THE EUROPEAN

DIRECTORATE FOR THE

QUALITY OF MEDICINES
& HEALTHCARE
(EDQM)

Module 8
The EDQM Inspection Programme

How to prepare for an Inspection

&
Most common GMP Deficiencies
Dr Thomas HECKER
GMP Inspector

Certification of Substances Department

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Agenda

AVOIDING DEFICIENCIES

or

or

GETTING PREPARED?
?

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Preparation - BEFORE
Product(s)
per Official
Workshop Document*

First Contact Second

2-3 months Contact Send via
Inspection = Countries ahead of
=
express
History supplied the mail/courier
Site Status inspection Notification of and email
Review* Inspection

Informs
Production
status about exact
(ongoing, dates, API
shutdowns and
inspectors
*Refusal may lead to
etc.)
*simplified regulatory actions

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BEFORE: The Company should

Prepare and provide Send Invitation Letters

requested documents
(e.g. SMF)

Provide support in
Hotel booking
Pay Travel Expenses &
Appoint skilled Inspection Fees
Interpreters
(if needed)

Organise lunch during

Organise transfers
the inspection
(hotel, airport, factory)

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BEFORE: The Company should not

Notify undeclared
Paint premises and
changes in the CEP Interrupt Production
equipment
dossier

Create, rewrite, Perform not scheduled Draft new or update

manipulate documents maintenance activities procedures (Except if already
foreseen)

Hire new staff

members (Except already
foreseen)

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Not yet over: BEFORE…

Some further points to be noted:

• 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

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DURING the inspection

General Points to consider:

• Ensure ability to retrieve any document:

• Documents to be provided as fast as possible

• Ensure that the “Inspection War Room” is close to the meeting room

• Even if requested documents are not embedded in the Company’s quality system, they

should be made available to the team as can provide valuable additional information

• Instruct the staff members to answer to inspectors’ questions straightforward, clearly and

honestly, in order to be able to maintain trust and confidence

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DURING: Plant Tour

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DURING: 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)

• Call for a daily wrap-up meeting if serious observations were made

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INSPECTION: After

• Replies to be fully documented:

• Commitments, deadline, description of the corrective action; commitments
should reflect what has or will actually be done
• Copies of procedures (translated into English if needed)
• Pictures
• Replies to be provided in electronic format
• Pdf format
• Annexes should be bookmarked
• Discrepancies with the CEP dossier are specifically addressed and
managed by the revision process at EDQM

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GMP Deficiencies

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EDQM on-site inspections deficiencies

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800 Classification of deficiencies per GMP area 2017-2019

726

700

600
Critical
500
Major

400 379 Other

293
300

206
200
130
104
100
43 40
31 30
19
3 1 3 0 1 0 3
0
QUALITY BUILDINGS & PRODUCTION, MATERIAL LABORATORY COMPLIANCE TO
RELATED EQUIPMENT REJECTION, MANAGEMENT, CONTROLS CEP DOSSIER
MATTERS REUSE STORAGE ETC.

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Quality related GMP violations: QA Oversight

Failure to effectively
control documentation
(both paper and
electronic)

Underreporting
and/or
insufficient
Inadequate Insufficient investigation of
overview of oversight of quality events
production and (complaints,
laboratory quality unit deviations, out-
activities over GMP of-specification
activities results, change
controls)

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Quality related GMP violations - Documentation

Rewriting documents
in order to Unavailability
demonstrate of records
acceptable,
expected or
presentable results, Untimely
values or dates recording
of operations, e.g.
before (sic!)
or far to late

Use of loose sheets

instead of bound logbooks

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Quality related GMP violations: Miscellaneous

• Quality Risk Management not applied or inadequately implemented in areas such

as production activities, deviations, change control, etc.
• Insufficient validation, e.g.:
o processes such as use of recovered solvents, blending or micronisation not always addressed;
o lack of sound knowledge of different approaches regarding cleaning validation.

• Insufficient personnel training, e.g.:

o no training given to upper management with regard to GMP related matters;
o no assessment of training’s efficiency or with limited value

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GMP Violations related to Buildings and Facilities

• Risks of contamination and/or cross-contamination arising from:

• improper design of facilities;
• inadequate cleaning of equipment;
• insufficient maintenance of equipment.
• Lack of appropriate user requirement specifications concerning equipment
qualification

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GMP Violations: Computerised Systems (CS)

No or insufficient
Lack of appropriate user management of access
requirement specifications levels (risk of loss of
traceability)

Insufficient knowledge of No or insufficient review of

CS validation requirements audit trail

IT staff lacking or without

Insufficient controls to
knowledge of GMP
prevent data manipulation
requirements

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GMP Violations: Other areas

Production:
• Blending of batches without prior appropriate testing;
• Lack of control of solvent recovery.
Materials management:
• Insufficient approval and/or management of vendors of key starting materials or
intermediates (e.g. unreliable on-site audits);
• Risk of loss of traceability due to insufficient identification of containers;
• Improper storage conditions (temperature, humidity, non-controlled storage
facilities…).
Sub-contracted activities:
• Insufficient qualification of subcontractors (against GMP)
• Quality agreements without or poorly identified responsibilities

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GMP Violations: Quality Control

Fraudulent practices Unreliable microbiological results

regarding testing
activities, e.g.:
pretesting or “testing
into compliance”;
deleting OOS results;
unreliability of Issues with Chemical reference standards,
analytical results e.g. absence of the Ph. Eur. CRS;
insufficient establishment of secondary standards

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GMP Violations: Data Integrity

200 7
2015-2019 DI deficiencies Usual breaches of data integrity:
180 • documentation practices;
160 81 • laboratory controls;
140

120 3 Critical
• validation and controls on
100
Major
Other
computerised systems
4 57
80 24 (absence or gaps).
60 112

40 57 55
20

0
Total Paper Electronic

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Acknowledgements
• Dr Sotirios Paraschos, Inspector, EDQM

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Thank you for your attention

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