GxP Inspections within the Centralised Procedure. Brendan Cuddy Inspections Sector

Transcription

1 GxP Inspections within the Centralised Procedure Brendan Cuddy Inspections Sector

2 Agenda Introduction to work of the Inspections Sector GxP Inspections within the centralised procedure Regulatory framework for inspections Common Principles Timetable for inspections Purpose of an Inspection Preparing, performing and reporting GxP Inspections Specific Aspects GMP GCP GLP GxP Inspections Information in the dossier Post-authorisation Inspections

3 COUNCIL REGULATION 726/2004 (CAP/EMEA) ART 57...THE AGENCY SHALL UNDERTAKE THE FOLLOWING TASKS WITHIN ITS COMMITTEES: i) co-ordinating the verification of compliance with the principles of good manufacturing practice, good laboratory practice and good clinical practice and the verification of compliance with pharmacovigilance obligations

4 Inspections Sector Activities Majority of Inspections Sector operations are related to applications submitted to the EMEA (centralised procedures, pre&postauthorisation and referrals) iemea co-ordinates Inspection activities within the agreed timetable, i.e. there are no inspectors at the EMEA, we use the expertise of the EU Member States

5 Inspections Contribution to Centralised Procedure PROCEDURES PRODUCT SPECIFIC Harmonisation and Provision of Guidance Scientific & Regulatory advice and guidance Submission & validation of applications Assessment reports, clock stop CHMP/CVMP Opinions and approvals Postauthorisation activities, incl. variations QWP GMP Inspectors Group GCP Inspectors Group (Liaison with other regulatory partners) MRA (Liaison with other regulatory partners) QWP GMP Inspectors Group GCP Inspectors Group GXP inspection coordination (pre-submission meetings) GXP inspection coordination (review of applications) GXP inspection coordination (inspection requests) GXP inspection coordination (inspection reports, manufacturing authorisations, compliance statements, contribution to EPARs) Certification of medicinal products Periodic GMP inspections GCP inspections of pharmacovigi lance systems Sampling and testing Rapid alerts (Product defects)

6 The Regulatory Framework GxP Inspections

7 REGULATORY FRAMEWORK Council and Parliament DIRECTIVE 2001/83/EC & 2001/82 and Amendments Marketing applications And marketing of Medicinal products for Human and veterinary use REGULATION 726/2004 Establishing EMEA and Centralised Procedure Council and Parliament DIRECTIVE Directive 2004/9/EC Council and Parliament DIRECTIVE Directive 2004/10/EC Council and Parliament DIRECTIVE 2001/20/EC Clinical trials Commission DIRECTIVE 2005/28/EC Principles, detailed guidelines GCP NATIONAL LEGISLATION Commission DIRECTIVE 2003/94/EC & 91/412/EC GMP Detailed guidances Commission, and Agency published guidance, European, ICH & OECD origin

8 Common Principles Timetable

9 Timetable for Inspections Pre-submission ALIDATION OF THE MAA DOSSIER ADOPTION OF THE INSPECTION REQUEST Primary Evaluation D. 80 ASSESSMENT REPORT Stop Clock Secondary Evaluation Opinion Decision D.0 D.120 D.121 D.210 D.277 ANNOUNCEMENT TO THE APPLICANT (WITHIN 5 DAYS SINCE THE Pre-Authorisation FINAL IR SUBMITTED TO EMEA/CXMP BY DAY CONDUCT OF THE INSPECTION - IR SENT TO INSPECTEE - INSPECTEE 15 D. TO RESPOND Post Authorisation Phv INS. -Cause - Surveillance -System focused GCP: specific obligation, new extensions, new clinic data GMP: Cause Surveillance

10 Shorter timetables Some procedures have shorter timetables; Generic Applications Applications granted accelerated assessment If inspection requested during the assessment then there will be a clock stop and secondary evaluation phase

11 Common Principles Purpose of an Inspection

12 Purpose of an inspection To verify if the information provided in the application is reliable and Accurate and obtained in an ethical and legal manner (GCP) To verify and confirm compliance with Good Practices and/or Community law To review the performance of the quality assurance systems and study specific documentation of the applicants to gather experience investigate issues raised by the assessor during the assessment To investigate reported deficiencies Verification of GCP compliance surveillance Promotion and education opportunities

13 Common Principles Announcing, performing and reporting

14 Inspection announcement EMEA informs applicant of the adopted inspection request within 5 working days of the CHMP giving details of the inspection team and the fees. EMEA informs the inspectorates and finalises the designation of the inspection team (reporting and lead inspectorates) Inspectors contact applicant and sites to be inspected and schedule inspection dates and request any additional documents needed (e.g SMF, Module 3, SOP s etc.)

15 Performing for the inspection ithe inspectors make the arrangements with the inspectee and fix an inspection date, which should be carried out within the proposed timetable.

16 Fees Council Regulation 297/95 specifies fees payable for inspections Implementing rules for Council Regulation adopted by EMEA management Board set the level of the fees. Inspection fee per site inspected, and subdivided between EMEA and inspectorates; Travel expenses etc. are payable separately.

17 Composition of Inspection Teams iinspection team: Leading inspector(s) Scientific experts and / or a Rapporteur appointed on the advice of the Rapporteur and / or Co-Rapporteur. inumber of inspectors: Normally two inspectors Higher numbers would need to be justified.

