New Frontiers in the Quality of Medicines

Transcription

1 New Frontiers in the Quality of Medicines Workshop Certification: How to use a Certificate (CEP) Moderators: Dr Jean-Louis Robert Prof Derek H. Calam EDQM International Conference June 2007 Strasbourg, France

2 How to use a CEP Mrs Hélène BRUGUERA Deputy Head Certification of Substances Division EDQM Conference, Strasbourg 06/ Summary The Certification procedure Recent developments/figures Some issues EDQM Conference, Strasbourg 06/2007 2

3 The Certification procedure EDQM Conference, Strasbourg 06/ The CEP procedure Show for a pharmaceutical substance (as required by Directives 2001/83/EC and 2001/82/EC): Suitability of the Ph. Eur. Monograph to control the quality of a substance Compliance with European regulatory requirements Created in 1994, scope enlarged Harmonisation of work - Protection of know how EDQM Conference, Strasbourg 06/2007 4

4 Scope of the procedure Substances covered by a specific Ph. Eur. monograph TSE risk products Not applicable for biotechnological products, products from human tissues, semi-finished or finished products, substances not included in Ph. Eur. Open to any manufacturer of these substances wherever in the world EDQM Conference, Strasbourg 06/ Recent developments EDQM Conference, Strasbourg 06/2007 6

5 Recent developments (1) Revision of Resolution: AP-CSP (07) 1 In line with Terms of Reference Revision of CEPs Suspension of CEPs Sending evaluation reports to Authorities Annexes deleted - formatting EDQM Conference, Strasbourg 06/ Recent developments (2) Revised «Content of the dossier for chemical purity» PA/PH/CEP (04) 1, 4R TLC methods in monographs to be replaced by quantitative methods Stability studies - need for accelerated studies Triethylamine - limit generally accepted Genotoxic impurities Other clarifications EDQM Conference, Strasbourg 06/2007 8

6 Recent developments (3) Renewal of CEPs: since 2006, only 1 renewal is necessary Sterile substances: evaluation of sterilisation data by EDQM Systematic inspection of the relevant sites «CEP on-line» (list of CEPs) changed EDQM Conference, Strasbourg 06/ Recent developments (4) EDQM Inspection program In compliance with Art. 111 of Directive 2001/83/EC and Art. 80 of Directive 2001/82/EC (Mandate of EU Commission) Communication: Technical advice procedure, Website, workshops, one-to-one meetings EDQM Conference, Strasbourg 06/

7 Recent developments (5) Transparency of CEPs: Additional impurities/solvents/catalysts with limits and methods Retest period, with storage conditions+container Use of substances of animal/human origin Production Section of monographs Omission of tests of the monograph when not relevant (TLC when replaced, specific solvent,..) Box of access/declaration of no changes EDQM Conference, Strasbourg 06/ Figures More than 3200 dossiers More than 2200 certificates granted About 500 TSE CEPs 750 substances or preparations 500 days/year of meetings in Strasbourg EDQM Conference, Strasbourg 06/

8 > 800 companies from 57 countries (1: India, 2: China, 3: USA) CEPs accepted in 35 countries + some observers Official acceptance by Health Canada (03/2007) EDQM Conference, Strasbourg 06/ > 100 manufacturing sites inspected in 22 countries (incl. China, India, Mexico) >12 cases with major/critical deficiencies EDQM Conference, Strasbourg 06/

9 Some issues: EDQM Point of View EDQM Conference, Strasbourg 06/ Some issues Deadlines! (1st assessment) Policy / Quality of applications Better communication with applicants/holders Better communication with authorities EDQM Conference, Strasbourg 06/

10 Some issues (2) Transparency of CEPs Alternative methods to the Ph. Eur Other?? Revision of CEPs Improve the system: reduce administrative work Work in cooperation with EMEA QWP and EU Commission EDQM Conference, Strasbourg 06/ Conclusion Feed-back welcome from: The Authorities (M. Dash) The Customers (M. Roesner) The Holders (M. Van Dalen) The Audience THANK YOU! EDQM Conference, Strasbourg 06/

