Working document QAS/23.

921
March 2023

1
2

3 DRAFT WORKING DOCUMENT FOR COMMENTS:

4

5 WHO good manufacturing practices

6 for excipients used in pharmaceutical
7 products
8
9
Please submit your comments through the online platform, PleaseReview™
([Link] If not registered or included in
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technical questions, you may contact Dr Steve Estevao Cordeiro, Technical Officer, Norms and Standards for
Pharmaceuticals, Technical Standards and Specifications (estevaos@[Link]), with a copy to Ms Bezawit Kibret
(Kibretb@[Link], nsp@[Link]). Comments should be submitted through the online platform by 21 May 2023. Please
note that only comments received by this deadline will be considered for the preparation of this document.
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13 © World Health Organization 2023
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15 All rights reserved.
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 in
18 whole, in any form or by any means without the permission of the World Health Organization
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20 Please send any request for permission to: Ms Bezawit Kibret, Norms and Standards for Pharmaceuticals, Technical Standards
21 and Specifications, Department of Health Products Policy and Standards, World Health Organization, CH-1211 Geneva 27,
22 Switzerland, email: kibretb@[Link].
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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.
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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 and
31 omissions excepted, the names of proprietary products are distinguished by initial capital letters.
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33 All reasonable precautions have been taken by the World Health Organization to verify the information contained in this draft.
34 However, the printed material is being distributed without warranty of any kind, either expressed or implied. The responsibility
35 for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for
36 damages arising from its use. This draft does not necessarily represent the decisions or the stated policy of the World Health
37 Organization.
38
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39
40 SCHEDULE FOR DRAFT WORKING DOCUMENT QAS/23.921:
41 WHO good manufacturing practices for pharmaceutical
42 Excipients
Description of Activity Date

Preparation of first draft working document. December 2022

Review and finalization of the first draft working document with an February 2023
informal drafting group.

Mailing of working document to the Expert Advisory Panel on the March 2023
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. May – June 2023

Preparation of working document for discussion.

Discussion of the feedback received on the working document in a June – July 2023
virtual meeting with an informal consultation group.

Preparation of a working document for discussion and possible August –

adoption by the ECSPP September 2023

Presentation to the Fifty-seventh meeting of the ECSPP. October 2023

Any other follow-up action as required.

43
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44 WHO good manufacturing practices

45 for excipients used in pharmaceutical
46 products
47
48 Background
49
50 The WHO guideline Good Manufacturing Practices: supplementary guidelines for the
51 manufacture of pharmaceutical excipients, was published in the WHO Technical Report
52 Series No 885, 1999.

53 As excipients are sometimes used in large quantities in pharmaceutical dosage forms, and
54 may contain impurities, they can affect the quality of a finished pharmaceutical product.

55 The manufacturer of the finished pharmaceutical product is normally dependent on the

56 manufacturer of the excipient to supply excipients meeting the required specification. An
57 appropriately established and implemented quality management system evaluating and
58 controlling risks in the production and quality control of such excipients is therefore required.

59 Some excipient manufacturers may be required to follow good manufacturing practices for
60 excipients used in pharmaceutical products. Reports of pharmaceutical products which
61 contain contaminated excipients, or excipients with impurities leading to the death of
62 patients, have further highlighted the need for a revision of the original guideline.
63 Furthermore, the concept of ongoing improvement, life cycle approach, better quality
64 management systems, risk management and management review should be described in such
65 a guideline, alongside the necessary good storage, good trade and good distribution practices
66 to ensure their reliability throughout the supply chain.

67 The manufacturer of excipients used in pharmaceutical products should be able to identify

68 risks associated with the production (including stages of manufacturing, route of synthesis)
69 and quality control of its products. This includes, but is not limited to, the premises,
70 equipment, utilities, storage and distribution. The manufacturer of such excipients should
71 assess those risks, and identify appropriate measures to mitigate such risks. The effectiveness
72 of the measures should be evaluated to ensure that they are appropriate.
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73 This document provides information on good manufacturing practices that should be

74 implemented to assist manufacturers to produce and control excipients used in
75 pharmaceutical products that will meet their intended specifications, in a consistent manner.
76 Risk assessment may be useful in determining which excipients should be manufactured in
77 accordance with this guideline.

78
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79 WHO good manufacturing practices

80 for excipients used in pharmaceutical
81 products
82
83 1. Introduction and scope
84 2. Glossary
85 3. Quality management
86 Quality Risk Management
87 Management review
88 4. Complaints
89 5. Recalls
90 6. Returns
91 7. Self-inspection, quality audits and supplier’s audits and approvals
92 8. Personnel
93 9. Sanitation and hygiene
94 10. Documentation
95 Standard operating procedures and records
96 Specifications
97 Batch documentation
98 Labels
99 11. Premises
100 12. Equipment and utilities
101 13. Materials
102 14. Production
103 Rework
104 Reprocessing
105 15. Qualification and validation
106 16. Quality control
107 17. Product life cycle and continuous improvement
108 18. Storage and distribution
109 Storage
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110 Distribution
111 References
112 Further reading
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113 1. Introduction and scope

114

115 1.1. The purpose of this document is to provide guidance for the production, control, storage
116 and distribution of excipients used in pharmaceutical products, focusing on good
117 manufacturing practices (GMP) under an appropriate system for managing quality. It is
118 also intended to help ensure that such excipients meet the requirements for quality and
119 purity that they purport or are represented to possess.
120
121 1.2. The document does not cover aspects of protection of the environment, nor safety
122 aspects for the personnel engaged in the manufacture and control of materials and
123 excipients.
124
125 1.3. Excipients are often used in large quantities in industrial chemistry, as well as the food
126 and cosmetic industry. Specifications for excipients used in these applications may vary
127 and may not always be appropriate for use in pharmaceutical products. It is the
128 responsibility of the finished product manufacturer and of the applicant to ensure that
129 the finished product is manufactured using excipients of a suitable grade conforming to
130 its intended use.
131
132 1.4. Excipients are often used in significant quantities in the production of pharmaceutical
133 products. They should be of appropriate quality as they could affect the quality of
134 finished pharmaceutical products.
135
136 1.5. The manufacturer of the finished pharmaceutical product is highly dependent on the
137 excipient manufacturer to provide materials that are homogeneous in chemical and
138 physical characteristics, and of the desired quality.
139
140 1.6. In general, excipients are used as purchased, with no further refining or purification.
141 Consequently, impurities present in the excipient will be carried over to the finished
142 pharmaceutical product.
143
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144 1.7. To achieve the objective of ensuring that excipients used in pharmaceutical products are
145 of appropriate quality, an appropriate level of GMP should be established, implemented
146 and maintained during their production, packaging, repackaging, labelling, quality
147 control, release, storage, distribution and other related activities. Additional measures
148 should be taken when manufacturing excipients for which scientific literature,
149 information in the public domain or historical data indicate that they present higher risk
150 because of potential formation of toxic impurities during the manufacturing process, or
151 due to potential contamination during storage and distribution.
152
153 1.8. Specific analytical procedures should be used by the excipient manufacturer, where the
154 excipient is intended to be used in a pharmaceutical product, to ensure that it is suitable
155 for its intended use. Pharmacopoeia and regulatory requirements should be considered
156 by the manufacturers as a reference for these analytical tests. Information in the public
157 domain may also be considered. Risk management principles should be implemented in
158 order to identify and mitigate risks.
159
160 1.9. A thorough knowledge and understanding of the processes and associated risks are
161 required. This includes all unit operations and processing steps, key steps in the process,
162 critical parameters (time, temperature, pressure, etc.), environment conditions,
163 equipment used, contamination protection and monitoring points.
164
165
166

