MULTISOURCE (GENERIC) PHARMACEUTICAL … · Working document QAS/14.583/Rev.1 July 2014 Document...

Working document QAS/14.583/Rev.1

July 2014

Document for comment

1

2

MULTISOURCE (GENERIC) PHARMACEUTICAL 3

PRODUCTS: GUIDELINES ON REGISTRATION 4

REQUIREMENTS TO ESTABLISH 5

INTERCHANGEABILITY. REVISION 6

(JULY 2014) 7

8

REVISED DRAFT FOR COMMENT 9

10

11

© World Health Organization 2014 12

All rights reserved. 13

This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. 14 The draft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or 15 in whole, in any form or by any means outside these individuals and organizations (including the organizations' 16 concerned staff and member organizations) without the permission of the World Health Organization. The draft should 17 not be displayed on any website. 18

Please send any request for permission to: 19

Dr Sabine Kopp, Group Lead, Medicines Quality Assurance, Technologies, Standards and Norms, Department of 20 Essential Medicines and Health Products, World Health Organization, CH-1211 Geneva 27, Switzerland. Fax: (41-22) 21 791 4730; email: [email protected]. 22

The designations employed and the presentation of the material in this draft do not imply the expression of any opinion 23 whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or 24 area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent 25 approximate border lines for which there may not yet be full agreement. 26

The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or 27 recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. 28 Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. 29

All reasonable precautions have been taken by the World Health Organization to verify the information contained in 30 this draft. However, the printed material is being distributed without warranty of any kind, either expressed or implied. 31 The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health 32 Organization be liable for damages arising from its use. 33

This draft does not necessarily represent the decisions or the stated policy of the World Health Organization. 34 35

Should you have any comments on the attached text, 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

([email protected]) and to Ms Marie Gaspard ([email protected]), by 15 September 2014.

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.


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SCHEDULE FOR THE PROPOSED ADOPTION PROCESS OF DOCUMENT QAS/14.583: 36

MULTISOURCE (GENERIC) PHARMACEUTICAL PRODUCTS: GUIDELINES ON 37

REGISTRATION REQUIREMENTS TO ESTABLISH INTERCHANGEABILITY. 38

REVISION 39

40

41

42

Preliminary feedback for chapters to be revised and

discussion during informal consultation with experts and

prequalification assessors

July 2013

Presentation of the outcome of the above consultation to

forty-eighth meeting of the WHO Expert Committee on

Specifications for Pharmaceutical Preparations

October 2013

Revision of guidelines developed by Mr J. Gordon with

input from the Prequalification Team and Professor J.D.

Dressman, WHO Collaborating Centre on

Bioequivalence Testing of Medicines, Frankfurt/Main,

Germany

April 2014

Circulation for comment May–June 2014

Collation of comments 2 July 2014

Discussion during an informal consultation held together

with the Prequalification Assessment Team

6–7 July 2014

Circulation of revised working document July 2014

Collation of comments and review by expert group September 2014

Presentation to forty-ninth meeting of the WHO Expert

Committee on Specifications for Pharmaceutical

Preparations

October 2014

Further follow-up action as required …


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BACKGROUND 43

Over the course of time and especially in view of the implementation of the existing 44

guidelines1 the users have indicated that there was a need to review and update certain 45

requirements. The forty-eighth meeting of the World Health Organization (WHO) Expert 46

Committee on Specifications for Pharmaceutical Products discussed this and included the 47

following passage in its report (extract from the forty-eighth report): 48

“WHO published Multisource (generic) pharmaceutical products: Guidelines on 49

registration requirements to establish interchangeability in 2006. In preparation 50

for the revision of the WHO document, the Expert Committee received a report 51

that compared the WHO guidance on interchangeability with that of the European 52

Medicines Agency (EMA) and the United States Food and Drug Administration 53

(US-FDA). Guidance issues proposed for revision were highlighted. It was stated 54

that a first draft of the revision would be available in due course. The Committee 55

was also asked to consider to what extent WHO guidance should extend to non-56

biological complex drugs (NBCDs). The Committee agreed that guidance for this 57

new group of products might be relevant if they were included in the EML and 58

asked the Secretariat to look into it.” 59

In connection with the revision of these guidelines, the following related guidance texts 60

are also under review and update: 61

• Proposal to waive in vivo bioequivalence requirements for WHO Model List of 62

Essential Medicines immediate-release, solid oral dosage forms 63

Annex 8, WHO Technical Report Series 937, 2006; 64

65

1 Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish

interchangeability. In: WHO Expert Committee on Specifications for Pharmaceutical Products. Fortieth

report. World Health Organization, Geneva. WHO Technical Report Series. No. 937, Annex 7, 2006.


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• Additional guidance for organizations performing in vivo bioequivalence studies 66


68

• Guidance on the selection of comparator pharmaceutical products for equivalence 69

assessment of interchangeable multisource (generic) products 70


72

• Guidance on the selection of pharmaceutical products for assessment of 73

interchangeable multisource (generic) products (working document QAS/14.594); 74

75

• List of international comparator products (working document QAS/14.595). 76

77


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MULTISOURCE (GENERIC) PHARMACEUTICAL PRODUCTS: GUIDELINES 78

ON REGISTRATION REQUIREMENTS TO ESTABLISH 79

INTERCHANGEABILITY. REVISION 80

Background 81

1. Introduction 82

2. Glossary 83

3. Documentation of equivalence for marketing authorization 84

4. When equivalence studies are not necessary 85

5. When equivalence studies are necessary and types of studies required 86

5.1 In vivo studies 87

5.2 In vitro studies 88

6. In vivo equivalence studies in humans 89

6.1 General considerations 90

6.1.1 Provisions for studies in humans 91

6.1.2 Justification of human bioequivalence studies 92

6.1.3 Selection of investigators 93

6.1.4 Study protocol 94

7. Pharmacokinetic comparative bioavailability (bioequivalence) studies in humans 95

7.1 Design of pharmacokinetic studies 96

7.1.1 Alternative study designs for studies in patients 97

7.1.2 Considerations for active pharmaceutical ingredients with long 98

elimination half-lives 99

7.1.3 Considerations for multiple-dose studies 100

7.1.4 Considerations for modified-release products 101

7.2 Subjects 102

7.2.1 Number of subjects 103

7.2.2 Drop-outs and withdrawals 104

7.2.3 Exclusion of subject data 105

7.2.4 Selection of subjects 106

7.2.5 Monitoring the health of subjects during the study 107

7.2.6 Considerations for genetic phenotyping 108


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7.3 Investigational product 109

7.3.1 Multisource pharmaceutical product 110

7.3.2 Choice of comparator product 111

7.4 Study conduct 112

7.4.1 Selection of strength 113

7.4.2 Study standardization 114

7.4.3 Co-administration of food and fluid with the dose 115

7.4.4 Wash-out interval 116

7.4.5 Sampling times 117

7.4.6 Sample fluids and their collection 118

7.4.7 Parameters to be assessed 119

7.4.8 Studies of metabolites 120

7.4.9 Measurement of individual enantiomers 121

7.5 Quantification of active pharmaceutical ingredient 122

7.6 Statistical analysis 123

7.6.1 Two-stage sequential design 124

7.7 Acceptance ranges 125

7.8 Reporting of results 126

7.9 Special considerations 127

7.9.1 Fixed-dose combination products 128

7.9.2 Clinically important variations in bioavailability 129

7.9.3 “Highly variable active pharmaceutical ingredients” 130

8. Pharmacodynamic studies 131

9. Clinical trials 132

10. In vitro equivalence testing 133

10.1 In vitro equivalence testing in the context of the Biopharmaceutics 134

Classification System 135

10.1.1 Biopharmaceutics Classification System 136

10.1.2 Determination of dissolution characteristics of multisource 137

products in consideration of a biowaiver based on the 138

Biopharmaceutics Classification System 139


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10.2 Qualification for a biowaiver based on the Biopharmaceutics Classification 140

System 141

10.2.1 Dissolution criteria for biowaivers based on the Biopharmaceutics 142

Classification System according to the properties of active 143

pharmaceutical ingredients 144

10.3 In vitro equivalence testing based on dose-proportionality of formulations 145

10.3.1 Proportional formulations 146

10.3.2 Qualification for biowaivers based on dose-proportionality of 147

formulations 148

10.3.3 Dissolution profile comparison for biowaivers based on dose- 149

proportionality of formulations 150

10.4 In vitro equivalence testing for non-oral dosage forms 151

10. 5 In vitro equivalence testing for scale-up and post-approval changes 152

References 153

Annex. Recommendations for conducting and assessing comparative dissolution profiles 154

155

1. INTRODUCTION 156

157

These guidelines are intended to provide recommendations to regulatory authorities when 158

defining requirements for approval of multisource (generic) pharmaceutical products in 159

their respective countries. The guidance provides appropriate in vivo and in vitro 160

requirements to assure interchangeability of the multisource product without 161

compromising the safety, quality and efficacy of the pharmaceutical product. 162

163

National regulatory authorities (NRA) should ensure that all pharmaceutical products 164

subject to their control conform to acceptable standards of safety, efficacy and quality, 165

and that all premises and practices employed in the manufacture, storage and distribution 166

of these products comply with good manufacturing practice (GMP) standards so as to 167

ensure the continued conformity of the products with these requirements until they are 168

delivered to the end-user. 169

170


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All pharmaceutical products, including multisource products, should be used in a country 171

only after approval by the national or regional authority. Regulatory authorities should 172

require the documentation of a multisource pharmaceutical product to meet the following: 173

174

‒ GMP; 175

‒ quality control specifications; 176

‒ pharmaceutical product interchangeability. 177

178

Multisource pharmaceutical products need to conform to the same appropriate standards 179

of quality, efficacy and safety as those required of the innovator’s (comparator) product. 180

In addition, reasonable assurance must be provided that the multisource product is 181

therapeutically equivalent and interchangeable with the comparator product. For some 182

classes of products, including – most evidently – aqueous parenteral solutions, 183

interchangeability is adequately assured by assessment of the composition, 184

implementation of GMP and evidence of conformity with appropriate specifications 185

including relevant pharmacopoeial specifications. For a wide range of pharmaceutical 186

products, the concepts and approaches covered by these guidelines will enable the 187

national regulatory authority to decide whether a given multisource product can be 188

approved. This guidance is generally applicable to orally-administered multisource 189

products, as well as to non-orally-administered pharmaceutical products for which 190

systemic exposure measures are suitable for documenting bioequivalence (e.g. 191

transdermal delivery systems and certain parenteral, rectal and nasal pharmaceutical 192

products). Some information applicable for locally acting products is also provided in this 193

document. For yet other classes of products, including many biologicals such as vaccines, 194

animal sera, products derived from human blood and plasma and products manufactured 195

by biotechnology, as well as non-biological complex products, the concept of 196

interchangeability raises issues that are beyond the scope of this document and these 197

products are consequently excluded from consideration. 198

199

To ensure interchangeability, the multisource product must be therapeutically equivalent 200

to the comparator product. Types of in vivo equivalence studies include comparative 201


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pharmacokinetic studies, comparative pharmacodynamic studies and comparative clinical 202

studies. 203

204

Direct demonstration of therapeutic equivalence through a comparative clinical trial is 205

rarely a practical choice, as these trials tend to be insensitive to formulation differences 206

and usually require a very large number of patients. Further, such studies in humans can 207

be financially daunting, are often unnecessary and may be unethical. For these reasons 208

the science of bioequivalence testing has been developed over the last 50 years. 209

According to the tenets of this science, therapeutic equivalence can be assured when the 210

multisource product is both pharmaceutically equivalent/alternative and bioequivalent. 211

212

Assuming that, in the same subject, an essentially similar plasma concentration-time 213

course will result in essentially similar concentrations at the site(s) of action and thus an 214

essentially similar therapeutic outcome, pharmacokinetic data may be used instead of 215

therapeutic results. Further, in selected cases, in vitro comparison of the dissolution 216

profiles of the multisource product with those of the comparator product may be 217

sufficient to provide an indication of equivalence. 218

219

It should be noted that interchangeability includes the equivalence of the dosage form as 220

well as of the indications and instructions for use. Alternative approaches to the 221

principles and practices described in this document may be acceptable provided they are 222

supported by adequate scientific justification. These guidelines should be interpreted and 223

applied without prejudice to obligations incurred through existing international 224

agreement on trade-related aspects of intellectual property rights (1). 225

226

2. GLOSSARY 227

228

Some important terms used in these guidelines are defined below. They may 229

have different meanings in other contexts. 230

231

232


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bioavailability 233

The rate and extent to which the active moiety is absorbed from a pharmaceutical dosage 234

form and becomes available at the site(s) of action. Reliable measurements of active 235

pharmaceutical ingredient (API) concentrations at the site(s) of action are usually not 236

possible. The substance in the systemic circulation, however, is considered to be in 237

equilibrium with the substance at the site(s) of action. Bioavailability can be therefore 238

defined as the rate and extent to which the API or active moiety is absorbed from a 239

pharmaceutical dosage form and becomes available in the systemic circulation. Based on 240

pharmacokinetic and clinical considerations it is generally accepted that in the same 241

subject an essentially similar plasma concentration time course will result in an 242

essentially similar concentration time course at the site(s) of action. 243

244

bioequivalence 245

Two pharmaceutical products are bioequivalent if they are pharmaceutically equivalent or 246

pharmaceutical alternatives, and their bioavailabilities, in terms of rate (Cmax and tmax) 247

and extent of absorption (area under the curve (AUC), after administration of the same 248

molar dose under the same conditions, are similar to such a degree that their effects can 249

be expected to be essentially the same. 250

251

biological medicinal product (ECBS) 252

Biological medicinal product is a synonym for biological product or biological described 253

in the WHO Technical Report Series. The definition of a medicinal substance used in 254

treatment, prevention or diagnosis as a“biological” has been variously based on criteria 255

related to its source, its amenability to characterization by physicochemical means alone, 256

the requirement for biological assays, or arbitrary systems of classification applied by 257

regulatory authorities. For the purposes of WHO, including the current document, the list 258

of substances considered to be biologicals is derived from their earlier definition as 259

“substances which cannot be fully characterized by physicochemical means alone, and 260

which therefore require the use of some form of bioassay”. However, developments in 261

the utility and applicability of physicochemical analytical methods, improved control of 262

biological and biotechnology-based production methods, and an increased applicability of 263


