WHO GENERAL GUIDANCE ON VARIATIONS TO MULTISOURCE ... · Working document QAS/14.575 February 2014...

Working document QAS/14.575

February 2014

Draft for comment

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WHO GENERAL GUIDANCE ON 3

VARIATIONS TO MULTISOURCE 4

PHARMACEUTICAL PRODUCTS 5

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(February 2014) 7

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DRAFT FOR COMMENT 9

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© World Health Organization 2014 19

All rights reserved. 20

This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The draft 21 may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in 22 any form or by any means outside these individuals and organizations (including the organizations' concerned staff and 23 member organizations) without the permission of the World Health Organization. The draft should not be displayed on any 24 website. 25

Please send any request for permission to: 26

Dr Sabine Kopp, Group Lead, Medicines Quality Assurance, Technologies, Standards and Norms, Department of Essential 27 Medicines and Health Products, World Health Organization, CH-1211 Geneva 27, Switzerland. Fax: (41-22) 791 4730; 28 email: [email protected]. 29

The designations employed and the presentation of the material in this draft do not imply the expression of any opinion 30 whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or 31 of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate 32 border lines for which there may not yet be full agreement. 33

The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or 34 recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors 35 and omissions excepted, the names of proprietary products are distinguished by initial capital letters. 36

All reasonable precautions have been taken by the World Health Organization to verify the information contained in this 37 draft. However, the printed material is being distributed without warranty of any kind, either expressed or implied. The 38 responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health 39 Organization be liable for damages arising from its use. 40

This draft does not necessarily represent the decisions or the stated policy of the World Health Organization. 41 42

Should you have any comments on the attached revision, please send these to Dr S. Kopp, Group

Lead, Medicines Quality Assurance, Technologies, Standards and Norms ([email protected]) with a

copy to Ms Marie Gaspard ([email protected]) by 7 April 2014.

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SCHEDULE FOR THE PROPOSED ADOPTION PROCESS OF DOCUMENT QAS/14.575: 43

WHO GENERAL GUIDANCE ON VARIATIONS TO MULTISOURCE 44

PHARMACEUTICAL PRODUCTS 45

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Development of draft based on WHO Expert Committee

on Specifications for Pharmaceutical Preparations

prepared by Ms G.N. Mahlangu, Director-General,

Medicines Control Authority of Zimbabwe, Harare,

Zimbabwe

October 2013–February 2014

Circulation for comments March–April 2014

Compilation of feedback May 2014

Review of feedback and comments with assessors and

experts

June 2014

Recirculation for feedback July 2014

Compilation of feedback September 2014

Discussion at forty-ninth meeting of the WHO Expert

Committee on Specifications for Pharmaceutical

Preparations

13–17 October 2014

Any further action, as necessary …


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Contents 50

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1. Introduction ……………………………………………………………………………... 54

1.1 Objectives ………………………………………………………………………. 55

1.2 Scope and application of the guideline …………………………………………. 56

2. Glossary …………………………………………………………………………………. 57

3. General considerations ………………………………………………………………….. 58

3.1 Reporting types …………………………………………………………………. 59

3.1.1 Notification ……………………………………………………………… 60

3.1.2 Minor variation ………………………………………………………….. 61

3.1.3 Major variation ………………………………………………………….. 62

3.2 New applications and extension applications …………………………………… 63

3.3 Labelling information …………………………………………………………… 64

3.4 Conditions to be fulfilled ……………………………………………………….. 65

3.5 Documentation required ………………………………………………………… 66

4. General stability considerations ………………………………………………………… 67

5. Comparative studies …………………………………………………………………….. 68

5.1 Comparative in vivo studies …………………………………………………….. 69

5.2 Comparative in vitro studies …………………………………………………….. 70

5.3 Variations (changes) to pharmaceutical aspects of registered products which … 71

may be made without prior approval 72

5.3.1 Annual notification ………………………………………………………. 73

5.3.2 Immediate notification – “Do and tell” ………………………………….. 74

5.4 Variations (changes) to pharmaceutical aspects of registered products which … 75

require prior approval before implementation 76

5.4.1 Minor variation …………………………………………………………... 77

5.4.2 Major variation …………………………………………………………… 78

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1. INTRODUCTION 84

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This guidance document is intended to provide supportive information on how to present an 86

application to implement a change to a registered multisource medicinal product. A marketing 87

authorization holder or applicant is responsible for the safety, efficacy and quality of a 88

medicinal product that is placed on the market throughout its life-cycle. As such, changes are 89

required or necessary for an approved or registered product to account for technical and 90

scientific progress, to improve the quality of the medicinal product, to meet market 91

requirements such as scale-up or additional manufacturing sites, or updates to product 92

information (e.g. updates to information on adverse reactions). The common areas for change 93

are pharmaceutical aspects (quality control, source of raw materials, manufacturing, shelf-life 94

etc.) and product information. Such changes, regardless of the nature of the change, are 95

referred to as variations and may require the approval of national medicines regulatory 96

authority (NMRA) prior to implementation. 97

98

Technical requirements for the different types of variations are set out in these guidelines in 99

order to facilitate the submission of appropriate documentation by applicants and their 100

assessment by NMRAs. 101

102

1.1 Objectives 103

104

This guidance document is intended to assist applicants with the classification of changes 105

made to a registered or approved finished pharmaceutical product (FPP) and provide 106

guidance on the technical and other general data requirements to support changes to the 107

quality attributes of the active pharmaceutical ingredient (API) or FPP. Variation applications 108

are categorized into major variation, minor variation (prior approval) and minor variation 109