167 2. Glossary

168 The definitions given below apply to the terms used in this document. They have been
169 aligned as much as possible with the terminology in related WHO guidelines and good
170 practices (GxP) and included in the WHO Quality Assurance of Medicines Terminology
171 Database - List of Terms and related guideline [Link]
172 source/medicines/norms-and-standards/guidelines/mqa-terminology-sept-
173 [Link]?sfvrsn=48461cfc_5, but may have different meanings in other contexts.
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174 Acceptance criteria. Numerical limits, ranges or other suitable measures for acceptance of
175 test results.

176 Batch (or lot). A specific quantity of material produced in a single process or series of
177 processes so that it is expected to be homogeneous within specified limits. In the case of
178 continuous production, a batch may correspond to a defi ned fraction of the production. The
179 batch size can be defined either by a fixed quantity or by the amount produced in a fixed time
180 interval.

181 Batch number (or lot number). A unique combination of numbers, letters and/or symbols
182 that identifies a batch (or lot) and from which the production and distribution history can be
183 determined.

184 Calibration. The demonstration that a particular instrument or device produces results within
185 specified limits by comparison with those produced by a reference or traceable standard over
186 an appropriate range of measurements.

187 Commingling / commingled. The blending of carry-over material from one grade of an
188 excipient with another, usually due to a continuous process.

189 Computer system. A group of hardware components and associated software, designed and
190 assembled to perform a specific function or group of functions.

191 Computerized system. A process or operation integrated with a computer system.

192 Contamination. The undesired introduction of impurities of a chemical or microbiological

193 nature or of foreign matter into or on to a raw material, intermediate or excipient during
194 production, sampling, packaging or repackaging, storage or transport.

195 Critical. Describes a process step, process condition, test requirement or other relevant
196 parameter or item that must be controlled within predetermined criteria to ensure that the
197 excipient meets its specification.

198 Cross-contamination. Contamination of a material or product with another material or

199 product.
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200 Deviation. Departure from an approved instruction or established standard.

201 Excipient for pharmaceutical use. Substances, other than the active ingredient, which
202 have been appropriately evaluated for safety and are included in a drug delivery system
203 to:

204  aid in the processing of the drug delivery system during its manufacture;
205  protect, support or enhance stability, bioavailability, or patient
206 acceptability;
207  assist in product identification; or
208  enhance any other attribute of the overall safety and effectiveness of the drug
209 during storage or use.

210

211 Expiry date (or expiration date). The date placed on the container or labels of an excipient
212 designating the time during which the excipient is expected to remain within established
213 shelf-life specifications if stored under defi ned conditions and after which it should not be
214 used.

215 Finished pharmaceutical product (FPP). WHO: A product that has undergone all stages of
216 production, including packaging in its final container and labelling. An FPP may contain one
217 or more APIs.

218 Impurity. Any component present in the intermediate or product that is not the desired
219 entity.

220 Impurity profile. A description of the identified and unidentified impurities present in an
221 intermediate or product.

222 In-process control (or process control). Checks performed during production in order to
223 monitor and, if appropriate, to adjust the process and/or to ensure that the intermediate or
224 product conforms to its specifications.
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225 Intermediate. A material produced during steps of the processing of an excipient for
226 pharmaceutical use that undergoes further molecular change or purification before it becomes
227 an excipient for pharmaceutical use. Intermediates may or may not be isolated.

228 Lot. See Batch.

229 Lot number. See Batch number.

230 Manufacture. All operations of receipt of materials, production, packaging, repackaging,

231 labelling, relabelling, quality control, release, storage and distribution of excipient and related
232 controls.

233 Material. A general term used to denote raw materials (starting materials, reagents, solvents),
234 process aids, intermediates, APIs and packaging and labelling materials.

235 Model product. A product which simulates a group of similar products.

236 Mother liquor. A concentrated solution from which the product is obtained by
237 evaporation, freezing, and/or crystallization. (Or: The residual liquid which remains after
238 the crystallization or isolation processes. A mother liquor may contain unreacted materials,
239 intermediates, levels of the excipient for pharmaceutical use and/or impurities. It may be used
240 for further processing).

241 Packaging material. Any material intended to protect an intermediate or excipient for
242 pharmaceutical use during storage and transport.

243 Procedure. A documented description of the operations to be performed, the precautions to

244 be taken and measures to be applied, directly or indirectly related to the manufacture of an
245 intermediate or excipient for pharmaceutical use.

246 Process aids. Materials, excluding solvents, used as an aid in the manufacture of an
247 intermediate or excipient for pharmaceutical use that do not themselves participate in a
248 chemical or biological reaction (e.g. filter aid or activated carbon).
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249 Production. All operations involved in the preparation of a excipient for pharmaceutical use
250 from receipt of materials through processing and packaging of the excipient for
251 pharmaceutical use.

252 Qualification. Action of proving and documenting that equipment or ancillary systems are
253 properly installed, work correctly and actually lead to the expected results. Qualification is
254 part of validation, but the individual qualification steps alone do not constitute process
255 validation.

256 Quality assurance (QA). The sum total of the organized arrangements made with the object
257 of ensuring that all excipients for pharmaceutical use are of the quality required for their
258 intended use and that quality systems are maintained.

259 Quality control (QC). Checking or testing that specifications are met.

260 Quality unit(s). An organizational unit independent of production which fulfils both quality
261 assurance (QA) and quality control (QC) responsibilities. This can be in the form of separate
262 QA and QC units or a single individual or group, depending upon the size and structure of the
263 organization.

264 Quarantine. The status of materials isolated physically or by other effective means pending
265 a decision on their subsequent approval or rejection.

266 Raw material. A general term used to denote starting materials, reagents and solvents
267 intended for use in the production of intermediates or excipient for pharmaceutical use.

