2 RegulatoryRequirements ENG

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Regulatory Regulatory Requirements with Requirements with

Relevance for Quality Relevance for Quality of APIof API

Jean-Louis ROBERTJean-Louis ROBERT

National Health LaboratoryNational Health Laboratory

L – 1011 LUXEMBOURGL – 1011 LUXEMBOURG

CHMP co-opted memberCHMP co-opted member

Chair CHMP/CVMP QWPChair CHMP/CVMP QWP

Beijing, March 2010Beijing, March 2010

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Topics addressedTopics addressed

General considerations – CTD-QGeneral considerations – CTD-Q Manufacturing: API starting materialsManufacturing: API starting materials ImpuritiesImpurities

Related substancesRelated substances Residual solventsResidual solvents Genotoxic impuritiesGenotoxic impurities Residual metal catalysts/reagentsResidual metal catalysts/reagents

StabilityStability EU Assessment Policy: known active substanceEU Assessment Policy: known active substance ConclusionConclusion Back-up: References relevant guidelinesBack-up: References relevant guidelines

Application file CTD-Q structureApplication file CTD-Q structure Decision tree identification/qualification impuritiesDecision tree identification/qualification impurities Example of structure of genotoxic impuritiesExample of structure of genotoxic impurities

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S.1 General InformationS.1 General Information

S.1.1 NomenclatureS.1.1 Nomenclature S.1.2 StructureS.1.2 Structure S.1.3 General PropertiesS.1.3 General Properties

Physicochemical propertiesPhysicochemical properties Properties affecting pharmacological Properties affecting pharmacological

efficacyefficacy ……………………....

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S.2 Manufacture (1)S.2 Manufacture (1)

S.2.1 Manufacturer(s)S.2.1 Manufacturer(s) S.2.2 Description of Manufacturing S.2.2 Description of Manufacturing

Process and Process and Process Controls Process Controls FlowchartFlowchart Sequential procedural narrativeSequential procedural narrative Scale, range, yield……..Scale, range, yield……..

S.2.3 Control of MaterialsS.2.3 Control of Materials API starting materialAPI starting material Information on all materials of biological Information on all materials of biological

origin, incl. viral safetyorigin, incl. viral safety

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S.2.3 Manufacture: API starting S.2.3 Manufacture: API starting material (2)material (2)

API starting material incorporated as a significant API starting material incorporated as a significant structural fragment into the structure of the ASstructural fragment into the structure of the AS

Proposal and justification by the applicantProposal and justification by the applicant Full characterisationFull characterisation Description of a one step synthesis not Description of a one step synthesis not

acceptable, unless described in the European acceptable, unless described in the European Pharmacopoeia (CEP or compliance with EP Pharmacopoeia (CEP or compliance with EP monograph to be demonstrated)monograph to be demonstrated)

Name of supplier has to be submittedName of supplier has to be submitted Detailed description of the synthesis and GMP Detailed description of the synthesis and GMP

compliance (ICH Q7) should go together.compliance (ICH Q7) should go together.

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S.2.3 Manufacture: API starting S.2.3 Manufacture: API starting materialmaterial

detailed description

only flow chart

AS

ASSM

ASSM

ASSM3

n

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Example: IbuprofenExample: Ibuprofen

N-Butyl-Ibuprofen as an impurity of N-Butyl-Ibuprofen as an impurity of IbuprofenIbuprofen

(n-butylbenzene present in starting material (n-butylbenzene present in starting material isobutylbenzene)isobutylbenzene)

CH

CH3

CH2

CH

CH3

CH3

COOHCH2

CH

CH3

CH3

Isobutyl-benzol Ibuprofen

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Résolution test

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S.2 Manufacture (2)S.2 Manufacture (2)

S.2.4 Controls for Critical Steps and S.2.4 Controls for Critical Steps and IntermediatesIntermediates Tests and acceptance criteria to be providedTests and acceptance criteria to be provided

S.2.5 Process Validation and/or EvaluationS.2.5 Process Validation and/or Evaluation Sterilisation processSterilisation process

