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Working document QAS/17.694
January 2017
Draft document for comment
STABILITY TESTING OF ACTIVE 1
PHARMACEUTICAL INGREDIENTS AND 2
FINISHED PHARMACEUTICAL PRODUCTS 3
(January 2017) 4
DRAFT FOR COMMENT 5
6
© World Health Organization 2017 7
All rights reserved. 8
This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. 9 The draft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in 10 part or in whole, in any form or by any means outside these individuals and organizations (including the 11 organizations' concerned staff and member organizations) without the permission of the World Health Organization. 12 The draft should not be displayed on any website. 13
Please send any request for permission to: 14
Dr Sabine Kopp, Group Lead, Medicines Quality Assurance, Technologies Standards and Norms, Department of 15 Essential Medicines and Health Products, World Health Organization, CH-1211 Geneva 27, Switzerland. 16 Fax: (41-22) 791 4730; email: [email protected]. 17
The designations employed and the presentation of the material in this draft do not imply the expression of any 18 opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, 19 territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines 20 on maps represent approximate border lines for which there may not yet be full agreement. 21
The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or 22 recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. 23 Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. 24
All reasonable precautions have been taken by the World Health Organization to verify the information contained in 25 this draft. However, the printed material is being distributed without warranty of any kind, either expressed or 26 implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the 27 World Health Organization be liable for damages arising from its use. 28
This draft does not necessarily represent the decisions or the stated policy of the World Health Organization.29
Should you have any comments on the attached text and the Stability conditions for WHO Member States
(MS) by Region, appendixed to the previous version of this guidance (http://www.who.int/medicines/areas/quality_safety/quality_assurance/regulatory_standards/en/), please send
these to: Dr Sabine Kopp, Group Lead, Medicines Quality Assurance, Technologies Standards and Norms,
World Health Organization, 1211 Geneva 27, Switzerland; email: [email protected]; fax: (+41 22) 791 4730; and to Mrs Ksenia Finnerty ([email protected]), by 15 March 2017. In line with the recommendations of
the WHO Expert Committee on Specifications for Pharmaceutical Preparations the list of MS Stability
conditions is maintained as a living document. Comments received after the indicated date will also be considered.
Working documents are sent out electronically and they will also be placed on the Medicines website
for comment. If you do not already receive directly our draft guidelines please let us have your email
address (to [email protected]) and we will add it to our electronic mailing list.
.
Working document QAS/17.694 page 2
SCHEDULE FOR THE PROPOSED ADOPTION PROCESS OF DOCUMENT 30
QAS/17.694: 31
STABILITY TESTING OF ACTIVE PHARMACEUTICAL INGREDIENTS 32
AND FINISHED PHARMACEUTICAL PRODUCTS 33 34
Development of the proposal to update the guideline for
stability testing of active pharmaceutical ingredients and
finished pharmaceutical products (TRS 953, Annex 2,
2009)
June 2016
Presentation of the proposal to the joint meeting on
regulatory guidance for multisource products with the
medicines quality assurance group and the WHO
Prequalification Team – Medicines (PQTm) and with
regulatory experts
July 2016
Presentation of the proposal to the fifty-first meeting of
the WHO Expert Committee on Specifications for
Pharmaceutical Preparations (ECSPP)
October 2016
Development of the draft guideline and preparation of
revised text by Mrs Lynda Paleshnuik, Canada
September–
December 2016
Mailing and posting of the working document on the
WHO website for public consultation as recommended
by the WHO ECSPP
January 2017
Compilation of comments received April 2017
Discussion of feedback received during an informal
consultation Date tbd
Circulation for comments August 2017
Compilation of comments received September 2017
Presentation to fifty-second meeting of the WHO ECSPP October 2017
Further follow-up action as required …
35
Working document QAS/17.694 page 3
Introduction and background 36
37
The Stability testing of active pharmaceutical ingredients and finished 38
pharmaceutical products was published as Annex 2 in the WHO Technical 39
Report Series, No. 953, 2009 (1). 40
41
These regulatory guidelines seek to exemplify the core stability data package 42
required for registration of active pharmaceutical ingredients (APIs) and finished 43
pharmaceutical products (FPPs), replacing the previous WHO guidelines in this 44
area. The guidelines cross-reference to the series of related International Council 45
on Harmonisation (ICH) guidelines (2) and other WHO guidelines. 46
47
It was recommended at the time of publication that these guidelines should also 48
be applied to products that are already being marketed, with allowance for an 49
appropriate transition period, e.g. upon re-registration or upon re-evaluation. 50
51
The 2009 update not only followed the usual consultation process, but it was 52
also the result of numerous interactions and discussions with the various 53
regulatory fora, including ICH. As a result the ICH parties withdrew at the time 54
one of their guidance texts (Q1F) and published the following on their website: 55
56
“ Explanatory Note on the Withdrawal of ICH Q1F for the ICH Website 57
58
ICH Q1 F Stability Data Package for Registration Applications in Climatic 59
Zones III and IV defined storage conditions for stability testing in countries 60
located in Climatic Zones III (hot and dry) and IV (hot and humid), i.e. countries 61
not located in the ICH regions and not covered by ICH Q1 A (R2) Stability 62
Testing for New Drug Substances and Drug Products. ICH Q1 F described 63
harmonised global stability testing requirements in order to facilitate access to 64
medicines by reducing the number of different storage conditions. In the course 65
of the discussions which led to the development of the guideline, WHO 66
conducted a survey amongst their member states to find consensus on 30°C/65% 67
RH as the long-term storage conditions for hot and humid regions. As no 68
significant objections were raised in this survey, 30°C/65% RH was defined as 69
the long-term storage condition for Climatic Zone III/IV countries in ICH Q1F. 70
The document was adopted by the ICH Steering Committee in February 2003 71
and subsequently implemented in the ICH regions. 72
However, based on new calculations and discussions, some countries in 73
Climatic Zone IV have expressed their wish to include a larger safety margin for 74
medicinal products to be marketed in their region than foreseen in ICH Q1F. As 75
a consequence, several countries and regions have revised their own stability 76
testing guidelines, defining up to 30°C/75% RH as the long-term storage 77
Working document QAS/17.694 page 4
conditions for hot and humid regions. Due to this divergence in global stability 78
testing requirements, the ICH Steering Committee has decided to withdraw ICH 79
Q1F and to leave definition of storage conditions in Climatic Zones III and IV to 80
the respective regions and WHO [web link to the WHO guidelines](1). 81
82
In assessing the impact of the withdrawal of ICH Q1F on intermediate testing 83
conditions defined in ICH Q1A (R2), the decision was reached to retain 84
30°C/65%RH. However, regulatory authorities in the ICH regions have agreed 85
that the use of more stringent humidity conditions such as 30°C/75% RH will be 86
acceptable should the applicant decide to use them.” 87
88
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Qualit89
y/Q1F/Q1F_Explanatory_Note.pdf 90
91
Based on recent developments an analysis was commissioned to evaluate 92
whether these guidelines would need to be updated. 93
94
During the Joint meeting on regulatory guidance for multisource products with 95
the medicines quality assurance group and the prequalification of medicines 96
team – assessment group held in Copenhagen on 8–9 July 2016, this analysis 97
report was discussed in detail and feedback provided by the participants to the 98
report as well as the various sections of the current guidelines. In conclusion, the 99
participants agreed that a revision of this text would be timely. 100
101
Working document QAS/17.694 page 5
Stability testing of active pharmaceutical ingredients and 102
finished pharmaceutical products 103
1. Introduction 104
1.1 Objectives of these guidelines 105
1.2 Scope of these guidelines 106
1.3 General principles 107
2. Guidelines 108
2.1 Active pharmaceutical ingredient 109
2.1.1 General 110
2.1.2 Stress testing 111
2.1.3 Selection of batches 112
2.1.4 Container closure system 113
2.1.5 Specification 114
2.1.6 Testing frequency 115
2.1.7 Storage conditions 116
2.1.8 Stability commitments 117
2.1.9 Evaluation 118
2.1.10 Statements and labelling 119
2.1.11 Ongoing stability studies 120
2.2 Finished pharmaceutical product 121
2.2.1 General 122
2.2.2 Stress testing 123
2.2.3 Selection of batches 124
2.2.4 Container closure system 125
2.2.5 Specification 126
2.2.6 Testing frequency 127
2.2.7 Storage conditions 128
2.2.8 Stability commitments 129
2.2.9 Evaluation 130
2.2.10 Statements and labelling 131
2.2.11 In-use and hold-time stability 132
2.2.12 Variations 133
2.2.13 Ongoing stability studies 134
3. Glossary 135
References 136
Appendix 1. Examples of testing parameters 137
Appendix 2. Recommended labelling statements 138
Appendix 3. Interpretation of storage statements for products approved in zone 139
II when the products are to be distributed in zone IV 140
Working document QAS/17.694 page 6
1. Introduction 141
1.1 Objectives of these guidelines 142
These guidelines seek to exemplify the core stability data package 143
required for registration of active pharmaceutical ingredients (APIs) and 144
finished pharmaceutical products (FPPs), replacing the previous WHO 145
guidelines in this area (1). However, alternative approaches can be used 146
when they are scientifically justified. Further guidance can be found in 147
International Council on Harmonisation (ICH) guidelines (2), in the 148
WHO guidelines on the active pharmaceutical ingredient master file 149
procedure (3), the WHO Guidelines on submission of documentation for 150
a multisource (generic) finished pharmaceutical product: quality part (4) 151
and the WHO Guidelines on submission of documentation for a 152
multisource (generic) finished pharmaceutical product for the WHO 153
Prequalification of Medicines Programme: quality part (5); and the 154
General guidance on hold time studies (6). 155
It is recommended that these guidelines should also be applied to 156
products that are already being marketed, e.g. upon re-registration or upon 157
re-evaluation. 158
159
1.2 Scope of these guidelines 160
These guidelines apply to new and existing APIs and address information 161
to be submitted in original and subsequent applications for marketing 162
authorization of their related FPP for human use. These guidelines are not 163
applicable to stability testing for biologicals. 164
165
1.3 General principles 166
The purpose of stability testing is to provide evidence of how the quality 167
of an API or FPP varies with time under the influence of a variety of 168
environmental factors such as temperature, humidity and light. The 169
stability programme also includes the study of product-related factors 170
that influence its quality, for example, interaction of API with excipients, 171
container closure systems and packaging materials. In fixed-dose 172
combination FPPs (FDCs) the interaction between two or more APIs also 173
has to be considered. 174
As a result of stability testing a re-test period for the API (in exceptional 175
cases, e.g. for unstable APIs, a shelf life is given) or a shelf life for the 176
FPP can be established and storage conditions can be recommended. 177
Various analyses have been done to identify suitable testing conditions 178
Working document QAS/17.694 page 7
for WHO Member States (MS) based on climatic data on the basis of 179
which each MS can make its decision on long-term (real-time) stability 180
testing conditions. Those MS that have notified WHO of the long-term 181
stability testing conditions they require when requesting a marketing 182
authorization are listed in Long-term stability testing conditions as 183
identified by WHO Member States 184
(http://www.who.int/medicines/areas/quality_safety/quality_assurance/re185
gulatory_standards/en/). 186
187
2. Guidelines 188
2.1 Active pharmaceutical ingredient 189
2.1.1 General 190
Information on the stability of the API is an integral part of the 191
systematic approach to stability evaluation. Potential attributes to be 192
tested on an API during stability testing are listed in the examples of 193
testing parameters (Appendix 1). 194
The re-test period or shelf life assigned to the API by the API 195
manufacturer should be derived from stability testing data. 196
197
2.1.2 Stress testing 198
Stress testing of the API can help identify the likely degradation 199
products, which in turn can help establish the degradation pathways and 200
