IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 1 Content of the application for a CEP Hélène BRUGUERA Deputy Head Certification of Substances Division.

IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe

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Content of the application for a CEP

Content of the application for a CEP

Hélène BRUGUERA

Deputy Head

Certification of Substances Division

Hélène BRUGUERA

Deputy Head



2

• Process to obtain a CEP: outlined in Resolution AP-CSP(07) 1

• “Content of the dossier”:– Chemical purity (revised May 2007)

– TSE risk

• See docs on web site www.edqm.eu

• Process to obtain a CEP: outlined in Resolution AP-CSP(07) 1

• “Content of the dossier”:– Chemical purity (revised May 2007)

– TSE risk

• See docs on web site www.edqm.eu

Send an application to EDQM


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How long does it take?How long does it take?

• Timeframes:– Applicant notified by EDQM on the assessment

conclusion• Within 5 months of receipt of new dossier• Within 4 months of receipt of additional information

– Responses expected• within 6 months for original demand • within 3 month for any subsequent demand

– Responses assessed within 4 months

• Timeframes:– Applicant notified by EDQM on the assessment

conclusion• Within 5 months of receipt of new dossier• Within 4 months of receipt of additional information

– Responses expected• within 6 months for original demand • within 3 month for any subsequent demand

– Responses assessed within 4 months


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The situationThe situation

• Mean time to obtain a CEP (chemical): 20 months

• 3% of CEPs obtained after 1st evaluation• 70% of CEPs: 2-3 rounds

• Mean time to obtain a CEP (chemical): 20 months

• 3% of CEPs obtained after 1st evaluation• 70% of CEPs: 2-3 rounds


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How can I speed up the granting of my CEP for chemical purity ?How can I speed up the granting of my CEP for chemical purity ?

• Send a complete application

• Submit a good technical documentation

• Prepare a good QOS

• Hints




• Hints


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Send a complete applicationSend a complete application

• Application form (for new application) www.edqm.eu

• Dossier in English preferably (or French); 1 copy;

• Quality Overall Summary (electronic+paper)

• Samples of 1 or 2 commercial batches

• Application form (for new application) www.edqm.eu

• Dossier in English preferably (or French); 1 copy;

• Quality Overall Summary (electronic+paper)

• Samples of 1 or 2 commercial batches


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At receiptAt receipt

• Validation of application: check of completeness• If application receivable: dossier nr allocated + clock

start• New applications blocked if deficient:

– Missing pieces (form, declarations, dossier,…)– Technical reasons:

• Refer to the current Ph. Eur monograph• Description of route of synthesis and/or impurity profile of

the starting material• Use of Class I solvents without proper justification and

control

• Validation of application: check of completeness• If application receivable: dossier nr allocated + clock

start• New applications blocked if deficient:

– Missing pieces (form, declarations, dossier,…)– Technical reasons:

• Refer to the current Ph. Eur monograph• Description of route of synthesis and/or impurity profile of

the starting material• Use of Class I solvents without proper justification and

control


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• Technical reasons (cont)– Suitable information on impurities, solvents,…– Presence of validation data– Quantitative method to replace a non-specific TLC

test of the monograph– Sterile substances: validation of the sterilisation

• If application not receivable: dossier nr allocated but clock does not start. The company has 6 months to submit info + clock start

• 30% of new applications blocked in 2007 (most of them unblocked)

• Technical reasons (cont)– Suitable information on impurities, solvents,…– Presence of validation data– Quantitative method to replace a non-specific TLC

test of the monograph– Sterile substances: validation of the sterilisation

• If application not receivable: dossier nr allocated but clock does not start. The company has 6 months to submit info + clock start

• 30% of new applications blocked in 2007 (most of them unblocked)


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How can I speed up the granting of a CEP for chemical purity ?How can I speed up the granting of a CEP for chemical purity ?




• Hints




• Hints


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Administrative info (applic. form)Administrative info (applic. form)

• Name and addresses of the parties involved (all sites)

• Declarations (GMP, Willingness to be inspected, Use of animal (TSE risk or other origin) / human material)

• History of the substance (give details)• Retest period requested ?

