international conference quality of active pharmaceutical ingredients hyderabad, 5-6-7 september...

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

Florence Benoit-Guyod, Sept. 2009 ©2009 EDQM, Council of Europe, All rights reserved 2

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


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


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)


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


Responsibility of the manufacturer

• In the CEP procedure the manufacturer has to declare:- Compliance to Good Manufacturing Practices (GMP) - Willingness to be inspected


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)


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


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


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


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)


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


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)


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


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


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


Statistics 1999-2008Number of EDQM inspections per year

05

101520253035

Outside EU/EEAEU/EEA


Statistics 2004-2008: locations

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

2004 2005 2006 2007 2008

ElsewhereEEAOther Asian countriesChinaIndia


Statistics 2008Geographic location of inspected sites - 2008

India32%

China46%

Other Asian countries

11%

EEA7%

Elsewhere4%


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


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)


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


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%


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


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


Perspectives• Further develop the risk-based approach

when elaborating the programme• Reinforce collaboration and sharing of

information with EU and International Inspectorates


THANK YOU FOR YOUR ATTENTION

international conference quality of active pharmaceutical ingredients hyderabad, 5-6-7 september...

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