Working document QAS/20.

863
November 2020

1
2

3 DRAFT WORKING DOCUMENT FOR COMMENTS:

4

5 Good manufacturing practices

6 for investigational products
7
8
Please send your comments to Dr Sabine Kopp, Team Lead, Norms and Standards for Pharmaceuticals,
Technical Standards and Specifications (kopps@who.int), with a copy to Ms Claire Vogel
(vogelc@who.int) before 6 January 2021. Please use the “Table of Comments” attached to this email for
this purpose.
Our working documents are sent out electronically and they will also be placed on the WHO Medicines
website (https://www.who.int/teams/health-product-and-policy-standards/standards-and-
specifications/pharmaceuticals/current-projects) for comments under the “Working documents in public
consultation” 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.
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10
11
12 © World Health Organization 2020
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14 All rights reserved.
15
16 This is a draft. The content of this document is not final, and the text may be subject to revisions before publication. The
17 document may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or
18 in whole, in any form or by any means without the permission of the World Health Organization.
19
20 Please send any request for permission to: Dr Sabine Kopp, Team Lead, Norms and Standards for Pharmaceuticals, Technical
21 Standards and Specifications, Department of Health Products Policy and Standards, World Health Organization, CH-1211
22 Geneva 27, Switzerland, email: kopps@who.int.
23
24 The designations employed and the presentation of the material in this draft do not imply the expression of any opinion
25 whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or
26 of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate
27 border lines for which there may not yet be full agreement.
28
29 The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or
30 recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors
31 and omissions excepted, the names of proprietary products are distinguished by initial capital letters.
32
33 All reasonable precautions have been taken by the World Health Organization to verify the information contained in this draft.
34
35 However, the printed material is being distributed without warranty of any kind, either expressed or implied. The responsibility
36 for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable
37 for damages arising from its use.
38
39 This draft does not necessarily represent the decisions or the stated policy of the World Health Organization.
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41 SCHEDULE FOR DRAFT WORKING DOCUMENT QAS/20.863:

42 Good manufacturing practices

43 for investigational products
44

Description of Activity Date

Following a recommendation by the Fifty-fifth Expert Committee October 2020

on Specifications for Pharmaceutical Preparations (ECSPP), the
WHO Secretariat was recommended to revise the existing
guideline on good manufacturing practices for investigational
products.

Preparation of first draft working document. October 2020

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

Consolidation of comments received and review of feedback. January 2021

Preparation of working document for discussion.

Discussion of the feedback received on the working document in a February-March 2021

virtual meeting with an expert working group

Preparation of working document for next round of public March 2021

consultation.

Mailing of revised working document inviting comments, including

to the EAP, and posting the working document on the WHO
April 2021
website for a second round of public consultation.

Consolidation of comments received and review of feedback. June – July 2021

Preparation of working document for discussion.

Discussion of the feedback received on the working document in a August 2021

virtual meeting with an expert working group

Presentation to the Fifty-sixth meeting of the ECSPP. October 2021

Any other follow-up action as required.

45
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46 Good manufacturing
47 practices
48 for investigational
49 products
50
51 1. Background
52 2. Introduction
53 3. Scope
54 4. Quality management
55 5. Quality risk management
56 6. Personnel
57 7. Documentation
58 • Specifications
59 • Order
60 • Product specification file(s)
61 • Manufacturing formulae and processing instructions
62 • Packaging instructions
63 • Labelling instructions
64 • Batch manufacturing records
65 • Coding (or randomization) systems
66 8. Premises
67 9. Equipment and utilities
68 10. Materials
69 11. Production
70 12. Quality control
71 13. Qualification and validation
72 14. Complaints
73 15. Recalls
74 16. Returns
75 17. Shipping
76 18. Destruction
77
78 Glossary
79 Abbreviations
80 References and further reading
81
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82 1. Background
83
84 1.1. In view of an old publication date, and the recent need for new guidelines arising from
85 inspections carried out for COVID-19 therapeutics, the World Health Organization (WHO)
86 Prequalification Team - Inspection Services (PQT INS) raised the urgency for a revision of the
87 WHO Good manufacturing practices for investigational pharmaceutical products for clinical
88 trials in humans (1). The Fifty-fifth Expert Committee on Specifications for Pharmaceutical
89 Preparations (ECSPP) concurred with this proposal.
90
91 1.2. The objective of this update is to bring the guideline in line with current expectations and
92 trends in good manufacturing practices and to harmonize the text with the principles from
93 other related international guidelines.
94

95 2. Introduction
96
97 2.1. Investigational products are used for testing purposes; as a reference in a clinical trial; for an
98 unauthorized indication; and to gain further information about the authorized form.
99
100 2.2. In some cases, marketed products which have been re-packaged or modified in some way, are
101 used for investigational purposes.
102
103 2.3. The legal status of investigational products for human and veterinary use varies from
104 country to country.
105
106 2.4. These products are sometimes not covered by legal and regulatory provisions in the areas
107 of good practices (GxP) and inspection. These complexities, such as lack of high level good
108 manufacturing practices (GMP) requirements, risk of contamination and cross-
109 contamination, clinical trial designs, blinding and randomization, increase the risk. In
110 addition, there are also instances where there is incomplete knowledge of the potency and
111 toxicity of the investigational product.
112
113 2.5. There are further risks associated with the production, validation, control, shipping, storage
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114 and use of investigational products.

