Working document QAS/20.

849
May 2020

2 DRAFT WORKING DOCUMENT FOR COMMENTS:

3

4 Points to consider on the different approaches –

5 including HBEL – to establish carryover limits in
6 cleaning validation for identification of contamination
7 risks when manufacturing in shared facilities
8
Please send your comments to Dr Valeria Gigante, Technical Officer, Norms and Standards for
Pharmaceuticals, Technical Standards and Specifications (gigantev@who.int), with a copy to Ms Claire
Vogel (vogelc@who.int) before 30 June 2020. Please use our attached Comments Table for this purpose.
Our working documents are sent out electronically and they will also be placed on the WHO Medicines
website (http://www.who.int/medicines/areas/quality_safety/quality_assurance/guidelines/en/) for
comments under the “Current projects” link. If you wish to receive all our draft guidelines, please send
your email address to jonessi@who.int and your name will be added to our electronic mailing list.
9
10 © W o rld Health Organization 2020
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12 All rights reserved.
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14 This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The draft
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19 Please send any request for permission to: Dr Sabine Kopp, Group Lead, Norms and Standards for Pharmaceuticals, Department
20 of Access to Medicines and Health Products, World Health Organization, CH-1211 Geneva 27, Switzerland, email:
21 kopps@who.int.
22
23 The designations employed and the presentation of the material in this draft do not imply the expression of any opinion
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25 of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate
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29 recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and
30 omissions excepted, the names of proprietary products are distinguished by initial capital letters.
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33 However, the printed material is being distributed without warranty of any kind, either expressed or implied. The responsibilit y
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37 This draft does not necessarily represent the decisions or the stated policy of the World Health Organization.
38
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39 SCHEDULE FOR DRAFT WORKING DOCUMENT QAS/20.849

40 Points to consider on the different approaches – including HBEL –

41 to establish carryover limits in cleaning validation for identification
42 of contamination risks when manufacturing in shared facilities

D escription of Activity D ate

During the Fifty-third Expert Committee on Specifications for October 2018

Pharmaceutical Preparations (ECSPP), the WHO Secretariat was
recommended to revise the Appendix 3, Cleaning Validation of
Annex 3, Good manufacturing practices: guidelines on validation
(WHO Technical Report Series, No. 1025, 2019).

The update of Appendix 3, Cleaning Validation, was further July 2019

discussed during the informal consultation on Good Practices for
Health Products Manufacture and Inspection.

Following a recommendation by the ECSPP, the WHO Secretariat October 2019

was recommended to develop a Points to consider document on
cleaning validation introducing the possibility of using HBEL-based
approaches to setting safe cleaning limits and establishing a
common understanding on which to develop guidelines that are
appropriate for all stakeholders.

Preparation of first draft working document. April – May 2020

Mailing of working document to the Expert Advisory Panel on the May – June 2020
International Pharmacopoeia and Pharmaceutical Preparations
(EAP) inviting comments and posting of the working document on
the WHO website for public consultation

Discussion of working document during the informal consultation June 2020

on Good Practices for Health Products Manufacture and Inspection

Revision of the working document based on comments received July 2020

during the informal Consultation on Good Practices for Health
Products Manufacture and Inspection.

Mailing of revised working document to the EAP inviting comments August – September 2020
and posting the working document on the WHO website for public
consultation.

Consolidation of comments received and review of feedback. End of September 2020

Preparation of working document for discussion.

Presentation to the Fifty-fourth meeting of the ECSPP. 12-16 October 2020

 Working document QAS/20.849
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Any other follow-up action as required.

