Summaries of the Parallel Question & Answer Sessions and of the Conference

Transcription

1 1 st EFCG Pharma Business Conference Barcelona, April 2006 Summaries of the Parallel Question & Answer Sessions and of the Conference This document provides summary and detailed information from the parallel Q&A sessions plus an overall summary of the conference as presented by Guy Villax, Conference Chairman. A. Parallel Question & Answer Sessions - Summary There were 5 separate parallel Q&A groups of ~25 delegates each organised by language, viz, French, German, Spanish and two English-speaking international groups. Each group was asked to answer the same 3 questions, which had been preselected by the delegates from a list compiled by EFCG (from delegates, regulators, EFCG and APIC members). Group answers to each question were recorded in English on a flipchart. The group Chairman translated the French answers into English. All the answers are attached (Annex A). At the end of the sessions, the Group Chairmen and Rapporteurs met with the Conference Chairman and together agreed a summary of the sessions. The Conference Chairman immediately presented this to the delegates, with a promise that a document containing the Summary and Annex A would be ed to all delegates. Summary of Feedback from all Q&A Sessions The issues raised by the questions were: 1. Flexibility 2. Reticense 3. Sanctions 4. Whistle-blowing 5. Consistency of Inspections 1. Flexibility - If Directive 2001/83 (as amended) has been transposed into MS Law... o Germany: transition period (explicit) o Dont wait for it to be transposed, we will inspect as if... - Supplier Qualification to back-up the choice of approved source(s) SOP o An audit is an element among others o Risk assessment / Risk based - User of API must know well his API manufacturer 1

2 - ie save resources: The QP may not need to have an Audit and a GMP certificate of the same year to take a view... - The QP must follow its SOP, that results in having a sound justification for his view this needs to meet the scrutiny of inspectors - An audit plan must be in place, must show commitment and intent to comply - Some group: with evidence that it has started, - With or without Law: Any new supplier MUST be audited within the context of a variation. - Different national audit implementtaion requirements complicates matters; (transposed Law may or may not specifically require an audit) free circulation of goods (parallel imports) may negate the QPs commitments - Share information through databases - Germany: Difficult to get GMP Certificates (competitive diasadvantage) 2. Reticence - No reticence, only now all MS have legal mandate - Not enough resources (inspectors and training) - No coordination - Culture barrier - Cost - Scale of issue needs international collaboration - Name and Shame - Health risk indices show greater risks in India and China we propose that the Trigger Guidance Document be used to do more inspections in high risk countries; costs/resources to be obtained by user fees. - Europe has no system to trace APIs used in Europe (such as NDC Nº system) 3. Sanctions (after the deadline) - Case by case - Responsaibility of AM holders is expanded from final dosage form to production process of API - Inspectors will consider dates (eg recent or old MA, upcoming 5 year renewal) - If false statements (ie Reality not equal to Filing; not an issue of meeting specs) then MA is invalid consequences depending on the magnitude of the falsehood can vary from warning to suspension of activities - EU has no system to follow this up o Many countries, free movement, no tracking system 2

3 4. Whistle-blowing - Unanimity - Contact your Health Authority 5. Consistent approach across EU Inspections - Primarily consistency is within each authority through o Training of the inspectors o Quality Control during inspections / period evaluation - PIC forum membership - Use of PIC aide-mémoire by all agencies in all MS B. Summing-Up of the Conference - Guy Villax, Conference Chairman 1. The Issues - Clarifications - Attendance - Legislation Old / New - The QP - Traders & Middlemen - Audits and reports - The GMP Certificate - CEPs - EDQM - Communication 2. Clarification - 80% of APIs coming from India and China o By volume o Includes OTC APIs o Number often quoted (including by Authorities) - Generics today >50% in number of prescriptions - Generics today vast majority of all medicines worldwide in number/volume - Under patent medicines are ¾ of the world value - Generics growing at 15% per year in value - Under patent medicines growing at 8% per year in value - NUMBER OF PATIENTS CORRELATES TO VOLUME 3. Attendance participants o Pharma 62 o API 28 o Regulators 20 3

4 o Traders countries 4. Old Legislation - Considerable confusion between Suppliers and Manufacturers - an indicator that at some point in time it was accepted that Manufacturers name not always known at odds with Q7a 5. New Legislation - Legislating: o Directives March 2004 o Deadline for transposition October 2005 o 2001/82 and 83 as amended not yet transposed! - Does this show commitment? Legislating is the easy part... - Slow so that: this is better / better harmonized? - Slow because lacking in commitment? - Some CA MS demonstrate that resources are being escalated to match new requirements: eg F, SP 6. The QP (Qualified Person) - Cornerstone of the pharma quality architecture in the EU - Flawed? o QP not personally liable o Only subject to fines.. - Different from financial auditors... o Are investors to be better protected than patients? - Are the new responsibilities resulting from the new requirements being communicated to the QPs across the EU? 7. Traders and Middlemen - Authorities appear unaware of the true dimension of this commercial reality - Suppliers versus Manufacturers - Middle-men may tend to: 4

