WHO DRAFT GUIDANCE ON TESTING OF “SUSPECT” SPURIOUS ...€¦ · Working document QAS/15.634/Rev.2 Draft page 7 3.153 GLOSSARY 154 155 chain of custody. A chronological record

Working document QAS/15.634/Rev.2 Draft

October 2016

Draft document for discussion

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WHO DRAFT GUIDANCE ON TESTING OF “SUSPECT” 3

SPURIOUS/FALSELY-LABELLED/ 4

FALSIFIED/COUNTERFEIT MEDICINES 5

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(October 2016) 7

DRAFT FOR COMMENT 8

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© World Health Organization 2016 15

All rights reserved. 16

This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The draft 17 may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in any 18 form or by any means outside these individuals and organizations (including the organizations' concerned staff and member 19 organizations) without the permission of the World Health Organization. The draft should not be displayed on any website. 20

Please send any request for permission to: 21

Dr Sabine Kopp, Group Lead, Medicines Quality Assurance, Technologies, Standards and Norms, Department of Essential 22 Medicines and Health Products, World Health Organization, CH-1211 Geneva 27, Switzerland. Fax: (41-22) 791 4730; email: 23 [email protected]. 24

The designations employed and the presentation of the material in this draft do not imply the expression of any opinion 25 whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its 26 authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines 27 for which there may not yet be full agreement. 28

The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended 29 by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions 30 excepted, the names of proprietary products are distinguished by initial capital letters. 31

All reasonable precautions have been taken by the World Health Organization to verify the information contained in this draft. 32 However, the printed material is being distributed without warranty of any kind, either expressed or implied. The responsibility 33 for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for 34 damages arising from its use. 35

This draft does not necessarily represent the decisions or the stated policy of the World Health Organization. 36

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

Group Lead, Medicines Quality Assurance, Technologies, Standards and Norms

([email protected]) with a copy to Ms Wendy Bonny ([email protected]) by 10 January 2017.

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SCHEDULE FOR THE PROPOSED ADOPTION PROCESS OF DOCUMENT QAS/15.634 Rev.2: 38

DRAFT Guidance on 39

testing of “suspect” spurious/falsely-labelled/falsified/counterfeit medicines 40

Discussion at forty-ninth meeting of the WHO Expert

Committee on Specifications for Pharmaceutical

Preparations

13–17 October 2014

Follow-up of the forty-ninth meeting of the WHO Expert


Preparations meeting recommendations for drafting if a

general text on the testing of “suspect” spurious/falsely-

labelled/falsified/counterfeit (SFFC) medicines,

including chapters on techniques and sampling

October–April 2015

Discussion at consultation on screening technology,

sampling and specifications for medicines

13–15 April 2015

Follow-up and drafting of a text based on the discussions

held and additional input from experts

15–30 May 2015

Recirculation for feedback to the working group May–July 2015

Circulation for comments to the national quality control

laboratories who participated in the survey

August–September 2015

Collation of comments received September–October 2015

Presentation to the fiftieth meeting of the WHO Expert


Preparations

12–16 October 2015

Follow-up and drafting of a text based on the discussions

held and additional input from experts related to two

Annexes, drafts prepared by Dr M. Guzzetti, Switzerland

November 2015–February 2016

Circulation to national quality control laboratories having

participated in the survey

March 2016

Collation of feedback received April 2016

Discussion at consultation on quality control laboratory

tools and specifications for medicines

9–11 May 2016

Revision of text based on the feedback and additional June–October 2016


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information received, including from the European

network of official quality control laboratories

specialized in this area

Circulation for comments October 2016

Presentation to the fifty-first meeting of the WHO Expert


Preparations

17–21 October 2016

Any follow-up action, as necessary


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Contents 58

page 59

1. Introduction .................................................................................................................. 5 60

1.1 “Suspect” medicines ............................................................................................. 5 61

1.2 Responsibility of regulatory authorities ................................................................ 5 62

1.3 The role of the World Health Organization .......................................................... 6 63

2. Scope .............................................................................................................................. 6 64

