Working document QAS/15.622/Rev.1

August 2015

Draft document for comment

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2

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GUIDANCE FOR ORGANIZATIONS PERFORMING IN VIVO 4

BIOEQUIVALENCE STUDIES 5

(August 2015) 6

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REVISED DRAFT FOR COMMENT 8

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© World Health Organization 2015 18

All rights reserved. 19

This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The draft 20 may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in 21 any form or by any means outside these individuals and organizations (including the organizations' concerned staff and 22 member organizations) without the permission of the World Health Organization. The draft should not be displayed on any 23 website. 24

Please send any request for permission to: 25

Dr Sabine Kopp, Group Lead, Medicines Quality Assurance, Technologies, Standards and Norms, Department of Essential 26 Medicines and Health Products, World Health Organization, CH-1211 Geneva 27, Switzerland. Fax: (41-22) 791 4730; 27 email: kopps@who.int 28

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

The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or 34 recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors 35 and omissions excepted, the names of proprietary products are distinguished by initial capital letters. 36 37 All reasonable precautions have been taken by the World Health Organization to verify the information contained in this 38 draft. However, the printed material is being distributed without warranty of any kind, either expressed or implied. The 39 responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health 40 Organization be liable for damages arising from its use. 41 42 This draft does not necessarily represent the decisions or the stated policy of the World Health Organization. 43

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

Group Lead, Medicines Quality Assurance, Technologies, Standards and Norms (kopps@who.int)

with a copy to Ms Marie Gaspard (gaspardm@who.int) by 1 October 2015.

Medicines Quality Assurance working documents will be sent out electronically only and will

also be placed on the Medicines website for comment under “Current projects”. If you do not

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Working document QAS/15.622/Rev.1

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SCHEDULE FOR THE PROPOSED ADOPTION PROCESS OF DOCUMENT QAS/15.622 45

Rev.1: 46

GUIDANCE FOR ORGANIZATIONS PERFORMING IN VIVO BIOEQUIVALENCE 47

STUDIES. 48

PROPOSAL FOR REVISION 49

50

51 52

53

Presented to and discussed at the informal consultation on

inspection, GMP and risk management guidance in

medicines’ manufacturing

28–30 April 2014

Presentation of meeting recommendations to the forty-

ninth meeting of the WHO Expert Committee on

Specifications for Pharmaceutical Preparations

13–17 October 2014

Preparation of draft proposal for revision by Dr Olivier

Le Blaye, ANSM, France and Dr Stephanie Croft,

Prequalification Team (PQT)-Inspections, WHO

October 2014–April 2015

Review and discussion with inspectors and colleagues in PQT-Inspections

April–May 2015

Draft text mailed out for public consultation May 2015

Consolidation of comments received 25 June 2015

Discussion of feedback received during informal

consultation on data management, bioequivalence, GMP

and medicines’ inspection

29 June–1 July 2015

Preparation of revised working document by the authors

based on the feedback received during the public

consultation, the meeting and from the PQT-Inspections

July-August 2015

Circulation of revised working document for public

consultation

August 2015

Consolidation of comments received and review of

feedback

10 October 2015

Presentation to fiftieth meeting of the WHO Expert

Committee on Specifications for Pharmaceutical

Preparations

12–16 October 2015

Any other follow-up action as required …

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BACKGROUND 54 55

During an informal consultation held in 2014 and the forty-ninth meeting of the World Health 56

Organization (WHO) Expert Committee on Specifications for Pharmaceutical Preparations 57

discussion took place regarding the possible revision of the guidance for organizations 58

performing in vivo bioequivalence studies (WHO Technical Report Series, No. 937, Annex 59

9, 2006). 60

61

The WHO Expert Committee on Specifications for Pharmaceutical Preparations agreed that in 62

light of the new developments a draft for revision be prepared. 63

64

This guideline is being revised to take into consideration the revision for the multisource 65

guideline, as well as the creation of a new guideline on good data management. It will also be 66

revised to take into consideration the experience accumulated in the area of assessing and 67

inspecting bioequivalence (BE) studies since 2006. The areas with recurrent inspection 68

findings are being clarified and supplementary detail has been added in the area of 69

bioanalysis. It also includes an increased level of insistence on subject safety and data 70

integrity. 71

72

Based on the first working document: 73

http://www.who.int/medicines/areas/quality_safety/quality_assurance/BE-invivo-studies-guidance-74

QAS15-622_21052015.pdf?ua=1 this second version is suggested including the numerous 75

comments and feedback received from the public consultation, the PQT as well as the consultation 76

on data management, bioequivalence, GMP and medicines’ inspection held in 2015. 77

78

The PQT was started in 2001 to assure that medicinal products supplied for procurement meet WHO 79

norms and standards with respect to quality, safety and efficacy (http://www.who.int/prequal/). 80

Specifically it is a requirement that the submitted product dossier with all its necessary contents is 81

assessed and found acceptable, and that the manufacturing sites for the finished pharmaceutical 82

product (FPP), as well as the active pharmaceutical ingredient (API), are both inspected and found to 83

comply with WHO good manufacturing practices (GMP). Since products submitted to the PQT are 84

usually multisource ("generic") products, therapeutic equivalence is generally demonstrated by 85

performing a BE study, for example in a contract research organization (also known as a clinical 86

research organization) (CRO). For prequalification of such a product it is vital that, in addition to the 87

above-mentioned requirements, the CRO used by the sponsor for BE studies is compliant with 88

respect to WHO good clinical practices (GCP) and considers relevant elements from WHO good 89

laboratory practices (GLP) and good practices for quality control (QC) laboratories to ensure 90

integrity and traceability of data. In addition, if local legal provisions exist, CROs should be licensed 91

by the respective national medicines authority. Where required by national regulations, BE studies 92

should be authorized by the national regulatory authority. Those involved in the conduct and analysis 93

of BE studies with products to be submitted for prequalification therefore need to ensure that they 94

comply with the mentioned WHO norms and standards to be prepared for any inspections by WHO. 95

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Contents 101

page 102 Background 103 Introduction 3 104 1. Scope 4 105 2. Glossary 6 5 106 GENERAL SECTION 107 3. Organization and management 10 108 4. Computer systems 11 109

General 11 110 Hardware 11 111 Software 11 112 Networks 12 113 Data management 12 114

5. Quality management 13 115 6. Archive facilities 14 116 7. Premises 14 117 8. Personnel 16 118 CLINICAL SECTION 119 9. Clinical phase 17 120 10. Clinical laboratory 18 121 11. Ethics 18 122 11.1 Independent ethics committee 18 123 11.2 Informed consent 19 124 12. Monitoring 19 125 13. Investigators 20 126 14. Receiving, storage and handling of investigational drug products 20 127 15. Case report forms 23 128 16. Volunteers, recruitment methods 23 129 17. Food and fluids 24 130 18. Safety, adverse events, adverse event reporting 25 131 BIOANALYTICAL SECTION 132 19. Method development 25 133 20. Method validation 26 134 21. Sample collection, storage and handling of biological material 26 135 22. Analysis of study samples 27 136 23. Data processing and documentation 27 137 24. Good laboratory practices 28 138 PHARMACOKINETIC, STATISTICAL CALCULATIONS AND 139 REPORTING SECTION 140 25. Pharmacokinetic and statistical calculations 29 141 26. Study report 30 142 REFERENCES 30 143 Appendix 1. Examples of the list of standard operating procedures at a contract research 32 144 organization 145

146

INTRODUCTION 147 148

Multisource pharmaceutical products need to conform to the same standards of quality, 149

efficacy and safety as required of the originator's (comparator) product. Specifically, the 150

multisource product should be therapeutically equivalent and interchangeable with the 151

comparator product. Testing the BE between a product and a suitable comparator 152

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(pharmaceutically equivalent or a pharmaceutical alternative) in a pharmacokinetic study with 153

a limited number of subjects is one way of demonstrating therapeutic equivalence without 154

having to perform a clinical trial involving many patients. In such a pharmacokinetic study 155

any statement about the safety and efficacy of the test product will be a prediction based on 156

measurement of systemic concentrations, assuming that essentially similar plasma 157

concentrations of the drug will result in essentially similar concentrations at the site of action 158

and therefore an essentially similar therapeutic outcome. The BE study thus provides indirect 159

evidence of the efficacy and safety of a multisource drug product. Often this will be the only 160

evidence that the product is safe and efficacious. It is therefore crucial that the BE study is 161

performed in an appropriate manner. Several guidance documents stress the importance of 162

onsite inspections to verify compliance with standards of GCP.i,4

163

164

1. SCOPE 165 166

The objective of this document is to provide guidance to organizations that are involved in the 167

conduct and analysis of in vivo BE studies. This guidance has been updated relative to the previous 168

version of this document. 169

170

BE studies should be performed in compliance with the general regulatory requirements and good 171

practices recommendations as specified in the WHO bioequivalence guideline1, GCP

2 and GLP

3 172

guidelines. It is acknowledged that GLP formally only apply to non-clinical safety studies. 173

However the WHO bioequivalence guidelines require that the validation of bioanalytical methods 174

and the analysis of BE study samples be performed following the principles of GLP. This does not 175

imply that the laboratory in charge of the bioanalytical part of the study should be monitored as part 176

of a national GLP compliance programme. 177

178

The text below lists general recommendations for organizations (including CROs and laboratories) 179

conducting BE studies and analysis of clinical trial samples. Recommendations for facilities and 180

equipment are listed in the respective paragraphs. Recommended documents, standard operating 181

procedures (SOP) and records are listed in Appendix 1, but this is not to be considered an 182

exhaustive list – others may be necessary depending on each individual CRO’s functional and 183

compliance needs. 184

185

This document provides information on: 186

187

‒ organization and management; 188

‒ study protocols; 189

‒ clinical phase of a study; 190

‒ bioanalytical phase of a study; 191

‒ pharmacokinetic and statistical analysis; 192

‒ study report; 193

‒ quality management system. 194

195

The present guideline targets organizations conducting BE studies and highlights certain important 196

aspects of the activities of such organizations. This document does not replace the above-mentioned 197

