Certification CEP Co S and inspection system Corinne Pouget

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Количество слайдов: 43

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 IPA-EDQM Mumbai 12/2007 © 2007 EDQM, Council of Europe 4

Legal background • Directives 2001/83/EC and 2001/82/EC Ø Ph Eur monographs are mandatory (specific and general) Ø Need to demonstrate that a specific monograph is suitable to control the quality of the active substance Ø 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 Ø Prevention of TSE risks Demonstration of compliance preferably by a CEP IPA-EDQM Mumbai 12/2007 © 2007 EDQM, Council of Europe 5

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 IPA-EDQM Mumbai 12/2007 © 2007 EDQM, Council of Europe 6

Scope of the procedure • Substances covered by a specific Ph. Eur 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 IPA-EDQM Mumbai 12/2007 © 2007 EDQM, Council of Europe 7

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. . ) IPA-EDQM Mumbai 12/2007 © 2007 EDQM, Council of Europe 8

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 IPA-EDQM Mumbai 12/2007 © 2007 EDQM, Council of Europe 9

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 IPA-EDQM Mumbai 12/2007 © 2007 EDQM, Council of Europe 10

Steering Committee • Appointment of assessors • Appointment of Technical Advisory Boards (TABs) and their Chairmen • Policy • Co-ordination of issues between the parties represented IPA-EDQM Mumbai 12/2007 © 2007 EDQM, Council of Europe 11

Technical advisory board’s (TAB) role • Assist assessors in case of doubt or disagreement • Technical guidance • Technical/scientific problems and seek advice for SC IPA-EDQM Mumbai 12/2007 © 2007 EDQM, Council of Europe 12

Assessors and Certification Division • Independent Assessors – evaluation of dossiers • Certification Division (EDQM scientific and administrative staff) – execution of the procedure and co-ordination IPA-EDQM Mumbai 12/2007 © 2007 EDQM, Council of Europe 13

EDQM Inspection programme In application of Directive 2001/83/EC as amended (Article 111) and Directive 2001/82/EC as amended (Article 80): Ø 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 IPA-EDQM Mumbai 12/2007 © 2007 EDQM, Council of Europe 15

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 IPA-EDQM Mumbai 12/2007 © 2007 EDQM, Council of Europe 16

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 Q 7 A (+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 IPA-EDQM Mumbai 12/2007 © 2007 EDQM, Council of Europe 17

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 IPA-EDQM Mumbai 12/2007 © 2007 EDQM, Council of Europe 18

Rationale for suspension of CEPs • In case of major/critical GMP deficiency(ies) Ø The company does not operate with a sufficient level of compliance • If major deviation(s) compared to the dossier Ø Failure in the declarations and commitments Decision to suspend the CEP (board) and/or to block applications IPA-EDQM Mumbai 12/2007 © 2007 EDQM, Council of Europe 19

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 IPA-EDQM Mumbai 12/2007 © 2007 EDQM, Council of Europe 20

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) Ø These figures cannot be extrapolated for a statistical overview of the status of the API sites IPA-EDQM Mumbai 12/2007 © 2007 EDQM, Council of Europe 22

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%) + = = = + - IPA-EDQM Mumbai 12/2007 © 2007 EDQM, Council of Europe 23

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 IPA-EDQM Mumbai 12/2007 © 2007 EDQM, Council of Europe 24

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) IPA-EDQM Mumbai 12/2007 © 2007 EDQM, Council of Europe 25

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 not involved in matters related to the quality of products Weakness of quality review IPA-EDQM Mumbai 12/2007 © 2007 EDQM, Council of Europe 26

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 IPA-EDQM Mumbai 12/2007 © 2007 EDQM, Council of Europe 27

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 IPA-EDQM Mumbai 12/2007 © 2007 EDQM, Council of Europe 28

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) IPA-EDQM Mumbai 12/2007 © 2007 EDQM, Council of Europe 33

Update on workload and deadlines • Workload increases: – 320 new applications in 2006, 350 in 2007 – 500 revisions/renewals in 2006, 600 in 2007 IPA-EDQM Mumbai 12/2007 © 2007 EDQM, Council of Europe 34

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) IPA-EDQM Mumbai 12/2007 © 2007 EDQM, Council of Europe 36

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) IPA-EDQM Mumbai 12/2007 © 2007 EDQM, Council of Europe 37

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 IPA-EDQM Mumbai 12/2007 © 2007 EDQM, Council of Europe 39

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 IPA-EDQM Mumbai 12/2007 © 2007 EDQM, Council of Europe 40

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 IPA-EDQM Mumbai 12/2007 © 2007 EDQM, Council of Europe 41

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 IPA-EDQM Mumbai 12/2007 © 2007 EDQM, Council of Europe 42