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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. General considerations – CTD-Q Manufacturing: API starting materials Impurities

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Regulatory requirements with relevance for quality of api

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
Topics addressed

  • General considerations – CTD-Q

  • Manufacturing: API starting materials

  • Impurities

    • Related substances

    • Residual solvents

    • Genotoxic impurities

    • Residual metal catalysts/reagents

  • Stability

  • EU Assessment Policy: known active substance

  • Conclusion

  • Back-up: References relevant guidelines

    • Application file CTD-Q structure

    • Decision tree identification/qualification impurities

    • Example of structure of genotoxic impurities


S 1 general information
S.1 General Information

  • S.1.1 Nomenclature

  • S.1.2 Structure

  • S.1.3 General Properties

    • Physicochemical properties

    • Properties affecting pharmacological efficacy

    • …………..


S 2 manufacture 1
S.2 Manufacture (1)

  • S.2.1 Manufacturer(s)

  • S.2.2 Description of Manufacturing Process and Process Controls

    • Flowchart

    • Sequential procedural narrative

    • Scale, range, yield……..

  • S.2.3 Control of Materials

    • API starting material

    • Information on all materials of biological origin, incl. viral safety


S 2 3 manufacture api starting material 2
S.2.3 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.


S 2 3 manufacture api starting material
S.2.3 Manufacture: API starting material

only flow chart

detailed

description

AS

SM3

AS

SM

AS

n

AS

SM


Example ibuprofen
Example: Ibuprofen

  • N-Butyl-Ibuprofen as an impurity of Ibuprofen

    (n-butylbenzene present in starting material isobutylbenzene)

Isobutyl-benzol

Ibuprofen



S 2 manufacture 2
S.2 Manufacture (2)

  • S.2.4 Controls for Critical Steps and Intermediates

    • Tests and acceptance criteria to be provided

  • S.2.5 Process Validation and/or Evaluation

    • Sterilisation process

  • S.2.6 Manufacturing Process Development

    • Changes in manufacturing occurring during development (pre-clinical, clinical, commercial)

    • Development of e.g. a design space, real time release testing


S 3 characterisation
S.3 Characterisation

  • S.3.1 Elucidation of Structure and other Characteristics

    • Full elucidation or with reference to a pharmacopoeial standard

  • S.3.2 Impurities

    • Classification of Impurities

      • Organic impurities, Inorganic impurities, Residual solvents

    • Drug substance impurities:

      • Process (synthetic) and drug related impurities (degradation);

    • Drug product impurities:

      • Degradation products


Impurities general considerations
Impurities: General Considerations

  • The ICH guidelines Q3A (R), [Q3B (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.

  • Extension to existing active substances and corresponding medicinal products.

  • European Pharmacopoeia: general monographs (e.g. Substances for Pharmaceutical Use) and chapters

  • New synthesis can generate new impurities (imp. profile)

    • Not necessarily qualified

  • In addition EU guidelines

    • Genotoxic Impurities Testing

    • Residual metal catalysts/ metal reagents


Q3a b r and q6a are complementary
Q3A/B(R) and Q6A are complementary

  • Q3A-B: address the chemistry aspects and

    the safety aspects of impurities and

    defines different thresholds

    • reporting,

    • identification,

    • qualification.

  • Q6A: addresses the setting and justification of acceptance criteria and the selection of test procedures


  • Listing of impurities
    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


    Thresholds active substance
    Thresholds (active substance)

    MDD < 2g MDD>2g

    Reporting T > 0.05% > 0.03%

    Identificat. T > 0.10% or > 0.05%

    1.0 mg per day intake,

    whichever is lower

    • Qualificat. T > 0.15% > 0.05%

      • 1.0 mg per day intake,

    • whichever is lower


    Active substances outside of the scope of the ich guideline
    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, the maximal daily dose, the duration of therapy, the ability of the analytical methods (current scientific status).

    • European Pharmacopoeia:

      • Organic impurities in peptides obtained by chemical synthesis:

        Reporting threshold: > 0.1%

        Identification threshold: > 0.5%

        Qualification threshold: > 1.0%


    Scientific discussion on impurities
    Scientific Discussion on Impurities

    • Summary of actual and potential impurities (sound scientific appraisal).

      Potential impurity: an impurity that can arise during manufacture or storage. It may or may not appear in the new drug substance.

    • Risk based approach (see also ICH Q9)

    • Thorough discussion by the applicant based on synthesis, reagents used, stability,...

    • 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.


    Impurities to be specified rationale for the inclusion or exclusion of impurities
    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


    Reminder control strategy ich q10
    Reminder: Control Strategy exclusion of impurities (ICH Q10)

    • A planned set of controls, derived from current product and process understanding, that assures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control.

    • Consider each unit operation but also an overall control strategy.


    Acceptance criteria for impurities
    Acceptance criteria for impurities exclusion of 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


    Reporting impurities content of batches
    Reporting impurities content of batches exclusion of impurities

    • Results to be provided for batches used for clinical, safety and stability testing, as well as batches representative of the proposed commercial process.