GCP or GLP guidelines, which are more complete. It is therefore not a stand-alone document. 198

199

200

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2. GLOSSARY1 201

202

The definitions given below apply to the terms used in this guidance. They may have different 203

meanings in other contexts. 204

205

adverse event. Any untoward medical occurrence in a clinical trial subject administered a 206

pharmaceutical product; it does not necessarily have a causal relationship with the treatment. 207

208

audit of a trial. A systematic examination, carried out independently of those directly 209

involved in the trial, to determine whether the conduct of a trial complies with the agreed protocol 210

and whether the data reported are consistent with the records on site, e.g. whether data reported or 211

recorded in the case-report forms are consonant with those found in hospital files and other original 212

records. 213

214

bioequivalence. Two pharmaceutical products are bioequivalent if they are 215

pharmaceutically equivalent or pharmaceutical alternatives, and their bioavailabilities, in terms of 216

rate (Cmax and tmax) and extent of absorption (area under the curve), after administration of the same 217

molar dose under the same conditions, are similar to such a degree that their effects can be expected 218

to be essentially the same. 219

220

calibration curve samples (or calibration standards).A matrix to which a known amount 221

of analyte has been added or spiked. Calibration standards are used to construct calibration curves. 222

223

case-report form. A document that is used to record data on each trial subject during the 224

course of the trial, as defined by the protocol. The data should be collected by procedures which 225

guarantee preservation, retention and retrieval of information and allow easy access for verification, 226

audit and inspection. 227

228

comparator product (or reference product). The comparator product is a pharmaceutical 229

product with which the multisource product is intended to be interchangeable in clinical practice. 230

The comparator product will normally be the innovator product for which efficacy, safety and 231

quality have been established. If the innovator product is no longer marketed in the jurisdiction, the 232

selection principle as described in Guidance on the selection of comparator pharmaceutical 233

products for equivalence assessment of interchangeable multisource (generic) products (WHO 234

Technical Report Series, No. 992, Annex 8, 2015) should be used to identify a suitable alternative 235

comparator product. 236

237

contract. A document, dated and signed by the investigator, institution and sponsor, that 238

sets out any agreements on financial matters and delegation/distribution of responsibilities. The 239

protocol may also serve as a contract when it contains such information and is signed. 240

Contracts can also be signed with other parties such as vendors supplying services to the contract 241

research organization. 242

243

contract research organization. A scientific organization (commercial, academic or other) 244

to which a sponsor may transfer some of its tasks and obligations. Any such transfer should be 245

defined in writing. 246

1 Unless otherwise stated, reproduced from Guidelines for WHO good clinical practice for trials on

pharmaceutical products. Geneva, World Health Organization. WHO Technical Report Series, No. 850, pp. 97–

137, 1995.

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In the context of this guidance document bioequivalence studies are often contracted by the sponsor 247

to a contract research organization (CRO), which will perform some of the tasks of the sponsor, but 248

which will also perform the trial. The investigator (clinical part of the study) and the study director 249

(bioanalytical part of the study) are then employees of the CRO. 250

To facilitate reading, the term "CRO" is used throughout this document to designate any 251

organization performing the trial, even though it is acknowledged that part or all of the study may 252

be performed in-house by the sponsor itself or at a hospital. 253

254

ethics committee6.

An independent body (a review board or a committee, institutional, 255

regional or national), constituted of medical professionals and non-medical members, whose 256

responsibility is to verify that the safety, integrity and human rights of the subjects participating in 257

a particular trial are protected and to consider the general ethics of the trial, thereby providing 258

public reassurance. Ethics committees should be constituted and operated so that their tasks can be 259

executed free from bias and from any influence of those who are conducting the trial. 260

261

final report. A comprehensive description of the trial after its completion including a 262

description of experimental methods (including statistical methods) and materials, a presentation 263

and evaluation of the results, statistical analysis and a critical, ethical, statistical and clinical 264

appraisal. 265

266

good clinical practice. A standard for clinical studies which encompasses the design, 267

conduct, monitoring, termination, audit, analysis, reporting and documentation of the studies and 268

which ensures that the studies are scientifically and ethically sound and that the clinical properties 269

of the pharmaceutical product (diagnostic, therapeutic or prophylactic) under investigation are 270

properly documented. 271

272

good laboratory practice. A quality system concerned with the organizational process and 273

the conditions under which non-clinical health and environmental safety studies are planned, 274

performed, monitored, recorded, archived and reported. 275

276

informed consent. A subject’s voluntary confirmation of willingness to participate in a 277

particular trial and the documentation thereof. This consent should be sought only after all 278

appropriate information has been given about the trial including an explanation of its status as 279

research, its objectives, potential benefits, risks and inconveniences, alternative treatment that may 280

be available, and of the subject’s rights and responsibilities in accordance with the current revision 281

of the Declaration of Helsinki. 282

283

inspection. An officially-conducted examination (i.e. review of the conduct of the trial, 284

including quality assurance, personnel involved, any delegation of authority and audit) by relevant 285

authorities at the site of investigation and/or at the site of the sponsor in order to verify adherence to 286

good clinical practices and good laboratory practices as set out in this document. 287

288

internal standard. Test compound(s) (e.g. a structurally similar analogue or stable isotope 289

labelled compound) added to calibration standards, quality control samples and study samples at a 290

known and constant concentration to correct for experimental variability during sample preparation 291

and analysis. 292

293

investigational labelling. Labelling developed specifically for products involved in a 294

clinical trial. 295

296

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investigational product (or study product). Any pharmaceutical product (see definition) 297

or placebo being tested or used as a reference in a clinical trial. 298

299

investigator. A person responsible for the trial and for the rights, health and welfare of the 300

subjects in the trial. The investigator should have qualifications and competence in accordance with 301

local laws and regulations as evidenced by an up-to-date curriculum vitae and other credentials. 302

Decisions relating to, and the provision of, medical or dental care must always be the responsibility 303

of a clinically competent person legally allowed to practise medicine or dentistry. 304

305

lower limit of quantification. The lower limit of quantification of an individual analytical 306

procedure is the lowest amount of analyte in a sample which can be quantitatively determined with 307

pre-defined precision and accuracy. 308

309

monitor. A person appointed by, and responsible to, the sponsor or contract research 310

organization for the monitoring and reporting of progress of the trial and for verification of data. 311

312

pharmaceutical product. Any substance or combination of substances which has a 313

therapeutic, prophylactic or diagnostic use, or is intended to modify physiological functions, and is 314

presented in a dosage form suitable for administration to humans. 315

316

principal investigator. The investigator serving as coordinator for certain kinds of clinical 317

trials, e.g. multicentre trials. 318

Note: "principle investigator" also has a specific, but different meaning in good laboratory 319

parctices, practically seldom used in bioequivalence studies. To avoid any misunderstanding, the 320

words "principal investigator" will only be used in this guidance document with their good clinical 321

practices meaning. 322

323

protocol. A document which states the background, rationale and objectives of the trial and 324

describes its design, methodology and organization, including statistical considerations, and the 325

conditions under which it is to be performed and managed. The protocol should be dated and 326

signed by the investigator, the institution involved and the sponsor. It can also function as a 327

contract. 328

329

quality assurance relating to clinical trials. Systems and quality control procedures that 330

are established to ensure that the trial is performed and the data are generated in compliance with 331

good clinical practices and good laboratory practices. These include procedures to be followed 332

which apply to ethical and professional conduct, standard operating procedures, reporting, and 333

professional qualifications or skills of personnel. 334

335

quality control samples. A spiked sample used to monitor the performance of a 336

bioanalytical method and to assess the integrity and validity of the results of the unknown samples 337

analysed in an individual batch. 338

339

raw data. All records or certified copies of original observations, clinical findings or other 340

activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Such material 341

includes laboratory notes, memoranda, calculations and documents, as well as all records of data 342

from automated instruments or exact, verified copies, e.g. in the form of photocopies or 343

microfiches. Raw data can also include photographic negatives, microfilm, magnetic media (e.g. 344

computer diskettes) and optical media (CD-ROMs). 345

346

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serious adverse event. An event that is associated with death, admission to hospital, 347

prolongation of a hospital stay, persistent or significant disability or incapacity, or is otherwise life-348

threatening in connection with a clinical trial. 349

350

sponsor. An individual, a company, an institution or an organization which takes 351

responsibility for the initiation, management and/or financing of a clinical trial. When an 352

investigator initiates and takes full responsibility for a trial, the investigator then also assumes the 353

role of the sponsor. 354

355

standard operating procedures. Standard, detailed, written instructions for the 356

management of clinical trials. They provide a general framework enabling the efficient 357

implementation and performance of all the functions and activities for a particular trial as described 358

in this document. 359

360

study director. According to the Organisation for Economic Co-operation and 361

Development principles of good laboratory practice: the individual responsible for the overall 362

conduct of the nonclinical health and environmental safety study. In a bioequivalence study the 363

individual responsible for the conduct of the bioanalytical part of the study. 364

365

study product. see investigational product 366

367

test product. Any pharmaceutical product (see definition) or placebo being tested against 368

the reference in a clinical trial. 369

In a bioequivalence study the multisource product being tested against the comparator product. 370

371

trial subject. An individual who participates in a clinical trial, either as a recipient of the 372

pharmaceutical product under investigation or as a control. The individual may be: 373

‒ a healthy person who volunteers to participate in a trial; 374

‒ a person with a condition unrelated to the use of the investigational product; 375