• Name and addresses of the parties involved (all sites)

• Declarations (GMP, Willingness to be inspected, Use of animal (TSE risk or other origin) / human material)

• History of the substance (give details)• Retest period requested ?


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Technical documentationTechnical documentation

• PA/PH/CEP (04) 1: Content of dossier for chemical purity

• <=> 3.2.S of CTD– General information– Route of synthesis– Impurities, solvents, catalysts– Control of the substance (specification and

methods)– Analytical validation-suitability of the monograph– (Stability is optional)

• PA/PH/CEP (04) 1: Content of dossier for chemical purity

• <=> 3.2.S of CTD– General information– Route of synthesis– Impurities, solvents, catalysts– Control of the substance (specification and

methods)– Analytical validation-suitability of the monograph– (Stability is optional)


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3.2.S.2.2 Manufacturing Process3.2.S.2.2 Manufacturing Process

• Flow chart

• Detailed description of the process, including quantities

• Maximum/typical batch size and yields

• Describe any reprocessing/recovery of materials

• Flow chart

• Detailed description of the process, including quantities

• Maximum/typical batch size and yields

• Describe any reprocessing/recovery of materials


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Semi-synthetic products: Fermentation steps involved in synthesis of starting material– Characterisation of fermented starting material, incl.

detailed impurity profile, compliance with the general monograph 1468

– Carry-over of fermentation impurities– Use TSE risk substances in manufacture?

• Different sites, different manufacturing methods or alternatives, reprocessing, in one dossier: – impurity profile of final substance unchanged– detailed information

Semi-synthetic products: Fermentation steps involved in synthesis of starting material– Characterisation of fermented starting material, incl.

detailed impurity profile, compliance with the general monograph 1468

– Carry-over of fermentation impurities– Use TSE risk substances in manufacture?

• Different sites, different manufacturing methods or alternatives, reprocessing, in one dossier: – impurity profile of final substance unchanged– detailed information


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3.2.S.2.3 Control of Materials3.2.S.2.3 Control of Materials

• Starting materials: TOP 2 deficiency in 2007– Propose and justify which substance(s) is the starting

material(s) e.g. incorporated as a significant structural fragment into the structure of the final substance. Is the substance purchased or manufactured in-house ?

– Short steps synthesis: description of its route of synthesis, and detailed impurity profile (related substances, reagents, solvents, catalysts)

– Suitable specifications - limits for impurities, solvents,…– Description of carry-over of its impurities to the final

substance– Where more than one supplier is used batch results for the

final substance manufactured from the different suppliers

• Starting materials: TOP 2 deficiency in 2007– Propose and justify which substance(s) is the starting

material(s) e.g. incorporated as a significant structural fragment into the structure of the final substance. Is the substance purchased or manufactured in-house ?

– Short steps synthesis: description of its route of synthesis, and detailed impurity profile (related substances, reagents, solvents, catalysts)

– Suitable specifications - limits for impurities, solvents,…– Description of carry-over of its impurities to the final

substance– Where more than one supplier is used batch results for the

final substance manufactured from the different suppliers


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3.2.S.2.3 Control of Materials3.2.S.2.3 Control of Materials

• Describe specifications for all reagents, solvents used– Purity tests for solvents (e.g benzene in toluene, acetone,

ethanol)– Specifications for pure and recovered solvents – Quality of water

• Include specification of recovered materials if any

• Describe specifications for all reagents, solvents used– Purity tests for solvents (e.g benzene in toluene, acetone,

ethanol)– Specifications for pure and recovered solvents – Quality of water

• Include specification of recovered materials if any


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3.2.S.3.2 Impurities3.2.S.3.2 Impurities

Need to address:• Organic impurities• Inorganic impurities (catalysts,…)• Residual solvents• Genotoxic impurities

Need to address:• Organic impurities• Inorganic impurities (catalysts,…)• Residual solvents• Genotoxic impurities


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3.2.S.3.2 Organic impurities3.2.S.3.2 Organic impurities

• Discussion on impurities should cover: – Potential impurities, origin, correspondence with

transparency list of the monograph and individual impurity results

– Use of monograph nomenclature or correlation with monograph nomenclature required