3. Glossary ......................................................................................................................... 7 65

4. Detection of samples of suspected SFFC products .................................................... 8 66

4.1 Entry points for detection ...................................................................................... 8 67

4.2 Detection methods................................................................................................. 9 68

4.3 Selection of analytical techniques ....................................................................... 10 69

5. Sampling and documentation .................................................................................... 10 70

5.1 Sampling ............................................................................................................. 10 71

5.2 Documentation of information on suspected SFFCs .......................................... 11 72

5.3 Chain of custody considerations ......................................................................... 11 73

6. Regulatory actions upon detection of suspected SFFC samples ............................ 13 74

6.1 Risk assessment................................................................................................... 13 75

6.2 Communication ................................................................................................... 14 76

7. Confirmatory laboratory testing ............................................................................... 14 77

7.1 Laboratory capacity ............................................................................................. 15 78

7.2 Standard operating procedure ............................................................................. 16 79

7.3 Questions to be answered by testing ................................................................... 17 80

7.4 Testing plan and test procedures ......................................................................... 18 81

7.5 Interpretation and reporting of results ................................................................. 19 82

8. Reporting of confirmed SFFC products ................................................................... 19 83

9. Archiving of samples and reports ............................................................................. 20 84

10. References ................................................................................................................... 20 85

Annex 1. Examples of analytical techniques that may be used for package 86

identification, screening and testing of suspected SFFC products ................. 22 87

Annex 2. Example of an information collection form ………………………..………….. 27 88

Annex 3. Example of a content of a standard operating procedure for testing of 89

suspected SFFC medicines .................................................................................. 30 90

Annex 4. Examples of flowcharts for testing of suspected SFFC tablets ......................... 36 91


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1. INTRODUCTION 92

93

1.1 “Suspect” medicines 94

95

Substandard/spurious/falsely-labelled/falsified/counterfeit (SSFFC) medicines can be divided 96

into two main categories of products: 97

98

substandard products that are produced and distributed – in principle – in accordance with 99

legal provisions but that do not meet their quality specifications due to error and/or 100

negligence during the manufacturing process and/or inappropriate storage; 101

spurious, falsely-labelled, falsified and/or counterfeit (SFFC) products, which are the 102

result of deliberate actions intended to deceive patients and health workers. 103

104

This document deals specifically with products that are suspected to belong to the second 105

category. 106

107

1.2 Responsibility of regulatory authorities 108

109

National and regional regulatory authorities (NRAs) have a duty to establish rules and 110

instruments that control the production, distribution and commercialization of medical products 111

in order to ensure their quality through rigorous regulatory oversight, including postmarketing 112

surveillance, in line with national legislation and regulations on pharmaceutical products. 113

Rigorous regulatory oversight of medical products throughout their life cycle is necessary to 114

recognize and remove illicit SFFC products and to protect the supply chain against infiltration of 115

such products. 116

117

SFFC products originate from outside the legal supply chain. It is important that NRAs control 118

the supply chain and raise awareness of health workers and patients of risks associated with 119

medicines from illegal sources. 120

121


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A legal definition of SFFC medicines and specific legal provisions to penalize acts related to 122

falsification of medical products will empower NRAs to take actions against this problem. In 123

implementing and enforcing legal provisions on SFFC medicines NRAs should collaborate with 124

enforcement agencies at the national and international level as appropriate. 125

126

1.3 The role of the World Health Organization 127

128

The World Health Organization (WHO), through its Expert Committee on Specifications for 129

Pharmaceutical Preparations, sets technical standards on quality assurance of pharmaceutical 130

products, including guidance on registration, good manufacturing practices (GMP), good 131

distribution practices (GDP) and quality control (QC) testing of medicines and other topics that 132

are relevant to the regulatory oversight of medicines. 133

134

The Committee provided a guideline on sampling and market surveillance (1). A survey 135

conducted among regulatory authorities of WHO Member States (2) indicated the need for 136

specific technical guidance on laboratory testing of suspected SFFC products. The present 137

document was developed in response to the survey findings. 138

139

The Member State Mechanism on SSFFC medical products, created in 2012, makes 140

recommendations to support regulatory authorities to prevent, detect and act against activities 141

and behaviours that result in SSFFC medical products (3). This document is intended to 142

complement the Member State Mechanism’s recommendations in accordance with resolution 143