‒ a person (usually a patient) whose condition is relevant to the use of the investigational 376

product. 377

378

upper limit of quantification. The upper limit of quantification of an individual analytical 379

procedure is the highest amount of analyte in a sample which can be quantitatively determined with 380

predefined precision and accuracy. 381

382

validation. Action of proving and documenting, in accordance with the principles of good 383

clinical practices and good laboratory practices, that any procedure, process, equipment (including 384

the software or hardware used), material, activity or system actually and consistently leads to the 385

expected results. 386

387

verification of data. The procedures carried out to ensure that the data contained in the 388

final report match original observations. These procedures may apply to raw data, data in case-389

report forms (in hard copy or electronic form), computer printouts and statistical analysis and 390

tables. 391

392

393

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GENERAL SECTION 394

395

3. ORGANIZATION AND MANAGEMENT 396 397

Note: the acronym “CRO” is used throughout this document to refer not only to a contract 398

research organization (CRO), but also to any organization involved in the conduct or analysis of in 399

vivo BE studies. 400

401

3.1 Where national requirements exist as to the legal status of a CRO these have to be complied 402

with. This also applies to the research unit which is a subsidiary of the manufacturer. 403

404

3.2 The CRO should have an organization chart reflecting key positions and the names of 405

responsible persons. The organization chart should be dated, authorized and kept up to date. 406

407

3.3 There should be job descriptions for all personnel, including a description of their 408

responsibilities. All job descriptions should be acknowledged and signed off by the staff member to 409

whom it applies. 410

411

3.4 There should be a list of signatures of authorized personnel participating in each study. 412

413

3.5 For the bioanalytical part of the trial, the principles of GLP clearly establish the 414

responsibilities of the test facility management. The CRO management should be aware that as the 415

investigator is an employee of the CRO, some of the responsibilities usually assigned to the 416

investigator would in a similar way reside with the CRO management. At a minimum, the CRO 417

management should: 418

‒ ensure that the principles of GCP and GLP, as appropriate, are complied with in the 419

CRO; 420

‒ ensure that a sufficient number of qualified personnel, appropriate facilities, 421

equipment and materials are available for the timely and proper conduct of the 422

study; 423

‒ ensure the maintenance of a record of the qualifications, training, experience and job 424

description for each professional and technical individual; 425

‒ ensure that personnel clearly understand the functions they are to perform and, 426

where necessary, provide training for these functions; 427

‒ ensure that appropriate and technically valid SOPs are established and followed, and 428

approve all original and revised SOPs. Ensure the maintenance of a historical file of 429

all SOPs; 430

‒ ensure that there is a quality assurance (QA) programme with designated personnel 431

and assure that the QA responsibility is being performed in accordance with the 432

principles of GLP and GCP, as appropriate; 433

‒ ensure that an individual is identified as responsible for the management of the 434

archive(s), and ensure that the documents transferred to the archives are kept under 435

adequate conditions for the appropriate duration; 436

‒ ensure that supplies meet requirements appropriate to their use in a study; 437

‒ establish procedures to ensure that computerized systems are suitable for their 438

intended purpose, and are validated, operated and maintained in accordance with the 439

principles of GCP and GLP, as appropriate. 440

441

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4. COMPUTER SYSTEMS 442 443

Note: this section highlights only some of the requirements for computer systems that are specific 444

to BE studies. Organizations involved in BE studies should ensure that the relevant principles of the 445

following guidelines are appropriately followed: 446

‒ GAMP 5: A risk-based approach to compliant GxP computerized systems4; 447

‒ Good Practices for Computerised Systems in Regulated “GXP” Environments, PIC/S 448

Guidance, Pharmaceutical Inspection Convention Pharmaceutical Inspection Co-operation 449

Scheme, PI 011-3, 25 September 20078; 450

‒ US FDA Code of Federal Regulations Part 119; 451

‒ EU guidelines to Good Manufacturing Practice and Medicinal Products for Human and 452

Veterinary Use Annex 11, Computerised systems10

; 453

‒ WHO Good data management practices guidelines7– [Note from the Secretariat: full 454

reference will be added once finalized]. 455 456 General 457

458

4.1 Computer systems should be qualified and validated (hardware, software, networks, data 459

storage systems and interfaces4,7,8,9,10

). Qualification is the planning, carrying out and recording of 460

tests on equipment and systems which form part of the validated process, to demonstrate that it will 461

perform as intended. 462

463

Hardware 464

465

4.2 There should be a sufficient number of computers to enable personnel to perform data entry 466

and data handling, required calculations and compiling of reports. 467

468

4.3 Computers should have sufficient capacity and memory for the intended use. 469

470

4.4 There should be access control to the trial-related information entered and stored in 471

computers. The method of access control should be specified (e.g. password protection) and a list 472

of people who have access to the database should be maintained. Secure and unique, individual-473

specific identifiers and passwords, should be used. 474

475

Software 476

477

4.5 The software programs used to perform key steps detailed in this guideline should be 478

suitable and validated for the intended use. Whether standard, off-the-shelf software is purchased or 479

whether bespoke software is developed, developer, vendor and/or service provider qualification 480

and/or validation certificates may be provided but it is the user’s responsibility to ensure that the 481

software is validated for its intended use. 482

483

4.6 As software, computer systems and related equipment can be technically complex, the user 484

should ensure that formal qualification and validation was carried out by the developer and that it 485

was developed in a controlled manner in accordance with a system of quality assurance. 486

487

4.7 Performance qualification should take account of the specific user’s requirements, of 488

regulatory/guideline requirements for BE studies, of the operating environment in which it will be 489

used, and of how it will be used by an organization’s staff in the context of a study. Quality risk 490

analysis should be applied when deciding which components need to be validated. All phases of 491

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their life cycle should be considered. For example, when a CRO decommissions the software in use 492

for high-performance liquid chromatography (HPLC) and mass spectrometric (MS) analysis (e.g. 493

HPLC-MS/MS), it should ensure that the data collected by the system using this software remains 494

fully readable. This could be done, for instance, by having the old software installed on a 495

workstation for inspection/verification purposes only. 496

497

4.8 There should be SOPs in place for usage of each software program that is used to perform 498

key steps of a BE study. 499

500

4.9 There should be a system in place for the implementation of regular updates to key software 501

programs (e.g. such as those used for control and data processing of chromatographic and mass 502

spectrometry systems) whenever required, following an appropriate risk assessment on the potential 503

impact that it could have on current data and on qualification/validation status. 504

505

4.10 Software programs used, frequency of virus testing, storage of data and the making and 506

archiving and keeping of back-ups should be specified in writing. 507

508

4.11 The programs used should be able to provide the required quality and management 509

information, reliably and accurately. Necessary programs for data management include word 510

processing, data entry, databases, graphics, pharmacokinetics and statistical programs. Self-511

designed software programs must be suitable and validated for their intended use. 512

513

4.12 Since data for BE studies is often transferred electronically between organizations 514

involved in the studies, there should be a verification that the software used between each 515

organization is compatible prior to commencing key study-related tasks. 516

517

4.13 These requirements apply to all systems used in clinical BE studies, e.g. subject database, 518

electronic case report forms, electrocardiogram (ECG) recording software, HPLC-MS/MS 519

software, software used for pharmacokinetic analysis, for statistical analysis, etc. 520

521

Networks 522

523

4.14 Networks, including the full client/server architecture and interfaces such as laboratory 524

information management systems, when used, should be appropriately designed, qualified, 525

managed and controlled. 526

527

4.15 Access to each component of the system by the different users at any given organization 528

involved in the studies, should be appropriately defined, controlled and documented. 529

530

4.16 There should be a documented inventory of all computerized systems on the network, with 531

a clear identification of those which are GxP regulated. Any changes to the network, including the 532

temporary addition or removal of systems from the network, should be documented. 533

534

Data management 535

536

4.17 Data entry includes transfer of the data from case report forms (CRF) and analytical data to 537

the computerized system for pharmacokinetic and statistical analysis and reporting. 538

539

4.18 Data entry procedures should be designed to prevent errors. The data entry process should 540

be specified in the SOP. 541

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542

4.19 Double entry of the data should be performed. Data validation methodology (proof-reading, 543

double data entry, electronic logical control) should be specified in writing. 544

545

4.20 Changes made to data entered in the database should be made by authorized persons only. 546

Changes should be specified and documented. 547

548

4.21 Electronic data should be backed up at regular intervals. The reliability and 549

completeness of these back-ups should be verified – data should not be selected but 550

comprehensively backed up. 551

552

4.22 All of the raw electronic data must be kept. This includes: 553

– all meta data associated to a computerized system and the equipment that is associated to it 554

(which includes the audit trails for integration, for projects and for the entire instrument); 555

– validation data and meta data in the form of their source electronic files. 556

PDF copies are not sufficient on their own, unless it can be demonstrated that these are the 557

raw data and that no alteration was possible after they were generated. 558

559

4.23 All electronic records obtained from HPLC and MS analysis (e.g. HPLC-MS/MS) are 560

required to be retained, maintained and backed-up. It should be ensured that back-up data are 561

exact and complete and that they are secure from alteration, inadvertent erasures or loss shall 562

be maintained. The printed paper copy of the chromatogram would not be considered a “true, 563

exact and complete copy” of the entire electronic raw data used to create that chromatogram. 564

Printed chromatograms do not generally include, for example, the sample sequence, 565

instrument method, processing method, integration settings or the full audit trail, of which all 566

were used to create the chromatogram or are associated with its validity. Therefore there 567

should be a higher emphasis on conservation of electronic data than paper data, as paper data 568

is usually not considered the true source data, except in the case of paper logbooks where the 569

original record was handwritten, for instance. 570

571

4.24 If data is transformed during processing steps (such as in the example of re-integration 572

of chromatographic data), it should always be possible to compare the original data with the 573

processed data. 574 575 5. QUALITY MANAGEMENT 576 577

5.1 The CRO should have appropriate QA and QC systems with written SOPs to ensure that 578

trials are conducted and data are generated, documented and reported in compliance with the 579

protocol, GCP, GLP and the applicable regulatory requirements. 580

581

5.2 QA personnel should be independent of the work they are quality assuring, including: 582

‒ conducting or monitoring of the trial; 583

‒ conducting bioanalysis; 584

‒ performing reporting and pharmacokinetic and statistical analyses. 585

As a consequence, QA personnel should not be directly involved in trial-related activities, and an 586

in-process audit by QA personnel does not replace oversight by another person when required. 587