(notification). 110

111

1.2 Scope and application of the guideline 112

113

These guidelines can be used by both NMRAs and applicants with respect to changes to the 114

quality sections of product dossiers for an API or an FPP. This guidance should be read in 115

conjunction with the Guidelines on submission of documentation for a multisource finished product 116


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(1) and Guidance on variations (2) as well as other related WHO guidelines or applicable 117

national guidelines. 118

119

The NMRAs reserve the rights to request for additional information where necessary, in line 120

with national requirements. 121

122

This guidance document is applicable only to APIs and excipients manufactured by chemical 123

synthesis or semisynthetic processes and FPPs containing such APIs and excipients. APIs 124

produced by fermentation and APIs of biological, biotechnological or herbal origin are treated 125

as special cases. 126

127

It is recommended that the principles established in this guidance document be applied to 128

similar quality changes that occur during the development of the product and that the 129

recommended supporting data be included with the initial application for registration of a 130

medicinal product. 131

132

When a variation leads to a revision of the package insert, the patient information leaflet 133

(PIL) and labelling,1 the updated product information should be submitted as part of the 134

application. 135

136

For variations that require generation of stability data on the API or FPP, the stability studies 137

required, including commitment batches, should always be continued to cover the currently 138

accepted retest or shelf-life period. The NMRAs should be informed immediately if any 139

problems with the stability of APIs or FPPs occur during storage, e.g. if found to be outside 140

specifications or potentially outside specifications. 141

142

Applicants should be aware that some variations might require the submission of additional 143

consequential variations. Therefore for any given change the applicant should consider 144

whether one or more variations might be required to be submitted. 145

146

If changes to the dossier only concern editorial changes, such changes need not be submitted 147

as a separate variation but can be included as a notification together with a subsequent 148

1 Different regions/countries use different terminology for product information. In this document package insert,

PIL and label are used to refer to product information.


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variation concerning that part of the dossier. In such a case a declaration should be provided 149

that the contents of the associated sections of the dossier have not been changed by the 150

editorial changes beyond the substance of the variation submitted. 151

152

2. GLOSSARY 153

154

The definitions provided below apply to the terms used in this guidance. They may have 155

different meanings in other contexts and documents. 156

157

active pharmaceutical ingredient (API) 158

A substance used in the FPP, intended to furnish pharmacological activity or to otherwise 159

have direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to 160

have direct effect in restoring, correcting or modifying physiological functions in human 161

beings. 162

163

active pharmaceutical ingredient (API) starting material 164

A raw material, intermediate, or an API that is used in the production of an API and that is 165

incorporated as a significant structural fragment into the structure of the API. An API starting 166

material can be an article of commerce, a material purchased from one or more suppliers 167

under contract or commercial agreement, or produced in-house. 168

169

applicant 170

For the purposes of this document, the term applicant refers to any person or entity that holds 171

the legal responsibility for the product on the market by submission of the required 172

documentation on a product that has been listed after evaluation as registered or approved. 173

174

biobatch 175

The batch used to establish bioequivalence or similarity to the comparator product as 176

determined in bioequivalence or biowaiver studies, respectively. 177

178

final intermediate 179

Product formed in the last reaction in the synthetic pathway that undergoes synthetic 180

transformation to the API or the crude API. Purification is not considered to be a synthetic 181

transformation. 182


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183

finished pharmaceutical product (FPP) 184

A finished dosage form of a pharmaceutical product, which has undergone all stages of 185

manufacture including packaging in its final container and labelling. 186

187

in-process control 188

Check performed during manufacture to monitor or to adjust the process in order to ensure 189

that the final product conforms to its specifications. 190

191

manufacturer 192

A company that carries out operations such as production, packaging, repackaging, labelling 193

and relabelling of pharmaceuticals. 194

195

multisource (generic) pharmaceutical product 196

Pharmaceutically equivalent products that may or may not be therapeutically equivalent. 197

198

officially recognized pharmacopoeia (or compendium) Those pharmacopoeias recognized by 199

the national regulatory agencies (e.g. national pharmacopoeia (if applicable), The 200

International Pharmacopoeia (Ph.Int.), the European Pharmacopoeia (PhEur.), the British 201

Pharmacopoeia (BP), the Japanese Pharmacopoeia (JP) and the United States Pharmacopeia 202

(USP)). 203

204

pilot-scale batch 205

A batch of an API or FPP manufactured by a procedure fully representative of and simulating 206

that to be applied to a full production-scale batch. For example, for solid oral dosage forms, a 207

pilot scale is generally, at a minimum, one-tenth that of a full production scale or 100 000 208

tablets or capsules, whichever is the larger, unless otherwise adequately justified. 209

