Working document QAS/16.673
June 2016
Draft document for comment
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GUIDELINES ON VALIDATION – APPENDIX 6
VALIDATION ON QUALIFICATION OF SYSTEMS, UTILITIES
AND EQUIPMENT
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(June 2016)
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DRAFT FOR COMMENTS
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Should you have any comments on the attached text, please send these to
Dr S. Kopp, Group Lead, Medicines Quality Assurance, Technologies,
Standards and Norms (kopps@who.int) with a copy to Ms Marie Gaspard
(gaspardm@who.int) by 15 August 2016.
Medicines Quality Assurance working documents will be sent out
electronically only and will also be placed on the Medicines website for
comment under “Current projects”. If you do not already receive our
draft working documents please let us have your email address (to
bonnyw@who.int) and we will add it to our electronic mailing list.
.
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© World Health Organization 2016
All rights reserved.
This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The draft
may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in any
form or by any means outside these individuals and organizations (including the organizations' concerned staff and member
organizations) without the permission of the World Health Organization. The draft should not be displayed on any website.
Please send any request for permission to:
Dr Sabine Kopp, Group Lead, Medicines Quality Assurance, Technologies, Standards and Norms, Regulation of Medicines and
other Health Technologies, Department of Essential Medicines and Health Products, World Health Organization, CH-1211
Geneva 27, Switzerland. Fax: (41-22) 791 4730; email: kopps@who.int.
The designations employed and the presentation of the material in this draft do not imply the expression of any opinion
whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its
authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines
for which there may not yet be full agreement.
The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended
by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions
excepted, the names of proprietary products are distinguished by initial capital letters.
All reasonable precautions have been taken by the World Health Organization to verify the information contained in this draft.
However, the printed material is being distributed without warranty of any kind, either expressed or implied. The responsibility
for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for
damages arising from its use.
This draft does not necessarily represent the decisions or the stated policy of the World Health Organization.
Working document QAS/16.673
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SCHEDULE FOR THE PROPOSED ADOPTION PROCESS OF DOCUMENT QAS/16.673:
GUIDELINES ON VALIDATION – APPENDIX 6
VALIDATION ON QUALIFICATION OF SYSTEMS, UTILITIES AND EQUIPMENT
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Discussion of proposed need for revision in view of the
current trends in validation during informal consultation
on data management, bioequivalence, GMP and
medicines’ inspection
Preparation of draft proposal for revision of the main text
and several appendices by specialists in collaboration
with the Medicines Quality Assurance Group and
Prequalification Team (PQT)-Inspections, based on the
feedback received during the meeting and from PQTInspections, draft proposals developed on the various
topics by specialists, as identified in the individual
working documents.
Presentation of the progress made to the fiftieth meeting
of the WHO Expert Committee on Specifications for
Pharmaceutical Preparations
Discussion at the informal consultation on good practices
for health products manufacture and inspection, Geneva
Preparation of revised text by Dr A.J. van Zyl, participant
at the above-mentioned consultation, based on the
feedback received during and after the informal
consultation by the meeting participants and members of
PQT-Inspections
Circulation of revised working document for public
consultation
Consolidation of comments received and review of
feedback
Presentation to the fifty-first meeting of the WHO Expert
Committee on Specifications for Pharmaceutical
Preparations
Any other follow-up action as required
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12–16 October 2015
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June 2016
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1 July 2015
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Background information
The need for revision of the published Supplementary guidelines on good manufacturing
practices: validation (World Health Organization (WHO) Technical Report Series, No. 937,
2006, Annex 4) was identified by the Prequalification of Medicines Programme and a draft
document was circulated for comment in early 2013. The focus of the revision was the Appendix
on non-sterile process validation (Appendix 7), which had been revised and was adopted by the
Committee at its forty-ninth meeting in October 2014.
The main text was sent out for consultation as Working document QAS/15.639 entitled
“Guidelines on Validation” which constitute the general principles of the new guidance on
validation.