11 Safeguarding public health Certification: How to use a Certificate Viewpoint of a Regulator Malcolm Dash Pharmaceutical Assessor Medicines and Healthcare products Regulatory Agency (MHRA), UK 14 th June 2007 Scope of Certification Active substances Sterile active substances TSE Excipients Herbals Malcolm N Dash Slide 1 14th June

12 Main Focus of Certification To ensure that all possible impurities from the particular route of manufacturing can be fully controlled by the tests of the pharmacopoeial monograph or, failing this, fulfilling this goal in combination with additional testing procedures provided by the manufacturer Malcolm N Dash Slide 2 14th June 2007 Transparency Publication of policies, procedures, content of dossier Availability of Report A to Competent Authorities Technical advice meetings Information included on CEP Malcolm N Dash Slide 3 14th June

13 High Value Information on the CEP Additional limits for impurities, catalysts, solvents Appended validated analytical methods Solvents used in last steps Sterile grade / review of validation data Optional re-test period and storage conditions Container/closure information Specific grades Statements on TSE status Malcolm N Dash Slide 4 14th June 2007 Impact of the Certification Process Wide international acceptance Effect on drug master files (DMFs) Content of the registration dossier Variations / notification scheme Facilitates new sources of active substance in supply chain - positive impact on product Quality Malcolm N Dash Slide 5 14th June

14 Benefits of Certification to Regulators Centralised evaluation and administration Minimises duplication of effort Consistent standards Facilitates monograph revision process On-line list of granted / suspended / withdrawn CEPs Malcolm N Dash Slide 6 14th June 2007 Strengths of Certification Process Assessors - Rapporteur / co-rapporteur - External expert assessors / chemistry expertise - Large input of assessors from Competent Authorities - 49 Chemical assessors (from 14 Member States) - 11 TSE, 14 herbal and 3 toxicology assessors EDQM secretariat - Consistency / links to Groups of Experts Published procedures & policies / How to submit Malcolm N Dash Slide 7 14th June

15 Strengths of Certification Process Steering Committee Technical Advisory Boards - chemical / TSE Links to QWP / SWP / Ad Hoc GMP Inspection Services Inspection programme Assessment in accordance with European guidelines Major input into monograph revision programme Malcolm N Dash Slide 8 14th June 2007 Inspection Programme Resourced by National Competent Authorities Risk-based approach Links into assessment process Rapid notification of suspension / withdrawal Malcolm N Dash Slide 9 14th June

16 Limitations of Certification to Regulators Dependent on availability of monograph Limited information on synthetic route What was considered during evaluation? Malcolm N Dash Slide 10 14th June 2007 Problems Experienced by Regulators Out of date CEPs submitted / revision whilst pending Regulatory burden from CEP revision Specification not provided Lack of transparency of analytical methods No stability data / re-test period in dossier No container / closure information Malcolm N Dash Slide 11 14th June

17 Future Development Mandatory stability data - agreed re-test period On-line Competent Authority access to current CEPs Quality-by-Design / PAT / Design Space concepts Herbals Malcolm N Dash Slide 12 14th June 2007 THANK YOU FOR YOUR ATTENTION Malcolm N Dash Slide 13 14th June

18 Industry s experience with the CEP EDQM Strasbourg June 2007 Overview Possibilities and Use of CEP for Generic Industry With the view of the API Industry View of a pharmaceutical MA holder Advantages and disadvantages 1

19 Pre-condition for a CEP EP Monograph Proof of the suitability of the correspondig test methods in the monograph Additonal Test methods for related substances Additional testing for residual solvents Re-test period Plan Application of marketing authorisation Qualified API suppliers Start of development for finished dosage form EP monograph available or under preparation Time Frame for API development DMF versus CEP 2