210

production batch 211

A batch of an API or FPP manufactured at production scale by using production equipment in 212

a production facility as specified in the application. 213

214

register 215

A list of all the pharmaceutical products authorized for marketing in a particular country. The 216


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medicines regulatory authority of the country in question maintains the register. 217

218

registered medicines products 219

Pharmaceutical products that have a marketing authorization. 220

221

stringent regulatory authority (SRA) 222

A stringent regulatory authority is: 223

• the medicines regulatory authority in a country which is: (a) a member of the 224

International Conference on Harmonisation (ICH) (European Union (EU), Japan and the 225

United States of America); or (b) an ICH Observer, being the European Free Trade 226

Association (EFTA) as represented by Swiss Medic and Health Canada (as may be 227

updated from time to time); or (c) a regulatory authority associated with an ICH member 228

through a legally-binding, mutual recognition agreement including Australia, Iceland, 229

Liechtenstein and Norway (as may be updated from time to time); 230

• only in relation to good manufacturing practices (GMP) inspections: a medicines 231

regulatory authority that is a member of the Pharmaceutical Inspection Co-operation 232

Scheme (PIC/S) as specified at http://www.picscheme.org. 233

234

validation 235

The demonstration, with documentary evidence, that any procedure, process, equipment, 236

material, activity or system actually leads to the expected results. 237

238

variation 239

A change to any aspect of a pharmaceutical product, including but not limited to a change to 240

formulation, method and site of manufacture, specifications for the finished product and 241

ingredients, container and container labelling and product information. 242

243

3. GENERAL CONSIDERATIONS 244

245

3.1 Reporting types 246

247

The definitions outlined in the following reporting types are intended to provide guidance 248

with respect to the classification of quality-related changes. Specific examples of changes are 249

provided in these guidelines. However, it should be noted that a change not covered by these 250


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guidelines, should be considered as a major change by default. Whenever the applicant is 251

unclear about the classification of a particular change, the respective NMRA should be 252

contacted. It remains the responsibility of the applicant to submit relevant documentation to 253

justify that the change will not have a negative impact on the quality of the product. 254

255

Individual changes normally require the submission of separate variations. Grouping of 256

variations is acceptable only under the following circumstances: 257

258

• when variations are consequential to each other, e.g. introduction of a new impurity 259

specification that requires a new analytical procedure; 260

• when the same change affects multiple FPPs, e.g. addition of a new API 261

manufacturing site for multiple FPPs; 262

• when all the changes fall under annual notification. 263

264

Applicants are also advised to exercise caution whenever several changes to the same FPP are 265

envisaged. Although each of the individual changes may be classified as a particular reporting 266

type, classification within a higher-risk category may be warranted as a result of the 267

composite effect of these changes. In all such cases, applicants are advised to contact the 268

NMRA prior to submission of the variation application to obtain guidance on classifying such 269

changes. 270

271

3.1.1 Notifications 272

273

Notifications are changes that could have minimal or no adverse effects on the overall safety, 274

efficacy and quality of the FPP. Such notifications may not require prior acceptance, but must 275

be notified to the NMRA immediately after implementation, i.e. immediate notification (IN), 276

or within 12 months following implementation, i.e. annual notification (AN). 277

278

3.1.2 Minor variation 279

280

Minor variations are changes that may have minor effects on the overall safety, efficacy and 281

quality of the FPP. Applicants must satisfy themselves that they meet all of the prescribed 282

conditions for the change and submit all required documentation with the variation 283

application. 284


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285

Prior approval by the NMRA may be required, before the changes can be implemented. The 286

“timeline” and “implementation of the variation” are subject to the NMRA’s specific 287

proposals and should be made publicly available. 288

289

3.1.3 Major variation 290

291

Major variations are changes that could have major effects on the overall safety, efficacy and 292

quality of the FPP. In general, a change that is supported by extensive documentation and/or 293

requires extensive assessment of the supporting documentation would be considered as major 294

variation, e.g. a change supported by in vivo studies. Prior approval by the NMRA is required 295

before the changes can be implemented. The “timeline” and “implementation of the 296

variation” are subject to the NMRA’s specific proposals. 297

298

The NMRA reserves the right to recategorize the application type, where deemed appropriate. 299

Subject to country specific procedure, recategorization may require the applicant to resubmit 300

a new application or additional data according to the correct category. 301

302

3.2 New applications and extension applications 303

304

Certain changes are so fundamental that they alter the terms of the accepted dossier and 305

consequently cannot be considered as changes. In these cases a new dossier must be 306

submitted in line with applicable national requirements for applications for registration of 307

medicines. 308

309

Examples of such changes are listed below: 310

311

1. Change of the API to a different API. 312

2. Inclusion of an additional API in a multicomponent product. 313

3. Removal of one API from a multicomponent product. 314

4. Change in the dose and/or strength of one or more APIs. 315

5. Change from an immediate-release product to an extended or delayed-release dosage form or 316

vice versa. 317

6. Change from a liquid to a powder for reconstitution or vice versa. 318

7. Changes in the route of administration. 319


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320

3.3 Labelling information 321

322

For any change to labelling information (package insert, PIL, labels), the NMRA must be 323

notified and submission of the revised labelling information is expected as per country 324

specific proposal or requirements. 325

326

3.4 Conditions to be fulfilled 327

328

For each variation, attempts have been made to identify particular circumstances where lower 329

reporting requirements, e.g. notifications, are possible. A change that does not meet all of the 330

conditions stipulated under general and specific circumstances for the notifications are 331

automatically considered at the next higher level of change, i.e. require prior approval before 332

implementation. 333

334

3.5 Documentation required 335

336

All data recommended to support a change should be provided with the submission. 337

