threshold > 0.5% Qualification threshold > 1.0% For other type of APIs, Justification to be provided for adequate thresholds the 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)

S.3. 2. Impurities Scientific discussion on impurities & rationale for setting acceptance criteria
Summary of actual and potential impurities & discussion on their origin and generation Discussion on impurity profiles found in preclinical and clinical batches for new APIs Discussion on impurity profile found in development, pilot, commercial batches for existing APIs Comparison to the pharmacopoeial monograph Impurities above the qualification thresholds have to be qualified, acceptance criteria cannot be higher than qualified level 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 Q3A Demonstration of similarity with the reference product possible

S.3. 2. Impurities Residual solvents
Safety limits for 3 classes of solvents Class 1 solvents highly toxic, to be avoided, suitable justification needed for their use Class 2 solvents to be limited with 2 options Concentration limit (ppm) and PDE (mg/day) NEW: cumene classified now in class 2 option 1 limit of NMT 70 ppm option 2 limit (PDE) of 0.7 mg/day See 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 nfg Class 3 solvents, low toxic potential Table 4, a non exhaustive list of solvents for which safety data are not available

S.3. 2. Impurities Residues of metal catalysts, metal reagents
EU nfg EMEA/CHMP/SWP/4446/2000 objectives To recommend maximum acceptable concentration limits for residues of metal catalysts/reagents in pharmaceutical substances or in drug products Control of residual metal with a suitable method Pharmacopoeial heavy metal test generally not acceptable Implementation 5 years for existing products ICH guideline for metal impurities ICH Q3D under preparation

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

S.3. 2. Impurities Genotoxic impurities (GTIs)
EU nfg CPMP/SWP/5199/02 and EMEA/CHMP/QWP/251344/2006 Joint SWP-QWP “Guideline on the Limits of Genotoxic Impurities” with 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”. An ICH guideline is under preparation, genotoxic impurities M7

EU nfg CPMP/SWP/5199/02 and EMEA/CHMP/QWP/251344/2006 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

EU nfg CPMP/SWP/5199/02 and EMEA/CHMP/QWP/251344/2006 Principles Identification guided by existing genotoxic data or the presence of alert structures Genotoxic 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 principle IF data not available Application of a generally applicable approach as defined by the threshold of Toxicological Concern TTC 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

EU nfg CPMP/SWP/5199/02 and EMEA/CHMP/QWP/251344/2006 Pharmaceutical considerations Try to avoid genotoxic reagents or their generation (design of synthesis) Limitations (if possible) at an intermediate rather at the end active 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

Joint SWP-QWP Q & A, EMA/ CHMP/ SWP/ / 2007 Rev . 3 Revision 3 adopted in September 2010 The aim of the Q&As, is to provide clarification and harmonisation of interpretation of the Guideline on the Limits of Genotoxic Impurities 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)

S.3. 2. Impurities Potentially genotoxic impurities with alert structures, Muller and al.

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 Genotox impurities Class 1 metal catalysts Class 1 solvents Example is given in following slides for GTIs Target limit is the limit in the corresponding guideline

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 Case 1 – A potential genotoxic impurity 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. This implies availability of a suitable method and testing to show absence of such impurity

S.4. Control of API Harmonisation of policies on setting specifications (GTI) QWP Q&A, part 1, June 2012, EMA website 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 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.

S.4. Control of API Harmonisation of policies on setting specifications (GTI) QWP Q&A, part 1, June 2012, EMA website 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 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. 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 routinely No control of genotoxic impurity at the intermediate stage, then the scenario of example 3 applies.

S.4. Control of API Harmonisation of policies on setting specifications (GTI) QWP Q&A, part 1, June 2012, EMA website 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 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. 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.

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 Not applicable to residues from fermentation process Active substances manufactured by semi-synthesis Reporting threshold: 0.05%/ 0.03% Identification threshold: 0.10% / 0.05% Qualification threshold: 0.15% / 0.05% Active substances manufactured by fermentation, single compound Reporting threshold: 0.10% Identification and qualification threshold: 0.15% Active substances manufactured by fermentation, family of compounds Identification threshold: 0.15% Qualification threshold: 0.50% / 0.2% (structurally close related compounds versus other related compounds)

S.7. Stability EU located in climatic zone I/II
Storage conditions according to ICH Guidelines: ICH Q1A (R2): new active substances EU nfg for existing active substances, derived from ICH, CPMP/QWP/122/02, rev 1 Same requirements between new active substances and existing active substances UNLESS for length of data at time of submission Retest period to be defined If no retest period, API should be tested against its specifications before use in production of DP Declarations of storage conditions according to CPMP/QWP/609/96/Rev 1 (different from WHO rules)

Conclusion 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 Much 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 use API starting material, very important topic Justify selection in view of EU nfg chemistry of new active substances & ICH Q11 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

Thank you for your attention

Glossary ALARP As low as reasonably practicable

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