      • To be reported: > Reporting threshold.

      • Batches: detailed information to be provided.

        • Identity / size

        • Date and site of manufacture

        • Manufacturing process

        • Impurities content, single, total

        • Use of batches

        • Reference to analytical procedure used


    New impurities
    New Impurities exclusion of impurities

    • Decision Tree for Identification and Qualification (ICH-Q3A 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 exclusion of impurities

    • Residual Solvents: Q3C

      • 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 q3c1
    Residual Solvents: Q3C exclusion of impurities

    • 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


    Residual solvents some comments chmp position paper
    Residual Solvents: some comments exclusion of impurities CHMP position paper

    • Class 2 solvents

      • As a principle:

        • Should be routinely controlled either in an intermediate or in the active substance;

      • Last step of the synthesis:

        • Routine control in the final active substance

      • Prior to the last step:

        • If <10% present in a suitable intermediate or in the active substance, need not be controlled routinely.


    Genotoxic impurities
    Genotoxic Impurities exclusion of 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, the quantification - detection limit of the analytical procedures should be commensurate with the level at which the impurities should be controlled”.


    Genotoxic impurities1
    Genotoxic Impurities exclusion of impurities

    • 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.


    Genotoxic impurities2
    Genotoxic Impurities exclusion of 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: 1.5 µg/day


    Genotoxic impurities3
    Genotoxic impurities exclusion of 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 impurities4
    Genotoxic impurities exclusion of 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


    Genotoxic impurities5
    Genotoxic impurities exclusion of 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. However, new knowledge may indicate a previously unknown “cause for concern”.

      • e.g. mesylate salt


    Metal catalysts metal reagents
    Metal Catalysts/Metal Reagents exclusion of impurities

    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.


    Metal catalysts metal reagents1
    Metal Catalysts/Metal Reagents exclusion of impurities

    • 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)


    Metal catalysts metal reagents2
    Metal Catalysts/Metal Reagents exclusion of impurities

    • Concept

      • Class 1 Metals: metals of high toxic potential

        • Known carcinogens

      • Class 2 Metals: metals with low toxic potential

        • Nutritional trace metals, common in food and food additives

      • Class 3 Metals: metals with no significant toxicity

        • Ubiquitous in environment, plants and animals

        • No need for health based exposure limit

      • Difference is made between oral, parenteral and inhalation exposure (class 1)


    Metal catalysts metal reagents3
    Metal Catalysts/Metal Reagents exclusion of impurities

    • 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


    Setting specifications considerations control of impurities
    Setting Specifications – exclusion of impurities 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.

      • Introduction of a specific purification step e.g. to limit a potential genotoxic impurity below TTC (degradation of this impurity).


    Regulatory requirements with relevance for quality of api

    Synthesis Indinavir Sulfate exclusion of impurities


    Setting specification gti case centralised authorised product
    Setting specification: GTI exclusion of impurities (case centralised authorised product)

    Final

    AS

    Intermediate II

    +

    Compound III

    Compound IV

    comp. III < 10 ppm

    (detection limit)

    < TTC

    (target)

    suspected GT


    S 4 control of drug substance
    S.4 Control of Drug Substance exclusion of impurities

    • S.4.1 Specification

    • S.4.2 Analytical Procedures

    • S.4.3 Validation of Analytical Procedures

    • S.4.4 Batch Analyses

    • S.4.5 Justification of Specification


    S 5 reference standards of materials
    S.5 Reference Standards of Materials exclusion of impurities

    • Full characterisation

    • Pharmacopoeial standards


    S 6 container closure system
    S.6 Container Closure System exclusion of impurities

    • Brief description of bulk container closure system


    S 7 stability 1
    S.7 Stability (1) exclusion of impurities

    • S.7.1 Stability summary and Conclusions

    • S.7.2 Post-approval Stability Protocol and Stability Commitment

    • S.7.3 Stability Data


    S 7 stability 2
    S.7 Stability (2) exclusion of impurities

    • 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.


    Stability storage conditions
    Stability: Storage conditions exclusion of impurities

    • General case

      * It is up to the applicant to decide whether long term stability studies are performed at 25°C ± 2°C/60% RH ± 5% RH or

      30°C ± 2°C/65% RH ± 5% RH. In the latter case, no additional data under intermediate conditions will have to be generated.


    Stability storage conditions1
    Stability: Storage conditions exclusion of impurities

    • Refrigerator

    • Freezer


    Stability further considerations
    Stability: Further Considerations exclusion of impurities

    • 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.


    Declaration storage conditions cpmp
    Declaration exclusion of impurities Storage Conditions (CPMP)


    Setting specifications future position paper
    Setting Specifications: exclusion of impurities future position paper

    • Harmonisation approach for residual solvents, heavy metals, genotoxic impurities

    • Last step of the synthesis

    • Prior to the last step of the synthesis

    • …..