115
116 2.6. To minimize risks and to ensure that the results of clinical trials are unaffected by inadequate
117 safety, quality or efficacy arising from unsatisfactory manufacture, investigational products
118 should be manufactured and managed in accordance with an effective quality management
119 system and the recommendations contained in this guideline.
120
121 2.7. Other guidelines and GxP should be taken into account, where relevant and as appropriate, as
122 to the stages of development, production and control of the product.
123
124 2.8. Procedures should be flexible to provide for changes whenever necessary, as knowledge of the
125 process increases over time, and in accordance with the stages of development of the product.
126
127 2.9. Investigational products should be manufactured in a manner:
128 • that is compliant to GxP, as appropriate;
129 • that ensures that subjects of clinical trials will be protected from poor quality
130 products due to unsatisfactory manufacturing;
131 • to assure consistency between and within batches of the investigational product;
132 and
133 • to assure consistency between the investigational product and the future
134 commercial product.
135
136 2.10. The selection of an appropriate dosage form for clinical trials is important. While it is
137 accepted that the dosage form may be very different from the anticipated final formulation
138 (e.g. a capsule instead of a tablet) in early trials, in the pivotal Phase III studies, it should be
139 similar to the projected commercial presentation; otherwise these trials will not necessarily
140 prove that the marketed product is both efficacious and safe. If there are significant differences
141 between the clinical and commercial dosage forms, data should be submitted to the registration
142 authorities to demonstrate that the final dosage form is equivalent, in terms of bioavailability
143 and stability, to that used in the clinical trials.
144
145 2.11. The quality of investigational products should be appropriate. For example, dosage forms in
146 Phase III clinical studies should be characterized and assured at the same level, as for routinely
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147 manufactured products.

148
149 2.12. Where production and/or quality control is transferred from one site to another, the
150 recommendations in the guideline for transfer of technology should be followed.
151
152 2.13. This document should be read in conjunction with other WHO GxP guidelines, including
153 good clinical practice (GCP) (2).
154

155 3. Scope
156
157 3.1. The recommendations in this guideline are applicable to investigational products for human
158 and veterinary use.
159
160 3.2. Although the focus is on medicinal (pharmaceutical) products, some of the principles may be
161 applied to other investigational products.
162

163 4. Quality management

164
165 4.1. There should be a comprehensively designed, clearly defined, documented and correctly
166 implemented quality management system in place. Senior management should assume
167 responsibility for this as well as the quality of the investigational product.
168
169 4.2. All parts of the quality system should be adequately resourced and maintained.
170
171 4.3. The quality system should incorporate GxP which would be applied to all the lifecycle stages of
172 the products, including the transfer of technology, and the interface between the manufacture
173 and the trial site (e.g. shipment, storage, labelling).
174
175 4.4. The quality system should ensure that:
176 • products are designed and developed in accordance with the requirements of this
177 document and other associated guidelines such as good laboratory practice (GLP) (3),
178 good clinical practice (GCP) (2) and good storage and distribution practices (GSDP) (4),
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179 where appropriate;

180 • managerial responsibilities are clearly specified in job descriptions;
181 • operations are clearly specified in a written form;
182 • arrangements are made for the manufacture, supply and use of the correct starting
183 and packaging materials;
184 • all necessary controls on starting materials, intermediate products, bulk products and
185 other in-process controls should be in place;
186 • calibrations and validations are carried out where necessary;
187 • the finished product is correctly processed and checked according to the defined
188 procedures;
189 • deviations and changes are investigated and recorded with an appropriate level of root
190 cause analysis done and appropriate corrective actions and/or preventive actions
191 (CAPAs) identified and taken;
192 • there is a system for quality risk management (5); and
193 • satisfactory arrangements exist to ensure, as far as possible, that the investigational
194 products are stored, distributed and subsequently handled so that their quality is
195 maintained.
196

197 5. Quality risk management

198
199 5.1. There should be a system for quality risk management.
200
201 5.2. The system for quality risk management should cover a systematic process for the assessment,
202 control, communication and review of risks to the quality of the product and, ultimately, to the
203 protection of the trial subject and patient.
204
205 5.3. The quality risk management system should ensure that:
206 • the evaluation of the risk is based on scientific knowledge and experience with the
207 process and product;
208 • procedures and records for quality risk management are retained; and
209 • the level of effort, formality and documentation of the quality risk management
210 process is commensurate with the level of risk.
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211
212 5.4. Quality risk management should be applied both proactively and retrospectively, when
213 appropriate.
214

