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 28- 29 September 2012, Mumbai, INDIA
59
Embed
EU requirements for quality of APIs in Marketing Authorisation Application Latest developments Maryam MEHMANDOUST, PhD ANSM, France Current Challenges.
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
EU requirements for quality of APIs in Marketing Authorisation Application
Latest developments
Maryam MEHMANDOUST, PhDANSM, FranceCurrent Challenges in Global Regulatory Compliance – Quality of Pharmaceutical Ingredients28- 29 September 2012, Mumbai, INDIA
2Agence nationale de sécurité du médicament et des produits de santé
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
3Agence nationale de sécurité du médicament et des produits de santé
Topics addressed EU Different options for submission of information on APIs CTD 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 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
4Agence nationale de sécurité du médicament et des produits de santé
Submission of data on APIs: Module 3EU nfg Summary of requirements for AS in the Q part of the dossier, EU nfg Summary of requirements for AS in the Q part of the dossier, CHMP/QWP/297/97 Rev 1 corrCHMP/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 For a pharmacopoeial substance demonstration of compliance with the monograph the monograph Option no more usedOption no more used
5Agence nationale de sécurité du médicament et des produits de santé
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
7Agence nationale de sécurité du médicament et des produits de santé
CTD quality part: Drug substance 3.2.S.
S.1 General InformationS.1 General Information(Nomenclature, Structure, General Properties)(Nomenclature, Structure, General Properties)
S.2 ManufactureS.2 Manufacture S.2.1 Manufacturer(s)S.2.1 Manufacturer(s) S.2.2 Description of Manufacturing Process and Process ControlsS.2.2 Description of Manufacturing Process and Process Controls S.2.3 Control of MaterialsS.2.3 Control of Materials S.2.4 Controls for Critical Steps and IntermediatesS.2.4 Controls for Critical Steps and Intermediates S.2.5 Process Validation and/or EvaluationS.2.5 Process Validation and/or Evaluation S.2.6 Manufacturing Process DevelopmentS.2.6 Manufacturing Process Development
S.3 CharacterisationS.3 Characterisation S.3.1 Elucidation of Structure and other CharacteristicsS.3.1 Elucidation of Structure and other Characteristics S.3.2 ImpuritiesS.3.2 Impurities
S.4 Control of Drug SubstancesS.4 Control of Drug Substances S.5 Reference Standards of MaterialsS.5 Reference Standards of Materials S.6 Container Closure SystemS.6 Container Closure System S.7 StabilityS.7 Stability
8Agence nationale de sécurité du médicament et des produits de santé
S.2. ManufactureS.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
9Agence nationale de sécurité du médicament et des produits de santé
S.2. ManufactureS.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
10Agence nationale de sécurité du médicament et des produits de santé
S.2. ManufactureMixture(s) of API(s) and excipientsQWP 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.
11Agence nationale de sécurité du médicament et des produits de santé
S.2.2. Description of the manufacturing process and process controlsEU 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
12Agence nationale de sécurité du médicament et des produits de santé
S.2.2. Description of the manufacturing process and process controlsEU 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
13Agence nationale de sécurité du médicament et des produits de santé
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
14Agence nationale de sécurité du médicament et des produits de santé
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?
15Agence nationale de sécurité du médicament et des produits de santé
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
16Agence nationale de sécurité du médicament et des produits de santé
API Starting MaterialICH 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.
17Agence nationale de sécurité du médicament et des produits de santé
API Starting materialEU 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.
18Agence nationale de sécurité du médicament et des produits de santé
API Starting materialEU 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
19Agence nationale de sécurité du médicament et des produits de santé
API Starting materialEU nfg chemistry of new active substance, CPMP/QWP/130/96, Rev 1
20Agence nationale de sécurité du médicament et des produits de santé
API Starting materialEU 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 1Publication 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)
21Agence nationale de sécurité du médicament et des produits de santé
API Starting materialEU 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. 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
22Agence nationale de sécurité du médicament et des produits de santé
API Starting materialExperience of EU assessors
Clopidogrel 5-Sulfosalicylate: not acceptable
23Agence nationale de sécurité du médicament et des produits de santé
API Starting materialExperience of EU assessors
Methy prednisolone hemisuccinate: not acceptable
24Agence nationale de sécurité du médicament et des produits de santé
API Starting materialExperience of EU assessors
Donepezil hydrochloride hydrate: not acceptable
25Agence nationale de sécurité du médicament et des produits de santé
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
26Agence nationale de sécurité du médicament et des produits de santé
API Starting materialExperience 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 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
27Agence nationale de sécurité du médicament et des produits de santé
API Starting materialICH 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
28Agence nationale de sécurité du médicament et des produits de santé
API Starting materialICH 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
29Agence nationale de sécurité du médicament et des produits de santé
API Starting materialICH 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.
