Working document QAS/16.

673
June 2016
Draft document for comment

1
2 GUIDELINES ON VALIDATION APPENDIX 6
3 VALIDATION ON QUALIFICATION OF SYSTEMS, UTILITIES
4 AND EQUIPMENT
5 (June 2016)
6 DRAFT FOR COMMENTS
7
8
9
10 Should you have any comments on the attached text, please send these to
11 Dr S. Kopp, Group Lead, Medicines Quality Assurance, Technologies,
12 Standards and Norms (kopps@who.int) with a copy to Ms Marie Gaspard
13
14 (gaspardm@who.int) by 15 August 2016.
15
16 Medicines Quality Assurance working documents will be sent out
17 electronically only and will also be placed on the Medicines website for
18
19 comment under Current projects. If you do not already receive our
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23
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26 World Health Organization 2016
27 All rights reserved.
28 This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The draft
29 may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in any
30 form or by any means outside these individuals and organizations (including the organizations' concerned staff and member
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32 Please send any request for permission to:
33 Dr Sabine Kopp, Group Lead, Medicines Quality Assurance, Technologies, Standards and Norms, Regulation of Medicines and
34 other Health Technologies, Department of Essential Medicines and Health Products, World Health Organization, CH-1211
35 Geneva 27, Switzerland. Fax: (41-22) 791 4730; email: kopps@who.int.
36 The designations employed and the presentation of the material in this draft do not imply the expression of any opinion
37 whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its
38 authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines
39 for which there may not yet be full agreement.
40 The mention of specific companies or of certain manufacturers products does not imply that they are endorsed or recommended
41 by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions
42 excepted, the names of proprietary products are distinguished by initial capital letters.
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47 This draft does not necessarily represent the decisions or the stated policy of the World Health Organization.
48
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49
50
51
52 SCHEDULE FOR THE PROPOSED ADOPTION PROCESS OF DOCUMENT QAS/16.673:
53 GUIDELINES ON VALIDATION APPENDIX 6
54 VALIDATION ON QUALIFICATION OF SYSTEMS, UTILITIES AND EQUIPMENT
55
56
Discussion of proposed need for revision in view of the 29 June 57
current trends in validation during informal consultation 1 July 2015 58
on data management, bioequivalence, GMP and 59
medicines inspection 60
Preparation of draft proposal for revision of the main text July 2015 61
and several appendices by specialists in collaboration April 2016 62
with the Medicines Quality Assurance Group and 63
Prequalification Team (PQT)-Inspections, based on the 64
feedback received during the meeting and from PQT- 65
Inspections, draft proposals developed on the various 66
topics by specialists, as identified in the individual 67
working documents. 68
Presentation of the progress made to the fiftieth meeting 1216 October 2015
69
of the WHO Expert Committee on Specifications for 70
Pharmaceutical Preparations
71
Discussion at the informal consultation on good practices 46 April 2016
72
for health products manufacture and inspection, Geneva
73
Preparation of revised text by Dr A.J. van Zyl, participant May 2016
74
at the above-mentioned consultation, based on the
75
feedback received during and after the informal
consultation by the meeting participants and members of 76
PQT-Inspections 77
Circulation of revised working document for public June 2016 78
consultation 79
Consolidation of comments received and review of AugustSeptember80
feedback 2016 81
Presentation to the fifty-first meeting of the WHO Expert 82
1721 October 2016
Committee on Specifications for Pharmaceutical 83
Preparations 84
Any other follow-up action as required 85
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91 Background information
92
93 The need for revision of the published Supplementary guidelines on good manufacturing
94 practices: validation (World Health Organization (WHO) Technical Report Series, No. 937,
95 2006, Annex 4) was identified by the Prequalification of Medicines Programme and a draft
96 document was circulated for comment in early 2013. The focus of the revision was the Appendix
97 on non-sterile process validation (Appendix 7), which had been revised and was adopted by the
98 Committee at its forty-ninth meeting in October 2014.
99
100 The main text was sent out for consultation as Working document QAS/15.639 entitled
101 Guidelines on Validation which constitute the general principles of the new guidance on
102 validation.
103
104 The draft on the specific topics, the appendices to this main text, will follow. One of them, i.e.
105 the Validation on qualification of systems, utilities and equipment, constitutes this working
106 document.
107
108 The following is an overview on the appendices that are intended to complement the general text
109 on validation:
110
111 Appendix 1
112 Validation of heating, ventilation and air-conditioning systems
113 will be replaced by cross-reference to WHO Guidelines on GMP for HVAC systems
114 for considerations in qualification of HVAC systems
115 (update - working document QAS/15.639/Rev.1)
116
117 Appendix 2
118 Validation of water systems for pharmaceutical use
119 will be replaced by cross-reference to WHO Guidelines on water for pharmaceutical
120 use for consideration in qualification of water purification systems
121
122 Appendix 3
123 Cleaning validation consensus to retain
124
125 Appendix 4
126 Analytical method validation
127 will be replaced by update - working document QAS/16.671
128
129 Appendix 5
130 Validation of computerized systems
131 will be replaced by update - working document QAS/16.667
132
133 Appendix 6
134 Qualification of systems, utilities and equipment updated text proposed in this
135 working document
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136
137 Appendix 7
138 Non-sterile process validation update already published as Annex 3, WHO Technical
139 Report Series, No. 992, 2015
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140 GUIDELINES ON VALIDATION APPENDIX 6