268 Reprocessing. Introducing an intermediate or excipient for pharmaceutical use, including one
269 that does not conform to standards or specifications, back into the process and repeating a
270 crystallization step or other appropriate chemical or physical manipulation steps (e.g.
271 distillation, filtration, chromatography or milling) that are part of the established
272 manufacturing process. Continuation of a process step after an in-process control test has
273 shown that the step is incomplete is considered to be part of the normal process and not to be
274 reprocessing.
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275 Retest date. The date when a material should be re-examined to ensure that it is still suitable
276 for use.

277 Reworking. Subjecting an intermediate or excipient for pharmaceutical use that does not
278 conform to standards or specifications to one or more processing steps that are different from
279 the established manufacturing process to obtain acceptable quality intermediate or excipient
280 for pharmaceutical use (e.g. recrystallizing with a different solvent).

281 Signature (signed). See Signed.

282 Signed (signature). The record of the individual who performed a particular action or
283 review. This record can be in the form of initials, full handwritten signature, personal seal or
284 an authenticated and secure electronic signature.

285 Solvent. An inorganic or organic liquid used as a vehicle for the preparation of solutions or
286 suspensions in the manufacture of an intermediate or excipient for pharmaceutical use.

287 Specification. A list of tests, references to analytical procedures and appropriate acceptance
288 criteria that are numerical limits, ranges or other criteria for the test described. It establishes
289 the set of criteria to which a material should conform to be considered acceptable for its
290 intended use. “Conformance to specification” means that the material, when tested according
291 to the listed analytical procedures, will meet the listed acceptance criteria.

292 Validation. A documented programme that provides a high degree of assurance that a
293 specific process, method or system will consistently produce a result meeting predetermined
294 acceptance criteria.

295 Validation protocol. A written plan stating how validation will be conducted and defining
296 acceptance criteria. For example, the protocol for a manufacturing process identifies
297 processing equipment, critical process parameters and operating ranges, product
298 characteristics, sampling, test data to be collected, number of validation runs and acceptable
299 test results.

300
301
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302 3. Quality management

303
304 3.1. Manufacturers involved in the production, control, storage and distribution of
305 excipients for pharmaceutical use should establish, document, implement and
306 maintain a comprehensively designed and clearly defined quality management
307 system.
308
309 3.2. Senior management should assume responsibility for the quality management system,
310 as well as the quality of the excipients for pharmaceutical use manufactured,
311 controlled, released, stored and distributed.
312
313 3.3. The quality management system should encompass the quality policy, organizational
314 structure, procedures, processes and resources. All parts of the quality management
315 system should be adequately resourced and maintained.
316
317 3.4. The quality management system should cover all activities necessary to ensure that
318 excipients for pharmaceutical use will meet their intended specifications, including
319 quality and purity.
320
321 3.5. The quality management system should incorporate the principles of good practices
322 (GxP) which should be applied to the life cycle stages of excipients for
323 pharmaceutical use. This includes steps such as the receipt of raw materials,
324 production, packaging, testing, release, storage and distribution.
325
326 3.6. All quality-related activities and procedures should be defined and documented
327 manually or electronically.
328
329 3.7. All quality-related activities should be recorded at the time they are performed.
330
331 3.8. The quality management system should ensure that:
332 a) sufficient resources are available (e.g. equipment, personnel, materials);
333 b) excipients for pharmaceutical use are manufactured, controlled, stored and
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334 distributed in accordance with the recommendations in this document and other
335 associated guidelines such as good quality control laboratory practices and good
336 storage and distribution practices, where appropriate;
337 c) managerial roles, responsibilities and authorities are clearly specified in job
338 descriptions;
339 d) operations and other activities are clearly described in a written form such as
340 standard operating procedures (SOPs) and work instructions;
341 e) arrangements are made for the manufacture, supply and use of the correct
342 containers and labels;
343 f) all necessary controls are in place;
344 g) calibrations and validations are carried out where necessary;
345 h) the excipient for pharmaceutical use is correctly processed and checked
346 according to the defined procedures and specifications;
347 i) deviations, suspected product defects, out-of-specification test results and any
348 other non-conformances or incidents are reported, investigated and recorded. An
349 appropriate level of root cause analysis is applied during such investigations and
350 the most likely root cause(s) is/are identified;
351 j) proposed changes are evaluated and approved prior to implementation. After
352 implementation of any change, an evaluation should be undertaken to confirm
353 that the quality objectives were achieved and that there was no unintended
354 adverse impact on product quality;
355 k) appropriate corrective actions and preventive actions (CAPAs) are identified and
356 taken where required processes are in place to ensure the management of any
357 outsourced activities that may impact product quality, purity and integrity;
358 l) excipients for pharmaceutical use are not released and supplied before it has been
359 certified that each batch has been produced and controlled in accordance with
360 product specifications, the recommendations in this document and any other
361 regulations relevant to the production, control and release of these products;
362 m) there is a system for handling complaints, returns and recalls;
363 n) there is a system for self-inspection;
364 o) there is a system for product quality review.
365
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366 3.9. The quality unit(s) should be independent of production. The responsibilities of the
367 unit should be clearly defined and documented.
368
369 3.10. The person(s) authorized to release excipients for pharmaceutical use should have
370 appropriate qualifications, and be specified.

371 Quality Risk Management

372 3.11. There should be a system for managing risks. The system for quality risk management
373 should be comprehensive and should cover a systematic process for the assessment,
374 control, communication and review of risks in the production, testing, storage and
375 distribution of excipients for pharmaceutical use. Controls identified should be
376 appropriate, ensure that risks are eliminated or mitigated, and ultimately protect the
377 patient from receiving a pharmaceutical product containing the wrong, contaminated
378 or unsuitable excipients for pharmaceutical use.
379
380 3.12. Risk assessments should be documented. Appropriate controls should be implemented
381 and their effectiveness checked and documented at suitable intervals.
382
383 Note: See WHO guidelines on quality risk management(1)
384
385 Management review
386
387 3.13. There should be a system for regular management review. All elements of the quality
388 management system should be included.
389
390 3.14. Management should ensure that the quality management system achieves its intended
391 objectives and measure managing and performance in areas such as, but not limited
392 to:
393 a) Self-inspections, inspections, quality audits and supplier's audits;
394 b) Complaints, returns and recalls;
395 c) Changes and deviations;
396 d) Rejected batches;
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397 e) Quality control, out of specifications and out of trend results;

398 f) Maintenance;
399 g) Qualification and validation;
400 h) Corrective and preventive actions;
401 i) Risk management;
402
403 3.15. Key performance indicators should be identified and monitored with the view of
404 continual improvement.
405
406 3.16. Records of meetings, discussions and actions should be maintained.
407