S.2.6 Manufacturing Process DevelopmentS.2.6 Manufacturing Process Development Changes in manufacturing occurring during Changes in manufacturing occurring during

development (pre-clinical, clinical, commercial)development (pre-clinical, clinical, commercial) Development of e.g. a design space, real time Development of e.g. a design space, real time

release testing release testing

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S.3 CharacterisationS.3 Characterisation

S.3.1 Elucidation of Structure and other CharacteristicsS.3.1 Elucidation of Structure and other Characteristics Full elucidation or with reference to a Full elucidation or with reference to a

pharmacopoeial standardpharmacopoeial standard S.3.2 ImpuritiesS.3.2 Impurities

Classification of ImpuritiesClassification of Impurities Organic impurities, Inorganic impurities, Residual Organic impurities, Inorganic impurities, Residual

solventssolvents Drug substance impurities: Drug substance impurities:

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

Drug product impurities: Drug product impurities: Degradation productsDegradation products

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Impurities: General Impurities: General ConsiderationsConsiderations

The ICH guidelines Q3A (R), [Q3B (R)], Q3C are The ICH guidelines Q3A (R), [Q3B (R)], Q3C are the general basis for the control of impurities in the general basis for the control of impurities in active substances and medicinal productsactive substances and medicinal products Consideration of chemistry and safety aspectsConsideration of chemistry and safety aspects GlossaryGlossary

Initial scopeInitial scope: new active substances and : new active substances and corresponding products.corresponding products.

Extension to existing active substances and Extension to existing active substances and corresponding medicinal products.corresponding medicinal products.

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

New synthesis can generate new impurities (imp. New synthesis can generate new impurities (imp. profile)profile) Not necessarily qualifiedNot necessarily qualified

In addition EU guidelinesIn addition EU guidelines Genotoxic Impurities TestingGenotoxic Impurities Testing Residual metal catalysts/ metal reagentsResidual metal catalysts/ metal reagents

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Q3A/B(R) and Q6A are Q3A/B(R) and Q6A are complementary complementary

Q3A-B:Q3A-B: address the chemistry aspects and address the chemistry aspects and

the safety aspects of impurities and the safety aspects of impurities and

defines different thresholdsdefines different thresholds reporting, reporting, identification, identification, qualification.qualification.

Q6A:Q6A: addresses the setting and justification of addresses the setting and justification of acceptance criteria and acceptance criteria and

the selection of the selection of test test proceduresprocedures

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Listing of Impurities Listing of Impurities

Each specified identified impurityEach specified identified impurity Each specified unidentified impurityEach specified unidentified impurity Any unspecified impurity with an Any unspecified impurity with an

acceptance criterion of not more than (acceptance criterion of not more than (<<) ) the identification thresholdthe identification threshold

Total impuritiesTotal impurities Residual SolventsResidual Solvents Inorganic impurities Inorganic impurities

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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

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Active substances outside of the Active substances outside of the scope of the ICH guidelinescope of the ICH guideline

For active substances outside of the scope of For active substances outside of the scope of ICH guideline:ICH guideline: The applicant should justify adequate The applicant should justify adequate

thresholds taking into account the nature of thresholds taking into account the nature of the active substance, the maximal daily dose, the active substance, the maximal daily dose, the duration of therapy, the ability of the the duration of therapy, the ability of the analytical methods (current scientific status).analytical methods (current scientific status).

European Pharmacopoeia:European Pharmacopoeia: Organic impurities in peptides obtained by Organic impurities in peptides obtained by

chemical synthesis:chemical synthesis:

Reporting threshold:Reporting threshold: > 0.1%> 0.1%

Identification threshold:Identification threshold: > 0.5%> 0.5%

Qualification threshold:Qualification threshold:> 1.0%> 1.0%

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Scientific Discussion on Scientific Discussion on ImpuritiesImpurities

Summary of actual and Summary of actual and potentialpotential impurities impurities (sound scientific appraisal).(sound scientific appraisal).

