EUROPEAN COMMISSION
ENTERPRISE DIRECTORATE-GENERAL
Single market, regulatory environment, industries under vertical legislation
Pharmaceuticals and cosmetics
Brussels, July 2001
Working Party on Control of Medicines and Inspections
Final Version of Annex 15 to the EU Guide to
Good Manufacturing Practice
Title: Qualification and validation
.
First discussion in drafting group
Discussion at the working Party on Control of Medicines and
16 September 1999
Inspection for release for consultation
Pharmaceutical Committee28 September 1999
Released for consultation30 October 1999
Deadline for comments28 February 2000 Final approval by Inspector’s working party December 2000
Pharmaceutical Committee (for information)April 2001 Date for coming into operation September 2001
Note that this document is based in the PICS/S recommendations
2 Table of Contents
Page
1. Qualification and Validation3
2. Planning for Validation4
3. Documentation4
4. Qualification5
5. Processs Validation.6
6. Cleaning Validation7
7. Change Control8
8. Revalidation9
9. Glossary      10
QUALIFICATION AND VALIDATION
Principle
1.This Annex describes the principles of qualification and validation which are
applicable to the manufacture of medicinal products. It is a requirement of
GMP that manufacturers identify what validation work is needed to prove
control of the critical aspects of their particular operations. Significant
changes to the facilities, the equipment and the processes, which may affect
the quality of the product, should be validated. A risk assessment approach
should be used to determine the scope and extent of validation.
PLANNING FOR VALIDATION
2.All validation activities should be planned. The key elements of a validation
programme should be clearly defined and documented in a validation master
plan (VMP) or equivalent documents.
3.The VMP should be a summary document which is brief, concise and clear.
4.The VMP should contain data on at least the following:
(a)validation policy;
(b)organisational structure of validation activities;
(c)summary of facilities, systems, equipment and processes to be validated;
(d)documentation format: the format to be used for protocols and reports;
(e)planning and scheduling;
(f)change control;
(g)reference to existing documents.
5.In case of large projects, it may be necessary to create separate validation
master plans.
DOCUMENTATION
6.  A written protocol should be established that specifies how qualification and
validation will be conducted. The protocol should be reviewed and approved.
The protocol should specify critical steps and acceptance criteria.
7.  A report that cross-references the qualification and/or validation protocol
should be prepared, summarising the results obtained, commenting on any
deviations observed, and drawing the necessary conclusions, including rec-
ommending changes necessary to correct deficiencies. Any changes to the
plan as defined in the protocol should be documented with appropriate justi-
fication.
8.After completion of a satisfactory qualification, a formal release for the next
step in qualification and validation should be made as a written authorisation.
QUALIFICATION
Design qualification
9.The first element of the validation of new facilities, systems or equipment
could be design qualification (DQ).
10.The compliance of the design with GMP should be demonstrated and
documented.
Installation qualification
11. Installation qualification (IQ) should be performed on new or modified
facilities, systems and equipment.
12. IQ should include, but not be limited to the following:
(a)installation of equipment, piping, services and instrumentation checked to
validation verificationcurrent engineering drawings and specifications;
(b)collection and collation of supplier operating and working instructions and
maintenance requirements;
(c)calibration requirements;
(d)verification of materials of construction.
Operational qualification
13. Operational qualification (OQ) should follow Installation qualification.
14. OQ should include, but not be limited to the following:
(a)tests that have been developed from knowledge of processes, systems and
equipment;
(b)tests to include a condition or a set of conditions encompassing upper and
lower operating limits, sometimes referred to as “worst case” conditions.
15.The completion of a successful Operational qualification should allow the
finalisation of calibration, operating and cleaning procedures, operator
training and preventative maintenance requirements. It should permit a
formal "release" of the facilities, systems and equipment.
Performance qualification
16. Performance qualification (PQ) should follow successful completion of
Installation qualification and Operational qualification.
17. PQ should include, but not be limited to the following:
(a)tests, using production materials, qualified substitutes or simulated product,
that have been developed from knowledge of the process and the facilities,
systems or equipment;
(b)tests to include a condition or set of conditions encompassing upper and
lower operating limits.
18. Although PQ is described as a separate activity, it may in some cases be
appropriate to perform it in conjunction with OQ.
Qualification of established (in-use) facilities, systems and equipment
19. Evidence should be available to support and verify the operating parameters
and limits for the critical variables of the operating equipment. Additionally,
the calibration, cleaning, preventative maintenance, operating procedures and
operator training procedures and records should be documented.
PROCESS VALIDATION
General
20. The requirements and principles outlined in this chapter are applicable to the
manufacture of pharmaceutical dosage forms. They cover the initial
validation of new processes, subsequent validation of modified processes and
re-validation.
21. Process validation should normally be completed prior to the distribution
and sale of the medicinal product (prospective validation).  In exceptional
circumstances, where this is not possible, it may be necessary to validate
processes during routine production (concurrent validation).  Processes in
use for some time should also be validated (retrospective validation).
22. Facilities, systems and equipment to be used should have been qualified and
analytical testing methods should be validated. Staff taking part in the vali-
dation work should have been appropriately trained.
23. Facilities, systems, equipment and processes should be periodically evalu-
ated to verify that they are still operating in a valid manner.
Prospective validation
24. Prospective validation should include, but not be limited to the following:
(a)short description of the process;
(b)summary of the critical processing steps to be investigated;
(c)list of the equipment/facilities to be used (including measur-
ing/monitoring/recording equipment) together with its calibration status
(d)finished product specifications for release;
(e)list of analytical methods, as appropriate;
(f)proposed in-process controls with acceptance criteria;
(g)additional testing to be carried out, with acceptance criteria and analytical
validation, as appropriate;
(h)sampling plan;

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