408 4. Complaints
409

410 4.1. There should be a written procedure describing the recording and investigation of
411 complaints.
412
413 4.2. All decisions made and measures taken as a result of a complaint should be recorded.
414
415 4.3. Complaint records should include at least the following:
416
417 a) Date of receiving the complaint;
418 b) Name, address and other relevant details of complainant;
419 c) Details of the complaint including name of the excipient and batch number;
420 d) Details of the investigation and action taken;
421 e) Copy of the response provided;
422 f) Final decision based on the outcome of the investigation.
423
424 4.4. Where necessary, the appropriate corrective action and follow-up action should be
425 taken after the investigation and evaluation of a complaint.
426
427 4.5. Where necessary, a recall of the batch or batches should be considered.
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428
429 4.6. Records of complaints should be retained in order to evaluate trends.
430

431 5. Recalls
432
433 5.1. There should be a written, authorized procedure describing the managing of a recall of
434 excipient for pharmaceutical use.
435
436 5.2. The recall procedure should indicate the responsibilities of personnel involved in the
437 recall, how the recall should be initiated, who should be informed about the recall and
438 how the recalled material should be handled.
439
440 5.3. The recall of an excipient for pharmaceutical use should be documented. Records
441 should be kept.

442

443 6. Returns

444
445 6.1. There should be a written, authorized procedure describing the handling of returned
446 excipients for pharmaceutical use.
447
448 6.2. The disposition of the returned product should be approved by the quality unit. The
449 conditions under which the excipient for pharmaceutical use had been stored and
450 shipped should be considered when deciding on the fate of the returned product. If the
451 condition of the container itself casts doubt on the safety, quality or purity of the
452 excipient, the product should be destroyed, unless scientific justification can be
453 provided that proves that the product meets the appropriate predefined quality
454 standards.
455
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456 6.3. Where returned excipient containers are reused, all previous labelling should be
457 removed. The containers should be appropriately cleaned and there should be no risk
458 of contamination from one material to another.
459

460 7. Self-inspection, quality audits and supplier’s

461 audits and approvals
462

463 7.1. There should be written SOPs and programs for periodic self-inspections, quality
464 audits and supplier audits.
465
466 7.2. Self-inspections should be performed routinely in accordance with a self-inspection
467 program.
468
469 7.3. The team responsible for self-inspection should consist of personnel with the
470 appropriate knowledge and experience. Team members may be from inside or outside
471 the manufacturer, but members of the team should be free from bias.
472
473 7.4. Areas to be covered in self-inspections may include for example:
474 a) Premises;
475 b) Personnel;
476 c) Equipment;
477 d) Maintenance and calibration;
478 e) Storage conditions of materials and finished products;
479 f) Production and in-process controls;
480 g) Quality control;
481 h) Documentation, data generation and data integrity; and
482 i) Change control and deviations management;
483 j) Complaints management;
484 k) Qualification and validation.
485 l) Cleaning procedures

486 7.5. The excipient's end use should be considered during inspection of excipient
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487 manufacturers. It is particularly important to know whether the excipient will be used
488 in the preparation of a sterile dosage form. The excipient manufacturer is responsible
489 for ensuring that excipients are pyrogen free if the manufacturer makes such a
490 representation in specifications, labels or a drug master file.

491 7.6. Self-inspection should also ensure that appropriate measures are in place to prevent
492 contamination of materials during storage and production.
493
494 7.7. The outcome of the self-inspection should be documented including corrective actions
495 and preventive actions.
496

497 8. Personnel
498
499 8.1. There should be an adequate number of personnel with appropriate qualifications,
500 training and/or experience to perform their respective activities.
501
502 8.2. Responsibilities should be specified in written job descriptions.
503
504 8.3. Training should be regularly conducted and should include for example, GMP and the
505 particular operations of the employee. Assessment of understanding of training topics
506 should be done and documented.
507
508 8.4. Records of training should be maintained.
509

510 9. Sanitation and hygiene

511
512 9.1. Excipients for pharmaceutical use should be protected from contamination.
513 Documented risk assessment should identify controls to be implemented to ensure
514 appropriate sanitation and hygiene actions are taken.
515
516 9.2. Written procedures should be followed for cleaning and sanitization, as appropriate,
517 for example manufacturing areas, equipment, and utilities.
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518
519 9.3. Personnel should practice good hygiene and health habits.
520
521 9.4. Personnel should wear clean clothing suitable for their activities. Additional personal
522 protective equipment should be worn when necessary.
523
524 9.5. Personnel should avoid direct contact with starting materials and excipients for
525 pharmaceutical use.
526
527 9.6. Smoking, eating, drinking, chewing and the storage of food should not be allowed in
528 production and quality control areas.
529
530 9.7. Personnel with an infectious disease or who have open lesions on the exposed surface
531 of the body should not engage in activities that could result in compromising the
532 quality of excipient for pharmaceutical use.
533
534 9.8. Jewellery and mobile phones should only be used in authorized areas.
535

536 10. Documentation

537
538 10.1. Documents such as SOPs, specifications and others related to the production and
539 control of excipients for pharmaceutical use should be prepared, reviewed, updated,
540 approved and distributed according to written procedures.
541
542 10.2. The issuance, revision, withdrawal and retention of documents should be
543 appropriately controlled.
544
545 10.3. Documents should be retained for a defined period of time.
546
547 10.4. Where documents require the entry of data, these entries should be clear, legible and
548 indelible. Entries should be in compliance with good documentation practices and
549 data integrity requirements.
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550
551 10.5. Records should be made or completed when any action is taken and in such a way that
552 all significant activities are traceable to the person making the entry including
553 signatures and dates. Corrections made to incorrect entries should be dated and signed
554 with a description of the reason for the change as appropriate.
555
556 10.6. Electronic documents and records should meet the requirements for good
557 documentation practices, and computerized systems.

558 Standard operating procedures and records

559 10.7. SOPs and associated records should be available for at least, but not limited to:
560 a) equipment;
561 b) analytical apparatus and instruments;
562 c) Out of specifications
563 d) maintenance and calibration;
564 e) cleaning and sanitization;
565 f) personnel matters such as training, clothing and hygiene;
566 g) qualification and validation;
567 h) self-inspection
568 i) complaints;
569 j) recalls; and
570 k) returns.
571
572 10.8. The SOPs for sampling should specify the person(s) authorized to take samples and
573 the sampling instructions.
574
575 10.9. The SOPs describing the details of the batch (lot) numbering system should ensure
576 that each batch of excipient for pharmaceutical use is identified with a specific batch
577 number.
578
579 10.10. Records of analysis should be maintained.
580
 Working document QAS/23.921
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581 10.11. Written release and rejection procedures should be available, in particular for the
582 release of the excipient for pharmaceutical use for sale.
583
584 10.12. Records should be maintained of the distribution of each batch of excipient for
585 pharmaceutical use.
586
587 10.13. Records should be kept for major and critical equipment, as appropriate, of any
588 qualifications, calibrations, maintenance, cleaning or repair operations, including the
589 dates and the identities of the people who carried out these operations.