the intrinsic stability of the molecule and validate the stability-indicating 201
power of the analytical procedures used. The nature of the stress testing 202
will depend on the individual API and the type of FPP involved. 203
For an API the following approaches may be used: 204
— when available, it is acceptable to provide the relevant data published 205
in the scientific literature to support the identified degradation 206
products and pathways; 207
— when no data are available, stress testing should be performed. 208
Stress testing may be carried out on a single batch of the API. It should 209
include the effect of temperature (in 10 °C increments (e.g. 50 °C, 60 °C, 210
etc.) above the temperature used for accelerated testing), humidity (e.g. 211
75% relative humidity (RH) or greater) and, where appropriate, oxidation 212
and photolysis on the API. The testing should also evaluate the 213
susceptibility of the API to hydrolysis across a justified range of pH 214
values when in solution or suspension (7). 215
Working document QAS/17.694 page 8
Assessing the necessity for photostability testing should be an integral part 216
of a stress testing strategy. More details can be found in other guidelines 217
(2). 218
The objective of stress testing is not to completely degrade the API but to 219
cause degradation to occur to a small extent, typically 10–30% loss of 220
API by assay when compared with non-degraded API. This target is 221
chosen so that some degradation occurs, but not enough to generate 222
secondary products. For this reason the conditions and duration may need 223
to be varied when the API is especially susceptible to a particular stress 224
factor. In the total absence of degradation products after 10 days the API 225
is considered stable under the particular stress condition. 226
Although examining degradation products under stress conditions is 227
useful in establishing degradation pathways and developing and 228
validating suitable analytical procedures, it may not be necessary to 229
examine specifically for certain degradation products if it has been 230
demonstrated that they are not formed under accelerated or long-term 231
storage conditions. 232
Results from these studies will form an integral part of the information 233
provided to regulatory authorities. 234
235
2.1.3 Selection of batches 236
Data from stability studies on at least three primary batches of the API 237
should normally be provided. The batches should be manufactured to a 238
minimum of pilot scale by the same synthesis route as production 239
batches, and using a method of manufacture and procedure that simulates 240
the final process to be used for production batches. The overall quality of 241
the batches of API placed on stability studies should be representative of 242
the quality of the material to be made on a production scale. 243
244
2.1.4 Container closure system 245
The stability studies should be conducted on the API packaged in a 246
container closure system that is the same as, or simulates, the packaging 247
proposed for storage and distribution. 248
249
2.1.5 Specification 250
Stability studies should include testing of those attributes of the API that 251
are susceptible to change during storage and are likely to influence 252
quality, safety and/or efficacy. The testing should cover, as appropriate, the 253
physical, chemical, biological and microbiological attributes. A guide as to 254
Working document QAS/17.694 page 9
the potential attributes to be tested in the stability studies is provided in 255
Appendix 1. 256
Validated stability-indicating analytical procedures should be applied. 257
Whether and to what extent replication should be performed will depend 258
on the results from validation studies (8, 9). 259
260
2.1.6 Testing frequency 261
For long-term studies, the frequency of testing should be sufficient to 262
establish the stability profile of the API. 263
For APIs with a proposed re-test period or shelf life of at least 12 months, 264
the frequency of testing at the long-term storage condition should 265
normally be every three months over the first year, every six months over 266
the second year, and annually thereafter throughout the proposed re-test 267
period or shelf life. 268
At the accelerated storage condition, a minimum of three time points, 269
including the initial and final time points (e.g. 0, 3 and 6 months), from a 270
six-month study is recommended. Where it is expected (based on 271
development experience) that results from accelerated studies are likely 272
to approach significant change criteria, increased testing should be 273
conducted either by adding samples at the final time point or by including 274
a fourth time point in the study design. When testing at the intermediate 275
storage condition is called for as a result of significant change at the 276
accelerated storage condition, a minimum of four time points, including 277
the initial and final time points (e.g. 0, 6, 9 and 12 months), from a 12-278
month study is recommended. 279
280
2.1.7 Storage conditions 281
In general an API should be evaluated under storage conditions (with 282
appropriate tolerances) that test its thermal stability and, if applicable, its 283
sensitivity to moisture. The storage conditions and the lengths of studies 284
chosen should be sufficient to cover storage and shipment. 285
Storage condition tolerances are defined as the acceptable variations in 286
temperature and relative humidity of storage facilities for stability 287
studies. The equipment used should be capable of controlling the storage 288
conditions within the ranges defined in these guidelines. The storage 289
conditions should be monitored and recorded. Short-term environmental 290
changes due to opening the doors of the storage facility are accepted as 291
unavoidable. The effect of excursions due to equipment failure should be 292
assessed, addressed and reported if judged to affect stability results. 293
Working document QAS/17.694 page 10
Excursions that exceed the defined tolerances for more than 24 hours 294
should be described in the study report and their effects assessed. 295
For new APIs, the long-term testing should normally take place over a 296
minimum of 12 months for the number of batches specified in section 297
2.1.3 at the time of submission, and should be continued for a period of 298
time sufficient to cover the proposed re-test period or shelf life. For 299
existing APIs, data covering a minimum of six months may be submitted. 300
Additional data accumulated during the assessment period of the 301
registration application should be submitted to the authorities when 302
submitting data in response to outstanding questions. Data from the 303
accelerated storage condition and, if appropriate, from the intermediate 304
storage condition can be used to evaluate the effect of short-term 305
excursions outside the label storage conditions (such as might occur 306
during shipping). 307
Long-term, accelerated and, where appropriate, intermediate storage 308
conditions for APIs are detailed in sections 2.1.7.1–2.1.7.3. The general 309
case applies if the API is not specifically covered by a subsequent 310
section. Alternative storage conditions can be used if justified. 311
If long-term studies are conducted at 25 °C ± 2 °C/60% RH ± 5% RH 312
and “significant change” occurs at any time during six months’ testing at 313
the accelerated storage condition, additional testing at the intermediate 314
storage condition should be conducted and evaluated against significant 315
change criteria. In this case, testing at the intermediate storage condition 316
should include all long-term tests, unless otherwise justified, and the 317
initial application should include a minimum of six months’ data from a 318
12-month study at the intermediate storage condition. 319
“Significant change” for an API is defined as failure to meet its 320
specification. 321
322
Working document QAS/17.694 page 11
323
2.1.7.1 General case 324
325
Study Storage condition Minimum time period
covered by data at
submission
Long-terma
25 °C ± 2 °C/60% RH ± 5% RH
or
30 °C ± 2 °C/65% RH ± 5% RH
or
30 °C ± 2 °C/75% RH ± 5% RH
12 months or six months as
described in section 2.1.7
Intermediate
b
30 °C ± 2 °C/65% RH ± 5% RH six months
Accelerated 40 °C ± 2 °C/75% RH ± 5% RH six months
a Whether long-term stability studies are performed at 25 °C ± 2 °C/60% RH ± 5% RH or 30 °C ± 2 °C/65% RH 326 ± 5% RH or 30 °C ± 2 °C/75% RH ± 5% RH is determined by the climatic condition under which the API is intended 327 to be stored (see http://www.who.int/medicines/areas/quality_safety/quality_assurance/regulatory_standards/en/ 328 Long-term stability testing conditions as identified by WHO Member States). Testing at a more severe long-term 329 condition can be an alternative to testing condition, i.e. 25 °C/60% RH or 30 °C/65% RH for zone II. 330 b If 30 °C ± 2 °C/65% RH ± 5% RH or 30 °C ± 2 °C/75% RH ± 5% RH is the long-term condition there is no 331
intermediate condition. 332
2.1.7.2 Active pharmaceutical ingredients intended for storage in a refrigerator 333
334
Study Storage condition Minimum time period
covered by data at
submission
Long-term 5 °C ± 3 °C 12 months or six months as
referred to in section 2.1.7
Accelerateda 25 °C ± 2 °C/60% RH ± 5% RH
or
30 °C ± 2 °C/65% RH ± 5% RH
or
30 °C ± 2 °C/75% RH ± 5% RH
six months
a Whether accelerated stability studies are performed at 25 °C ± 2 °C/60% RH ± 5% RH or 30 °C ± 2 °C/65% RH ± 335 5% RH or 30 °C ± 2 °C/75% RH ± 5% RH is based on a risk-based evaluation. Testing at a more severe 336 accelerated condition can be an alternative to storage testing at 25 °C/60%RH or 30 °C/65%RH. 337
Working document QAS/17.694 page 12
338
Data on refrigerated storage should be assessed according to the 339
evaluation section of these guidelines, except where explicitly noted 340
below. 341
If significant change occurs between three and six months’ testing at the 342
accelerated storage condition, the proposed re-test period should be based 343
on the data available at the long-term storage condition. 344
If significant change occurs within the first three months’ testing at the 345
accelerated storage condition a discussion should be provided to address 346
the effect of short-term excursions outside the label storage condition, 347
e.g. during shipping or handling. This discussion can be supported, if 348
appropriate, by further testing on a single batch of the API for a period 349
shorter than three months but with more frequent testing than usual. It is 350
considered unnecessary to continue to test an API for the whole six 351
months when a significant change has occurred within the first three 352
months. 353
354
2.1.7.3 Active pharmaceutical ingredients intended for storage in a freezer 355
356
Study Storage condition Minimum time period covered
by data at submission
Long-term -20 °C ± 5 °C 12 months or six months as
referred to in section 2.1.7
357
In the rare case of any API of non-biological origin being intended for 358
storage in a freezer, the re-test period or shelf life should be based on the 359
long-term data obtained at the long-term storage condition. In the absence 360
of an accelerated storage condition for APIs intended to be stored in a 361
freezer, testing on a single batch at an elevated temperature (e.g. 5 °C ± 3 362
°C or 25 °C ± 2 °C or 30 °C ± 2 °C) for an appropriate time period should 363
be conducted to address the effect of short-term excursions outside the 364
proposed label storage condition, e.g. during shipping or handling. 365
366
367
368
Working document QAS/17.694 page 13
369
2.1.7.4 Active pharmaceutical ingredients intended for storage below -20 °C 370
APIs intended for storage below -20 °C should be treated on a case-by-371
case basis. 372
373
2.1.8 Stability commitments 374
When the available long-term stability data on primary batches do not 375
cover the proposed re-test period or shelf life granted at the time of 376
approval, a commitment should be made to continue the stability studies 377
post-approval in order to firmly establish the re-test period or shelf-life. 378
Where the submission includes long-term stability data on the number of 379
production batches specified in section 2.1.3 covering the proposed re-380
test period or shelf life, a post-approval commitment is considered 381
unnecessary. Otherwise one of the following commitments should be 382
made: 383
• if the submission includes data from stability studies on three 384
production batches, a commitment should be made to continue these 385
studies through the proposed re-test period or shelf life; 386
• if the submission includes data from stability studies on fewer than 387
three production batches, a commitment should be made to continue 388
these studies through the proposed re-test period and to place additional 389
production batches, to a total of at least three, in long-term stability 390
studies through the proposed re-test period or shelf life; 391
• if the submission does not include stability data on production batches, 392
a commitment should be made to place the first three production 393
batches (see section 2.1.3) on long-term stability studies through the 394
proposed re-test period or shelf life. 395
The stability protocol used for long-term studies for the stability 396
commitment should be the same as that for the primary batches, unless 397
otherwise scientifically justified. 398
See also 2.1.11 Ongoing stability. 399
400
2.1.9 Evaluation 401