    Eu assessment policy known ass
    EU Assessment Policy (known ASs) exclusion of impurities

    • 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).

    • 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)


    Eu assessment policy known ass 2
    EU Assessment Policy (known ASs) (2) exclusion of impurities

    • Applications for a MA of medicinal products containing existing active substances are assessed according to their own merit (based on quality risk management).

    • A summary of impurities present in batches of the active substance(s) …………..(and decomposition products arising during storage) as proposed for use in the product to be marketed together with an evaluation of these impurities.

    • For existing/known active substances, the European Pharmacopoeia general monograph “Substances for pharmaceutical use” is applicable.


    Eu assessment policy known ass 3
    EU Assessment Policy (known ASs) (3) exclusion of impurities

    • Each active substance with regard to impurities has ultimately to be assessed on its own merits. If the impurity profile of the proposed product is different from that of the reference product, this fact is not a ground for rejection of the application if the impurities are considered qualified.

    • In the development part of the application, it is expected to find a discussion whether the product is likely to have a different impurity profile as compared to the original product.


    Eu assessment policy known ass 4
    EU Assessment Policy (known ASs) (4) exclusion of impurities

    • 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, either by reference to expected similarity with the originator or by other means e.g. 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, the full qualification or other adequate information about the safety of these impurities will be requested.


    Outlook
    Outlook exclusion of impurities

    • Preparation of an ICH API (chemical and biotechnological origin) guideline (Q11) taking into account the concepts and principles described in Q8R (Pharmaceutical Development).

      • enhanced/systematic development

      • establishment of design space

      • establishment of real time release testing

    • New Paradigm: combination of enhanced process understanding, formal use risk management tools and establishment of an efficient quality system


    Conclusion
    Conclusion exclusion of impurities

    • The pharmaceutical quality requirements for the API (AS) are very much guided by the harmonised ICH guidelines: Impurities, stability, analytical validation,………

    • From a pharmaceutical quality point of view there is no difference between new ASs and existing/known ASs.

    • The section on impurities is one of the most important section in an application file. Thorough preparation and presentation of this section is most helpful for the assessor.

    • During lifetime of the product, attention has to be paid to changes in the manufacturing process including change in suppliers of starting materials.

    • Impurities profile depends very much on the route of synthesis.!!


    Back up slides
    Back-up slides exclusion of impurities


    References relevant guidelines api
    References - Relevant Guidelines (API) exclusion of impurities

    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: Chemistry on new active substances

    • CHMP NfG: 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


    References relevant guidelines api1
    References - Relevant Guidelines (API) exclusion of impurities

    • 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…….

    • CHMP NfG: Stability: existing active substances…….

    • European Pharmacopoeia

      • General monograph: Substances for pharmacopoeial use

      • General chapter:

        • Control of Impurities (5.10)

        • Residual Solvents (5.4)

    • EMEA Website: www.emea.europa.eu including Q&As


    Application file ctd q drug substances 3 2 s
    Application file: CTD-Q: Drug Substances 3.2.S exclusion of impurities

    • S.1 General Information

      • S.1.1 Nomenclature

      • S.1.2 Structure

      • S.1.3 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


    Applicatin file ctd q drug substances 3 2 s
    Applicatin file: CTD-Q: Drug Substances 3.2.S exclusion of impurities

    • S.3 Characterisation

      • S.3.1 Elucidation of Structure and other Characteristics

      • S.3.2 Impurities

    • S.4 Control of Drug Substances

      • S.4.1 Specification

      • S.4.2 Analytical Procedures

      • S.4.3 Validation of Analytical Procedures

      • S.4.4 Batch Analyses

      • S.4.5 Justification of Specification


    Application file ctd q drug substances 3 2 s1
    Application file: CTD-Q: Drug Substances 3.2.S exclusion of impurities

    • S.5 Reference Standards of Materials

    • S.6 Container Closure System

    • S.7 Stability

      • S.7.1 Stability Summary and Conclusions

      • S.7.2 Post-approval Stability Protocol and Stability Commitment

      • S.7.3 Stability Data


    Decision tree for identification and qualification

    Is impurity greater than identification exclusion of impurities

    Threshold?

    Structure identified?

    Any known human

    relevant risks?

    Any clinically relevant

    adverse effects?

    Reduce to not

    more than (≤)

    identification threshold

    Reduce to not

    more than (≤)

    identification threshold

    Greater

    than qualification

    Threshold?

    Decision Tree for Identification and Qualification

    No action

    Yes

    No

    Reduce to save level

    Yes

    Yes

    No further

    action

    No

    No

    Yes

    Yes

    No

    action

    Yes

    No

    No

    No

    • Consider patient population and duration of use and consider conducting:

    • Genotoxicity studies (point mutation, chromosomal aberration)

    • General toxicity studies (one species, usually 14 to 90 days)

    • Other specific toxicity endpoints, as appropriate

    Reduce to save level

    Qualified

    Yes

    No