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Regulatory Requirements with Relevance for Quality of API

Beijing, March 2010
Jean-Louis ROBERT National Health Laboratory L – 1011 LUXEMBOURG CHMP co-opted member Chair CHMP/CVMP QWP


Topics addressed
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General considerations – CTD-Q Manufacturing: API starting materials Impurities
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Related substances Residual solvents Genotoxic impurities Residual metal catalysts/reagents

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Stability EU Assessment Policy: known active substance Conclusion Back-up: References relevant guidelines
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Application file CTD-Q structure Decision tree identification/qualification impurities Example of structure of genotoxic impurities

S.1 General Information

S.1.1 Nomenclature S.1.2 Structure S.1.3 General Properties

Physicochemical properties Properties affecting pharmacological efficacy …………..


3 Control of Materials   .2 Description of Manufacturing Process and Process Controls    Flowchart Sequential procedural narrative Scale.2.1 Manufacturer(s) S. range. viral safety 4  S.2. API starting material Information on all materials of biological origin. incl..S.2. yield…….2 Manufacture (1)   S.

S.3 Manufacture: API starting material (2)       API starting material incorporated as a significant structural fragment into the structure of the AS Proposal and justification by the applicant Full characterisation Description of a one step synthesis not acceptable. unless described in the European Pharmacopoeia (CEP or compliance with EP monograph to be demonstrated) Name of supplier has to be submitted Detailed description of the synthesis and GMP compliance (ICH Q7) should go together. 5 .2.

2.3 Manufacture: API starting material only flow chart AS SM AS SM3 detailed description AS AS SM n 6 .S.

Example: Ibuprofen  N-Butyl-Ibuprofen as an impurity of Ibuprofen (n-butylbenzene present in starting material isobutylbenzene) CH3 H3C C C H H2 Isobutyl-benzol CH3 H3C C C H H2 Ibuprofen CH3 C H COOH 7 .

Résolution test 8 .

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6 Manufacturing Process Development   .2 Manufacture (2)  S.2. a design space. clinical. real time release testing 10  S.2.4 Controls for Critical Steps and Intermediates  Tests and acceptance criteria to be provided Sterilisation process Changes in manufacturing occurring during development (pre-clinical.5 Process Validation and/or Evaluation   S.S.2. commercial) Development of e.g.

2 Impurities  Classification of Impurities  Organic impurities.S. Residual solvents  Drug substance impurities:  Process (synthetic) and drug related impurities (degradation).1 Elucidation of Structure and other Characteristics  Full elucidation or with reference to a pharmacopoeial standard S.3.3 Characterisation   S. Inorganic impurities.3.  Drug product impurities:  Degradation products 11 .

Impurities: General Considerations       The ICH guidelines Q3A (R). Q3C are the general basis for the control of impurities in active substances and medicinal products  Consideration of chemistry and safety aspects  Glossary Initial scope: new active substances and corresponding products. [Q3B (R)].g. European Pharmacopoeia: general monographs (e. Extension to existing active substances and corresponding medicinal products. profile)  Not necessarily qualified In addition EU guidelines  Genotoxic Impurities Testing  Residual metal catalysts/ metal reagents 12 . Substances for Pharmaceutical Use) and chapters New synthesis can generate new impurities (imp.

 identification.  qualification.Q3A/B(R) and Q6A are complementary  Q3A-B:  Q6A: address the chemistry aspects and the safety aspects of impurities and defines different thresholds  reporting. addresses the setting and justification of acceptance criteria and the selection of test procedures 13 .

Listing of Impurities       Each specified identified impurity Each specified unidentified impurity Any unspecified impurity with an acceptance criterion of not more than (<) the identification threshold Total impurities Residual Solvents Inorganic impurities 14 .

Thresholds (active substance) MDD < 2g Reporting T Identificat.0 mg per day intake.0 mg per day intake.10% or 1. whichever is lower MDD>2g > 0.05% 15 .03% > 0. T > 0. whichever is lower > 0.05% Qualificat.15% 1. T > 0.05% > 0.