141 VALIDATION ON QUALIFICATION OF SYSTEMS, UTILITIES AND
142 EQUIPMENT
143
144 1. Principle
145 2. Scope
146 3. Glossary
147 4. General
148 5. User requirement specifications
149 6. Factory acceptance test and site acceptance test
150 7. Design qualication
151 8. Installation qualication
152 9. Operational qualication
153 10. Performance qualication
154 11. Requalication
155 12. Qualication of in use systems and equipment
156
157 1. PRINCIPLE
158
159 1.1 Systems, utilities and equipment should be appropriately designed, located, installed,
160 operated, cleaned and maintained to suit their intended purpose.
161
162 1.2 Products should be manufactured on qualified equipment to ensure batch-to-batch
163 consistency
164
165 1.3 Procedures should be in place to ensure that systems, utilities and equipment remain in a
166 qualified state throughout the life of the system, utility and equipment.
167
168 2. SCOPE
169
170 2.1 These guidelines describe the general aspects of qualication for systems, utilities and
171 equipment.
172
173 2.2 The principles in this guideline may also be applied to the qualification of instruments
174 and testing devices, where appropriate.
175
176 2.3 Systems, utilities and equipment that may have an impact on the quality of products,
177 should be appropriately qualied. These may include, where appropriate: computerized systems;
178 water purication systems; heating, ventilation and air conditioning systems; compressed air
179 systems; steam systems; production and quality control of equipment and instruments.
180
181 2.4 Documented impact assessments should support decisions for the exclusion of systems,
182 utilities and equipment from qualification.
183
184
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185 3. GLOSSARY
186
187 design qualification. Documented evidence that the premises, supporting systems,
188 utilities, equipment and processes have been designed in accordance with the requirements of
189 good manufacturing practices.
190
191 factory acceptance test. A test conducted at the vendors premises to verify that the
192 system, equipment or utility, as assembled or partially assembled, meets expected specifications.
193 (new)
194
195 installation qualification. The performance of tests to ensure that the installations (such
196 as machines, measuring devices, utilities and manufacturing areas) used in a manufacturing
197 process are appropriately selected and correctly installed and operate in accordance with
198 established specifications.
199
200 operational qualification. Documented verification that the system or subsystem
201 performs as intended over all anticipated operating ranges.
202
203 performance qualification. Documented verification that the equipment or system
204 operates consistently and gives reproducibility within defined specifications and parameters for
205 prolonged periods. (In the context of systems, the term process validation may also be used.)
206
207 site acceptance test. A test conducted at the site of use to verify that the system,
208 equipment or utility, as assembled or partially assembled meets expected specifications. (new)
209
210 system. A regulated pattern of interacting activities and techniques that are united to form
211 an organized whole.
212
213 user requirement specifications. An authorized document that defines the requirements
214 for use of the system, equipment or utility in its intended production environment. (amended)
215
216 utility. A system consisting of one or more components to form a structure designed to
217 collectively operate, function or perform and provide a service such as electricity, water,
218 ventilation or other. (new)
219
220 4. GENERAL
221
222 4.1 The validation master plan, or other relevant document, should specify the policy,
223 organization, planning, scope and stages applied in qualification for systems, utilities and
224 equipment and should cover, e.g. production, quality control and engineering.
225
226 4.2 The scope and extent of qualification and requalification should be determined based on
227 the principles of impact assessment and risk assessment. Risk management principles should be
228 considered in all areas of the scope and stages of qualification.
229
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230 4.3 Where appropriate, new systems, utilities and equipment should pass through all stages of
231 qualication including the preparation of user requirement specifications (URS), design
232 qualication (DQ), installation qualication (IQ), operational qualication (OQ) and
233 performance qualication (PQ) (see Figure 1 as an example).
234
235 Figure 1. Examples of stages of qualification

