Certification procedure

The Certification Procedure 

Dr. Andrew McMATH 

Certification of Substances Division, 

EDQM 

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

Summary 

• 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 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» 

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 suitability 

2.2 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” 

2.1 Certificate of suitability 

Since 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 & ASMF 

- Scope: 

•CEP: pharmacopoeial substances only, 

-> active subst. or excipient 

• ASMF : active substances only, 

-> new or pharmacopoeial 



- 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 



- 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 CEP 

Provides: 

• 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 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 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 procedure 

- Substances described in monographs in the Ph. Eur.: 

Active substances, excipients, herbal drugs / herbal 

preparations “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 geographical 

origin 


Out of Scope of the Certification 

procedure 

- Substances not included in Ph. Eur. 

- Biologicals 

- Human tissues derivatives, blood derivatives, 

vaccines 

- Finished products 


Certification: organisation 

• Steering Committee 

• Technical Advisory Boards (TAB) 

Chemical 

TSE 

Herbals 

• Assessors 

• EDQM Certification Division 


Steering 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) 

• 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 Division 

A 

• Assessors appointed by agencies 

(about 80 from 16 countries) 

– Role : evaluation of dossiers 

1 

1 

2 

1 

5 

8 

10 

5 2 

7 

5 

3 

3 

5 4 

19 

B 

CH 

CND 

D 

DK 

E 

F 

IE 

IT 

H 

NL 

P 

UK 

S 

SF 

• Certification Division 

(EDQM scientific and administrative staff ) 

– Role : execution of the procedure and co-ordination 


Content of the dossier: 

For details Nathalie Vicente 


How it works: 

Application 

Up-dating : 

- at any change (minor/major) 

- After 5 years (renewal) 

Request for 

inspection 

Revision of 

monograph 

Transfer to EDQM 

experts group 

Validation 

Evaluation (2 assessors) 

+ TAB if necessary 

CEP granted 

Possibility 

of hearing 

Request for add info 

refusal 

Info of 

licensing auth. 


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 CEP 


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 : 

• 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: 

• 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: 

• 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: 

• 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 its 

validation needs to be submitted separately in the 

marketing authorisation dossier 


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: 


How to use a CEP: 


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 FIGURES 


Certificates of Suitability 

• > 4000 applications since procedure launched 

• ~ 2500 valid certificates 

• > 760 substance monographs involved 

• … 


Certificates of Suitability 

… > 560 manufacturers from 43 countries 

Repartition of manufacturing sites covered by CEPs (2008) 

America 

15% 

Middle East 

1% Africa 

Pacific zone 

1% 

4% 

Europe 

41% 

Asia 

38% 


RECENT DEVELOPMENTS 


Recent developments 

1. 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). 



2. Revision of general monograph 2034 Substances for 

Pharmaceutical Use: 

- New limits for synthetic peptides: 

- Updated limits for substance for vet. use only 

- Published in Supplement 6.5 

- Implemented on 1 July 2009 



3. Substances extracted from animal tissues: 

(heparin, enoxaparin, …), the t 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 

CMD(h) web-sitehttp://www.hma.eu/uploads/media/070618.pdf 


Certification: 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 ! ☺

Certification procedure

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