How Bayer prepares for Pharmacovgilance Regulatory Inspections Dr Axel Röhrkasten Head Global GCP/PV System Audit Management Bayer Schering Pharma AG China Pharmacovigilance Forum 2009 September 21st, 2009, Beijing, China Global
Agenda Setting the scene Preparation of the Inspection Conduct of the Inspection Follow-up activities Recent trends Conclusion 2
y Health Authority PV Inspections Setting the scene A Pharmacovigilance Regulatory Inspection may be an extreme test of your capacity for delivery timely and proper responses on the company as a whole - Numerous document requests within several inspection days (to be collected from all around the world) 3
y Health Authority PV Inspections Setting the scene Types of PV Inspections - Routine To determine that the Marketing Authorization Holder (MAH) has personnel, systems and facilities in place to meet their regulatory obligations - Targeted Do not relate to specific concerns e.g. MAH has not previously been inspected Relate to specific concerns e.g. submission of poor quality or incomplete PSURs 4
y Health Authority PV Inspections Setting the scene Factors which may additionally trigger PV Inspections - Number of MAs held - MAH recently been involved in a merger or takeover process - Significant changes to PV System (e.g. new database system) - Number of products with known safety risks - Inspection history with specific non-compliances 5
y Health Authority PV Inspections Setting the scene Recent experience with PV Inspections at Bayer - FDA (Food and Drug Administration), the USA Health Authority - MHRA (Medicines and Healthcare products Regulatory Agency), the UK Medicines Agency - AFSSAPS (Agence Française de Sécurité Sanitaire des Produits de Santé), the French Medicines Agency - BfArM (Federal Institute for Drugs and Medical Devices)/ PEI (Paul-Ehrlich-Institute), li h t the German Medicines i Agency - Other country Health Authorities world-wide 6
y Health Authority PV Inspections Preparation Companies should have a global Quality System document covering Regulatory Inspections - At Bayer the following SOP covers all Pharmacovgilance & GCP Inspections (incl. audits conducted by Development Partners) 7
y Health Authority PV Inspections Preparation All quality processes (incl. Regulatory Inspections) should be managed in a centralized database - At Bayer one system exists to plan all Global activities and to collect, process, and report all quality data as part of a continual improvement process in order to improve regulatory compliance and efficiency - GREAT (TrackWise) is a web-based tracking software tool for electronically logging, managing, and trending quality issues and action items in accordance with cgxp standards 8
y Health Authority PV Inspections Preparation Notification of PV Inspection - Health Authority usually notifies sponsor several months in advance of inspection (However, on occasions, it may happen that inspections are conducted unannounced or announced only at short notice) - Recipient of inspection announcement immediately notifies relevant parties as defined in sponsor SOP i.e. Global at Bayer: CQA have an integral role in hosting and facilitating before, during and post regulatory inspection activities 9
y Health Authority PV Inspections Preparation IDRAC - collection of published Regulatory Affairs reference text (incl. translations) - e.g. Expert Reports 10
y Health Authority PV Inspections Preparation Frequently asked questions for Good Pharmacovigilance Practice - e.g. MHRA is regularly updating these Q&A news - e.g. MHRA Q&A news are published on http://www.mhra.gov.uk/howweregulate/medicines/inspectionan dstandards/goodpharmacovigilancepractice/frequentlyaskedqu estions/index.htm 11
y Health Authority PV Inspections Preparation Inspection Metrics - e.g. MHRA is currently producing metrics reports every 6 months July to December 2006 January to June 2007 July to December 2007 January to June 2008 July to December 2008 - e.g. MHRA metrics reports are published on http://www.mhra.gov.uk/howweregulate/medicines/inspectionan dstandards/goodpharmacovigilancepractice/news/index.htm 12
y Health Authority PV Inspections Preparation Inspection Metrics (cont.) - e.g. Types of Critical Findings identified during Inspections (Source: MHRA Metrics Report July December 2008) A high proportion of critical findings were identified in the area of case processing during this period. 13