215 6. Personnel
216
217 6.1. There should be a sufficient number of appropriately qualified personnel available to carry out
218 all the tasks for which the manufacturer of investigational products is responsible.
219
220 6.2. Individual responsibilities should be clearly defined, recorded as written descriptions and
221 understood by the persons concerned.
222
223 6.3. A designated person, with a broad knowledge of product development and clinical trial
224 processes should ensure that there are systems in place that meet the requirements of this
225 guideline and other relevant GxP guidelines.
226
227 6.4. Personnel involved in the development, production and control of investigational products
228 should be appropriately trained in relevant GxP and the requirements specific to investigational
229 products.
230
231 6.5. Production and quality control operations should be carried out under the control of
232 clearly identified responsible persons who are separately designated and independent,
233 one from the other.
234

235 7. Documentation
236
237 7.1. Good documentation is an essential part of a quality management system. Documents should
238 be appropriately designed, prepared, reviewed and distributed. They should also be
239 appropriate for their intended use.
240
241 7.2. Documents should be approved, signed and dated by the appropriate responsible persons. No
242 authorized document should be changed without the prior authorization and approval of
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243 another.
244
245 Specifications
246
247 7.3. Specifications (for starting materials, primary packaging materials, intermediate, bulk and
248 finished products) should be available.
249
250 7.4. In developing specifications, attention should be paid to the characteristics which affect
251 the efficacy and safety of products, namely:
252 • the accuracy of the therapeutic or unitary dose: homogeneity, content uniformity;
253 • the release of active ingredients from the dosage form: dissolution time, etc.;
254 • the package size should be suitable for the requirements of the trial, where
255 applicable;
256 • the estimated stability, if necessary, under accelerated conditions; and
257 • the preliminary storage conditions and the shelf life of the product.
258
259 7.5. As a result of new experience in the development of an investigational product, specifications
260 may be changed by following a documented procedure. Changes should be authorized by a
261 responsible person. Each new version should take into account the latest data and
262 information, current technology, regulatory and pharmacopoeia requirements. There should
263 be traceability of the previous version(s). The reasons for changes should be recorded. The
264 impact of the change on any on-going clinical trials, on product quality, stability, bio-availability,
265 and bio equivalence (where applicable) should be considered.
266
267 Order
268
269 7.6. An order should be available for the request of a certain number of units for processing,
270 packaging, storage and their shipping.
271
272 7.7. The order should be given by the sponsor to the manufacturer of an investigational product.
273
274 7.8. The order should be in writing (e.g. by paper or electronic means), be authorized and
275 contain sufficient detail including the approved product specification file (see below) and
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276 the relevant clinical trial protocol, as appropriate, to avoid any ambiguity.
277
278 7.9. Where commercially available products are obtained to be used as reference products,
279 such as for use in bio-equivalence studies, the relevant documentation, such as a purchase
280 order, an invoice, storage and transport records, should be maintained and available for
281 inspection.
282
283 Product specification file(s)
284
285 7.10. A product specification file (or files) should contain the information necessary to prepare
286 detailed written instructions on processing, packaging, quality control testing, batch
287 release, storage conditions and/or shipping.
288
289 7.11. The product specification file should indicate who has been designated or trained as the
290 designated responsible person(s) for the release of batches.
291
292 7.12. The product specification file should be continuously updated while, at the same time,
293 ensuring appropriate traceability to the previous version(s).
294
295 7.13. The information should form the basis for assessment of the suitability for certification and
296 release of a particular batch by the designated responsible person. It should include or refer
297 to the following documents:
298 • specifications for starting materials, packaging materials, intermediate, bulk and
299 finished product;
300 • analytical methods for starting materials, packaging materials, intermediate, bulk and
301 finished product;
302 • manufacturing methods;
303 • in-process testing and methods;
304 • approved label;
305 • relevant clinical trial protocols;
306 • randomization codes, as appropriate;
307 • relevant technical agreements, as appropriate;
308 • stability data; and
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309 • storage and shipment conditions.