The purpose of the stability study is to establish, based on testing at 402
minimum three batches, unless otherwise justified and authorized, of the 403
API and evaluating the stability information (including, as appropriate, 404
results of the physical, chemical, biological and microbiological tests), a 405
re-test period or shelf life applicable to all future batches of the API 406
manufactured under similar circumstances. The degree of variability of 407
Working document QAS/17.694 page 14
individual batches affects the confidence that a future production batch 408
will remain within specification throughout the assigned re-test period or 409
shelf life. 410
The data may show so little degradation and so little variability that it is 411
apparent from looking at them that the requested re-test period or shelf 412
life will be granted. Under these circumstances it is normally unnecessary 413
to go through the statistical analysis; providing a justification for the 414
omission should be sufficient. 415
An approach for analysing the data on a quantitative attribute that is 416
expected to change with time is to determine the time at which the 95% 417
one-sided confidence limit for the mean curve intersects the acceptance 418
criterion. If analysis shows that the batch-to-batch variability is small, it is 419
advantageous to combine the data into one overall estimate. This can be 420
done by first applying appropriate statistical tests (e.g. p values for level 421
of significance of rejection of more than 0.25) to the slopes of the 422
regression lines and zero time intercepts for the individual batches. If it is 423
inappropriate to combine data from several batches, the overall re-test 424
period or shelf life should be based on the minimum time a batch can be 425
expected to remain within acceptance criteria. 426
The nature of any degradation relationship will determine whether the 427
data should be transformed for linear regression analysis. Usually the 428
relationship can be represented by a linear, quadratic or cubic function on 429
an arithmetic or logarithmic scale. As far as possible, the choice of model 430
should be justified by a physical and/or chemical rationale and should 431
also take into account the amount of available data (parsimony principle 432
to ensure a robust prediction). Statistical methods should be employed to 433
test the goodness of fit of the data on all batches and combined batches 434
(where appropriate) to the assumed degradation line or curve. 435
Limited extrapolation of the long-term data from the long-term storage 436
condition beyond the observed range to extend the re-test period or shelf 437
life can be undertaken if justified. This justification should be based on 438
what is known about the mechanism of degradation, the results of testing 439
under accelerated conditions, the goodness of fit of any mathematical 440
model, batch size and existence of supporting stability data. However, this 441
extrapolation assumes that the same degradation relationship will 442
continue to apply beyond the observed data. 443
444
Any evaluation should cover not only the assay but also the levels of 445
degradation products and other appropriate attributes. 446
Working document QAS/17.694 page 15
447
2.1.10 Statements and labelling 448
A storage statement should be established for display on the label based 449
on the stability evaluation of the API. Where applicable, specific 450
instructions should be provided, particularly for APIs that cannot tolerate 451
freezing or excursions in temperature. Terms such as “ambient 452
conditions” or “room temperature” should be avoided. 453
The recommended labelling statements for use if supported by the 454
stability studies are provided in Appendix 2. 455
A re-test period should be derived from the stability information, and a 456
re-test date should be displayed on the container label if appropriate. 457
After this re-test period a batch of API destined for use in the 458
manufacture of an FPP could be re-tested and then, if in compliance with 459
the specification, could be used immediately (e.g. within 30 days). If re-460
tested and found compliant, the batch does not receive an additional 461
period corresponding to the time established for the re-test period. 462
However, an API batch can be re-tested multiple times and a different 463
portion of the batch used after each re-test, as long as it continues to 464
comply with the specification. For APIs known to be labile (e.g. certain 465
antibiotics) it is more appropriate to establish a shelf life than a re-test 466
period. 467
468
2.1.11 Ongoing stability studies 469
The stability of the API should be monitored according to a continuous 470
and appropriate programme that will permit the detection of any stability 471
issue (e.g. changes in levels of degradation products). The purpose of the 472
ongoing stability programme is to monitor the API and to determine that 473
the API remains, and can be expected to remain, within specifications 474
under the storage conditions indicated on the label, within the re-test 475
period or shelf life in all future batches. 476
The ongoing stability programme should be described in a written 477
protocol and the results presented in a formal report. 478
The protocol for an ongoing stability programme should extend to the 479
end of the re-test period or shelf life and should include, but not be 480
limited to, the following parameters: 481
482
483
Working document QAS/17.694 page 16
— number of batch(es) and different batch sizes, if applicable; 484
— relevant physical, chemical, microbiological and biological test 485
methods; 486
— acceptance criteria; 487
— reference to test methods; 488
— description of the container closure system(s); 489
— testing frequency; 490
— description of the conditions of storage (standardized conditions for 491
long-term testing as described in these guidelines, and consistent with 492
the API labelling, should be used); and 493
— other applicable parameters specific to the API. 494
495
At least one production batch per year of API (unless none is produced 496
during that year) should be added to the stability monitoring programme 497
and tested at least annually to confirm the stability (8). In certain situations 498
additional batches should be included in the ongoing stability 499
programme. For example, an ongoing stability study should be conducted 500
after any significant change or significant deviation to the synthetic route, 501
process or container closure system that may have an impact upon the 502
stability of the API (9). 503
Out-of-specification (OOS) results or significant atypical trends should be 504
investigated. Any confirmed significant change, OOS result, or significant 505
atypical trend should be reported immediately to the relevant finished 506
product manufacturer. The possible impact on batches on the market 507
should be considered in consultation with the relevant finished product 508
manufacturers and the competent authorities. 509
A summary of all the data generated, including any interim conclusions 510
on the programme, should be written and maintained. This summary 511
should be subjected to periodic review. 512
513
2.2 Finished pharmaceutical product 514
2.2.1 General 515
The design of the stability studies for the FPP should be based on 516
knowledge of the behaviour and properties of the API, information from 517
stability studies on the API and on experience gained from 518
preformulation studies and investigational FPPs. 519
520
521
Working document QAS/17.694 page 17
2.2.2 Stress testing 522
Photostability testing, which is an integral part of stress testing, should be 523
conducted on at least one primary batch of the FPP if appropriate. More 524
details can be found in other guidelines (2). 525
Additional stress testing of specific types of dosage forms may be 526
appropriate, e.g. cyclic studies for semi-solid products or freeze–thaw 527
studies for liquid products. 528
529
2.2.3 Selection of batches 530
For FPPs containing new APIs, data from stability studies should be 531
provided on at least three primary batches of the FPP. Two of the three 532
batches should be at least pilot-scale batches and the third batch can be 533
smaller, if justified. 534
For FPPs containing existing APIs (e.g. generics), data should be provided on 535
not less than two batches of at least pilot scale, or in the case of an 536
uncomplicated1 FPP (e.g. immediate-release solid FPPs (with noted exceptions) 537
or non-sterile solutions), at least one batch of at least pilot scale and a second 538
batch which may be smaller (e.g. for solid oral dosage forms, 25 000 or 50 000 539
tablets or capsules) of each proposed strength of the FPP. 540
The primary batches should be of the same formulation and packaged in 541
the same container closure system as proposed for marketing. The 542
manufacturing process used for primary batches should simulate that to 543
be applied to production batches and should provide product of the same 544
quality and meeting the same specification as that intended for 545
marketing. 546
When a batch size smaller than pilot scale is used as a primary batch, 547
data or a discussion is required to confirm that the smaller batch is 548
representative of the intended production size including formulation and 549
method of manufacture. 550
Where possible, batches of the FPP should be manufactured using 551
different batches of the API(s). 552
Stability studies should be performed on each individual strength, dosage 553
1 The term “complicated FPP” includes sterile products, metered dose inhaler
products, dry powder inhaler products and transdermal delivery systems. Solid oral
products considered “complicated” include products containing problematical APIs
such as ritonavir and FDCs containing APIs such as rifampicin or an artemisinin.
Working document QAS/17.694 page 18
form and container type and size of the FPP unless bracketing or 554
matrixing is applied. 555
556
2.2.4 Container closure system 557
Stability testing should be conducted on the dosage form packaged in the 558
primary container closure systems proposed for marketing. If the 559
secondary container closure system has protective properties and 560
labelling clearly indicates to store in the primary and secondary 561
packaging (e.g. “store tablets in blisters in the provided cartons”), the 562
secondary packaging may also form part of the packaging system for 563
stability samples. Any available studies carried out on the FPP outside its 564
immediate container or in other packaging materials can form a useful 565
part of the stress testing of the dosage form or can be considered as 566
supporting information, respectively. 567
568
2.2.5 Specification 569
Stability studies should include testing of those attributes of the FPP that 570
are susceptible to change during storage and are likely to influence 571
quality, safety, and/or efficacy. The testing should cover, as appropriate, the 572
physical, chemical, biological and microbiological attributes, 573
preservative content (e.g. antioxidant or antimicrobial preservatives) and 574
functionality tests (e.g. for a dose delivery system). Examples of testing 575
parameters in the stability studies are listed in Appendix 1. Analytical 576
procedures should be fully validated and stability-indicating. Whether 577
and to what extent replication should be performed will depend on the 578
results of validation studies. 579
Shelf life acceptance criteria should be derived from consideration of all 580
available stability information. It may be appropriate to have justifiable 581
differences between the shelf life and release acceptance criteria based on 582
the stability evaluation and the changes observed on storage. Any 583
differences between the release and shelf life acceptance criteria for 584
antimicrobial preservative content should be supported by a validated 585
correlation of chemical content and preservative effectiveness 586
demonstrated during development of the pharmaceutical product with the 587
product in its final formulation (except for preservative concentration) 588
intended for marketing. A single primary stability batch of the FPP should 589
be tested for effectiveness of the antimicrobial preservative (in addition to 590
preservative content) at the proposed shelf life for verification purposes, 591
regardless of whether there is a difference between the release and shelf 592
life acceptance criteria for preservative content. 593
Working document QAS/17.694 page 19
2.2.6 Testing frequency 594
For long-term studies, frequency of testing should be sufficient to 595
establish the stability profile of the FPP. 596
For products with a proposed shelf life of at least 12 months, the 597
frequency of testing at the long-term storage condition should normally 598
be every three months over the first year, every six months over the 599
second year and annually thereafter throughout the proposed shelf life. 600
At the accelerated storage condition, a minimum of three time points, 601
including the initial and final time points (e.g. 0, 3 and 6 months), from a 602
six-month study is recommended. Where an expectation (based on 603
development experience) exists that results from accelerated testing are 604
likely to approach significant change criteria, testing should be increased 605
either by adding samples at the final time point or by including a fourth 606
time point in the study design. 607
When testing at the intermediate storage condition is called for as a result 608