43
44
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45 Points to consider on the different

46 approaches – including HBEL – to
47 establish carryover limits in cleaning
48 validation for identification of
49 contamination risks when manufacturing
50 in shared facilities
51
52 1. Introduction and background
53 2. Scope
54 3. Glossary
55 4. Traditional approach
56 5. New approaches
57 References

58
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59 1. Introduction and background

60
61 The World Health Organization (WHO) has published the guideline entitled Good Manufacturing
62 Practices for pharmaceutical products: main principles in the WHO Technical Report Series, No. 986,
63 Annex 2, 2014 (1).
64
65 The WHO Supplementary guidelines on good manufacturing practice: validation were published in 2006
66 and were supported by seven appendices. In 2019, the WHO Good manufacturing practices: guidelines
67 on validation (2) were updated and republished. Some of the seven appendices were also individually
68 updated between 2013 and 2019:
69 • Appendix 1. Validation of heating, ventilation and air conditioning systems (3).
70 • Appendix 2. Validation of water systems for pharmaceutical use (4).
71 • Appendix 3. Cleaning validation (5).
72 • Appendix 4. Analytical procedure validation (6).
73 • Appendix 5. Validation of computerized systems (7).
74 • Appendix 6. Guidelines on qualification (8).
75 • Appendix 7. Non-sterile process validation (9).
76
77 Appendix 3, relating to cleaning validation (5), was not updated at that time. Its revision, however, was
78 discussed during an informal consultation held in Geneva, Switzerland, in July 2019. The outcome of
79 the discussion was presented to the WHO Expert Committee on Specifications for Pharmaceutical
80 Products (ECSPP) meeting in October 2019. The ECSPP acknowledged the importance of
81 harmonization in regulatory expectations with regards to cleaning validation approaches. The Expert
82 Committee recommended a “Points to consider” document be prepared in order to describe the
83 current approaches used in cleaning validation and highlighting the complexities involved in order to
84 establish a common understanding. A revision of the relevant appendix would then be considered by
85 the Expert Committee thereafter.
86
87 Many manufacturers produce products in multi-product facilities where there is a risk of contamination
88 and cross-contamination. Some of the main principles of good manufacturing practices (GMP) include
89 the prevention of mix-ups and the prevention of contamination and cross-contamination. It is
90 therefore important that manufacturers identify all risks for contamination and cross-contamination
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91 and identify and implement the appropriate controls to mitigate these risks. These controls include,
92 for example, technical and organizational measures, dedicated facilities, closed systems, cleaning and
93 cleaning validation.
94

95 2. Scope
96
97 The scope of this document is to discuss the different possible approaches – including methods that
98 account for pharmacological and toxicological data (Health-Based Exposure Limits {HBEL}) – that could
99 be used when establishing safe Carryover limits when manufacturing in shared facilities.
100
101 This document further provides clarification on cleaning validation and presents points to consider
102 when reviewing the current status and approaches to cleaning validation in multiproduct facilities. It
103 reflects the current regulatory guidance and expectations. It further focuses on approaches where
104 HBELs setting need to be considered in cleaning and cleaning validation approaches.
105
106 The principles should be applied in manufacturing facilities with active pharmaceutical ingredients
107 (APIs) and finished pharmaceutical products (FPPs).
108
109 This document should be read in conjunction with the main GMP text and supplementary texts on
110 validation (1-10).
111

112 3. Glossary
113
114 cleaning validation. Documented evidence to establish that cleaning procedures are removing residues
115 to predetermined levels of acceptability, taking into consideration factors such as batch size, dosing,
116 toxicology and equipment size.
117
118 contamination. The undesired introduction of impurities of a chemical or microbiological nature, or of
119 foreign matter, into or on to a starting material or an intermediate or pharmaceutical product during
120 handling, production, sampling, packaging, repackaging, storage or transport.
121
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122 cross-contamination. Contamination of a starting material, intermediate product or finished product

123 with another starting material or product during production.
124
125 margin of safety. The margin of safety is the distance between a calculated acceptance limit and the
126 actual residues after cleaning. It indicates the probability that a patient has to be exposed to the API
127 residues resulting from cleaning.
128
129 maximum safe Carryover (MSC). Mathematically calculated quantity of residue from a previous product
130 when carried over into a different product that can represent potential harm to the patients.
131
132 maximum safe surface residue (MSSR). The maximum safe surface residue is mathematically calculated
133 dividing the quantity of residue on a contact surface by the total area of contact (Maximum Safe
134 Carryover/Total Equipment Surface Area).
135
136 verification. The application of methods, procedures, tests and other evaluations, in addition to
137 monitoring, in order to determine compliance with GMP principles.
138