WHA67.20 on Regulatory system strengthening for medical products (4). 144

145

2. SCOPE 146

147

This document provides technical guidance on laboratory testing of samples of suspected SFFC 148

products detected on the market of WHO Member States and related aspects of sampling and 149

reporting. 150

151

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3. GLOSSARY 153

154

chain of custody. A chronological record of the seizure and custody of the suspect 155

product and the subsequent transfer of a sample of the suspect product to the laboratory as well 156

as the handling of the sample within the laboratory. 157

158

forensic. Related to analysis for law enforcement purposes. 159

160

marketing authorization (product license, registration certificate). A legal document 161

issued by the competent medicines regulatory authority that authorizes the marketing or free 162

distribution of a pharmaceutical product in the respective country after evaluation for safety, 163

efficacy and quality. In terms of quality it establishes inter alia the detailed composition and 164

formulation of the pharmaceutical product and the quality requirements for the product and its 165

ingredients. It also includes details of packaging, labelling, storage conditions, shelf life and 166

approved conditions of use. 167

168

quality control. All measures taken, including the setting of specifications, sampling, 169

testing and analytical clearance, to ensure that raw materials, intermediates, packaging materials 170

and finished pharmaceutical products conform with established specifications for identity, 171

strength, purity and other characteristics. 172

173

quality management. A wide-ranging concept covering all matters that individually or 174

collectively influence the quality of a product. It is the totality of the arrangements made with the 175

object of ensuring that pharmaceutical products are of the quality required for their intended use. 176

177

screening technologies. The qualitative and/or quantitative technologies which could 178

rapidly acquire the analytical information or data for preliminary identification of suspect 179

medical products in the field. 180

181

spurious/falsely-labelled/falsified/counterfeit product. For the purposes of this 182

document, a product for which a false representation is deliberately given of its identity and/or 183


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source and/or record keeping for traceability, and/or regulatory approval, and which therefore 184

requires testing beyond the routine quality control testing. 185

186

standard operating procedure. An authorized written procedure giving instructions for 187

performing standardized operations both general and specific. 188

189

substandard product. For the purposes of this document, a substandard product is a 190

pharmaceutical product that does not meet its quality standards and specifications according to 191

the requirements in the territory of use, which are normally reviewed, assessed and approved by 192

the applicable national or regional medicines regulatory authority before the product is 193

authorized for marketing. 194

195

4. DETECTION OF SAMPLES OF SUSPECTED SFFC PRODUCTS 196

197

4.1 Entry points for detection 198

199

Regulatory authorities are responsible for establishing mechanisms to detect SFFC products 200

circulating in their territories and to remove them from the market.1 201

202

Suspected SFFC products can be detected using a range of approaches, including routine 203

inspections performed by national or regional authorities and enforcement agencies, targeted 204

risk-based surveys (1), investigation of complaints, follow-up of reports on any suspicious 205

observations in the supply chain (for example, inconsistent documentation, unexpected stock 206

levels) and investigation of unexpected adverse events reported to have occurred with a specific 207

product. It is important to evaluate any information on suspected SFFC products which may 208

come from, e.g. customs authorities, procurement agencies, pharmacies, health-care institutions 209

or patients. 210

211

1 See also reference (3), Paragraph II.1. Quality monitoring and control.


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4.2 Detection methods2 212

213

SFFC products may be identified by their fake packaging and/or by physical and chemical 214

testing. 215

216

The packaging and patient information leaflets of suspect SFFC medicines should always be 217

examined visually and compared with samples or images of genuine products if available. 218