y Health Authority PV Inspections Preparation Good Pharmacovigilance Practice Guide e.g. Purple Guide - Compiled by the MHRA - Intended to complement currently available EU legislation and guidance - Provide practical advice to key stakeholders, in particular Marketing Authorization Holders, about achieving an appropriate system of Pharmacovigilance Contents: 1. EEA Qualified Person Responsible for Pharmacovigilance; 2. Management of Pharmacovigilance Data; 3. Spontaneous Case Processing; 4. Literature Searching; 5. Periodic Safety Update Reports; 6. Evaluation of Safety Data; 7. Risk Management Plans; 8. Reference Safety Information; 9. Quality Management System; 10. Interactions Between Pharmacovigilance and Other Functions; 11. Contracts and Agreements; 12. Safety Reporting for Clinical Trials; Annexes 14
y Health Authority PV Inspections Preparation Inspection Committee established - Represented by appropriate functions, main driver CQA - Tasks: Define Action Plan to prepare for inspection Ensure execution of actions Identify key sponsor contact to inspector Determine personnel to be present during inspection 15
y Health Authority PV Inspections Preparation Inspection Committee Action Plan Issues - Action any outstanding issues known for the system/facility to be inspected - Review files and organization documents for completeness and validity - Organize and update files and documents as appropriate - Review audit reports, if available 16
y Health Authority PV Inspections Preparation Inspection Committee Action Plan Issues (cont.) - Review any previous inspection documentation from the inspectorate, if relevant - Consult previous final summary reports of any relevant previous inspection to implement improvements, if applicable - Develop a pre-inspection audit plan, if required - Perform a pre-inspection audit, Mock inspection, if required - Other considerations 17
y Health Authority PV Inspections Preparation Briefing of sponsor staff - How to behave during an inspection Show professionalism during the inspection Friendly behavior in a spirit of partnership Interest in the inspector s s comments and recommendations Use the inspector s expertise for problem solving React quickly to requests 18
y Health Authority PV Inspections Preparation Briefing of sponsor staff (cont.) - How to behave during an inspection Reactions to questions Be clear of questions asked Answer known: quick and to the point Answer not known: admit it and show willingness to find out the answer Not sure. Ask for time to think about it and take the time you need No opinions, do not speculate, responses based on facts 19
y Health Authority PV Inspections Preparation Carefully yprepare p requested pre-inspection p PV documentation for Health Authority, e.g. - Description of Pharmacovigilance system - Procedural documents (e.g. SOPs/OMs) - Organograms - CVs, job descriptions - Contracts and agreements - Line listings - PSURs for selected products - etc. 20
y Health Authority PV Inspections Preparation Logistics - Inform all relevant sponsor staff of inspections - Inform all relevant external parties of inspection - Ensure equipment requested by inspector is available - Ensure translation of documents, if required for foreign inspections - Arrange for translator to be present during inspection - Arrange practicalities as necessary (travel, communication lines, etc.) - Make suitable catering arrangements 21
y Health Authority PV Inspections Conduct Inspectors Scribe Runner Inspector Inspector in same room Individuals in backroom : as defined; decision as to which individuals and which documents are made available to inspector(s) 22
y Health Authority PV Inspections Conduct Internal Procedures - Scribe to map relevant discussions - Channeling any request via Scribe Runner to gather requested information - Backroom personnel to support interviewees and to prepare requested documentation: Copies are marked and stamped confidential to distinguish from originals i and to ensure confidentiality A duplicate set is made for the company A document log is maintained 23
y Health Authority PV Inspections Conduct 24
y Health Authority PV Inspections Conduct Interviews - Generally very detailed and probing - Large numbers of staff may be interviewed, even in groups - Non PV staff interviewed (e.g. Sales Reps, Webmasters, Security, Medical Information, Regulatory Affairs, Product Quality) - Focus on interfaces (e.g. reconciliation of data) - Course of interview may trigger number of requests for documentation 25
y Health Authority PV Inspections Conduct Potential PV Inspection Agenda Day 1-4 Opening Meeting Roles and responsibilities of the EU/EEA Qualified Person Interactions with Medical Information Processing and follow-up of spontaneous ADR reports Interactions with Product Quality Interactions with Regulatory Affairs Clinical Trial Safety Monitoring and PASS studies PSUR and ASR production Proposed time Staff to be interviewed 26