139 4. Traditional approach

140
141 For details on the traditional approaches in cleaning validation, see the WHO Technical Report Series,
142 No. 1019, Annexure 3, Appendix 3, 2019 (5).
143
144 One traditional approach is that cleaning validation is performed and the appropriateness of the
145 cleaning procedure was based on acceptance criteria suggested in GMP texts. This approach may no
146 longer be acceptable and justifiable as HBELs were not considered.
147
148 Where traditional acceptance limits are used, the decision should be discussed and justified as an
149 alternative to new approaches in setting acceptance criteria.
150
151 In view of the risks of contamination and cross-contamination, the new approaches, as described
152 below, should be implemented without delay.
153
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154 5. New approaches

155
156 Traditional cleaning validation approaches were often based on verifying that a cleaning procedure was
157 effective. However, in many instances, no development work or cleanability studies were performed
158 for these cleaning procedures.
159
160 Manufacturers should ensure that their cleaning is effective and appropriate and that their cleaning
161 validation provides scientific evidence that identified products can be manufactured in shared facilities
162 – with control measures implemented to mitigate the risks of contamination and cross-contamination.
163
164 This approach should include at least the following points which are further described in the text below:
165 • cleanability studies;
166 • risk assessment and risk control;
167 • technical and organizational controls;
168 • HBELs setting;
169 • analytical procedures; and
170 • cleaning verification with proven capability through statistical evaluation.
171
172 Manufacturers should describe their policy and approaches, including the points mentioned above, in
173 a document such as a master plan.
174
175 It is strongly recommended that manufacturers review their existing technical and organizational
176 measures, suitability of cleaning procedures and appropriateness of cleaning validation. Genotoxic and
177 carcinogenic substances, degradants and other contaminants should be identified and the appropriate
178 action should be taken in order to ensure that materials and products are not contaminated when
179 produced in shared facilities.
180

181 5.1 Documentation

182
183 Risk management principles, as described in other WHO guidelines on quality risk management
184 (10), should be applied to assist in identifying risks and controls to mitigate contamination and
185 cross-contamination.
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186 Procedures, protocols, reports and other related and supportive documentation should be
187 prepared, used and maintained.
188
189 The policy and approaches in cleaning and cleaning validation may be described in a Cleaning
190 Validation Master Plan. Experiments and validation should be performed in accordance with
191 predefined, authorized standard operating procedures, protocols and reports.
192
193 The design and layout of documents, and the reporting of data and information, should be in
194 compliance with the principles of good documentation practices (11) and should also meet
195 data integrity requirements (12).
196

197 5.2 Equipment

198
199 Consideration for cleaning validation should cover contact surfaces, as well as non-contact
200 surfaces, where the latter have been identified as areas of risk.
201
202 Authorized drawings of equipment should be current, accurate and available. These should be
203 used when equipment surface areas are calculated. Source data for these calculations should
204 be available. The calculated values should be used in the calculations in cleaning validation.
205
206 Equipment and components that are difficult to clean, such as sieves, screens and bags, should
207 also be included in the cleaning validation and calculations.
208

209 5.3 Detergents and solvents

210
211 Solvents and detergents used in cleaning processes should be selected with care. They should
212 also be appropriate for their intended use. The selection of the relevant solvent and detergent
213 should be justified.
214
215 There should be proof of effectiveness and appropriateness of the selected solvent and
216 detergent.
217
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218 Other points to consider include the concentration in which these are used, their composition,
219 and removal of their residues after cleaning.
220
221 The use of solvents and detergents should be included in cleanability studies.
222