V-Model for Direct Impact Systems

PQ Test Plan
User Requirement Performance
Specification Qualification
(incl. UAT)

OQ Test Plan
Functional Design Operational
Qualification

Specification Qualification
Design

(incl. FAT)

Detail Design and IQ Test Plan

DQ Test Plan Installation
Configuration
Qualification
Specifications (incl. PDI)

Build & Project

Implementation

236
237 (Note: For description of stages, see below)
238
239 4.4 Scientific justification should be provided where it is decided that not all stages of
240 qualication are required.
241
242 [Note from the Secretariat: The references below will be updated upon finalization of the related
243 texts.]
244
245 4.5 See WHO TRS XXX for aspects to be considered for inclusion in qualification of water
246 purication systems
247
248 4.6 See WHO TRS XXX for aspects to be considered for inclusion in qualification of
249 heating, ventilation and air-conditioning (HVAC) systems.
250
251 4.7 See WHO TRS XXX for aspects to be considered for inclusion in qualification and
252 validation of computerized systems.
253
254
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255 4.8 Qualication should be done in accordance with predetermined and approved
256 qualication protocols.
257
258 4.9 The results of the qualication should be recorded and reected in qualication reports.
259
260 4.10 Rooms or areas, as appropriate, should be qualified prior to the qualification of utilities.
261
262 4.11 Utilities should be qualified prior to the qualification of equipment.
263
264 4.12 Equipment should qualified and brought into routine use only once there is documented
265 evidence that it is t for its intended purpose.
266
267 4.13 Certain stages of the qualication may be done by the supplier or a third party, subject to
268 the conditions and responsibilities as defined in an agreement between the two parties. The
269 contract giver remains responsible to ensure that the qualification is done in accordance with
270 good manufacturing practices (GMP).
271
272 4.14 There should be a logical sequence in performing qualification. For example, operational
273 qualification should follow after the successful completion of installation qualification.
274
275 4.15 The relevant documentation associated with qualication including standard operating
276 procedures (SOPs), specications and acceptance criteria, certicates and manuals should be
277 maintained and be traceable.
278
279 4.16 Systems, utilities and equipment should be maintained in a qualified state and undergo
280 periodic requalication where appropriate, as well as requalication after change when needed.
281
282 4.17 Processes should be validated on qualified equipment.
283
284 5. USER REQUIREMENT SPECIFICATIONS
285
286 5.1 URS should be prepared for systems, utilities and equipment, where appropriate
287
288 5.2 URS should be used to verify, at a later stage, that the purchased and supplied system,
289 utility or equipment is in accordance with the manufacturers needs as specified.
290
291 6. FACTORY ACCEPTANCE TEST AND SITE ACCEPTANCE TEST
292
293 6.1 Where a system, utility or equipment is assembled, or partially assembled at a site other
294 than that of the purchaser or end-user, testing and verification should be done to ensure that the
295 system, utility or equipment is appropriate and ready for dispatch.
296
297 6.2 The checks and tests during assembly or partial assemble, should be recorded.
298
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299 6.3 The acceptability of the assembly and overall status of the system, utility or equipment
300 should be described in a conclusion of the report for the factory acceptance test (FAT), prior to
301 shipment.
302
303 6.4 When the system, utility or equipment is received at the end user, tests should be
304 performed to verify the acceptability of the system, utility or equipment.
305
306 6.5 The results of the tests should be recorded and the outcome of the acceptability of the
307 system, utility or equipment recorded in the conclusion of the report for the site acceptance test
308 (SAT).
309
310 7. DESIGN QUALIFICATION
311
312 7.1 URS should be considered when deciding on the specific design of a system, utility or
313 equipment.
314
315 7.2 A suitable supplier should be selected for the appropriate system, utility or equipment.
316
317 7.3 The supplier should be approved prior to purchasing the system, utility or equipment
318
319 7.4 On delivery of the system, utility or equipment, the user should verify that it meets the
320 agreed design specifications and satisfies the URS
321
322 7.5 Once DQ is completed, IQ may commence.
323
324 8. INSTALLATION QUALIFICATION
325
326 8.1 Systems, utilities and equipment should be correctly installed, in an appropriate location
327 and in accordance with an installation plan
328
329 8.2 There should be documented evidence of the installation. This should be in accordance
330 with the IQ protocol which contains all the required detail.
331
332 8.3 IQ should include identication and verication of all system elements, parts, services,
333 controls, gauges and other components.
334
335 8.4 Measuring, control and indicating devices being installed should be calibrated. The
336 calibration should be traceable to relevant national or international standards. Certificates should
337 be available.
338
339 8.5 The execution of the protocol should be recorded in the IQ report.
340
341 8.6 The report should include at least the title, objective, site, details of the supplier and
342 manufacturer, system or equipment name and unique identification number, model and serial
343 number, date of installation, components and their identification numbers or codes, actual results
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344 of tests and measurements, spare parts list, relevant procedures followed for tests and certicates
345 as applicable.
346
347 8.7 All deviations and non-conformances from URS, DQ and acceptance criteria specified,
348 observed during installation, should be recorded and investigated.
349
350 8.8 The outcome of the IQ should be recorded in the conclusion of the report, before OQ is
351 started.
352
353 8.9 Requirements and procedures for calibration, maintenance and cleaning should be drawn
354 up during installation.
355
356
357 Figure 2. Example of an installation qualification protocol
358
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360
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361
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362
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363
364 9. OPERATIONAL QUALIFICATION
365
366 9.1 Systems, utilities and equipment should operate correctly and their operation should be
367 veried in accordance with an OQ protocol.
368
369 9.2 Critical operating parameters should be identied. Studies on the critical variables should
370 include conditions encompassing normal, upper and lower operating limits and circumstances
371 (this includes worst-case conditions).
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372
373 9.3 OQ should include verication of operation of all system elements, parts, services,
374 controls, gauges and other components.
375
376 9.4 The results for the verification of operation should be documented in the OQ report to
377 indicate the satisfactory operation.
378
379 9.5 SOPs for the operation should be finalized and approved during this phase of
380 qualification.
381
382 9.6 Training of operators for the systems, utilities and equipment should be provided and
383 training records maintained.
384
385 9.7 Systems, utilities and equipment, as appropriate, should be released for PQ or routine use
386 after completion of OQ.
387
388 9.8 All calibration, cleaning, maintenance, training and related tests and results should be
389 verified to be acceptable. Any discrepancy or deviation should be recorded and investigated.
390
391 9.9 The outcome of the OQ should be recorded in the conclusion of the report, before PQ is
392 started.
393
394
395 Figure 3. Example of an operational qualification protocol
396
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397
398
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399
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400
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401
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402
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403
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404
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405
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406
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407
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408 10. PERFORMANCE QUALIFICATION