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

Risk based approach (see also ICH Q9) Risk based approach (see also ICH Q9) Thorough discussion by the applicant based on Thorough discussion by the applicant based on

synthesis, reagents used, stability,...synthesis, reagents used, stability,... Summary of laboratory studies conducted to Summary of laboratory studies conducted to

detect impuritiesdetect impurities Negative results can be helpful !Negative results can be helpful !

Discussion on the impurity profiles found in Discussion on the impurity profiles found in preclinical and clinical trials: impurities above preclinical and clinical trials: impurities above the qualification threshold have to be qualified.the qualification threshold have to be qualified.

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Impurities to be specified - Impurities to be specified - Rationale for the inclusion or Rationale for the inclusion or

exclusion of impurities exclusion of impurities Scientific knowledge/understanding about the Scientific knowledge/understanding about the

manufacturing process of the active substancemanufacturing process of the active substance Knowledge about how an impurity is generatedKnowledge about how an impurity is generated

Establishment of a control strategyEstablishment of a control strategy Specifications of AS starting materialsSpecifications of AS starting materials Control of impurities at intermediates rather than on Control of impurities at intermediates rather than on

final ASfinal AS Identification of critical process parameters influencing Identification of critical process parameters influencing

the impurity profilethe impurity profile Process controlsProcess controls Purification steps: influence on the impurity profile of Purification steps: influence on the impurity profile of

the final active substancethe final active substance Knowledge about the degradation pathwayKnowledge about the degradation pathway

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Reminder: Control StrategyReminder: Control Strategy (ICH (ICH Q10)Q10)

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

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

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Acceptance criteria for impuritiesAcceptance criteria for impurities

Acceptance criteria should be based onAcceptance criteria should be based on Relevant development dataRelevant development data Test data for the active substance used in Test data for the active substance used in

toxicological and clinical studiestoxicological and clinical studies Results from long term and accelerated Results from long term and accelerated

stability datastability data Range of expected analytical and Range of expected analytical and

manufacturing variabilitymanufacturing variability Actual results obtained should form the primary Actual results obtained should form the primary

basis for establishing the acceptance criteriabasis for establishing the acceptance criteria They should not be higher than the qualification They should not be higher than the qualification

levellevel

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Reporting impurities content of Reporting impurities content of batchesbatches

Results to be provided for batches used for Results to be provided for batches used for clinical, safety and stability testing, as well clinical, safety and stability testing, as well as batches representative of the proposed as batches representative of the proposed commercial process.commercial process. To be reported: > Reporting threshold.To be reported: > Reporting threshold. Batches: detailed information to be provided.Batches: detailed information to be provided.

Identity / sizeIdentity / size Date and site of manufactureDate and site of manufacture Manufacturing processManufacturing process Impurities content, single, totalImpurities content, single, total Use of batchesUse of batches Reference to analytical procedure usedReference to analytical procedure used

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New ImpuritiesNew Impurities

Decision Tree for Identification and Decision Tree for Identification and Qualification (ICH-Q3A R2)Qualification (ICH-Q3A R2) Description of considerations for the Description of considerations for the

qualification and identification of qualification and identification of impurities when thresholds are exceeded.impurities when thresholds are exceeded.

Recommendation what to do when new Recommendation what to do when new impurities appear during later stage of impurities appear during later stage of development or after authorisation.development or after authorisation.

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Residual Solvents: Q3CResidual Solvents: Q3C

Residual Solvents:Residual Solvents: Q3C Q3C Defines safety limits for solvents (class 1, 2, Defines safety limits for solvents (class 1, 2,

3 and (4) solvents)3 and (4) solvents) Option 1 based on concentrationOption 1 based on concentration Option 2 based on MDD and PDEOption 2 based on MDD and PDE When the acceptance criteria are identical When the acceptance criteria are identical

to the safety limits (as indicated in the to the safety limits (as indicated in the NfG): no justification is needed (option 1).NfG): no justification is needed (option 1).