20 API development DMF compilation Specification, test methods CEP application versus DMF submission Process development Pilot batches EP Monograph under development?? Stability studies Application of Marketing authorisation Goal Marketing authorisation in time Planned application date DMF availability/versus CEP CEP procedure timing critical Consequences for API manufacturer DMF Possible influences on specification CEP one European specification 3

21 Marketing Authorisation granted Introduction of an alternative API supplier Variation procedure Comparability of the specifications Specifications identical Type I variation (A or B) Unlikely, usually Residual solvents different Type II In case of API supplier, holding CEP Type I variation, however in case of additional specification to the EP, e.g. residual solvent?? CEP revisions consequences to Marketing authorisations CEP revision following to variations in the dossier ( slight changes in way of synthesis) Submission of a CEP revision for MA based on a MRP, DCP Type I A variation Submission for MA s granted nationally reassessment of the new revision, additional data Consequences MA holder has to use new revision and previous revision API in parallel due to differences in approval time ( MRP, DCP versus national 4

22 Introduction of a CEP ivariation exchanging a DMF with a CEP MA with DMF, introduction of the CEP meanwhile granted (same manufacturer) DMF contains stability data and following retest period CEP introduction Type I A variation However in case CEP does not contain retest period, stability data of DMF still applicable. Possible Changes in shelf life specification or test method additional variation Stability data and retest period will remain in the dossier Co-operation R & D and production CEP pro s and con s Pro s One assessment In case of revision, one assessment No further assessment in MRP, DCP Harmonised specification Con s availability of EP monographs Submission of revision on national basis not harmonized 5

23 Summary Pre condition EP monograph available If yes, early CEP application clear priority Harmonisation of the regulations for variations appreciated Thank you 6

24 Organon 18-juin-07 HOW TO USE A CEP View of the holders Author Marieke van Dalen Date June 2007 Marieke van Dalen Senior Scientific project Leader within Organon API (holder of 22 CEPs) Company representative within CEFIC/APIC, head of the Regulatory Affairs working group for several years in the past Today's presentation based on personal experience, but also on experiences from other CEFIC/APIC members Organon presentation 1

25 Organon 18-juin-07 Why use a CEP? How to obtain a CEP How to keep the CEP valid Practical use of a CEP Related issues Recommendations Focus of this presentation is on chemical CEPs. TSE CEPs are also issued by EDQM, but these serve a different cause. TSE CEPs are used to show compliance with the EU requirement that the manufacturer of a medicinal product must take place in accordance with the requirements of the guideline on minimizing the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products. These CEPs can also be granted for materials not described in a Ph. Eur. monograph. Organon presentation 2

26 Organon 18-juin-07 Why use a CEP? A (chemical) CEP from a regulatory point of view is used to provide information on the drug substance in the pharmaceutical dossier. There is a choice: - CMC section of the dossier - reference to a Drug Master File - CEP (limited to products for which an EP monograph is available) The latter two options are meant to protect the intellectual property of the drug substance manufacturer. Why use a CEP? Points to consider when making this choice: Confidentiality of the information (if the information is to be used by third parties, inclusion in the CMC section is often not an option) Timelines (it takes time to get a CEP granted; a Drug Master File can be referred to as soon as it is submitted) Assessment (single -but difficult- assessment for CEPs, multiple assessment for DMFs / CMC sections) Ease of registration (better when using a CEP, e.g. when filing variations) Organon presentation 3

27 Organon 18-juin-07 Why use a CEP? Considerations often lead to choosing a CEP as the preferred option Using a CEP normally means that no or few questions on the drug substance will be raised during the evaluation (exception: items not covered by the CEP: particle size, retest period), hence no delays in the approval. The CEP thus is a great marketing advantage The variations guidelines favor the use of a CEP. Many changes, which would be type II when referring to a Drug Master File, are then Type Ia Why use a CEP? Experiences from industry: Although preference for the CEP system, DMFs are still very often filed as a result of the long timelines within EDQM. If you have a new product you like to have it marketed as soon as possible. Sometimes the marketing approval has been obtained before the CEP was granted! If you have the CEP in place the system works fairly well. Organon presentation 4

