Inspection of API manufacturers by
EDQM:
how to prepare for an inspection
IPA / EDQM / WHO Mumbai Conference
27 September 2012
Dr Florence Benoit-Guyod, EDQM Inspector,
Certification of substances Division, EDQM
How to prepare for an inspection
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Overview of the EU regulation background
Before the inspection
During the inspection
After the inspection
Dr Florence Benoit-Guyod ©2012 EDQM, Council of Europe. All rights reserved.
EDQM Inspection programme
• Integral part of the Certification Procedure (Article
111 of Directive 2001/83/EC and Article 80 of Directive
2001/82/EC, Compilation of Community Procedures)
• Performed before or after the CEP is granted
• Aim: to verify the compliance with
9submitted dossier
9EU GMP Part II
9EU GMP Annexes (e.g. Annex 1 / sterile substances)
Dr Florence Benoit-Guyod ©2012 EDQM, Council of Europe. All rights reserved.
BEFORE THE INSPECTION:
preliminary comment
• The company representative of the manufacturer
has signed a declaration of
¾ willingness to be inspected
¾manufacture as per EU GMP part II
(ICH Q7)
• The company may be inspected at any time for
checking compliance to GMP & dossier
• A company inspected once may be
inspected twice…
Dr Florence Benoit-Guyod ©2012 EDQM, Council of Europe. All rights reserved.
Prerequisite
• GMP compliance should be effective at the time of
submission of the CEP application
• Compliance with the dossier should be effective at
any time
1 In case some changes have been implemented they
should be submitted to EDQM in accordance to the
revision/renewal policy http://www.edqm.eu/en/Revisions-
amp-Renewals-663.html
Dr Florence Benoit-Guyod ©2012 EDQM, Council of Europe. All rights reserved.
BEFORE THE INSPECTION
Dr Florence Benoit-Guyod ©2012 EDQM, Council of Europe. All rights reserved.
First contact with EDQM inspectors:
preliminary information request
• Contact by email
• Questions are asked regarding the
– Inspection and audit history
– Amount of substances produced
– Planned shutdowns
– GPS coordinates, list of APIs
– Other questions as relevant
• Data provided are used to assess relevance to
schedule an inspection
Dr Florence Benoit-Guyod ©2012 EDQM, Council of Europe. All rights reserved.
First contact with EDQM inspectors:
preliminary information request
• Not replying indicates concealing of facts and
increases the relevance of a prompt inspection
• Exchange of information with other Authorities
to avoid duplication (inspection reports or GMP
certificates)
Dr Florence Benoit-Guyod ©2012 EDQM, Council of Europe. All rights reserved.
Second contact: notification of
inspection
• By express mail and email
Update your email address and contact name
• Notification that the inspection will take place
• Usually, exact dates and substance are mentioned
(as a minimum the time period is specified and more
details given later)
• In most cases, only one substance is covered
Dr Florence Benoit-Guyod ©2012 EDQM, Council of Europe. All rights reserved.
Second contact: notification of
inspection
• Not accepting the inspection at the scheduled
dates is considered a refusal of inspection,
followed by the suspension of the concerned
CEP and/or closure of application
• Exceptions are possible if a sound justification
has been provided
Dr Florence Benoit-Guyod ©2012 EDQM, Council of Europe. All rights reserved.
Company’s task (working language)
When most of the staff members cannot speak
English:
Need to pay great attention to the qualification of
the person selected as interpreter (technical/
scientific, linguistic and regulatory/ GMP skills)
Dr Florence Benoit-Guyod ©2012 EDQM, Council of Europe. All rights reserved.
Company’s tasks (logistic)
• Send invitation letter by express mail and
scanned by email for visa application
• Support EDQM for hotel booking; short
driving time preferred
• Provide transfers (hotel/airports/factory)
• Provide meals during the inspection
Dr Florence Benoit-Guyod ©2012 EDQM, Council of Europe. All rights reserved.
Company’s tasks (financial aspect)
• Inspection (or reinspection) fees
– Initiated by EDQM (3 days) 5000 €
– Requested by company + approved by EDQM 9000 €
– Initiated by EDQM (2 days) 3500 €
– Initiated by EDQM (1 day) 2000 €
• Travel expenses
– Travel, accommodation invoiced by EDQM to company
– Pick up and drop off to be taken in charge directly by
company
Dr Florence Benoit-Guyod ©2012 EDQM, Council of Europe. All rights reserved.
Company’s tasks (technical)
– Provide Site Master File (SMF) based on the PIC/SEU template
http://www.picscheme.org/publication.php?id=15
– SMF should be carefully filled in, preferably from
experienced staff and cross-checked by QA. Core
document(s) for the preparation of the inspection
– Check the actuality of any layout (site, workshops,
PIDs, HVAC, water systems…)
Dr Florence Benoit-Guyod ©2012 EDQM, Council of Europe. All rights reserved.
