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GxP Inspections within the Centralised Procedure
Brendan CuddyInspections Sector
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
COUNCIL REGULATION 726/2004COUNCIL REGULATION 726/2004(CAP/EMEA)(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
• Majority of Inspections Sector operations are related to applications submitted to the EMEA (centralised procedures, pre&post-authorisation 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
Inspections Sector Activities
Inspections’ Contribution toCentralised Procedure
Submission & validation of applications
Assessment reports, clock stop
Scientific &Regulatoryadvice andguidance
CHMP/CVMPOpinions and approvals
Post-authorisationactivities, incl. variations
Harmonisationand Provision ofGuidance
PROCEDURES PRODUCT SPECIFIC
•QWP
•GMPInspectors Group
•GCP Inspectors Group
(Liaison withother regulatorypartners)
•QWP
•GMPInspectors Group
•GCP Inspectors Group
•GXP inspection coordination(pre-submissionmeetings)
•GXP inspection coordination
(review of applications)
•GXP inspection coordination
(inspectionrequests)
•GXP inspection coordination
(inspectionreports,manufacturing authorisations, compliance statements, contribution to EPARs)
•Certification of medicinal products
•Periodic GMP inspections
•GCP inspections of pharmacovigilance systems
•Sampling and testing
•Rapid alerts (Product defects)
•MRA(Liaison withother regulatorypartners)
The Regulatory Framework
GxP Inspections
REGULATORY FRAMEWORKREGULATORY FRAMEWORK
Council and ParliamentDIRECTIVE 2001/20/EC
Clinical trials
Council and Parliament DIRECTIVE 2001/83/EC & 2001/82 and Amendments Marketing applications And marketing of Medicinal products for Human and veterinary use
CommissionDIRECTIVE 2003/94/EC &
91/412/ECGMP
CommissionDIRECTIVE 2005/28/EC
Principles, detailed guidelines
GCP
Detailed guidances
Commission, and Agency published guidance, European, ICH & OECD origin
REGULATION 726/2004 Establishing EMEA and Centralised Procedure
NATIONAL LEGISLATION
Council and ParliamentDIRECTIVE
Directive 2004/9/EC
Council and ParliamentDIRECTIVE
Directive 2004/10/EC
Common Principles
Timetable
Timetable for InspectionsTimetable for Inspections
StopClock
Opinion
Decision
Pre-submission PrimaryEvaluation
SecondaryEvaluation
PostAuthorisation
D.0 D.121D.120 D.210 D.277
ALIDATION OF THE MAA DOSSIER
- CONDUCT OF THE INSPECTION
- IR SENT TO INSPECTEE
- INSPECTEE 15 D. TO RESPOND
ANNOUNCEMENT TO THE APPLICANT (WITHIN 5 DAYS
SINCE THE
ADOPTION OF THE
INSPECTION REQUEST
D. 80ASSESSMENT
REPORT
FINAL IR SUBMITTED TO EMEA/CXMP BY
DAY 150
Pre-Authorisation
Phv INS.
- Cause
- Surveillance
- System focused
GCP: specific obligation, new extensions, new clinicdata
GMP:
– Cause
– Surveillance
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
Common Principles
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
Purpose of an inspection
Common Principles
Announcing, performing and reporting
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.gSMF, Module 3, SOP’s etc.)
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.
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 sub-
divided between EMEA and inspectorates;– Travel expenses etc. are payable separately.
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.
Composition of Inspection Teams
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 beprovided within 15 calendar days of receipt.
- Responses are reviewed by the inspectors
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
Specific Aspects
Co-ordinating GMP Inspections
2/20/2007 21
i Pre-authorisation: in order to complete the assessment process.
iLegal basis: Article 8.2 (or 30.2 for vet medicinal products) Council Regulation 726/2004.
iResponsibility for carrying out inspections rests with the Supervisory AuthorityiSupervisory Authority, which is defined as the
Competent Authority of the MS in which the product is either manufactured or imported within the EEA.
Co-ordination of GMP Inspections
iType 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)
Co-ordination of GMP Inspections
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
Specific Aspects
GCP Inspections
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
Co-ordination of GCP Inspections
• EU And third countries
• SPONSOR, CRO, Investigator, Laboratory/technical Facility, Manufacturer, MAH
• Systems and data/document verification
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
Specific Aspects
GLP Inspections
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
• 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.
Co-ordination of GLP Inspections
Inspections Information in the Dossier
GMP
• Part 1A Application Form• Annexes – manufacturing licences, GMP
Certificates, QP Declaration.• Module 3.
GCP
• Application cover letter - List of inspections• Module 1.9 - Statement concerning Ethical
requirements• Module 2 - Clinical Overview• Module 5 -Individual Clinical Study reports
GLP
• Module 2 : Non-clinical overview• Module 4 : Individual non-clinical study
reports
Post-authorisationInspections
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, combinationwith national products).
– Inspections should be carried out at least every 2-3 years, unless a more frequent basis is recommended by the inspectors.
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
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 1.8.1
– 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.
Contacting Inspections Sector
• For general questions concerning GMP: [email protected]• For questions concerning GMP inspections:
[email protected]• For general questions concerning GCP: [email protected]• For general questions concerning GLP: [email protected]• To report a suspected product defect or recall:
• Web :http://www.emea.europa.eu/Inspections/index.html
SME WorkshopSME Workshop
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