API Inspections in Emerging Markets: The EDQM Experience

Transcription

1 API Inspections in Emerging Markets: The EDQM Experience 18 October 2010 Sträter Life Science Gründungsymposium Dr Florence Benoit-Guyod, EDQM Inspector Certification of Substances Division European Directorate for the Quality of Medicines and Healthcare Council of Europe

2 Overview: The certification procedure, EU regulatory framework EDQM and the European authorities Collaboration between assessors and inspectors GMP for APIs in a globalised market The EDQM inspection program Statistics: activity review, compliance trends 2

3 The Certification Procedure Intended to be applied for the assessment of the quality of pharmaceutical substances with regards to the criteria of the Ph. Eur. monograph(s) It ensures that all possible impurities can be fully controlled by the requirements of the monograph(s) Additional benefits: Centralised assessment for APIs: attractive to applicants and National Competent Authorities Identification of potential divergent practices by national assessors may contribute to more consistent assessment approaches across Europe 3

4 Inspection Optional part of the Certification Procedure (Article 111 of Directive 2001/83/EC and Article 80 of Directive 2001/82/EC, Compilation of Community Procedures: EMEA/INS/GMP/313538/2006 ) Performed before or after the CEP is granted Aim: to verify the compliance with EU GMP Part II EU GMP Annexes (e.g. Annex 1 / sterile substances) Submitted dossier 4

5 Role of the National Competent Authority The Competent Authority may inspect an API manufacturer in order to ensure that the manufacturing authorisation holder of a medicinal product has fulfilled its obligations under Article 46 (f) and/or Article 50 (f) of the below mentioned Directives (Article 111 of Directive 2001/83/EC and Article 80 of Directive 2001/82/EC) NB: in contrast to medicinal products, API inspections are not carried out systematically 5

6 Responsibility of the marketing authorisation holder (MAH) APIs must be produced according to EU GMP (Directives 2001/83/EC and 2001/82/EC) It is the responsibility of the manufacturer to ensure EU GMP compliance of the active substance manufacturer Declaration of the Qualified Person (QP) of the manufacturer in the marketing authorisation application (and any subsequent variation) 6

7 Responsibility of the API manufacturer In the CEP application the API manufacturer has to declare: - Compliance to EU Good Manufacturing Practices (GMP) - Willingness to be inspected 7

8 Conditions for an inspection When requested by A Member State, EMA, European Commission EDQM A manufacturer 8

9 European Authorities EUROPEAN UNION, EUROPEAN COMMISSION, DG SANCO (HEALTH & CONSUMERS) EUROPEAN DIRECTORATE FOR THE QUALITY OF MEDICINES (EDQM) EUROPEAN MEDICINES AGENCY (EMA) GMP INSPECTORATES NATIONAL LICENSING AUTHORITIES 9

10 EDQM and the European Commission The European Commission gave a mandate to the EDQM to establish an annual program for API inspections (application of Directives 2001/82/EC and 2001/83/EC as amended) 10

11 EDQM and the EMA GMP/GDP inspectors working group Discussions of EU Regulations, GMPs, GDPs Management of MRAs in the field of GMP Management of the Community Procedures EudraGMP database access International API Inspection Pilot Program (2007) Gathers authorities performing significant number of API inspections outside their territories: FR, DE, IT, UK, EDQM, AU, US, IE Aim: to make best use of Inspectorate s resources Based on sharing inspection reports or/and performing joint inspections 11

12 EDQM and the GMP inspectorates Inspection performed by team composed of an EDQM inspector and an inspector coming from an EU/EEA or *MRA National Competent Authority Austria Czech Republic Denmark Finland France Germany Hungary Ireland Italy Latvia Netherland Romania UK Sweden Spain *Switzerland *Australia + WHO 12

13 EDQM and the licensing authorities: the certification procedure Assessment of the dossier: On the premises of EDQM (Strasbourg) Two rapporteurs for new applications External assessor and EDQM assessor Evaluation report (parts A, B and C) 13

14 EDQM and the licensing authorities: the certification procedure Report A Exhaustive critical review of the dossier Confidential (copy may be given to national authority on request) Report B Request for monograph update Drafted when necessary Report C Reference of applied GMP or QA system Inspection request / comments for inspectors Drafted when necessary 14