409
410 10.1 Systems, utilities and equipment should consistently perform in accordance with their
411 design specications. The performance should be veried in accordance with a PQ protocol.
412
413 10.2 There should be records for the PQ (report) to indicate the satisfactory performance over
414 a period of time. Manufacturers should justify the selected period over which PQ is done.
415
416 10.3 PQ should be done once OQ is successfully completed.
417
418 10.4 Where two stages of qualification (e.g. OQ and PQ) are performed simultaneously, or
419 where PQ is executed at the same time as process validation, appropriate justification for such a
420 decision should be documented
421
422
423 Figure 4. Example of a performance qualification protocol
424
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425
426
427
428
429
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430
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431
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432
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433
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434
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435
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436
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437 11. REQUALIFICATION

438
439 11.1 Systems, utilities and equipment should be maintained in a qualified state through the life
440 of the system, utility or equipment.
441
442 11.2 Routine requalication of systems, utilities and equipment should be considered based
443 on the outcome of risk management principles which include factors such as calibration,
444 verication and maintenance data and information.
445
446 11.3 The qualification status and requalification due dates should be documented in a dened
447 schedule.
448
449 11.4 The scope and extent of qualification should be determined based on risk assessment
450 when changes to an existing system, utility or equipment are made.
451
452 12. QUALIFICATION OF IN-USE SYSTEMS, UTILITIES AND EQUIPMENT
453
454 12.1 There should be data to support and verify the suitable design, operation and performance
455 of systems, utilities and equipment that have been in use for a period of time and which have
456 not been subjected to IQ and or OQ.
457
458 12.2 In such cases, a qualification protocol and report should be prepared where elements of
459 design, operation and performance are verified for acceptability. These should include operating
460 parameters and limits for critical variables, calibration, maintenance and preventive maintenance,
461 SOPs and records.
462

463 ***