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Residual Solvents: Q3CResidual Solvents: Q3C

Class 1 solventsClass 1 solventsIn all cases, the limit of a class 1 solvent in the In all cases, the limit of a class 1 solvent in the final active substance should comply with the final active substance should comply with the requirements of the NfG, even if initially not requirements of the NfG, even if initially not used as a solvent.used as a solvent.

e.g. benzene: e.g. benzene: - use as starting material - use as starting material (synthesis)(synthesis)

- present as contaminant e.g. - present as contaminant e.g. toluenetoluene

- by-product from a chemical - by-product from a chemical reactionreaction

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Residual Solvents: some Residual Solvents: some commentscomments

CHMP position paperCHMP position paper

Class 2 solventsClass 2 solvents As a principle:As a principle:

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

Last step of the synthesis:Last step of the synthesis: Routine control in the final active substanceRoutine control in the final active substance

Prior to the last step:Prior to the last step: If <10% present in a suitable intermediate If <10% present in a suitable intermediate

or in the active substance, need not be or in the active substance, need not be controlled routinely.controlled routinely.

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Genotoxic ImpuritiesGenotoxic Impurities

Joint SWP-QWP “Guideline on the Limits of Joint SWP-QWP “Guideline on the Limits of Genotoxic Impurities”Genotoxic Impurities” published 2006published 2006 came into effect on 1 January 2007came into effect on 1 January 2007

Basis: ICH Q3A/B guideline: Basis: ICH Q3A/B guideline: “ “For impurities known to be unusually potent For impurities known to be unusually potent

or to produce toxic or unexpected or to produce toxic or unexpected pharmacological effects, the quantification - pharmacological effects, the quantification - detection limit of the analytical procedures detection limit of the analytical procedures should be commensurate with the level at should be commensurate with the level at which the impurities should be controlled”.which the impurities should be controlled”.

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Genotoxic ImpuritiesGenotoxic Impurities ScopeScope

New active substancesNew active substances New applications for existing active substances, New applications for existing active substances,

where assessment of the route of synthesis, where assessment of the route of synthesis, process control and impurity profile does not process control and impurity profile does not provide reasonable assurance that no new or provide reasonable assurance that no new or higher levels of GTIs are introduced as higher levels of GTIs are introduced as compared to products currently authorised in compared to products currently authorised in the EU containing the same active substance the EU containing the same active substance (idem variations)(idem variations)

No need for retrospectively application to No need for retrospectively application to authorised products, unless there is a specific authorised products, unless there is a specific cause for concern.cause for concern.

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Genotoxic ImpuritiesGenotoxic Impurities

PrinciplesPrinciples Identifications guided by existing genotoxic Identifications guided by existing genotoxic

data or the presence of structure alertsdata or the presence of structure alerts Genotoxic compounds with sufficient evidence Genotoxic compounds with sufficient evidence

for a threshold-related mechanism for a threshold-related mechanism Genotoxic compounds without sufficient Genotoxic compounds without sufficient

evidence for a threshold-related mechanism evidence for a threshold-related mechanism

Threshold of Toxicological concern:Threshold of Toxicological concern:

TTC value: 1.5 TTC value: 1.5 µµg/dayg/day

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Genotoxic impuritiesGenotoxic impurities

Pharmaceutical considerationsPharmaceutical considerations Try to avoid genotoxic reagentsTry to avoid genotoxic reagents Limitations (if possible) at an intermediate Limitations (if possible) at an intermediate

rather at the end active substancerather at the end active substance Introduction of a specific purification step Introduction of a specific purification step

(destruction of genotoxic impurity)(destruction of genotoxic impurity) Assessment from the applicant justifying the Assessment from the applicant justifying the

potential presence or non presence of the potential presence or non presence of the genotoxic impuritygenotoxic impurity

Discussion/collaboration with safety experts Discussion/collaboration with safety experts important.important.