0% 16 . the maximal daily dose.5% Qualification threshold: > 1. the duration of therapy.1% Identification threshold: > 0. the ability of the analytical methods (current scientific status).   European Pharmacopoeia: Organic impurities in peptides obtained by chemical synthesis: Reporting threshold: > 0.Active substances outside of the scope of the ICH guideline  For active substances outside of the scope of ICH guideline:  The applicant should justify adequate thresholds taking into account the nature of the active substance.

. Summary of laboratory studies conducted to detect impurities  Negative results can be helpful ! Discussion on the impurity profiles found in preclinical and clinical trials: impurities above the qualification threshold have to be qualified.Scientific Discussion on Impurities      Summary of actual and potential impurities (sound scientific appraisal)... stability. reagents used. Potential impurity: an impurity that can arise during manufacture or storage. It may or may not appear in the new drug substance. 17 . Risk based approach (see also ICH Q9) Thorough discussion by the applicant based on synthesis.

Impurities to be specified .Rationale for the inclusion or exclusion of impurities   Scientific knowledge/understanding about the manufacturing process of the active substance  Knowledge about how an impurity is generated Establishment of a control strategy  Specifications of AS starting materials  Control of impurities at intermediates rather than on final AS  Identification of critical process parameters influencing the impurity profile  Process controls  Purification steps: influence on the impurity profile of the final active substance  Knowledge about the degradation pathway 18 .

Consider each unit operation but also an overall control strategy. 19 . in-process controls. facility and equipment operating conditions. and the associated methods and frequency of monitoring and control.Reminder: Control Strategy (ICH Q10)   A planned set of controls. derived from current product and process understanding. The controls can include parameters and attributes related to drug substance and drug product materials and components. that assures process performance and product quality. finished product specifications.

Acceptance criteria for impurities    Acceptance criteria should be based on  Relevant development data  Test data for the active substance used in toxicological and clinical studies  Results from long term and accelerated stability data  Range of expected analytical and manufacturing variability Actual results obtained should form the primary basis for establishing the acceptance criteria They should not be higher than the qualification level 20 .

Identity / size  Date and site of manufacture  Manufacturing process  Impurities content. total  Use of batches  Reference to analytical procedure used  21 . Batches: detailed information to be provided. safety and stability testing. as well as batches representative of the proposed commercial process.Reporting impurities content of batches  Results to be provided for batches used for clinical.   To be reported: > Reporting threshold. single.

New Impurities

Decision Tree for Identification and Qualification (ICHQ3A R2)  Description of considerations for the qualification and identification of impurities when thresholds are exceeded.  Recommendation what to do when new impurities appear during later stage of development or after authorisation.


Residual Solvents: Q3C

Residual Solvents: Q3C

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Defines safety limits for solvents (class 1, 2, 3 and (4) solvents) Option 1 based on concentration Option 2 based on MDD and PDE When the acceptance criteria are identical to the safety limits (as indicated in the NfG): no justification is needed (option 1).


Residual Solvents: Q3C

Class 1 solvents
In all cases, the limit of a class 1 solvent in the final active substance should comply with the requirements of the NfG, even if initially not used as a solvent. e.g. benzene: - use as starting material (synthesis) - present as contaminant e.g. toluene - by-product from a chemical reaction


need not be controlled routinely. 25  Last step of the synthesis:   Prior to the last step:  .Residual Solvents: some comments CHMP position paper  Class 2 solvents  As a principle:  Should be routinely controlled either in an intermediate or in the active substance. Routine control in the final active substance If <10% present in a suitable intermediate or in the active substance.

26 .Genotoxic Impurities  Joint SWP-QWP “Guideline on the Limits of Genotoxic Impurities”   published 2006 came into effect on 1 January 2007  Basis: ICH Q3A/B guideline: “For impurities known to be unusually potent or to produce toxic or unexpected pharmacological effects.detection limit of the analytical procedures should be commensurate with the level at which the impurities should be controlled”. the quantification .