5 o o obscure the relationship, reduce traceability, limit technical dialogue, frustrate change control information affects accountability 8. The Audit - The Audit report is only one element among many on which the QP must form his view, his view must be taken following an SOP, he may need an audit report... - Audit report format and contents o Who can do the audit? Whether it lists facts? Whether it has a conclusion? Is unlikely to ever be defined It s format will be whatever does the job, and is seen to be credible and solid per the QP s view; a view influenced by the standard set by the inspectors - Audit report format will be an issue o some past experience... Danish client... o Quantification enabled format - It will need to stand up in court - Ít will need to be backed up by a contract 9. The Audit - Downsides - Authorities have access to the report o Different from FDA s 5 decade tradition o So unlikely to be as good a document as in the past... - Traders now sell API kilos with o Certificates of Analysis, and o Audit report The GMP Certificate - Given that the format requests that active substances be listed as object of the inspection - inevitable that the inspection be product oriented - Depth and detail on check that Filing = Reality depends on inspector training and any guidance, Aide Mémoire they may have. 11. CEPs - EDQM - EDQM s CEP system is a major success: 2000 in existence. o Resource efficient o Cost efficient savings across Europe - But 5

6 o o EDQM provides an aura of credibility that is may not be unjustified CEPs are often assumed to represent that the filing = reality: if such representation was good enough for EDQM, then good enough for the QP... - No harmonized position as to what CA in MS do when they get a letter saying CEP suspended - No clarity as to what should EDQM do when they have 20 CEPs from a company that just received a Warning Letter from FDA where there is indiciae of fraud 11. Communicate - Associations should support communication of best practices... Join APIC! Enjoy the Intranet... - An example of a typical APIC communication From: abo@cefic.be [mailto:abo@cefic.be] Sent: quinta-feira, 13 de Outubro de :15 To: Annick Bonneure; + All APIC Members & contacts (>150 in total) Subject: APIC Members Extranet Forum - New Response Dear Wxxxx, A response to your message entitled Shelf-life solutions and reagents has been posted to the APIC Members Extranet Forum by Annick Bonneure. The response is: The two are often unrelated. For example, CaCl2 is very hygroscopic, but this plays no role once in an aqueous solution. In this case, the solution will be more stable. Solids that may hydrolyse will be less stable in solution than as a solid. Therefore, especially for analytical reagents, shelflifes should be based on actual tests of the aged solutions, without taking into account the stability of the original solid salt. Common sense should also be used, for example, a full one litre bottle containing 0.01N NaOH will be more stable than a bottle containing 50 g (CO2 absorption, evaporation etc...) I don't know of any guidelines on the subject. Henri Leblanc To view the question and all its responses, please visit If you now wish to close this message to future responses, please visit and mark your message as complete. 6

7 This has been sent via the APIC Extranet Summary - We will always have diversity in Europe - Doing things right, takes time - Putting pressure also helps, and not just in hydrogenations o We need the new requirements to have Business Impact soon - Lots of good questions - Progress on several answers - Lots of sharing of information - Lots of collaboration between all stakeholders -... summary paper in May - Thank you everyone See you next year 13. Acknowledgements - especially to Chris Oldenhof, DSM Anti-Infectives Thank you. For more information, please contact: Guy Villax gvillax@hovione.com Tel: Tony Scott, Adviser Specialty & Fine Chemicals, Cefic ts42@supanet.com Tel: Pieter van der Hoeven, Business Groups Manager, Cefic pvd@cefic.be Tel: This presentation and EFCG's final report on the responses to the benchmarking questionnaire will become available in June at 7

8 ANNEX A PARALLEL QUESTION & ANSWER SESSIONS QUESTION 1 What flexibility exists regarding the deadline for completion of all API? supplier/producer audits by MA holders/dosage form manufacturers? ANSWERS A1. GROUP 1 - No flexibility for GMP compliance - No API is accepted with no GMP compliance - For audits, a program is required based on risk analysis - However, different national audit implementation complicates life o Capacity of API manufacturer to be audited o Free circulation of goods in EU A1. GROUP 2 - No deadline in German-speaking countries today - Implementation ongoing (transition period) - Difficulties to get GMP Certificates from German authorities (competitive disadvantage) A1. GROUP 3 - Agency representatives: There is no deadline according to the Directive. Judgement should take into account the means put into place by the producer (Audit new supplier, risk analysis) - Other answers: Key: P = Pharma Industry; A = API manufacturer P. Make planning based on risk analysis A. Ask GMP Certificate (x2) P. Install means / risk analysis (supplier / substance) Acceptance of audits by agents P. Idem + history of inspection Screening MP A Audits to organise P. Number of audits / feasibility Assessment in accordance with level 8