588

5.3 The QA unit should be responsible for: 589

Working document QAS/15.622/Rev.1

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‒ verifying all activities undertaken during the study; 590

‒ ensuring that the quality management systems, are followed, reviewed and updated; 591

‒ determining that the protocol and SOPs are made available to study personnel and are being 592

followed; 593

‒ checking all the study data for reliability and traceability; 594

‒ planning and performing self-inspections (internal audits) at regular and defined intervals in 595

accordance with an SOP, and following up on any corrective action as required, to 596

determine if all studies are conducted in accordance with GCP and GLP; 597

‒ ensuring that contract facilities adhere to GCP and, if applicable, to GLP. This would 598

include auditing of such facilities, and following up on any corrective action as required; 599

‒ verifying that the trial report accurately and completely reflects the data of the study and the 600

methods and procedures followed; 601

‒ promptly reporting audit findings in writing to management, to the investigator and to the 602

study director, as applicable. 603

604

5.4 The CRO should allow the sponsor to monitor the studies and to perform audits of the 605

clinical and analytical study and sites and should provide suitable office space for these activities.. 606

607

5.5 Both retrospective and in-process (e.g. in bioanalysis, as the samples and standards 608

are being prepared and tested) QA verifications should be performed. 609

610

5.6 The quality management system should include root cause analysis, tracking for trends 611

and ensuring all aspects of data integrity. 612

613

6. ARCHIVE FACILITIES 614 615

Note: The CRO should have sufficient and appropriately secure storage space, which should be 616

fire proof, humidity-controlled and pest-controlled, for archiving of trial-related 617

documentation and product samples. Archives should be protected from flooding. 618

619

6.1 An SOP should be in place for archiving. 620

621

6.2 Access to archive storage areas should be controlled and restricted to authorized personnel. 622

623

6.3 Records should be maintained of document access and return. 624

625

6.4 The length of period for which study documentation including raw data is kept in the 626

archive should be defined in the SOP and may vary depending on country requirements. This 627

duration should be specified in the contract between the sponsor and the CRO, which should 628

include provisions for financing of the archival. 629

630

6.5 All data, including both paper and electronic, should be easy to retrieve and traceable. 631

632

7. PREMISES 633 634

7.1 The facilities should be maintained clean and should have adequate conditions of lighting, 635

ventilation and, if required, environmental control. Floor, walls and working benches surfaces 636

should facilitate the cleaning and decontamination. 637

638

Working document QAS/15.622/Rev.1

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7.2 Clinical trials must be carried out under conditions which ensure adequate safety for the 639

subjects. The site selected should be appropriate to the potential risk involved. 640

641

7.3 The CRO should have sufficient space to accommodate the personnel and activities required 642

to perform the studies. The trial site must have adequate facilities, including laboratories, and 643

equipment. The facilities used for the clinical phase of the study, including areas listed in paragraph 644

9.6 should be well organized in order to carry out the activities in logical order. 645

646

7.4 The entry to the facility should be restricted and controlled. There should be alarm systems 647

to detect the exit of subjects from clinical facilities or the doors should be locked (however, doors 648

should be locked only if emergency evacuation can still be ensured). Any entry and exit to the 649

facility should be recorded. 650

651

7.5 Sites involved in clinical activities should include a pharmacy where investigational 652

products should be stored under appropriate conditions with entry and exit restricted by access 653

control. Appropriate entry/exit records of each visit to the pharmacy should be maintained. 654

655

7.6 Utilities such as water, air, gas and electricity should be adequate, stable and uninterrupted. 656

657

7.7 There should be access to telephone, email and facsimile facilities to ensure proper 658

communication. The CRO should have the necessary office equipment (printer, copy machine) to 659

perform the required activities. 660

661

7.8 Laboratory premises should be designed to suit the operations to be carried out in them. 662

Sufficient space should be given to avoid mix ups, contamination and cross-contamination. There 663

should be adequate suitable storage space for samples, standards, solvents, reagents and records. 664

665

7.9 Laboratory premises should be designed to provide adequate protection to all employees 666

and visitors, including inspectors or auditors, by ensuring their safety while handling or working in 667

the presence of chemicals and biological samples. Improper working conditions can negatively 668

impact on the quality of the work performed and of the data generated. 669

670

The following general rules for safe working in accordance with national regulations and SOPs 671

normally include the following requirements: 672

(a) safety data sheets should be available to staff before testing is carried out; staff working in 673

the laboratory should be familiar with and knowledgeable of the material safety data sheets for 674

the chemicals and solvents that they are handling; 675

(b) smoking, eating and drinking in the laboratory should be prohibited; 676

(c) staff should be familiar with the use of fire-fighting equipment, including fire extinguishers, 677

fire blankets and gas masks; 678

(d) staff should wear laboratory coats or other protective clothing, including eye protection; 679

(e) special care should be taken, as appropriate, in handling, for example, highly potent, 680

infectious or volatile substances; 681

(f) highly toxic and/or genotoxic samples should be handled in a specially designed facility to 682

avoid the risk of contamination; 683

(g) all containers of chemicals should be fully labelled and include prominent warnings (e.g. 684

“poison”, “flammable”, “radioactive”) whenever appropriate; 685

(h) adequate insulation and spark-proofing should be provided for electrical wiring and 686

equipment, including refrigerators; 687

Working document QAS/15.622/Rev.1

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(i) rules on safe handling of cylinders of compressed gases should be observed and staff should 688

be familiar with the relevant colour identification codes; 689

(j) staff should be aware of the need to avoid working alone in the laboratory; 690

(k) first-aid materials should be provided and staff instructed in first-aid techniques, emergency 691

care and the use of antidotes: 692

(l) containers containing volatile organic solvents, such as mobile phases or liquid/liquid 693

extraction solvents, should be closed with an appropriate seal; 694

(m) volatile organic chemicals should be handled under certified fume-hoods or air extractors 695

and safety and eye showers should be available in the laboratory. 696

697

7.10 Premises should have suitable systems in place to dispose of waste, to treat fumes and to 698

protect the environment in conformance to local or national regulation. 699

700

8. PERSONNEL 701 702

8.1 There should be a sufficient number of qualified and appropriately trained medical, 703

paramedical, technical and clerical staff to support the trial and to be able to respond effectively to 704

all reasonably foreseeable emergencies. The number of members of staff required depends on the 705

number and complexity of the trials performed by the CRO. At all stages during the trial, including 706

at night, there should be a sufficient number of appropriately qualified and trained personnel to 707

ensure that the rights, safety and well-being of the subjects are maintained, and to take care of the 708

subjects in emergency situations. 709

710

8.2 The delegation of significant trial-related duties should be documented in writing. 711

712

8.3 Contract workers may be employed to perform certain activities. All contract workers 713

having access to the clinical or bioanalytical areas or performing trial-related activities should be 714

provided with adequate information, training and job descriptions. Their contracts should be signed 715

before the performance of work. 716

717

8.4 Current curriculum vitae and training records should be kept for full-time and contract 718

workers. 719

720

8.5 The personnel responsible for the planning and conduct of the study should have 721

appropriate qualifications and sufficient knowledge and experience in the relevant field. They 722

should receive the study-specific information and training required for the performance of their 723

work. 724

725

8.6 Records for training and assessment of knowledge of GCP, GLP and any other relevant area 726

or technique should be maintained. 727

728

8.7 There should be adequate measures in place to protect personnel from accidental 729

contamination (e.g. from accidental needle pricks) while obtaining blood samples from subjects or 730

while handling the samples that are derived from blood products (e.g. plasma and its extracts) or 731

while handling or disposing of infectious waste. 732

733

734

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CLINICAL SECTION 735 736

9. CLINICAL PHASE 737 738

Note: As in vivo BE trials are considered as clinical trials, specifically a Phase I study, the 739

general requirements and recommendations of GCP apply to all BE trials. Clinical trials 740

must be carried out under conditions which ensure adequate safety of the subjects. The 741

clinical phase of the study can be performed in the premises of a CRO or by contracting 742

suitable premises in a hospital. 743

744

9.1 A CRO should have rooms meeting the requirements listed in the sections below. 745

746

9.2 There should be sufficient space to accommodate the study subjects. 747

748

9.3 Where appropriate, beds should be available for the subjects. The necessity of beds and 749

overnight stay depends on the type of trial and investigational drug and should be specified in the 750

trial protocol. Overnight stays are usually required during the night prior to dosing to ensure 751

adequately controlled conditions and that there was no outside food/medication intake within the 752

number of hours that is specified in the trial protocol. 753

754

9.4 Systems should be in place in the housing facilities and toilets so that subjects can alert 755

CRO staff in case of need. 756

757

9.5 Facilities for changing and storing clothes and for washing and toilet purposes should be 758

clean, well ordered, easily accessible and appropriate for the number of users. Closed toilets should 759

be alarmed and doors should be designed to ensure that they can be opened from the outside should 760

there be a medical emergency. 761

762

9.6 The study site should have the following facilities which should be separate areas where 763

appropriate: 764

‒ rooms (areas) for subjects registration and screening; 765

‒ room (area) for individual subjects to obtain informed consent without compromising 766

privacy; 767

‒ room for subjects housing; 768

‒ room (area) for subjects (recreation area); 769

‒ restricted-access room for pharmaceutical operations (e.g. storage, repacking, dispensing, 770

documentation) (see also section 14); 771

‒ rooms (areas) for administration of the drug(s) under investigation and sample collection; 772

‒ room (area) for sample processing (e.g. plasma separation) and storage (freezer); 773

‒ controlled access storage areas for study materials, medication and documentation including 774