– Which impurities are actually present? Levels found in production batches (actual data needed) - chromatograms

• Discussion on impurities should cover: – Potential impurities, origin, correspondence with

transparency list of the monograph and individual impurity results

– Use of monograph nomenclature or correlation with monograph nomenclature required

– Which impurities are actually present? Levels found in production batches (actual data needed) - chromatograms


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Organic impurities (cont)Organic impurities (cont)

Need to address:• Suitability of the method(s) of the

monograph for the detection of all impurities present in the material

• If the monograph is not suitable then need to supplement it with an additional (validated!) method

• Set appropriate limits

Need to address:• Suitability of the method(s) of the

monograph for the detection of all impurities present in the material

• If the monograph is not suitable then need to supplement it with an additional (validated!) method

• Set appropriate limits


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3.2.S.3.2 Residual solvents3.2.S.3.2 Residual solvents

ICH guideline Q3C CPMP Concept paper (2003)

• Data for ALL solvents used during synthesis (incl. 1st steps)

• Batch results + typical chromatograms• Solvents likely to be present/used in the last

steps• justified limits (ICH or lower) • validated test methods • mentioned on CEP (+ method appended)

ICH guideline Q3C CPMP Concept paper (2003)

• Data for ALL solvents used during synthesis (incl. 1st steps)

• Batch results + typical chromatograms• Solvents likely to be present/used in the last

steps• justified limits (ICH or lower) • validated test methods • mentioned on CEP (+ method appended)


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3.2.S.3.2 Other impurities3.2.S.3.2 Other impurities

• Demonstrate the absence of particular reagents in the final substance or set a limit

• Demonstrate absence of residues of catalysts or set a limit – EMEA draft guideline on catalysts

(CPMP/SWP/4446/00)

• Demonstrate the absence of particular reagents in the final substance or set a limit

• Demonstrate absence of residues of catalysts or set a limit – EMEA draft guideline on catalysts

(CPMP/SWP/4446/00)


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3.2.S.3.2 Genotoxic impurities3.2.S.3.2 Genotoxic impurities

TOP 1 Question in 2007

• Cf NfG CPMP/SWP/5199/02 since 01/2007• Applicable to:

• substances not yet marketed in Europe• new routes of synthesis

• Specific discussion with regard to genotoxic impurities:• Look for potential genotoxicity (structural alerts)• Consult literature and databases

TOP 1 Question in 2007

• Cf NfG CPMP/SWP/5199/02 since 01/2007• Applicable to:

• substances not yet marketed in Europe• new routes of synthesis

• Specific discussion with regard to genotoxic impurities:• Look for potential genotoxicity (structural alerts)• Consult literature and databases


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GTI (cont)GTI (cont)• Principles:

– Data available on maximal exposure– TTC approach (1.5 g/day)– Tox tests (AMES)

• Analytical (sensitive) methods to show residual levels• Demonstrate absence (<30% of max exposure or

TTC) or justify a limit• The use of the substance may be taken into

consideration

==> « Questions and Answers » to be published on EMEA website

• Principles:– Data available on maximal exposure– TTC approach (1.5 g/day)– Tox tests (AMES)

• Analytical (sensitive) methods to show residual levels• Demonstrate absence (<30% of max exposure or

TTC) or justify a limit• The use of the substance may be taken into

consideration

==> « Questions and Answers » to be published on EMEA website


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3.2.S.4 Control of Drug Substance3.2.S.4 Control of Drug Substance

• Refer to the right monograph and its tests• Include additional/alternative tests if necessary• Use quantitative method for related substances • Appropriate limits for impurities, solvents,…in

accordance with the process and relevant guidelines - General monograph 2034

• Adequate methods description -> format to be appended to the CEP

• Refer to the right monograph and its tests• Include additional/alternative tests if necessary• Use quantitative method for related substances • Appropriate limits for impurities, solvents,…in

accordance with the process and relevant guidelines - General monograph 2034

• Adequate methods description -> format to be appended to the CEP


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3.2.S.4 Control of Drug Substance3.2.S.4 Control of Drug Substance

For monographs which still include a

non-specific & non-quantitative TLC method:

suitably validated QUANTITATIVE method for related substances & suitable limits for impurities to be proposed in the application

For monographs which still include a

non-specific & non-quantitative TLC method:

suitably validated QUANTITATIVE method for related substances & suitable limits for impurities to be proposed in the application


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3.2.S.4 How to set limits for related substances3.2.S.4 How to set limits for related substances

• Impurities of the monograph: limits of the monograph• “Other detectable impurities” of the monograph are known

substances detected by the method but NOT normally present above the identification threshold from general monograph (2034).