590 Specifications

591 10.14. Specifications should be established and maintained for starting materials, packaging
592 materials, excipients for pharmaceutical use, and other related materials where
593 necessary.
594
595 10.15. Quality attributes, acceptance limits and test procedures should be defined. Relevant
596 pharmacopoeia monographs, when available, should be considered for use or to be
597 used as a basis for the development of internal manufacturer's specifications.
598
599 10.16. A positive identification test uniquely applicable to the excipients should be
600 established through analytical technology, such as infrared spectrophotometry and
601 chromatography.
602
603 10.17. Appropriate limits for impurities should be specified. These limits should be based
604 upon appropriate toxicological data, or limits described in national compendial
605 requirements. Manufacturing processes should be adequately controlled so that the
606 impurities do not exceed such established specifications.
607
608 10.18. Where excipients are extracted from or purified by the use of organic solvents,
609 specifications should include tests and limits for residues of solvents and other
610 reactants.
611
 Working document QAS/23.921
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612 10.19. Container specifications should be established for all excipients to assure consistency
613 in protecting the product during storage and transport, to maintain the stability of the
614 product, and for protection against contamination, infestation, and handling.
615

616 Batch documentation

617 10.20. A master batch manufacturing document with instructions for each excipient for
618 pharmaceutical use should be prepared and authorized (dated and signed)
619
620 10.21. A master batch manufacturing document should include for example:
621 a) the name of the excipient for pharmaceutical use being manufactured;
622 b) a complete list of materials (formula) and quantities;
623 c) the production location;
624 d) equipment to be used;
625 e) detailed production instructions, in process controls and flow chart if needed
626 f) where appropriate, precautions to be followed;
627 g) labelling and packaging materials and instructions;
628
629 10.22. A batch manufacturing record should be prepared for each batch of excipient for
630 pharmaceutical use produced. It should contain detailed information relating to the
631 production and control of the batch.
632
633 10.23. The batch manufacturing record should provide traceable information including for
634 example:
635 a) the batch number;
636 b) dates and, when appropriate, times;
637 c) identification number of equipment used;
638 d) actual results from testing;
639 e) information regarding any sampling performed;
640 f) signatures of operators and supervisors;
641 g) records of packaging, packaging materials and labels;
642 h) records of any deviations that occurred;
643 i) results of release testing.
 Working document QAS/23.921
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644
645 10.24. The manufacturer should demonstrate that:
646 a) the batch is homogeneous and compliant with its specification;
647 b) a capable process is used to assure batch to batch consistency;
648 c) a batch has not been commingled with material from other batches for the
649 purpose of either hiding or diluting an adulterated substance;
650 d) samples have been taken, where required, in accordance with a sampling
651 plan that ensures a representative sample was taken;
652 e) the batch has been analysed using scientifically established tests and
653 procedures;
654 f) scientific data support the shelf life of the excipient for pharmaceutical use.
655

656 10.25. Where computerized systems are used in the production of a batch, the electronic data
657 and records should comply with the guidelines on good practices for computerized
658 systems. The system should be suitable for the intended use.
659
660 10.26. When computerised systems are in use, access and privileges, data integrity, audit
661 trail, and back-up systems should be considered during risk assessment.

662 Labels

663 10.27. Excipients for pharmaceutical use should be labelled. Labels should be clear,
664 unambiguous and in compliance with national or regional legislation as appropriate
665
666 10.28. Information on labels may include for example:
667 a) the name of the excipient;
668 b) the batch number assigned by the manufacturer;
669 c) the expiry or use-before date, if applicable;
670 d) any special storage conditions or handling precautions that may be necessary;
671 e) warnings and precautions;
672 f) the name and address of the manufacturer.
673
 Working document QAS/23.921
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674 11. Premises

675
676 11.1. The premises where excipients for pharmaceutical use are manufactured should
677 provide sufficient space for the production, quality control testing and storage
678 operations.
679
680 11.2. The premises should be located, constructed, cleaned and maintained to suit the
681 operations to be carried out.
682
683 11.3. The layout and design of the premises should aim to minimize the risk of errors, mix-
684 ups, contamination and cross-contamination. In addition, it should allow for effective
685 cleaning and maintenance without any adverse effect on the quality of the products.
686
687 11.4. Only authorized persons should have access to relevant areas.
688
689 11.5. Adequate lighting should be provided.
690
691 11.6. Separate, dedicated facilities should be used for the production of highly sensitizing
692 and toxic materials, herbicides and pesticides
693
694 Note: The method used to achieve this separation will depend on the nature, extent and risk
695 of the overall operation.
696

697 12. Equipment and utilities

698
699 12.1. Equipment and utilities should be selected, located, designed, constructed and
700 maintained to suit the operations to be carried out.
701
702 12.2. The installation and use of equipment and utilities should aim to minimize the risk of
703 errors and contamination, cross-contamination, build-up of dust or dirt and, in
704 general, any adverse effect on the quality of products.
705
 Working document QAS/23.921
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706 12.3. Written procedures should be established and followed for repairs, maintenance,
707 and cleaning. These operations should not have any adverse effect on the quality of
708 the excipient for pharmaceutical use. Records of these activities should be maintained.
709
710 12.4. Equipment and instruments identified as being part of the quality management
711 system, should be appropriately controlled. This includes those used in production
712 and quality control. The control programme should include standardization or
713 calibration of reagents, instruments, apparatus, gauges and recording devices at
714 defined, suitable intervals. Written procedures should contain specific
715 instructions, schedules, acceptance limits. Records should be maintained.
716
717 12.5. Reagents, lubricants, instruments, apparatus, gauges and recording devices that can
718 affect the quality of the product should not be used.
719
720 12.6. Computerized systems that may impact on the quality of the excipient for
721 pharmaceutical use should be suitable for their intended use. These should be
722 appropriately validated. Quality data should comply with the requirements for data
723 integrity including but not limited to data management, audit trails, access and
724 privileges for users.
725
726 12.7. An appropriate level of validation should be performed for computerized systems.
727
728 12.8. Equipment and utilities should be commissioned and qualified as appropriate.
729
730 12.9. Utilities such as heating, ventilation and air conditioning (HVAC), water, nitrogen
731 and compressed air systems should be appropriate for their intended use, not have any
732 negative impact on operations and the quality of the excipient for pharmaceutical use,
733 and not be a source of contamination.
734
735 12.10. Where HVAC systems are used, air should be filtered to an appropriate level. The
736 design should ensure that the risk of contamination or cross-contamination is
737 minimized, that specified environmental conditions where required are achieved and
738 maintained such as grade or class, temperature and relative humidity.
 Working document QAS/23.921
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739
740 12.11. Water purification systems, where used, should be suitably designed, installed,
741 maintained and operated. Water should be sampled, tested, and should meet the its
742 relevant specification.
743
744 12.12. Compressed air and nitrogen generation systems should be designed and controlled in
745 accordance with the outcomes of risk assessment.
746
747 12.13. Measuring and control devices, where so determined, should be calibrated at defined
748 intervals.
749