9 Additional investigation See audit P. State of the sites - Quality history / Certificates - All information on audits P. New suppliers Audited Other suppliers? Limit API Excipient? P. Planning / Risk assessment Additional resources? Collect evidence of GMP e.g. FDA A1. GROUP 4 - No derogation of obligation for the Directive - Demonstration of intent to comply via an audit programme using a risk-based approach A1. GROUP 5 - No actual deadline on audits - There should be a supplier evaluation plan. Audits are just part of the evaluation. Plan for audits should be in place, progress with audits should be concrete QUESTION 2 Why is there so much reticence from inspecting in India and China where 80% of EU APIs come from? Why is the obvious issue avoided? ANSWERS A2. GROUP 1 - It is the MA holders / Final Dosage Form (FDF) manufacturers who audit, not authorities, except in health risk. - However, there are health risk indices from India/China. Therefore, we propose new EU legislation to carry out (authority) inspections in risk countries - Improve communications (Re: Inspections) between countries, make it public if negative A2. GROUP 2 - Insufficient resources especially qualified inspectors for API production - Possible solution: outsourcing, independent agency - Global markets require a global standards 9

10 A2. GROUP 3 - Agency representatives: - There is no reticence, but there is a lack of European coordination. - 3rd Party audits are accepted under conditions. - P/A: o Resources / Costs o Need for support from the sector (mutualisation of audits) A2. GROUP 4 - No reticence - Until November 2005 some Member States did not have legal authority to inspect outside region - Suggested Heads of Medicines Agencies be asked to take action - Scale of the issue need international collaboration, for which a lot is already in place within authorities (EMEA, National authorities, FDA etc) A2. GROUP 5 - There is no reticence by inspectors to inspect in Asia. MHRA and EDQM already do that. - The Inspection Trigger Guidance Document is the way to set inspections. - Not a matter of reticence but of resources QUESTION 3 What will be the sanctions against MA holders and dosage form manufacturers respectively if APIs are used from suppliers / producers not audited after the deadline has passed? ANSWERS A3. GROUP 1 - Legislation in Spain includes sanctions - Depends on case and can vary from warning to temporary suspension of activities A3. GROUP 2 - Responsibility of MA holders expanded from final dosage form to production process of API - Invalid statement regarding API production process (= quality) results in invalid marketing authorisation (MA) - Consequence depends on severity A3. GROUP 3 10

11 - Agency representatives: o There is no deadline regarding verification but some dates / events to consider: o Renewal of the MA - Suppliers GMP statements o New suppliers o Sanctions: Case by case (Evaluation) - P. Risk of withdrawal of MA. A3. GROUP 4 - Sanction proportionate to the potential damage (risk) - Examples include QP and/or MA holder being suspended A3. GROUP 5 As it was clear from answers to Question 1 that there is no deadline, the question was changed into: What will be the sanctions against MA holders and dosage form manufacturers respectively if APIs are used from suppliers / producers not audited when the authorities would definitely expect a supplier evaluation plan to be running with GMP audits already started. - Sanctions are possible but not purely based on not having audited. - Sanctions more likely if there is evidence that the API quality is at risk. - Possible sanctions are withdrawal of MA and Product Recall. QUESTION 4 What actions exactly should a company take when it possesses information on the use by others of non-compliant APIs for the manufacture of medicinal products for the EU market? ANSWERS A4. GROUP 5 - The company should inform the local authorities. - There could be sensitivities regarding competitors. QUESTION 5 What guidance to inspectors is given regarding the new regulations / guidelines? 11

12 ANSWERS A5. GROUP 5 - One Member State: Training / guidance is given to inspectors; single approach within the agency. - Other Member State: Inspectors are given info to have a common approach - Third Member State: Aide Memoire for inspectors - PIC/S Forum: o Reviews training process o Evidence of training o Periodic audit of performance of inspectors for consistency QUESTION 6 What will be the sanctions and measures to be taken against an API manufacturer, API trader, dosage form manufacturer, MA holder respectively when as a result of an API inspection a CEP is withdrawn or other serious non-compliance and/or fraud is detected? ANSWERS A6. GROUP 5 - Assess each case for criticality - CEP would be cancelled: DMF or GMP critical - There needs to be a transparent EU system installed to inform other authorities of serious compliance issues with APIs and to enable them to take action QUESTION 7 Is there a possibility for a company to join inspectors during inspection of another company, with the aim to get familiar with the standards and approach used? ANSWER A7. GROUP 5 - No, highly unlikely. QUESTION 8 Can national inspectorates issue API GMP Certificates? 12

13 ANSWER A8. GROUP 5 - Yes END 13