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chemical synthesis to larger molecules have made it effectively impossible to base a 264

definition of a biological on any single criterion related to methods of analysis, source or 265

method of production. Nevertheless, many biologicals are produced using in vitro culture 266

systems. 267

268 In small print: Developers of such medicinal products that do not fit the definition of biological medicinal 269

products provided in this document should consult the relevant NRAs for product classification and the 270

licensing application pathway. 271

272

Biopharmaceutics Classification System (BCS) 273

The BCS is a scientific framework for classifying active pharmaceutical ingredients (API) 274

based upon their aqueous solubility and intestinal permeability. When combined with the 275

dissolution of the pharmaceutical product and the critical examination of the excipients of 276

the pharmaceutical product, the BCS takes into account the major factors that govern the 277

rate and extent of API absorption (exposure) from immediate-release oral solid dosage 278

forms: excipient composition, dissolution, solubility, and intestinal permeability. 279

280

biowaiver 281

The term biowaiver is applied to a regulatory pharmaceutical product approval process 282

when the dossier (application) is approved based on evidence of equivalence other than 283

through in vivo equivalence testing. 284

285

comparator product 286

The comparator product is a pharmaceutical product with which the multisource product 287

is intended to be interchangeable in clinical practice. The comparator product will 288

normally be the innovator product for which efficacy, safety and quality have been 289

established. If the innovator product is no longer marketed in the jurisdiction, the 290

selection principle as described in “Guidance on the selection of comparator 291

pharmaceutical products for equivalence assessment of interchangeable multisource 292

(generic) products” should be used to identify a suitable alternative comparator product. 293

294

295


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dosage form 296

The form of the completed pharmaceutical product, e.g. tablet, capsule, elixir or 297

suppository. 298

299

equivalence requirements 300

In vivo and/or in vitro testing requirements for approval of a multisource pharmaceutical 301

product for a marketing authorization. 302

303

equivalence test 304

A test that determines the equivalence between the multisource product and the 305

comparator product using in vivo and/or in vitro approaches. 306

307

fixed-dose combination (FDC) 308

A combination of two or more active pharmaceutical ingredients in a fixed ratio of doses. 309

This term is used generically to mean a particular combination of active pharmaceutical 310

ingredients irrespective of the formulation or brand. It may be administered as single-311

entity products given concurrently or as a finished pharmaceutical product. 312

313

fixed-dose combination finished pharmaceutical product (FDC-FPP) 314

A finished pharmaceutical product that contains two or more active pharmaceutical 315

ingredients. 316

317

generic product 318

See multisource pharmaceutical products. 319

320

innovator pharmaceutical product 321

Generally, the innovator pharmaceutical product is that which was first authorized for 322

marketing, on the basis of complete documentation of quality, safety and efficacy. 323

324

interchangeable pharmaceutical product 325


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An interchangeable pharmaceutical product is one which is therapeutically equivalent to 326

a comparator product and can be interchanged with the comparator in clinical practice. 327

328

in vitro equivalence dissolution test 329

An in vitro equivalence test is a dissolution test that includes comparison of the 330

dissolution profile between the multisource product and the comparator product, typically 331

in at least three media: pH 1.2, pH 4.5 and pH 6.8 buffer solutions. 332

333

in vitro quality control dissolution test 334

A dissolution test procedure identified in the pharmacopoeia for routine quality control of 335

product batches, generally a one-time point dissolution test for immediate-release 336

products and a three- or more time points dissolution test for modified-release products. 337

338

multisource pharmaceutical products 339

Pharmaceutically equivalent or pharmaceutically alternative products that may or may 340

not be therapeutically equivalent. Multisource pharmaceutical products that are 341

therapeutically equivalent are interchangeable. 342

343

non-biological (Oxford) 344

Not involving or derived from biology or living organisms. 345

346

pharmaceutical alternatives 347

Products are pharmaceutical alternative(s) if they contain the same active pharmaceutical 348

moiety(s) but differ in dosage form (e.g. tablets versus capsules), strength, and/or 349

chemical form (e.g. different salts, different esters). Pharmaceutical alternatives deliver 350

the same active moiety by the same route of administration but are otherwise not 351

pharmaceutically equivalent. They may or may not be bioequivalent or therapeutically 352

equivalent to the comparator product. 353

354

355

356


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pharmaceutical equivalence 357

Products are pharmaceutical equivalents if they contain the same molar amount of the 358

same active pharmaceutical ingredient(s) (API) in the same dosage form, if they meet 359

comparable standards, and if they are intended to be administered by the same route. 360

Pharmaceutical equivalence does not necessarily imply therapeutic equivalence, as 361

differences in the API solid state properties, the excipients and/or the manufacturing 362

process and some other variables can lead to differences in product performance. 363

364

quantitatively similar amounts (concentrations) of excipients 365

The relative amount of excipient present in two solid oral FPPs is considered to be 366

quantitatively similar if the differences in amount fall within the limits described in the 367

following table. 368

369

Excipient type Percentage difference (w/w) out of

total product (core) weight

Filler 5.0%

Disintegrant

Starch

Other

3.0%

1.0%

Binder 0.5%

Lubricant

Ca or Mg stearate

Other

0.25%

1.0%

Glidant

Talc

Other

1.0%

0.1%

370

If an excipient serves multiple functions (e.g. microcrystalline cellulose as a filler and as 371

a disintegrant), then the most conservative recommended range should be applied (e.g. ± 372

1.0% for microcrystalline cellulose should be applied in this example). 373

374


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The relative concentration of an excipient present in two aqueous solution FPPs is 375

considered to be similar if the difference is ≤ 10%. 376

377

therapeutic equivalence 378

Two pharmaceutical products are considered to be therapeutically equivalent if they are 379

pharmaceutically equivalent or pharmaceutical alternatives and after administration in the 380

same molar dose, their effects, with respect to both efficacy and safety, are essentially the 381

same when administered to patients by the same route under the conditions specified in 382

the labelling. This can be demonstrated by appropriate equivalence studies, such as 383

pharmacokinetic, pharmacodynamic, clinical or in vitro studies. 384

385

3. DOCUMENTATION OF EQUIVALENCE FOR MARKETING AUTHORIZATION 386

387

Multisource pharmaceutical products must be shown, either directly or indirectly, to be 388

therapeutically equivalent to the comparator product if they are to be considered 389

interchangeable. Suitable test methods to assess equivalence are: 390

391

‒ comparative pharmacokinetic studies in humans, in which the active 392

pharmaceutical ingredient (API) and/or its metabolite(s) are measured as a 393

function of time in an accessible biological fluid such as blood, plasma, serum or 394

urine to obtain pharmacokinetic measures, such as AUC and Cmax that are 395

reflective of the systemic exposure; 396

‒ comparative pharmacodynamic studies in humans; 397

‒ comparative clinical trials; 398

‒ comparative in vitro tests. 399

400

The applicability of each of these four methods is discussed below. Detailed information 401

is provided on conducting an assessment of equivalence studies using pharmacokinetic 402

measurements and in vitro methods, which are currently the methods most often used to 403

document equivalence for most orally-administered pharmaceutical products for systemic 404

exposure. 405


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406

Acceptance of any test procedure in the documentation of equivalence between two 407

pharmaceutical products by a NRA depends on many factors, including the 408

characteristics of the API and the pharmaceutical product. Where an API produces 409

measurable concentrations in an accessible biological fluid such as plasma, comparative 410

pharmacokinetic studies can be performed. This type of study is considered to be the gold 411

standard in equivalence testing; however, where appropriate, in vitro testing, e.g. BCS-412

based biowaivers for immediate-release pharmaceutical products can also assure 413

equivalence between the multisource product and the comparator product (see sections 5 414

and 10). Where an API does not produce measurable concentrations in an accessible 415

biological fluid and a BCS-based biowaiver is not an option, comparative 416

pharmacodynamics studies may be an alternative method for documenting equivalence. 417

Further, in certain cases when it is not possible to assess equivalence through other 418

methods, comparative clinical trials may be considered appropriate. 419

420

The criteria that indicate when equivalence studies are necessary are discussed in the 421

following two sections of the guideline. 422

423

4. WHEN EQUIVALENCE STUDIES ARE NOT NECESSARY 424

425

The following types of multisource pharmaceutical product are considered to be 426

equivalent without the need for further documentation: 427

428

(a) when the pharmaceutical product is to be administered parenterally (e.g. 429

intravenously, subcutaneously or intramuscularly) as an aqueous solution 430

containing the same API in the same molar concentration as the comparator product 431

and the same or similar excipients in comparable concentrations as in the 432

comparator product. Certain excipients (e.g. buffer, preservative and antioxidant) 433

may be different provided it can be shown that the change(s) in these excipients 434

would not affect the safety and/or efficacy of the pharmaceutical product. The same 435

principles are applicable for parenteral oily solutions, but in this case the use of the 436


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same oily vehicle is essential. Similarly, for micellar solutions, solutions containing 437

complexing agents or solutions containing co-solvents of the same qualitative and 438

quantitative composition of the functional excipients, is necessary to waive 439

equivalence studies and the change of other excipients should be critically reviewed; 440

441

(b) when pharmaceutically-equivalent products are solutions for oral use (e.g. syrups, 442

elixirs and tinctures), contain the API in the same molar concentration as the 443

comparator product, and contain the same excipients in similar concentrations. 444

445

(c) when pharmaceutically-equivalent products are in the form of powders for 446

reconstitution as an aqueous solution and the resultant solution meets either 447

criterion (a) or criterion (b) above; 448

449

(d) when pharmaceutically-equivalent products are gases; 450

451

(e) when pharmaceutically-equivalent products are otic or ophthalmic products 452

prepared as aqueous solutions and contain the same API(s) in the same molar 453

concentration and the same excipients in similar concentrations. Certain excipients 454

(e.g. preservative, buffer, substance to adjust tonicity or thickening agent) may be 455

different provided their use is not expected to affect bioavailability, safety and/or 456

efficacy of the product; 457

458

(f) when pharmaceutically-equivalent products are topical products prepared as 459

aqueous solutions and contain the same API(s) in the same molar concentration and 460

the same excipients in similar concentrations (note that this waiver does not apply 461

to other topical dosage forms like gels, emulsions or suspensions, but might be 462

applicable to oily solutions if the vehicle composition is sufficiently similar); 463

464

(g) when pharmaceutically-equivalent products are aqueous solutions for nebulization 465

or nasal drops, intended to be administered with essentially the same device, 466

contain the same API(s) in the same concentration and contain the same excipients 467


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in similar concentrations (note that this waiver does not apply to other dosage forms 468

like suspensions for nebulization, nasal drops where the API is in suspension, nasal 469

sprays in solution or suspension, dry powder inhalers, or pressurized metered dose 470

inhalers in solution or suspensions). The pharmaceutical product may include 471

different excipients provided their use is not expected to affect bioavailability, 472

safety and/or efficacy of the product. 473

474

For situations (b), (c), (e), (f) and (g) above, it is incumbent upon the applicant to 475

demonstrate that the excipients in the pharmaceutically-equivalent product are the same 476

and in concentrations similar to those in the comparator product or, where applicable (i.e. 477

(e) and (g)), that their use is not expected to affect the bioavailability, safety and/or 478

efficacy of the product. In the event that the applicant cannot provide this information 479

and the NRA does not have access to the relevant data, it is incumbent upon the applicant 480

to perform appropriate studies to demonstrate that differences in excipients or devices do 481

not affect product performance. 482

483

5. WHEN IN VIVO EQUIVALENCE STUDIES ARE NECESSARY AND 484

TYPES OF STUDY REQUIRED 485

486

Except for the cases discussed in section 4, these guidelines recommend that 487

documentation of equivalence with the comparator product be required by registration 488

authorities for a multisource pharmaceutical product. Studies must be carried out using 489

the product intended for marketing (see also section 7.3). 490

491

5.1 In vivo studies 492

493

For certain APIs and dosage forms in vivo documentation of equivalence, through either 494

a pharmacokinetic comparative bioavailability (bioequivalence) study, a comparative 495

pharmacodynamic study or a comparative clinical trial, is regarded as especially 496

important. In vivo documentation of equivalence is necessary when there is a risk that 497


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possible differences in bioavailability may result in therapeutic inequivalence (2). 498

Examples are listed below. 499

500

(a) Oral, immediate-release pharmaceutical products with systemic action, except for 501

the conditions outlined in section 10. 502

503

(b) Non-oral, non-parenteral pharmaceutical products designed to act systemically 504

(such as transdermal patches, suppositories, nicotine chewing gum, testosterone gel 505

and skin-inserted contraceptives). 506

507

(c) Modified-release pharmaceutical products designed to act systemically, except for 508

the conditions outlined in section 10. 509

510

(d) Fixed-dose combination (FDC)products with systemic action, where at least one of 511

the APIs requires an in vivo study (3). 512

513

(e) Non-solution pharmaceutical products, which are for non-systemic use (e.g. for oral, 514

nasal, ocular, dermal, rectal or vaginal application) and are intended to act without 515

systemic absorption. In these cases, the equivalence is established through, e.g. 516

comparative clinical or pharmacodynamic studies, local availability studies and/or 517

in vitro studies. In certain cases, measurement of the concentration of the API may 518

still be required for safety reasons, i.e. in order to assess unintended systemic 519

absorption. 520

521

5.2 In vitro studies 522

523

For certain APIs and dosage forms, in vitro documentation of equivalence may be 524

appropriate. In vitro approaches for systemically-acting oral products are discussed in 525

section 10. 526

527

6. IN VIVO EQUIVALENCE STUDIES IN HUMANS 528


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529

6.1 General considerations 530

531

6.1.1 Provisions for studies in humans 532

533

Pharmacokinetic, pharmacodynamic and clinical studies are clinical trials and should 534

therefore be carried out in accordance with the provision and prerequisites for a clinical 535

trial, as outlined in the World Health Organization (WHO) guidelines for good clinical 536

practice (GCP) for trials on pharmaceutical products (4). Additional guidance for 537

organizations performing in vivo equivalence studies is available from WHO (5). 538

539

All research involving human subjects should be conducted in accordance with the 540

ethical principles contained in the most recent version of the Declaration of Helsinki, 541

including respect for persons, beneficence (“maximize benefits and minimize harms and 542

wrongs”) and non-maleficence (“do no harm”). 543

544

As defined by the International Ethical Guidelines for Biomedical Research Involving 545

Human Subjects issued by the Council for International Organizations of Medical 546