338

When recommended supporting data cannot be submitted, a detailed rationale should be 339

provided. Regardless of the documents specified, applicants should ensure that they have 340

provided all relevant information to support the variation. Additional documentation may be 341

required. For all changes it remains the responsibility of the applicant to provide all necessary 342

documents to demonstrate that the change does not have a negative impact on the safety, 343

efficacy or quality of the FPP. 344

345

Where applicable, the following should be included in the application for variations requiring 346

prior approval: 347

348

• a covering letter (including a list of changes describing each in sufficient detail to allow for a 349

quick assessment as to whether the appropriate reporting category has been used); 350

• section of the original dossier affected by the change(s); 351

• current and proposed condition(s); 352

• reason for the change(s); 353


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• where relevant, a side-by-side comparison of the previously approved and the proposed 354

information; 355

• replacement of the relevant sections of the dossier as per acceptable dossier format for the 356

respective NMRAs with the proposed changes clearly annotated; 357

• copies of package insert, PIL and labels, if relevant; 358

• registration status and date of the proposed change(s) in other countries/agencies that had 359

approved the variation(s), especially the country of origin and the reference agencies. 360

361

It should be noted that the NMRA reserves the right to request further information not 362

explicitly described in these guidelines. 363

364

Alternative approaches to the principles and practices described in this document may be 365

acceptable provided they are supported by adequate scientific justification. It is also important 366

to note that the NMRA may request information or material, or defines conditions not 367

specifically described in this guidance, in order to adequately assess the safety, efficacy and 368

quality of an FPP. 369

370

4. GENERAL STABILITY CONSIDERATIONS 371

372

The effect of the changes on an approved medicinal product on the stability of the medicinal 373

product should be evaluated. For general guidance on conducting stability studies, applicants 374

are referred to the WHO Guideline on Stability Studies [3]. For variation submissions, the 375

following points also should be considered: 376

• In most cases (except those involving scale up), stability data from pilot scale batches will be 377

acceptable to support the proposed change. 378

• Where stability data show a trend toward potency loss or degradant increase under accelerated 379

conditions, it is recommended that historical accelerated stability data from a representative 380

pre-change batch be submitted for comparison. It is also recommended that under these 381

circumstances, all available long-term data on test batches from ongoing studies be provided 382

in the supplement. Submission of historical accelerated and available long-term data would 383

facilitate review and approval of the supplement. 384

• A commitment should be included to conduct long-term stability studies through the 385

expiration-dating period, according to the approved protocol, on the first or first three 386

production batches and to report the results in the annual reports. 387

388


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5. COMPARATIVE STUDIES 389

390

5.1 Comparative in vivo studies 391

392

A number of changes outlined include recommendations for supporting comparative in vivo 393

studies (e.g. comparative bioavailability studies). 394

395

Applicants should consult the ICH Q5E guideline and applicable WHO guidance documents 396

when conducting comparative in vivo studies. 397

398

5.2 Comparative in vitro studies 399

400

A number of changes outlined include recommendations for supporting comparative in vitro 401

studies (e.g. comparative dissolution studies). Where an in vitro comparison is recommended 402

to support a variation, the comparison should be made to the product manufactured according 403

to the same formulation and manufacturing process used in the pivotal clinical and/or 404

comparative bioavailability studies approved for the original drug submission (e.g. including 405

batch formula, manufacturing process). This is referred to as the "approved product" in the 406

appendices. 407

408

Alternative approaches to this recommendation may be acceptable if scientifically justified. 409

For example, a comparison to an applicant's marketed product (rather than the product used in 410

the pivotal clinical and/or comparative bioavailability studies) could be justified if a 411

significant body of information has been established for the marketed drug product. For the 412

purposes of this document, a significant body of information for the marketed drug product is 413

likely to exist after a reasonable number of batches of the drug product will be marketed 414

during the specified period of time (e.g. a minimum of 10 batches). 415

416

Applicants should refer to the General Chapters available in the current Schedule B 417

pharmacopoeia for general dissolution and drug release specifications (e.g. United States 418

Pharmacopeia (USP) <711>, USP <724>, European Pharmacopoeia (Ph.Eur.) 2.9.3). 419

420

5.3 Variations (changes) to pharmaceutical aspects of registered products which may be 421

made without prior approval 422


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423

5.3.1 Annual notification 424

425

Changes that may be applied without prior approval but included in annual notifications (AN) 426

are listed below: 427

428

1. Changes in batch size of the API or intermediate involving up to 10-fold compared to the 429

currently accepted batch size on condition that (a) the product continues to meet specifications, (b) the 430

dissolution profile is not significantly altered, (c) a stability study has been commenced on at least one 431

full-scale production batch and (d) the change does not concern a sterile API. 432