CRFs; 775

‒ rooms (areas) in which to prepare standardized meals and a dining hall; 776

‒ availability of emergency or first-aid equipment and appropriate rescue medication for use 777

in emergencies. 778

‒ adequate facilities for the proper care of subjects who require emergency or other medical 779

care; 780

‒ archiving facilities. 781

782

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9.7 Provisions should be made for the urgent transportation of subjects to a hospital or clinic 783

equipped for the emergency care of subjects, if required by their condition. 784

785

9.8 Access to key documents, such as the randomization list, should be restricted to only certain 786

specific members of personnel such as the pharmacist in charge of the study. Such documents 787

should be password-secured (if electronic) or kept under lock and key (if distributed as a hard-788

copy) and their distribution should be documented. 789

790

9.9 Equipment used to obtain clinical measurements should be appropriately calibrated at pre-791

defined intervals. 792

793

9.10 The adequate function and performance of emergency-use equipment (e.g. defibrillators) 794

should be verified at appropriate intervals. 795

796

10. CLINICAL LABORATORY 797 798

10.1 A suitable qualified clinical laboratory should be used for analysing samples. An accredited 799

laboratory should be used whenever possible. 800

801

10.2 Haematological tests, urine analysis and other tests should be performed during the clinical 802

trial as specified in the study protocol. 803

804

10.3 Sample labelling, receipt storage and chain of custody should ensure full traceability and 805

sample integrity.11

806

807

10.4 The CRO should be supplied with information about analytical methods used in the 808

laboratory, a dated list of laboratory normal ranges and accreditation certificate of the laboratory, if 809

available. These should be available for inspection by regulatory authorities, if required. 810

811

10.5 A current and signed curriculum vitae of the responsible analyst should be available in the 812

laboratory information file. 813

814

10.6 Individual reports should be established by the laboratory for each subject and should be 815

included in the CRFs. Source or raw data for all tests performed should be archived by the 816

laboratory in electronic or paper formats, depending on their source and storage capacity. 817

Electronic formats are preferred. 818

819

10.7 Data integrity requirements apply to all tests related to the study (full reference to be 820

confirmed once the WHO data integrity guidelines are finalized.) For instance, raw data should be 821

adequately protected from modification or deletion. 822

823

11. ETHICS 824 825 11.1 Independent ethics committee 826

Trials must be approved by an independent ethics committee (IEC) (or equivalent) before a study is 827

conducted, according to WHO Operational guidelines for Ethics Committees that review 828

biomedical research6 and to the enforced legislation. This committee must be independent from the 829

sponsor, the investigator and of the CRO. The discussions, recommendations and decisions of the 830

Working document QAS/15.622/Rev.1

page 19

IEC meetings should be documented in detailed minutes of the meeting. The IEC should be given 831

sufficient time for reviewing protocols, informed consent forms (ICFs) and related documentation. 832

833

11.2 Informed consent 834

• Information for study participants should be given in a language and on a level of 835

complexity appropriate and understandable to the subject, both orally and in writing. 836

837

• Informed consent must always be given by the subject and documented in writing before the 838

start of any trial-related activities, in accordance with GCP. If informed consent is also 839

recorded by video this recording should be retained following local legal requirements . 840

841

• The information must make clear that participation is voluntary and that the subject has the 842

right to withdraw from the study on his or her own initiative at any time, without having to 843

give a reason (compensation should be paid prorata temporis). If subjects who withdraw 844

from the study offer their reasons for doing so, those reasons should be included in the 845

study records. 846

847

• The subject must have access to information about insurance and other procedures for 848

compensation or treatment should he or she be injured or disabled by participating in the 849

trial or during screening. 850

851

• The volunteers/subjects should be given opportunity to discuss their concerns with a 852

physician regarding potential side effects or reactions from the use of the investigational 853

products before participation in the trial. They should also be given the opportunity and 854

sufficient time to discuss their concerns with their participation in the trial with individuals 855

outside of the CRO, such as friends and family members, if they wish. 856

857

• If the ICF is available in several languages (e.g. in English and in the local language, or in 858

several vernacular languages), it should be ensured that all versions of the form contain the 859

same information. 860

861

12. MONITORING 862 863

Note: monitoring is an essential activity to ensure the quality of the clinical trial. 864

865

12.1 The monitor should be qualified (see section 8, Personnel). The main responsibility of the 866

monitor for a BE study is to ensure that the study is conducted in accordance with the protocol, 867

GCP, GLP and applicable ethical and regulatory requirements. This includes verification of the use 868

of correct procedures for completion of CRFs and verification of the accuracy of data obtained. 869

870

12.2 The sponsor can delegate the monitoring function to the CRO. In such cases the CRO 871

should be able to arrange for the monitoring of the trial according to regulatory requirements. In 872

such a case attention should be paid to the independence of the monitoring function in order to 873

avoid conflicts of interest and pressure on the monitors. The monitoring reports should always be 874

provided to the sponsor. 875

876

12.3 A risk-based approach to monitoring can be considered. However, a pre- and post-study 877

visit as well as a monitoring visit during the conduct of the trial are usually performed. The monitor 878

should prepare a written report after each site visit and communicate any issues to the CRO and to 879

Working document QAS/15.622/Rev.1

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the sponsor as promptly as possible, even during conduct of the study if possible, to enable prompt 880

corrective action. Such communications and corrective actions should be documented. 881

882

12.4 When the monitoring is delegated to the CRO, SOPs should be available to describe: 883

‒ the designation of monitors, who should be independent from the personnel performing the 884

trial; 885

‒ monitoring visit procedures; 886

‒ the extent of source data verification, including with regards to accountability of the 887

investigational products and adherence to the protocol. 888

The extent of the monitoring, including the number of visits to be performed, should be agreed 889

upon with the sponsor. 890

891

12.5 Separate SOPs (with checklists for the monitor) for the initiation visit, routine monitoring 892

visits and a closing visit are recommended. 893

894

12.6 Appropriate entry/exit record of each monitoring visit should be maintained. 895

896

13. INVESTIGATORS 897 898

13.1 The principal investigator (PI) should have the overall responsibility for the clinical conduct 899

of the study, including clinical aspects of study design, administration of the products under 900

investigation, contacts with local authorities and the ethics committee and for signing the protocol 901

and the final study report. 902

903

13.2 The investigator(s) should have appropriate qualifications, be suitably trained and 904

have experience in the conduct of BE studies (the legal status of persons authorized to act as 905

investigators differs between countries) and at least one investigator must be legally allowed 906

to practise medicine. 907

908

13.3 The medically-qualified investigator should be responsible for the integrity, health and 909

welfare of the subjects during the trial and the accurate documentation of all trial-related clinical 910

data. 911

912

13.4 The CRO is responsible for selecting investigator(s). In cases where the investigators are 913

not permanent employees of the CRO external investigators should be contracted and adequately 914

trained. 915

916

14. RECEIVING, STORAGE AND HANDLING OF INVESTIGATIONAL DRUG 917

PRODUCTS 918 919

14.1 CROs should document all the information concerning the receipt, storage, handling 920

and accountability of investigational and comparator products at any stage of the trial. CROs 921

must keep records of information about the shipment, delivery, receipt, storage (including 922

storage conditions), dispensing, administration, reconciliation, return and/or destruction of 923

any remaining pharmaceutical products. Detail of the pharmaceutical product used should 924

include dosage form and strength, lot number, expiry date and other coding that identifies the 925

specific characteristics of the product tested. 926

927

Working document QAS/15.622/Rev.1

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14.2 A suitable location within the CRO or a local pharmacy or hospital pharmacy should 928

assume responsibility for storage, delivery, return and record keeping of the investigational 929

products. 930

931

14.3 Pharmaceutical products should be stored under appropriate storage conditions as specified 932

in the official drug information provided by the sponsor. 933

934

14.4 All study medication should be kept in a securely locked area accessible only to authorized 935

persons. 936

937

14.5 Randomization should be performed in accordance with an SOP and records should be 938

maintained, including the randomization list and seed, if applicable. Under normal operations the 939

randomization list should be accessible only to the person who generates it, a dispensing 940

pharmacist and the statistician and should not be circulated or made available to other staff 941

members via any medium. A system should be in place which allows the PI or delegated staff to 942

access the randomization list in case of emergencies. 943

944

14.6 Labelling should be performed in accordance with the following requirements: 945

‒ the printing step should be done in a manner that reduces potential risks of mislabelling and 946

should be done in accordance with a SOP; 947

‒ each label should include the following information 948

• name of the sponsor, 949

• a statement of “for clinical trial use only”, 950

• trial reference number or study number, 951

• batch number, 952

• subject identification number (to which the product is destined to be given to), 953

• period, 954

• active ingredient and dosage, 955

• the storage conditions, 956

• expiry date (month/year) or retest date, 957

• identification of the product (test or reference). 958

‒ compliance of all labels with the randomization list should be verified once printed, prior to 959

labelling of the containers; 960

‒ labelling should be done on the container, not on the lid, to ensure that the information is 961

not lost once the lid is removed; 962

‒ the system used for labelling and documenting the administration of the product should 963

make it possible to verify that each subject indeed received the product dispensed for him, 964

for instance, by using labels with a tear-off portion. In such a case, labels should be 965

designed in such a way that two identical labels are pasted to the container and that the 966

second label can be easily cut or detached and pasted onto the CRFs at the time of dosing 967

(e.g. two labels printed side by side, with only one that is actually pasted onto the container 968

and the other one which remains attached but unpasted – it should be torn off or cut with 969

scissors at the time of dosing. Using two independent labels – one stuck on the container, 970

one kept loose – should be avoided due to the risk of mix-ups); 971

‒ the empty containers should be labelled separately for the test and the reference 972

investigational products and should remain adequately segregated and placed in a secure 973

area under lock and key, to ensure absence of risk of any potential mix ups, until the 974

dispensing stage; 975

Working document QAS/15.622/Rev.1

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‒ label reconciliation should be performed; 976

‒ appropriate, detailed records should be maintained for each of the above steps. 977