• Additional impurities (any impurity not on the transparency list) : apply the general monograph (2034)

- Individual limits for specified impurities- Individual limits for identified non-qualified

impurities- Limit for unspecified impurities

• Impurities of the monograph: limits of the monograph• “Other detectable impurities” of the monograph are known

substances detected by the method but NOT normally present above the identification threshold from general monograph (2034).

• Additional impurities (any impurity not on the transparency list) : apply the general monograph (2034)

- Individual limits for specified impurities- Individual limits for identified non-qualified

impurities- Limit for unspecified impurities


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Limits for related substancesLimits for related substances

• For products out of the scope of the general monograph 2034 (antibiotics, peptides,…):– Characterise the impurity profile– Apply the principles of the general monograph

(limits for specified, unspecified, total impurities)– Propose justified limits (not necessarily ICH Q3A)

on the CEP

• For products out of the scope of the general monograph 2034 (antibiotics, peptides,…):– Characterise the impurity profile– Apply the principles of the general monograph

(limits for specified, unspecified, total impurities)– Propose justified limits (not necessarily ICH Q3A)

on the CEP


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Qualification of Additional Impurities

• Qualification by use– History of the product: – Consistency with manufacturing capability– Shown to be present in other products

already approved in Europe• Qualification by toxicological data• Or limited to qualification/identification

threshold

Qualification of Additional Impurities

• Qualification by use– History of the product: – Consistency with manufacturing capability– Shown to be present in other products

already approved in Europe• Qualification by toxicological data• Or limited to qualification/identification

threshold


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3.2.S.4.3 Method validation3.2.S.4.3 Method validation

• All in-house methods should be validated (incl. non-routine methods)ICH Q2B for methodologyTypical chromatograms

• Cross-validation against Ph. Eur methods: comparative results obtained from the same

samples

• All in-house methods should be validated (incl. non-routine methods)ICH Q2B for methodologyTypical chromatograms

• Cross-validation against Ph. Eur methods: comparative results obtained from the same

samples


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3.2.S.4.4 Batch data3.2.S.4.4 Batch data

– Should be in line with specification– Details on batches tested (batch nr, size, dates of

manufacture, analysis)– Numerical figures (“complies” not appropriate)

– Should be in line with specification– Details on batches tested (batch nr, size, dates of

manufacture, analysis)– Numerical figures (“complies” not appropriate)


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3.2.S.5 Reference Standards or materials3.2.S.5 Reference Standards or materials

• Use the Ph. Eur. standards (EPCRS) or provide traceability to these standards and certificates for the in-house standards used

• Use the Ph. Eur. standards (EPCRS) or provide traceability to these standards and certificates for the in-house standards used

3.2.S.6 Container closure system3.2.S.6 Container closure system

• Provide a description of the commercial packaging

• Provide specification for all materials used• Reference compliance with appropriate guidelines

(i.e. EMEA CHMP Plastic Primary Packaging Materials (CPMP/QWP/4359/03))

• Provide a description of the commercial packaging

• Provide specification for all materials used• Reference compliance with appropriate guidelines

(i.e. EMEA CHMP Plastic Primary Packaging Materials (CPMP/QWP/4359/03))


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3.2.S.7 Stability 3.2.S.7 Stability

Option ! EMEA guideline “Stability testing of existing active substances” EMEA guideline on “Declaration of storage conditions for

medicinal products”

• ICH conditions incl accelerated• Study description - relevant parameters•Detailed results• Validation of in-house methods (stability

indicating)