223 5.4 Sampling

224
225 Traditionally, cleaning validation included the sampling of equipment and other areas in order
226 to determine whether or not there was any residue remaining on the surfaces. The focus was
227 mainly on contact surface areas. Non-contact surface areas were sometimes considered by
228 some manufacturers.
229
230 A combination of at least two or three sampling methods should be used. These include a
231 combination of swab samples, rinse samples and visual inspection.
232
233 The appropriate sampling procedures and techniques should be selected and used to collect
234 samples. These should be clearly described in procedures and protocols. The location (swab
235 sample) and the manner in which the samples are collected should be clearly described and be
236 scientifically justifiable.
237
238 The manner in which a rinse sample is collected should be described in detail. The procedure
239 should be clear and unambiguous.
240
241 The manner in which samples collected are prepared for analysis should be appropriate and
242 described in detail.
243

244 5.5 Cleanability studies

245
246 Before a cleaning procedure is validated and adopted for routine use, a cleanability study
247 should be performed in order to determine the appropriateness of the procedure for removing
248 material, product residue, cleaning agents and microorganisms.
249
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250 The lowest concentration of a substance that can be removed by following the cleaning
251 procedure should be established for different materials, intermediates and products on
252 different materials of construction. The concentration can be expressed in mg/m2.
253
254 Cleanability studies should be described in authorised documents, such as protocols and
255 procedures. The method should be scientific and may include spiking on coupons made from
256 different materials of construction. The so-called beaker method, or other appropriate
257 method, may be used.
258
259 Consideration should be given to all substances and different procedures where different
260 processes or solvents are used, including different surface materials.
261
262 The results should be documented in authorized reports and used in further determinations,
263 such as Maximum Safe Residue.
264

265 5.6 Risk assessment and risk control

266
267 Risk identification should be performed with a focus on the assessment of risks and defining
268 and implementing controls to mitigate the risk of contamination and cross-contamination.
269
270 These should include technical and organization controls, including but not limited to,
271 premises, equipment, utilities, containment, closed systems, cleaning and cleaning validation.
272

273 5.7 Technical and organizational controls

274
275 The appropriate technical and organizational controls should be defined and implemented.
276
277 Their appropriateness and effectiveness should be evaluated. Note: Cleaning and cleaning
278 validation are considered additional and supplementary controls to technical and
279 organizational controls.
280
281 Technical and organizational controls should be justifiable and clearly documented.
282
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283 Technical controls, such as the design of the premises and utilities (e.g. heating, ventilation and
284 air-conditioning {HVAC}, water and gas), should be appropriate for the range of products
285 manufactured (e.g. pharmacological classification, activities and properties).
286
287 Organizational controls, such as dedicated equipment, procedural control, and campaign
288 production, should be considered where appropriate as a means to reduce the risk of cross-
289 contamination.
290

291 5.8 Health Based Exposure Limits (HBELs) setting

292
293 Manufacturers should establish, document and implement a company-wide policy on HBELs
294 setting for shared facilities.
295
296 APIs and products manufactured in shared facilities should be reviewed based on scientific
297 evidence in order to determine whether production and control activities in shared facilities
298 may be considered acceptable or whether dedicated facilities are required for the production
299 and control of identified products.
300
301 This is applicable to legacy products as well as the introduction of new products introduced
302 into a facility through a change control procedure.
303
304 Procedures should be established and implemented describing how scientific data and
305 toxicological information on HBELs should be obtained.
306
307 Data and information should be gathered and presented in a report. The data should be free
308 from bias. Where this service is outsourced, the appropriate measures should be put in place
309 in order to ensure that the data obtained are reliable. GMP requirements, such as vendor
310 qualification, agreements and other related aspects, should be considered.
311
312 The report should include scientific detail, including information on:
313 • chemical structure;
314 • hazard identification;
315 • mode of action;
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316 • identification of critical effects;