978

14.7 Dispensing/packaging should be performed in accordance with the following requirements: 979

‒ the surface area on to which the product will be handled should be thoroughly cleaned prior 980

to bringing bottles of the product in the area. Any product container (full or empty), lone 981

dosage formulations, labelling materials contaminants/dirt/debris should be removed from 982

the area; 983

‒ a second person should verify that the surface area (otherwise referred to as “line”) is indeed 984

clear and clean prior to bringing and opening containers of the product: 985

‒ test and reference products should be handled using an appropriate instrument, such as a 986

spatula or spoon, as opposed to gloved hands; 987

‒ tablets should be distributed in each container in accordance with the randomization list 988

either for the comparator or for the test product. Both products should never be handled at 989

the same time. This also applies to the labelled containers; 990

‒ records should be made of this step in a manner that is similar to manufacturing batch 991

records, as described in WHO GMP guidelines, i.e. each and every step should be recorded 992

sequentially in detail; 993

‒ the surface area used to handle the product and its surroundings should be cleared and 994

cleaned immediately after and/or prior to initiating the dispensing of the next product (it is 995

important to note that this also applies to different products used in the same study); 996

‒ drug accountability and dispensing records should be maintained at all times. Each activity 997

should be documented at the time it is performed. This includes 998

• records of doses dispensed and returned or destroyed, 999

• records of cleaning and clearance of the area prior to dispensing, 1000

• record of verification of adequate cleaning and clearance of the area, 1001

• record of verification by a second person of each step; 1002

‒ any factors that could affect the integrity of the data relating to investigational medicinal 1003

products and comparators should be recorded, monitored and controlled. 1004

1005

[Please refer for further guidance on labelling and dispensing to the WHO good manufacturing 1006

practices: supplementary guidelines for the manufacture of investigational pharmaceutical 1007

products for clinical trials in humans, WHO Technical Report Series, No. 964, Annex 7, 1996.] 1008

1009

14.8 Dosing should be performed in accordance with the following requirements: 1010

‒ dosing should be performed in accordance with a SOP; 1011

‒ it should be performed under the supervision of the investigator or of qualified staff to 1012

whom this task has been explicitly delegated in writing; 1013

‒ whenever possible, just prior to dosing, a check should be performed of vial contents 1014

matching the information on the label; 1015

‒ the exact time of dosing should be documented; 1016

‒ in order to ensure that the subject has swallowed the product, a mouth check should be 1017

performed by looking under the tongue, under the lips, in the corners of the mouth and 1018

between gums and cheeks, using a tongue depressor or a spatula and a flashlight, in the case 1019

of solid oral dosage forms. For other types of dosage forms verification of adequate 1020

administration should be performed by other suitable means. It should be documented; 1021

‒ if more than one dosage unit is administered this should be clearly documented; 1022

Working document QAS/15.622/Rev.1

page 23

‒ dosing can be documented directly in the case report forms. If retranscribed in the case of 1023

report forms from other documents the original documents should be retained; 1024

‒ drug reconciliation, after dosing, should be verified by a second responsible person. 1025

1026

14.9 The investigator should follow the protocol requirements, randomization scheme and where 1027

required, blinding. The investigator should ensure that the investigational product use is 1028

documented in such a way as to ensure appropriate dosage. 1029

1030

14.10 Samples of the product in the original container should be retained for possible 1031

confirmatory testing in the future for a period of at least one year after the expiry date of the newest 1032

product (test or reference) or in compliance with the applicable national requirements or 1033

international recommendations, as appropriate. Sample retention should be defined and described in 1034

an SOP and be specified in the contract between the sponsor and the CRO. Dispensed products that 1035

were not administered should also be retained. 1036

1037

15. CASE REPORT FORMS 1038 1039

15.1 CRFs should be used to record data on each subject during the course of the trial. 1040

1041

15.2 The CRO should have a procedure for designing CRFs if the sponsor requests the CRO to 1042

design them. It is recommended to use a standardized format or template which should be amended 1043

for each study protocol in accordance with the requirements for the particular study. The CRF 1044

should be reviewed against other trial documentation such as the protocol and trial database to 1045

ensure that appropriate information and data is captured and that the CRF is consistent with other 1046

trial documentation. 1047

1048

15.3 The required data to be collected on each volunteer should be specified in the trial protocol. 1049

Any data to be recorded directly on the CRF (i.e. no prior written or electronic record of data), and 1050

to be considered to be source data, should be identified in the protocol. 1051

1052

15.4 CRFs should reflect the actual results obtained during the study and allow easy access to 1053

verification, audit and inspection of the data. 1054

1055

15.5 Appropriate procedures should be established and followed to document the investigator's 1056

certification of the accuracy of CRFs. Any errors or omissions should be clarified with the 1057

investigator, corrected, dated and signed and explained on the CRF. 1058

1059

15.6 Copies of the clinical laboratory reports and all ECGs should be included with the CRFs for 1060

each subject and should be submitted along with the dossier, if applicable, according to 1061

requirements of the regulatory authority to whom the dossier is submitted. 1062

1063

16. VOLUNTEERS, RECRUITMENT METHODS 1064 1065

Note: The selection of subjects should be performed sufficiently in advance to ensure that a 1066

sufficient number of subjects will be available. The last-minute selection of additional 1067

subjects may result in non-compliance with the inclusion and exclusion criteria, 1068

possibly compromising the safety of the subjects and the integrity of the trial data. The 1069

use of a generic screening process to select a pool of subjects which can be enrolled in 1070

any bioequivalence study conducted at the CRO (unless the protocol foresees specific 1071

inclusion or exclusion criteria) can help to achieve this goal. 1072

Working document QAS/15.622/Rev.1

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1073

16.1 Procedures for the recruitment of volunteers should be available and should include a 1074

description of the potential methods that can be used by the CRO for recruitment of volunteers. A 1075

database should be maintained for volunteers to avoid cross-participation and to specify a minimum 1076

time interval between a volunteer’s participation in two studies. Access to the database should be 1077

password controlled in order to secure confidential volunteer/subject information. 1078

1079

16.2 Volunteer and subject identification should be ensured by reliable means. If a biometric 1080

system is used for the identification of volunteers this system should be validated on a periodic 1081

basis as well as after any change made to the validated system that could impact its function. 1082

1083

16.3 Informed consent of potential subjects should be obtained for any screening procedures 1084

required to determine eligibility for the study, in addition to informed consent for participation in 1085

the research portion of the study. 1086

1087

16.4 Subject selection criteria (inclusion and exclusion criteria) and recruitment procedures 1088

should be described in the clinical trial protocol. 1089

1090

16.5 Subject screening results and trial participation should be recorded in a validated 1091

database maintained by the CRO. If a regional or national volunteer database exists then trial 1092

participation should be checked and participation data uploaded to this central repository to 1093

prevent over-volunteering. Access to the database should be password controlled in order to 1094

secure confidential subject information. 1095

1096

16.6 Ideally the CRO's database should record and allow the users to query: 1097

– contact details; 1098

– gender; 1099

– status: eligible, disqualified, not eligible, quarantined, etc., and the reason for this 1100

status if applicable; 1101

– date and place of last study participation, if applicable/if known; 1102

– date of last screening; 1103

– a unique code assigned to the subject which will never change; 1104

– outcome of last trial: Completed, randomised but not dosed, withdrawn for personal 1105

reason, withdrawn for medical reason, etc. 1106

These data should be backed up daily and be available for review at any time. 1107

1108

16.7 Medical records should be generated for each subject and should include information 1109

obtained during each screening visit and each study participation, which could be relevant for 1110

the inclusion and follow-up of the subject into subsequent trials. Access to previous medical 1111

records for individual subjects should be available and a consistency check conducted where 1112

trial-specific medical records are generated. This is important to ensure safety issues can be 1113

assessed before enrolment in a study. 1114

1115

17. FOOD AND FLUIDS 1116 1117

17.1 As meals can significantly affect absorption of drugs fasting and meals should be 1118

standardized and adequately controlled and scheduled during the study days. The CRO should be 1119

able to arrange for standardized meals, snacks and drinks to study subjects as described in the 1120

clinical trial protocol. 1121

Working document QAS/15.622/Rev.1

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1122

17.2 Records should be maintained for timing, duration and amount of food and fluids 1123

consumed. Subjects should be asked for food and drink consumption prior to ambulatory samples 1124

being obtained, if the protocol contains specific requirements. 1125

1126

17.3 Standardized meals should be designed by a dietician with appropriate qualification, 1127

training and experience. If such services are contracted out a formal contract with terms of 1128

reference should be available. 1129

1130

18. SAFETY, ADVERSE EVENTS, ADVERSE EVENT REPORTING 1131 1132

18.1 Appropriate study planning includes adequate evaluation of risk to the subjects. The study 1133

should be planned, organized, performed and monitored so that the safety profile will be 1134

acceptable, including to the volunteers. 1135

1136

18.2 First-aid emergency equipment and appropriate rescue medication should be available at the 1137

study site and adequate facilities of the proper care of subjects who require emergency or other 1138

medical care. Any treatment given to a subject should be documented and included in the CRF and 1139

supporting documentation as necessary. 1140

1141

18.3 A medical doctor should be responsible for medical decisions in case of adverse events and 1142

for notifying the relevant health authorities, the sponsor and, when applicable, the Ethics 1143