310
311 Note: The contents will vary depending on the product and stage of development.
312
313 Manufacturing formulae and processing instructions
314
315 7.14. Normally, detailed manufacturing formulae, processing and packaging instructions and
316 records should be available. Where this is not possible, other clear, written instructions and
317 written records should be available for every manufacturing operation or supply.
318
319 7.15. As a result of new experience in the development of an investigational product, manufacturing
320 formulae and processing instructions may be changed by following a documented procedure.
321 Each new version should take into account the latest data and information, current technology,
322 regulatory and other requirements. There should be traceability to previous versions. The
323 reasons for changes should be recorded. The impact of the change on any on-going clinical
324 trial, product quality, stability, bio-availability and bio equivalence (where applicable) should be
325 considered. Changes should be authorized by a responsible person.
326
327 7.16. These records should be used when preparing the final version of the documents to be
328 used in routine manufacture.
329
330 7.17. Batch processing and packaging records should be retained for at least two years after the
331 termination or discontinuance of the clinical trial, or after the approval of the investigational
332 product.
333
334 7.18. Where the data are intended for inclusion in an application for product registration (marketing
335 authorization) purposes, the records should be maintained until the end of the life cycle of the
336 product.
337
338 Packaging instructions
339
340 7.19. The number of units to be packaged should be specified before the start of the packaging
341 operation. This should include the number of units necessary for carrying out quality controls
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342 and the number of samples from each batch used in the clinical trial to be kept as retention
343 samples. Reconciliation should be carried out at defined intervals, where required, and at the
344 end of the packaging and labelling process.
345
346 7.20. Investigational products may be packed in an individual way for each subject included in the
347 clinical trial, or as bulk if required.
348
349 Labelling instructions
350
351 7.21. Investigational products should be labelled in accordance with relevant legislation or best
352 practices. The label should contain information such as:
353 • the name, address and telephone number of the sponsor, contract research
354 organization or investigator;
355 • the statement: "For clinical research use only";
356 • a reference number indicative of the trial, site, investigator and sponsor, if not given
357 elsewhere;
358 • a batch or code number;
359 • the trial subject or patient identification number;
360 • a reference to the directions for use;
361 • information on storage conditions;
362 • an expiry date, use-by date or re-test date (month and year);
363 • a dosage form and route of administration;
364 • the quantity of dosage units and, in the case of open trials, the name/identifier and
365 strength/potency; and
366 • the statement: “Keep out of reach of children”.
367
368 7 . 2 2 . Additional information may be displayed in accordance with the order (e.g. treatment period,
369 standard warnings).
370
371 7.23. When necessary for blinding purposes, the batch number may be provided separately (see also
372 "Blinding operations").
373
374 7.24. A copy of each type of label should be kept in the batch packaging record.
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375 7.25. The address and telephone number of the main contact for information on the product, clinical
376 trial and for emergency unblinding need not appear on the label where the subject has been
377 given a leaflet or card which provides these details and who has been instructed to keep this in
378 their possession at all times.
379
380 7.26. Particulars should appear in the official language(s) of the country in which the investigational
381 medicinal product is to be used.
382
383 7.27. Where all the required information cannot be displayed on primary packaging, secondary
384 packaging should be provided bearing a label with those particulars. The primary packaging
385 should nevertheless contain information such as the name of sponsor, contract research
386 organization or investigator; route of administration; batch and/or code number; trial
387 reference code and the trial subject identification number.
388
389 7.28. Symbols or pictograms may be included to clarify certain information. Warnings and/or
390 handling instructions may be displayed.
391
392 7.29. If it becomes necessary to change the use-by date, an additional label should be affixed to the
393 investigational medicinal product. This additional label should state the new use-by date and
394 repeat the batch number. This labelling activity should be performed in accordance with GMP
395 principles, standard operating procedures and should be checked by a second person. This
396 additional labelling should be recorded in both the trial documentation and in the batch
397 records.
398
399 Batch manufacturing records
400
401 7.30. Processing, packaging and testing records should be kept in sufficient detail for the sequence
402 of operations to be accurately traced. They should contain any relevant remarks which
403 increase the existing knowledge of the product, allow and reflect changes and improvements
404 in the manufacturing operations, and justify the procedures used.
405
406
407
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408 Coding (or randomization) systems

409
410 7.31. Procedures should be established for the generation, security, distribution, handling and
411 retention of any randomization code used in packaging investigational products and code-
412 break mechanisms. The appropriate records should be maintained.
413
414 7.32. The coding system must permit the determination of the identity of the actual treatment
415 product received by individual subjects, without delay, in an emergency situation.
416

417 8. Premises
418
419 8.1. Premises, where investigational products are manufactured, should be located, designed,
420 constructed and maintained to suit the operations to be carried out.
421
422 8.2. The layout and design of premises should aim to minimize the risk of errors and mix-ups and permit
423 effective cleaning and maintenance in order to avoid contamination, cross-contamination and, in
424 general, any adverse effect on the quality of the products.
425
426 8.3. Attention should be paid to line clearance in order to avoid mix-ups.
427
428 8.4. Because the toxicity of some materials may not be fully known, cleaning is of particular
429 importance. Validated cleaning procedures should be followed in order to prevent cross-
430 contamination. The visual inspection after cleaning, sampling and test procedures should
431 be appropriate and the acceptance limits used after cleaning should be justifiable. Where
432 cleaning agents are used, their selection should be justifiable.
433
434 8.5. Where identified through risk assessment, campaign production should be considered. In
435 other cases based on risk, dedicated and self-contained facilities should be used.
436

437 9. Equipment and utilities

438
439 9.1. Equipment and utilities should be selected, located, constructed and maintained to suit the
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440 operations to be carried out.

441
442 9.2. The layout, design, installation and use of equipment and utilities should aim to minimize the
443 risk of errors and permit effective cleaning and maintenance in order to avoid cross-
444 contamination, a build-up of dust or dirt and, in general, any adverse effect on the quality of
445 products.
446

