Certification (CEP/CoS)
and inspection system
Corinne Pouget
Certification of Substances Division
EDQM & HealthCare
IPA-EDQM Mumbai 12/2007 ©2007 EDQM,
Council of Europe
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Overview
•
•
•
•
Scope and running the system
The EDQM inspection programme
Update and key figures
Perspectives 2008
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Scope and running the
system
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The Certification procedure
• To show for a pharmaceutical substance:
– Suitability of the Ph. Eur. Monograph to control
the quality of a substance
– Compliance with European regulatory
requirements
• Created in 1994, scope enlarged
• Managed by EDQM
• Harmonisation and centralisation of work
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Legal background
• Directives 2001/83/EC and 2001/82/EC
 Ph Eur monographs are mandatory (specific and
general)
 Need to demonstrate that a specific monograph is
suitable to control the quality of the active substance
 Where there is a monograph in Ph Eur:
- CEP ‘deemed to replace the relevant section of the module’
(3.2.S)
- CEP holder must give assurance in writing to the
applicant…no change since CEP granted by EDQM
 Prevention of TSE risks
Demonstration of compliance preferably by a CEP
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Legal background (2)
• Note for guidance : « Summary of
requirements for active substances
“(CHMP/QWP/297/97 rev. 1 EMEA/CVMP/1069/02):
– CEP
– ASMF
– Full information in Marketing Application
• Resolution AP-CSP(07) 1 of the
Council of Europe: Procedural aspects
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Scope of the procedure
• Substances covered by a specific PhEur monograph:
Active, excipients, herbal drugs / herbal preparations
• TSE risk products (SM, intermediates, reagents,..)
• Not applicable for biotechnological products, products
from human tissues, semi-finished or finished products,
substances not included in Ph. Eur
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Scope (2)
• Open to any manufacturer of active substance /
expicient whatever the geographical origin
• Centralised evaluation
• Facilitates management of Marketing Applications
• CEP accepted in all EP countries (36) + others
(eg Canada, Australia, Morocco, Tunisia, New
Zealand..)
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Confidentiality respected
• CEP dossiers submitted directly by
manufacturers
– No applicant part (≠ ASMF)
• Independently of any marketing application
• Archived in a specific restricted area
(EDQM)
• Assessment on the premises of EDQM
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Who is involved?
The different stakeholders and their roles are defined in Terms of
Reference (PA/PH/CEP (01) 1 (see EDQM web-site)
• Steering Committee
– 11 members : representative bodies of EU and Ph. Eur countries
• Assessors from 16 countries
– About 80: chemical purity, TSE, toxicologists, for herbal drugs,
sterility
• Technical Advisory Boards (TAB)
Chemical TAB
TSE TAB
• Certification Division
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Steering Committee
• Appointment of assessors
• Appointment of Technical Advisory Boards
(TABs) and their Chairmen
• Policy
• Co-ordination of issues between the parties
represented
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Technical advisory board’s (TAB)
role
• Assist assessors in case of doubt or
disagreement
• Technical guidance
• Technical/scientific problems and seek
advice for SC
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Assessors and Certification
Division
• Independent Assessors
– evaluation of dossiers
• Certification Division (EDQM scientific and
administrative staff)
– execution of the procedure and co-ordination
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The EDQM Inspection
programme
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EDQM Inspection programme
In application of Directive 2001/83/EC as
amended (Article 111) and Directive 2001/82/EC
as amended (Article 80):
 Mandate is given to EDQM (by EC) to establish
an annual programme for inspections:
– Manufacturing sites and brokers/distributors holding
CEPs
– Inspections inside and outside EU
– Authorities notified of issues arising
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EDQM inspection programme
• In line with EMEA ‘trigger document’:
–
–
–
–
–
If requested during assessment
Sterile substances
CEP held by brokers/traders/distributors
To join a scheduled national inspection
On justified requests from manufacturers
• Adopted by the CEP Steering Committee
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Inspection progress
• Lasts about 3 days
• Team of 2 inspectors (of Ph. Eur member states)
– Local inspector invited in non-Ph. Eur countries
– EDQM representative
• References:
– ICH Q7A (+annex 1 of EU guideline for sterile subst.) and any other
relevant GMP documents
– Certification Dossier
• Visit of the manufacturing facilities (process flow)
• Study of production and QA management documents
• Conclusions presented orally to the company at the end of the inspection
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Follow-up of an inspection
• Report sent to the company
• Company requested to address deficiencies
• When positive inspectors’ opinion:
 EDQM Attestation of Inspection
 GMP certificate drafted by the EU leader
inspector
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Rationale for suspension of
CEPs
• In case of major/critical GMP deficiency(ies)
 The company does not operate with a sufficient level of
compliance
• If major deviation(s) compared to the dossier
 Failure in the declarations and commitments
 Decision to suspend the CEP (board)
and/or to block applications
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In case of suspension of a CEP
• Holder (and manufacturer) notified:
– justification, conditions for restoration, possibility for
hearing
• All relevant authorities informed, incl. EMEA
Working groups + EU Commission
• Public information: EDQM website + CEP on-line
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Frequent findings
noticed by inspectors
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Frequent findings
• Few critical deviations
• About 25% were major deviations
• In some cases combination of major/minor lead to
a critical situation
• 110 inspections carried out - 15 defective
! Selected sites, suspected to be non-compliant
before inspection (eg. request from assessors)
 These figures cannot be extrapolated for a statistical
overview of the status of the API sites