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SWP – QWP Q&As SWP – QWP Q&As Revision 1 issued June 2008 Revision 1 issued June 2008 The aim of the Q&As document is to The aim of the Q&As document is to

provide clarification and harmonisation provide clarification and harmonisation of interpretation of the Guideline on the of interpretation of the Guideline on the Limits of Genotoxic ImpuritiesLimits of Genotoxic Impurities

Addresses 7 key areasAddresses 7 key areas

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““Cause for concern”:Cause for concern”: If a manufacturing procedure for API If a manufacturing procedure for API

remains essentially unchanged, a re-remains essentially unchanged, a re-evaluation with respect to the presence of evaluation with respect to the presence of potentially genotoxic impurities is potentially genotoxic impurities is generally not needed. However, new generally not needed. However, new knowledge may indicate a previously knowledge may indicate a previously unknown “cause for concern”. unknown “cause for concern”.

e.g. mesylate salte.g. mesylate salt

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Metal Catalysts/Metal ReagentsMetal Catalysts/Metal Reagents

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

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EMEA/145858/2006EMEA/145858/2006 General considerationsGeneral considerations

Same principles as for Residual Solvents ICH Same principles as for Residual Solvents ICH Q3CQ3C

Conservative approach compared to food Conservative approach compared to food additivesadditives

3 classes3 classes Class limit for class 1BClass limit for class 1B Reporting similar to ICH Q3CReporting similar to ICH Q3C Implementation 5 years (for existing products)Implementation 5 years (for existing products)

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ConceptConcept Class 1 Metals: metals of high toxic potentialClass 1 Metals: metals of high toxic potential

Known carcinogensKnown carcinogens Class 2 Metals: metals with low toxic potentialClass 2 Metals: metals with low toxic potential

Nutritional trace metals, common in food and Nutritional trace metals, common in food and food additivesfood additives

Class 3 Metals: metals with no significant Class 3 Metals: metals with no significant toxicitytoxicity

Ubiquitous in environment, plants and animalsUbiquitous in environment, plants and animals No need for health based exposure limitNo need for health based exposure limit

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

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Expectation:Expectation: The relevant residual metal should be controlled The relevant residual metal should be controlled

with a suitable methodwith a suitable method Pharmacopoeial heavy metal test generally not Pharmacopoeial heavy metal test generally not

acceptableacceptable Further discussion at international level Further discussion at international level

ongoing both on the methodology and the ongoing both on the methodology and the limitslimits

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Setting Specifications – Setting Specifications – Considerations Control of Considerations Control of

ImpuritiesImpurities Drug substance:Drug substance:

Identification of process parameter(s) (CQP) in Identification of process parameter(s) (CQP) in the synthesis influencing the generation of a the synthesis influencing the generation of a specific impurity in the final product: specific impurity in the final product: introduction of a specific in-process control: introduction of a specific in-process control: tightening of pH range.tightening of pH range.

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

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Synthesis Indinavir Sulfate

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Setting specification: GTISetting specification: GTI(case centralised authorised (case centralised authorised

product)product)

Intermediate II Compound III Compound IV Final

AS

suspected GT comp. III < 10 ppm

(detection limit)

< TTC

(target)

+

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S.4 Control of Drug SubstanceS.4 Control of Drug Substance

S.4.1 SpecificationS.4.1 Specification S.4.2 Analytical ProceduresS.4.2 Analytical Procedures S.4.3 Validation of Analytical ProceduresS.4.3 Validation of Analytical Procedures S.4.4 Batch AnalysesS.4.4 Batch Analyses S.4.5 Justification of SpecificationS.4.5 Justification of Specification

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S.5 Reference Standards of S.5 Reference Standards of MaterialsMaterials

Full characterisationFull characterisation Pharmacopoeial standardsPharmacopoeial standards

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S.6 Container Closure SystemS.6 Container Closure System

Brief description of bulk container closure Brief description of bulk container closure systemsystem

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S.7 Stability (1)S.7 Stability (1)

S.7.1 Stability summary and ConclusionsS.7.1 Stability summary and Conclusions S.7.2 Post-approval Stability Protocol and S.7.2 Post-approval Stability Protocol and

Stability CommitmentStability Commitment S.7.3 Stability DataS.7.3 Stability Data

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S.7 Stability (2)S.7 Stability (2)

EU in climatic zone I/IIEU in climatic zone I/II Storage conditions according to ICHStorage conditions according to ICH Guidelines:Guidelines:

ICH 1A (R2): new active substancesICH 1A (R2): new active substances CHMP: existing active substances derived CHMP: existing active substances derived

from ICH guidelinefrom ICH guideline In principle no difference in requirements In principle no difference in requirements

between new active substances and between new active substances and existing active substances.existing active substances.