447 10. Materials

448
449 Starting materials
450
451 10.1. The consistency of the production of investigational products may be influenced by the
452 quality of the starting materials. Their physical, chemical and, when appropriate,
453 microbiological properties should therefore be defined, documented in their specifications,
454 and controlled.
455
456 10.2. Existing compendial standards, when available, should be taken into consideration.
457
458 10.3. Specifications for active ingredients should be as comprehensive as possible, given the current
459 state of knowledge.
460
461 10.4. Specifications for both active ingredients and excipients should be periodically reassessed and
462 updated as required.
463
464 10.5. Detailed information on the quality of active ingredients and excipients (as well as of packaging
465 materials) should be available so as to make it possible to recognize and, as necessary, allow
466 for any variation in production.
467
468 Chemical and biological reference standards for analytical purposes
469
470 10.6. Reference standards from reputable sources (WHO or national standards) should be used, if
471 available; otherwise the reference substance(s) for the active ingredient(s) should be prepared,
472 tested and released as reference material(s) by the producer of the investigational
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473 pharmaceutical product, or by the producer of the active ingredient( s) used in the manufacture
474 of that product.
475
476 Principles applicable to reference products for clinical trials
477
478 10.7. In studies in which an investigational product is compared with a marketed product, steps
479 should be taken in order to ensure the integrity and quality of the reference products (final
480 dosage form, packaging materials, storage conditions, etc.).
481
482 10.8. If significant changes are to be made in the product, data should be available (e.g. on
483 stability, comparative dissolution) that demonstrate that these changes do not influence the
484 original quality characteristics of the product.
485

486 11. Production

487
488 11.1. Products intended for use in clinical trials (late Phase II and Phase III studies) should, as far
489 as possible, be manufactured at a licensed facility. The batch size for investigational
490 products manufactured in a pilot plant or small-scale facility, as opposed to the commercial
491 batch size, may vary widely.
492
493 11.2. The guidelines in this document are applicable to the following licensed facilities:
494 • a pilot plant, primarily designed and used for process development; and
495 • a small-scale facility (sometimes called a "pharmacy"), separate both from the
496 company's pilot plant and from routine production.
497
498 11.3. Facilities, as listed below, should be subject to all GMP requirements for pharmaceutical
499 products;
500 • a large-scale production line assembled to manufacture materials in larger batches
501 (e.g. for late Phase III trials and first commercial batches); and
502 • the normal production line used for licensed commercial batches, and sometimes
503 for the production of investigational products if the number of, for example,
504 ordered ampoules, tablets or other dosage forms, is large enough.
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505 11.4. Where activities are outsourced to contract facilities, the contract must then clearly state,
506 inter alia, the responsibilities of each party, compliance with GMP or of this guideline, and
507 that the product(s) to be manufactured or controlled are intended for use in clinical trials.
508 Close cooperation between the contracting parties is essential.
509
510 Manufacturing operations
511
512 11.5. As process validation may not always be complete during the development phase of
513 products, provisional quality attributes, process parameters and in-process controls should
514 be identified, based on risk management principles and experience with analogous
515 products.
516
517 11.6. The necessary instructions should be identified and may be adapted based on the
518 experience gained in production.
519
520 11.7. Where processes such as mixing have not been validated, additional quality control testing may
521 be necessary.
522
523 11.8. For sterile investigational products, the assurance of sterility should be no less than for licensed
524 products (see GMP for sterile products (6)).
525
526 Packaging and labelling
527
528 11.9. The packaging and labelling of investigational products are likely to be more complex and more
529 liable to errors (which are also harder to detect) when "blinded" labels are used than for
530 licensed products. Supervisory procedures such as label reconciliation, line clearance, and so
531 on, and the independent checks by quality unit personnel, should be intensified accordingly.
532
533 11.10. The packaging must ensure that the investigational product remains in good condition during
534 transport and storage. Any opening of, or tampering with, the outer packaging during transport
535 should be readily discernible.
536
537
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538 Blinding operations

539
540 11.11. In the preparation of "blinded" products, the blind should be maintained until it is required to
541 allow for the identification of the “blinded” product. In-process control should include a check
542 on the similarity in appearance and any other required characteristics of the different products
543 being compared.
544
545 11.12. A coding system should be introduced to permit the proper identification of "blinded"
546 products. The code, together with the randomization list, must permit the proper identification
547 of the product, including any necessary traceability to the codes and batch number of the
548 product before the blinding operation.
549

550 12. Quality control

551
552 12.1. Quality control should cover, for example, the sampling and testing of materials and products,
553 ensuring that these are not released for use, sale or supply until their quality has been judged
554 to be compliant with the specifications.
555
556 12.2. Each batch of product should be tested in accordance with a Product Specification File and
557 should meet its specification. Product release is often carried out in two stages; that is, before
558 final packaging (bulk product testing) and after final packaging (finished product testing).
559
560 12.3. Bulk product testing should cover all relevant factors including production conditions, the
561 results of in-process testing, a review of manufacturing documentation and compliance with
562 the Product Specification File and the order. Finished product testing should cover, in addition
563 to the bulk product assessment, all relevant factors including packaging conditions, the results
564 of in-process testing, a review of packaging documentation and compliance with the Product
565 Specification File and the order.
566
567 12.4. When necessary, quality control should also be used to verify the similarity in appearance and
568 other physical characteristics such as the odour of "blinded" investigational products.
569
570 12.5. End-product testing should be carried out in order to ensure that each batch meets its
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571 specification.
572
573 12.6. Reference and retention samples of each batch of product should be retained
574
575 12.7. Samples should be retained in the primary container used for the study or in a suitable
576 bulk container for at least two years after the termination or completion of the relevant
577 clinical trial. If the sample is not stored in the pack used for the study, stability data should
578 be available to justify the shelf life in the pack used.
579
580 12.8. Retention samples should be kept until the clinical report has been prepared in order to enable
581 the confirmation of product identity in the event of, and as part of an investigation into,
582 inconsistent trial results.
583
584 12.9. The storage location of reference and retention samples should be defined in a technical
585 agreement between the sponsor and manufacturer(s) and should allow for timely access by
586 the competent authorities.
587
588 12.10. The reference sample should be of sufficient size to permit the carrying out on, at least, two
589 occasions of the full analytical controls on the batch in accordance with the Investigational
590 Product dossier submitted for authorization in order to conduct the clinical trial.
591
592 12.11. In the case of retention samples, it is acceptable to store information related to the final
593 packaging as written or electronic records if such records provide sufficient information. In the
594 case of reference samples, the system should comply with the requirements of WHO guidelines
595 for computerized systems (7).
596
597 12.12. The release of a batch of an investigational product should only occur after the designated
598 responsible person has certified that the product meets the relevant requirements. These
599 requirements include the assessment of, as appropriate:
600 • batch records, including control reports, in-process test reports, changes, deviations
601 and release reports demonstrating compliance with the product specification file, the
602 order, protocol and randomization code;
603 • production conditions;
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604 • the validation status of facilities, processes and methods, as appropriate;