Committee, without delay in the case of serious adverse events. Appropriate timelines should be 1144

respected as governed by national regulations. 1145

1146

18.4 The CRO should have appropriate adverse event registration and reporting forms, which 1147

should be provided to the investigator; these forms can be part of the CRF. If required the 1148

respective sponsor's forms may be used. 1149

1150

BIOANALYTICAL SECTION 1151

1152

Note: The analysis of drug concentrations may be performed in the same CRO which conducted 1153

the clinical study, or may be contracted to another laboratory or CRO. 1154

1155

19. METHOD DEVELOPMENT 1156

1157 19.1 The bioanalytical laboratory should provide detail on how a bioanalytical method was 1158

developed. The laboratory should keep a copy of any publication used to develop the bioanalytical 1159

method. The modifications and adaptations to the published method made by the laboratory should 1160

be documented. 1161

1162 19.2 Selection of the internal standard should be justifiable by sound scientific principles. In 1163

general, chemical and physical properties of the internal standard should be as close to those of the 1164

analyte as possible. Both stable isotope-labelled and non-isotope labelled internal standards are 1165

acceptable, though the use of stable isotope-labelled internal standard is recommended when MS 1166

methods are used. The selection of a stable isotope labelled internal standard should take into 1167

consideration factors such as the isotope labelling positions in order to limit the risk of exchange 1168

reactions. 1169

1170

Working document QAS/15.622/Rev.1

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19.3 Method development should ensure that methods are created in a manner which will 1171

minimize any potential human error. 1172

1173

20. METHOD VALIDATION 1174 1175

The most up-to-date guidelines from stringent regulatory authorities (SRAs) on the topic 1176

of bioanalytical method validation should be followed. 1177

1178 20.1 Validation requirements for the analytical method should be described in the protocol. 1179

There should be separate SOPs for analytical method validation. 1180

1181

20.2 Data to support the stability of the samples under the stated conditions and period of storage 1182

should be available preferably before the start of the study. 1183

1184

20.3 Method validation should be performed with at least one run that is comparable in length to 1185

those that are expected to be used for analysis of samples. 1186

1187

21. SAMPLE COLLECTION, STORAGE AND HANDLING OF BIOLOGICAL 1188

MATERIAL 1189 1190

21.1 The specification of the samples (serum, plasma or urine), sampling method, volume and 1191

number of samples should be stated in the clinical trial protocol and the information provided to the 1192

volunteer. 1193

1194

21.2 There should be documented procedures for the collection, preparation, transport or 1195

shipping and storage of samples. 1196

1197

21.3 Any specific lighting conditions foreseen by the protocol or other documents should be 1198

complied with. This should be documented. 1199

1200

21.4 Actual sampling times and deviations from the prespecified sampling times should be 1201

recorded. Deviations should be reported in the study report and should be taken into consideration 1202

when calculating the pharmacokinetic parameters. 1203

1204

21.5 Labelling of collected samples should be clear to ensure correct identification and 1205

traceability of each sample. 1206

1207

21.6 The storage conditions of samples depend on the investigational drug. However, all storage 1208

conditions (e.g. freezer temperature) should be specified in the study protocol, controlled, 1209

monitored and recorded throughout the storage period and transportation. Procedures should be in 1210

place to ensure sample integrity in case of system failures. 1211

1212

21.7 Records for the storage and retrieval of samples should be maintained. 1213

1214

21.8 It is recommended to keep duplicate or back-up samples, and store and ship them 1215

separately. 1216

1217

21.9 The duration of storage of bioanalytical samples should be specified in the contract between 1218

the sponsor and the CRO. 1219

1220

Working document QAS/15.622/Rev.1

page 27

21.10 Local requirements for the handling and destruction of remaining biological materials 1221

should be followed. 1222

1223

22. ANALYSIS OF STUDY SAMPLES 1224

1225 The most up-to-date guidelines from SRAs on the topic of bioanalytical method validation should 1226

be applied. Additionally: 1227

1228 22.1 The results of the method validation should be available before the initiation of study 1229

sample analysis, with the possible exception of the evaluation of the long-term stability of the 1230

analyte in matrix. However these results should be available before the study report is issued and 1231

should be submitted with the validation report in the application. 1232

1233 22.2 Each analytical run should include calibration curve (CC) standards, QC samples and 1234

subject samples processed simultaneously. The exact sequence of processing should be 1235

documented. All samples collected from a given subject during all trial periods should be analysed 1236

in the same run unless scientifically justified (e.g. due to the limited stability of samples, requiring 1237

the analysis of period one samples before period two is conducted). 1238

1239

22.3 Equipment with an adequate capacity should be used to be able to process all samples in a 1240

run simultaneously, rather than splitting the samples into several extraction batches. However, if 1241

using several extraction batches within a single analytical run cannot be avoided, each batch should 1242

include QC samples. The acceptance criteria for the analytical run should be defined in a SOP first 1243

for the full run, then if the run is acceptable, for each individual extraction batch. 1244

1245

22.4 Every effort should be made during method development to avoid carry-over effects. If 1246

carry-over cannot be avoided, procedures should be implemented to limit its influence, for instance, 1247

by inserting wash samples into runs after samples with a high level of concentration. 1248

1249

22.5 With regards to the use of blank plasma in the preparation of CCs and QCs: 1250

‒ the number of freeze-thaw cycles and the storage duration that a given blank plasma sample 1251

can be submitted to, should be limited as much as possible to ensure absence of degradation 1252

and/or change of its properties. Freezing blank plasma in small volumes should be 1253

considered to help limit the number of freeze-thaw cycles for any given blank plasma 1254

sample; 1255

‒ the anticoagulant that was used for the blank plasma should be documented. It should match 1256

the anticoagulant that was used in study samples, in nature and in proportion. 1257

1258

22.6 With regards to incurred sample reanalysis: 1259

‒ incurred sample reanalysis should be performed in line with the European Medicines 1260

Agency (EMA) Guideline on Bioanalytical Method Validation (2011)5; 1261

‒ large differences between results may indicate analytical issues and should be investigated. 1262

1263

23. DATA PROCESSING AND DOCUMENTATION 1264 1265

23.1 Integration settings should be science-based and fully justifiable. Smoothing should be kept 1266

low enough not to mask possible interferences and changes in peak geometry. 1267

1268

Working document QAS/15.622/Rev.1

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23.2 The different iterations used to obtain a CC should be saved – if a given CC fails, it is not 1269

acceptable to exclude CCs which meet acceptance criteria or similarly, to include CC standards 1270

which do not meet criteria, just to make the calibration or the QC standards pass. The source data 1271

should contain the original, first evaluation of runs (containing all calibration samples). If several 1272

calibration samples are excluded sequentially the CC obtained at each step should be retained to 1273

document that the criteria to exclude the next sample were met. If electronic raw data are used it is 1274

acceptable to only save the final calibration if it is possible to revert to the initial calibration during 1275

an inspection. The process and criteria for acceptance and exclusion of CC standards should be 1276

described in an SOP. 1277

1278

23.3 If the first or last calibration sample is rejected the calibration range should be truncated, i.e. 1279

the second calibration sample becomes the lower limit of quantification (LLOQ) in that run (or the 1280

one before last calibration sample becomes the upper limit of quantification (ULOQ). Samples with 1281

a concentration below the revised LLOQ (or above the revised ULOQ) should be reanalysed. 1282

Alternatively, the whole run may be repeated but this is not the preferred option. 1283

1284

23.4 Internal standard variation should be trended and used as part of the verifications of result 1285

validity. Significant changes in internal standard response could signal an analytical problem which 1286

could require an investigation and/or sample reanalysis. Significant differences between the internal 1287

standard results of CC standards or QC standards vs samples could also signal problems affecting 1288

the reliability of the results. 1289

1290

23.5 Full audit trails should be activated at all times and on all analytical instruments in a given 1291

facility, both prior, during and after the method validation and the study of interest. 1292

1293

23.6 All original analytical raw data (e.g. calculations, chromatograms and their associated audit 1294

trails, etc.) should be documented in a manner that will ensure traceability with respect to the 1295

sample number, equipment used, date and time of analysis and the name(s) of the technician(s). If 1296

several audit trail files are generated all should be retained (e.g. results table audit trail, project 1297

audit trail, instrument audit trail). 1298

1299

23.7 Each data point should be traceable to a specific sample, including sample number, time of 1300

collection of the sample, time of centrifugation, if applicable, time when the sample was placed in 1301

the freezer, time of sample analysis, etc., to be able to determine whether any aberrant results might 1302

have been due to sample mishandling. 1303

1304

24. GOOD LABORATORY PRACTICES 1305

1306 24.1 Although most GLP guidelines

3 apply formally only to non-clinical safety studies, general 1307

principles of GLP should also be followed during the bioanalytical part of bioequivalence studies. 1308

1309

24.2 Analysis should be performed in a laboratory with established QA systems. 1310

1311

24.3 Key sample storage systems or other areas requiring environmental controls should be 1312

adequately qualified, calibrated and maintained. There should be an alarm system or an adequate 1313

monitoring system to control the temperature of the critical stage areas and key sample storage 1314

systems, such as freezers. If there is an automatic alarm system it has to be tested regularly for its 1315

functionality. The daily monitoring and all the alarm checks should be documented. There should 1316

be a system in place to ensure that timely and appropriate action is taken following an alarm. 1317

1318

Working document QAS/15.622/Rev.1

page 29

24.4 For purposes of qualification and requalification the temperature mapping of the freezers 1319

and refrigerators should be run for between 24 and 72 hours, or more if justified. Remapping 1320

should be done after any significant modifications to the storage units. 1321

1322

24.5 Appropriate repairs and/or sample transfer to other equivalent storage units should be 1323

considered whenever an analysis of temperature monitoring records show unexplained variability 1324

outside normal operating limits. 1325

1326

24.6 Balances, other measuring devices and equipment/instruments used during the conduct of a 1327

trial should be periodically calibrated and verified before use. They should be fit for their intended 1328

purpose. 1329

1330

24.7. There should be SOPs for the operation, use, calibration, checks and preventive 1331

maintenance of equipment. Records should be maintained. Equipment used during the course of the 1332

trial should be identified to be able to verify that they have been appropriately qualified and 1333

calibrated. 1334

1335

24.8 Chemicals, reference substances, reagents, solvents and solutions should be labelled to 1336

indicate identity, purity concentration (if appropriate), expiry date and specific storage instructions. 1337

Information concerning source, preparation date and stability should be available. 1338

