international conference quality of active pharmaceutical ingredients hyderabad, 5-6-7 september...
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Florence Benoit-Guyod, Sept ©2009 EDQM, Council of Europe, All rights reserved 3 Inspection An inspection may be part of the Certification Procedure The inspection is performed either before or after the CEP is granted The inspection aim is to verify the compliance with the submitted dossier and with the EU GMP Part II For sterile substances compliance with Annex 1 EU GMPTRANSCRIPT
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International conferenceQuality of Active Pharmaceutical Ingredients
Hyderabad, 5-6-7 September 2009API Inspections: the EDQM experience – 7 September 2009
Florence Benoit-Guyod, EDQM InspectorCertification of substances Division, EDQM
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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 and contamination 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
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Inspection• An inspection may be part of the Certification
Procedure• The inspection is performed either before or
after the CEP is granted • The inspection aim is to verify the compliance
with the submitted dossier and with the EU GMP Part II
• For sterile substances compliance with Annex 1 EU GMP
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Role of the National Competent Authority
• The Competent Authority may carry out an inspection of an active substance manufacturer in order to ensure that a 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)
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Conditions for an inspection• When requested by a member State,
EMEA, European Commission or EDQM (if there are grounds for suspicion of non-compliance, need to verify data submitted)
• When requested by the manufacturer itself
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Responsibility of the manufacturer
• In the CEP procedure the manufacturer has to declare:- Compliance to Good Manufacturing Practices (GMP) - Willingness to be inspected
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EDQM Inspection Program• In application of Directives 2001/82/EC and
2001/83/EC as amended, the European Commission gave a mandate to the EDQM to establish an annual program for inspections
• Inspections are performed inside and outside Europe and involve manufacturing sites and brokers/distributors holding CEP(s)
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EDQM Inspection Program• The draft program is circulated to the Member
States for comments and presented to the GMP/GDP Inspectors Working Group at EMEA for discussion.
• The program is finally adopted by the CEP Steering Commitee.
• The final program is circulated to all EEA Member States Competent Authorities
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Selection of the sites• Done in accordance with the EMEA guidance
EMEA/INSP/GMP/313538/ 2006• According to a risk-based approach:
- main criteria: request from the assessors- sterile substances- inspection by equivalent authority- several triggers involved- regulatory environment of the manufacturing site
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How the system works• Inspection performed by team composed of an
EDQM inspector and an inspector coming from an EU/EEA or MRA National Competent Authority
• The compliance to the submitted dossier and to the EU Good Manufacturing Practices Part II is verified
• An inspection report is issued within 6 weeks• Immediate actions are taken in case of major or
critical deficiencies
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Inspection Outcome• According to the inspection results the
Company is quoted as compliant, borderline or non compliant.
• Companies found compliant may be re-inspected/re-evaluated within 3-5 years depending on the numbers and classification of deficiencies found.
• Companies found borderline may be re-inspected earlier (about 2 years)
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Inspection follow-up• The company must reply to the deficiencies
found within one month from the receipt of the inspection report
• The replies should be fully documented and reflect actual measures in place
• Discrepancies with the certification dossier are specifically addressed and managed by the revision process at DCEP
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Positive Outcome• In case of positive conclusion of the inspection,and
if any expected changes for CEP revision have been submitted, an inspection attestation is delivered, stating the compliance with the CEP and with the GMP
• A GMP Certificate may be issued by the participating Inspectorate (EMEA/INS/GMP/871/04)
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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) the corresponding CEP is suspended and/or on-going CEP application is rejected
• Suspension is endorsed by an Ad Hoc Committee• All PhEur Member States/Observers/Partners,
EMEA, EU Commission and local Inspectorate are informed
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Negative Outcome• Information published on the EDQM
website (CEP database and Certification webpages)
• Holder and manufacturer are informed and a possibility of hearing is given
• Statement of GMP non-compliance is issued by the EEA Inspectorate
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Suspension of the CEP• With effect of 2009 the CEPs are suspended
for a period of two years• 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• Lifting the suspension can only be done after
an inspection with positive outcome
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Statistics 1999-2008Number of EDQM inspections per year
05
101520253035
Outside EU/EEAEU/EEA
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Statistics 2004-2008: locations
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
2004 2005 2006 2007 2008
ElsewhereEEAOther Asian countriesChinaIndia
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Statistics 2008Geographic location of inspected sites - 2008
India32%
China46%
Other Asian countries
11%
EEA7%
Elsewhere4%
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General compliance trendsNon compliant sites:• 2007: 18%• 2008: 21%• 2009: 35% (updated to June)
This is the result of the ability of EDQM to identify sites with higher risk of non-compliance and to focus on them
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2008 Review• 28 inspections performed• 2 refusals of inspection• 6 sites non GMP compliant • Results: 16 CEPs were suspended and
9 dossiers blocked (the current policy is now to withdraw the application)
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2009 Review (end June)• 17 sites inspected (9 China, 7 India, 1 Hungary)• 6 sites non compliant• 4 sites borderline (follow-up on going)• CEPs suspended: 8• Dossier closed: 2• CEPs withdrawn after suspension due to negative re-
inspection: 2• Outcome: 35% of the sites were found non compliant;
an additional 18% has a borderline level of compliance
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2008 main GMP deficienciesRepartition of deficiencies - 2008
Compliance to CEP dossier & EP
6%
Production & IPC, Rejection & reuse of
materials (chapt.8 &14)5%
Buildings & facilities (chapt.4)
14%Process equipment (chapt.5)
21%
Materials management, Storage & distribution, Packaging (chapt.7,10,
9, 17)18%
Quality related matters (chapt.1, 3, 6, 12, 13,
15, 16)27% Laboratory controls
(chapt.11) 9%
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2008 main GMP deficienciesQuality related mattersValidation of processes, qualification of equipment,
quality review, change controlProcess equipment, buildings and facilitiesCleanliness, maintenanceMaterials management Traceability, key starting material vendor approval,
storage
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Conclusions• Experience shows that the inspection
remains a powerful tool to detect non compliant manufacturers
• Finished product manufacturers must improve their ability to select API manufacturers who comply to the EU GMP Part II
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Perspectives• Further develop the risk-based approach
when elaborating the programme• Reinforce collaboration and sharing of
information with EU and International Inspectorates
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THANK YOU FOR YOUR ATTENTION