433

2. Additional tests and limits for starting materials or finished products on condition that these 434

do not reflect a change in processing, e.g. from a fine to microfine particle size. 435

436

3. A change in the content of an excipient of up to ±5%. 437

438

4. Alteration of the quantitative composition of a tablet or capsule coating amounting to less than 439

2% of the total weight of the tablet or capsule. On condition that (a) the coating has no modified- 440

release properties, (b) there is no API in the coating, (c) any new colours are permitted by the 441

European Commission’s List of Permitted Food Colours (4), or the United States Food and Drug 442

Agency’s (US-FDA) Summary of Color Additives for Use in the United States in Foods, Drugs, 443

Cosmetics, and Medical Devices (5) and (d) the change is notified. 444

445

5. Changes to the volume of granulating fluid of up to ±15%, provided that (a) the product 446

continues to meet specifications and (b) the dissolution profile is not significantly altered. 447

448

6. Changes to the quantitative content of agents whose only function is to make the product 449

viscous. On condition that (a) it has been demonstrated that any solid material present is at least 450

equally well suspended and (b) a stability study has been commenced on at least two batches of the 451

altered product. 452

453

7. Change in weight of tablet coatings or capsule shells involving immediate-release oral FPPs. 454

On condition that (a) multipoint in vitro dissolution profiles of the proposed version of the product 455

(determined in the routine release medium on at least two batches of pilot- or production-scale) are 456

similar to the dissolution profiles of the biobatch, (b) coating is not a critical factor for the release 457

mechanism and (c) specifications for the FPP are updated only with respect to weight and dimensions, 458


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if applicable. 459

460

8. Alteration of methods of manufacture and manufacturing equipment on condition that (a) the 461

product is not a slow- or otherwise modified-release product, (b) a new stability study has been 462

commenced on at least two batches of the altered product, (c) no change in the specifications of the 463

intermediates or the FPP, (d) the dissolution profiles are similar to those of the biobatch and (e) the 464

manufacturing processes for the currently accepted and proposed products use the same principles 465

(e.g. a change from wet to dry granulation, from direct compression to wet or dry granulation, or vice 466

versa, would be considered a change in manufacturing principle), the same processing intermediates 467

and there are no changes to any manufacturing solvent used in the process. 468

469

9. Change in the batch size of the FPP involving downscaling. On condition that (a) the change 470

does not affect the reproducibility and/or consistency of the product, (b) the change pertains only to 471

immediate-release oral pharmaceutical forms and to non-sterile liquid forms and (c) changes to the 472

manufacturing method and/or to the in-process controls are only those necessitated by the change in 473

batch size, e.g. use of different-sized equipment. 474

475

10. Change to in-process tests or limits applied during the manufacture of the FPP or intermediate 476

involving (a) tightening of in-process limits, (b) deletion of a test and (c) addition of new tests and 477

limits. 478

479

11. Additional tests and limits for starting materials or finished products on condition that these 480

do not reflect a change in processing, e.g. from a fine to microfine particle size. 481

482

12. Change in specifications of an excipient to comply with an officially-recognized 483

pharmacopoeia provided that there is no change to the specifications other than those required to 484

comply with the pharmacopoeia (e.g. no change in particle size distribution). 485

486

13. Update to the specifications to comply with an officially-recognized pharmacopoeial 487

monograph as a result of an update to this monograph to which the FPP is controlled 488

489

14. Change in the analytical procedures for the FPP involving updating the analytical procedure 490

with an officially-recognized pharmacopoeial monograph as a result of an update to that monograph. 491

492

493

5.3.2 Immediate notification – “do and tell” 494

495


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496

497

Applicants must satisfy themselves that they meet all of the prescribed conditions for the 498

change and submit all required documentation with the notification application. Such changes 499

can be implemented immediately at the time of submission and they can be considered 500

accepted if an objection is not issued by the NMRA within a reasonable period subject to 501

country specific proposal after the date of acknowledgement of receipt of the application. 502

503

Examples of such changes are listed below: 504

505

1. Change to the marketing authorization holder (name, address and/or legal entity). On 506

condition that there is no change to the product, including sites of manufacture. 507

508

2. Change in the name and/or corporate address of the supplier of the FPP on condition 509

that the supplier of the product remains the same legal entity. 510

511

3. Deletion of a manufacturing site or manufacturer involving production or testing of 512

the API/FPP intermediate or API/FPP provided that at least one other site continues to 513

perform the same function(s) as the site(s) intended to be deleted and that the deletion of the 514

site is not a result of critical deficiencies in manufacturing. 515

516

4. Change in the manufacturing process of the API. On condition (a) that there is no 517

change in the physical state (e.g. crystalline, amorphous) of the API, (b) for low solubility 518

APIs, there is no change in the polymorphic form and whenever particle size is critical 519

(including low solubility APIs) there is no significant change in the particle size distribution 520

compared to that of the API lot used in the preparation of the biobatch, (c) where materials of 521

human or animal origin are used in the process, the manufacturer does not use any new 522

process for which assessment of viral safety data or transmissible spongiform encephalopathy 523