of significant change at the accelerated storage condition, a minimum of 609
four time points, including the initial and final time points (e.g. 0, 6, 9 610
and 12 months) from a 12-month study is recommended. 611
612
The initial date of storage should be considered t0 and stability time 613
points should be defined as a date with respect to t0. For example, if t0 is 614
1 January 2020 then the one-month time point corresponds to the date 1 615
February 2020. For each time point, testing should be done at or after the 616
corresponding date, and should not be later than 30 days or one calendar 617
month after. For example, if the six-month time point corresponds to the 618
date 1 July 2020, the product should be tested no later than 619
1 August 2020. The actual test dates should be recorded. 620
Reduced designs, i.e. matrixing or bracketing, where the testing 621
frequency is reduced or certain factor combinations are not tested at all, 622
can be applied if justified (2). 623
624
2.2.7 Storage conditions 625
Stability data must demonstrate stability of the medicinal product 626
throughout its intended shelf life under the climatic conditions prevalent 627
in the target countries. Merely applying the same requirements applicable 628
to other markets could potentially lead to substandard products if stability 629
studies are conducted at the storage conditions for countries in climatic 630
zone I/II when the products are supplied in countries in climatic zones III 631
and IV. 632
Working document QAS/17.694 page 20
In general an FPP should be evaluated under storage conditions with 633
specified tolerances that test its thermal stability and, if applicable, its 634
sensitivity to moisture or potential for solvent loss. The storage 635
conditions and the lengths of studies chosen should be sufficient to cover 636
storage, shipment and subsequent use with due regard to the climatic 637
conditions in which the product is intended to be marketed. 638
The orientation of the product during storage, i.e. upright versus inverted, 639
may need to be included in a protocol where contact of the product with 640
the closure system may be expected to affect the stability of the products 641
contained (e.g. liquids and semisolids), or where there has been a change 642
in the container closure system. 643
Storage condition tolerances are usually defined as the acceptable 644
variations in temperature and relative humidity of storage facilities for 645
stability studies. The equipment used should be capable of controlling the 646
storage conditions within the ranges defined in these guidelines. The 647
storage conditions should be monitored and recorded. Short-term 648
environmental changes due to opening of the doors of the storage facility 649
are accepted as unavoidable. The effect of excursions due to equipment 650
failure should be assessed, addressed and reported if judged to affect 651
stability results. Excursions that exceed the defined tolerances for more 652
than 24 hours should be described in the study report and their effects 653
assessed. 654
At the time of submission, the long-term testing should cover a minimum 655
of six months for FPPs containing existing APIs or 12 months for FPPs 656
containing new APIs and should be continued for a period of time 657
sufficient to cover the proposed shelf life. The length of data required at the 658
time of submission may be shortened in some circumstances, for example, to 659
address drug shortages (for example, the three-month requirement for second-line 660
tuberculosis and reproductive health medicines to the WHO Prequalification Team 661
– Medicines (PQTm) (see who.int/prequal/)). 662
Additional data accumulated during the assessment period of the 663
registration application should be submitted to the authorities when 664
submitting data in response to outstanding questions. Data from the 665
accelerated storage condition and from the intermediate conditions, 666
where appropriate, can be used to evaluate the effect of short-term 667
excursions outside the label storage conditions (such as might occur 668
during shipping). 669
Long-term, accelerated and, where appropriate, intermediate storage 670
conditions for FPPs are detailed in the sections below. The general case 671
Working document QAS/17.694 page 21
applies if the FPP is not specifically covered by a subsequent section. 672
Alternative storage conditions can be used if justified. 673
674
2.2.7.1 General case 675
676
Study Storage condition Minimum time period
covered by data at
submission
Long-terma
25 °C ± 2 °C/60% RH ± 5% RH
or
30 °C ± 2 °C/65% RH ± 5% RH
or
30 °C ± 2 °C/75% RH ± 5% RH
12 months or six months
as referred to in section
2.2.7
Intermediateb 30 °C ± 2 °C/65% RH ± 5% RH six months
Accelerated 40 °C ± 2 °C/75% RH ± 5% RH six months
a Whether long-term stability studies are performed at 25 °C ± 2 °C/60% RH ± 5% RH or 30 °C ± 2 °C/65% RH 677 ± 5% RH or 30 °C ± 2 °C/75% RH ± 5% RH is determined by the climatic zone in which the FPP is intended to be 678 marketed. Testing at a more severe long-term condition can be an alternative to storage at 25 °C/60% RH or 30 679 °C/65% RH. 680 b If 30 °C ± 2 °C/65% RH ± 5% RH or 30 °C ± 2 °C/75% RH ± 5% RH is the long-term condition, there is no 681
intermediate condition. 682
683
If long-term studies are conducted at 25 °C ± 2 °C/60% RH ± 5% RH 684
and “significant change” occurs at any time during six months’ testing at 685
the accelerated storage condition, additional testing at the intermediate 686
storage condition should be conducted and evaluated against significant 687
change criteria. In this case the initial application should include a 688
minimum of six months’ data from a 12-month study at the intermediate 689
storage condition. 690
In general, “significant change” for an FPP is defined as: 691
• a change from the initial content of API(s) of 5% or more detected by 692
assay, or failure to meet the acceptance criteria for potency when using 693
biological or immunological procedures (Note: Other values may be 694
applied, if justified, to certain products, such as multivitamins and 695
herbal preparations.); 696
• any degradation product exceeding its acceptance criterion; 697
Working document QAS/17.694 page 22
• failure to meet the acceptance criteria for appearance, physical attributes 698
and functionality test (e.g. colour, phase separation, 699
resuspendability, caking, hardness, dose delivery per actuation). 700
However, some changes in physical attributes (e.g. softening of 701
suppositories, melting of creams, partial loss of adhesion for 702
transdermal products) may be expected under accelerated conditions. 703
Also, as appropriate for the dosage form: 704
• failure to meet the acceptance criterion for pH; or 705
• failure to meet the acceptance criteria for dissolution for 12 dosage units. 706
707
2.2.7.2 FPPs packaged in impermeable containers 708
Parameters required to classify the packaging materials as permeable or 709
impermeable depend on the characteristics of the packaging material, 710
such as thickness and permeability coefficient. The suitability of the 711
packaging material used for a particular product is determined by its 712
product characteristics. Containers generally considered to be moisture-713
impermeable include glass ampoules. 714
Sensitivity to moisture or potential for solvent loss is not a concern for 715
FPPs packaged in impermeable containers that provide a permanent 716
barrier to passage of moisture or solvent. Thus stability studies for 717
products stored in impermeable containers can be conducted under any 718
controlled or ambient relative humidity condition. 719
720
2.2.7.3 FPPs packaged in semipermeable containers 721
Aqueous-based products packaged in semipermeable containers should 722
be evaluated for potential water loss in addition to physical, chemical, 723
biological and microbiological stability. This evaluation can be carried 724
out under conditions of low relative humidity, as discussed below. 725
Ultimately it should be demonstrated that aqueous-based FPPs stored in 726
semipermeable containers could withstand environments with low 727
relative humidity. 728
Other comparable approaches can be developed and reported for non- 729
aqueous, solvent-based products. 730
731
732
Working document QAS/17.694 page 23
Study Storage condition Minimum time period
covered by data at
submission
Long-terma 25 °C ± 2 °C/40% RH ± 5% RH
or
30 °C ± 2 °C/35% RH ± 5% RH
12 months or six months
as referred to in section
2.2.7
Intermediateb 30 °C ± 2 °C/65% RH ± 5% RH six months
Accelerated 40°C ± 2°C/not more than
(NMT) 25% RH
six months
a Whether long-term stability studies are performed at 25 °C ± 2 °C/40% RH ± 5% RH or 30 °C ± 2 733 °C/35% RH ± 5% RH is determined by the climatic condition under which the FPP is intended to be 734 marketed. Testing at 30 °C/35% RH can be an alternative to the storage condition at 25 °C/40% RH. 735
b If 30 °C ± 2 °C/35% RH ± 5% RH is the long-term condition, there is no intermediate condition. 736
Products meeting the accelerated conditions and the long-term storage 737
conditions appropriate to the intended market, as specified in the table above, 738
have demonstrated the integrity of the packaging in semipermeable 739
containers. A significant change in water loss alone at the accelerated storage 740
condition does not necessitate testing at the intermediate storage condition. 741
However, data should be provided to demonstrate that the pharmaceutical 742
product would not have significant water loss throughout the proposed shelf 743
life if stored at 25 °C/40% RH or 30 °C/35% RH. 744
For long-term studies conducted at 25 °C ± 2 °C/40% RH ± 5% RH, that fail 745
the accelerated testing with regard to water loss and show significant change 746
with respect to any other parameters, additional testing at the “intermediate” 747
storage condition should be performed as described under the general case to 748
evaluate the temperature effect at 30 °C. 749
A 5% loss in water from its initial value is considered a significant change 750
for a product packaged in a semipermeable container after an equivalent of 751
three months’ storage at 40 °C not more than (NMT) 25% RH. However, for 752
small containers (1 mL or less) or unit-dose products, a water loss of 5% or 753
more after an equivalent of three months’ storage at 40 °C/NMT 25% RH 754
may be appropriate, if justified. 755
An alternative approach to studies at the low relative humidity as 756
recommended in the table above (for either long-term or accelerated testing) 757
Working document QAS/17.694 page 24
is to perform the stability studies under higher relative humidity and deriving 758
the water loss at the low relative humidity through calculation. This can be 759
achieved by experimentally determining the permeation coefficient for the 760
container closure system or, as shown in the example below, using the 761
calculated ratio of water loss rates between the two humidity conditions at 762
the same temperature. The permeation coefficient for a container closure 763
system can be experimentally determined by using the worst-case scenario 764
(e.g. the most diluted of a series of concentrations) for the proposed FPP. 765
766
Example of an approach for determining water loss 767
For a product in a given container closure system, container size and fill, an 768
appropriate approach for deriving the rate of water loss at the low relative 769
humidity is to multiply the rate of water loss measured at an alternative 770
relative humidity at the same temperature, by a water loss rate ratio shown in 771
the table below. A linear water loss rate at the alternative relative humidity over 772
the storage period should be demonstrated. 773
For example, at a given temperature, e.g. 40 °C, the calculated rate of water 774
loss during storage at NMT 25% RH is the rate of water loss measured at 775
75% RH multiplied by 3.0, the corresponding water loss rate ratio. 776
777
Low-humidity
testing
conditions
Alternative
testing
condition
Ratio of
water loss
rates
Calculation
25 °C/40% RH 25 °C/60% RH 1.5 (100-40)/(100-60)
30 °C/35% RH 30 °C/65% RH 1.9 (100-35)/(100-65)
30 °C/35% RH 30 °C/75% RH 2.6 (100-35)/(100-75)
40 °C/NMT 25%
RH
40 °C/75% RH 3.0 (100-25)/(100-75)
778
Valid water loss rate ratios at relative humidity conditions other than 779
those shown in the table above can also be used. 780
781
782
Working document QAS/17.694 page 25
2.2.7.4 FPPs intended for storage in a refrigerator 783
784
Study Storage condition Minimum time period
covered by data at
submission
Long-term 5 °C ± 3 °C 12 months or six months
as referred to in section
2.2.7
Accelerateda 25 °C ± 2 °C/60% RH ± 5% RH
or
30 °C ± 2 °C/65% RH ± 5% RH
or
30 °C ± 2 °C/75% RH ± 5% RH
six months
a Whether accelerated stability studies are performed at 25 °C ± 2 °C/60% RH ± 5% RH or 30 °C ± 2 °C/65% RH 785 ± 5% RH or 30 °C ± 2 °C/75% RH ± 5% RH is based on a risk-based evaluation. Testing at a more severe 786 accelerated condition can be an alternative to the storage condition at 25 °C/60% RH or 30 °C/65% RH. 787
788
If the FPP is packaged in a semipermeable container, appropriate 789
information should be provided to assess the extent of water loss. 790
Data from refrigerated storage should be assessed according to the 791
evaluation section of these guidelines, except where explicitly noted 792
below. 793
If significant change occurs between three and six months’ testing at the 794