27 .Genotoxic Impurities  Scope    New active substances New applications for existing active substances. 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. where assessment of the route of synthesis.

5 µg/day 28 .Genotoxic Impurities  Principles    Identifications guided by existing genotoxic data or the presence of structure alerts Genotoxic compounds with sufficient evidence for a threshold-related mechanism Genotoxic compounds without sufficient evidence for a threshold-related mechanism Threshold of Toxicological concern: TTC value: 1.

29 .Genotoxic impurities   Pharmaceutical considerations  Try to avoid genotoxic reagents  Limitations (if possible) at an intermediate rather at the end active substance  Introduction of a specific purification step (destruction of genotoxic impurity)  Assessment from the applicant justifying the potential presence or non presence of the genotoxic impurity Discussion/collaboration with safety experts important.

Genotoxic impurities SWP – QWP Q&As  Revision 1 issued June 2008  The aim of the Q&As document is to provide clarification and harmonisation of interpretation of the Guideline on the Limits of Genotoxic Impurities  Addresses 7 key areas 30 .

mesylate salt 31 . new knowledge may indicate a previously unknown “cause for concern”. However. e.g.Genotoxic impurities  “Cause for concern”:   If a manufacturing procedure for API remains essentially unchanged. a re-evaluation with respect to the presence of potentially genotoxic impurities is generally not needed.

Metal Catalysts/Metal Reagents Recommendation of acceptable concentration limits for the residues of metal catalysts or metal reagents that may be present in pharmaceutical substances or in drug products. 32 .

Metal Catalysts/Metal Reagents   EMEA/145858/2006 General considerations       Same principles as for Residual Solvents ICH Q3C Conservative approach compared to food additives 3 classes Class limit for class 1B Reporting similar to ICH Q3C Implementation 5 years (for existing products) 33 .

plants and animals  No need for health based exposure limit   Difference is made between oral. common in food and food additives  Class 3 Metals: metals with no significant toxicity Ubiquitous in environment. parenteral and inhalation exposure (class 1) 34 .Metal Catalysts/Metal Reagents  Concept  Class 1 Metals: metals of high toxic potential  Known carcinogens  Class 2 Metals: metals with low toxic potential  Nutritional trace metals.

Metal Catalysts/Metal Reagents  Expectation:   The relevant residual metal should be controlled with a suitable method Pharmacopoeial heavy metal test generally not acceptable  Further discussion at international level ongoing both on the methodology and the limits 35 .

g. Introduction of a specific purification step e. 36 . to limit a potential genotoxic impurity below TTC (degradation of this impurity).Setting Specifications – Considerations Control of Impurities  Drug substance:   Identification of process parameter(s) (CQP) in the synthesis influencing the generation of a specific impurity in the final product: introduction of a specific in-process control: tightening of pH range.

Synthesis Indinavir Sulfate 37 .

Setting specification: GTI (case centralised authorised product) Final AS suspected GT comp. III < 10 ppm (detection limit) < TTC (target) Intermediate II + Compound III Compound IV 38 .

S.1 Specification S.3 Validation of Analytical Procedures S.4.5 Justification of Specification 39 .2 Analytical Procedures S. Batch Analyses S.4 Control of Drug Substance      S.4.

S.5 Reference Standards of Materials   Full characterisation Pharmacopoeial standards 40 .

6 Container Closure System  Brief description of bulk container closure system 41 .S.

7.2 Post-approval Stability Protocol and Stability Commitment S.7 Stability (1)    S.S.3 Stability Data 42 .7.7.1 Stability summary and Conclusions S.

S.7 Stability (2)    EU in climatic zone I/II Storage conditions according to ICH Guidelines:   ICH 1A (R2): new active substances CHMP: existing active substances derived from ICH guideline  In principle no difference in requirements between new active substances and existing active substances. 43 .

