stability testing of active pharmaceutical ingredients and ... · 2 pharmaceutical ingredients and...

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.

.

mailto:[email protected]

http://www.who.int/medicines/areas/quality_safety/quality_assurance/regulatory_standards/en/)




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


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


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

http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q1F/Q1F_Explanatory_Note.pdf

http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q1F/Q1F_Explanatory_Note.pdf


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










2.2.11 In-use and hold-time stability 132

2.2.12 Variations 133


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


447


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


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


— 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



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


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.


form and container type and size of the FPP unless bracketing or 554

matrixing is applied. 555

556


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


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



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


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


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


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


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


• 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



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


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


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


2.2.7.4 FPPs intended for storage in a refrigerator 783

784


covered by data at

submission

Long-term 5 °C ± 3 °C 12 months or six months


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


2.2.7.5 FPPs intended for storage in a freezer 808

809


covered by data at

submission

Long-term –20 °C ± 5 °C 12 months or six months


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


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


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


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


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


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


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


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


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


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


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


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

http://www.who.int/medicines/areas/quality_safety/quality_assurance/regulatory_standards/en/


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

http://www.who.int/medicines/areas/quality_safety/quality_assurance/regulatory_standards/en/


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


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


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


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


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

http://www.ich.org/LOB/media/


http://www.ich.org/LOB/media/MEDIA413.pdf)




International Council on Harmonisation. ICH Q2R1): Validation of 1314

analytical procedures: text and methodology 1315


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







http://www.ich.org/cache/compo/276-254-1.html


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


(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

http://mednet3.who.int/prequal/)


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


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


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


• 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


Transdermal patches 1540

In vitro release rates, leakage, level of microbial contamination/sterility, 1541

peel and adhesive forces. 1542

1543


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)


30 °C/75% RH (long-term) 40 °C/75% RH

(accelerated)


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


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)


25 °C/60% RH (long-term)

30 °C/65% RH (intermediate, failure of

accelerated)


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)


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


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


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

www.who.int/medicines/publications/pharmprep/WHO_TRS_996_annex06.pdf?ua=1

www.who.int/medicines/publications/pharmprep/WHO_TRS_996_annex06.pdf?ua=1

www.who.int/medicines/areas/quality_safety/quality_assurance/GuideGoodStoragePracticesTRS908Annex9.pdf?ua=1

www.who.int/medicines/areas/quality_safety/quality_assurance/GuideGoodStoragePracticesTRS908Annex9.pdf?ua=1

http://www.who.int/medicines/areas/quality_safety/quality_assurance/GoodDistributionPracticesTRS957Annex5.pdf?ua=1

http://www.who.int/medicines/areas/quality_safety/quality_assurance/GoodDistributionPracticesTRS957Annex5.pdf?ua=1


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


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. [EU]

Zone IVa +

accelerated [FPP is

stable at long-term

conditions, with

significant change at

accelerated]



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]




OR

Store at controlled

room temperature (15-

30 °C).

[Canada]

Note: zone II is 25 °C/60%RH, zone IVa is 30 °C/65%RH and zone IVb is 30 1632

°C/75%RH. 1633

1634

*** 1635

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