accelerated storage condition, the proposed shelf life should be based on 795
the data available from the long-term storage condition. 796
If significant change occurs within the first three months’ testing at the 797
accelerated storage condition, a discussion should be provided to address 798
the effect of short-term excursions outside the label storage condition, e.g. 799
during shipment and handling. This discussion can be supported, if 800
appropriate, by further testing on a single batch of the FPP for a period 801
shorter than three months but with more frequent testing than usual. It is 802
considered unnecessary to continue to test a product throughout six months 803
when a significant change has occurred within the first three months of 804
accelerated studies at the specific condition chosen in accordance with the 805
risk analysis. 806
807
Working document QAS/17.694 page 26
2.2.7.5 FPPs intended for storage in a freezer 808
809
Study Storage condition Minimum time period
covered by data at
submission
Long-term –20 °C ± 5 °C 12 months or six months
as referred to in section
2.2.7
810
For FPPs intended for storage in a freezer, the shelf life should be based 811
on the long-term data obtained at the long-term storage condition. In the 812
absence of an accelerated storage condition for FPPs intended to be 813
stored in a freezer, testing on a single batch at an elevated temperature 814
(e.g. 5 °C ± 3 °C or 25 °C ± 2 °C or 30 °C ± 2 °C) for an appropriate time 815
period should be conducted to address the effect of short-term excursions 816
outside the proposed label storage condition. 817
818
2.2.7.6 FPPs intended for storage below -20 °C 819
FPPs intended for storage at temperatures below -20 °C should be treated 820
on a case-by-case basis. 821
822
2.2.8 Stability commitments 823
One or more of the following commitments should be made: 824
• when the available long-term stability data on primary batches do not 825
cover the proposed shelf life granted at the time of approval, a 826
commitment should be made to continue the stability studies post-827
approval throughout the proposed shelf life. This is the primary batch 828
stability commitment; 829
• if the submission includes data from stability studies on fewer than 830
three production batches, a commitment should be made to place the 831
next production batches, to a total of at least three, on long-term 832
stability studies throughout the proposed shelf life and on accelerated 833
studies for six months. This is the production batch stability 834
commitment; 835
• for each product, an ongoing stability programme is required to 836
monitor the product over its shelf life and to determine that the product 837
remains and can be expected to remain within specifications under the 838
Working document QAS/17.694 page 27
storage conditions on the label. Unless otherwise justified, at least one 839
batch per year of product manufactured in every strength and every 840
container closure system, if relevant, should be included in the stability 841
programme (unless none is produced during that year). Bracketing and 842
matrixing may be applicable. A written commitment (signed and dated) 843
to this effect should be included in the dossier. This is the ongoing 844
stability commitment. 845
846
The stability protocol used for studies on commitment batches should be 847
the same as that for the primary batches, unless otherwise scientifically 848
justified. 849
850
2.2.9 Evaluation 851
A systematic approach should be adopted to the presentation and 852
evaluation of the stability information, which should include, as 853
appropriate, results from the physical, chemical, biological and 854
microbiological tests, including particular attributes of the dosage form 855
(for example, dissolution rate for solid oral dosage forms). 856
The purpose of the stability study is to establish, based on testing a 857
minimum number of batches of the FPP as specified in section 2.2.3, a 858
shelf life and label storage instructions applicable to all future batches of 859
the FPP manufactured and packaged under similar circumstances. The 860
degree of variability of individual batches affects the confidence that a 861
future production batch will remain within specification throughout its 862
shelf life. 863
Where the data show so little degradation and so little variability that it is 864
apparent from looking at the data that the requested shelf life will be 865
granted, it is normally unnecessary to go through the statistical analysis. 866
An approach for analysing the data on a quantitative attribute that is 867
expected to change with time is to determine the time at which the 95% 868
one-sided confidence limit for the mean curve intersects the acceptance 869
criterion. If analysis shows that the batch-to-batch variability is small, it is 870
advantageous to combine the data into one overall estimate. This can be 871
done by first applying appropriate statistical tests (e.g. p values for level of 872
significance of rejection of more than 0.25) to the slopes of the regression 873
lines and zero time intercepts for the individual batches. If it is 874
inappropriate to combine data from several batches, the overall shelf life 875
should be based on the minimum time a batch can be expected to remain 876
within acceptance criteria. 877
Working document QAS/17.694 page 28
The nature of any degradation relationship will determine whether the 878
data should be transformed for linear regression analysis. Usually the 879
relationship can be represented by a linear, quadratic or cubic function on 880
an arithmetic or logarithmic scale. As far as possible, the choice of model 881
should be justified by a physical and/or chemical rationale and should 882
also take into account the amount of available data (parsimony principle 883
to ensure a robust prediction). 884
Statistical methods should be employed to test the goodness of fit of the 885
data on all batches and combined batches (where appropriate) to the 886
assumed degradation line or curve. 887
Limited extrapolation of the long-term data from the long-term storage 888
condition beyond the observed range to extend the shelf life can be 889
undertaken, if justified. This justification should be based on what is 890
known about the mechanisms of degradation, the results of testing under 891
accelerated conditions, the goodness of fit of any mathematical model, 892
batch size and the existence of supporting stability data. However, this 893
extrapolation assumes that the same degradation relationship will 894
continue to apply beyond the observed data. 895
Any evaluation should consider not only the assay but also the 896
degradation products and other appropriate attributes. 897
898
2.2.10 Statements and labelling 899
A storage statement should be established for the label based on the 900
stability evaluation of the FPP. Where applicable, specific instructions 901
should be provided, particularly for FPPs that cannot tolerate freezing. 902
Terms such as “ambient conditions” or “room temperature” must be 903
avoided. 904
There should be a direct link between the storage statement on the label 905
and the demonstrated stability of the FPP. An expiry date should be 906
displayed on the container label. 907
The recommended labelling statements for use, if supported by the 908
stability studies, are provided in Appendix 2. Information on the 909
interpretation and conversion of storage statements for products approved 910
in zone II when the products are to be distributed in zone IV is provided 911
in Appendix 3. 912
In principle, FPPs should be packed in containers that ensure stability and 913
protect the FPP from deterioration. A storage statement should not be 914
used to compensate for inadequate or inferior packaging. Additional 915
Working document QAS/17.694 page 29
labelling statements could be used in cases where the results of the 916
stability testing demonstrate limiting factors (see Appendix 2). 917
918
2.2.11 In-use and hold-time stability 919
The purpose of in-use stability testing is to provide information for the 920
labelling on the preparation, storage conditions and utilization period of 921
multidose products after opening, reconstitution or dilution of a solution. 922
Examples include an antibiotic injection supplied as a powder for 923
reconstitution, or a moisture-sensitive or hygroscopic solid oral FPP in a 924
large format multidose container (e.g. HDPE bottle of 500 tablets). In 925
general, a 30 day in-use period is normally considered acceptable without 926
further supporting data. 927
As far as possible the test should be designed to simulate the use of the 928
FPP in practice, taking into consideration the filling volume of the 929
container and any dilution or reconstitution before use. At intervals 930
comparable to those that occur in practice appropriate quantities should 931
be removed by the withdrawal methods normally used and described in 932
the product literature. 933
The physical, chemical and microbial properties of the FPP susceptible to 934
change during storage should be determined over the period of the 935
proposed in-use shelf life. If possible, testing should be performed at 936
intermediate time points and at the end of the proposed in-use shelf life on 937
the final amount of the FPP remaining in the container. Specific 938
parameters, e.g. for liquids and semisolids, preservatives, per content and 939
effectiveness, need to be studied. 940
A minimum of two batches, at least pilot-scale batches (with the 941
exceptions outlined in section 2.2.3), should be subjected to the test. At 942
least one of these batches should be chosen towards the end of its shelf 943
life. If such results are not available, one batch should be tested at the 944
final point of the submitted stability studies. 945
This testing should be performed on primary batches of the reconstituted 946
or diluted FPP or the solid oral FPP (as above), throughout the proposed 947
in-use period as part of the stability studies at the initial and final time 948
points and, if long-term data covering the shelf life are not available at the 949
time of submission, at 12 months or the last time point at which data will 950
be available. 951
In general this testing need not be repeated on commitment batches (see 952
section 2.2.8). 953
Working document QAS/17.694 page 30
Consideration should also be given to hold-time studies of bulk products, 954
e.g. coated tablets prior to final packaging. For example, when the bulk 955
product may be stored for a period exceeding 30 days before being packaged 956
and/or shipped from a manufacturing site to a packaging site, the stability of 957
the bulk product in the intended bulk container should be evaluated and 958
studied. Similar considerations should apply to intermediates that are stored 959
and used for periods exceeding 30 days. Further guidance can be found in 960
the WHO General guidance on hold time studies (6). 961
962
2.2.12 Variations 963
Once the FPP has been registered, additional stability studies are required 964
whenever variations are made that may affect the stability of the API or 965
FPP. The applicant should investigate whether the intended change will or 966
will not have an impact on the quality characteristics of APIs and/or FPPs 967
and consequently on their stability. The scope and design of the stability 968
studies for variations and changes are based on the knowledge and 969
experience acquired on APIs and FPPs. 970
The available variation guidelines should be referenced for guidance on 971
the expectations regarding stability requirements to support changes to 972
the API and FPP. Note that the requirements of the guidelines of the 973
specific regulatory authority or region prevail for a given region, 974
however in the absence of such guidelines, the WHO PQTm guidelines 975
can provide guidance (10, 11). Depending on the variation, either the 976
results of a stability study or a commitment to conduct such as study is 977
required. Variation guidelines are specific detailed guidelines; therefore, 978
the following are general categories and the guidelines should be 979
referenced for exact circumstances and requirements. In the 980
aforementioned guidance document (10) changes requiring supporting 981
data include certain changes to the API re-test period or storage 982
conditions, and to the FPP formulation, manufacturing process, container 983
closure system, shelf life, in-use period and storage conditions. Other 984
changes, such as certain changes to the API certificate of suitability, 985
certificate of prequalification, manufacturing site or manufacturing 986
process, or certain changes to the FPP manufacturing site, batch size or 987
container closure system, require a commitment for stability studies to 988
support the variations. 989
Additional guidance is available in the European Medicines Agency 990
Guideline on stability testing for applications for variations to a 991
marketing authorization (12). 992
993
Working document QAS/17.694 page 31
The results of these stability studies should be communicated to the 994
regulatory authorities concerned, following the applicable variation 995
guideline requirements for the region. 996
997
2.2.13 Ongoing stability studies 998
After a marketing authorization has been granted, the stability of the FPP 999
should be monitored according to a continuous appropriate programme 1000
that will permit the detection of any stability issue (e.g. changes in levels 1001