317 • establishing NOAELs (no-observed-adverse-effect level);
318 • adjustment factors;
319 • pre-clinical, clinical and non-clinical data;
320 • pharmacokinetics and pharmacodynamics;
321 • expert assessment;
322 • identification of the critical effect;
323 • assignment of adjustment factors (AF);
324 • argumentation for the selected HBEL;
325 • routes of administration;
326 • point of departure (POD);
327 • justification for critical effect of POD; and
328 • justification for factor.
329
330 The Permitted Daily Exposure (PDE) should be calculated based on the data and information
331 obtained. For example:
332
333 PDE = NOAEL x weight adjustment
334 F1 x F2 x F3 x F4 x F5
335
336 Where NOAEL is no-observed adverse event level, and
337 F represents various factors. The value selected should be justifiable.
338
339 The report should be reviewed by the manufacturer’s in-house team for completeness and
340 appropriateness. Team members should have the appropriate qualifications and experience in
341 the field of toxicology. A summary report should be prepared for each product and contain
342 information on the PDE value, genotoxicity and carcinogenicity (13).
343
344 These scientific reports should be used when considering the cleaning validation control
345 measures.
346
347 Manufacturers should periodically review and update PDE reports. The appropriate action
348 should be taken where such a report needs to be updated.
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349 5.9 Acceptance criteria

350
351 Limits established in cleaning validation should be justifiable.
352
353 Manufacturers often specified acceptance limits based on historical GMP texts. These
354 traditional limits may no longer be acceptable as HBELs (PDE) and cleanability studies were not
355 performed in many cases.
356
357 Criteria such as Margin of safety, Maximum Safe Carryover (MSC) and Maximum Safe Surface
358 Residue (MSSR) values should be calculated. Calculations and data should be available and
359 comply with data integrity principles. The calculation should include values of PDE, maximum
360 daily dose, batch size and equipment surface areas.
361
362 Maximum Safe Surface Residue (MSSR) should be calculated and presented, for example, in
363 table form listing preceding and following product values. The cleanability value obtained
364 should be considered in determining the acceptability of the procedure(s) and whether other
365 controls including separate, dedicated facilities are required. (See Annex 1 as an example.)
366

367 5.10 Grouping by therapeutic use

368
369 The risk associated with contamination and cross-contamination from one product to another
370 product in one therapeutic group, and between products in different therapeutic groups in
371 shared facilities, should be considered. For example, due to the risk, certain products should
372 be manufactured in dedicated or segregated self-contained facilities, including certain
373 antibiotics, certain hormones, certain cytotoxics and certain highly-active drugs – even though
374 these are in the same therapeutic class.
375
376 The risk assessment should include, for example, PDE values, batch size, maximum daily dose
377 of the next product, as well as other criteria associated with cleaning.
378
379 The higher the PDE value, the lower the risk. The products and therapeutic groups considered
380 for manufacturing should be plotted based on an identified scale of risk (14, 15). An illustration
381 is presented in figure 1 where hazard is plotted against risk
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382 Fig ure 1. Increasing hazard and PDE values

Increasing hazard

Health Based Exposure Limit (HBEL) – PDE

>10 000ug/day <10ug/day

383

384 5.11 Analytical procedures

385
386 Samples obtained in cleaning validation should be analyzed by using specific, validated
387 procedures. The procedures should be developed, validated and appropriate for their intended
388 use.
389
390 Specific methods, such as HPLC, should be used where possible. Non-specific methods
391 including UV spectrophotometry should only be used where specific methods cannot be
392 employed.
393
394 Testing for total organic carbon (TOC) may be used where indicated and where justified.
395
396 Analytical procedures validation should be done on-site. Where analytical procedures were
397 developed and validated off-site, the scope and extent of validation should be defined and
398 justified. This includes procedures that are transferred from research and development
399 laboratories to site laboratories. (For analytical procedure validation, see reference 6).
400
401 Manufacturers should ensure that the procedures remain in a validated state.
402
403
404
405
406
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407 5.12 Data integrity

408
409 Data, information and results pertaining to, for example, HBELs, PDE reports, results obtained
410 from cleaning validation and calculations should be scientific and should be in compliance with
411 the principles as contained in data integrity guidelines (12).
412