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Stability: Storage conditionsStability: Storage conditions

General caseGeneral case

** It is up to the applicant to decide whether long term It is up to the applicant to decide whether long term stability studies are performed at stability studies are performed at 25°C ± 2°C/60% RH ± 25°C ± 2°C/60% RH ± 5% RH or5% RH or

30°C ± 2°C/65% RH ± 5% RH30°C ± 2°C/65% RH ± 5% RH. In the latter case, no . In the latter case, no additional data under intermediate conditions will additional data under intermediate conditions will have to be generated.have to be generated.

StudyStudy Storage conditionStorage condition Minimum time period Minimum time period covered by data at covered by data at submissionsubmission

Long Long term*term*

25°C ± 2°C/60% RH ± 5% 25°C ± 2°C/60% RH ± 5% RH orRH or

30°C ± 2°C/65% RH ± 5% 30°C ± 2°C/65% RH ± 5% RHRH

New AS. 1 yearNew AS. 1 year

Exi. AS: 6 mo. (opt. a Exi. AS: 6 mo. (opt. a and b)and b)

IntermediIntermediateate

30°C ± 2°C/65% RH ± 5% 30°C ± 2°C/65% RH ± 5% RHRH

6 months6 months

AcceleratAccelerateded

40°C ± 2°C/75% RH ± 5% 40°C ± 2°C/75% RH ± 5% RHRH

6 months6 months

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Stability: Storage conditionsStability: Storage conditions

RefrigeratorRefrigerator

FreezerFreezer


Long Long termterm

25°C ± 2°C/60% RH ± 5% 25°C ± 2°C/60% RH ± 5% RH orRH or

New AS. 1 yearNew AS. 1 year

Exi. AS: 6 mo. (opt. a Exi. AS: 6 mo. (opt. a and b)and b)

AcceleratAccelerateded

25°C ± 2°C/60% RH ± 5% 25°C ± 2°C/60% RH ± 5% RHRH

6 months6 months


Long Long termterm

-20°C ± 5°C-20°C ± 5°C New AS. 1 yearNew AS. 1 year

Exi. AS: 6 mo. (opt. a and b)Exi. AS: 6 mo. (opt. a and b)

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Stability: Further ConsiderationsStability: Further Considerations

Retest period to be definedRetest period to be defined Pharmacopoeial substances: monographs Pharmacopoeial substances: monographs

cover synthetic and degradation products: cover synthetic and degradation products: if no retest date, batch has to be if no retest date, batch has to be controlled immediately prior to be controlled immediately prior to be manufactured in the medicinal product.manufactured in the medicinal product.

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DeclarationDeclaration Storage Storage Conditions Conditions (CPMP)(CPMP)

Testing conditions Testing conditions where stability has where stability has

been shownbeen shown

Required labelRequired label Additional Additional label, where label, where

relevantrelevant

25°C/60%RH25°C/60%RH

alt. 30°C/65%RHalt. 30°C/65%RH

40°C/75%RH40°C/75%RH

NoneNone Do not Do not refrigerate or refrigerate or freezefreeze

25°C/60%RH +25°C/60%RH +

30°C/60%RH (interm)30°C/60%RH (interm)

or 30°C/65%RHor 30°C/65%RH

Do not store Do not store above 30°Cabove 30°C

Do not Do not refrigerate or refrigerate or freezefreeze

25°C/60%RH25°C/60%RH Do not store Do not store above 25°Cabove 25°C

Do not Do not refrigerate or refrigerate or freezefreeze

5°C±3°C5°C±3°C Store at 2-8°CStore at 2-8°C Do not freezeDo not freeze

Below 0°CBelow 0°C Store in freezerStore in freezer

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Setting Specifications: Setting Specifications: future position future position

paper paper Harmonisation approach for residual Harmonisation approach for residual

solvents, heavy metals, genotoxic solvents, heavy metals, genotoxic impuritiesimpurities

Last step of the synthesisLast step of the synthesis Prior to the last step of the synthesisPrior to the last step of the synthesis ……....

