Inspection of API manufacturers by EDQM: how to prepare ...ipapharma.org/events/edqmphotospresentation2012/5.pdf · Inspection of API manufacturers by EDQM: how to prepare for an

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

• 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

submitted dossierEU GMP Part IIEU GMP Annexes (e.g. Annex 1 / sterile substances)


BEFORE THE INSPECTION: preliminary comment

• The company representative of the manufacturer has signed a declaration of

willingness to be inspected manufacture 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…


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

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


BEFORE THE INSPECTION


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


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)


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


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


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)


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


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


Company’s tasks (technical)

– Provide Site Master File (SMF) based on the PIC/S-EU 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…)


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


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


Hiring new staff members(except if already

foreseen)

Notification of Inspection: what the company is not supposed to do ?

Notifying Notifying undeclared undeclared changes in changes in the CEP the CEP dossierdossier

Interrupting Interrupting productionproduction Putting brand new labels everywhere

Painting the premises and

equipment

Replacing all

flanges,

gaskets,

hosepipes,

curtains…

Drafting new

procedures or update old

ones (outside the regular intervals)

Manipulating

Manipulating documentsdocuments

Building Building

wallswalls


New requirement : GPS / DUNS• GPS coordinates and DUNS number requested• EDQM specific requirements:

GPS is mandatory, DUNS is optionalSystem: WGS 84 (World Geodetic System 1984)Unit: degree minutes seconds (or decimal equivalent)Recorded at the entrance of the site

http://www.edqm.eu/medias/fichiers/cep_data_for_localisation_of_manufacturing_sites_p.pdf

• Use a GPS device or application (eg Google Earth or equivalent)


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°

EDQM EDQM premises in premises in StrasbourgStrasbourg


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


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”)


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


DURING THE INSPECTION


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


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)


Plant tour


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


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


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


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


AFTER THE INSPECTION


Definition of deficiencies• CRITICAL DEFICIENCY:Has produced, or leads to a significant risk of producing a product:

which is harmful to the human or veterinary patientwhich could result in a harmful residue in a food producing animal

• MAJOR DEFICIENCY: A non-critical deficiency which has or may produce a product which does not comply with its marketing authorisationOr 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 dutiesOr a combination of several “other” deficiencies, which may together represent a major deficiency

• OTHER DEFICIENCYA non-critical /non-major deficiency, but which indicates a departure from GMPA deficiency may be “other” either because it is judged as minor, or because there is insufficient information to classify it as major or critical


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


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


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)


Negative 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

Positive OutcomePositive Outcome

• CEP is suspended or withdrawn, on-going CEP application is rejectedhttp://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


Suspension vs withdrawal: what’s the difference ?

• Suspension: A temporary cancellationCEP can be restored

• Withdrawal: A definitive cancellation When no corrective actions are deemed possible (e.g. extensive cases of falsification of data, repeated non-compliance)A new dossier should be applied for


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 withdrawalLifting the suspension or withdrawal• Can only be decided after a reinspection• Application or CEP withdrawn: new application

has to be (re)submitted and approvedDr Florence Benoit-Guyod ©2012 EDQM, Council of Europe. All rights reserved.

Thank you for your attention


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