The draft on the specific topics, the appendices to this main text, will follow. One of them, i.e.
the Validation on qualification of systems, utilities and equipment, constitutes this working
document.
The following is an overview on the appendices that are intended to complement the general text
on validation:
Appendix 1
Validation of heating, ventilation and air-conditioning systems
 will be replaced by cross-reference to WHO Guidelines on GMP for HVAC systems
for considerations in qualification of HVAC systems
(update - working document QAS/15.639/Rev.1)
Appendix 2
Validation of water systems for pharmaceutical use
 will be replaced by cross-reference to WHO Guidelines on water for pharmaceutical
use for consideration in qualification of water purification systems
Appendix 3
Cleaning validation – consensus to retain
Appendix 4
Analytical method validation
 will be replaced by update - working document QAS/16.671
Appendix 5
Validation of computerized systems
 will be replaced by update - working document QAS/16.667
Appendix 6
Qualification of systems, utilities and equipment – updated text proposed in this
working document
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Appendix 7
Non-sterile process validation – update already published as Annex 3, WHO Technical
Report Series, No. 992, 2015
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GUIDELINES ON VALIDATION – APPENDIX 6
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1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
Principle
Scope
Glossary
General
User requirement specifications
Factory acceptance test and site acceptance test
Design qualification
Installation qualification
Operational qualification
Performance qualification
Requalification
Qualification of “in use” systems and equipment
1.
PRINCIPLE
1.1
Systems, utilities and equipment should be appropriately designed, located, installed,
operated, cleaned and maintained to suit their intended purpose.
1.2
Products should be manufactured on qualified equipment to ensure batch-to-batch
consistency
1.3
Procedures should be in place to ensure that systems, utilities and equipment remain in a
qualified state throughout the life of the system, utility and equipment.
2.
SCOPE
2.1
These guidelines describe the general aspects of qualification for systems, utilities and
equipment.
2.2
The principles in this guideline may also be applied to the qualification of instruments
and testing devices, where appropriate.
2.3
Systems, utilities and equipment that may have an impact on the quality of products,
should be appropriately qualified. These may include, where appropriate: computerized systems;
water purification systems; heating, ventilation and air conditioning systems; compressed air
systems; steam systems; production and quality control of equipment and instruments.
2.4
Documented impact assessments should support decisions for the exclusion of systems,
utilities and equipment from qualification.
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3.
GLOSSARY
design qualification. Documented evidence that the premises, supporting systems,
utilities, equipment and processes have been designed in accordance with the requirements of
good manufacturing practices.
factory acceptance test. A test conducted at the vendor’s premises to verify that the
system, equipment or utility, as assembled or partially assembled, meets expected specifications.
(new)
installation qualification. The performance of tests to ensure that the installations (such
as machines, measuring devices, utilities and manufacturing areas) used in a manufacturing
process are appropriately selected and correctly installed and operate in accordance with
established specifications.
operational qualification. Documented verification that the system or subsystem
performs as intended over all anticipated operating ranges.
performance qualification. Documented verification that the equipment or system
operates consistently and gives reproducibility within defined specifications and parameters for
prolonged periods. (In the context of systems, the term “process validation” may also be used.)
site acceptance test. A test conducted at the site of use to verify that the system,
equipment or utility, as assembled or partially assembled meets expected specifications. (new)
system. A regulated pattern of interacting activities and techniques that are united to form
an organized whole.
user requirement specifications. An authorized document that defines the requirements
for use of the system, equipment or utility in its intended production environment. (amended)
utility. A system consisting of one or more components to form a structure designed to
collectively operate, function or perform and provide a service such as electricity, water,
ventilation or other. (new)
4.
GENERAL
4.1
The validation master plan, or other relevant document, should specify the policy,
organization, planning, scope and stages applied in qualification for systems, utilities and
equipment and should cover, e.g. production, quality control and engineering.
4.2
The scope and extent of qualification and requalification should be determined based on
the principles of impact assessment and risk assessment. Risk management principles should be
considered in all areas of the scope and stages of qualification.