605 • the examination of finished packs;
606 • where relevant, the results of any analyses or tests performed after importation;
607 • stability reports;
608 • the source and verification of conditions of storage and shipment;
609 • audit reports concerning the quality system of the manufacturer, where applicable;
610 • documents certifying that the manufacturer is authorized to manufacture
611 investigational medicinal products or comparators for export by the appropriate
612 authorities in the country of export; and
613 • where relevant, regulatory requirements for marketing authorization, GMP standards
614 applicable and any official verification of GMP compliance.
615
616 Note: The relevance of the above elements is affected by the country of origin of the product,
617 the manufacturer and the marketed status of the product
618

619 13. Qualification and validation

620
621 13.1. The extent of qualification and validation may be different to that necessary for a routine
622 production operation.
623
624 13.2. The scope of qualification and validation required should be determined based on risk
625 assessment.
626
627 13.3. For sterile products, there should be no reduction in the degree of validation of sterilizing
628 equipment required. Validation of aseptic processes presents special problems when the batch
629 size is small since the number of units filled may be not adequate for a validation exercise.
630 Filling and sealing, which is often done by hand, can compromise the maintenance of
631 sterility. Greater attention should therefore be given to environmental monitoring
632

633 14. Complaints

634
635 14.1. There should be a written procedure describing the managing of complaints.
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636 14.2. Any complaint concerning a product defect should be recorded with all the original details and
637 thoroughly investigated.
638
639 14.3. Where necessary, appropriate follow-up action, possibly including product recall, should be
640 taken after investigation and evaluation of the complaint.
641
642 14.4. All decisions made and measures taken as a result of a complaint should be recorded and
643 referenced to the corresponding batch records.
644
645 14.5. The competent authorities should be informed if a manufacturer is considering action following
646 the identification of serious quality problems with a product that may be impacting trial
647 subjects or patients.
648
649 14.6. The conclusions of the investigations carried out in response to a complaint should be
650 discussed between the manufacturer and the sponsor (if different) or between the persons
651 responsible for manufacture and those responsible for the relevant clinical trial in order to
652 assess any potential impact on the trial and on the product development, in order to
653 determine the cause, and to take any necessary corrective action.
654

655 15. Recalls

656
657 15.1. There should be a written procedure describing the managing of a recall of investigational
658 products.
659
660 15.2. Recall procedures should be understood by the sponsor, investigator and monitor, in
661 addition to the person(s) responsible for recalls.
662
663 15.3. The recall of a product should be documented and inventory records should be kept.
664

665 16. Returns

666
667 16.1. Investigational products should be returned under agreed conditions defined by the
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668 sponsor, specified in written procedures and approved by authorized staff members.
669
670 16.2. Returned investigational products should be clearly identified and stored in a dedicated
671 area in a controlled manner.
672
673 16.3. Inventory records of returned products should be kept.
674

675 17. Shipping

676
677 17.1. The shipping of investigational products should be carried out in accordance with written
678 procedures laid down in the protocol or shipping order given by the sponsor.
679
680 17.2. A shipment is sent to an investigator after following the defined release procedures, for
681 example, quality control and authorization by the sponsor. Both releases should be
682 recorded.
683
684 17.3. The sponsor should ensure that the shipment will be received and acknowledged by the
685 correct addressee as stated in the protocol.
686
687 17.4. A detailed inventory of the shipments made by the manufacturer should be maintained
688 and should make particular mention of the addressee's identification.
689
690 17.5. The transfer of investigational products from one trial site to another should be done in
691 exceptional cases only. Such transfers should be justifiable, documented and carried out in
692 accordance with a written procedure. Repackaging or relabelling should normally be done by
693 the manufacturer. Records should be maintained and provide full traceability of the product
694 and activities.
695

696 18. Destruction

697
698 18.1. The sponsor is responsible for the destruction of unused investigational products. Unused
699 products should normally not be destroyed by the manufacturer without prior
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700 authorization by the sponsor.