413 5.13 Cleaning validation and cleaning verification

414
415 The cleaning procedure should be validated after the cleaning procedure had been developed
416 and the cleanability study had been done.
417
418 Cleaning validation should include proof of, for example, the applicability of the procedure to
419 clean equipment that:
420 • had been kept in an unclean state for a period of time (dirty equipment hold time);
421 • are used after product change-over;
422 • are used in a campaign, where multiple batches of a product are produced one after
423 the other; and/or
424 • are stored in a clean state for defined periods of time (clean equipment hold time).
425
426 Cleaning validation should include consideration of HBELs when the appropriate method used
427 in establishing Carryover limits. Where HBELs are not used, scientific justification should be
428 provided.
429
430 The company should describe the policy and approach to cleaning verification. The
431 effectiveness of the validated cleaning procedure should be routinely verified. The approach
432 may include swab or rinse samples. The results obtained from testing on a routine basis should
433 be reviewed and subjected to statistical trending.
434

435 5.14 Visually clean

436
437 Visually clean is an important criterion in cleaning validation and should be one of the
438 acceptance criteria used on a routine basis.
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439 Visible residue limits (VRLs) should be determined. The process to determine the limit should
440 be appropriately described in procedures and protocols including concentrations, method of
441 spiking, surface areas, material of construction and other conditions such as light and angles.
442
443 VRLs should be quantitatively established for APIs, excipients, detergents and pharmaceutical
444 products.
445
446 Visual Detection Index (VDI) may be calculated using MSSR.
447

448 5.15 Cleaning verification and process capability

449
450 The cleaning procedure should remain in a validated state. Cleaning verification and process
451 capability may be used to provide data to support this. For example, the results from cleaning
452 verification sample analysis could be statistically trended. The capability of the cleaning
453 process is then calculated through an appropriate statistical process.
454
455 The presentation of individual results and data used in the calculation, such as with a Central
456 Processing Unit (Cpu) and acceptable daily exposure (ADE) base limit, should meet ALCOA
457 principles.
458
459 Data should be presented, for example, in graph form, and the capability of the process in
460 relation to control limits and the margin of safety should be discussed as part of continuous
461 improvement.

462

463 5.16 Personnel

464
465 Personnel should be trained in the principles of cleaning validation, with an emphasis on
466 contamination and cross-contamination control, HBELs setting, equipment disassembly,
467 sampling, testing and statistical calculations.
468
469
470
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471 5.17 Quality metrics and performance indicators

472
473 Aspects of HBELs setting, cleanability studies, cleaning validation and cleaning verification, as
474 well as process capability, should be considered in quality metrics, with performance indicators
475 identified and to be monitored.
476

477 5.18 Life cycle

478
479 HBEL reports, protocols, cleaning validation and cleaning verification should be included in a
480 company policy and life cycle approach in preventing cross-contamination in shared facilities.
481
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482 References
483
484 1. Guidelines on good manufacturing practices for pharmaceutical products: main principle. In:
485 WHO Expert Committee on Specifications for Pharmaceutical Preparations, forty-eighth report.
486 Geneva: World Health Organization; 2013: Annex 2 (WHO Technical Report Series, No. 986;
487 https://www.who.int/medicines/areas/quality_safety/quality_assurance/TRS986annex2.pdf?
488 ua=1, accessed 4 May 2020).
489 2. Good Manufacturing Practices: Guidelines on Validation. In: WHO Expert Committee on
490 Specifications for Pharmaceutical Preparations, fifty-third report. Geneva: World Health
491 Organization; 2019: Annex 3 (WHO Technical Report Series, No. 1019;
492 http://digicollection.org/whoqapharm/documents/s23430en/s23430en.pdf, accessed 5 May
493 2020).
494 3. Guidelines on heating ventilation and air-conditioning systems for non-sterile pharmaceutical
495 products and Part 2: interpretation of guidelines on heating ventilation and air-conditioning
496 systems for non-sterile pharmaceutical products. In: WHO Expert Committee on Specifications
497 for Pharmaceutical Preparations: fifty-third report. Geneva: World Health Organization; 2019:
498 Annex 2 (WHO Technical Report Series, No. 1019; https://www.who.int/
499 medicines/areas/quality_safety/quality_assurance/WHO_TRS_1019_Annex3.pdf?ua=1,
500 accessed 4 May 2020).
501 4. Good manufacturing practices: guidelines on validation. Appendix 4. Validation of water
502 systems for pharmaceutical use. In: WHO Expert Committee on Specifications for
503 Pharmaceutical Preparations, fortieth report. Geneva: World Health Organization; 2006: Annex
504 3 (WHO Technical Report Series, No. 937; https://www.who.int/medicines/areas/
505 quality_safety/quality_assurance/WHO_TRS_1019_Annex3.pdf?ua=1 accessed 4 May 2020).
506 5. Good manufacturing practices: guidelines on validation. Appendix 3. Cleaning validation. In:
507 WHO Expert Committee on Specifications for Pharmaceutical Preparations: fifty-third report.
508 Geneva: World Health Organization; 2019: Annex 3 (WHO Technical Report Series, No. 1019;
509 https://www.who.int/medicines/areas/quality_safety/quality_assurance/WHO_TRS_1019_An
510 nex3.pdf?ua=1, accessed 4 May 2020).
511 6. Good manufacturing practices: guidelines on validation. Appendix 4. Analytical procedure
512 validation. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations: fifty-
513 third report. Geneva: World Health Organization; 2019: Annex 3 (WHO Technical Report Series,
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514 No. 1019; https://www.who.int/medicines/areas/quality_safety/quality_assurance/