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4.3
Where appropriate, new systems, utilities and equipment should pass through all stages of
qualification including the preparation of user requirement specifications (URS), design
qualification (DQ), installation qualification (IQ), operational qualification (OQ) and
performance qualification (PQ) (see Figure 1 as an example).
Figure 1. Examples of stages of qualification
V-Model for Direct Impact Systems
PQ Test Plan
User Requirement
Specification
Performance
Qualification
Design
Qualification
(incl. UAT)
OQ Test Plan
Functional Design
Specification
Operational
Qualification
(incl. FAT)
DQ Test Plan
IQ Test Plan
Detail Design and
Configuration
Specifications
(incl. PDI)
Installation
Qualification
Build & Project
Implementation
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(Note: For description of stages, see below)
4.4 Scientific justification should be provided where it is decided that not all stages of
qualification are required.
[Note from the Secretariat: The references below will be updated upon finalization of the related
texts.]
4.5
See WHO TRS XXX for aspects to be considered for inclusion in qualification of water
purification systems
4.6
See WHO TRS XXX for aspects to be considered for inclusion in qualification of
heating, ventilation and air-conditioning (HVAC) systems.
4.7
See WHO TRS XXX for aspects to be considered for inclusion in qualification and
validation of computerized systems.
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4.8
Qualification should be done in accordance with predetermined and approved
qualification protocols.
4.9
The results of the qualification should be recorded and reflected in qualification reports.
4.10
Rooms or areas, as appropriate, should be qualified prior to the qualification of utilities.
4.11
Utilities should be qualified prior to the qualification of equipment.
4.12 Equipment should qualified and brought into routine use only once there is documented
evidence that it is fit for its intended purpose.
4.13 Certain stages of the qualification may be done by the supplier or a third party, subject to
the conditions and responsibilities as defined in an agreement between the two parties. The
contract giver remains responsible to ensure that the qualification is done in accordance with
good manufacturing practices (GMP).
4.14 There should be a logical sequence in performing qualification. For example, operational
qualification should follow after the successful completion of installation qualification.
4.15 The relevant documentation associated with qualification including standard operating
procedures (SOPs), specifications and acceptance criteria, certificates and manuals should be
maintained and be traceable.
4.16 Systems, utilities and equipment should be maintained in a qualified state and undergo
periodic requalification where appropriate, as well as requalification after change when needed.
4.17
Processes should be validated on qualified equipment.
5.
USER REQUIREMENT SPECIFICATIONS
5.1
URS should be prepared for systems, utilities and equipment, where appropriate
5.2
URS should be used to verify, at a later stage, that the purchased and supplied system,
utility or equipment is in accordance with the manufacturer’s needs as specified.
6.
FACTORY ACCEPTANCE TEST AND SITE ACCEPTANCE TEST
6.1
Where a system, utility or equipment is assembled, or partially assembled at a site other
than that of the purchaser or end-user, testing and verification should be done to ensure that the
system, utility or equipment is appropriate and ready for dispatch.
6.2
The checks and tests during assembly or partial assemble, should be recorded.
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6.3
The acceptability of the assembly and overall status of the system, utility or equipment
should be described in a conclusion of the report for the factory acceptance test (FAT), prior to
shipment.
6.4
When the system, utility or equipment is received at the end user, tests should be
performed to verify the acceptability of the system, utility or equipment.
6.5
The results of the tests should be recorded and the outcome of the acceptability of the
system, utility or equipment recorded in the conclusion of the report for the site acceptance test
(SAT).
7.
DESIGN QUALIFICATION
7.1
URS should be considered when deciding on the specific design of a system, utility or
equipment.
7.2
A suitable supplier should be selected for the appropriate system, utility or equipment.
7.3
The supplier should be approved prior to purchasing the system, utility or equipment
7.4
On delivery of the system, utility or equipment, the user should verify that it meets the
agreed design specifications and satisfies the URS
7.5
Once DQ is completed, IQ may commence.