Company’s tasks (technical)
• Ensure ability to retrieve any quality document
• Instruct the staff members to answer to
inspector’s questions straightforward, clear and
honestly, in order to be able to maintain trust
and confidence
Dr Florence Benoit-Guyod ©2012 EDQM, Council of Europe. All rights reserved.
Notification of inspection:
what should the company avoid to do ?
From the inspector’s perspective, if an efficient
quality system is in place, notification of
inspection is not supposed to trigger:
• Last minute changes
• Hiding problems instead of solving them
Dr Florence Benoit-Guyod ©2012 EDQM, Council of Europe. All rights reserved.
Notification of Inspection:
what the company is not supposed to do ?
Notifying undeclared changes in the CEP dossier
g all n
i
c
a
l
p
e
R
flanges, gaskets, s , hosepipe
curtains…
Interrupting production
Ma n
ipula
do cu
t
men ing ts
0
Building walls
Painting the premises and equipment
Drafting new procedures or update old ones (outside the regular intervals)
Dr Florence Benoit-Guyod ©2012 EDQM, Council of Europe. All rights reserved.
Putting brand ne
w labels everywh
ere
Hiring new staff members
(except if already foreseen)
New requirement : GPS / DUNS
• GPS coordinates and DUNS number requested
• EDQM specific requirements:
9GPS is mandatory, DUNS is optional
9System: WGS 84 (World Geodetic System 1984)
9Unit: degree minutes seconds (or decimal equivalent)
9Recorded at the entrance of the site
http://www.edqm.eu/medias/fichiers/cep_data_for_localisation_of_ma
nufacturing_sites_p.pdf
• Use a GPS device or application (eg Google Earth or
equivalent)
Dr Florence Benoit-Guyod ©2012 EDQM, Council of Europe. All rights reserved.
GPS: example
• Unit in WGS 84:
DD° MM’ SS’’
Or DD° MM,MMM’
Or DD, DDDDD°
Example:
• N 48° 35’ 45’’ E 7° 46’ 40’’
• N 48° 35.750’’ E 7° 46.667’
• N 48.59610° E 7.77786°
Dr Florence Benoit-Guyod ©2012 EDQM, Council of Europe. All rights reserved.
EDQM
premises in
Strasbourg
Who are the inspectors ?
• Team composed of
– an EDQM inspector (background: NCA inspector)
– an inspector coming from a National Competent Authority
of an EEA member state or MRA partner
• Background :
– Pharmacist, Chemist, Biologist, engineer…
– Preferably with professional experience in pharmaceutical
manufacturing operation
• Continuous training
– Around 10 days per year
– Within PIC/S or professional training providers in the field of
GMP
Dr Florence Benoit-Guyod ©2012 EDQM, Council of Europe. All rights reserved.
Code of conduct of the inspectors
• Our primary role : protection of public health
• Our key concerns:
- Handle confidential information with integrity and great care
- Having a consistent approach to evaluation of the GMP
standard of companies
- Answer questions without entering the role of a consultant but
including educational and motivating elements
- Be aware of our influence in decision making processes
- Take care not to put the product at risk and not to disturb the
normal work patterns
- Strive to create a positive atmosphere during the inspection
(Based on EU Compilation of Community Procedure “Conduct of inspections of pharmaceutical
manufacturers”)
Dr Florence Benoit-Guyod ©2012 EDQM, Council of Europe. All rights reserved.
Some more important points
before the inspection
• EDQM informs local Inspectorate about the
dates and scope of the inspection
• EDQM welcomes the presence of local
inspectors as observers
• An inspection schedule is sent to the
company about one week before inspection
starts
Dr Florence Benoit-Guyod ©2012 EDQM, Council of Europe. All rights reserved.
DURING THE INSPECTION
Dr Florence Benoit-Guyod ©2012 EDQM, Council of Europe. All rights reserved.
Opening meeting
• Introduction of the inspection team and the
program (scope and aim)
• Introduction of company and activities on the
site to be inspected
• Overview about supply chain and outsourced
activities
Dr Florence Benoit-Guyod ©2012 EDQM, Council of Europe. All rights reserved.
Before plant tour
• Review QA, main QA procedures, Annual
product quality review
• Presentation of current manufacturing process
(including solvent /mother liquor /catalyst recovery)
• Company should provide
– Current layout of the complete facility
– List of raw materials (bilingual, local language + English if
applicable)
Dr Florence Benoit-Guyod ©2012 EDQM, Council of Europe. All rights reserved.
Plant tour
Dr Florence Benoit-Guyod ©2012 EDQM, Council of Europe. All rights reserved.
Plant tour, cont.
Inspectors may:
– Deviate from schedule and suggested directions
– Split during the plant tour
– Request access to any area if they feel that they can
be related to the scope of the inspection
– Ask questions directly to staff members involved in
manufacturing operations
– Use digital cameras as auxiliary means (unless not
permitted for safety reasons)
– Record GPS coordinates of the facility
Dr Florence Benoit-Guyod ©2012 EDQM, Council of Europe. All rights reserved.