Option ! EMEA guideline “Stability testing of existing active substances” EMEA guideline on “Declaration of storage conditions for

medicinal products”

• ICH conditions incl accelerated• Study description - relevant parameters•Detailed results• Validation of in-house methods (stability

indicating)


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• Proposed retest period and storage conditions:– In accordance with stability results (real time +

accelerated)– Extrapolation possible (according to ICH)

• Proposed retest period and storage conditions:– In accordance with stability results (real time +

accelerated)– Extrapolation possible (according to ICH)

3.2.S.7 Stability 3.2.S.7 Stability


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• Hints




• Hints


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The QOSThe QOS

• QOS = Quality Overall Summary

• Summary of the application highlighting the key points+suitability of the monograph

• The expert can be anyone having sufficient knowledge/experience in the topic, i.e. from the applicant’s company

• CV of the expert to be appended

• QOS = Quality Overall Summary

• Summary of the application highlighting the key points+suitability of the monograph

• The expert can be anyone having sufficient knowledge/experience in the topic, i.e. from the applicant’s company

• CV of the expert to be appended


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The QOS (cont)The QOS (cont)

• Use template of QOS available on EDQM website– Helps to prepare the QOS– Helps for the assessment report

• Submit electronic QOS (Word) to EDQM in addition to paper copy

• Use template of QOS available on EDQM website– Helps to prepare the QOS– Helps for the assessment report

• Submit electronic QOS (Word) to EDQM in addition to paper copy


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• Hints




• Hints


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HintsHints

• The dossier should be Clear, Concise, Readable, Obtained from recent data

• The e-QOS should be in line with the dossier• Follow recommendations described in

“Content of the dossier” + “TOP TEN deficiencies”

• Technical Advice procedure, workshops,…• Submit electronic files

• The dossier should be Clear, Concise, Readable, Obtained from recent data

• The e-QOS should be in line with the dossier• Follow recommendations described in

“Content of the dossier” + “TOP TEN deficiencies”

• Technical Advice procedure, workshops,…• Submit electronic files


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Electronic submissionsElectronic submissions

Electronic dossier (new appl., revisions, add info): pdf files welcome– e-QOS obtained from EDQM template

(Word)– Paper copies still required if > 10 pages– Dropbox to exchange files– EDQM sends requests for info by e-mail

Electronic dossier (new appl., revisions, add info): pdf files welcome– e-QOS obtained from EDQM template

(Word)– Paper copies still required if > 10 pages– Dropbox to exchange files– EDQM sends requests for info by e-mail


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Additional informationAdditional information

• Submit in time and in 2 parts:– Questions/Anwers document addressing all

deficiencies. To be submitted electronically + paper copies

– Updated sections of the dossier as annexes (electronic + paper)

• Submit in time and in 2 parts:– Questions/Anwers document addressing all

deficiencies. To be submitted electronically + paper copies

– Updated sections of the dossier as annexes (electronic + paper)


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And also…And also…

• Timetables noted on the letter of acknowledgement of receipt

• No AR for additional info, but treated in time

• Do not contact EDQM before the expected dates

• No possibility of « special fast track »

• Timetables noted on the letter of acknowledgement of receipt

• No AR for additional info, but treated in time

• Do not contact EDQM before the expected dates

• No possibility of « special fast track »


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You have got the CEP, it is not finished….

You have got the CEP, it is not finished….

The CEP has to be maintained through the Revision systemThe CEP has to be maintained through the Revision system


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Revisions/Renewals of CEPs

Revisions/Renewals of CEPs

Hélène BRUGUERA

Deputy Head


Hélène BRUGUERA

Deputy Head



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Basic principles for maintaining a CEPBasic principles for maintaining a CEP• Any change (administrative or

technical) to be reported to EDQM for approval Revised CEP granted

• Holder to inform customers and/or authorities with revised CEP

• Original CEP: valid 5 years. Need to apply for renewal in time.

• After renewal, CEP valid for an unlimited period, provided the dossier is kept up-to-date

• Any change (administrative or technical) to be reported to EDQM for approval Revised CEP granted

• Holder to inform customers and/or authorities with revised CEP

• Original CEP: valid 5 years. Need to apply for renewal in time.