Sciences (CIOMS), or laws and regulations of the country in which the research is 547

conducted, whichever represents the greater protection for subjects. 548

549

6.1.2 Justification of human bioequivalence studies 550

551

Most pharmacokinetic and pharmacodynamic equivalence studies are non-therapeutic 552

studies in which no direct clinical benefit accrues to the subject. 553

554

It is important for anyone preparing a trial of a medicinal product in humans that the 555

specific aims, problems and risks or benefits of the proposed human study be thoroughly 556

considered and that the chosen design be scientifically sound and ethically justified. It is 557

assumed that people involved in the planning of a study are familiar with 558

pharmacokinetic theories underlying bioavailability and bioequivalence studies. The 559


page 21

overall design of the bioequivalence study should be based on the knowledge of the 560

pharmacokinetics, pharmacodynamics and therapeutics of the API. Information about 561

manufacturing procedures and data from tests performed on the product batch to be used 562

in the study should establish that the product under investigation is of suitable quality. 563

564

6.1.3 Selection of investigators 565

566

The investigator(s) should have the appropriate expertise, qualifications and competence 567

to undertake the proposed study. Prior to the trial the investigator(s) and the sponsor 568

should draw up an agreement on the protocol, monitoring, auditing, standard operating 569

procedures (SOP) and the allocation of trial-related responsibilities. The identity and 570

duties of the individuals responsible for the study and safety of the subjects participating 571

in the study must be specified. The logistics and premises of the trial site should comply 572

with requirements for the safe and efficient conduct of the trial. 573

574

6.1.4 Study protocol 575

576

A bioequivalence study should be carried out in accordance with a protocol agreed upon 577

and signed by the investigator and the sponsor. The protocol and its attachments and/or 578

appendices should state the aim of the study and the procedures to be used, the reasons 579

for proposing the study to be undertaken in humans, the nature and degree of any known 580

risks, assessment methodology, criteria for acceptance of bioequivalence, the groups 581

from which it is proposed that trial subjects be selected and the means for ensuring that 582

they are adequately informed before they give their consent. The investigator is 583

responsible for ensuring that the protocol is strictly followed. Any change(s) required 584

must be agreed on and signed by the investigator and sponsor and appended as 585

amendments, except when necessary to eliminate an apparent immediate hazard or 586

danger to a trial subject. 587

588

The protocol and attachments/appendices should be scientifically and ethically appraised 589

by one or, if required by local laws and regulations, more review bodies, e.g. institutional 590


page 22

review board, peer review committee, ethics committee, NRA, constituted appropriately 591

for these purposes and independent of the investigator(s) and sponsor. 592

593

The signed and dated study protocol should be approved by the NRA before commencing 594

the study, if required by national and regional laws and regulations. The study report 595

forms the integral part of the registration dossier of the multisource product in order to 596

obtain the marketing authorization for the multisource product. 597

598

7. PHARMACOKINETIC COMPARATIVE BIOAVAILABILITY 599

(BIOEQUIVALENCE) STUDIES IN HUMANS 600

601

7.1 Design of pharmacokinetic studies 602

603

Bioequivalence studies are designed to compare the in vivo performance of a multisource 604

product with that of a comparator product. Such studies on products designed to deliver 605

the API for systemic exposure serve two purposes: 606

607

• as a surrogate for clinical evidence of the safety and efficacy of the multisource 608

product; 609

• as an in vivo measure of pharmaceutical quality. 610

611

The design of the study should maximize the sensitivity to detect difference between 612

products, minimize the variability that is not caused by formulation effects and eliminate 613

bias as far as possible. Test conditions should reduce variability within and between 614

subjects. In general, for a bioequivalence study involving a multisource product and a 615

comparator product, a randomized, two-period, two-sequence, single-dose, cross-over 616

study conducted with healthy volunteers is the preferred study design. In this design each 617

subject is given the multisource and the comparator product in randomized order. An 618

adequate wash-out period should follow the administration of each product. 619

620


page 23

It should be noted however that under certain circumstances an alternative, well-621

established and statistically-appropriate study design may be more appropriate. 622

623

7.1.1 Alternative study designs for studies in patients 624

625

For APIs that are very potent or too toxic to administer in the highest strength to healthy 626

volunteers (e.g. because of the potential for serious adverse events, or the trial 627

necessitates a high dose), it is recommended that the study be conducted using the API at 628

a lower strength in healthy volunteers. For APIs that show unacceptable pharmacological 629

effects in healthy volunteers, even at lower strengths, a study conducted in patients may 630

be required. Depending on the dosing posology, this may be a multiple dose, steady state 631

study. As above, such studies should employ a cross-over design if possible; however, a 632

parallel group-design study in patients may be required in some situations.The use of 633

such an alternative study design should be fully justified by the sponsor and should 634

include patients whose disease process is stable for the duration of the bioequivalence 635

study if possible. 636

637

7.1.2 Considerations for active pharmaceutical ingredients with long elimination half- 638

lives 639

640

A single-dose, cross-over bioequivalence study of an orally-administered product with a 641

long elimination half-life is preferred, provided an adequate wash-out period between 642

administrations of the treatments is possible. The interval between study days should be 643

long enough to permit elimination of essentially all of the previous dose from the body. 644

Ideally the interval should not be less than five terminal elimination half-lives of the 645

active compound or metabolite, if the latter is measured. If the cross-over study is 646

problematic due to a very long elimination half-life, a bioequivalence study with a 647

parallel design may be more appropriate. A parallel design may also be necessary when 648

comparing some depot formulations. 649

650


page 24

For both cross-over and parallel-design studies of oral products, sample collection time 651

should be adequate to ensure completion of GI transit (approximately 2–3 days) of the 652

pharmaceutical product and absorption of the API. Blood sampling should be conducted 653

for up to 72 hours following administration but sampling beyond this time is not 654

generally necessary. 655

656

The number of subjects should be derived from statistical calculations but generally more 657

subjects are needed for a parallel study design than for a cross-over study design. 658

659

7.1.3 Considerations for multiple-dose studies 660

661

In certain situations multiple-dose studies may be considered appropriate. 662

Multiple-dose studies in patients are most useful in cases where the API being studied is 663

considered to be too potent and/or too toxic to be administered to healthy volunteers, 664

even in single doses (see also 7.1.1). In this case, a multiple-dose, cross-over study in 665

patients may be performed without interrupting therapy. 666

667

The dosage regimen used in multiple-dose studies should follow the usual dosage 668

recommendations. 669

670

Other situations in which multiple-dose studies may be appropriate are as follows: 671

672

‒ cases where the analytical sensitivity is too low to adequately characterize the 673

pharmacokinetic profile after a single dose; 674

‒ extended-release dosage forms with a tendency to accumulate (in addition to 675

single-dose studies). 676

677

In steady-state studies the wash-out of the last dose of the previous treatment can overlap 678

with the approach to steady state of the second treatment, provided the approach period is 679

sufficiently long (at least five times the terminal half-life). Appropriate dosage 680


page 25

administration and sampling should be carried out to document for the attainment of a 681

steady state. 682

683

7.1.4 Considerations for modified-release products 684

685

Modified-release products include extended-release products and delayed-release 686

products. Extended-release products are variously known as controlled-release, 687

prolonged-release and sustained-release products. 688

689

Due to the more complex nature of modified-release products relative to immediate-690

release products, additional data is required to ensure the bioequivalence of two 691

modified-release products. Factors such as the co-administration of food, which 692

influences API bioavailability and also, in certain cases, bioequivalence, must be taken 693

into consideration. The presence of food can affect product performance both by 694

influencing the release of the API from the formulation and by causing physiological 695

changes in the GI tract. In this regard a significant concern with regard to modified-696

release products is the possibility that food may trigger a sudden and abrupt release of the 697

API leading to “dose dumping”. This would most likely be manifested as a premature and 698

abrupt rise in the plasma concentration time profile. Therefore, bioequivalence studies 699

conducted under both fasted and fed conditions are required for orally-administered, 700

modified-release pharmaceutical products. 701

702

Unless single-dose studies are not possible for reasons such as those discussed above in 703

section 7.1.1 single-dose, cross-over bioequivalence studies conducted under both fasted 704

and fed conditions comparing the highest strength of the multisource product and the 705

comparator product must be performed to demonstrate bioequivalence. Single-dose 706

studies are preferred to multiple-dose studies as single-dose studies are considered to 707

provide more sensitive measurement of the release of API from the pharmaceutical 708

product into the systemic circulation. In addition to single-dose studies, multiple-dose 709

studies may be considered for extended-release dosage forms with a tendency to 710


page 26

accumulate, e.g. after a single dose of the highest strength the AUC for the dosing 711

interval covers <90% of AUC extrapolated to infinity. 712

713

The comparator product in these studies should be a pharmaceutically-equivalent, 714

modified-release product. The bioequivalence criteria for modified-release products are 715

essentially the same as for conventional-release dosage forms except acceptance criteria 716

should also be applied to Cmin (Ctau) in case of multiple dose studies. As release 717

mechanisms of pharmaceutical products become more complex, e.g. products with an 718

immediate-release and modified-release component, additional parameters such as partial 719

AUC measures may be necessary to ensure the bioequivalence of two products. 720

721

The fed-state bioequivalence study should be conducted after the administration of an 722

appropriate standardized meal at a specified time (usually not more than 30 minutes) 723

before taking the pharmaceutical product. A meal that will promote the greatest change in 724

GI tract conditions relative to the fasted state should be employed. Refer to section 7.4.3 725

for more recommendations for the content of the meal. The composition of the meal 726

should take local diet and customs into consideration. The composition and caloric 727

breakdown of the test meal should be provided in the study protocol and report. 728

729

7.2 Subjects 730

731

7.2.1 Number of subjects 732

733

The number of subjects required for a bioequivalence study is determined by: 734

735

‒ the error variance (coefficient of variation) associated with the primary 736

parameters to be studied, as estimated from a pilot experiment, from previous 737

studies or from published data; 738

‒ the significance level desired (5%); 739

‒ the statistical power desired; 740


page 27

‒ the mean deviation from the comparator product compatible with bioequivalence 741

and with safety and efficacy; 742

‒ the need for the 90% confidence interval around the geometric mean ratio to be 743

within bioequivalence limits, normally 80–125%, for log-transformed data. 744

745

The number of subjects to be recruited for the study should be estimated by considering 746

the standards that must be met using an appropriate method (see, for example, Julious 747

2004 (6)). In addition, an extra number of subjects should be recruited, dosed and their 748

samples analysed based on the expected rate of drop-outs and/or withdrawals, which 749

depends on the safety and tolerability profile of the API. The number of subjects 750

recruited should always be justified by the sample-size calculation provided in the study 751

protocol. A minimum of 12 subjects is required. 752

753

In some situations reliable information concerning the expected variability in the 754

parameters to be estimated may not be available. In such situations, a two-stage 755

sequential study design can be employed as an alternative to conducting a pilot study. 756

Refer to section 7.6.1 for more information. 757

758

7.2.2 Drop-outs and withdrawals 759

760

Sponsors should select a sufficient number of study subjects to allow for possible drop-761

outs or withdrawals. Because replacement of subjects during the study could complicate 762

the statistical model and analysis, drop-outs generally should not be replaced. Reasons for 763

withdrawal (e.g. adverse reaction or personal reasons) must be reported. If a subject is 764

withdrawn due to an adverse event after receiving at least one dose of the study 765

medication, the subject’s plasma/serum concentration data should be provided. 766

767

The concentration-time profiles of subjects who exhibit pre-dose concentrations higher 768

than 5% of the corresponding Cmax should be excluded from the statistical analysis. The 769

concentration-time profiles of subjects who exhibit pre-dose concentrations equal to or 770


page 28

less than 5% of the corresponding Cmax should be included in the statistical analysis 771

without correction. 772

773

7.2.3 Exclusion of subject data 774

775

Extreme values can have a significant impact on bioequivalence study data because of the 776

relatively small number of subjects typically involved; however, it is rarely acceptable to 777

exclude data. Potential reasons for excluding subject data and the procedure to be 778

followed should be included in the study protocol. Exclusion of data for statistical or 779

pharmacokinetic reasons alone is not acceptable. Retesting of subjects is not 780

recommended. 781

782

7.2.4 Selection of subjects 783

784

Bioequivalence studies should generally be performed with healthy volunteers. Clear 785

criteria for inclusion and exclusion should be stated a priori in the study protocol. If the 786

pharmaceutical product is intended for use in both sexes, the sponsor should include both 787

males and females in the study. The potential risk to women will need to be considered 788

on an individual basis and, if necessary, they should be warned of any possible dangers to 789

the foetus if they should become pregnant. The investigators should ensure that female 790

volunteers are not pregnant or likely to become pregnant during the study. Confirmation 791

should be obtained by urine tests just before administration of the first and last doses of 792

the product under study. 793

794

Generally subjects should be between the ages of 18 and 55 years, and their weight 795

should be within the normal range with a Body Mass Index (BMI) between 18 and 30 796

kg/m2. The subjects should have no history of alcohol or drug-abuse problems and should 797

preferably be non-smokers. 798

799

The volunteers should be screened for their suitability using standard laboratory tests, a 800

medical history and a physical examination. If necessary, special medical investigations 801


page 29

may be carried out before and during studies depending on the pharmacology of the 802

individual API being investigated, e.g. an electrocardiogram if the API has a cardiac 803

effect. The ability of the volunteers to understand and comply with the study protocol has 804

to be assessed. Subjects who are being or have previously been treated for any GI 805

problems, or convulsive, depressive or hepatic disorders, and in whom there is a risk of a 806

recurrence during the study period, should be excluded. 807

808

If a parallel design-study is planned standardization of the two groups of subjects is 809

important in order to minimize variation not attributable to the investigational products 810

(see 7.2.6.). 811

812

If the aim of the bioequivalence study is to address specific questions (e.g. 813

bioequivalence in a special population) the selection criteria should be adjusted 814

accordingly. 815

816

7.2.5 Monitoring the health of subjects during the study 817

818

In keeping with GCP (4), the health of volunteers should be monitored during the study 819

so that onset of side-effects, toxicity or any intercurrent disease may be recorded and 820

appropriate measures taken. The incidence, severity and duration of any adverse reactions 821

and side-effects observed during the study must be reported. The probability that an 822

adverse effect is API-induced is to be judged by the investigator. 823

824

Health-monitoring before, during and after the study must be carried out under the 825

supervision of a qualified medical practitioner licensed in the jurisdiction in which the 826

study is conducted. 827

828

7.2.6 Considerations for genetic phenotyping 829

830

Phenotyping for metabolizing activity can be of importance for studies with high-831

clearance APIs that are metabolized by enzymes that are subject to genetic polymorphism, 832


page 30

e.g. propranolol. In such cases slow metabolizers will have a higher bioavailability of the 833

active parent moiety while the bioavailability of possible active metabolites will be lower. 834

Phenotyping of subjects can be considered for studies of APIs that show phenotype-835

linked metabolism and for which a parallel group design is to be used, because it allows 836

fast and slow metabolizers to be evenly distributed between the two groups of subjects. 837