701
702 18.2. Destruction operations should be carried out in accordance with written procedures and
703 environmental safety requirements.
704
705 18.3. The delivered, used and recovered quantities of a product should be recorded, reconciled and
706 verified by or on behalf of the sponsor for each trial site and each trial period. The destruction
707 should be carried out only after any discrepancies have been investigated, satisfactorily
708 explained and the reconciliation has been accepted.
709
710 18.4. Destruction operations should be recorded in such a manner that all operations are
711 accounted for. These records should be kept by the sponsor.
712
713 18.5. If the manufacturer is requested to destroy products, a Certificate of Destruction should be
714 provided to the sponsor.
715

716 Glossary
717
718 The definitions given below apply to the terms used in this guideline. They may have different meanings
719 in other contexts.
720
721 clinical trial. Any systematic study on pharmaceutical products in human subjects, whether in patients
722 or other volunteers, in order to discover or verify the effects of, and/or identify any adverse reaction
723 to, investigational products, and/or to study the absorption, distribution, metabolism and excretion of
724 the products with the object of ascertaining their efficacy and safety.
725
726 Clinical trials are generally divided into Phases I-IV. It is not possible to draw clear distinctions between
727 these phases, and different opinions about details and methodology do exist. However, the individual
728 phases, based on their purposes as related to the clinical development of pharmaceutical products, can
729 be briefly defined as follows:
730 ➢ Phase I. These are the first trials of a new active ingredient or new formulations in humans,
731 often carried out in healthy volunteers. Their purpose is to make a preliminary evaluation of
732 safety, and an initial pharmacokinetic/pharmacodynamic profile of the active ingredient.
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733 ➢ Phase II. The purpose of these therapeutic pilot studies is to determine activity and to assess
734 the short-term safety of the active ingredient in patients suffering from a disease or condition
735 for which it is intended. The trials are performed in a limited number of subjects and are
736 often, at a later stage, of a comparative (e.g. placebo-controlled) design. This phase is also
737 concerned with the determination of appropriate dose ranges/regimens and (if possible) the
738 clarification of dose-response relationships in order to provide an optimal background for the
739 design of extensive therapeutic trials.
740 ➢ Phase III: This phase involves trials in large (and possibly varied) patient groups for the purpose
741 of determining the short- and long-term safety-efficacy balance of formulation(s) of the
742 active ingredient, and assessing its overall and relative therapeutic value. The pattern and
743 profile of any frequent adverse reactions must be investigated and special features of the
744 product must be explored (e.g. clinically relevant drug interactions, factors leading to
745 differences in effect, such as age). The trials should preferably be randomized double-blind
746 but other designs may be acceptable for example,. long-term safety studies. In general,
747 the conditions under which the trials are conducted should be as close as possible to the
748 normal conditions of use.
749 ➢ Phase IV. In this phase, studies are performed after the pharmaceutical product has been
750 marketed. They are based on the product characteristics on which the marketing
751 authorization was granted and normally take the form of post-marketing surveillance and
752 assessment of therapeutic value or treatment strategies. Although methods may differ,
753 the same scientific and ethical standards should apply to Phase IV studies as are applied in
754 premarketing studies. After a product has been placed on the market, clinical trials
755 designed to explore new indications, new methods of administration or new
756 combinations, and so on, are normally regarded as trials of new pharmaceutical products.
757
758 investigational product. Any pharmaceutical product (new product or reference product) or
759 placebo being tested or used as a reference in a clinical trial.
760
761 investigator. The person responsible for the trial and for protecting the rights, health and welfare
762 of the subjects in the trial. The investigator must be an appropriately qualified person, legally
763 allowed to practice medicine/dentistry.
764
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765 monitor. A person appointed by, and responsible to, the sponsor for monitoring and reporting the
766 progress of the trial and for the verification of data.
767
768 order. An instruction to process, package and/or ship a certain number of units of an
769 investigational product.
770
771 pharmaceutical product. For the purpose of this document, this term is defined in the same way
772 as in the WHO guidelines on GCP (3), i.e. as any substance or combination of substances which
773 has a therapeutic, prophylactic or diagnostic purpose, or is intended to modify physiological
774 functions, and is presented in a dosage form suitable for administration to humans.
775
776 product specification file(s). Reference file(s) containing all the information necessary to draft the
777 detailed written instructions on processing, packaging, labelling, quality control testing, batch
778 release, storage conditions and shipping.
779
780 protocol. A document which gives the background, rationale and objectives of the trial and describes·
781 its design, methodology and organization, including statistical considerations and the conditions under
782 which it is to be performed and managed. It should be dated and signed by the investigator/ institution
783 involved and the sponsor, and can, in addition, function as a contract.
784
785 reference sample. A sample of a batch of starting material, packaging material, product contained in
786 its primary packaging or finished product which is stored for the purpose of being analysed, should the
787 need arise.
788
789 retention sample. A sample of a packaged unit from a batch of finished product for each packaging
790 run/trial period. It is stored for identification purposes: for example, presentation, packaging, labelling,
791 leaflet, batch number and expiry date, should the need arise.
792
793 shipping/dispatch. The assembly, packing for shipment and sending of ordered medicinal products for
794 clinical trials.
795
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796 sponsor. An individual, company, institution or organization which takes responsibility for the
797 initiation, management and/or financing of a clinical trial. When an investigator independently initiates
798 and takes full responsibility for a trial, the investigator also then assumes the role of the sponsor.
799