44 . no additional data under intermediate conditions will have to be generated. a and b) Study Long term* Intermediate 30°C ± 2°C/65% RH ± 5% RH 6 months Accelerated to 40°C ± 2°C/75% RH ± 5% 6 months * It is up the applicant to decide whether long term stability studies areRH performed at 25°C ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH. 1 year Exi. AS: 6 mo.Stability: Storage conditions  General case Storage condition 25°C ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH Minimum time period covered by data at submission New AS. In the latter case. (opt.

1 year Exi. AS: 6 mo. (opt. a and b) 6 months Study Long term Accelerated  25°C ± 2°C/60% RH ± 5% RH or 25°C ± 2°C/60% RH ± 5% RH Freezer Storage condition Minimum time period covered by data at submission Study Long term -20°C ± 5°C New AS. (opt. a and b) 45 . AS: 6 mo.Stability: Storage conditions  Refrigerator Storage condition Minimum time period covered by data at submission New AS. 1 year Exi.

Stability: Further Considerations   Retest period to be defined Pharmacopoeial substances: monographs cover synthetic and degradation products: if no retest date. batch has to be controlled immediately prior to be manufactured in the medicinal product. 46 .

Declaration Storage Conditions (CPMP) Testing conditions where stability has been shown 25°C/60%RH alt. where relevant Do not refrigerate or freeze Do not refrigerate or freeze Do not refrigerate or freeze Do not store above 30°C Do not store above 25°C 5°C±3°C Below 0°C Store at 2-8°C Store in freezer Do not freeze 47 . 30°C/65%RH 40°C/75%RH 25°C/60%RH + 30°C/60%RH (interm) or 30°C/65%RH 25°C/60%RH Required label None Additional label.

genotoxic impurities Last step of the synthesis Prior to the last step of the synthesis …. 48 .Setting Specifications: future position paper     Harmonisation approach for residual solvents.. heavy metals.

This is also highlighted in the European Pharmacopoeia where relevant ICH or CHMP guidelines or the policy adopted have been adopted:  Impurities  Residual solvents  Genotoxic impurities (EP policy)  Residual metal catalysts/reagents (EP policy) 49 .EU Assessment Policy (known ASs)   From a pharmaceutical quality point of view no difference is made between new active substances and “existing or known” active substances (and their corresponding products).

. 50 . A summary of impurities present in batches of the active substance(s) …………. For existing/known active substances.EU Assessment Policy (known ASs) (2)    Applications for a MA of medicinal products containing existing active substances are assessed according to their own merit (based on quality risk management). the European Pharmacopoeia general monograph “Substances for pharmaceutical use” is applicable.(and decomposition products arising during storage) as proposed for use in the product to be marketed together with an evaluation of these impurities.

this fact is not a ground for rejection of the application if the impurities are considered qualified. If the impurity profile of the proposed product is different from that of the reference product.EU Assessment Policy (known ASs) (3)  Each active substance with regard to impurities has ultimately to be assessed on its own merits. it is expected to find a discussion whether the product is likely to have a different impurity profile as compared to the original product. In the development part of the application.  51 .

the full qualification or other adequate information about the safety of these impurities will be requested.g. either by reference to expected similarity with the originator or by other means e. 52  . compliance with relevant (V)ICH guidelines. In the case where the impurity profile of a generic product differs qualitatively from the originator. or where higher amount of impurities are seen.EU Assessment Policy (known ASs) (4)  It is expected that the applicant of a generic product justifies why he considers the impurities in his product safe for the intended use and qualified.

   enhanced/systematic development establishment of design space establishment of real time release testing  New Paradigm: combination of enhanced process understanding.Outlook  Preparation of an ICH API (chemical and biotechnological origin) guideline (Q11) taking into account the concepts and principles described in Q8R (Pharmaceutical Development). formal use risk management tools and establishment of an efficient quality system 53 .

The section on impurities is one of the most important section in an application file. Impurities profile depends very much on the route of synthesis. Thorough preparation and presentation of this section is most helpful for the assessor.Conclusion      The pharmaceutical quality requirements for the API (AS) are very much guided by the harmonised ICH guidelines: Impurities. attention has to be paid to changes in the manufacturing process including change in suppliers of starting materials. stability. analytical validation.……… From a pharmaceutical quality point of view there is no difference between new ASs and existing/known ASs.!! 54 . During lifetime of the product.