838

Phenotyping could also be important for safety reasons, determination of sampling times 839

and wash-out periods in cross-over design studies. 840

841

842

7.3 Investigational product 843

844

7.3.1 Multisource pharmaceutical product 845

846

The multisource pharmaceutical product used in the bioequivalence studies for 847

registration purposes should be identical to the projected commercial pharmaceutical 848

product. Therefore, not only the composition and quality characteristics (including 849

stability), but also the manufacturing methods (including equipment and procedures) 850

should be the same as those to be used in the future routine production runs. Test 851

products must be manufactured under GMP regulations. Batch-control results, lot number, 852

manufacturing date and, if possible, expiry date for the multisource product should be 853

stated. 854

855

Samples should ideally be taken from batches of industrial scale. When this is not 856

feasible pilot or small-scale production batches may be used, provided that they are not 857

smaller than 10% of expected full production batches, or 100 000 units, whichever is 858

larger, and are produced with the same formulation and similar equipment and process as 859

that planned for commercial production batches. A biobatch of less than 100 000 units 860

may be accepted on provision that this is the proposed production batch size, with the 861

understanding that future scale up for production batches will not be accepted. 862

863


page 31

It is recommended that potency and in vitro dissolution characteristics of the multisource 864

and the comparator pharmaceutical products be ascertained prior to performance of an 865

equivalence study. Content of the API(s) of the comparator product should be close to the 866

label claim and the difference between two products being compared should not be more 867

than ± 5%. If, because of the lack of availability of different batches of the comparator 868

product, it is not possible to study batches with potencies within ± 5%, potency correction 869

may be required on the statistical results from the bioequivalence study. 870

871

7.3.2 Choice of comparator product 872

873

The innovator pharmaceutical product is usually the most logical comparator product for 874

a multisource pharmaceutical product because its quality, safety and efficacy should have 875

been well assessed and documented in premarketing studies and postmarketing 876

monitoring schemes. Preferably this will mean employing the innovator product available 877

on the market when studying multisource products for national and regional approval. 878

There will be situations, however, where this is not feasible. Detailed guidance for the 879

selection of comparator products for use in national and regional applications is provided 880

in the comparator guidance (7). 881

882

7.4 Study conduct 883

884

7.4.1 Selection of strength 885

886

In bioequivalence studies the molar equivalent dose of multisource and comparator 887

product must be used. 888

889

For a series of strengths that can be considered proportionally formulated (see section 890

10.3), the strength with the greatest sensitivity for bioequivalence assessment should be 891

administered as a single unit. This will usually be the highest marketed strength. A higher 892

dose, i.e. more than one dosage unit, may be employed when analytical difficulties exist. 893

In this case the total single dose should not exceed the maximal daily dose of the dosage 894


page 32

regimen. In certain cases a study performed with a lower strength can be considered 895

acceptable if this lower strength is chosen for reasons of safety or if the API is highly 896

soluble and its pharmacokinetics are linear over the therapeutic range. 897

898

7.4.1.1 Non-linear pharmacokinetics 899

900

When the API in a series of strengths, that are considered proportionally formulated, 901

exhibits non-linear pharmacokinetics over the range of strengths, special consideration is 902

necessary when selecting the strength for study. 903

904

For APIs exhibiting non-linear pharmacokinetics within the range of strengths resulting 905

in greater than proportional increases in AUC with increasing dose, the comparative 906

bioavailability study should be conducted on at least the highest marketed strength. 907

908

For APIs with non-linear pharmacokinetics within the range of strengths due to saturable 909

absorption and resulting in less than proportional increases in AUC with increasing dose, 910

the bioequivalence study should be conducted on at least the lowest strength (or a 911

strength in the linear range). 912

913

For APIs with non-linear pharmacokinetics within the range of strengths due to limited 914

solubility of the API and resulting in less than proportional increases in AUC with 915

increasing dose, bioequivalence studies should be conducted on at least the lowest 916

strength (or a strength in the linear range) and the highest strength. 917

918

7.4.2 Study standardization 919

920

Standardization of study conditions is important to minimize the magnitude of variability 921

other than in the pharmaceutical products. Standardization between study periods is 922

critical to a successful study. Standardization should cover exercise, diet, fluid intake, 923

posture, as well as the restriction of the intake of alcohol, caffeine, certain fruit juices and 924

concomitant medicines for a specified time period before and during the study. 925


page 33

926

Volunteers should not take any other medicine, alcoholic beverages or over-the-counter 927

(OTC) medicines and supplements for an appropriate interval before or during the study. 928

In the event of emergency the use of any non-study medicine must be reported (dose and 929

time of administration). 930

931

Physical activity and posture should be standardized as far as possible to limit their 932

effects on GI blood flow and motility. The same pattern of posture and activity should be 933

maintained for each day of the study. The time of day at which the study product is to be 934

administered should be specified. 935

936

7.4.3 Co-administration of food and fluid with the dose 937

938

Finished pharmaceutical products (FPPs) are usually given after an overnight fast of at 939

least 10 hours and participants are allowed free access to water. On the morning of the 940

study no water is allowed during the hour prior to FPP administration. The dose should 941

be taken with a standard volume of water (usually 150–250 ml). Two hours after FPP 942

administration water is again permitted ad libitum. A standard meal is usually provided 943

four hours after FPP administration. All meals should be standardized and the 944

composition stated in the study protocol and report. 945

946

There are situations when the investigational products should be administered following 947

consumption of a meal (under fed conditions). These situations are described below. 948

949

7.4.3.1 Immediate-release formulations 950

951

Fasted-state studies are generally preferred. However, when the product is known to 952

cause GI disturbances if given to subjects in the fasted state, or if the labelling of the 953

comparator product restricts administration to subjects in the fed state, then the fed-state 954

study becomes the preferred approach. 955

956


page 34

For products with specific formulation characteristics (e.g. micro-emulsions, solid 957

dispersions), bioequivalence studies performed under both fasted and fed conditions are 958

required, unless the product taken is only in a fasted or fed state. 959

960

Typically a meal meeting the composition recommendations identified below in section 961

7.4.3.2 should be employed in fed-state studies. The exact composition of the meal may 962

depend on local diet and customs as determined by the NRA. For studies conducted with 963

immediate-release products, there may be situations where it is appropriate to employ a 964

pre-dose meal with a different caloric/fat content. 965

966

The test meal should be consumed beginning 30 minutes prior to administration of the FPP. 967

968

7.4.3.2 Modified-release formulations 969

970

In addition to a study conducted under fasted conditions, food-effect studies are 971

necessary for all multisource modified-release formulations to ensure that the interaction 972

between the varying conditions in the GI tract and the product formulations does not 973

differentially impact the performance of the multisource and comparator products. The 974

presence of food can affect product performance both by influencing the release of the 975

API from the formulation and by causing physiological changes in the GI tract. A 976

significant concern with regard to modified-release products is the possibility that food 977

may trigger a sudden and abrupt release of the API leading to “dose dumping”. 978

979

In these cases the objective is to select a meal that will challenge the robustness of the 980

new multisource formulation to prandial effects on bioavailability. To achieve this a meal 981

that will provide a maximal perturbation to the GI tract relative to the fasted state should 982

be employed, e.g. a high-fat (approximately 50% of the total caloric content of the meal), 983

high-calorie (approximately 800 to 1000 kilocalories) test meal has been recommended 984

(FDA, EMA guidelines referenced). The meal selected should take into account local 985

customs and diet. The caloric breakdown of the test meal should be provided in the study 986

report. 987


page 35

988

The test meal should be consumed within a 30-minute interval prior to administration of 989

the FPP. 990

991

7.4.4 Wash-out interval 992

993

The interval (wash-out period) between doses of each formulation should be long enough 994

to permit the elimination of essentially all of the previous dose from the body. The wash-995

out period should be the same for all subjects and should normally be more than five 996

times the median terminal half-life of the API. Consideration should be given to 997

extending this period in some situations, e.g. if active metabolites with longer half-lives 998

are produced or if the elimination rate of the API has high variability between subjects. In 999

this second case a longer wash-out period should be considered to allow for the slower 1000

elimination in subjects with lower elimination rates. Just prior to administration of the 1001

treatment during the second study period, blood samples are collected and assayed to 1002

determine the concentration of the API or metabolites. The minimum wash-out period 1003

should be at least seven days unless a shorter period is justified by a short half-life. The 1004

adequacy of the wash-out period can be estimated from the pre-dose concentrations of the 1005

API in the second study period which should be less than 5% of the observed Cmax. 1006

1007

7.4.5 Sampling times 1008

1009

Blood samples should be taken at a frequency sufficient for assessing Cmax, AUC and 1010

other parameters. Sampling points should include a pre-dose sample, at least 1–2 points 1011

before Cmax, 2 points around Cmax and 3–4 points during the elimination phase. 1012

Consequently at least seven sampling points will be necessary for estimation of the 1013

required pharmacokinetic parameters. 1014

1015

For most APIs the number of samples necessary will be higher to compensate for 1016

between-subject differences in absorption and elimination rate and thus enable accurate 1017

determination of the maximum concentration of the API in the blood (Cmax) and 1018


page 36

terminal elimination rate constant in all subjects. Generally sampling should continue for 1019

long enough to ensure that 80% of the AUC (0→infinity) can be accrued, but it is not 1020

necessary to sample for more than 72 hours. The exact duration of sample collection 1021

depends on the nature of the API and the input function from the administered dosage 1022

form. 1023

1024

7.4.6 Sample fluids and their collection 1025

1026

Under normal circumstances blood should be the biological fluid sampled to measure the 1027

concentrations of the API. In most cases the API or its metabolites are measured in serum 1028

or plasma. If it is not possible to measure the API in blood/plasma/serum, the API is 1029

excreted unchanged in the urine and there is a proportional relationship between plasma 1030

and urine concentrations; urine can be sampled for the purpose of estimating exposure. 1031

The volume of each sample must be measured at the study centre, where possible 1032

immediately after collection and included in the report. The number of samples should be 1033

sufficient to allow the estimation of pharmacokinetic parameters. However, in most cases 1034

the exclusive use of urine excretion data should be avoided as this does not allow 1035

estimation of the tmax and the maximum concentration. Blood/plasma/serum/urine 1036

samples should be processed and stored under conditions that have been shown not to 1037

cause degradation of the analytes. These conditions should be included in the analytical 1038

validation report (see section 7.5). 1039

1040

The sample collection methodology must be specified in the study protocol. 1041

1042

7.4.7 Parameters to be assessed 1043

1044

In bioavailability studies the shape and area under the plasma concentration versus time 1045

curves are mostly used to assess rate (Cmax, tmax) and extent (AUC) of exposure. 1046

Sampling points or periods should be chosen such that the concentration versus time 1047

profile is sufficiently defined to allow calculation of relevant parameters. For single-dose 1048

studies, the following parameters should be measured or calculated: 1049


page 37

1050

• area under the plasma/serum/blood concentration–time curve from time zero to 1051

time t (AUC0–t), where t is the last sampling time point with a measurable 1052

concentration of the API in the individual formulation tested. The method of 1053

calculating AUC values should be specified. Non-compartmental methods should 1054

be used for pharmacokinetic calculations in bioequivalence studies; 1055

• Cmax is the maximum or peak concentration observed representing peak exposure 1056

of API (or metabolite) in plasma, serum or whole blood. 1057

1058

Usually AUC0–t and Cmax are considered to be the most relevant parameters for 1059

assessment of bioequivalence. In addition it is recommended that the following 1060

parameters be estimated: 1061

1062

• area under the plasma/serum/blood concentration–time curve from time zero to 1063

time infinity (AUC0-∞) representing total exposure, where AUC0-∞ = AUC0–t + 1064

Clast/Ke; Clast is the last measurable analyte concentration and Ke is the terminal 1065

or elimination rate constant calculated according to an appropriate method; 1066

• tmax is the time after administration of the FPP at which Cmax is observed. 1067

1068

For additional information the elimination parameters can be calculated: 1069

1070

• T1/2 is the plasma (serum, whole blood) half-life. 1071

1072

For steady-state studies conducted with modified-release products, the following 1073

parameters should be calculated: 1074

1075

• AUCτ is AUC over one dosing interval (τ) at steady state; 1076

• Cmax; 1077

• Cmin (Ctau) is concentration at the end of a dosing interval; 1078

• peak trough fluctuation is percentage difference between Cmax and Cmin. 1079

1080


page 38

As release mechanisms of pharmaceutical products become more complex, e.g. products 1081

with an immediate-release and a modified-release component, additional parameters such 1082

as partial AUC measures may be necessary to ensure the bioequivalence of two products. 1083

1084

When urine samples are used cumulative urinary recovery (Ae) and maximum urinary 1085

excretion rate are employed instead of AUC and Cmax. 1086

1087

7.4.8 Studies of metabolites 1088

1089

Generally evaluation of bioequivalence will be based on the measured concentrations of 1090

the active parent moiety released from the dosage form rather than the metabolite. The 1091

concentration–time profile of the active parent moiety is more sensitive to changes in 1092

formulation performance than a metabolite, which is more reflective of metabolite 1093

formation, distribution and elimination. 1094

1095

It is important to state a priori in the study protocol which chemical entities (pro-drug, 1096

active moiety or metabolite) will be analysed in the samples. 1097

1098

In rare cases it may be necessary to measure concentrations of a primary active 1099

metabolite rather than those of the active parent moiety if concentrations of the active 1100

parent moiety are too low to allow reliable analytical measurement in blood, plasma or 1101

serum for an adequate length of time, or when the parent compound is unstable in the 1102

biological matrix. 1103

1104

It is important to note that measurement of one analyte, API or metabolite, carries the risk 1105

of making a type-I error (the consumer risk) to remain at the 5% level. However, if more 1106

than one of several analytes is selected retrospectively as the bioequivalence determinant, 1107

then both the consumer and producer risks change (8). The analyte whose data will be 1108

used to assess bioequivalence cannot be changed retrospectively. 1109

1110


page 39

When measuring active metabolites, wash-out period and sampling times may need to be 1111

adjusted to enable adequate characterization of the pharmacokinetic profile of the 1112

metabolite. 1113

1114

7.4.9 Measurement of individual enantiomers 1115

1116

A non-stereoselective assay is acceptable for most bioequivalence studies. A 1117

stereospecific assay measuring the individual enantiomers should be employed when the 1118

enantiomers exhibit different pharmacokinetic properties, different pharmacodynamic 1119

properties and the exposure of the enantiomers, as estimated by their AUC ratio or Cmax 1120

ratio, changes when there is a change in the rate of absorption. 1121

1122

7.5 Quantification of active pharmaceutical ingredient 1123

1124

For the measurement of concentrations of the active compound and/or metabolites in 1125

biological matrices, such as serum, plasma, blood, urine and saliva, the applied 1126

bioanalytical method should be well-characterized, fully validated and documented to a 1127

satisfactory standard in order to yield reliable results. 1128

1129

The validation of bioanalytical methods and the analysis of subject samples for clinical 1130

trials in humans should be performed following the principles of good clinical practices 1131