(TSE) risk assessment is required, (d) no change in qualitative and quantitative impurity 524

profile or in physicochemical properties of the API, (e) the change does not affect the 525

sterilization procedures of a sterile API, (f) the change involves only steps before the final 526

intermediate and (g) the change does not require revision of the starting material, intermediate 527

or API specifications. 528


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529

5. Change in batch size of the API or intermediate involving downscaling on condition 530

that (a) no changes to the manufacturing process other than those necessitated by changes in 531

scale (e.g. use of a different size of equipment) and (b) the change does not affect the 532

reproducibility of the process. 533

534

6. Changes to the test parameters, acceptance criteria or analytical procedures of the API 535

manufacturer that do not require a change to the FPP manufacturer’s API specifications. 536

537

7. Change to the test parameters or acceptance criteria of the API specifications of the 538

FPP manufacturer involving (a) replacement of a test parameter, (b) relaxation of an 539

acceptance criterion and (c) addition of test parameter. On condition that (a) for insoluble 540

APIs there is no change in the polymorphic form and whenever particle size is critical 541

(including low-solubility APIs), there is no change in particle size distribution acceptance 542

criteria, (b) no additional impurity found over the International Conference on Harmonisation 543

of Technical Requirements for Registration of Human Medicines (ICH) identification 544

threshold and (c) the change does not concern sterility testing. 545

546

8. Change to the analytical procedures used to control the API by the FPP manufacturer 547

involving change from a currently accepted in-house analytical procedure to an analytical 548

procedure in an officially-recognized pharmacopoeia or from the analytical procedure in one 549

officially-recognized pharmacopoeia to an analytical procedure in another officially-550

recognized pharmacopoeia. 551

552

9. Changes to the container-closure system in immediate contact with the product or 553

additional types of container-closure on condition that (a) the product is not a sterile product, 554

(b) the new system offers equal or better protection to the product, (c) stability data are 555

available on two batches of the product in the new container for at least three months under 556

accelerated conditions (as defined in relevant guidelines) or one year under non-accelerated 557

conditions, (d) a stability study has been commenced on at least two batches of the altered 558

product for the full duration of the shelf-life and (e) the change is notified. Changes may not 559

be made to labelling without prior approval. 560

561

10. Reduction in the retest period or shelf-life of the API provided the change is not 562


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necessitated by unexpected events arising during manufacture or because of stability 563

concerns. 564

565

11. Change in the composition of a solution dosage form. On condition that (a) the 566

affected excipient(s) does/do not function to affect the solubility and/or the absorption of the 567

API, (b) the affected excipient(s) does/do not function as a preservative or preservative 568

enhancer, (c) no change in the specifications of the affected excipient(s) or the FPP, (d) no 569

change in the physical characteristics of the FPP (e.g. viscosity, osmolality, pH), (e) the 570

change does not concern a sterile FPP and (f) the excipients are qualitatively the same. The 571

change in the amount (or concentration) of each excipient is within ±10% of the amount (or 572

concentration) of each excipient in the originally approved product. 573

574

12. Changes to flavours, perfumes or colours on condition that (a) any new colours are 575

permitted by the European Commission’s List of Permitted Food Colours (4), or the United States 576

Food and Drug Agency’s (US-FDA) Summary of Color Additives for Use in the United States in 577

Foods, Drugs, Cosmetics, and Medical Devices (5), (b) the change is notified, (c) stability data are 578

available on two batches of the altered product for at least three months under accelerated 579

conditions (as defined in relevant guidelines) or one year under non-accelerated conditions 580

and (d) a new stability study has been commenced on at least two batches of the altered 581

product for the full duration of the shelf-life. 582

583

13. A change or addition of imprints, embossing or other markings on solid dosage forms, 584

including replacement or addition of inks used for product markings and change in scoring 585

configuration. On condition that (a) these do not imply an unapproved indication or patient 586

population, (b) no unapproved colour (as defined above) is introduced, (c) any changes to 587

scoring are consistent with the dose schedules in the approved product information and (d) 588

the change is notified. 589

590

14. Change in dimensions without change in qualitative or quantitative composition and 591

mean mass of tablets, capsules, suppositories and pessaries. On condition that (a) 592

specifications for the FPP are updated only with respect to dimensions of the FPP and (b) 593

multipoint in vitro dissolution profiles of the current and proposed versions of the product 594