8.
INSTALLATION QUALIFICATION
8.1
Systems, utilities and equipment should be correctly installed, in an appropriate location
and in accordance with an installation plan
8.2
There should be documented evidence of the installation. This should be in accordance
with the IQ protocol which contains all the required detail.
8.3
IQ should include identification and verification of all system elements, parts, services,
controls, gauges and other components.
8.4
Measuring, control and indicating devices being installed should be calibrated. The
calibration should be traceable to relevant national or international standards. Certificates should
be available.
8.5
The execution of the protocol should be recorded in the IQ report.
8.6
The report should include at least the title, objective, site, details of the supplier and
manufacturer, system or equipment name and unique identification number, model and serial
number, date of installation, components and their identification numbers or codes, actual results
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of tests and measurements, spare parts list, relevant procedures followed for tests and certificates
as applicable.
8.7
All deviations and non-conformances from URS, DQ and acceptance criteria specified,
observed during installation, should be recorded and investigated.
8.8
The outcome of the IQ should be recorded in the conclusion of the report, before OQ is
started.
8.9
Requirements and procedures for calibration, maintenance and cleaning should be drawn
up during installation.
Figure 2. Example of an installation qualification protocol
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9.
OPERATIONAL QUALIFICATION
9.1
Systems, utilities and equipment should operate correctly and their operation should be
verified in accordance with an OQ protocol.
9.2
Critical operating parameters should be identified. Studies on the critical variables should
include conditions encompassing normal, upper and lower operating limits and circumstances
(this includes “worst-case conditions”).
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9.3
OQ should include verification of operation of all system elements, parts, services,
controls, gauges and other components.
9.4
The results for the verification of operation should be documented in the OQ report to
indicate the satisfactory operation.
9.5
SOPs for the operation should be finalized and approved during this phase of
qualification.
9.6
Training of operators for the systems, utilities and equipment should be provided and
training records maintained.
9.7
Systems, utilities and equipment, as appropriate, should be released for PQ or routine use
after completion of OQ.
9.8
All calibration, cleaning, maintenance, training and related tests and results should be
verified to be acceptable. Any discrepancy or deviation should be recorded and investigated.
9.9
The outcome of the OQ should be recorded in the conclusion of the report, before PQ is
started.
Figure 3. Example of an operational qualification protocol
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10.
PERFORMANCE QUALIFICATION
10.1 Systems, utilities and equipment should consistently perform in accordance with their
design specifications. The performance should be verified in accordance with a PQ protocol.
10.2 There should be records for the PQ (report) to indicate the satisfactory performance over
a period of time. Manufacturers should justify the selected period over which PQ is done.
10.3
PQ should be done once OQ is successfully completed.
10.4 Where two stages of qualification (e.g. OQ and PQ) are performed simultaneously, or
where PQ is executed at the same time as process validation, appropriate justification for such a
decision should be documented
Figure 4. Example of a performance qualification protocol
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11.
REQUALIFICATION
11.1 Systems, utilities and equipment should be maintained in a qualified state through the life
of the system, utility or equipment.
11.2 Routine requalification of systems, utilities and equipment should be considered based
on the outcome of risk management principles which include factors such as calibration,
verification and maintenance data and information.
11.3 The qualification status and requalification due dates should be documented in a defined
schedule.
11.4 The scope and extent of qualification should be determined based on risk assessment
when changes to an existing system, utility or equipment are made.
12.
QUALIFICATION OF “IN-USE” SYSTEMS, UTILITIES AND EQUIPMENT
12.1 There should be data to support and verify the suitable design, operation and performance
of systems, utilities and equipment that have been “in use” for a period of time and which have
not been subjected to IQ and or OQ.
12.2 In such cases, a qualification protocol and report should be prepared where elements of
design, operation and performance are verified for acceptability. These should include operating
parameters and limits for critical variables, calibration, maintenance and preventive maintenance,
SOPs and records.
***