of impurities or dissolution profile) associated with the formulation in the 1002
container closure system in which it is marketed. The purpose of the 1003
ongoing stability programme is to monitor the product over its shelf life 1004
and to determine that the product remains, and can be expected to remain, 1005
within specifications under the storage conditions on the label. The 1006
ongoing stability programme should be described in a written protocol 1007
and results formalized as a report. 1008
The protocol for an ongoing stability programme should extend to the 1009
end of the shelf life period and should include, but not be limited to, the 1010
following parameters: 1011
— number of batch(es) per strength and different batch sizes, if 1012
applicable. The batch size should be recorded, if different batch sizes 1013
are employed; 1014
— relevant physical, chemical, microbiological and biological test 1015
methods; 1016
— acceptance criteria; 1017
— reference to test methods; 1018
— description of the container closure system(s); 1019
— testing frequency (generally at six months and annual time points is 1020
sufficient for ongoing studies); 1021
— description of the conditions of storage (standardized conditions for 1022
long-term testing as described in these guidelines, and consistent with 1023
the product labelling, should be used); and 1024
— other applicable parameters specific to the FPP. 1025
The protocol for the ongoing stability programme can be different from 1026
that of the initial long-term stability study as submitted in the marketing 1027
authorization dossier provided that this is justified and documented in the 1028
protocol (for example, the frequency of testing as above, or when 1029
updating to meet revised recommendations). 1030
The number of batches and frequency of testing should provide sufficient 1031
data to allow for trend analysis. Unless otherwise justified, at least one 1032
Working document QAS/17.694 page 32
batch per year of product manufactured in every strength and every 1033
primary packaging type, if relevant, should be included in the stability 1034
programme (unless none is produced during that year). The principle of 1035
bracketing and matrixing designs may be applied if scientifically justified 1036
in the protocol. 1037
In certain situations additional batches should be included in the ongoing 1038
stability programme. For example, an ongoing stability study should be 1039
conducted after any significant change or significant deviation to the 1040
process or container-closure system. Any reworking, reprocessing or 1041
recovery operation should also be considered for inclusion. Refer to 1042
section 2.2.12 for further details. 1043
OOS results or significant atypical trends should be investigated. Any 1044
confirmed significant change, OOS result, or significant atypical trend 1045
should be reported immediately to the relevant competent authorities. The 1046
possible impact on batches on the market should be considered in 1047
consultation with the relevant competent authorities. 1048
A summary of all the data generated, including any interim conclusions 1049
on the programme, should be written and maintained. This summary 1050
should be subjected to periodic review. 1051
1052
3. Glossary 1053
The definitions provided below apply to the words and phrases used in 1054
these guidelines. Although an effort has been made to use standard 1055
definitions as far as possible, they may have different meanings in other 1056
contexts and documents. The following definitions are provided to 1057
facilitate interpretation of the guidelines. The definitions are consistent 1058
with those published in other WHO quality assurance guidelines. The 1059
Quality Assurance of Medicines Terminology Database was established 1060
in August 2005 and includes the definitions of terms related to quality 1061
assurance of medicines. This database is intended to help harmonize 1062
terminology and to avoid misunderstandings that may result from the 1063
different terms and their interpretations used in various WHO 1064
publications. The main publications used as a source of information to 1065
create the Quality Assurance of Medicines Terminology Database are the 1066
quality assurance guidelines included in the 36th–51st reports of the WHO 1067
Expert Committee on Specifications for Pharmaceutical Preparations. 1068
1069
accelerated testing. Studies designed to increase the rate of chemical 1070
degradation and physical change of an API or FPP by using exaggerated 1071
Working document QAS/17.694 page 33
storage conditions as part of the stability testing programme. The data 1072
thus obtained, in addition to those derived from long-term stability 1073
studies, may be used to assess longer-term chemical effects under non-1074
accelerated conditions and to evaluate the impact of short-term 1075
excursions outside the label storage conditions, as might occur during 1076
shipping. The results of accelerated testing studies are not always 1077
predictive of physical changes. 1078
1079
active pharmaceutical ingredient (API). Any substance or mixture of 1080
substances intended to be used in the manufacture of a pharmaceutical 1081
dosage form and that, when so used, becomes an active ingredient of that 1082
pharmaceutical dosage form. Such substances are intended to furnish 1083
pharmacological activity or other direct effect in the diagnosis, cure, 1084
mitigation, treatment, or prevention of disease or to affect the structure 1085
and function of the body. 1086
1087
batch. A defined quantity of starting material, packaging material or 1088
finished pharmaceutical product (FPP) processed in a single process or 1089
series of processes so that it is expected to be homogeneous. It may 1090
sometimes be necessary to divide a batch into a number of subbatches, 1091
which are later brought together to form a final homogeneous batch. In 1092
the case of terminal sterilization, the batch size is determined by the 1093
capacity of the autoclave. In continuous manufacture, the batch must 1094
correspond to a defined fraction of the production, characterized by its 1095
intended homogeneity. The batch size can be defined either as a fixed 1096
quantity or as the amount produced in a fixed time interval. 1097
1098
bracketing. The design of a stability schedule such that only samples at 1099
the extremes of certain design factors, e.g. strength and package size, are 1100
tested at all time points as in a full design. The design assumes that the 1101
stability of any intermediate levels is represented by the stability of the 1102
extremes tested. Where a range of strengths is to be tested, bracketing is 1103
applicable if the strengths are identical or very closely related in 1104
composition (e.g. for a tablet range made with different compression 1105
weights of a similar basic granulation, or a capsule range made by filling 1106
different plug fill weights of the same basic composition into different 1107
size capsule shells). Bracketing can be applied to different container sizes 1108
or different fills in the same container closure system. 1109
1110
climatic zone. The zones into which the world is divided based on the 1111
prevailing annual climatic conditions (see 1112
http://www.who.int/medicines/areas/quality_safety/quality_assurance/reg1113
Working document QAS/17.694 page 34
ulatory_standards/en/.). 1114
1115
commitment batches. Production batches of an API or FPP for which 1116
the stability studies are initiated or completed post-approval through a 1117
commitment made in a regulatory application. 1118
1119
container closure system. The sum of packaging components that 1120
together contains and protects the dosage form. This includes primary 1121
packaging components and secondary packaging components, if the 1122
latter are intended to provide additional protection to the FPP. A 1123
packaging system is equivalent to a container closure system. 1124
1125
dosage form. The form of the FPP, e.g. tablet, capsule, elixir or 1126
suppository. 1127
1128
excipient. A substance or compound, other than the API and packaging 1129
materials, that is intended or designated to be used in the manufacture of 1130
a FPP. 1131
1132
expiry date. The date given on the individual container (usually on the 1133
label) of a product up to and including which the API and FPP are 1134
expected to remain within specifications, if stored under the long-term 1135
conditions at which stability was established. It is set for each batch by 1136
adding the shelf life to the date of manufacture. 1137
1138
finished pharmaceutical product (FPP). A product that has 1139
undergone all stages of production, including packaging in its final 1140
container and labelling. An FPP may contain one or more APIs. 1141
1142
impermeable containers. Containers that provide a permanent barrier 1143
to the passage of gases or solvents, e.g. sealed aluminium tubes for 1144
semisolids, sealed glass ampoules for solutions and 1145
aluminium/aluminium blisters for solid dosage forms. 1146
1147
in-use period. A period of time during which a reconstituted 1148
preparation of the finished dosage form in a multidose container, or a 1149
moisture sensitive product in a large format final container (e.g. HDPE 1150
bottles of 500s) can be used after opening. 1151
1152
long-term stability studies. Experiments on the physical, chemical, 1153
biological, biopharmaceutical and microbiological characteristics of an 1154
API or FPP, during and beyond the expected shelf-life and storage 1155
Working document QAS/17.694 page 35
periods of samples under the storage conditions expected in the intended 1156
market. The results are used to establish the re-test period or the shelf life, 1157
to confirm the projected re-test period and shelf life, and to recommend 1158
storage conditions. 1159
1160
matrixing. The design of a stability schedule such that a selected 1161
subset of the total number of possible samples for all factor combinations 1162
is tested at a specified time point. At a subsequent time point, another 1163
subset of samples for all factor combinations is tested. The design 1164
assumes that the stability of each subset of samples tested represents the 1165
stability of all samples at a given time point. The differences in the 1166
samples for the same FPP should be identified as, for example, covering 1167
different batches, different strengths, different sizes of the same container 1168
closure system, and, possibly in some cases, different container closure 1169
systems. 1170
1171
ongoing stability study. The study carried out by the manufacturer on 1172
production batches according to a predetermined schedule in order to 1173
monitor, confirm and extend the projected re-test period (or shelf life) of 1174
the API, or confirm or extend the shelf life of the FPP. 1175
1176
pilot-scale batch. A batch of an API or FPP manufactured by a 1177
procedure fully representative of and simulating that to be applied to a 1178
full production-scale batch. For example, for solid oral dosage forms, a 1179
pilot scale is generally, at a minimum, one-tenth that of a full production 1180
scale or 100 000 tablets or capsules, whichever is the larger unless 1181
otherwise adequately justified. 1182
1183
primary batch. A batch of an API or FPP used in a stability study, from 1184
which stability data are submitted in a registration application for the 1185
purpose of establishing a re-test period or shelf life, as the case may be. 1186
Primary batch requirements are outlined in 2.1.3 and 2.2.3 for the API 1187
and FPP, respectively. 1188
1189
production batch. A batch of an API or FPP manufactured at production 1190
scale by using production equipment in a production facility as specified in 1191
the application. 1192
1193
provisional shelf life. A provisional expiry date that is based on 1194
acceptable accelerated and available long-term data for the FPP to be 1195
marketed in the proposed container closure system. 1196
1197
Working document QAS/17.694 page 36
release specification. The combination of physical, chemical, 1198
biological, and microbiological tests and acceptance criteria that 1199
determine the suitability of an API or FPP at the time of its release. 1200
1201
re-test date. The date after which an active API should be re-examined 1202
to ensure that the material is still in compliance with the specification and 1203
thus is still suitable for use in the manufacture of an FPP. 1204
1205
re-test period. The period of time during which the API is expected to 1206
remain within its specification and, therefore, can be used in the 1207
manufacture of a given FPP, provided that the API has been stored under 1208
the defined conditions. After this period a batch of API destined for use 1209
in the manufacture of an FPP should be re-tested for compliance with the 1210
specification and then used immediately. A batch of API can be re-tested 1211
multiple times and a different portion of the batch used after each re-test, 1212
as long as it continues to comply with the specification. For most 1213
substances known to be labile, it is more appropriate to establish a shelf 1214
life than a re-test period. The same may be true for certain antibiotics. 1215
1216
semipermeable containers. Containers that allow the passage of 1217
solvent, usually water, while preventing solute loss. The mechanism for 1218
solvent transport occurs by adsorption onto one container surface, 1219
diffusion through the bulk of the container material, and desorption from 1220