Back-up slides 55 .

Relevant Guidelines (API) From a pharmaceutical quality point of view no difference is made between new active substances and “existing or known” active substances (and their corresponding products).        CHMP NfG: CHMP NfG: Chemistry on new active substances Summary of requirements for Active Substances in the Quality Part of the Dossier Q3A (R2): Impurities Testing in new drug substances Q3C: Impurities: Guideline for Residual Solvents CHMP position paper class 1/class 2 solvents CHMP NfG: Testing on Genotoxic Impurities CHMP HfG: Specification limits for residues of metal catalysts or metal reagents 56 .References .

References .4) 57  EMEA Website: www.Relevant Guidelines (API)  Q6A:     Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products Q2R: Validation of analytical procedures Q1A (R2): Stability: new active substances…….eu including Q&As . CHMP NfG: Stability: existing active substances…….10) Residual Solvents (5.europa.emea. European Pharmacopoeia   General monograph: Substances for pharmacopoeial use General chapter:   Control of Impurities (5.

4 Controls for Critical Steps and Intermediates S.2.1.2 Description of Manufacturing Process and Process Controls S.1 Nomenclature S.1.6 Manufacturing Process Development  S.S  S.3 General Properties S.2.3 Control of Materials S.2.2.2 Manufacture       58 .2.2.2 Structure S.1 Manufacturer(s) S.5 Process Validation and/or Evaluation S.Application file: CTD-Q: Drug Substances 3.1 General Information    S.1.2.

3.1 Specification S.S  S.4 Batch Analyses S.5 Justification of Specification 59  S.3 Validation of Analytical Procedures S.4 Control of Drug Substances      .4.3 Characterisation   S. Analytical Procedures S.4.4.Applicatin file: CTD-Q: Drug Substances 3.3.1 Elucidation of Structure and other Characteristics S.2 Impurities S.

2.7.3 Stability Data 60 .1 Stability Summary and Conclusions S.6 Container Closure System S.5 Reference Standards of Materials S.S    S.2 Post-approval Stability Protocol and Stability Commitment S.7.Application file: CTD-Q: Drug Substances 3.7.7 Stability    S.

Genotoxicity studies (point mutation. chromosomal aberration) .Other specific toxicity endpoints.Decision Tree for Identification and Qualification Is impurity greater than identification Threshold? No action Yes No Yes Structure identified? Any known human relevant risks? Yes No further No Yes Yes Reduce to save level action No Reduce to not more than (≤) identification threshold Reduce to not more than (≤) identification threshold Yes No Greater than qualification Threshold? No No No action Consider patient population and duration of use and consider conducting: . usually 14 to 90 days) .General toxicity studies (one species. as appropriate Reduce to save level Any clinically relevant adverse effects? Yes No Qualified 61 .

Intercalators.) 62 . Aryl or H X = F.Examples of Structure of Genotoxic Impurities Group 1: Aromatic Groups OH N A N-hydroxyaryls A N O A N O A N A Purines. Cl. Pyrimidines. Br. I EWG = Electron withdrawing group (CN. C=O. etc. ester. PNAs or PNAHs N-Acylated aminoaryls Aza-aryl N-oxides (Alkylated) Aminoaryls Group 2: Alkyl and Aryl Groups O A H A N Aldehydes OH A H N A Epoxides A A N O NO A NO2 A O NH2 S or N Nitro compounds Carbamates (Urethanes) X N-methylols N-Nitrosoamines S or N Mustards (beta haloethyl) O A A O O A Propiolactones O O S Propiosultones A R N N A A Hydrazines and Azo compounds Aziridines EWG Micheal-reactive Acceptors Group 3: Heteroatomic Groups O O A S P X OR OR Alkyl esters of phosphonates or sulfonates X Halo-alkenes Primary halides (Alkyl and Aryl-CH2) Legend: A = Alkyl.