• After renewal, CEP valid for an unlimited period, provided the dossier is kept up-to-date


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Revisions of CEPs: BackgroundRevisions of CEPs: Background

• Based on EU Regulations on Variations to Marketing Applications

• Guideline on requirements on revision / renewal of CEPs (PA/PH/CEP (04) 2)

• New procedures for management of revision / renewal of CEPs (PA/PH/Exp. CEP/T (04) 18)

• Available on EDQM website

• Based on EU Regulations on Variations to Marketing Applications

• Guideline on requirements on revision / renewal of CEPs (PA/PH/CEP (04) 2)

• New procedures for management of revision / renewal of CEPs (PA/PH/Exp. CEP/T (04) 18)

• Available on EDQM website


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Guideline on Requirements: documentationGuideline on Requirements: documentation• Application form (specific for revisions)• Technical data:

– Justification of change– Assurance that the conditions are fulfilled– Updated pages of the dossier– Specific supporting documents– COMPARATIVE DATA - Full batch results

• Application form (specific for revisions)• Technical data:

– Justification of change– Assurance that the conditions are fulfilled– Updated pages of the dossier– Specific supporting documents– COMPARATIVE DATA - Full batch results


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Types of changesTypes of changes

• Notifications

• Minor changes

• Major changes

• Renewal

• Update following revision of the monograph / regulatory change

• Notifications

• Minor changes

• Major changes

• Renewal

• Update following revision of the monograph / regulatory change


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NotificationsNotifications

• Change in holder, manufacturer references: holder name, address (no move),...

• Change in batch size by ≤ x 10• Minor changes to test procedures (no changes in

performances - few cases in practice)• Tightening limits (methods not affected)• Post-stability commitment data• Deletion of information from CEP: manuf. site, retest

period, country of origin for TSE

• Change in holder, manufacturer references: holder name, address (no move),...

• Change in batch size by ≤ x 10• Minor changes to test procedures (no changes in

performances - few cases in practice)• Tightening limits (methods not affected)• Post-stability commitment data• Deletion of information from CEP: manuf. site, retest

period, country of origin for TSE


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NotificationNotificationTimescales and Fees

• Simple 2 weeks/500 euros • Multiple (max. 3) 30 days/1000 euros

Workflow: • No Acknowledgement of Receipt• Letter sent to advise that either the notifications has been

accepted as valid or has been rejected - No demand for additional information sent

• Revised CEP only issued when the information on the CEP is changed (i.e. and address)

Timescales and Fees• Simple 2 weeks/500 euros • Multiple (max. 3) 30 days/1000 euros

Workflow: • No Acknowledgement of Receipt• Letter sent to advise that either the notifications has been

accepted as valid or has been rejected - No demand for additional information sent

• Revised CEP only issued when the information on the CEP is changed (i.e. and address)


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Typical minor changesTypical minor changes

• Minor change in manufacture• Up scaling > x10• Change in specification (new or replaced test

parameter)• Change/Addition of manufacturing site• Change from a TSE risk to a non-TSE risk

material• Change/Addition of retest period on CEP

• Minor change in manufacture• Up scaling > x10• Change in specification (new or replaced test

parameter)• Change/Addition of manufacturing site• Change from a TSE risk to a non-TSE risk

material• Change/Addition of retest period on CEP


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Minor ChangeMinor ChangeTimescales and Fees

• Single 1 month /1000 euros • Multiple (max. 3) 2 months /1500 euros

Workflow: • Acknowledgement of Receipt sent within 5 days• One demand for additional information sent if neccessary• Holder has 30 days to respond to this demand• EDQM has 30 days to evaluate the response• Revised CEP issued or demand for revision rejected

Timescales and Fees• Single 1 month /1000 euros • Multiple (max. 3) 2 months /1500 euros

Workflow: • Acknowledgement of Receipt sent within 5 days• One demand for additional information sent if neccessary• Holder has 30 days to respond to this demand• EDQM has 30 days to evaluate the response• Revised CEP issued or demand for revision rejected


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Major changesMajor changes

• Any changes not included in the guideline (or conditions not fulfilled)