Documentation review
• The company should:
– Make all GMP related documentation available to the
inspector’s (core documents are mentioned in the inspection
schedule)
– Provide requested documents as quick as possible
– Ensure the presence of the appropriate staff in order
to answer questions in due time
– Recording documents and operating documents are
expected to be seen on their usual place of
use/storage
Dr Florence Benoit-Guyod ©2012 EDQM, Council of Europe. All rights reserved.
Documentation review, cont.
• The inspectors will:
– Check the compliance of the process /
specifications / analytical methods with the
submitted certification dossier
• The inspectors may:
– Request financial documentation if felt necessary
for the achieving the scope of the inspection
– Check any raw data
Dr Florence Benoit-Guyod ©2012 EDQM, Council of Europe. All rights reserved.
Closing meeting
• Key personnel should be present
• Oral presentation of findings to the company
• Explanation of inspection follow-up procedure
(particularly if serious non-compliance)
• No new documents or discussion at this step…
but last opportunity to clarify misunderstandings
Dr Florence Benoit-Guyod ©2012 EDQM, Council of Europe. All rights reserved.
AFTER THE INSPECTION
Dr Florence Benoit-Guyod ©2012 EDQM, Council of Europe. All rights reserved.
Definition of deficiencies
• CRITICAL DEFICIENCY:
Has produced, or leads to a significant risk of producing a product:
9 which is harmful to the human or veterinary patient
9 which could result in a harmful residue in a food producing animal
• MAJOR DEFICIENCY:
9 A non-critical deficiency which has or may produce a product which does not comply with its
9
9
9
9
marketing authorisation
Or which indicates a major deviation from EU GMP;
Or (within EU) which indicates a major deviation from the terms of the manufacturing
authorisation;
Or which indicates a failure to carry out satisfactory procedures for release of batches or (within EU) a
failure of the Qualified Person to fulfil his legal duties
Or a combination of several “other” deficiencies, which may together represent a major deficiency
• OTHER DEFICIENCY
9 A non-critical /non-major deficiency, but which indicates a departure from GMP
9 A deficiency may be “other” either because it is judged as minor, or because there is insufficient
information to classify it as major or critical
Dr Florence Benoit-Guyod ©2012 EDQM, Council of Europe. All rights reserved.
Inspection follow-up
• Inspection report sent within 6 weeks
• Company’s reply within 1 month (from the
receipt of the inspection report)
• No corrective action plan should be submitted
before the inspection report is received
Dr Florence Benoit-Guyod ©2012 EDQM, Council of Europe. All rights reserved.
Inspection follow-up
• Replies to be fully documented
– Commitments, deadline, description of the corrective action
– Copies of procedures (translated into English)
– Pictures
• Replies to be provided in electronic format
- Pdf format
- In case of annexes they should be bookmarked
• Commitments should reflect what has or will
actually be done
• Discrepancies with the certification dossier are
specifically addressed and managed by the revision
process at DCEP
Dr Florence Benoit-Guyod ©2012 EDQM, Council of Europe. All rights reserved.
Inspection follow-up: case of
borderline outcome
• Provisional outcome, only at the stage of the
initial report
• Based on the corrective action plan, the
inspectors may decide to turn the outcome to
compliant or to non-compliant (and advise for
CEP suspension)
Dr Florence Benoit-Guyod ©2012 EDQM, Council of Europe. All rights reserved.
Positive Outcome
... After issuance of the final inspection report
• Attestation of inspection is issued by EDQM
• GMP Certificate is issued by the EU/EEA
participating Inspectorate
Negative Outcome
• CEP is suspended or withdrawn, on-going CEP
application is rejected
http://www.edqm.eu/medias/fichiers/cep_suspension_or_withdrawal_
of_a_cep.pdf
Statement of GMP non-compliance is issued by the
EU/EEA participating Inspectorate
Dr Florence Benoit-Guyod ©2012 EDQM, Council of Europe. All rights reserved.
Suspension vs withdrawal:
what’s the difference ?
• Suspension: A temporary cancellation
¾CEP can be restored
• Withdrawal: A definitive cancellation
¾When no corrective actions are deemed possible
(e.g. extensive cases of falsification of data,
repeated non-compliance)
¾A new dossier should be applied for
Dr Florence Benoit-Guyod ©2012 EDQM, Council of Europe. All rights reserved.
Procedure for requesting a hearing
• A manufacturer or holder may challenge a
decision taken by EDQM concerning his
application / CEP and request a hearing
• To be requested by a written justification detailing
the reasons for disputing the deficiencies that led
to the decision
Lifting the suspension or withdrawal
• Can only be decided after a reinspection
• Application or CEP withdrawn: new application
has to be (re)submitted and approved
Dr Florence Benoit-Guyod ©2012 EDQM, Council of Europe. All rights reserved.
Thank you for your attention
Dr Florence Benoit-Guyod ©2012 EDQM, Council of Europe. All rights reserved.