515 WHO_TRS_1019_Annex3.pdf?ua=1, accessed 4 May 2020).
516 7. Good manufacturing practices: guidelines on validation. Appendix 5. Validation of
517 computerized systems. In: WHO Expert Committee on Specifications for Pharmaceutical
518 Preparations: fifty-third report. Geneva: World Health Organization; 2019: Annex 3 (WHO
519 Technical Report Series, No. 1019; https://www.who.int/medicines/areas/
520 quality_safety/quality_assurance/WHO_TRS_1019_Annex3.pdf?ua=1, accessed 4 May 2020).
521 8. Good manufacturing practices: guidelines on validation. Appendix 6. Guidelines on
522 qualification. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations:
523 fifty-third report. Geneva: World Health Organization; 2019: Annex 3 (WHO Technical Report
524 Series, No. 1019; https://www.who.int/medicines/areas/quality_safety/quality_assurance/
525 WHO_TRS_1019_Annex3.pdf?ua=1, accessed 4 May 2020).
526 9. Guidelines on good manufacturing practices: validation, Appendix 7: non-sterile process
527 validation. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations:
528 forty-ninth report. Geneva: World Health Organization; 2015: Annex 3 (WHO Technical Report
529 Series, No. 992; https://www.who.int/medicines/areas/quality_safety/quality_assurance/
530 Annex3-TRS992.pdf?ua=1, accessed 4 May 2020).
531 10. WHO guidelines on quality risk management. In: WHO Expert Committee on Specifications for
532 Pharmaceutical Preparations: forty-seventh report. Geneva: World Health Organization; 2013:
533 Annex 2 (WHO Technical Report Series, No. 981; https://www.who.int/
534 medicines/areas/quality_safety/quality_assurance/Annex2TRS-981.pdf, accessed 4 May
535 2020).
536 11. Guidance on good data and record management practices. In: WHO Expert Committee on
537 Specifications for Pharmaceutical Preparations: fiftieth report. Geneva: World Health
538 Organization; 2016: Annex 5 (WHO Technical Report Series, No. 996;
539 https://www.who.int/medicines/publications/pharmprep/WHO_TRS_996_annex05.pdf,
540 accessed 4 May 2020).
541 12. Guideline on data integrity. Draft for comments. Geneva: World Health Organization; 2019
542 (working document QAS/19.819; https://www.who.int/medicines/areas/quality_safety/
543 quality_assurance/QAS19_819_data_integrity.pdf?ua=1, accessed 4 February 2020).
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545 manufacture of different medicinal products in shared facilities, European Medicines Agency,
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556 ***