(GCP). 1132

1133

State of the art principles and procedures for bioanalytical method validation and analysis 1134

of study samples should be employed. 1135

1136

The main characteristics of a bioanalytical method that are essential to ensure the 1137

acceptability of the performance and the reliability of analytical results are: selectivity; 1138

lower limit of quantification; the response function and calibration range (calibration 1139

curve performance); accuracy; precision; matrix effects; stability of the analyte(s) in the 1140

biological matrix; stability of the analyte(s) and of the internal standard in the stock and 1141


page 40

working solutions, and in extracts under the entire period of storage and processing 1142

conditions. 1143

1144

In general: 1145

1146

• the analytical method should be able to differentiate the analyte(s) of interest, and 1147

if employed, the internal standard (IS) from endogenous components in the matrix 1148

or other components in the sample; 1149

• the lower limit of quantification (LLOQ), being the lowest concentration of 1150

analyte in a sample, should be estimated to prove that the analyte at this 1151

concentration can be quantified reliably, with an acceptable accuracy and 1152

precision; 1153

1154

• the response of the instrument with regard to the concentration of analyte should 1155

be known and should be evaluated over a specified concentration range. The 1156

calibration curve should be prepared in the same matrix as the matrix of the 1157

intended subject samples by spiking the blank matrix with known concentrations 1158

of the analyte. A calibration curve should consist of a blank sample, a zero sample 1159

and 6–8 non-zero samples covering the expected range; 1160

• within-run and between-run accuracy and precision should be assessed on 1161

samples spiked with known amounts of the analyte, the quality control (QC) 1162

samples, at a minimum of three different concentrations; 1163

• matrix effects should be investigated when using mass spectrometric methods; 1164

• stability of the analyte in the stock solution and in the matrix should be proven 1165

covering every step taken during sample preparation and sample analysis, as well 1166

as the storage conditions used; 1167

• when more than one analyte is present in subject samples, it is recommended to 1168

demonstrate the stability of the analytes in the matrix in the presence of the other 1169

analytes; 1170


page 41

• in case changes are made to an analytical method that has already been validated, 1171

a full validation may not be necessary, depending on the nature of the changes 1172

implemented. A partial validation may be acceptable; 1173

• a cross-validation is needed in cases where data are obtained from different 1174

methods within and across studies or when data are obtained within a study from 1175

different laboratories, applying the same method; 1176

• analysis of subject samples should be carried out after validation of the analytical 1177

method. Before the start of the analysis of the subject samples the performance of 1178

the bioanalytical method should have been verified; 1179

• reasons for reanalysis, reinjection and reintegration of subject samples should be 1180

predefined in the protocol, study plan or SOP. Re-injection of a full analytical run 1181

or of individual calibration standard samples or QC samples, simply because the 1182

calibration or QCs failed, without any identified analytical cause, is considered 1183

not acceptable For bioequivalence studies, reanalysis, reinjection or reintegration 1184

of subject samples for reasons related to pharmacokinetic fit is normally not 1185

acceptable, as this may affect and bias the outcome of such a study; 1186

• it is recommended to evaluate accuracy of incurred samples by reanalysis of 1187

subject samples in separate runs at different days; 1188

• it is recommended that all the samples from one subject (all periods) should be 1189

analysed in the same analytical run, if possible. 1190

1191

Validation procedures, methodology and acceptance criteria should be specified in the 1192

analytical protocol and/or the SOP. All experiments used to support claims or draw 1193

conclusions about the validity of the method should be described in a report (method 1194

validation report). 1195

1196

The results of subject sample determination should be given in the analytical report 1197

together with calibration and quality control sample results, repeat analyses, reinjections 1198

and reintegrations (if any) and a representative number of sample chromatograms. 1199

1200

1201


page 42

7.6 Statistical analysis 1202

1203

The primary concern in bioequivalence assessment is to limit the risk of a false 1204

declaration of equivalence. Statistical analysis of the bioequivalence trial should 1205

demonstrate that a clinically significant difference in bioavailability between the 1206

multisource product and the comparator product is unlikely. The statistical procedures 1207

should be specified in the protocol before the data collection starts. 1208

1209

The statistical method for testing bioequivalence is based on the determination of the 90% 1210

confidence interval around the ratio of the log-transformed population means 1211

(multisource/comparator) for the pharmacokinetic parameters under consideration and by 1212

carrying out two one-sided tests at the 5% level of significance (9). To establish 1213

bioequivalence, the calculated confidence interval should fall within a preset 1214

bioequivalence limit. The procedures should lead to a decision scheme which is 1215

symmetrical with respect to the formulations being compared (i.e. leading to the same 1216

decision whether the multisource formulation is compared to the comparator product or 1217

the comparator product to the multisource formulation). 1218

1219

All concentration-dependent pharmacokinetic parameters (e.g. AUC and Cmax) should be 1220

log-transformed using either common logarithms to the base 10 or natural logarithms. 1221

The choice of common or natural logs should be consistent and should be stated in the 1222

study report. 1223

1224

Logarithmically transformed, concentration-dependent pharmacokinetic parameters 1225

should be analysed using analysis of variance (ANOVA). Normally the ANOVA model 1226

should include formulation, period, sequence and subject factors. 1227

1228

Parametric methods, i.e. those based on normal distribution theory, are recommended for 1229

the analysis of log-transformed bioequivalence measures. 1230

1231


page 43

The general approach is to construct a 90% confidence interval for the quantity µT−µR 1232

and to reach a conclusion of pharmacokinetic equivalence if this confidence interval is 1233

within the stated limits. The nature of parametric confidence intervals means that this is 1234

equivalent to carrying out two one-sided tests of the hypothesis at the 5% level of 1235

significance (9, 10). The antilogs of the confidence limits obtained constitute the 90% 1236

confidence interval for the ratio of the geometric means between the multisource and 1237

comparator products. 1238

1239

The same procedure should be used for analysing parameters from steady-state trials or 1240

cumulative urinary recovery, if required. 1241

1242

For tmax descriptive statistics should be given. In those cases where tmax is considered 1243

clinically relevant, median and range of tmax should be compared between test and 1244

comparator to exclude numerical differences with clinical importance. A formal 1245

statistical comparison is rarely necessary. Generally the sample size is not calculated to 1246

have enough statistical power for tmax. However, if tmax is to be subjected to a statistical 1247

analysis this should be based on non-parametric methods and should be applied to 1248

untransformed data. A sufficient number of samples around predicted maximal 1249

concentrations should have been taken to improve the accuracy of the tmax estimate. For 1250

parameters describing the elimination phase (T1/2), only descriptive statistics should be 1251

given. 1252

1253

See section 7.2.3 for information on the handling of extreme data. Exclusion of data for 1254

statistical or pharmacokinetic reasons alone is not acceptable. 1255

1256

7.6.1 Two-stage sequential design 1257

1258

In some situations reliable information concerning the expected variability in the 1259

parameters to be estimated may not be available. In such situations a two-stage sequential 1260

study design can be employed such that an accurate estimate of the variability can be 1261

determined in the first stage of the study. The number of subjects employed in the first 1262


page 44

stage is generally based on the most likely intra-subject variance estimate with some 1263

added subjects to protect against drop-outs. The analysis undertaken at the end of the first 1264

stage is treated as an interim analysis. If bioequivalence is proven at this point the study 1265

can be terminated. If bioequivalence is not proven at the end of the first stage, the second 1266

stage is conducted employing an appropriate number of additional subjects as determined, 1267

based on the variance estimates and point estimate calculated from the stage 1 data. At 1268

the end of the second stage the results from both groups combined are used in the final 1269

analysis. In order to employ a two-stage design, adjustments must be made to protect the 1270

overall Type I error rate and maintain it at 5%. In order to do this both the interim and 1271

final analyses must be conducted at adjusted levels of significance, with the confidence 1272

intervals calculated using the adjusted values. 1273

1274

It is recommended that the same alpha for both stages be employed which gives an alpha 1275

of 0.0294 for this case (11), however, the amount of alpha to be spent at the time of the 1276

interim analysis can be set at the study designer’s discretion. For example, the first stage 1277

may be planned as an analysis where no alpha is spent in the interim analysis since the 1278

objective of the interim analysis is to obtain information on the point estimate difference 1279

and variability and where all the alpha is spent in the final analysis with the conventional 1280

90% confidence interval. In this case no test against the acceptance criteria is made 1281

during the interim analysis and bioequivalence cannot be proven at that point. The 1282

proposed statistical plan must be clearly defined in the study protocol, including the 1283

adjusted significance level that is to be employed during each analysis. 1284

1285

A factor for stage should be included in the ANOVA model for the final analysis of the 1286

combined data from the two stages. 1287

1288

This approach can be employed in both cross-over and parallel study designs. 1289

1290

1291

1292

1293


page 45

7.7 Acceptance ranges 1294

1295

Area under the curve-ratio 1296

The 90% confidence interval for this measure of relative bioavailability should lie within 1297

a bioequivalence range of 80.00–125.00%. If the API is determined to possess a narrow 1298

therapeutic index (NTI) the bioequivalence acceptance range should be restricted 90.00–1299

111.11%. 1300

1301

Cmax-ratio 1302

For maximal concentration data the acceptance limit of 80.00–125.00% should be applied 1303

to the 90% confidence interval for the mean Cmax-ratio. However, this measure of relative 1304

bioavailability is inherently more variable than, for example, the AUC-ratio, and in 1305

certain cases this variability can make proving bioequivalence challenging. Refer to 1306

section 7.9.3 for information on an approach for proving bioequivalence when the Cmax 1307

parameter intra-subject variability is high. If the API is determined to possess a narrow 1308

therapeutic index (NTI) the bioequivalence acceptance range may need to be restricted to 1309

90.00–111.11%, if appropriate. 1310

1311

tmax-difference 1312

Statistical evaluation of tmax makes sense only if there is a clinically relevant claim for 1313

rapid onset of action or concerns about adverse effects. In such a case comparison of the 1314

median and range data for each product should be undertaken. 1315

1316

For other pharmacokinetic parameters the same considerations as outlined above apply. 1317

1318

7.8 Reporting of results 1319

1320

The report of a bioequivalence study should give the complete documentation of its 1321

protocol, conduct and evaluation complying with GCP rules (4). The relevant ICH 1322

guideline (12) can be used in the preparation of the study report. The responsible 1323

investigator(s) should sign the respective sections of the report. Names and affiliations of 1324


page 46

the responsible investigator(s), site of the study and period of its execution should be 1325

stated. 1326

1327

The names and batch numbers of the pharmaceutical products used in the study as well as 1328

the composition(s) of the tests product(s) should be given. Results of in vitro dissolution 1329

tests conducted in pH 1.2, 4.5 and 6.8 media and the QC media, if different, should be 1330

provided. In addition the applicant should submit a signed statement confirming that the 1331

test product is identical to the pharmaceutical product that is submitted for registration. 1332

1333

The bioanalytical validation report should be attached. The bioanalytical report should 1334

include the information recommended in the SRA guidance chosen as a guide for the 1335

bioanalytical portion of a study (see section 7.5). 1336

1337

All results should be presented clearly. All concentrations measured in each subject and 1338

the sampling time should be tabulated for each formulation. Tabulated results showing 1339

API concentration analyses according to analytical run (including runs excluded from 1340

further calculations, including all calibration standards and quality control samples from 1341

the respective run) should also be presented. The tabulated results should present the date 1342

of run, subject, study period, product administered (multisource or comparator) and time 1343

elapsed between FPP administration and blood sampling in a clear format. The procedure 1344

for calculating the parameters used (e.g. AUC) from the raw data should be stated. Any 1345

deletion of data should be documented and justified. 1346

1347

Individual blood concentration/time curves should be plotted on a linear/linear and 1348

log/linear scale. All individual data and results should be given, including information on 1349

those subjects who dropped out. The drop-outs and/or withdrawn subjects should be 1350

reported and accounted for. All adverse events that occurred during the study should be 1351

reported along with the study physician’s classification of the events. Further, any 1352

treatments employed to address adverse events should be reported. 1353

1354


page 47

Results of all measured and calculated pharmacokinetic parameters should be tabulated 1355

for each subject–formulation combination together with descriptive statistics. The 1356

statistical report should be sufficiently detailed to enable the statistical analyses to be 1357

repeated if necessary. If the statistical methods applied deviate from those specified in the 1358

study protocol the reasons for the deviations should be stated. 1359

1360

7.9 Special considerations 1361

1362

7.9.1 Fixed-dose combination products 1363

1364

If the bioequivalence of FDC products is assessed by in vivo studies the study design 1365

should follow the same general principles as described in previous sections. The 1366

multisource FDC product should be compared with the pharmaceutically-equivalent 1367

comparator FDC product. In certain cases (e.g. when no comparator FDC product is 1368

available on the market) separate products administered in free combination can be used 1369

as a comparator (3). Sampling times should be chosen to enable the pharmacokinetic 1370

parameters of all APIs to be adequately assessed. The bioanalytical method should be 1371

validated with respect to all analytes measured in the presence of the other analytes. 1372

Statistical analyses should be performed with pharmacokinetic data collected on all active 1373

ingredients; the 90% confidence intervals of test/comparator ratio of all active ingredients 1374

should be within acceptance limits. 1375

1376

7.9.2 Clinically important variations in bioavailability 1377

1378

Innovators should make all efforts to provide formulations with good bioavailability 1379

characteristics. If a better formulation is developed over time by the innovator this should 1380

then serve as the comparator product. A new formulation with a bioavailability outside 1381

the acceptance range for an existing pharmaceutical product is not interchangeable by 1382

definition. 1383

1384

1385


page 48

7.9.3 “Highly variable active pharmaceutical ingredients” 1386

1387

A “highly variable API” has been defined as an API with a within-subject variability of > 1388

30% in terms of the ANOVA-CV (13). Proving the bioequivalence of FPPs containing 1389

“highly variable APIs” can be problematic because the higher the ANOVA-CV, the 1390

wider the 90% confidence interval. Thus large numbers of subjects must be enrolled in 1391

studies involving “highly variable APIs” to achieve adequate statistical power. 1392