28 Organon 18-juin-07 How to obtain a CEP Clear guidance available on the dossier to be submitted. Assessment seems to be more stringent than single country assessments No difference in the evaluation between old/new products (e.g. stability data, residual catalysts, genotoxic impurities) Following certification, the monograph could be revised. The certificate serves as proof that that the Ph. Eur. monograph methods are suitable to adequately control the substance (provided it is manufactured according to the method described in the dossier). How to obtain a CEP Industry experience First assessment takes over 1 year! For old products, new guidelines are applied (although sometimes specifically excluded from the scope of the guideline) Difficulties with providing information on length of time on the market. Drug Substance producers can never be sure whether their product is actually being used on certain markets. Organon presentation 5

29 Organon 18-juin-07 How to obtain a CEP Industry recommendations: EDQM has published a list with the most common deficiencies. Read it carefully, and take those points into account when preparing your dossier. Share your knowledge: very often information is available which is not put in the dossier, whereas it could be worthwhile to do so. Since the main focus of the assessment is the suitability of the Ph. Eur. methods, be sure to address those! How to keep the CEP valid Clear guidance available on what to submit in case of changes. Every submission leads to the revision of the CEP With this revised CEP your customers need to file a variation (usually type Ia). Many authorities/customers will ask for a statement explaining why the revised CEP was issued. It may be worthwhile to send this to your customers together with the revised CEP Organon presentation 6

30 Organon 18-juin-07 How to keep the CEP valid Industry experience The current situation, where a CEP is revised, even though the text on the CEP has not changed, is the source of many questions/problems. According to the QWP this is necessary since EDQM can not assess the impact of a change on the specific marketing authorization. Timelines for revision are usually met. Problem for holder: when to implement the change. Questions raised when impurities/solvents are deleted from the CEP. Practical use of a CEP Always make sure that the access box is completed CEPs are accepted in a large range of countries, e.g. EU +, Australia, New Zealand, Canada. However, this is not a fixed list; some countries accept CEPs in some cases, but not in others (e.g. Turkey, South Africa). Not all countries accept the CEP as such, but ask for additional information (although sometimes covered by the CEP dossier) (requests for letters of access -next to the access box-, signed declaration on changes, TSE certificates, GMP evidence). This also holds for EU countries! Organon presentation 7

31 Organon 18-juin-07 Practical use of a CEP Some countries raise questions on points already covered by CEP assessment (residual solvents, impurity levels) Deletion of impurities from revised CEPs (because the monograph has in the mean time been adjusted) is apparently very confusing. Revision of CEPs treated differently in different countries (pushed to Type II variations, which is according to the guidelines only necessary in very few cases) Practical use of a CEP Industry experience In general CEPs are widely and easily accepted. As stated before some problems arise because not every country treats the CEPs similarly: France pushing a variation to a type II variation since the limit for palladium on the CEP was increased (from 1 to 2 ppm) Spain not willing to accept a CEP where a TLC method was mentioned for related substances Italy requiring additional information in the access box: position of the person who signs + GMP certificate Organon presentation 8

32 Organon 18-juin-07 Related issues Inspections (on basis of an EDQM priority list): applauded by CEFIC/APIC Lack of follow-up after suspension of CEPs by EDQM: huge concern. Apparently national authorities are not able to track which MAA s are linked to certain CEPs, and no link with DMFs that the same holder may have Recommendations Within EDQM Improve the timelines Use new guidance according to the scope of the guidance For revisions of CEPs: expand the list of notifications (not leading to a revision of the CEP). Organon presentation 9

33 Organon 18-juin-07 Recommendations Within EU Ensure that all countries within EU follow the same procedures, e.g. not asking for GMP certificates/tse certificates (which are already part of the CEP dossier) Ensure that the rapid alert when a CEP is suspended is followed-up adequately, that is the material is taken from the market. This represents a serious health risk. Organon presentation 10