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EU Assessment Policy (known ASs)EU Assessment Policy (known ASs)

From a pharmaceutical quality point of view no From a pharmaceutical quality point of view no difference is made between new active difference is made between new active substances and “existing or known” active substances and “existing or known” active substances (and their corresponding products).substances (and their corresponding products).

This is also highlighted in the European This is also highlighted in the European Pharmacopoeia where relevant ICH or CHMP Pharmacopoeia where relevant ICH or CHMP guidelines or the policy adopted have been guidelines or the policy adopted have been adopted:adopted: ImpuritiesImpurities Residual solventsResidual solvents Genotoxic impurities (EP policy)Genotoxic impurities (EP policy) Residual metal catalysts/reagents (EP policy)Residual metal catalysts/reagents (EP policy)

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EU Assessment Policy (known ASs) EU Assessment Policy (known ASs) (2)(2)

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

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

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

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

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

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It is expected that the applicant of a generic It is expected that the applicant of a generic product justifies why he considers the impurities product justifies why he considers the impurities in his product safe for the intended use and in his product safe for the intended use and qualified, either by reference to expected qualified, either by reference to expected similarity with the originator or by other means similarity with the originator or by other means e.g. compliance with relevant (V)ICH guidelines.e.g. compliance with relevant (V)ICH guidelines.

In the case where the impurity profile of a generic In the case where the impurity profile of a generic product differs qualitatively from the originator, product differs qualitatively from the originator, or where higher amount of impurities are seen, or where higher amount of impurities are seen, the full qualification or other adequate the full qualification or other adequate information about the safety of these impurities information about the safety of these impurities will be requested.will be requested.

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Outlook Outlook

Preparation of an ICH API (chemical and Preparation of an ICH API (chemical and biotechnological origin) guideline (Q11) taking biotechnological origin) guideline (Q11) taking into account the concepts and principles into account the concepts and principles described in Q8R (Pharmaceutical described in Q8R (Pharmaceutical Development).Development). enhanced/systematic developmentenhanced/systematic development establishment of design spaceestablishment of design space establishment of real time release testingestablishment of real time release testing

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

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ConclusionConclusion

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

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

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

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

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

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Back-up slidesBack-up slides

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References - Relevant Guidelines References - Relevant Guidelines (API)(API)

From a pharmaceutical quality point of view no difference is From a pharmaceutical quality point of view no difference is made between new active substances and “existing or made between new active substances and “existing or known” active substances (and their corresponding known” active substances (and their corresponding products).products).

CHMP NfG: CHMP NfG: Chemistry on new active substancesChemistry on new active substances CHMP NfG:CHMP NfG: Summary of requirements for Active Summary of requirements for Active

Substances in the Quality Part of the Substances in the Quality Part of the DossierDossier

Q3A (R2):Q3A (R2): Impurities Testing in new drug substancesImpurities Testing in new drug substances Q3C:Q3C: Impurities: Guideline for Residual SolventsImpurities: Guideline for Residual Solvents CHMP position paper class 1/class 2 solventsCHMP position paper class 1/class 2 solvents CHMP NfG:CHMP NfG: Testing on Genotoxic ImpuritiesTesting on Genotoxic Impurities CHMP HfG:CHMP HfG: Specification limits for residues of metal Specification limits for residues of metal

catalysts or metal reagentscatalysts or metal reagents

57

References - Relevant Guidelines References - Relevant Guidelines (API)(API)

Q6A: Q6A: Specifications: Test Procedures and Specifications: Test Procedures and Acceptance Criteria for New Drug Acceptance Criteria for New Drug Substances and New Drug ProductsSubstances and New Drug Products

Q2R: Q2R: Validation of analytical proceduresValidation of analytical procedures Q1A (R2): Q1A (R2): Stability: new active substances…….Stability: new active substances……. CHMP NfG: CHMP NfG: Stability: existing active Stability: existing active

substances…….substances……. European PharmacopoeiaEuropean Pharmacopoeia

General monograph: Substances for pharmacopoeial useGeneral monograph: Substances for pharmacopoeial use General chapter:General chapter:

