The Certification Procedure - The Indian Pharmaceutical ... - EDQM pdf/Andrew McMath... · in the...

The Certification ProcedureThe Certification Procedure

Dr. Andrew McMATHCertification of Substances Division,

EDQM

Andrew McMath 29/01/10 ©2010 EDQM, Council of Europe, All rights reserved

SummarySummary

• Place of Certification as a regulatory tool• Comparison of CEP & ASMF• How it works • How to read & use a CEP • Key figures• Recent developments


Regulatory backgroundRegulatory background

Active substances in marketing applications :

Directive 2003/63/EC and the various quality guidelines give options on how to fulfil the same basic requirements.

The information required is the same regardless of the route selected (CEP or ASMF or Marketing Application)


NfG CHMP/QWP/297/97 rev. 1 corr«Summary of requirements for active substances in the quality part of the dossier»

NfG CHMP/QWP/297/97 rev. 1 corr«Summary of requirements for active substances in the quality part of the dossier»

This document describes how to communicate the information on the active substance (API) to authorities in Europe.

It gives three choices:

2.1 Certificate of suitability2.2 Active Substance Master File (ASMF)2.3 Full details of manufacture


NfG CHMP/QWP/297/97 rev. 1 corr“Summary of requirements for active substances in the quality part of the dossier”

NfG CHMP/QWP/297/97 rev. 1 corr“Summary of requirements for active substances in the quality part of the dossier”

2.1 Certificate of suitabilitySince this procedure requires a Ph. Eur. monograph, it is used for existing substances and the guideline states : “ where applicable, option 2.1 has the advantage of generally avoiding any subsequent reassessment ”

2.2 Active substance Master File (ASMF)2.3 Full details of manufacture in licence application

Since these procedures do not require a Ph. Eur. monograph they can be used for new substances;but may also be used for existing substances.


Differences between CEP & ASMFDifferences between CEP & ASMF

- Scope:

• CEP : pharmacopoeial substances only, -> active subst. or excipient

• ASMF : active substances only, -> new or pharmacopoeial


Differences between CEP & ASMFDifferences between CEP & ASMF- Specificity of ASMF:• Full dossier sent by API manufacturer to National Authorities• Applicant’s part sent by API manufacturer to MA applicant or

holder of medicinal Product• Letter of access (to be sent by API manufacturer)• Assessment of ASMF by each national authority in the

context of assessing a specific marketing authorisation application or variation for medicinal products


Differences between CEP & ASMFDifferences between CEP & ASMF- Specificity of CEP procedure:

• Full dossier sent directly by manufacturer to EDQM• Single evaluation centralised at EDQM• By assessors nominated by national authorities /

Certification Steering Committee• Independent from marketing applications of medicinal

products• Certificate including annexes (additional tests to be

performed) granted to manufacturer who supplies a copy of it to its users


Advantages of the CEPAdvantages of the CEPProvides:• Easier management of RA documentation for API

manufacturer (no open part)• Savings of time and resources• Easier management of MAA - replaces main part of

3.2.S• CEP accepted in all Ph. Eur. Member states (36) +

others (eg. Canada (MoU 03/2007), Australia, Morocco, New Zealand etc.)


Useful backgroundUseful background

• Resolution AP-CSP(07) 1 of the CoE:Describes the process for the Certification

procedure

• Content of the (CEP) dossier PA/PH/CEP (04) 1, 4R

Both available on EDQM website


Useful backgroundUseful background• Notes for guidance (ICH + CHMP/CVMP) apply, in

particular:• Impurities testing (ICH Q3A + Ph. Eur. General Monograph 2034,

Substances for Pharmaceutical Use)• Solvents (ICH Q3C = Ph. Eur. general text 5.4 )• Specifications limits for residues of metal catalysts or metal

reagents (CHMP/SWP)• Limits of genotoxic impurities (CHMP-SWP)• (Stability testing (ICH Q1 + CHMP guidelines for existing

substances.)• GMP (ICH Q7, Annex 1 to EU GMP)• TSE (CPMP/CVMP guideline = PhEur general text 5.2.8)


Scope of the Certification procedureScope of the Certification procedure

- Substances described in monographs in the Ph. Eur.:Active substances, excipients, herbal drugs / herbalpreparations � “Chemical” CEP

- Products with risk of TSE (SM, intermediates, reagents,..) �“TSE “CEP

- Substances described in monographs in the Ph. Eur.and with risk of TSE � “Double “CEP

Open to any manufacturer regardless of geographicalorigin


Out of Scope of the Certification procedureOut of Scope of the Certification procedure

- Substances not included in Ph. Eur.- Biologicals- Human tissues derivatives, blood derivatives,

vaccines- Finished products


Certification: organisationCertification: organisation

• Steering Committee • Technical Advisory Boards (TAB)

ChemicalTSEHerbals

• Assessors • EDQM Certification Division


Steering CommitteeSteering Committee• Representatives of main regulatory bodies (14 members

from EMA WP, EU Commission, Ph. Eur Commission, Non-EU licensing authorities,...)