1339

PHARMACOKINETIC, STATISTICAL CALCULATIONS AND 1340

REPORTING SECTION 1341

1342

25. PHARMACOKINETIC AND STATISTICAL CALCULATIONS 1343 1344

25.1 The statistical model underlying any primary BE analysis should be stated in the 1345

protocol and/or a statistical analysis plan. It should be made clear which factors are fixed and 1346

which are random. It should be stated if the model is a mixed effects model, a normal linear 1347

model, etc. If the methods of statistical analysis are amended following protocol approval 1348

then this should be documented in a protocol amendment and should also be reported in the 1349

clinical study report including the reason for change. 1350

1351

25.2 Calculations should be made by qualified persons (see Section 8: Personnel). 1352

1353

25.3 The means of performing pharmacokinetic and statistical calculations (both software and 1354

scripts) should be specified in the study protocol and/or a pharmacokinetic analysis plan and a 1355

statistical analysis plan. Data analysis should conform to these requirements. This should include 1356

the manner in which AUCinf is derived (i.e. how the points used for extrapolation are selected). 1357

1358

25.4 Calculations should be made using validated software and scripts. Software and scripts 1359

should be validated or qualified using an SOP, ideally with datasets of varying complexity and with 1360

the alpha level(s) actually in use. Self-designed software should be demonstrated as suitable for 1361

intended use. For guidance on the use of computerized systems (5) (see Section 4: Computer 1362

Systems). 1363

1364

25.5 Data values input should be double-checked by a second qualified person as per an SOP. 1365

1366

Working document QAS/15.622/Rev.1

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25.6 A database of trial records should be maintained and it should preferably be locked as soon 1367

as possible after completion of the study. Once it is locked the study can be unblinded and 1368

statistical analysis performed. The dates of locking and statistical analysis should be documented, 1369

mentioned in the study report and the process should be defined in a suitable procedure. 1370

1371

26. STUDY REPORT 1372 1373

26.1 The clinical study report should reflect the complete study procedures and results in an 1374

accurate manner. 1375

1376

26.2 The clinical study report should be well written and presented. All deviations from the 1377

protocol in the performance of the study should be reported. 1378

1379

26.3 There should be no discrepancies between the results stated in the report and the actual 1380

original (raw) data. 1381

1382

26.4 The report should comply with regulatory requirements as applicable and be presented in a 1383

standard format. 1384

1385

26.5 The study report should include a report on the bioanalytical part of the trial, including a 1386

description of the bioanalytical method used and the validation report of this method. 1387

1388

26.6 The procedure for approval of the clinical study report by the investigator and sponsor and 1389

for approval of the bioanalytical report by the study director should be specified. 1390

1391

26.7 The report should be approved (signed and dated) by the responsible persons. 1392

1393

26.8 All monitoring and audit reports should be available before release of the final study report. 1394

1395

REFERENCES 1396 1397

1. Multisource (generic) pharmaceutical products: guidelines on registration requirements to 1398

establish interchangeability. In: Expert Committee on Specifications for Pharmaceutical 1399

Preparations. Forty-ninth report. World Health Organization, Geneva. WHO Technical 1400

Report Series, No. 992, Annex 7, 2015, pp. 347–390. 1401

1402

2. Guidelines for good clinical practice for trials on pharmaceutical products. WHO Technical 1403

Report Series, No. 850, 1995 (pp. 97–137). 1404

1405

3. WHO Handbook on Good Laboratory Practice/OECD Series on Principles of Good 1406

Laboratory Practice and Compliance Monitoring, Number 1: OECD Principles on Good 1407

Laboratory Practice (as revised in 1997). Organization for Economic Co-operation and 1408

Development. ENV/MC/CHEM(98)17. 26.Jan, 1998. 1409

1410

4. The Good Automated Manufacturing Practice (GAMP) Guide - A risk-based approach to 1411

compliant GxP computerized systems (GAMP5). ISPE - International Society for 1412

Pharmaceutical Engineering, December 2009. 1413

1414

5. Guidelines on Bioanalytical Method Validation EMEA/CHMP/EWP/192217/2009 Rev.1 1415

Corr.* Committee for Medicinal Products for Human Use (CHMP), 1 February 2012. 1416

Working document QAS/15.622/Rev.1

page 31

1417

6. WHO Operational guidelines for Ethics Committees that review biomedical research (7). 1418

WHO, TDR/PRD/ETHICS/2000.1. http://www.who.int/tdr/publications/ 1419

documents/ethics.pdf?ua=1). 1420

1421

7. WHO Good data management practices guidelines (full reference to be confirmed once 1422

finalized.) 1423

1424

8. Good Practices for Computerised Systems in Regulated “GXP” Environments, PIC/S 1425

Guidance, Pharmaceutical Inspection Convention Pharmaceutical Inspection Co-operation 1426

Scheme, PI 011-3, 25 September 2007. 1427

1428

9. US FDA Code of Federal Regulations Part 11. 1429

1430

10. EU guidelines to Good Manufacturing Practice and Medicinal Products for Human and 1431

Veterinary Use Annex 11, Computerised systems. 1432

1433

1434

Working document QAS/15.622/Rev.1

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APPENDIX 1 (REVISED) 1435 EXAMPLES OF THE LIST OF STANDARD OPERATING PROCEDURES AT A CONTRACT 1436

RESEARCH ORGANIZATION 1437 1438

The following are examples of the list of standard operating procedures (SOPs) that should be 1439

used at contract research organizations (CROs). This list is not exhaustive as other procedures 1440

may be necessary depending on the functional and compliance requirements at each facility. 1441

All of the documents at the CRO related to a bioequivalence (BE)/clinical trial should be 1442

controlled (version date, approved, etc.) documents. This control is easier if the documents 1443

are in the SOP format or are appended to SOPs. 1444

SOPs should be in place at least for all the critical and major operations in the BE/clinical 1445

trial. 1446

Number and name of SOP 1447

1. Conduct of BE study. 1448

2. Archiving and retrieval of documents related to a BE study. 1449

3. Quality assurance of a BE study; audits of clinical and bioanalytical part of the study 1450

and the study report. 1451

4. Study files. 1452

5. Preparation and review of the protocol for the study. 1453

6. Amendment to the protocol for the study. 1454

7. Protocol deviations/violation recording and reporting. 1455

8. Sponsor/CRO quality assurance agreement in conducting the BE study. 1456

9. Study approval process by ethical committee . 1457

10. Bioavailability (BA)/BE report. 1458

11. Study report. 1459

12. Written informed consent. 1460

13. Obtaining written informed consent for screening from study volunteers. 1461

14. Allotment of identification numbers to volunteers at various stages in BE study. 1462

15. Investigator’s brochure. 1463

16. Case-report form (CRF). 1464

17. Preparation of CRF, review and completion. 1465

18. Data collection and CRF completion. 1466

19. Adverse/serious adverse event monitoring, recording and reporting. 1467

20. Organization chart of the study. 1468

21. Training of the personnel. 1469

22. Responsibilities of the members of the research team. 1470

23. Monitoring of the study by the sponsor. 1471

24. Conduct of pre-study meeting. 1472

25. Study start-up. 1473

26. Subject management. 1474

27. SOP on mobilization of individuals for registration into volunteer bank. 1475

28. Eligibility criteria for registration and registration of individuals into volunteer bank. 1476

29. Handling of subject withdrawal. 1477

30. Allotment of identification numbers to volunteers at various stages in the biostudy. 1478

31. Screening of enrolled volunteers for the study. 1479

32. Collection of urine samples of subjects for detection of drugs of abuse and 1480

transportation of samples to pathology laboratory. 1481

33. Custodian duties. 1482

Working document QAS/15.622/Rev.1

page 33

34. Payments to research subjects for BA/BE studies. 1483

35. Procedures for entry into and exit from clinical unit 1484

36. Handling of subject check-in and check-out. 1485

37. Housekeeping at clinical unit. 1486

38. Planning, preparation, evaluation and service of standardized meals for bio-studies. 1487

39. Distribution of meals to study subjects. 1488

40. Operation and maintenance of nurse calling system. 1489

41. Administration of oral solid dosage form of the drug to human subjects during BA/BE 1490

study. 1491

42. Cannulation of study subjects. 1492

43. Collection of blood samples from study subjects. 1493

44. Identification of biological samples. 1494

45. Recording of vital signs of subjects. 1495

46. Operation and verification of fire alarm system. 1496

47. Oxygen administration to subject from medical oxygen cylinder. 1497

48. Emergency care of subjects during BA/BE study. 1498

49. Availability of ambulance during BA/BE study. 1499

50. Centrifugation and separation of blood samples. 1500

51. Storage of plasma/serum samples. 1501

52. Segregation of bio-samples. 1502

53. Transfer of plasma/serum samples to bioanalytical laboratory. 1503

54. Procedures for washing glassware. 1504

55. Recording temperature and relative humidity of rooms. 1505

56. Instruction on operation and maintenance procedures for all the equipment in the 1506

clinical unit. 1507

57. Numbering the equipment and log books for use in the clinical unit. 1508

58. Control of access to pharmacy. 1509

59. Pharmacy area requirements. 1510

60. Authorization related to drug storage, dispensing and retrieval from storage for BE study. 1511

61. Study drug receipt, return and accountability documentation. 1512

62. Study drug receipt and return procedures. 1513

63. Storage of drugs in the pharmacy. 1514

64. Line clearance before and after dispensing. 1515

65. Documentation of line clearance and dispensing; packaging records and release of 1516

dispensed drugs. 1517

66. Retention of samples of study drugs. 1518

67. Disposal of archived study drugs. 1519

68. Disposal of biological materials. 1520

69. Procedures for bioanalytical laboratory (SOPs for the different equipment, analytical 1521

methods, reagent preparation). 1522

70. Out-of-specification in the laboratory. 1523

71. Acceptance criteria for analytical runs: acceptance of calibration curves, acceptance of 1524

the runs based on quality control samples results. 1525

72. Chromatographic acceptance criteria, chromatogram integration. 1526

73. Sample re-assay. 1527

74. Pharmacokinetic data from bioanalytical data. 1528

75. Statistics in a BE study. 1529

i

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