1393

Although there is variability in how regulatory authorities deal with the issue of highly 1394

variable APIs, the most rigorous of the current approaches involve the scaling of 1395

bioequivalence acceptance criteria based on the within-subject standard deviation 1396

observed in the relevant parameters for the comparator product (14-16). Of the two most 1397

common assessment parameters Cmax is the parameter that is subject to the highest 1398

variability and hence, the parameter for which a modified approach is most needed. 1399

1400

For highly variable FPPs it is recommended that a three-way partial replicate (where the 1401

comparator product is administered twice) or four-way fully replicated cross-over 1402

bioequivalence study be conducted and reference-scaled average bioequivalence be 1403

employed to widen the acceptance interval for the Cmax parameter, if the within-subject 1404

variability for Cmax following replicate administrations of the comparator product 1405

is >30%. If this is the case, the acceptance criteria for Cmax can be widened to a maximum 1406

of 69.84 – 143.19%. The applicant should justify that the calculated intra-subject 1407

variability is a reliable estimate and that it is not the result of outliers. 1408

1409

The extent of the widening of the acceptance interval for Cmax is defined based upon the 1410

within-subject variability seen in the bioequivalence study using scaled-average-1411

bioequivalence according to [U, L] = exp [±k·sWR], where U is the upper limit of the 1412

acceptance range, L is the lower limit of the acceptance range, k is the regulatory 1413

constant set to 0.760 and sWR is the within-subject standard deviation of the log-1414

transformed values of Cmax of the reference product. The table below gives examples of 1415


page 49

how different levels of variability lead to different acceptance limits using this 1416

methodology. 1417

1418

Within-subject CV (%) Lower limit Upper limit

30 80.00 125.00

35 77.23 129.48

40 74.62 134.02

45 72.15 138.59

≥50 69.84 143.19

1419

��%� = �� − 1

1420

The geometric mean ratio (GMR) for Cmax should lie within the conventional acceptance 1421

range 80.00-125.00%. 1422

1423

The standard bioequivalence acceptance criterion for AUC should be maintained without 1424

scaling. If the within-subject variability for Cmax, following replicate administration of the 1425

comparator, is found to <30%, standard bioequivalence acceptance criteria should be 1426

applied to both AUC and Cmax without scaling. 1427

1428

The approach to be employed should be clearly defined prospectively in the study 1429

protocol. The regulatory authority of the country to which the study data will be 1430

submitted should be consulted prior to study conduct to confirm that the proposed 1431

approach is acceptable for that jurisdiction. 1432

1433

8. PHARMACODYNAMIC STUDIES 1434

1435

Studies in healthy volunteers or patients using pharmacodynamic measurements may be 1436

used for establishing equivalence between two pharmaceutical products when the 1437

pharmacokinetic approach is not feasible. Pharmacodynamic equivalence studies may 1438

become necessary if quantitative analysis of the API and/or metabolite(s) in plasma or 1439

urine cannot be made with sufficient accuracy and sensitivity; however, this is extremely 1440

unlikely given current technology. Furthermore, pharmacodynamic equivalence studies in 1441

humans are required if measurements of API concentrations cannot be used as surrogate 1442


page 50

end-points for the demonstration of efficacy and safety of the particular pharmaceutical 1443

product such as pharmaceutical products designed to act locally. However, local 1444

availability studies based on pharmacokinetic studies alone or in combination with in 1445

vitro dissolution studies, are being considered as surrogate end-points for the 1446

demonstration of equivalent biopharmaceutical quality and release at the site of action for 1447

some products acting locally. In addition, bioequivalence studies are also required in 1448

order to demonstrate equivalent systemic exposure for systemic safety purposes. 1449

1450

Pharmacodynamic studies are not recommended for orally-administered, pharmaceutical 1451

products for systemic action when the API is absorbed into the systemic circulation and a 1452

pharmacokinetic approach can be used to assess systemic exposure and establish 1453

bioequivalence. This is because the sensitivity to detect differences between products in 1454

their biopharmaceutical quality, release and absorption is lower with pharmacodynamic 1455

or clinical end-points. As the dose–response curve for pharmacodynamics or clinical end-1456

points is usually flatter than the relationship between dose and PK parameters, it is 1457

essential to ensure the internal validity of the study by showing assay sensitivity, i.e. the 1458

ability to distinguish the response obtained by adjacent doses (two-fold or even four-fold 1459

difference in dose).It is essential to perform the comparison at the dose level where the 1460

dose response is steepest, which may require a previous pilot study for its identification. 1461

Furthermore, variability in pharmacodynamic measures is usually greater than that in 1462

pharmacokinetic measures. In addition, pharmacodynamic measures are often subject to 1463

significant placebo effects, which add to the variability and complicate experimental 1464

design. The result is often that huge numbers of patients would have to be enrolled in 1465

pharmacodynamic studies to achieve adequate statistical power. 1466

1467

If pharmacodynamic studies are to be used they must be performed as rigorously as 1468

bioequivalence studies and the principles of GCP must be followed (4). 1469

The following requirements must be recognized when planning, conducting and assessing 1470

the results of a study intended to demonstrate equivalence by measuring 1471

pharmacodynamic responses: 1472

1473

• the response measured should be a pharmacological or therapeutic 1426 effect which 1474


page 51

is relevant to the claims of efficacy and/or safety; 1475

• the methodology must be validated for precision, accuracy, reproducibility and 1476

specificity; 1477

• neither the test product nor the comparator product should produce a maximal 1478

response in the course of the study, since it may be impossible to detect differences 1479

between formulations given in doses which give maximum or near maximum effects. 1480

Investigation of dose–response relationships may be a necessary part of the design; 1481

• the response should be measured quantitatively, preferably under double-blind 1482

conditions, and be recordable by an instrument that produces and records the results of 1483

repeated measurements to provide a record of the pharmacodynamic events, which are 1484

substitutes for measurements of plasma concentrations. Where such measurements are 1485

not possible, recordings on visual analogue scales may be used. Where the data are 1486

limited to qualitative (categorized) measurements appropriate special statistical 1487

analysis will be required; 1488

• participants should be screened prior to the study to exclude non-responders. The 1489

criteria by which responders are distinguished from non-responders must be stated in 1490

the protocol; 1491

• in instances where an important placebo effect can occur, comparison between 1492

pharmaceutical products can only be made by a priori consideration of the potential 1493

placebo effect in the study design. This may be achieved by adding a third phase with 1494

placebo treatment in the design of the study; 1495

• the underlying pathology and natural history of the condition 1455 must be considered 1496

in the study design. There should be knowledge of the reproducibility of baseline 1497

conditions; 1498

• a cross-over design can be used. Where this is not appropriate a parallel group study 1499

design should be chosen. 1500

1501

The selection basis for the multisource and comparator products should be the same as 1502

described in section 7.3. 1503

1504

1505


page 52

In studies in which continuous variables can be recorded, the time-course of the intensity 1506

of the action can be described in the same way as in a study in which plasma 1507

concentrations are measured and parameters can be derived which describe the area under 1508

the effect–time curve, the maximum response and the time at which the maximum 1509

response occurred. 1510

1511

The comparison between the test and the comparator product can be performed in two 1512

different ways: 1513

1514

(a) dose-scale analysis or relative potency, which is defined as the ratio of the 1515

potency of the test product to that of the reference product. It is a way of 1516

summarising the relationship between the dose-response curves of the test and 1517

comparator product; 1518

1519

(b) response-scale analysis, which consist of demonstration of equivalence (for at 1520

least two dose levels) on the pharmacodynamic end-point. 1521

1522

For either approach to be acceptable a minimum requirement is that the study has assay 1523

sensitivity. For a study to have assay sensitivity at least two non-zero levels need to be 1524

studied and one dose level needs to be shown to be superior to the other. Therefore, it is 1525

recommended that unless otherwise justified more than one dose of both the test and 1526

reference products are studied. However, it is essential that doses on the steep part of the 1527

dose-response curve are studied. If a dose too low on the dose response curve is chosen 1528

then demonstrating equivalence between two products is not convincing, as this dose 1529

could be sub-therapeutic. Equally if a dose at the top of the dose response curve is 1530

included similar effects will be seen for doses much higher than that studied and hence 1531

demonstrating equivalence at this dose level would also not be convincing. 1532

1533

The results using both approaches should be provided. In both cases the observed 1534

confidence intervals comparing test and reference products should lie within the chosen 1535

equivalence margins to provide convincing evidence of equivalence. Like in 1536


page 53

bioequivalence studies, 90% confidence intervals should be calculated for relative 1537

potency, whereas 95% confidence intervals should be calculated for the response-scale 1538

analysis. It should be noted that the acceptance range as applied for bioequivalence 1539

assessment may not be appropriate. For both approaches the chosen equivalence ranges 1540

should be pre-specified and appropriately justified in the protocol. 1541

1542

9. CLINICAL TRIALS 1543

1544

In some instances (see example (e) in section 5.1, “In vivo studies”) plasma concentration 1545

time–profile data may be not suitable for assessing equivalence between two 1546

formulations. Although in some cases pharmacodynamic equivalence studies can be an 1547

appropriate tool for establishing equivalence, in others this type of study cannot be 1548

performed because of a lack of meaningful pharmacodynamic parameters that can be 1549

measured; a comparative clinical trial then has to be performed to demonstrate 1550

equivalence between two formulations. However, it is preferable to assess equivalence by 1551

performing a pharmacokinetic equivalence study rather than a clinical trial that is less 1552

sensitive and would require a huge number of subjects to achieve adequate statistical 1553

power. For example, it has been calculated that 8600 patients would be required to give 1554

adequate statistical power to detect a 20% improvement in response to the study API 1555

compared with placebo (18). Similarly it was calculated that 2600 myocardial infarct 1556

patients would be required to show a 16% reduction in risk. A comparison of two 1557

formulations of the same API based on such end-points would require even greater 1558

numbers of subjects (19). 1559

1560

If a clinical equivalence study is considered as being undertaken to prove equivalence, 1561

the same statistical principles apply as for the bioequivalence studies, although a 95% 1562

confidence interval might be necessary for pharmacodynamic and clinical end-points in 1563

contrast to the 90% confidence level employed conventionally for pharmacokinetic 1564

studies. The number of patients to be included in the study will depend on the variability 1565

of the target parameters and the acceptance range and is usually much higher than the 1566

number of subjects needed in bioequivalence studies. 1567


page 54

1568

The methodology for establishing equivalence between pharmaceutical products by 1569

means of a clinical trial in patients with a therapeutic end-point has not yet evolved as 1570

extensively as for bioequivalence studies. However, some important items that need to be 1571

defined in the protocol can be identified as follows: 1572

1573

• the target parameters that usually represent relevant clinical end-points from 1574

which the onset, if applicable and relevant, and intensity of the response are to be 1575

derived; 1576

• the size of the acceptance range has to be defined case by case, taking into 1577

consideration the specific clinical conditions. These include, among others, the 1578

natural course of the disease, the efficacy of available treatments and the chosen 1579

target parameter. In contrast to bioequivalence studies (where a conventional 1580

acceptance range is applied) the size of the acceptance range in clinical trials 1581

should be set individually according to the therapeutic class and indication(s); 1582

• the presently used statistical method is the confidence interval approach; 1583

• the confidence intervals can be derived from either parametric or nonparametric 1584

methods; 1585

• where appropriate a placebo leg should be included in the design; 1586

• in some cases it is relevant to include safety end-points in the final comparative 1587

assessments. 1588

1589

The selection basis for the multisource and comparator products should be the same as 1590

described in section 7.3. 1591

1592

10. IN VITRO EQUIVALENCE TESTING 1593

1594

Over the past three decades dissolution testing has evolved into a powerful tool for 1595

characterizing the quality of oral pharmaceutical products. The dissolution test, at first 1596

exclusively a quality control test, is now emerging as a surrogate equivalence test for 1597

certain categories of orally-administered, pharmaceutical products. For these products 1598


page 55

(typically solid oral dosage forms containing APIs with suitable properties) similarity in 1599

in vitro dissolution profile, in addition to excipient comparisons and a risk benefit 1600

analysis, can be used to document equivalence of a multisource product with a 1601

comparator product. 1602

1603

It should be noted that, although the dissolution tests recommended in The International 1604

Pharmacopoeia (Ph.Int.) (20) for quality control have been designed to be compatible 1605

with the biowaiver dissolution tests, they do not fulfill all the requirements for evaluating 1606

equivalence of multisource products with comparator products. Dissolution tests for 1607

quality control purposes do not generally correspond to the test conditions required for 1608

evaluating equivalence of multisource products and should not be applied for this purpose. 1609

1610

10.1 In vitro equivalence testing in the context of the Biopharmaceutics 1611

Classification System 1612

1613

10.1.1 Biopharmaceutics Classification System 1614

1615

The Biopharmaceutics Classification System (BCS) is based on aqueous solubility and 1616

intestinal permeability of the API. It classifies the API into one of four classes: 1617

1618

— Class 1: high solubility, high permeability 1619

— Class 2: low solubility, high permeability 1620

— Class 3: high solubility, low permeability 1621

— Class 4: low solubility, low permeability. 1622

1623

Combining the dissolution results and a critical examination of the excipients of the 1624

pharmaceutical product with these two properties of the API takes the four major factors 1625

that govern the rate and extent of API absorption from immediate-release, solid dosage 1626

forms into account (21). On the basis of their dissolution properties, immediate-release 1627

dosage forms can be categorized as having “very rapid”, “rapid”, or “not rapid” 1628

dissolution characteristics. 1629


page 56

1630

On the basis of solubility and permeability of the API, excipient nature, excipient content 1631

and dissolution characteristics of the dosage form, the BCS approach provides an 1632

opportunity to waive in vivo bioequivalence testing for certain categories of immediate-1633

release FPPs. Oral FPPS containing an API possessing a narrow therapeutic index are not 1634

eligible for a so-called “biowaiver” based on the BCS approach.. 1635

1636

10.1.1.1 High solubility 1637

1638

An API is considered highly soluble when the highest dosage strength or highest single 1639

therapeutic dose as determined by the relevant regulatory authority, typically defined by 1640

the labelling for the innovator product, is soluble in 250 ml or less of aqueous media over 1641

the pH range of 1.2–6.8. The pH-solubility profile of the API should be determined at 37 1642