• Examples (chemical):– Introduction of new reagents, solvents– Alternative process ( Spec of the final substance

identical, otherwise new certificate)– Process replaced

• Examples (TSE):– Addition of new source countries or suppliers of

materials

• Any changes not included in the guideline (or conditions not fulfilled)

• Examples (chemical):– Introduction of new reagents, solvents– Alternative process ( Spec of the final substance

identical, otherwise new certificate)– Process replaced

• Examples (TSE):– Addition of new source countries or suppliers of

materials


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Major ChangeMajor ChangeTimescales and Fees

• Single 3 months /1500 euros • Multiple (max. 3, 1 major) 3 months /1500 euros

Workflow: • Acknowledgement of Receipt sent within 5 days• One demand for additional information sent if necessary• Holder has 30 days to respond to this demand• DCEP has 30 days to evaluate the response• Revised CEP issued or demand for revision rejected

Timescales and Fees• Single 3 months /1500 euros • Multiple (max. 3, 1 major) 3 months /1500 euros



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Consolidated RevisionConsolidated RevisionTimescales and Fees

• Multiple revisions (> 3) 4 months/2500 euros


Timescales and Fees• Multiple revisions (> 3) 4 months/2500 euros



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Monograph revisionMonograph revision

• Revised monographs published 3 times a year

• EDQM gives instructions to the holders:– Compliance with the monograph– Suitability of the monograph

• Timescales and Fees90 days/No fee

• Revised CEP issued if necessary after approval

• Revised monographs published 3 times a year

• EDQM gives instructions to the holders:– Compliance with the monograph– Suitability of the monograph

• Timescales and Fees90 days/No fee

• Revised CEP issued if necessary after approval


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RenewalRenewal

• Holder shall apply about 6 months prior to expiry date• Declaration that no change occurred or• Updated dossier (CTD) with comprehensive list of

changes– General Monograph “Substances for

Pharmaceutical Use”– Recent European quality guidelines: eg impurities,

residual solvents, residual catalysts

Not an administrative job!

• Holder shall apply about 6 months prior to expiry date• Declaration that no change occurred or• Updated dossier (CTD) with comprehensive list of

changes– General Monograph “Substances for

Pharmaceutical Use”– Recent European quality guidelines: eg impurities,

residual solvents, residual catalysts

Not an administrative job!


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RenewalRenewalTimescales and Fees

• 4 months /1500 euros

Workflow: • Acknowledgement of Receipt sent within 5 days• 120 days to evaluate the request • Revised CEP issued, demand for additional information sent or

demand for revision rejected• If Demand for additional information sent

• Holder has 30 days to respond to this demand• EDQM has 30 days (90 for TSE) to evaluate the response

Timescales and Fees• 4 months /1500 euros

Workflow: • Acknowledgement of Receipt sent within 5 days• 120 days to evaluate the request • Revised CEP issued, demand for additional information sent or

demand for revision rejected• If Demand for additional information sent

• Holder has 30 days to respond to this demand• EDQM has 30 days (90 for TSE) to evaluate the response


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Common deficienciesCommon deficiencies

• Change in the analytical method: N7/R3• Replacement of a solvent: Major• Change of strain in fermentation

process: Major• New supplier of starting material when

route of synthesis is not identical: Major• Alternative process: if the specs are

changed : New application

• Change in the analytical method: N7/R3• Replacement of a solvent: Major• Change of strain in fermentation

process: Major• New supplier of starting material when

route of synthesis is not identical: Major• Alternative process: if the specs are

changed : New application


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What to do with a revised CEPWhat to do with a revised CEP

• CEP ref number incremented– RX-CEP 2007-001-Rev YY

• Provide a copy to customers

• Update of relevant Marketing Applications Type IA variation in most cases

(cf. European regulations)

• CEP ref number incremented– RX-CEP 2007-001-Rev YY

• Provide a copy to customers

• Update of relevant Marketing Applications Type IA variation in most cases

(cf. European regulations)


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Thank you !

IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 1 Content of the application for a CEP Hélène BRUGUERA Deputy Head Certification of Substances Division.

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