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Frequent deviations
Based on 110 inspections incl. 9% traders , 3% TSE subst; sterile excluded)
•
•
•
•
•
•
•
•
Process equipment (15%)
Materiel management (12%)
Documentation and records (11%)
Buildings & facilities (10%)
Quality management, Lab controls (8%)
Production and IPC (7%)
Compliance with CEP dossier (7%)
Packaging & labelling, validation (4%)
+
=
=
=
+
-
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Frequent deviations
• Process equipment:
•
•
•
•
Identification of equipment insufficient
Handling of closed equipment not satisfactory
Cleaning procedures poorly defined or applied
Non-calibrated apparatus for IPC
• Material management:
• Lack of qualification of suppliers
• ‘Critical’ suppliers not well defined
• Incomplete tracing-back of animal-origin materials
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Frequent deviations (2)
• Documentation and records:
-
Lack of procedures, or insufficient details
Weak management of the documentation system
Contradiction between procedures and reality
Incomplete batch records
• Batch release:
- Insufficiently described (written procedures)
- Unclear (weakness of adequate checks)
- Responsibilities unclear (no defined or inappropriate responsible
person)
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Frequent deviations (3)
• Buildings and facilities:
– Areas not well defined for storage / quarantine / sampling
– Inadequate protection of environment and production areas
– Systems for air, steam, gases,… not sufficiently qualified and
monitored
• Quality Management:
−
−
−
−
Role of QA inadequately resourced, insufficiently described
Poor training and knowledge of the QA staff
QA staff not involved in matters related to the quality of products
Weakness of quality review
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Frequent deviations (4)
• Laboratory:
– Use of non registered methods
– Standards not appropriate
– Equipment not properly qualified/monitored
• Production / IPC:
–
–
–
–
Critical parameters insufficiently defined and controlled
Equipment inappropriate or badly maintained
Risks of contamination/cross-contamination
Deviations not sufficiently documented, explained/investigated, no
reporting system in place
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For sterile substances
≤ 10 % of inspections carried out
1.
2.
3.
General aspects (clean areas, classification, monitoring) and
processing (reduction of contamination, bio burden monitoring..)
Personnel (training, clothing) and premises (pipes, air-flow and
pressure, warning systems)
Sterilisation validation, and filtration (integrity, re-use of filters)
! New policy for manufacturing sites on the CEP
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Update and Key figures
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Update on communication
• Technical advice procedure (5 meetings in
2007)
• Workshops
• One-to-one meetings
• EDQM website redesigned
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« CEP on-line »: is my CEP valid?
www.edqm.eu
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Holder name (on CEP)
Status
Full CEP number
Issue date of the current CEP
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Contacts with Licensing Authorities
• Transmission of CEP evaluation reports
– Upon request from an authority
– In the context of a marketing application or any justified
reason
– Copy of the report(s) sent also to the holder
– Reports from 20 dossiers sent in 2007, 44 in 2006 (incl.
15 for TPD/Health Canada)
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Update on workload and
deadlines
• Workload increases:
– 320 new applications in 2006, 350 in 2007
– 500 revisions/renewals in 2006, 600 in 2007
Cum ulative num be r of applications re ce ive d
T otal
500
T SE Doubles
451
450
Chemical
420
350
317
300
280
250
229
199199
200
191
233 239
218
200
284
322
305
297
277
270
250
249
155155
132132
150
109109
0
0
0
0
0
1994
1995
1996
1997
1998
1999
31
33
28
25
20
2007
0
2006
9 9
0
1993
39
18 18
0
1992
50
2005
48 48 52 52
2004
100
2003
number of applications
400
2002
2001
2000
0
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Since beginning of procedure
•
•
•
•
> 3300 applications
> 2300 certificates granted
> 650 substances
> 560 manufacturers from 43 countries
Repart it ion of manuf acturers by zone
03/2006
America
15%
Pacific
1%
Africa
0%
Europe
47%
Asia
18%
Middle East
19%
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inspections
110 manufacturing sites inspected
• in 22 countries (incl. China, India, Mexico, Canada,
Europe)
• 12 cases where major/critical deficiencies led to
suspension of CEPs
– Some being held by European wholesalers/distributors
– cases where ‘sterile ’ grade was refused
– some CEPs ‘restored’ already after re-inspection (CEP revised)
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Deadlines
• Deadlines improved:
– New appl.: up to 6 months delay in 2006, 34 months in 2007
– Renewals: up to 6 months delay in 2006, 34 months in 2007
– Intermediate revisions: on time in 2006 and
2007
– Add info: in time in 2006 (4 months) and in
2007 (3 months)
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Perspectives 2008
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Perspectives for EDQM
inspection programme
• Programme to be continued in application of the
EU mandate
• Follow-up of defective inspections - reinspections
• Enlarge experience
– > 35 inspections/year
– with other inspectorates, groups…
– And other countries
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EDQM inspection programme (2)
• Promote inspections of drug substances
and establish an adequate system
– Reinforce collaboration with EU/EMEA
– Collaboration with European/international
inspection working groups
– System for harmonised decisions for
sites/batches/MA concerned after suspension
of CEPs
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Procedural aspects
• Deadlines:
– Reduce delay for new applications (be on time ??)
– EDQM commits to treat RQs without changes on time
from 01/01/2008
• Electronic submissions:
– Instructions for applicants to develop electronic
applications
– Prepare for e-CTD
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Revision of CEPs
• Revise the system to reduce administrative
work, in cooperation with EMEA QWP:
– Define minor changes which will not lead to a
revised CEP after approval
– Access to CEP database for Authorities (history
of revisions,..)
• Wait for revision of EU Regulation
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THANK YOU FOR YOUR
ATTENTION
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