± 1 °C in aqueous media. A minimum of three replicate determinations of solubility at 1643

each pH condition is recommended. 1644

1645

[Note from the Secretariat: 1646

1647

Major discussion took place on whether or not to use highest dosage strength or highest 1648

single therapeutic dose, or both. A number of regulatory authorities favour the highest 1649

single therapeutic dose approach; however, some favour the highest dosage strength. In 1650

view of this discussion during the informal consultation there was a proposal to have 1651

both options in the text. Your feedback is sought. The approach used will have 1652

repercussions on the biowaiver guidance document, which is based on the essential 1653

medicines list.] 1654

1655

10.1.1.2 High permeability 1656

1657

An API is considered highly permeable when the extent of absorption in humans is 85% 1658

or more based on a mass balance determination or in comparison with an intravenous 1659

comparator dose. Ideally the mass balance study /i.v. comparison would be conducted at 1660


page 57

the same dose as that used for the solubility classification. If this is not possible, dose 1661

linearity of pharmacokinetics should be used to justify the use of other doses. 1662

1663

An acceptable alternative test method for permeability determination of the 1664

API could be: 1665

1666

(i) in vivo intestinal perfusion in humans. 1667

1668

When this method is used for permeation studies, suitability of the methodology should 1669

be demonstrated, including determination of permeability relative to that of a reference 1670

compound whose fraction of dose absorbed has been documented to be at least 85%, as 1671

well as use of a negative control. 1672

1673

Supportive data can be provided by the following additional test methods: 1674

1675

(ii) in vivo or in situ intestinal perfusion using animal models; 1676

1677

(iii) in vitro permeation across a monolayer of cultured epithelial cells (e.g. Caco-2) 1678

using a method validated using APIs with known permeabilities, although data from 1679

neither method (ii) nor (iii) would be considered acceptable on a stand-alone basis. In 1680

these experiments high permeability is assessed with respect to the high permeability of a 1681

series of reference compounds with documented permeabilities and fraction absorbed 1682

values, including some for which fraction of dose absorbed is at least 85% (22). 1683

1684

1685

10.1.2 Determination of dissolution characteristics of multisource products in 1686

consideration of a biowaiver based on the Biopharmaceutics Classification System 1687

1688

For exemption from an in vivo bioequivalence study, an immediate-release, multisource 1689

product should exhibit very rapid or rapid in vitro dissolution characteristics (see below), 1690


page 58

depending on the BCS properties of the API. In vitro data should also demonstrate the 1691

similarity of dissolution profiles between the test and comparator products. 1692

1693

10.1.2.1 Very rapidly dissolving 1694

1695

A multisource product is considered to be very rapidly dissolving when no less than 85% 1696

of the labelled amount of the API dissolves in 15 minutes at 37 ± 1oC using a paddle 1697

apparatus at 75 rpm or a basket apparatus at 100 rpm in a volume of 900 mL or less in 1698

each of the following media: 1699

1700

‒ pH 1.2 HCl solution or buffer; 1701

‒ a pH 4.5 acetate buffer; 1702

‒ a pH 6.8 phosphate buffer. 1703

1704

Pharmacopoeial buffers (e.g. Ph.Int.) are recommended for use at these three pH values. 1705

Surfactants should not be used in the dissolution media. Enzymes (pepsin at pH 1.2 and 1706

pancreatin at pH 6.8) may be used if the pharmaceutical product contains gelatin (e.g. 1707

capsules or caplets), due to the possibility of cross linking. 1708

1709

(See also section 10.2, dissolution profile comparison.) 1710

1711

10.1.2.2 Rapidly dissolving 1712

1713

A multisource product is considered to be rapidly dissolving when no less than 85% of 1714

the labelled amount of the API dissolves in 30 minutes at 37 ± 1oC using a paddle 1715

apparatus at 75 rpm or a basket apparatus at 100 rpm in a volume of 900 mL or less in 1716

each of the following media: 1717

1718

‒ pH 1.2 HCl solution or buffer; 1719

‒ pH 4.5 acetate buffer; 1720

‒ pH 6.8 phosphate buffer. 1721


page 59

1722

Surfactants should not be employed. 1723

1724

10.2 Qualification for a biowaiver based on the Biopharmaceutics Classification 1725

System 1726

1727

A biowaiver based on the BCS considers: 1728

1729

(a) the solubility and permeability of the API (see section 10.1); 1730

1731

(b) the similarity of the dissolution profiles of the multisource and comparator 1732

products in pH 1.2, 4.5 and 6.8 media (see below); 1733

1734

(c) the excipients used in the formulation (see below); 1735

1736

(d) the risks of an incorrect biowaiver decision in terms of the therapeutic index of, 1737

and clinical indications for, the API (see section 5.1 for cases where an in vivo study 1738

would be required to demonstrate bioequivalence). Only when there is an acceptable 1739

benefit–risk balance in terms of public health and risk to the individual patient should 1740

bioequivalence testing be waived and the in vitro methods described in this section 1741

applied as a test of product equivalence. 1742

1743

Risk reduction and assessment of excipients 1744

1745

The risk of reaching an incorrect decision that the multisource product is equivalent to the 1746

comparator product can be reduced by correct classification of the API and by following 1747

the recommendations for dissolution testing and comparison of the dissolution profiles. In 1748

all cases it should be further demonstrated that the excipients included in the formulation 1749

of the multisource product are well established for use in products containing that API 1750

and that the excipients used will not lead to differences between the comparator and 1751

multisource product with respect to processes affecting absorption (e.g. by effects on 1752


page 60

GI motility or interactions with transport processes), or which might lead to interactions 1753

that alter the pharmacokinetics of the API. 1754

1755

In all cases well-established excipients in usual amounts should be employed in 1756

multisource products. Excipients that might affect the bioavailability of the API, e.g. 1757

mannitol, sorbitol or surfactants, should be identified and an assessment of their impact 1758

provided. These critical excipients should not differ qualitatively and must be 1759

quantitatively similar between the test product and comparator product. 1760

1761

For biowaivers for products containing Class 1 APIs, there is some flexibility in the 1762

excipients employed with the exception of critical excipients as discussed above. It is 1763

recommended that the excipients employed be present in the comparator product or be 1764

present in other products which contain the same API as the multisource product and 1765

which have marketing authorizations in ICH-associated countries. 1766

1767

For biowaivers for products containing Class 3 APIs, all excipients in the proposed 1768

product formulation should be qualitatively the same and quantitatively similar to that of 1769

the comparator product, as defined by the WHO quality limits on allowable quantitative 1770

changes in excipients for a variation (23). 1771

1772

As a general rule the closer the composition of the multisource product to that of the 1773

comparator product with regard to excipients, the lower the risk of an inappropriate 1774

decision on equivalence using a biowaiver based on the BCS. 1775

1776

Sub- and supra-bioavailable products 1777

1778

A further consideration is the potential risk to public health and to the individual patient, 1779

should an inappropriate decision with respect to bioequivalence be reached. Essentially 1780

there are two possible negative outcomes. 1781

1782


page 61

The first arises when the multisource product is sub-bioavailable. In this case substitution 1783

of the comparator with the multisource product could lead to reduced therapeutic efficacy. 1784

APIs which must reach a certain concentration to be effective (e.g. antibiotics) are most 1785

susceptible to problems of sub-bioavailability. 1786

1787

The second negative outcome arises when the multisource product is supra-bioavailable. 1788

In this case substitution of the comparator with the multisource product could lead to 1789

toxicity. APIs which exhibit toxic effects at concentrations close to the therapeutic range 1790

are most susceptible to problems of supra-bioavailability. For these reasons therapeutic 1791

index is an important consideration in determining whether the biowaiver based on BCS 1792

can be applied or not. 1793

1794

Dissolution profile comparison 1795

1796

Approval of multisource formulations using comparative in vitro dissolution studies 1797

should be based on the generation of comparative dissolution profiles rather than a 1798

single-point dissolution test. For details refer to the Annex. 1799

1800

10.2.1 Dissolution criteria for biowaivers based on the Biopharmaceutics 1801

Classification System according to the properties of active pharmaceutical ingredients 1802

1803

The major application of BCS is to provide criteria for biowaiver of multisource products. 1804

It is recommended that products containing the following BCS classes of APIs be eligible 1805

for a biowaiver: 1806

1807

• BCS Class 1 APIs, if the multisource and comparator product are very rapidly 1808

dissolving or similarly rapidly dissolving; 1809

• BCS Class 3 APIs, if the multisource and comparator product are very rapidly 1810

dissolving. 1811

1812


page 62

In summary, biowaivers for solid oral dosage forms based on BCS can be considered 1813

under the following conditions: 1814

1815

1. Dosage forms of APIs that are highly soluble, highly permeable (BCS Class 1) 1816

with acceptable excipient content and favourable risk-benefit analysis, and which are 1817

rapidly dissolving, are eligible for a biowaiver based on the BCS provided: 1818

1819

(i) the dosage form is rapidly dissolving (as defined in section 10.1.2.2) and the 1820

dissolution profile of the multisource product is similar to that of the 1821

comparator product at pH 1.2, pH 4.5 and pH 6.8 buffer using the paddle 1822

method at 75 rpm or the basket method at 100 rpm (as described in section 1823

10.2) and meets the criteria of dissolution profile similarity, f2 ≥50 (or 1824

equivalent statistical criterion); 1825

(ii) if both the comparator and the multisource dosage forms are very rapidly 1826

dissolving (as defined in section 10.1.2.1) the two products are deemed 1827

equivalent and a profile comparison is not necessary. 1828

1829

2. Dosage forms of APIs that are highly soluble and have low permeability (BCS 1830

Class 3) are eligible for biowaivers provided all the criteria (a–d) listed in section 10.2 are 1831

met and the risk–benefit is additionally addressed in terms of extent, site and mechanism 1832

of absorption. 1833

1834

In general the risks of reaching an inappropriate biowaiver decision need to be more 1835

critically evaluated when the extent of absorption is lower (especially if fabs < 50%); 1836

therefore it is essential that the excipients in the proposed product formulation be 1837

scrutinized carefully. In order to minimize the risk of an inappropriate decision, 1838

excipients in the proposed product formulation should be qualitatively the same and 1839

quantitatively similar to that of the comparator. 1840

1841

If it is deemed that the risk of reaching an inappropriate biowaiver decision and its 1842

associated risks to public health and for individual patients is acceptable, the multisource 1843


page 63

product is eligible for a biowaiver based on BCS when both the comparator and the 1844

multisource dosage forms are very rapidly dissolving (85% dissolution in 15 minutes as 1845

described in section 10.1.2.1). 1846

1847

10.3 In vitro equivalence testing based on dose-proportionality of formulations 1848

1849

Under certain conditions approval of different strengths of a multisource product can be 1850

considered on the basis of dissolution profiles if the formulations have proportionally 1851

similar compositions. 1852

1853

10.3.1 Proportional formulations 1854

1855

For the purpose of this guidance proportional formulations can be defined in two ways, 1856

based on the strength of dosage forms. 1857

1858

(i) All active and inactive ingredients are exactly in the same proportions in the 1859

different strengths (e.g. a tablet of 50 mg strength has all the active and inactive 1860

ingredients exactly half that of a tablet of 100 mg strength and twice that of a 1861

tablet of 25 mg strength). 1862

1863

(ii) For an FPP, where the amount of the API in the dosage form is relatively low (up 1864

to 10 mg per dosage unit or not more than 5% of the weight of the dosage form), 1865

the total weight of the dosage form remains similar for all strengths. 1866

1867

A waiver is considered: 1868

1869

• if the amounts of the different excipients or capsule contents are the same for the 1870

concerned strengths and only the amount of the API has changed; 1871

• if the amount of filler is changed to account for the change in amount of API: the 1872

amounts of other core excipients or capsule content should be the same for the 1873

concerned strengths. 1874


page 64

1875

10.3.2 Qualification for biowaivers based on dose-proportionality of formulations 1876

1877

10.3.2.1 Immediate-release tablets 1878

1879

A biowaiver based on dose-proportionality of formulations for a series of strengths of a 1880

multisource product, when the pharmaceutical products are manufactured with the same 1881

manufacturing process may be granted when: 1882

1883

(i) an in vivo equivalence study has been performed on at least one of the strengths 1884

of the formulation (see section 7.4.1 Selection of strength, usually the highest 1885

strength, unless a lower strength is chosen for reasons of safety or the API is 1886

highly soluble and displays linear pharmacokinetics); 1887

1888

(ii) all strengths are proportionally similar in formulation to that of the strength 1889

studied; 1890

1891

(iii) the dissolution profiles for the different strengths are similar at pH 1.2, 4.5, 6.8 1892

and the QC media, unless justified by the absence of sink conditions. In case the 1893

different strengths of the test product do not show similar dissolution profiles due 1894

to the absence of sink conditions in any of the above media, this should be 1895

substantiated by showing similar dissolution profiles when testing the same dose 1896

per vessel (e.g. two tablets of 5 mg vs one tablet of 10 mg) or by showing the 1897

same behaviour in the comparator product. 1898

1899

As for the BCS-based biowaiver, if both strengths release 85% or more of the label 1900

amount of the API in 15 minutes, using all three dissolution media as recommended in 1901

section 10.2, the profile comparison with an f2 test is unnecessary. 1902

1903


page 65

In the case where an immediate-release dosage form with several strengths deviates from 1904

proportionality, a bracketing approach is possible, so that only two strengths representing 1905

the extremes need to be studied in vivo. 1906

1907

10.3.2.2 Delayed-release tablets and capsules 1908

1909

For delayed-release tablets, for a series of strengths of a multisource product where the 1910

strengths are proportionally similar in formulation to that of the strength studied in an in 1911

vivo equivalence study, a lower strength can be granted a biowaiver if it exhibits similar 1912

dissolution profiles, f2 ≥ 50, in the recommended test condition for delayed-release 1913

product, e.g. dissolution test in acid medium (pH 1.2) for 2 hours followed by dissolution 1914

in pH 6.8. When evaluating proportionality in composition, it is recommended to 1915

consider the proportionality of gastro-resistant coating with respect to the surface area 1916

(not to core weight) to have the same gastro-resistance (mg/cm2). 1917

1918

For delayed-release capsules, where different strengths have been achieved solely by 1919

means of adjusting the number of beads containing the API, similarity in the dissolution 1920

profile of the new (lower) strength to that of the approved strength (f2 > 50) under the 1921

test conditions recommended for delayed-release products (see above) is sufficient for a 1922

biowaiver. 1923

1924

10.3.2.3 Extended-release tablets and capsules 1925

1926

(a) For extended-release tablets, when there is a series of strengths of a multisource 1927

product that are proportionally similar in their active and inactive ingredients and 1928

have the same API-release mechanism, in vivo bioequivalence studies should be 1929

conducted with the lowest and highest strengths; however, an intermediate 1930

strength can be granted a biowaiver if it exhibits similar dissolution profiles, f2 ≥ 1931