30Agence nationale de sécurité du médicament et des produits de santé
API Starting materialICH 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
31Agence nationale de sécurité du médicament et des produits de santé
API Starting materialICH Q11 adopted (applicable in EU in November 2012)
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
32Agence nationale de sécurité du médicament et des produits de santé
API Starting materialICH Q11 adopted (applicable in EU in November 2012)
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)
33Agence nationale de sécurité du médicament et des produits de santé
API Starting materialICH Q11 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) 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.
34Agence nationale de sécurité du médicament et des produits de santé
API Starting materialICH 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
35Agence nationale de sécurité du médicament et des produits de santé
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
36Agence nationale de sécurité du médicament et des produits de santé
S.3. CharacterisationS.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)
37Agence nationale de sécurité du médicament et des produits de santé
S.3. 2. ImpuritiesRelated 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
38Agence nationale de sécurité du médicament et des produits de santé
S.3. 2. ImpuritiesAPIs 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)
39Agence nationale de sécurité du médicament et des produits de santé
S.3. 2. ImpuritiesScientific 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
40Agence nationale de sécurité du médicament et des produits de santé
S.3. 2. ImpuritiesResidual 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
41Agence nationale de sécurité du médicament et des produits de santé
S.3. 2. ImpuritiesResidues 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
42Agence nationale de sécurité du médicament et des produits de santé
S.3. 2. ImpuritiesResidues of metal catalysts, metal reagents
EU nfg EMEA/CHMP/SWP/4446/2000 objectives Class 1 Metals: metals of high toxic potential
Known carcinogens3 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 toxicityUbiquitous in environment, plants and animals: Fe, Zn
Difference is made between requirements for oral, parenteral and inhalation exposure
43Agence nationale de sécurité du médicament et des produits de santé
S.3. 2. ImpuritiesGenotoxic 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
44Agence nationale de sécurité du médicament et des produits de santé
S.3. 2. ImpuritiesGenotoxic impurities (GTIs)
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
45Agence nationale de sécurité du médicament et des produits de santé
S.3. 2. ImpuritiesGenotoxic impurities (GTIs)
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
46Agence nationale de sécurité du médicament et des produits de santé
S.3. 2. ImpuritiesGenotoxic impurities (GTIs)
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
47Agence nationale de sécurité du médicament et des produits de santé
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)
48Agence nationale de sécurité du médicament et des produits de santé
S.3. 2. ImpuritiesPotentially genotoxic impurities with alert structures, Muller and al.
NA
OH
N
A
A
O NO
NA
A
A H
O
AN
A
OH
AN
NO
A
ANO2
A
O NH2
O
A A
O
A A
N
H
CO
O
N
Halogen
N NA
A
A
A
EWG P
O
ORS
OR
O HalogenA
Halogen
(or S)
S or
N-Hydroxyaryls N-Acylated aminoaryls Aza-aryl N-oxides Aminoaryls and alkylated aminoaryls
Group 1: Aromatic groups
Purines or Pyrimidins, Intercalators, PNAs or PNAHs
49Agence nationale de sécurité du médicament et des produits de santé
S.4. Control of APIHarmonisation 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
50Agence nationale de sécurité du médicament et des produits de santé
S.4. Control of APIHarmonisation 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 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
51Agence nationale de sécurité du médicament et des produits de santé
S.4. Control of APIHarmonisation 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.
52Agence nationale de sécurité du médicament et des produits de santé
S.4. Control of APIHarmonisation 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 synthesisPossible 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.
53Agence nationale de sécurité du médicament et des produits de santé
S.4. Control of APIHarmonisation 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.
54Agence nationale de sécurité du médicament et des produits de santé
S.4. Control of APISetting specifications for impurities in antibioticsNEW, 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
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 Reporting threshold: 0.10% Identification threshold: 0.15% Qualification threshold: 0.50% / 0.2%
(structurally close related compounds versus other related compounds)
55Agence nationale de sécurité du médicament et des produits de santé
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)
56Agence nationale de sécurité du médicament et des produits de santé
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
57Agence nationale de sécurité du médicament et des produits de santé
Thank you for your attention
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.
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.