Attention should be paid to any irregularities or inconsistencies, such as spelling mistakes, 219

unusual batch numbers, unexpected or modified manufacturing or expiry dates, signs of 220

repacking, for example, to circumvent inspection activities, or instructions in a language that 221

does not match the area of their distribution. Microscopy and other analytical techniques 222

(including but not limited to optical techniques) may be utilized for the package examination. 223

224

A list of technologies that can be used to discriminate between genuine products and SFFC 225

products and to screen the market for SFFC products is provided in Annex 1. More detailed 226

descriptions of available technologies are found in published literature and online guidance (6, 227

7). 228

229

In the context of law enforcement, the result of a screening test is only indicative (preliminary or 230

presumptive adverse analytical result) and other analytical techniques must be applied to 231

unequivocally confirm that an SFFC product has been detected. 232

233

Some of the methods shown in Annex 1 rely on a comparison with suitable reference materials 234

or data available in a library or a reference database. Sharing of reference values and screening 235

results through access controlled information technology (IT) interfaces can be a strong support 236

for the application of rapid medical product screening technologies. 237

2 Further guidance on screening technologies is provided by the Working Group of the WHO Member State Mechanism

on substandard/spurious/falsely-labelled/falsified/counterfeit medical products (3) through its prioritized activities 2014–

2015, specifically Activity C aiming to establish and convene a working group comprised of Member States experts to

assess and report on: (a) existing “track and trace” technologies in use by Member States; and (b) existing field detection

devices in use or available to Member States.


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238

4.3 Selection of analytical techniques 239

240

Annex 1 provides an overview of available analytical techniques at the time of developing these 241

guidelines. To ensure efficient use of available resources, the regulatory authority should obtain 242

updated information about available analytical techniques before making decisions on the use of 243

analytical techniques mentioned, taking into account: 244

245

the expected benefits of each technology (scientifically based), given its applicability and 246

performance characteristics; 247

opportunities for efficient use within existing postmarketing surveillance activities such 248

as inspections for compliance with licencing requirements, GMP or GDP; 249

the availability of adequately trained operators in-country and cost of training; 250

the expected cost of equipment, including periodic calibration and qualification; 251

ongoing cost of consumables, reference materials/libraries and maintenance; 252

any other factors that may influence the use of analytical techniques in the national 253

context. 254

255

5. SAMPLING AND DOCUMENTATION 256

257

5.1 Sampling 258

259

Sampling of suspected SFFC products is typically performed by inspectors or enforcement 260

officers (such as police or customs officers) upon detection of a suspicious product. Care should 261

be taken to ensure that the sample is representative of the suspect product. A sufficient number 262

of dosage units should be taken to enable further analyses; some guidance in this regard is found 263

in reference (1), and a suitably qualified laboratory can be consulted to provide advice. 264

265

266

267


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5.2 Documentation of information on suspected SFFCs 268

269

Documentation should be prepared with information on everything that is known about the 270

sample, including the point of detection, the volume of suspect product found, a visual 271

description of its packaging and the dosage units including any signs of irregularities, the supply 272

history of the product and what led to its detection – including, e.g. adverse effects and any other 273

relevant information. This information should accompany the sample from the time it is taken up 274

to its final fate. An example of an information collection form that may be used is presented in 275

Annex 2. 276

277

5.3 Chain of custody considerations3 278

279

A rigorous chain of custody should be maintained, not only during the collection of the suspect 280

medical products but also during the testing thereof, until the reporting to the court, if applicable, 281

providing evidence – including for legal purposes – that the integrity of the sample and its 282

accompanying documentation has been preserved. Secure packing and labelling as well as 283

adequate transport and storage conditions must be ensured to prevent mix ups and damage. 284