50, in three different pH buffers (between pH 1.2 and 7.5) and the QC media by 1932

the recommended test method. 1933

1934


page 66

(b) For extended release tablets, with an osmotic pump release mechanism the 1935

dissolution profile comparison (f2 ≥ 50) under one recommended test condition is 1936

sufficient for a biowaiver based on dose-proportionality of formulation. 1937

1938

(c) For extended-release, beaded capsules, where different strengths have been 1939

achieved solely by means of adjusting the number of beads containing the API, 1940

dissolution profile comparison (f2 ≥ 50) under one recommended test condition is 1941

sufficient for a biowaiver based on dose-proportionality of formulation. 1942

1943

10.3.3 Dissolution profile comparison for biowaivers based on dose-proportionality of 1944

formulations 1945

1946

As for biowaivers based on the BCS a model independent mathematical approach (e.g. f2 1947

test) can be used for comparing the dissolution profiles of two products. The dissolution 1948

profile of the two products (reference strength2 and additional strength) should be 1949

measured under the same test conditions. 1950

1951

The dissolution sampling times for both reference strength and additional strength 1952

profiles should be the same, for example: 1953

1954

‒ for immediate-release products 5, 10, 15, 20, 30, 45 and 60 minutes; 1955

‒ for 12-hour extended-release products 1, 2, 4, 6 and 8 hours; 1956

‒ for 24-hour extended-release products 1, 2, 4, 6, 8 and 16 hours. 1957

1958

For the application of the f2 value, please refer to the Annex. 1959

1960

1961

1962

1963

2 The reference strength is the strength of the FPP that was compared to the comparator product in an in

vivo equivalence study.


page 67

10.4 In vitro equivalence testing for non-oral dosage forms 1964

1965

In the case of intravenous micellar solutions with the same qualitative and quantitative 1966

composition of the surfactant, but significant changes in other excipients, an in vitro 1967

comparison might avoid the need for in vivo studies if a similar micellar system and API 1968

release from the micelle after dilution of the FPP or API administration into the blood 1969

system is ensured (26). 1970

1971

Locally-applied, locally-acting products in the form of aqueous suspensions containing 1972

the same API(s) in the same molar concentration and essentially the same excipients in 1973

comparable concentrations might be waived from the demonstration of equivalence by 1974

means of local availability, pharmacodynamic or clinical studies if in vitro 1975

characterization is able to ensure a similar crystallographic structure and particle size 1976

distribution as well as any other in vitro test specific for each dosage form, e.g. 1977

dissolution. The methodological details for the techniques mentioned below are not 1978

covered in this guideline. Additional information regarding these techniques should be 1979

sought from guidelines of stringent regulatory authorities or state-of-the-art literature. 1980

1981

(a) Suspensions for nebulization with the same qualitative and quantitative 1982

composition as the comparator product might be waived from in vivo studies if the 1983

particles in the suspensions are shown to have the same crystallographic structure, 1984

and particle size distribution as those from the comparator product, as well as 1985

comparability in any other appropriate in vitro test, e.g. dissolution. In addition, 1986

the nebulized droplets should exhibit a similar aerodynamic particle size 1987

distribution to that of the comparator product. 1988

1989

(b) Suspensions for nebulization with the different qualitative and quantitative 1990

composition might be waived if, in addition to the requirements defined above 1991

under (a), the difference in excipient composition does not alter the nebulizer 1992

efficiency (e.g. by the presence or absence of a different surfactant/preservative) 1993

and the aerodynamic particle size distribution (e.g. altering product hygroscopicity 1994


page 68

by the presence of a different amount of salt as isotonic agent). To this end the 1995

appropriate state-of-the-art in vitro test should be conducted to ensure product 1996

equivalence. Any excipient difference should be critically reviewed because 1997

certain excipients that are considered irrelevant in other dosage forms (e.g. 1998

preservative, substance to adjust tonicity or thickening agent) may affect safety 1999

and/or efficacy of the product. 2000

2001

(c) Nasal drops where the API is in suspension with the same qualitative and 2002

quantitative composition as the comparator product might be waived from in vivo 2003

studies if the particles in suspension are shown to have the same crystallographic 2004

structure and similar particle size distribution to that of the comparator product, as 2005

well as comparability in any other appropriate in vitro test, e.g. dissolution. 2006

2007

(d) Nasal drops where the API is in suspension with qualitative or quantitative 2008

differences in excipient composition with respect to the comparator product might 2009

be waived from in vivo studies if, in addition to the requirements defined above 2010

under (c), the difference in excipient composition does not affect efficacy and 2011

safety (e.g. a different preservative may affect the safety profile due to a greater 2012

irritation and a different viscosity or thixotropy may affect the residence time in 2013

the site of action). Therefore any excipient difference should be critically 2014

reviewed. 2015

2016

(e) Nasal sprays in solution with the same qualitative and quantitative composition in 2017

excipients can be waived based on a battery of in vitro tests as defined by SRAs 2018

(17, 29). 2019

2020

(f) Nasal sprays in solution with qualitative and quantitative differences in the 2021

excipient composition might be waived if, in addition to showing similarity in the 2022

battery of in vitro tests referenced under (e), excipients differences are critically 2023

reviewed as described above under (d). 2024

2025


page 69

(g) Nasal sprays in suspension with the same qualitative and quantitative composition 2026

in excipients might be waived if, in addition to the battery of in vitro tests 2027

referenced above under (e), the particles in suspension are shown to have the same 2028

crystallographic structure and similar particle size distribution, as well as 2029

comparability in any other appropriate in vitro test, e.g. dissolution. 2030

2031

(h) Nasal sprays in suspension with qualitative and quantitative differences in 2032

excipient composition might be waived if, in addition to the battery of in vitro 2033

tests referenced above under (e) and (g), excipients differences are critically 2034

reviewed as described above under (d). 2035

2036

(i) In case of pressurized metered dose inhalers in solution or suspension, in vivo 2037

studies might be waived if similarity is shown in a battery of in vitro tests as 2038

described in specific guidelines of stringent regulatory authorities (27). 2039

2040

(j) When pharmaceutically-equivalent products are topical prepared gels where the 2041

API is in solution, contain the same API(s) in the same molar concentration and 2042

essentially the same excipients in comparable concentrations, equivalence can be 2043

demonstrated by means of in vitro membrane diffusion studies (28). 2044

2045

(k) Otic and ophthalmic suspensions with the same qualitative and quantitative 2046

composition in excipients might be waived if the particles in suspension are 2047

shown to have the same crystallographic structure and similar particle size 2048

distribution, as well as comparability in any other appropriate in vitro test, e.g. 2049

dissolution. 2050

2051

(l) Locally-acting products acting in the GI tract containing highly soluble APIs (as 2052

defined by the BCS) in immediate release dosage forms might be waived from in 2053

vivo equivalence studies based on the same dissolution requirements applied for 2054

the BCS based biowaiver. 2055

2056


page 70

10.5 In vitro equivalence testing for scale-up and post-approval changes 2057

2058

Although these guidelines comment primarily on registration requirements for 2059

multisource pharmaceutical products, it should be noted that under certain conditions, 2060

following permissible formulation or manufacturing changes after FPP approval, in vitro 2061

dissolution testing may also be suitable to confirm similarity of product quality and 2062

performance characteristics. More information on when dissolution testing may be used 2063

to support product variations is provided in WHO guidances on variations in 2064

pharmaceutical products. 2065

2066

[Note from the Secretariat: references will be updated when the document is finalized.] 2067

2068

REFERENCES 2069

2070

1. Marrakesh Agreement Establishing the World Trade Organization. Marrakesh, 2071

General Agreement on Tariffs and Trade, 1994, Annex 1 C, Article 39. 2072

2073

2. HHS/FDA Guidance for industry: bioavailability and bioequivalence studies 2074

for orally administered medicine products – general considerations. Rockville, MD, 2075

Department of Health and Human Services, US Food and Drug Administration. 2076

2003 (http://www.fda.gov/cder/guidance/index.htm). 2077

2078

3. Guidelines for registration of fixed-dose combination medicinal products. In: 2079

WHO Expert Committee on Specifications for Pharmaceutical Preparations. 2080

Thirty-ninth report. Geneva, World Health Organization, 2005 (WHO Technical 2081

Report Series, No. 929), Annex 5:94–142. 2082

2083

4. Guidelines for good clinical practice for trials on pharmaceutical products. 2084

In: The use of essential drugs. Sixth report of the WHO Expert Committee. 2085

Geneva, World Health Organization, 1995 (WHO Technical Report 2086

Series, No. 850):97–137. 2087


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2088

5. Guidelines for organizations performing in vivo bioequivalence studies. In: 2089

WHO Expert Committee on Specifications for Pharmaceutical Preparations. 2090

Fortieth report. Geneva, World Health Organization (WHO Technical Report 2091

Series, No. 937), 2006, Annex 9. 2092

2093

6. Julious SA. Sample sizes for clinical trials with normal data. Statistics in Medicine, 2094

2004, 23(12): 1921-1986. 2095

2096

7. Revision/update of the guidance on the selection of comparator pharmaceutical 2097

products for equivalence assessment of interchangeable multisource (generic) 2098

products. (In preparation for WHO Technical Report Series.) 2099

2100

8. Midha KK, Rawson MJ, Hubbard JW. Commentary: The Role of Metabolites 2101

in Bioequivalence. Pharmaceutical Research, 2004, 21:1331–1344. 2102

2103

9. Schuirmann DJ. A comparison of the two one-sided tests procedure and the 2104

power approach for assessing the equivalence of average bioavailability. 2105

Journal of Pharmacokinetics and Biopharmaceutics, 1987, 15:657–680. 2106

2107

10. Westlake WJ. Bioavailability and bioequivalence of pharmaceutical formulations. 2108

In: Peace KE, ed. Biopharmaceutical statistics for drug development. 2109

New York, Marcel Dekker, Inc., 1988: 329–352. 2110

2111

11. Pocock SJ. Group sequential methods in the design and analysis of clinical trials. 2112

Biometrika, 1977, 64(2): 191-199. 2113

2114

12. ICH E3, Structure and content of clinical study reports. Geneva, International 2115

Conference on Harmonisation (ICH) Secretariat: IFPMA, 1995. 2116

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highly variable drugs and for the special case of Cmax. International 2127

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16. Tothfalusi L, Endrenyi L. Limits for scaled average bioequivalence of highly 2130

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21. Amidon GL, et al. A theoretical basis for a biopharmaceutic drug classification: 2146

The correlation of in vitro drug product dissolution and in vivo bioavailability. 2147

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24. Moore JW, Flanner HH. Mathematical comparison of curves with an emphasis 2158

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25. Shah VP, et al. In vitro dissolution profile comparison – statistics and analysis 2161

of the similarity factor, f2. Pharmaceutical Research, 1998, 15:889–896. 2162

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26. HHS/FDA Draft Guidance for Industry, Bioavailability and Bioequivalence Studies 2164

for Nasal Aerosols and Nasal Sprays for Local Action U.S. Department of Health 2165

and Human Services, Food and Drug Administration, Center for Drug Evaluation 2166

and Research (CDER) April 2003. 2167

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27. Guideline on the requirements for clinical documentation for orally inhaled 2169

products (OIP) including the requirements for demonstration of therapeutic 2170

equivalence between two inhaled products for use in the treatment of Asthma and 2171

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European Medicines Agency 2009. (http://www.ema.europa.eu). 2174

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ANNEX 2202

RECOMMENDATIONS FOR CONDUCTING AND ASSESSING 2203

COMPARATIVE DISSOLUTION PROFILES 2204

2205

2206

The dissolution measurements of the two FPPs (e.g. test and comparator or two different 2207

strengths) should be made under the same test conditions. A minimum of three time-2208

points (zero excluded) should be included, the time-points for both reference (comparator) 2209

and test product being the same. The sampling intervals should be short for a 2210

scientifically sound comparison of the profiles (e.g. 5, 10, 15, 20, 30, 45 (60, 90, 120) 2211

minutes). The 15-minute time-point is critical to determine whether a product is very 2212

rapidly dissolving and to determine whether f2 must be calculated. For extended release 2213

FPPs, the time-points should be set to cover the entire duration of expected release, e.g. 1, 2214

2, 3, 5 and 8 hours for a 12-hour release and additional test intervals for longer duration 2215

of release. 2216

2217

Studies should be performed in at least three media covering the physiological range, 2218

including pH 1.2 hydrochloric acid, pH 4.5 buffer and pH 6.8 buffer. International 2219

Pharmacopoeia buffers are recommended; other pharmacopoeial buffers with the same 2220

pH and buffer capacity are also accepted. Water may be considered as an additional 2221

medium, especially when the API is unstable in the buffered media to the extent that the 2222

data are unusable. 2223

2224

If both the test and reference (comparator) products show more than 85% dissolution in 2225

15 minutes, the profiles are considered similar (no calculations required). Otherwise: 2226

2227

• similarity of the resulting comparative dissolution profiles should be calculated 2228

using the following equation that defines a similarity factor (f2): 2229

; 2230


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• where Rt and Tt are the mean per cent API dissolved in reference (comparator) 2231

and test product, respectively, at each time-point. An f2 value between 50 and 100 2232

suggests that the two dissolution profiles are similar; 2233

2234

• a maximum of one time-point should be considered after 85% dissolution of the 2235

reference (comparator) product has been reached; 2236

2237

• in the case where 85% dissolution cannot be reached due to poor solubility of the 2238

API, the dissolution should be conducted until an asymptote (plateau) has been 2239

reached; 2240

2241

• at least 12 units should be used for determination of each profile. Mean 2242

dissolution values can be used to estimate the similarity factor, f2. To use mean 2243

data, the percentage coefficient of variation at time points up to 10 minutes should 2244

be not more than 20% and at other time-points should be not more than 10%; 2245

2246

• when delayed-release products (e.g. enteric coated) are being compared, the 2247

recommended conditions are acid medium (pH 1.2) for 2 hours and buffer pH 6.8 2248

medium; 2249

2250

• when comparing extended-release beaded capsules, where different strengths 2251

have been achieved solely by means of adjusting the number of beads containing 2252

the API, one condition (normally the release condition) will suffice; 2253

2254

• surfactants should be avoided in comparative dissolution testing. 2255

2256

A statement that the API is not soluble in any of the media is not sufficient and profiles in 2257

the absence of surfactant should be provided. The rationale for the choice and 2258

concentration of surfactant should be provided. The concentration of the surfactant 2259

should be such that the discriminatory power of the test will not be compromised. 2260

*** 2261

MULTISOURCE (GENERIC) PHARMACEUTICAL … · Working document QAS/14.583/Rev.1 July 2014 Document...

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