750 13. Materials

751
752 13.1. Materials, including raw materials and packaging materials, should be sourced from
753 approved suppliers.
754
755 13.2. A procedure for supplier approval should be followed. Records should be maintained.
756
757 13.3. Written procedures should be followed for the receiving, sampling, storage and
758 testing of materials.
759
760 13.4. Materials should meet their agreed specifications. Materials that may have a negative
761 impact on the quality of the excipient for pharmaceutical use should not be used.
762
763 13.5. Materials should be stored in accordance with their status and labelling requirements.
764
765 13.6. Specific tests, based on risk assessment of the material and pharmacopoeia
766 requirements, should be done where applicable. Impurities should be identified and
767 appropriately controlled.
768
769 13.7. A procedure for handling nonconforming products should be established covering the
770 investigation, evaluation and treatment of nonconforming products. The disposition of
 Working document QAS/23.921
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771 nonconforming materials, intermediates and finished products shall be approved by

772 the quality unit and recorded.
773
774 13.8. Recovered or recycled materials such as solvents, should only be used if scientifically
775 justifiable, and meeting their relevant specification. The process of recovery should
776 follow written procedures and records should be maintained.
777
778 13.9. Blending or mixing of batches should be controlled and validated. Procedures and
779 records should be maintained.
780
781 13.10. Materials used in batches of excipients for pharmaceutical use should be traceable.
782
783 13.11. Material from waste should be appropriately treated and discarded in a manner that
784 will not have any negative effect on the environment.
785
786 13.12. A procedure for waste management should be followed. Records of waste treatment
787 and disposal should be maintained.
788

789 14. Production

790
791 14.1. Raw materials for manufacturing of excipients for pharmaceutical use should be
792 weighed or measured in appropriate areas, under appropriate conditions, using
793 suitable devices.
794
795 14.2. This material to be used in production, should be kept in suitable containers bearing
796 labels with required details such as the name of the material, traceable control
797 number, weight or volume.
798
799 14.3. Equipment in production areas should be labelled for example with an asset or other
800 unique identification number, calibration status if applicable.
801
802 14.4. Where appropriate, materials should not be kept for periods longer than the validated
 Working document QAS/23.921
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803 hold time.

804
805 14.5. The extent, stringency and type of testing (e.g. in-process) as well as acceptance
806 criteria should be defined. All tests and results should be fully documented as part of
807 the batch record.
808
809 14.6. The sampling process should not increase the risk of contamination of the material.
810 Samples should be handled with care and their integrity maintained.
811
812 14.7. Production operations should be conducted in a manner that will prevent
813 contamination and cross-contamination.
814
815 14.8. Manufacturers should have written procedures and related documents for the
816 production and control of excipients for pharmaceutical use.
817
818 14.9. Batches should be produced following written instructions as reflected in batch
819 manufacturing documentation.
820
821 14.10. Manufacturing process should be described in detail, and risks associated with the
822 production and control of the excipient for pharmaceutical use should be
823 appropriately controlled. This include, but is not limited to requirements specified in
824 the recognized pharmacopoeia, TSE/BSE, impurities, and others.
825
826 14.11. Batches should be produced on suitable equipment, in an appropriate environment,
827 protected from possible contamination and cross-contamination.
828
829 14.12. In-process sampling and testing should be done in accordance with written
830 instructions. Records should be maintained.
831
832 14.13. Batch manufacturing records should be kept. These records should, as appropriate,
833 include relevant information such as the following:
834 a) name of the product;
835 b) batch number;
 Working document QAS/23.921
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836 c) identification of the person(s) carrying out each significant step;

837 d) equipment used (e.g. reaction vessels, driers, centrifuges, filling manifold);
838 e) operations performed;
839 f) key parameters to be controlled
840 g) results of appropriate checks and quality control tests (including reference to the
841 calibration status of the test equipment);
842 h) any deviation from instructions;
843 i) batch quantity and yield;
844 j) date of testing and certification statement;
845
846 14.14. Checks and maintenance operations should not affect the quality of the excipient for
847 pharmaceutical use.
848
849 14.15. Changes and deviations in production should be managed through the relevant
850 procedures.
851
852 14.16. Blending operations should be controlled to ensure homogeneity of the final batch. A
853 blended batch should be assigned a unique batch number, and batches used in the
854 blend should be traceable.
855
856 14.17. A sampling procedure should be followed to ensure that a sample collected from the
857 blend is representative of the batch.
858
859 14.18. Each batch of product to be mixed should be produced in accordance with the batch
860 manufacturing document, tested separately and meet the corresponding specifications.
861 The mixed batch should be tested and should be in compliance with its specification.
862 The expiry date of the mixed batch should be based on the production date of the
863 earliest batch included in the mix.
864
865 14.19. Blending of batches to salvage out of specification batches or adulterated material is
866 not an acceptable practice.
867
868 14.20. Where solvents and mother liquors are recovered, appropriate procedures should be
 Working document QAS/23.921
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869 followed to ensure that they meet their specifications. Recovery procedures for
870 reactants and intermediates are acceptable provided that the recovered materials meet
871 suitable specifications.
872
873 14.21. Manufacturers should regularly review the capability of the process and ensure batch-
874 to-batch consistency of the excipient for pharmaceutical use meeting its specification.
875
876 14.22. Written procedures should be followed for the receipt, identification, quarantine,
877 sampling, examination and/or testing and release/rejection and handling of packaging
878 and labelling materials. Records should be kept.
879
880 14.23. Packaging materials such as containers should provide adequate protection against
881 deterioration or contamination of the excipient for pharmaceutical use. They should
882 be clean and dry, should not be reactive, additive or absorptive.
883
884 14.24. Printed packaging material such as labels, should be in the prescribed format.
885
886 14.25. Access to printed packaging material storage areas should be controlled.
887
888 14.26. Stock should be reconciled at periodic intervals including receipt, issued, and returned
889 quantities. Discrepancies found should be investigated.
890
891 14.27. Batch coded labels not used for the specified batch, obsolete and outdated labels
892 should be destroyed.
893
894 14.28. Written procedures should be followed for packaging operations. Controls should be
895 in place to prevent any mix-ups during packaging. These should include line opening
896 and line closing checks, segregation between packaging lines, and verification of
897 materials on the packaging line prior to the start of packaging.