800 Abbreviations
801
802 CAPA corrective actions and/or preventive actions
803 GCP good clinical practices
804 GLP good laboratory practices
805 GMP good manufacturing practices
806 GSDP good storage and distribution practices
807 GxP good practices
808

809 References
810
811 1. WHO Good manufacturing practices for investigational pharmaceutical products for clinical
812 trials in humans. In: WHO Expert Committee on Specifications for Pharmaceutical
813 Preparations: thirty-fourth report. Geneva: World Health Organization; 1996: Annex 7 (WHO
814 Technical Report Series, No. 863; (https://www.who.int/docs/default-
815 source/medicines/norms-and-standards/guidelines/production/trs863-annex7-who-gmp-
816 investigational-pharmaceutical-products-clinical-trials-humans.pdf?sfvrsn=2432f236_0
817 (accessed 4 November 2020).
818
819 2. WHO Handbook for Good clinical research practices, 2002;
820 (https://www.who.int/medicines/areas/quality_safety/safety_efficacy/gcp1.pdf, accessed
821 4 November 2020).
822
823 3. WHO Handbook: Good laboratory practice, Quality practices for regulated non-clinical
824 research and development, , TDR/PRD/GLP/01.2, 2001;
825 (https://www.who.int/tdr/publications/training-guideline-publications/good-laboratory-
826 practice-handbook-ver1/en/, accessed 4 November 2020).
827
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828 4. WHO Good storage and distribution practices (GSDP). In: WHO Expert Committee on
829 Specifications for Pharmaceutical Preparations: fifty-third report. Geneva: World Health
830 Organization; 2020: Annex 7 (WHO Technical Report Series, No. 1025;
831 https://www.who.int/publications/m/item/trs-1025-annex-7-gdp-medical-products, accessed
832 4 November 2020).
833
834 5. WHO Guidelines on quality risk management. In: WHO Expert Committee on Specifications
835 for Pharmaceutical Preparations: forty-seventh report. Geneva: World Health Organization;
836 2013: Annex 2 (WHO Technical Report Series, No. 981; https://www.who.int/docs/default-
837 source/medicines/norms-and-standards/guidelines/production/trs981-annex2-who-quality-
838 risk-management.pdf?sfvrsn=2fa44bc4_2, accessed 4 November 2020).
839
840 6. WHO Good manufacturing practices for pharmaceutical product for sterile products. In:
841 WHO Expert Committee on Specifications for Pharmaceutical Preparations: forty-seventh
842 report. Geneva: World Health Organization; 2011: Annex 6 (WHO Technical Report Series,
843 No. 961; https://www.who.int/docs/default-source/medicines/norms-and-
844 standards/guidelines/production/trs961-annex6-gmp-sterile-pharmaceutical-
845 products.pdf?sfvrsn=61682f0c_0 accessed 4 November 2020).
846
847 7. Good manufacturing practices: guidelines on validation. Appendix 5. Validation of
848 computerized systems. In: WHO Expert Committee on Specifications for Pharmaceutical
849 Preparations: fifty-third report. Geneva: World Health Organization; 2019: Annex 3 (WHO
850 Technical Report Series, No. 1019;
851 https://www.who.int/medicines/areas/quality_safety/quality_assurance/WHO_TRS_1019_An
852 nex3.pdf?ua=1, accessed 12 August 2020).
853

854 Further reading

855
856 • International Ethical Guidelines for Health-related Research Involving Humans Prepared by
857 the Council for International Organizations of Medical Sciences (CIOMS) in collaboration with
858 the World Health Organization (WHO), Geneva, 2016 (https://cioms.ch/wp-
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859 content/uploads/2017/01/WEB-CIOMS-EthicalGuidelines.pdf, accessed 4 November

860 2020).
861
862 • The International Pharmacopoeia. Geneva, World Health Organization; updated regularly
863 (https://www.who.int/medicines/publications/pharmacopoeia/en/ and https://apps.who.int/
864 phint/2019/index.html#p/home, accessed 1 May 2020).
865
866 • EudraLex - Volume 4 - Good Manufacturing Practice (GMP) guidelines, EU Commission
867 Directives 91/356/EEC, as amended by Directive 2003/94/EC, and 91/412/EEC
868 (https://ec.europa.eu/health/documents/eudralex/vol-4_fr, accessed 4 November 2020).
869
870 • WHO Good manufacturing practices for pharmaceutical products: main principles. In: WHO
871 Expert Committee on Specifications for Pharmaceutical Preparations: forty-eight report.
872 Geneva: World Health Organization; 2014: Annex 2 (WHO Technical Report Series, No. 986
873 https://www.who.int/medicines/areas/quality_safety/quality_assurance/TRS986annex2.
874 pdf?ua=1 accessed 4 November 2020).
875
876
877 ***