(determined in the routine release medium, on at least one batch of pilot- or production-scale) 595

are comparable. 596


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597

15. Addition or replacement of a manufacturing site for part or all of the manufacturing 598

process for an FPP involving (a) secondary packaging of all types of FPPs, (b) primary 599

packaging site of solid FPPs (e.g. tablets, capsules), semi-solid FPPs (e.g. ointments, creams) 600

and solution liquid FPPs and (c) primary packaging site of other liquid FPPs (suspensions, 601

emulsions). On condition that (a) satisfactory good manufacturing practices (GMP) inspection 602

in the last three years and (b) site appropriately authorized by an NMRA (to manufacture the 603

pharmaceutical form and the product concerned). 604

605

16. Change in the batch size of the FPP involving up to and including a factor of 10 606

compared to the biobatch. On condition that (a) the change does not affect the reproducibility 607

and/or consistency of the product, (b) the change pertains only to immediate-release oral 608

pharmaceutical forms and to non-sterile liquid forms, (c) changes to the manufacturing 609

method and/or to the in-process controls are only those necessitated by the change in batch 610

size, e.g. use of different-sized equipment, (d) a validation protocol is available or validation 611

of the manufacture of three production-scale batches has been successfully undertaken in 612

accordance with the current validation protocol and (f) the biobatch size was at least 100 000 613

units in the case of solid oral dosage forms. 614

615

17. Change to in-process tests or limits applied during the manufacture of the FPP or 616

intermediate involving revision or replacement of a test. 617

618

18. Change in the specifications of the FPP involving test parameters and acceptance 619

criteria: (a) relaxation of an acceptance criterion; or (b) replacement of a test parameter 620

provided that the change to the specifications does not affect the stability and the performance 621

of the product and the change does not concern sterility testing. 622

623

19. Analytical methodology for the finished product on condition that (a) validation shows 624

that the new method is equivalent to or better than the existing method and (b) major changes 625

(e.g. ultra violet assay to high-pressure liquid chromatography (HPLC)) are notified. 626

627

20. Change in the package size involving: (a) change in the number of units (e.g. tablets, 628

ampoules, etc.) in a package; and (b) change in the fill weight or fill volume of non-parenteral 629

multidose products. On condition that (a) the change is consistent with the posology and 630


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treatment duration accepted in the package insert and (b) no change in the primary packaging 631

material. 632

633

21. Changes to the container-closure system in immediate contact with the product or 634

additional types of container-closure. On condition that (a) the product is not a sterile product, 635

(b) the new system offers equal or better protection to the product, (c) stability data are 636

available on two batches of the product in the new container for at least three months under 637

accelerated conditions (as defined in relevant guidelines) or one year under non-accelerated 638

conditions, (d) a stability study has been commenced on at least two batches of the altered 639

product for the full duration of the shelf-life and (e) the change is notified. Changes may not 640

be made to labelling without prior approval. 641

642

22. Change in any part of the (primary) packaging material not in contact with the FPP 643

formulation (e.g. colour of flip-off caps, colour code rings on ampoules or change of needle 644

shield), provided the change does not concern a fundamental part of the packaging material, 645

which affects the delivery, use, safety or stability of the FPP. 646

647

23. Reduction in the shelf-life of the FPP (as packaged for sale) or in the in-use period of 648

the FPP (after first opening or after reconstitution or dilution). 649

650

New sites of manufacture require prior approval because the NMRA should see evidence of 651

compliance with GMP, e.g. a WHO-type certificate of pharmaceutical product (6). Changes 652

or additions to pack size also require prior approval because the new size must be consistent 653

with the approved uses of the product. 654

655

Changes may not be made to labelling without prior approval, except for changes to layout 656

without alteration of text or meaning. Pictures or diagrams may not be added without prior 657

approval because they may imply an unapproved indication. 658

659

Notifications of variations, and applications to vary, must be accompanied by this statement: 660

661

“No variations have been made other than (1) those notified herewith and (2) changes 662

which are permitted without notification or prior approval according to the guidelines of 663

the medicines regulatory authority of ...........” 664


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5.4 Variations (changes) to pharmaceutical aspects of registered products which require 665

prior approval before implementation 666

667

5.4.1 Minor variation 668

669

Below is a list of variations considered minor. In addition to the general documents stated in 670

section 3.5. Documentation required, specific documentation in support of each type of 671

variation should be provided. 672

673

1. Replacement or addition of a new manufacturing site or manufacturer of an API involving 674

API testing only provided the transfer of analytical methods has been successfully undertaken and 675

no change in the FPP manufacturer’s API specifications. 676

677

2. Change of drug product name. 678

679

3. Change of the specification of drug substance a) specification limits are tightened and b) 680

addition of new test parameter and limits. 681

682

4. Change in product labelling should be in accordance to country specific labelling requirement 683

and this includes: 684

685

686

a) change of the layout/artwork without altering meaning; 687

b) addition/deletion/replacement of pictures, diagrams, bar code, logos and/or texts that do not 688

imply an unapproved indication; 689

c) addition/strengthening of warnings, precautions, contraindications and/or adverse 690

events/effects to the approved product labelling; 691

d) tightening of product’s target population; 692

e) deletion of indication. 693

694

5. Change in batch size of the API or intermediate involving more than 10-fold increase 695

compared to the currently accepted batch size. 696

697

6. Change to the specifications or analytical procedures applied to materials used in the 698

manufacture of the API (e.g. raw materials, starting materials, reaction intermediates, solvents, 699

reagents, catalysts) involving addition or replacement of a specification parameter as a result of a 700


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safety or quality issue. 701