898 Rework

899 14.29. Reworking should only be undertaken when the outcome of a risk assessment
 Working document QAS/23.921
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900 indicates that this is acceptable and approved by quality unit.

901
902 14.30. Batches that have been reworked should be subjected to appropriate quality control
903 testing and stability testing, if required. A reworked batch should be released by the
904 quality unit only once it has been evaluated and confirmed to meet the relevant
905 specification.
906
907 14.31. Specific attention should be given to the review of the impurity profile of each
908 reworked batch against batches manufactured by the established process. Appropriate
909 analytical procedures should be used.
910
911 14.32. Records should be maintained.

912 Reprocessing

913 14.33. Reprocessing should only be undertaken if this activity has been evaluated and found
914 to be acceptable.
915
916 14.34. Records should be maintained.
917

918 15. Qualification and validation

919
920 15.1. The scope and extent of qualification and validation should be determined based on
921 risk management principles.
922
923 15.2. Manufacturers should be able to provide documented evidence to show that, for
924 example, premises, equipment, utilities, procedures and processes are appropriate and
925 are consistently rendering the specified outcome.
926
927 15.3. Authorized procedures, protocols and records should be maintained for qualification
928 and validation executed.
929
930 15.4. The extent of qualification and validation may be further justified when considering
 Working document QAS/23.921
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931 the data from development and scale up, process capability studies, and product
932 quality reviews.
933

934 16. Quality control

935
936 16.1. The layout of the quality control section should be appropriate.
937
938 16.2. Personnel should be suitably qualified and trained.
939
940 16.3. Materials, including but not limited to raw materials, packaging materials and finished
941 excipients for pharmaceutical use, should be tested for compliance with their
942 specifications, by following authorized procedures.
943
944 16.4. Laboratory equipment and instruments should be appropriate for their intended use.
945 These should be suitably designed, installed, labelled, used, maintained and calibrated
946 (where so determined) according to written procedures. Records should be kept.
947
948 16.5. Laboratory equipment and instruments that are out of order, or out of calibration,
949 should not be used.
950
951 16.6. Authorized procedures should be used for activities including sampling, operation of
952 equipment and instruments, and analysis.
953
954 16.7. Risk assessments should be done to identify impurities and to determine controls and
955 limits for impurities. Appropriate tests and test procedures should be developed,
956 validated and used routinely to ensure that each batch meets the specification.
957
958 16.8. To facilitate traceability of each analysis, a record of analysis should be maintained.
959 This includes a certificate of analysis.
960
961 16.9. Records of analysis should normally include at least the following:
962 a) name of the excipient for pharmaceutical use;
 Working document QAS/23.921
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963 b) batch number;

964 c) test results and reference to any specifications (limits) and test procedures;
965 d) date(s) and reference number(s) of testing;
966 e) date and initials of the persons performed the testing and the person who verified
967 the testing and the calculations, where appropriate; and
968 f) a clear statement of release or rejection (or other status decision) and the date and
969 signature of the designated responsible person.
970
971 16.10. Test results should be incorporated into a certificate of analyst. Data should be
972 reviewed and trended.
973
974 16.11. Out of specification results should be thoroughly investigated. Appropriate actions
975 should be taken.
976
977 16.12. Reference and retention samples should be kept where identified.
978
979 16.13. Where stability testing is indicated, a procedure and programme should be followed.
980 The procedure and program should include for example:
981 a) A written schedule that is reviewed at least annually;
982 b) Reference to the number of batches and frequency of a batch to be placed on
983 stability;
984 c) Type of containers to be used;
985 d) Conditions of storage including stress conditions (e.g. elevated temperature, light,
986 humidity or freezing) where appropriate;
987 e) Ensuring that stability-indicating test procedures are used;
988
989 16.14. The results from stability testing should be reviewed and trended. An expiry or re-test
990 date should be allocated based on scientific data.
991
992 16.15. Storage conditions should be specified on the label if these are identified (e.g.
993 protection from light, heat).
994
 Working document QAS/23.921
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995 17. Life cycle and continuous improvement principles

996
997 17.1. Manufacturers of excipients for pharmaceutical use should implement the life
998 cycle approach and continuous improvement philosophy. These principles should
999 be applied in the relevant areas of the premises, equipment, instruments, utilities,
1000 products and processes.
1001
1002 17.2. Manufacturers should implement measures to continuously improve the quality
1003 management system, manufacturing and testing procedures and the quality of their
1004 products. These measures may include for example the review of root causes of non-
1005 conformances, quality complaint investigations and outcomes, results from self-
1006 inspections and audits and other trends.
1007

1008 18. Storage and distribution

1009 Storage

1010 18.1. Storage areas should be appropriately designed, constructed and maintained. They
1011 should be kept clean and dry. There should be sufficient space and suitable
1012 ventilation.
1013
1014 18.2. Storage areas should normally be under cover with sufficient space. Where excipients
1015 for pharmaceutical use are stored outside buildings, risk assessment should be done to
1016 determine the necessary controls to protect the products from contamination and
1017 deterioration.
1018
1019 18.3. Excipients for pharmaceutical use should be stored in suitable containers, under
1020 appropriate storage conditions. Where special storage conditions are required, these
1021 should be provided, controlled, monitored and recorded
1022
1023 18.4. There should be a written programme for pest control.
 Working document QAS/23.921
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1024 Distribution

1025 18.5. Excipients for pharmaceutical use should be distributed through traceable routes.
1026 Product, batch and container identity should be maintained at all times. All labels
1027 should remain legible.
1028
1029 18.6. Excipients for pharmaceutical use should be transported in accordance with the
1030 conditions stated on the labels.
1031
1032 18.7. Distribution records should be sufficiently detailed to allow for traceability in case of
1033 a recall, when required.
1034
1035 Note: See WHO Good trade and distribution practices for pharmaceutical starting materials
1036 (2)
1037

1038
 Working document QAS/23.921
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1039

1040 References

1041 1. WHO guidelines on quality risk management. In: WHO Expert Committee on
1042 Specifications for Pharmaceutical Preparations: forty-seventh report. WHO Technical
1043 Report Series No. 981, Annex 2. Geneva: World Health Organization; 2013
1044 ([Link] accessed on 1 February 2023)
1045 2. WHO Good trade and distribution practices for pharmaceutical starting materials. In:
1046 WHO Expert Committee on Specifications for Pharmaceutical Preparations: fiftieth
1047 report. WHO Technical Report Series No. 996, Annex 6. Geneva: World Health
1048 Organization; 2016 ([Link] accessed
1049 on 1 February 2023)