18 Reporting the inspection i Inspection and transmission of the report: - At the end of the inspection, the inspectors make a report of the main findings to the company inspected. - The deficiencies observed are classified as critical or non-critical with references to EU legislation and guidelines such as the EU- Guide on GMP, to ICH guidelines and/or national legislation. - The IR is sent to the site with a request for comments on major factual errors, points of disagreement or remedial actions to be provided within 15 calendar days of receipt. - Responses are reviewed by the inspectors

19 Consequences Of GxP non-compliance For ongoing applications and authorised products Negative opinion Lost of certain data or trials Consequential restriction on claims in SPC Refusal, suspension or revocation of marketing authorisation Refusal, suspension or revocation of manufacturing authorisation For individual sponsors, investigators, CRO s, manufacturers or other involved parties/facilities Loss of revenue Loss of reputation Legal sanctions - civil and or criminal penalties at member state level Future surveillance

20 Specific Aspects Co-ordinating GMP Inspections

21 Co-ordination of GMP Inspections i Pre-authorisation: in order to complete the assessment process. i Legal basis: Article 8.2 (or 30.2 for vet medicinal products) Council Regulation 726/2004. i Responsibility for carrying out inspections rests with the Supervisory Authority i Supervisory Authority, which is defined as the Competent Authority of the MS in which the product is either manufactured or imported within the EEA. 2/20/

22 Co-ordination of GMP Inspections i Type of inspections: - GMP: - For sites located in third countries, where EU-GMP is unconfirmed (no satisfactory EU inspection in the last 2 years on same building, similar type of product and equipment. - Product & Process: - To assess Quality issues raised by Rapp/CoRapp during assessment of Part II of the application. - Can apply to all sites wherever they are located (EEA/Third countries)

23 Co-ordination of GMP Inspections Pre-authorisation GMP inspections GMP compliance for sites outside the EU Production / process issues from assessment of application So far 565 inspections (to Sep 2006): USA 73.1%, Switzerland 7.1%, EU 6.9 %, Puerto Rico 6.5%, Japan 3%, Canada 1.8%, Israel 0.4%, South Africa 0.2%, Singapore 0.4%, Australia 0.2%, South Korea 0.4% (pre-authorisation: 347 post-authorisation: 218) Post-authorisation GMP inspections Checks on technology transfer and process validation Routine inspections for compliance with GMP

24 Specific Aspects GCP Inspections

25 Co-ordination of GCP Inspections Triggered Targeted Issues identified by assessors or other information Routine Random No specific cause for concern in advance Range of applications to be selected and clinical trials within them

26 Co-ordination of GCP Inspections EU And third countries SPONSOR, CRO, Investigator, Laboratory/technical Facility, Manufacturer, MAH Systems and data/document verification

27 Co-ordination of GCP Inspections Pre-authorisation GCP inspections Verification of GCP compliance and data validity in clinical trials submitted triggered and random So far there have been 105 GCP inspections (to Sep 2006): EU/EEA/Switzerland 53%, USA (32%); GCP (86%), PhV (14%); Pre-authorization (74%), post- authorization(26%) Post-authorisation GCP inspections Type II variations involving extension of indication Monitoring of compliance with specific obligations, follow-up measures or pharmacovigilance obligations

28 Specific Aspects GLP Inspections

29 Co-ordination of GLP Inspections Co-ordination of the verification of compliance with the principles of GLP. Procedures adopted by the CHMP/CVMP in 2004 Covers Human and Veterinary applications So far there have been 2 GLP inspections for 1 centralised application on ad hoc basis and 7 GLP for 7 centralised applications using new GLP SOP. 6 in Canada 1 in EU

30 Co-ordination of GLP Inspections Inspection requests triggered by assessors, prepared by EMEA and adopted by CxMP For 3rd country(co)- Rapporteur MS to provide inspection resources; If EU, GLP monitoring authority of MS where lab located & experts if nominated Inspections are predominantly study audits although exceptionally facility audits can be requested.

31 Inspections Information in the Dossier

32 GMP Part 1A Application Form Annexes manufacturing licences, GMP Certificates, QP Declaration. Module 3.

33 GCP Application cover letter - List of inspections Module Statement concerning Ethical requirements Module 2 - Clinical Overview Module 5 -Individual Clinical Study reports

34 GLP Module 2 : Non-clinical overview Module 4 : Individual non-clinical study reports

35 Post-authorisation Inspections

36 GMP Inspections Co-ordination of routine GMP inspections The EMEA prepares a program of re-inspections in Third Countries (TC) for centralised products. Re-inspections are also adopted by the CxMP. MSs may provide feedback on the program (e.g. delegation, assistance from another MS, combination with national products). Inspections should be carried out at least every 2-3 years, unless a more frequent basis is recommended by the inspectors.

37 Pharmacovigilance Inspections Any MAH of a Centrally Approved Product can be subject to inspection. To obtain assurance that MAHs are complying with pharmacovigilance regulatory obligations the CXMP may request for a PhV inspection

38 Pharmacovigilance Inspections The objective of a PhV inspection requested by the CXMP is: To verify that the MAH has personnel, systems and facilities in place to meet their regulatory obligations for Centrally Approved Products; To confirm that the Pharmacovigilance system is functional, complies with requirements, and is consistent with the "Detailed description of the Pharmacovigilance system" submitted in the MAA dossier section To check whether the safety information included in a Centrally Approved Product dossier and related product information (SPC.. etc) appears credible and accurate, specially applicable to triggered inspections. To help MAH improve compliance To use the inspection results as a basis for enforcement action Inspections will be routine as well as targeted to MAHs suspected of being non-compliant. The results of an inspection will be routinely provided to the inspected MAH who will be given the opportunity to comment on the findings.

39 Contacting Inspections Sector For general questions concerning GMP: For questions concerning GMP inspections: For general questions concerning GCP: For general questions concerning GLP: To report a suspected product defect or recall: qdefect@emea.europa.eu Web :

40 SME Workshop THANK YOU FOR YOUR ATTENTTION