15 Collaboration between inspectors and assessors: issuance of report C Sterile Grade Inspection is routinely performed for any sterile substance Preferably prior granting the CEP Draw attention to a specific point; e.g. tray lyophilisation Suspicion regarding the dossier Inconsistencies in the data Suspicion of fake data Potential weak points: process-related or specification-related Starting material close to the final step is not prepared by the manufacturer itself + lack of information Complex or badly explained process steps Subcontracting some steps of manufacturing process Potential weak points: site-related Suspicion of low awareness and knowledge of the GMP principles Suspicion of risk of cross-contamination 15

16 Collaboration between inspectors and assessors: issuance of report C States if an inspection is requested or not Gives the rationale for the request Details the request: States which site should be inspected (if several sites) States the items to be checked Report C is then: Reviewed by the inspector Discussed with assessor if necessary Approved as an inspection request (with priority level) Fuels inspection programme 16

17 Collaboration between inspectors and assessors: shared tools Same department, same premises: daily, living, smooth communication fostered Common QA system (ISO 9001) Same database managing assessment and inspection Various working groups to share knowledge/approach: API starting material Recovery of solvents/materials Skip testing Atypical active substances 17

18 Collaboration between inspectors and assessors: benefits The collaboration between assessment and inspection at EDQM demonstrates several benefits: Most sustainable assessment of certification dossiers in combination with an inspection scheme Holistic approach via an effective discussion and communication of issues and appropriate feed back 18

19 GMP for APIs in a globalised market: the situation Customer side: In most of the «developped» countries, ICH Q7 is now implemented (e.g. EU, USA, Australia, Japan, Canada) + WHO and some PIC/S members Supplier side: keyplayers India and China have Their own GMPs and enforcement Several markets with specific requirements (developped, internal, emerging) 19

20 GMP for APIs in a globalised market: the challenge Select suppliers having an in-depth understanding and control of ICHQ7 GMP Importance of a detailed technical agreement Importance of traceability of the supply chain Keep regular connection with suppliers Overcome difficulties such as: distance, language, different mindsets (cultural / religious / historical aspects) etc 20

21 GMP for APIs in a globalised market: the challenge Quality, reliability of a supplier are important issues in supplier selection! Sustainability of GMP compliance and traceability should be monitored! 21

22 The EU GMPs for API: ICH Q7 Quality Management Personnel Buildings and Facilities Process Equipment Documentation and Records Materials Management Production and In-Process Controls Packaging and Identification Labelling of APIs and Intermediates Storage and Distribution 22

23 The EU GMPs for API: ICH Q7 Laboratory Controls Validation / Qualification Change Control Rejection and Reuse of Materials Complaints and Recalls Contract Manufacturers (incl. Labs) Agents, Brokers, Traders, Distributors, Repackers, and Relabellers APIs Manufactured by Cell Culture/Fermentation APIs for Use in Clinical Trials Glossary 23

24 EDQM Inspection Program: selection of sites According to EU guidance published by EMA: EMEA/INSP/GMP/313538/ 2006 According to a risk-based approach. Main criteria: o Request from the assessors (report C) o Sterile substances o Suspicions o Potential weak points Other criteria can also be taken into account o Inspection by equivalent authority o Several triggers involved o Regulatory environment of the manufacturing site 24

25 EDQM Inspection Program Elaborated in close connection with the national inspectorates, through GMP-GDP IWG / EMA Finally adopted by the CEP Steering Commitee Circulated to all EEA Member States Competent Authorities Shared within the API pilot program 25

26 Inspection Outcome According to the inspection results the company is quoted as compliant, borderline, non compliant Borderline status is only provisional: after assessment of the corrective action plan, the outcome is upgraded or downgraded to compliant or non-compliant Companies found compliant may be re-inspected / re-evaluated within 2-5 years 26

27 Inspection follow-up The initial report is sent to the company (6 weeks) The company must reply to the deficiencies (1 month) The replies should be fully documented and reflect actual measures in place Discrepancies with the CEP dossier specifically addressed and managed by the revision process at DCEP Final report is issued 27