the other surface. Transport is driven by a partial-pressure gradient. 1221
Examples of semipermeable containers include plastic bags and semi-1222
rigid, low-density polyethylene (LDPE) pouches for large volume 1223
parenterals (LVPs), and LDPE and HDPE ampoules, bottles and vials. 1224
1225
shelf life. The period of time during which an API or FPP, if stored 1226
under the conditions in which stability was established, is expected to 1227
comply with the specification as determined by stability studies on a 1228
number of batches of the API or FPP. The shelf life is used to establish the 1229
expiry date of each batch. 1230
1231
shelf life specification. The combination of physical, chemical, 1232
biological, and microbiological tests and acceptance criteria that an API 1233
or FPP should meet throughout its re-test period or shelf life. 1234
1235
significant change. (See sections 2.1.7 and 2.2.7.) 1236
“Significant change” for an API is defined as failure to meet its 1237
specification. 1238
Working document QAS/17.694 page 37
In general “significant change” for an FPP is defined as: 1239
A 5% or more change in assay from its initial content of API(s), or 1240
failure to meet the acceptance criteria for potency when using biological or 1241
immunological procedures. (Note: other values may be applied, if 1242
justified, to certain products, such as multivitamins and herbal 1243
preparations.) 1244
1245
Any degradation product exceeding its acceptance criterion. 1246
1. Failure to meet the acceptance criteria for appearance, physical attributes 1247
and functionality test (e.g. colour, phase separation, resuspendability, 1248
caking, hardness, dose delivery per actuation). However, some changes in 1249
physical attributes (e.g. softening of suppositories, melting of creams or 1250
partial loss of adhesion for transdermal products) may be expected under 1251
accelerated conditions. 1252
Also, as appropriate for the dosage form: 1253
2. Failure to meet the acceptance criterion for pH. Or 1254
3. Failure to meet the acceptance criteria for dissolution for 12 dosage units. 1255
1256
specification. A list of tests, references to analytical procedures, and 1257
appropriate acceptance criteria, which are numerical limits, ranges or 1258
other criteria for the tests described. It establishes the set of criteria to 1259
which an API or FPP should conform to be considered acceptable for its 1260
intended use. See “release specification” and “shelf life specification”. 1261
1262
stability indicating methods. Validated analytical procedures that can 1263
detect the changes with time in the chemical, physical or microbiological 1264
properties of the API or FPP, and that are specific so that the content of 1265
the API, degradation products, and other components of interest can be 1266
accurately measured without interference. 1267
1268
stability studies (stability testing). Long-term and accelerated (and 1269
intermediate) studies undertaken on primary and/or commitment batches 1270
according to a prescribed stability protocol to establish or confirm the re-1271
test period (or shelf life) of an API or the shelf life of an FPP. 1272
1273
stress testing (of the API). Studies undertaken to elucidate the intrinsic 1274
stability of an API. Such testing is part of the development strategy and is 1275
normally carried out under more severe conditions than those used for 1276
accelerated testing. 1277
1278
Working document QAS/17.694 page 38
stress testing (of the FPP). Studies undertaken to assess the effect of 1279
severe conditions on the FPP. Such studies include photostability testing 1280
and specific testing on certain products (e.g. metered dose inhalers, 1281
creams, emulsions, refrigerated aqueous liquid products). 1282
1283
supporting stability data. Supplementary data, such as stability data 1284
on small-scale batches, related formulations, and products presented in 1285
containers not necessarily the same as those proposed for marketing, and 1286
scientific rationales that support the analytical procedures, the proposed 1287
re-test period or the shelf life and storage conditions. 1288
1289
utilization period. (See “in-use period”.) 1290
1291
References 1292
1. Stability testing of active pharmaceutical ingredients and finished 1293
pharmaceutical products. Forty-third report. Geneva, World Health 1294
Organization, 2009, Annex 2 (WHO Technical Report Series, No. 1295
953). 1296
2. The following ICH Guidelines may be consulted in the context of 1297
stability testing (Note from the Secretariat: ICH links need updating, 1298
which will be done closer to the publication date.) 1299
International Council on Harmonisation. ICH Q1A (R2): Stability 1300
testing of new drug substances and products 1301
(http://www.ich.org/LOB/media/ MEDIA419.pdf). 1302
International Council on Harmonisation. ICH Q1B: Photostability 1303
testing of new drug substances and products 1304
(http://www.ich.org/LOB/media/ MEDIA412.pdf). 1305
International Council on Harmonisation. ICH Q1C: Stability testing 1306
of new dosage forms 1307
(http://www.ich.org/LOB/media/MEDIA413.pdf). 1308
International Council on Harmonisation. ICH Q1D: Bracketing and 1309
matrixing designs for stability testing of new drug substances and 1310
products (http://www.ich.org/LOB/media/MEDIA414.pdf). 1311
International Council on Harmonisation. ICH Q1E: Evaluation for 1312
stability data (http://www.ich.org/LOB/media/MEDIA415.pdf). 1313
Working document QAS/17.694 page 39
International Council on Harmonisation. ICH Q2R1): Validation of 1314
analytical procedures: text and methodology 1315
(http://www.ich.org/LOB/media/ MEDIA417.pdf). 1316
International Council on Harmonisation. ICH Q3A: Impurities in new 1317
drug substances (http://www.ich.org/LOB/media/MEDIA422.pdf). 1318
International Council on Harmonisation. ICH Q3B: Impurities in new 1319
drug products (http://www.ich.org/LOB/media/MEDIA421.pdf). 1320
International Council on Harmonisation. ICH Q5C: Stability testing of 1321
biotechnological/biological products (http://www.ich.org/LOB/media/ 1322
MEDIA427.pdf). 1323
International Council on Harmonisation. ICH Q6A: Specifications: Test 1324
procedures and acceptance criteria for new drug substances and new 1325
drug products: Chemical substances 1326
(http://www.ich.org/LOB/media/MEDIA430.pdf). 1327
International Council on Harmonisation. ICH Q6B: Specifications: Test 1328
procedures and acceptance criteria for biotechnological/biological 1329
products (http://www.ich.org/LOB/media/MEDIA432.pdf). 1330
International Council on Harmonisation. ICH Q7: Good manufacturing 1331
Practice guide for active pharmaceutical ingredients 1332
International Council on Harmonisation. ICH Q8: Pharmaceutical 1333
development 1334
International Council on Harmonisation. ICH Q9: Quality risk 1335
management 1336
International Council on Harmonisation. ICH Q11: Development and 1337
manufacture of drug substances (chemical entities and 1338
biotechnological/biological entities) 1339
Further information can be found on the ICH homepage: 1340
http://www.ich.org/cache/compo/276-254-1.html. 1341
3. Guidelines on submission of documentation for a multisource (generic) 1342
finished pharmaceutical product: quality part. Forty-eighth report. 1343
Geneva, World Health Organization, 2014, Annex 4 (WHO Technical 1344
Report Series, No. 986). 1345
Working document QAS/17.694 page 40
4. Guidelines on submission of documentation for a multisource (generic) 1346
finished pharmaceutical product for the WHO Prequalification of 1347
Medicines Programme: quality part. Forty-sixth report. Geneva, World 1348
Health Organization, 2012, Annex 4 (WHO Technical Report Series, No. 1349
970). 1350
5. Guidelines on active pharmaceutical ingredient master file procedure. In: 1351
WHO Expert Committee on Specifications for Pharmaceutical 1352
Preparations. Forty-second report. Geneva, World Health Organization, 1353
2008, Annex 4 (WHO Technical Report Series, No. 948). 1354
6. General guidance on hold time studies. In: WHO Expert Committee on 1355
Specifications for Pharmaceutical Preparations. Forty-ninth report. 1356
Geneva, World Health Organization, 2015, Annex 4 (WHO Technical 1357
Report Series, No. 992). 1358
7. Guidelines for registration of fixed-dose combination medicinal products. 1359
Appendix 3: Pharmaceutical development (or preformulation) studies. 1360
Table A1: Typical stress conditions in preformulation stability studies. In: 1361
WHO Expert Committee on Specifications for Pharmaceutical 1362
Preparations. 1363
Thirty-ninth report. Geneva, World Health Organization, 2005, Annex 5 1364
(WHO Technical Report Series, No. 929). 1365
8. Guidelines on good manufacturing practices: validation. 1366
In: Quality assurance of pharmaceuticals. WHO guidelines, good 1367
practices, related regulatory guidance and GXP training materials, CD-1368
ROM (updated regularly) Geneva, World Health Organization, 2016 1369
9. WHO good manufacturing practices: main principles for pharmaceutical 1370
products. In: WHO guidelines, good practices, related regulatory 1371
guidance and GXP training materials, CD-ROM (updated regularly) 1372
Geneva, World Health Organization, 2016 . 1373
10. WHO guidelines on variations to a prequalified product. Forty-seventh 1374
report. Geneva, World Health Organization, 2013, Annex 3 (WHO 1375
Technical Report Series, No. 981). 1376
11. Prequalification Programme – Priority Essential Medicines. A United 1377
Nations Programme managed by WHO. Information for applicants 1378
Working document QAS/17.694 page 41
(http://mednet3.who.int/prequal/). 1379
12. European Medicines Agency Guideline on stability testing for 1380
applications for variations to a marketing authorization. 1381
EMA/CHMP/CVMP/QWP/441071/2011- Rev.2, 21 March 2014. 1382
1383
1384
1385
Working document QAS/17.694 page 42
Appendix 1 1386
Examples of testing parameters 1387
Section I for APIs 1388
In general, appearance, assay and degradation products should be 1389
evaluated for all APIs. Since some related substances might only be 1390
identified as degradation products in the outcome of the stability studies, 1391
all specified related substances should be monitored as part of API 1392
stability studies. Other API parameters that may be susceptible to change 1393
should also be studied where applicable (e.g. particle size and/or 1394
polymorphism when relevant for low solubility APIs). 1395
1396
Section II for FPPs 1397
The following list of parameters for each dosage form is presented as a 1398
guide to the types of tests to be included in a stability study. In general, 1399
appearance, assay and degradation products should be evaluated for all 1400
dosage forms, as well as the preservative and antioxidant content if 1401
applicable. 1402
The microbial quality of multiple-dose sterile and non-sterile dosage 1403
forms should be controlled. Challenge tests should be carried out at least 1404
at the beginning and at the end of the shelf life. Such tests would 1405
normally be performed as part of the development programme, for 1406
example, within primary stability studies. They need not be repeated for 1407
subsequent stability studies unless a change has been made which has a 1408
potential impact on microbiological status. 1409
It is not expected that every test listed be performed at each time point. 1410
This applies in particular to sterility testing, which may be conducted for 1411
most sterile products at the beginning and at the end of the stability test 1412
period. Tests for pyrogens and bacterial endotoxins may be limited to the 1413
time of release. Sterile dosage forms containing dry materials (powder-1414
filled or lyophilized products) and solutions packaged in sealed glass 1415
ampoules may need no additional microbiological testing beyond the 1416
initial time point. The level of microbiological contamination in liquids 1417
packed in glass containers with flexible seals or in plastic containers 1418
should be tested no less than at the beginning and at the end of the 1419
stability test period; if the long-term data provided to the regulatory 1420
authorities for marketing authorization registration do not cover the full 1421
shelf life period, the level of microbial contamination at the last time 1422
Working document QAS/17.694 page 43
point should also be provided. Weight loss from plastic containers should 1423
be reported over the shelf life. 1424
The list of tests presented for each dosage form is not intended to be 1425
exhaustive, nor is it expected that every test listed be included in the 1426
design of a stability protocol for a particular FPP (for example, a test for 1427
odour should be performed only when necessary and with consideration 1428
for the analyst’s safety). 1429
1430
The storage orientation of the product, i.e. upright versus inverted, may 1431
need to be included in a protocol when contact of the product with the 1432
closure system may be expected to affect the stability of the products 1433
contained (e.g. liquids or semisolids), or where there has been a change 1434
in the container closure system. 1435
1436
Tablets 1437
Dissolution, disintegration, water content and hardness/friability. 1438
Dispersible tablets should additionally be tested for disintegration (with a 1439
limit of not more than three minutes) and fineness of dispersion. 1440
1441
Capsules 1442
• Hard gelatin capsules: brittleness, dissolution, disintegration, water 1443
content and level of microbial contamination. 1444