702

7. Change of the specification of drug substance a) specification limits are tightened and b) 703

addition of new test parameter and limits. 704

705

8. Change to the test parameters or acceptance criteria of the API specifications of the FPP 706

manufacturer a) addition of a test parameter, b) replacement of test parameter and c) relaxation of 707

an acceptance criterion. 708

709

9. Change to the analytical procedures used to control the API by the FPP manufacturer 710

involving modification or replacement of an analytical procedure. 711

712

10. Change in the immediate packaging (primary and functional secondary components) for the 713

storage and shipment of the API provided the change is not due to instability issues. 714

715

11. Change in the retest period or shelf-life of the API involving extension provided (a) no change 716

to the primary packaging in direct contact with the API or to the recommended condition of 717

storage and (b) stability data were generated in accordance with the currently accepted stability 718

protocol. 719

720

12. Any change in the labelled storage conditions of the API provided (a) the stability studies 721

must show compliance with specification and (b) no change in shelf-life/retest period. 722

723

13. Change or addition of imprints, embossing or other markings, including replacement or 724

addition of inks used for product markings and change in scoring configuration involving addition 725

of a score line. On condition that (a) the change does not affect the stability or performance 726

characteristics (e.g. release rate) of the FPP, (b) changes to the FPP specifications are those 727

necessitated only by the change to the appearance or to the scoring and (c) addition or deletion of 728

a score line from a generic product is consistent with a similar change in the comparator product 729

or was requested by NMRA. 730

731

14. Change in dimensions without change in qualitative or quantitative composition and mean 732

mass of gastroresistant, modified or prolonged-release FPPs and scored tablets. On condition that 733

specifications for the FPP are updated only with respect to dimensions of the FPP and multipoint 734

in vitro dissolution profiles of the current and proposed versions of the product (determined in the 735

routine release medium, on at least one batch of pilot- or production-scale) are comparable. 736

737


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15. Addition or replacement of a manufacturing site for part or all of the manufacturing process 738

for an FPP involving all other manufacturing operations except batch control and/or release 739

testing. On condition that (a) no change in the batch formula, description of manufacturing 740

process and process controls, equipment class and process controls, controls of critical steps and 741

intermediates or FPP specifications, (b) satisfactory inspection in the last three years, (c) site 742

appropriately authorized by an NMRA (to manufacture the pharmaceutical form and the product 743

concerned) and (d) validation protocol is available or validation of the manufacturing process at 744

the new site has been successfully carried out on at least three production-scale batches in 745

accordance with the current protocol. 746

747

16. Change in the manufacturing process of the FPP. 748

749

17. Change in the specifications or analytical procedures for an excipient involving change or 750

replacement of an analytical procedure. 751

752

18. Replacement or addition of a primary packaging type provided the change does not concern a 753

sterile FPP. 754

755

19. Change in qualitative and/or quantitative composition of the immediate packaging material for 756

semisolid and liquid FPPs. On condition that (a) the change does not concern a sterile FPP, (b) no 757

change in the packaging type and material (an example of an allowable change is blister to blister) 758

and (c) the relevant properties of the proposed packaging are at least equivalent to those of the 759

currently accepted material. 760

761

20. Extension in the shelf-life of the FPP (as packaged for sale) provided there is no change to the 762

primary packaging type in direct contact with the FPP and to the recommended conditions of 763

storage and stability data were generated in accordance with the currently accepted stability 764

protocol. 765

766

21. Extension in the in-use period of the FPP (after first opening or after reconstitution or 767

dilution). 768

769

22. Change in the labelled storage conditions of the FPP (as packaged for sale), the product 770

during the in-use period or the product after reconstitution or dilution. 771

772

773

5.4.2 Major variation 774


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775

776

Variations, which fail to fulfil the conditions for notifications or minor variations 777

automatically, become major variations. In addition, variations, which are not covered by 778

these guidelines, should be considered as a major change by default. 779

780

References 781

782

1. Guidelines on submission of documentation for a multisource (generic) finished 783

pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part. 784

In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-sixth 785

report. Geneva, World Health Organization. Technical Report Series, No. 970, 2012, Annex 4. 786

787

2. Guidance on variations to a prequalified dossier. In: WHO Expert Committee on Specifications 788

for Pharmaceutical Preparations. Forty-first report. Geneva, World Health Organization. 789

Technical Report Series, No. 943, 2007, Annex 6. 790

791

3. Guidelines for stability testing of active pharmaceutical ingredients and finished pharmaceutical 792

products. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. 793

Forty-third report. Geneva, World Health Organization. Technical Report Series, No. 953, 794

2009, Annex 2. 795

796

4. European Commission. List of permitted food colours: EC Directive 94/36/EC. Official Journal 797

of the European Communities 1994; L237. 798

799

5. FDA. Summary of Color Additives for Use in the United States in Foods, Drugs, Cosmetics, 800

and Medical Devices. 2010. 801

802

6. Guidelines for implementation of the WHO Certification Scheme on the Quality of 803

Pharmaceutical Products Moving in International. In: WHO Expert Committee on Specifications 804

for Pharmaceutical Preparations. Thirty-fourth report. Geneva, World Health Organization. 805

Technical Report Series, No. 863, 1996, Annex 10. 806

807

808

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WHO GENERAL GUIDANCE ON VARIATIONS TO MULTISOURCE ... · Working document QAS/14.575 February 2014...

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