1050

1051 Further reading

1052  WHO good manufacturing practices for pharmaceutical products: main principles. In:
1053 WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-
1054 eight Report. WHO Technical Report Series, No. 986, Annex 2. Geneva: World
1055 Health Organization, 2014 ([Link]
1056 accessed on 1 February 2023)
1057  WHO good manufacturing practices for active pharmaceutical ingredients. In: WHO
1058 Expert Committee on Specifications for Pharmaceutical Preparations: forty-fourth
1059 report. WHO Technical Report Series No. 957, Annex 2. Geneva: World Health
1060 Organization; 2010 ([Link]
1061 accessed on 1 February 2023)
1062  WHO guidelines for sampling of pharmaceutical products and related materials. In:
1063 WHO Expert Committee on Specifications for Pharmaceutical Preparations: thirty-
1064 ninth report. WHO Technical Report Series No. 929, Annex 4. Geneva: World Health
 Working document QAS/23.921
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1065 Organization; 2005 ([Link]

1066 accessed on 1 February 2023)
1067  WHO good practices for pharmaceutical quality control laboratories. In: WHO Expert
1068 Committee on Specifications for Pharmaceutical Preparations: forty-fourth report.
1069 WHO Technical Report Series No. 957, Annex 1. Geneva: World Health
1070 Organization; 2010 ([Link] accessed
1071 on 1 February 2023)
1072  WHO good manufacturing practices for pharmaceutical products containing
1073 hazardous substances. In: WHO Expert Committee on Specifications for
1074 Pharmaceutical Preparations: forty-fourth report. WHO Technical Report Series No.
1075 957, Annex 3. Geneva: World Health Organization; 2010
1076 ([Link] accessed on 1 February
1077 2023)
1078  WHO good manufacturing practices for sterile pharmaceutical products. In: WHO
1079 Expert Committee on Specifications for Pharmaceutical Preparations: fifty-sixth
1080 report. WHO Technical Report Series No. 1044, Annex 2. Geneva: World Health
1081 Organization; 2022 ([Link]
1082 accessed on 1 February 2023)
1083  Model guidance for the storage and transport of time- and temperature-sensitive
1084 pharmaceutical products. In: WHO Expert Committee on Specifications for
1085 Pharmaceutical Preparations: forty-fifth report. WHO Technical Report Series No.
1086 961, Annex 9. Geneva: World Health Organization; 2011
1087 ([Link]
1088 modelguidanceforstoragetransport accessed on 1 February 2023)
1089  WHO good practices for pharmaceutical microbiology laboratories. In: WHO Expert
1090 Committee on Specifications for Pharmaceutical Preparations: forty-fifth report.
1091 WHO Technical Report Series No. 961, Annex 2. Geneva: World Health
1092 Organization; 2011 ([Link] accessed
1093 on 1 February 2023)
1094  WHO Guidelines on good manufacturing practices: validation. Appendix 7: Non-
1095 sterile process validation. In: WHO Expert Committee on Specifications for
1096 Pharmaceutical Preparations: fifty-third report. WHO Technical Report Series No.
 Working document QAS/23.921
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1097 1019, Annex 3. Geneva: World Health Organization; 2019

1098 ([Link] accessed on 1 February
1099 2023)
1100  WHO General guidance on hold-time studies. In: WHO Expert Committee on
1101 Specifications for Pharmaceutical Preparations: forty-ninth report. WHO Technical
1102 Report Series No. 992, Annex 4. Geneva: World Health Organization; 2015
1103 ([Link] accessed on 1 February
1104 2023)
1105  WHO Technical supplements to model guidance for storage and transport of time-
1106 and temperature-sensitive pharmaceutical products. In: WHO Expert Committee on
1107 Specifications for Pharmaceutical Preparations: forty-ninth report. WHO Technical
1108 Report Series No. 992, Annex 5. Geneva: World Health Organization; 2015
1109 ([Link] accessed on 1 February
1110 2023)
1111  Guidelines on heating, ventilation and air-conditioning systems for non-sterile
1112 pharmaceutical products. In: WHO Expert Committee on Specifications for
1113 Pharmaceutical Preparations: fifty-second report. WHO Technical Report Series No.
1114 1010, Annex 8. Geneva: World Health Organization; 2018
1115 ([Link] accessed on 1 February
1116 2023)
1117  Stability testing of active pharmaceutical ingredients and finished pharmaceutical
1118 products. In: WHO Expert Committee on Specifications for Pharmaceutical
1119 Preparations: fifty-second report. WHO Technical Report Series No. 1010, Annex 10.
1120 Geneva: World Health Organization, 2018
1121 ([Link] accessed on 1 February
1122 2023)
1123  WHO Good chromatography practices. In: WHO Expert Committee on Specifications
1124 for Pharmaceutical Preparations. fifty-forth Report. WHO Technical Report Series,
1125 No. 1025, Annex 4. Geneva: World Health Organization, 2020
1126 ([Link] accessed on 1 February
1127 2023)
 Working document QAS/23.921
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1128  Points to consider for manufacturers and inspectors: environmental aspects of

1129 manufacturing for the prevention of antimicrobial resistance. In: WHO Expert
1130 Committee on Specifications for Pharmaceutical Preparations. fifty-forth Report.
1131 WHO Technical Report Series, No. 1025, Annex 6. Geneva: World Health
1132 Organization, 2020 ([Link]
1133 accessed on 1 February 2023)
1134  WHO Good manufacturing practices: water for pharmaceutical use. In: WHO Expert
1135 Committee on Specifications for Pharmaceutical Preparations: fifty-fifth report. WHO
1136 Technical Report Series No. 1033, Annex 3. Geneva: World Health Organization;
1137 2021 ([Link] accessed on 1
1138 February 2023)
1139  WHO Guideline on data integrity. In: WHO Expert Committee on Specifications for
1140 Pharmaceutical Preparations: fifty-fifth report. WHO Technical Report Series No.
1141 1033, Annex 4. Geneva: World Health Organization; 2021
1142 ([Link] accessed on 1 February
1143 2023)
1144  Good manufacturing practices for pharmaceutical excipients. National Sanitation
1145 Foundation (NSF), International Pharmaceutical Excipient Council (IPEC) and
1146 American National Standards Institute (ANSI): NSF/IPEC/ANSI 363-2019.
1147  General Chapter 〈1078〉 Good Manufacturing Practices for Bulk Pharmaceutical
1148 Excipients. USP-NF. Rockville, MD: United States Pharmacopeia 2023
1149  WHO pharmaceutical starting materials certification scheme (SMACS): guidelines on
1150 implementation. In: WHO Expert Committee on Specifications for Pharmaceutical
1151 Preparations: thirty-eight report. WHO Technical Report Series No. 917, Annex 3.
1152 Geneva: World Health Organization; 2003
1153 ([Link] accessed on 1 February
1154 2023).