• Monitoring Certification procedure• Appointment of assessors• Appointment of Technical Advisory Boards (TABs) and

their Chairperson• Policy adoption• Review and comment on issues raised by TABs• Co-ordination of issues between the represented parties


Technical advisory boards (TAB)Technical advisory boards (TAB)

• Consists of experienced assessors involved in the CEP procedure for a period of time

Role:

• To assist assessors in case of doubt or disagreement• To prepare technical guidance• To identify technical/scientific problems and seek advice

for SC


Assessors and Certification DivisionAssessors and Certification Division

• Assessors appointed by agencies(about 80 from 16 countries)– Role : evaluation of dossiers

• Certification Division(EDQM scientific and administrative staff ) – Role : execution of the procedure and co-ordination

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Content of the dossier:Content of the dossier:

For details Nathalie Vicente


How it works:How it works:Application

CEP granted

Up-dating :- at any change (minor/major)

- After 5 years (renewal)

Request for add info

Evaluation (2 assessors)+ TAB if necessary

Request for inspection

Revision of monograph

refusal

Transfer to EDQM experts group Possibility

of hearingInfo of licensing auth.

Validation


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, once validated

– Responses from applicant expected within 6 months for original demand

– Responses assessed within 4 months

NB. Since 1/09/2008: strict procedure applied - only one request for additional information


HOW TO READ A CEPHOW TO READ A CEP


The certificate of suitability, chemical:The certificate of suitability, chemical:

• Certifies that the quality of a given substance can be suitably controlled by the Ph.Eur. monograph -with additional tests if necessary (stated on the CEP).

• It DOES NOT certify that a batch or batches of the substance complies with the Pharmacopoeia monograph.

• It IS NOT a GMP certificate


The CEP, TSE :The CEP, TSE :

• Certifies that the substance complies with the EMEA NfG on minimising the TSE risk

• It DOES NOT certify that the quality of the substance can be suitably controlled by the Ph.Eur. monograph

• It DOES NOT certify that a batch of the substance complies with the monograph

• It IS NOT a GMP certificate


All CEPs specify:All CEPs specify:• Unique Reference number

(e.g. R0-CEP 2000-001-Rev01)• Title: clear definition of the substance

+ grade when requested (eg. micronised, sterile,…)• Holder + manufacturing site(s)• Monograph(s) concerned• Starting validity date • Line numbering and annex details if appropriate


And as necessary, chemical CEPs:And as necessary, chemical CEPs:

• Additional impurities/Solvents/Catalysts– With limits and methods

• Re-test period– With storage conditions + container

• Specs (limit + test) for a specific grade• Tests of the monograph which can be omitted• Use or non-use of materials of animal origin


And if for a sterile material:And if for a sterile material:

• Description of sterilisation method and container/closure

• Statement that the validation of the sterilisation has been evaluated

NB: the information on the sterilisation process and itsvalidation needs to be submitted separately in themarketing authorisation dossier


And for a TSE certificate:And for a TSE certificate:

• Country(ies) of origin of animals• Animal and nature of tissue(s) used• Manufacturing process applied (when relevant,

e.g. gelatins)• Quality assurance system applied


The CEP looks like:The CEP looks like:


How to use a CEP:How to use a CEP:


What should be addressed at the level of the MAA ?What should be addressed at the level of the MAA ?• Stability if no re-test period mentioned on the CEP• All data relating to physico-chemical characteristics

(e.g. particle size) if no grade claimed • Assessment is performed taking into account the

general use of the substance. Specific uses should be addressed at the level of the marketing authorisation application


KEY FIGURESKEY FIGURES


Certificates of SuitabilityCertificates of Suitability

• > 4000 applications since procedure launched• ~ 2500 valid certificates• > 760 substance monographs involved • …


Certificates of SuitabilityCertificates of Suitability

… > 560 manufacturers from 43 countries


Repartition of manufacturing sites covered by CEPs (2008)

Europe41%

Asia38%

America15%

Pacific zone4%

Middle East1% Africa

1%

RECENT DEVELOPMENTSRECENT DEVELOPMENTS


Recent developmentsRecent developments1. New procedure for the assessment of “sister files”

when a manufacturer has been granted a CEP for a substance and where they apply for a second CEP for the same substance to cover an alternative process, generally because the existing one cannot cover the new process/conditions,

fast track procedure focusing the evaluation on the variations compared to the approved CEP dossier.

(see EDQM web-site PA/PH/CEP (09) 141).


Recent developmentsRecent developments

2.2. Revision of general monograph 2034 Revision of general monograph 2034 Substances for Substances for Pharmaceutical UsePharmaceutical Use::

-- New limits for synthetic peptides:New limits for synthetic peptides:

-- Updated limits for substance for vet. use onlyUpdated limits for substance for vet. use only

-- Published in Supplement 6.5Published in Supplement 6.5

-- Implemented on 1 July 2009Implemented on 1 July 2009


Recent developmentsRecent developments

3.3. Substances extracted from animal tissues: Substances extracted from animal tissues: (heparin, enoxaparin, (heparin, enoxaparin, ……), t), the EDQM no longer accepts any new application for a CEP for biological substances. . See Certification website / New Applications

- A list of these biological products is available on the on the CMD(h) web-site-http://www.hma.eu/uploads/media/070618.pdf


Certification: benefitsCertification: benefits

• Single & harmonised assessment• Replaces Active Substance Master File• Savings of time and resources• Updating of monographs (impurities)• Revision of monographs (new or replacement test

methods)• CEPs are recognised in Europe and beyond


Thank you ! ☺


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