• Soft gelatin capsules: dissolution, disintegration, level of microbial 1445
contamination, pH, leakage and pellicle formation. 1446
1447
Oral solutions, suspensions and emulsions 1448
Formation of precipitate, clarity (for solutions), pH, viscosity, 1449
extractables, level of microbial contamination. 1450
Additionally for suspensions, dispersibility, rheological properties, mean 1451
size and distribution of particles should be considered. Also polymorphic 1452
conversion may be examined, if applicable. 1453
Additionally for emulsions, phase separation, mean size and distribution 1454
of dispersed globules should be evaluated. 1455
1456
Powders and granules for oral solution or suspension 1457
Water content and reconstitution time. 1458
Reconstituted products (solutions and suspensions) should be evaluated 1459
as described above under “Oral solutions suspensions and emulsions”, 1460
Working document QAS/17.694 page 44
after preparation according to the recommended labelling, through the 1461
maximum intended use period. 1462
1463
Metered-dose inhalers and nasal aerosols 1464
Dose content uniformity, labelled number of medication actuations per 1465
container meeting dose content uniformity, aerodynamic particle size 1466
distribution, microscopic evaluation, water content, leak rate, level of 1467
microbial contamination, valve delivery (shot weight), 1468
extractables/leachables from plastic and elastomeric components, weight 1469
loss, pump delivery, foreign particulate matter and 1470
extractables/leachables from plastic and elastomeric components of the 1471
container, closure and pump. Samples should be stored in upright and 1472
inverted/on-the-side orientations. 1473
For suspension-type aerosols, microscopic examination of appearance of 1474
the valve components and container’s contents for large particles, 1475
changes in morphology of the API particles, extent of agglomerates, 1476
crystal growth, foreign particulate matter, corrosion of the inside of the 1477
container or deterioration of the gaskets. 1478
1479
Nasal sprays: solutions and suspensions 1480
Clarity (for solution), level of microbial contamination, pH, particulate 1481
matter, unit spray medication content uniformity, number of actuations 1482
meeting unit spray content uniformity per container, droplet and/or 1483
particle size distribution, weight loss, pump delivery, microscopic 1484
evaluation (for suspensions), foreign particulate matter and 1485
extractables/leachables from plastic and elastomeric components of the 1486
container, closure and pump. 1487
1488
Topical, ophthalmic and otic preparations 1489
Included in this broad category are ointments, creams, lotions, paste, gel, 1490
solutions, eye drops and cutaneous sprays. 1491
• Topical preparations should be evaluated for clarity, homogeneity, pH, 1492
suspendability (for lotions), consistency, viscosity, particle size distribution 1493
(for suspensions, when feasible), level of microbial contamination/sterility 1494
and weight loss (when appropriate). 1495
• Evaluation of ophthalmic or otic products (e.g. creams, ointments, 1496
solutions and suspensions) should include the following additional 1497
attributes: sterility, particulate matter and extractable volume. 1498
1499
1500
Working document QAS/17.694 page 45
• Evaluation of cutaneous sprays should include: pressure, weight loss, net 1501
weight dispensed, delivery rate, level of microbial contamination, spray 1502
pattern, water content and particle size distribution (for suspensions). 1503
1504
Suppositories 1505
Disintegration and dissolution (at 37 °C) and as appropriate for the type, 1506
net filled content, rupture time, melting and solidification, 1507
liquefaction/softening time, leakage, pellicles and pH. 1508
1509
Small volume parenterals (SVPs) 1510
Colour, clarity (for solutions), particulate matter, pH, sterility, 1511
endotoxins. 1512
Stability studies for powders for injection solution should include 1513
monitoring for colour, reconstitution time and water content. Specific 1514
parameters to be examined at appropriate intervals throughout the 1515
maximum intended use period of the reconstituted drug product, stored 1516
under condition(s) recommended on the label, should include clarity, 1517
colour, pH, sterility, pyrogen/endotoxin and particulate matter. It may be 1518
appropriate to consider monitoring of sterility after reconstitution into a 1519
product, e.g. dual-chamber syringe, where it is claimed that reconstitution 1520
can be performed without compromising sterility. 1521
1522
The stability studies for suspension for injection should include, in 1523
addition, particle size distribution, dispersibility, specific gravity, 1524
resuspendability, rheological properties and dissolution (when 1525
applicable). Content uniformity may be considered a stability-indicating 1526
parameter for the primary stability studies of a depot injection such as 1527
DMPA (refer to the WHO PQTm DMPA guidance document published 1528
on the PQTm website: who.int/prequal/). 1529
1530
• The stability studies for emulsion for injection should include, in addition, 1531
phase separation, viscosity, mean size and distribution of dispersed phase 1532
globules. 1533
1534
Large volume parenterals (LVPs) 1535
Colour, clarity, particulate matter, pH, sterility, pyrogen/endotoxin and 1536
volume. 1537
1538
1539
Working document QAS/17.694 page 46
Transdermal patches 1540
In vitro release rates, leakage, level of microbial contamination/sterility, 1541
peel and adhesive forces. 1542
1543
Working document QAS/17.694 page 47
Appendix 2 1544
Recommended labelling statements 1545
1546
1. Active pharmaceutical ingredients 1547
The statements that should be used if supported by the stability studies 1548
for active pharmaceutical ingredients (APIs) are listed in Table 1. 1549
1550
Table 1. Recommended labelling statements for APIs 1551
1552
Testing condition under which the
stability of the API has been
demonstrated
Recommended labelling
statementa
25 °C/60% RH (long-term) 40 °C/75% RH
(accelerated)
“Do not store above 25 °C”
25 °C/60% RH (long-term)
30 °C/65% RH (intermediate, failure of
accelerated)
“Do not store above 25 °C”b
30 °C/65% RH (long-term) 40°C/75% RH
(accelerated)
“Do not store above 30 °C”b
30 °C/75% RH (long-term) 40 °C/75% RH
(accelerated)
“Do not store above 30 °C”
5 °C ± 3 °C ”Store in a refrigerator (2 °C
to 8 °C)”
-20 °C ± 5 °C “Store in freezer”
a During storage, shipment and distribution of the API, the current good trade and distribution practices 1553 (GTDP) for pharmaceutical starting materials are to be observed (1). Details on storage and labelling 1554 requirements can be found in the WHO guide to good storage practices for pharmaceuticals (2). 1555
b “Protect from moisture” should be added as applicable. 1556
1557
Working document QAS/17.694 page 48
2. Finished pharmaceutical products 1558
The statements that should be used if supported by the stability studies 1559
for FPPs are listed in Table 2. 1560
1561
Table 2. Recommended labelling statements for FPPs 1562
1563
Testing condition under which the
stability of the FPP has been
demonstrated
Recommended labelling
statementa
25 °C/60% RH (long-term) 40 °C/75% RH
(accelerated)
“Do not store above 25 °C”
25 °C/60% RH (long-term)
30 °C/65% RH (intermediate, failure of
accelerated)
“Do not store above 25 °C”b
30 °C/65% RH (long-term) 40 °C/75% RH
(accelerated)
“Do not store above 30 °C” b
30 °C/75% RH (long-term) 40 °C/75% RH
(accelerated)
“Do not store above 30 °C”
5 °C ± 3 °C ”Store in a refrigerator (2 °C
to 8 °C)”
-20 °C ± 5 °C “Store in freezer”
a During storage, shipment and distribution of the FPP, the current good distribution practices (GDP) 1564 for pharmaceutical products are to be observed (3). Details on storage and labelling requirements can 1565 be found in WHO guide to good storage practices for pharmaceuticals (2). 1566
b “Protect from moisture” should be added as applicable. 1567
1568
In principle, FPPs should be packed in containers that ensure stability and 1569
protect the FPP from deterioration. A storage statement should not be 1570
used to compensate for inadequate or inferior packaging. Additional 1571
Working document QAS/17.694 page 49
labelling statements that could be used in cases where the result of the 1572
stability testing demonstrates limiting factors are listed in Table 3. 1573
1574
Table 3. Additional labelling statements for use where the result of the 1575
stability testing demonstrates limiting factors 1576
1577
Limiting factors Additional labelling
statement, where relevant FPPs that cannot tolerate refrigeration “Do not refrigerate or
freeze”a
FPPs that cannot tolerate freezing “Do not freeze”a
Light-sensitive FPPs “Protect from light”
FPPs that cannot tolerate excessive heat,
e.g. suppositories
“Store and transport not
above 30 °C”
Hygroscopic FPPs “Store in dry condition”
Packaging (with the packaging format
specified in the statement, e.g. bottle,
blister)
Store in the original
<package>
Keep the {container} in the
outer carton
Keep the {container}
tightly closed
…in order to protect from
<light> <moisture>
a Depending on the pharmaceutical form and the properties of the FPP, there may be a risk of 1578
deterioration due to physical changes if subjected to low temperatures, e.g. liquids and semisolids. 1579
Low temperatures may also have an effect on the packaging in certain cases. An additional statement 1580
may be necessary to take account of this possibility. 1581
1582
1583
Working document QAS/17.694 page 50
References 1584
1585
Good trade and distribution practices for pharmaceutical starting materials. In: 1586
WHO Expert Committee on Specifications for Pharmaceutical Preparations. 1587
Fiftieth report. Geneva, World Health Organization, 2016, Annex 6 1588
(http://www.who.int/medicines/publications/pharmprep/WHO_TRS_996_annex06.pd1589
f?ua=1). 1590
Please also see: 1591
http://www.who.int/medicines/areas/quality_safety/quality_assurance/GuideGoodStor1592
agePracticesTRS908Annex9.pdf?ua=1 and 1593
http://www.who.int/medicines/areas/quality_safety/quality_assurance/GoodDistributio1594
nPracticesTRS957Annex5.pdf?ua=1. 1595
1. Guide to good storage practices for pharmaceuticals. In: WHO Expert 1596
Committee on Specifications for Pharmaceutical Preparations. 1597
Thirty-seventh report. Geneva, World Health Organization, 2003, 1598
Annex 9 (WHO Technical Report Series, No. 908). 1599
2. Good distribution practices for pharmaceutical products. In: WHO 1600
Expert Committee on Specifications for Pharmaceutical 1601
Preparations. Forty-fourth report. Geneva, World Health 1602
Organization, 2010, Annex 5 (WHO Technical Report Series, No. 1603
957). 1604
1605
1606
Working document QAS/17.694 page 51
Appendix 3 1607
Interpretation of storage statements for products approved in zone II 1608
when the products are to be distributed in zone IV. 1609
1610
In order to ensure the safe use of medicines in recipient countries, labelling 1611
storage statements must be considered in the context of both the region in and 1612
for which the stability studies were conducted and the region(s) in which the 1613
products are intended to be distributed. 1614
For example, for products approved in a zone II region the stability testing has 1615
usually been conducted at accelerated conditions and at zone II long-term 1616
conditions. Demonstrated stability at zone II conditions may result in a label 1617
storage statement of “Store between 15 and 30 C” in line with the convention 1618
of some zone II regions. A product with such a statement, received in a zone 1619
IV country, would be expected to have demonstrated stability at zone IVa or 1620
IVb long-term stability conditions. However, when the stability was 1621
demonstrated at zone II long-term conditions, the appropriate statement for 1622
distribution in a zone IV region would be “Do not store above 25 C”. 1623
Typical examples of the storage statements for products approved in zone II, 1624
with examples of the stability data on which the statements are based and the 1625
corresponding WHO-recommended storage statement for distribution in zone 1626
IV are provided in Table 1. 1627
1628
Working document QAS/17.694 page 52
Table 1. Examples of stability data and storage statements for products 1629
approved in zone II and WHO-recommended storage statements (for zone IV) 1630
based on the same data. 1631
Storage statement for
products approved in
zone II
Examples of
stability data on
which the
statements are
based
WHO-recommended
storage statement for
products to be
distributed in zone IV
This medicinal product
does not require any
special storage
conditions (or similar,
i.e. no temperature
mentioned). [EU]
Zone II + accelerated
[FPP is stable at
long-term conditions,
with no significant
change at
accelerated]
Do not store above 25 °C.
Protect from moisture.
This medicinal product
does not require any
special storage
conditions. [EU]
Zone II + Zone IVb +
accelerated
[FPP is stable at
long-term conditions
(zones II and IVb),
with no significant
change at
accelerated]
Do not store above 30 °C.
Do not store above 30
°C. [EU]
Zone IVa +
accelerated [FPP is
stable at long-term
conditions, with
significant change at
accelerated]
Do not store above 30 °C.
Protect from moisture.
Avoid excursions above
30 °C.
Store at 15 °C to 30 °C
[US, Canada]
OR
Store at 25 °C;
excursions permitted to
15 °C to 30 °C [US]
Zone II + accelerated
[FPP is stable at
long-term conditions,
with no significant
change at
accelerated]
Do not store above 25 °C.
Protect from moisture.