Control of Impurities (5.10)Control of Impurities (5.10) Residual Solvents (5.4)Residual Solvents (5.4)

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

58

Application file: CTD-Q: Drug Application file: CTD-Q: Drug Substances 3.2.SSubstances 3.2.S

S.1 General InformationS.1 General Information S.1.1 NomenclatureS.1.1 Nomenclature S.1.2 StructureS.1.2 Structure S.1.3 General PropertiesS.1.3 General Properties

S.2 ManufactureS.2 Manufacture S.2.1 Manufacturer(s)S.2.1 Manufacturer(s) S.2.2 Description of Manufacturing Process S.2.2 Description of Manufacturing Process

and Process and Process Controls Controls S.2.3 Control of MaterialsS.2.3 Control of Materials S.2.4 Controls for Critical Steps and S.2.4 Controls for Critical Steps and

IntermediatesIntermediates 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

59

Applicatin file: CTD-Q: Drug Applicatin file: CTD-Q: Drug Substances 3.2.SSubstances 3.2.S

S.3 CharacterisationS.3 Characterisation S.3.1 Elucidation of Structure and other S.3.1 Elucidation of Structure and other

CharacteristicsCharacteristics S.3.2 ImpuritiesS.3.2 Impurities

S.4 Control of Drug SubstancesS.4 Control of Drug Substances S.4.1 SpecificationS.4.1 Specification S.4.2 Analytical ProceduresS.4.2 Analytical Procedures S.4.3 Validation of Analytical ProceduresS.4.3 Validation of Analytical Procedures S.4.4 Batch AnalysesS.4.4 Batch Analyses S.4.5 Justification of SpecificationS.4.5 Justification of Specification

60

Application file: CTD-Q: Drug Application file: CTD-Q: Drug Substances 3.2.SSubstances 3.2.S

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

S.7.1 Stability Summary and ConclusionsS.7.1 Stability Summary and Conclusions S.7.2 Post-approval Stability Protocol and S.7.2 Post-approval Stability Protocol and

Stability Stability Commitment Commitment S.7.3 Stability DataS.7.3 Stability Data

61

Decision Tree for Identification and Qualification

Is impurity greater than identification Threshold?

Structure identified? Any known humanrelevant risks?

No actionYes No

Yes Reduce to save

level

Yes

Reduce to not more than (≤)

identification threshold

No

No further

actionYes

No

action

Reduce to save level Qualified

Any clinically relevantadverse effects?

Greaterthan qualification

Threshold?

Reduce to not more than (≤)

identification threshold

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

Yes

No

YesNoNo

NoYes

No

62

Examples of Structure of Examples of Structure of Genotoxic ImpuritiesGenotoxic Impurities

N

OH

AN

A

O

AN

O N

A

A

Group 1: Aromatic Groups

N-hydroxyaryls N-Acylated aminoaryls Aza-aryl N-oxides (Alkylated) Aminoaryls

Purines,Pyrimidines, Intercalators, PNAs or PNAHs

Group 2: Alkyl and Aryl Groups

A

O

H AN

A

OH

AN

A

NO ANO2 O

O

NH2A

O

AA

HN

AAO

OO S

O

S or N

X

N NA

RA

A

EWG POR

OS

OR

O

XA

X

Aldehydes N-methylols N-Nitrosoamines Nitro compounds Carbamates (Urethanes)

Epoxides

Micheal-reactiveAcceptors

Alkyl esters of phosphonates or sulfonates

Halo-alkenes Primary halides(Alkyl and Aryl-CH2)

Hydrazines andAzo compounds

S or N Mustards(beta haloethyl)

PropiosultonesPropiolactonesAziridines

Legend: A = Alkyl, Aryl or H X = F, Cl, Br, IEWG = Electron withdrawing group (CN, C=O, ester, etc.)

Group 3: Heteroatomic Groups

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