28 Positive Outcome Prerequisite: any expected changes for CEP revision have been submitted an inspection attestation is delivered, stating the compliance with the CEP and with the EU-GMPs A GMP Certificate may be issued by the participating Inspectorate (EMEA/INS/GMP/871/04) 28

29 Negative Outcome In case of critical/major GMP deficiencies or in case of major deviation compared to the dossier (failure in the declarations and commitments) CEP(s) suspended or withdrawn on-going CEP application(s) rejected Suspension/Application rejection is Advised by the inspectors Discussed within the Certification Division (Internal Decision Board) Endorsed (Ad Hoc Committee) Manufacturer (and Holder if different) are informed A possibility of hearing is given 29

30 Negative Outcome Information published on the EDQM website CEP database Certification webpages PhEur Member States, EMA, EU Commission and local Inspectorate are informed Statement of GMP non-compliance is issued by the EEA Inspectorate 30

31 Suspension of the CEPs CEPs are suspended for a period of 2 years Lifting the suspension can only be done after an inspection with positive outcome Company is requested to apply within this timeframe for a re-inspection Based on a valid justification, the company may ask for an extension of this period 31

32 Suspension of CEPs: risk for customers /need for further actions Be able to answer questions from the national authorities Each national authority to decide for batch recall financial and reputation impact Need to have a back up supplier in the MA Need to have an efficient system to select and monitor suppliers 32

33 EDQM inspections: statistics End 2009: 195 inspections performed in 24 countries since

34 Statistics : locations 100% 90% 80% 70% 60% 50% 40% 30% Elsewhere EEA Asia other China India 20% 10% 0%

35 General trends in sites covered by EDQM inspections 32 sites covered by exchange of information (inspections by EEA inspectorates) 2 sites refused to be inspected ( suspension of CEPs) 35

36 General compliance trends Non compliant sites: 2007: 18% 2008: 21% 2009: 34% (10 sites out of 29 inspected) Fine-tuning of risk-assessment in the selection of inspection sites has improved EDQM s ability to identify sites with higher risk of non-compliance and to focus on them 36

37 2009 main GMP deficiencies Repartition of deficiencies Process equipment (5) 15% Materials management (7) / Storage & distribution (10) / Packaging / distribution (9, 17) 13% Production and IPC (8) / Rejection and reuse of materials (14) 10% Laboratory controls (11) 7% Compliance to CEP dossier and EP 4% Buildings & facilities (4) 17% Quality related matters (1 quality management, 3 personnel, 6 documentation, 12 validation, 13 change ctrl, 15 complaints and recalls, 16 contract manuf): 34% 37

38 Main GMP deficiencies Quality related matters Validation of processes: CPP not based on scientific rationale, micronisation not adressed Cleaning validation Qualification of equipment: lack of appropriate user requirement specification, weakness of water systems Quality review: not a quality tool for companies Change control / Deviation management: not a deep-rooted practice 38

39 Main GMP deficiencies Process equipment / Buildings and facilities Cleanliness Maintenance Materials management Traceability Key starting material vendor approval Storage 39

40 Some short term actions taken by companies prior inspections or audits Building walls Hiding compromising logbooks 40

41 Perspectives for EDQM inspections Further develop the risk-based approach when elaborating the programme Reinforce collaboration and sharing of information with EEA and International Inspectorates in order to optimise inspection ressources, through: Pilot program for exchange of information on API (EMA) Inspector working group GMP/GDP (EMA): EEA members Committee of officials of PIC Scheme (PIC/S): 36 members, 4 partners Confidentiality agreement with PIC/S, TGA Australia, USFDA EUDRA GMP database 41

42 Conclusions Finished products manufacturers must improve their ability to Select GMP compliant pharmaceutical ingredients suppliers Audit / monitor them accordingly Inspection remains a powerful tool to detect noncompliances and take necessary actions Close collaboration between assessors and inspectors is necessary Optimising inspection ressources is of paramount importance 42

43 THANK YOU FOR YOUR ATTENTION VIELEN DANK FÜR IHRE AUFMERKSAMKEIT 43