y Health Authority PV Inspections Conduct Potential PV Inspection Agenda (cont.) Day 1-4 Safety signal detection and ongoing product safety review Processing and follow-up of literature t searches Safety database: validation, change control, back-up, security, maintenance & disaster recovery Management of PV SOPs and policies/procedures and PV training QA audits of the PV system Closing meeting Proposed time Staff to be interviewed 27
y Health Authority PV Inspections Conduct Daily Wrap-up p Meetings - With inspector(s), if possible: Clarification of outstanding issues/pending requests of documentation Agreement on agenda for next day (if different from original plan) - Internally: Determination of actions and definition of responsible persons 28
y Health Authority PV Inspections Conduct Closing Meeting - Inspectors will provide general overview of the outcome, address specific findings, and might offer advice - Sponsor has the chance to clarify inconsistencies and provide appropriate response to all observations - Sponsor should make no attempts to whitewash known deficiencies or weak points - Timeframe for written response defined d by Inspectors - Inspectors may take documentation with them 29
y Health Authority PV Inspections Conduct Findings and Observations - Generally 3 categories, i.e. critical, major and other/minor - A critical finding may trigger an early re-inspection (e.g. MHRA - within 12 months) Inspection Report - Inspectors usually issue inspection report several weeks/months after inspection - Sponsor is expected to reply on inspection report to Health Authority in time 30
y Health Authority PV Inspections Follow-up Findings and Observations Format of response, e.g. MHRA - Response Corrective Action Preventative Action http://www.mhra.gov.uk/howweregulate/medicines/inspectionan dstandards/goodclinicalpractice/index.htm 31
y Health Authority PV Inspections Follow-up Corrective and Preventive Action (CAPA) Process - Inspection Committee at Bayer agrees on appropriate CAPA activities and prepares response to Health Authority - Responses must be realistic in both content and timelines - CAPA Compliance Manager monitors status via GREAT and escalates agreed actions which are not progressing on schedule - Database support assures systematic measurement of CAPA effectiveness - Trend reports across several PV inspections and internal PV audits support continuous process improvement 32
y Health Authority PV Inspections Recent trends MHRA - MHRA launched their new risk-based inspection program in April 2009 - It is now considered that the scope, frequency and depth of inspections should be dependent on how organizations take responsibility for their own compliance with the regulations - Companies to complete self assessment questionnaire once a year (not mandatory, but otherwise automatic high risk ranking) - Individual algorithms for each of the GxPs (GLP, GCP, GDP, GMP & GPvP) - Completed compliance reports were expected to be submitted to MHRA by 30 June 2009 (later extended to 01 September 2009) 33
y Health Authority PV Inspections Recent trends MHRA (cont.) - Companies will not be given the precise risk score, only a relative ranking of high, medium or low risk - Inspections are prioritized for companies within the high-risk category - For control purposes, a small number of organizations from the other categories will also be randomly selected - The inspection process itself will be largely l indistinguishable i from that followed in recent years http://www.mhra.gov.uk/howweregulate/medicines/inspectionan dstandards/goodpharmacovigilancepractice/riskbasedinspectio ns/index.htm 34
y Health Authority PV Inspections Recent trends Harmonizing EU Inspection Processes - First meeting of the EU Pharmacovigilance Inspectors Working party was held in July 2008 - Joint inspections are occurring with other Member State Inspectorates in the EU and in third countries EMEA, FDA launch joint GCP inspection initiative - A bilateral initiative aimed at maximizing resources for Good Clinical i l Practice (GCP) inspections was recently announced by the European Medicines Agency (EMEA) and the US Food and Drug Administration (FDA) and was said to start with an 18- month pilot phase on September 1st, 2009 (incl. informationsharing and collaborative GCP inspections) 35
y Health Authority PV Inspections Conclusion and always remember that the goals of the company and of the inspectors are the same to protect public health 36
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