Rigorous security arrangements must be in place to prevent any theft, tampering, substitution or 285

unauthorized disclosure of information. 286

287

The chain of custody of a sample consists of two parts. The first starts at the location where the 288

suspected SFFC product was seized or purchased by the inspector and includes all stages of the 289

process to deliver the sample to the analytical testing laboratory. The second part concerns the 290

laboratory to ensure that the sample is always considered to be in custody. All transfers of the 291

sample must be recorded so that the analytical report generated by the laboratory can be 292

unequivocally linked to the source of the sample. 293

294

3 See also reference (3), Paragraph IV.1.1. 30.


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The inspectors or enforcement officers should document details of the suspected SFFC product 295

including: 296

297

location of detection (name or title and address); 298

pharmaceutical product type; 299

quantity and/or volume; 300

date and time of seizure/purchase; 301

names and signatures of the inspector/enforcement officer and the owner of the suspected 302

SFFC medicine at the location; 303

description of packaging; 304

supply chain; 305

other relevant information. 306

307

The inspector/enforcement officer is responsible for sample transport and, if appropriate, should 308

consider refrigerating or freezing the samples to minimize sample degradation due to factors like 309

time delays and hot temperature conditions if the samples are not to be transported immediately. 310

The samples are to be secured until delivered to the analytical testing laboratory. Where possible, 311

samples are to be stored in a cool environment, with warm conditions avoided. 312

313

The inspector/enforcement officer includes a copy the appropriate documentation in each 314

transport bag/container, containing the samples, to ensure that the laboratory can verify the 315

contents on delivery. 316

317

Samples may be taken directly to the analytical testing laboratory by the inspector/enforcement 318

officer or handed over to a courier for transportation . 319

320

If an approved courier company is used to transport the samples, it should be documented in the 321

chain of custody of the samples and the inspector/enforcement officer should record the waybill 322

number of the shipment. 323

324

Within the laboratory, samples are considered to be in custody when: 325


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326

in the physical possession of authorized staff; 327

within the view of authorized staff after being in his/her physical possession; and 328

stored in a secure location. 329

330

The laboratory chain of custody is the documentation, which includes log books, work sheets, 331

forms, etc., where the custody of the samples during analysis and storage is recorded with the 332

signature of the staff member and the date and time of the action. The laboratory chain of 333

custody shall be a continuous record of authorized staff with custody of the samples at all stages 334

of the process from receipt to disposal of the samples. At each stage, the authorized staff 335

involved must sign and date for the action performed. 336

337

It is essential to ensure traceability throughout the process – from the seizure/purchase of the 338

suspected SFFC product to the conclusion of the investigation. 339

340

6. REGULATORY ACTIONS UPON DETECTION OF SUSPECTED SFFC 341

SAMPLES 342

343

6.1 Risk assessment 344

345

When a suspected SFFC product has been found the NRA of the country where the product was 346

found should be informed. The NRA should then perform a risk assessment of the issue to 347

determine further action required to protect public health.4 This assessment should be done in 348

communication and collaboration with the marketing authorization /license/registration holder, if 349

applicable, or manufacturer of the genuine product and other entities such as a testing laboratory 350

with experience in testing suspected SFFC products. WHO and other regulatory authorities 351

should also be informed as appropriate. 352

353

4 See reference (3), Section III. Assessment of alerts, reports and notifications received.


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In most cases, further action will include confirmatory laboratory testing of the suspect samples. 354

355

6.2 Communication 356

357

Care should be taken to convey clear and appropriate messages in communicating information 358

about suspected or confirmed SFFC products. Patients should be advised not to stop taking their 359

medication without consulting their health professional. Health professionals and procurement 360

agencies should be instructed on the action(s) to be taken to enable a continued supply and 361

treatment while ensuring patient safety. In all communication the manufacturer whose name is 362

printed on the packaging products should be described as the “Stated manufacturer”, making it 363

clear that the SFFC medicine might not have originated from that manufacturer. 364

Miscommunication can amount to falsely accusing the legal manufacturer of falsifying a 365

product, which would be grounds for legal action by that manufacturer. 366

367

Dissemination of information should be well planned to reach all relevant stakeholders while 368

ensuring confidentiality as appropriate. NRAs should keep a record of the date, recipients and 369

content of information disseminated. 370

371

7. CONFIRMATORY LABORATORY TESTING 372

373

If further laboratory analysis is to be conducted, NRAs should refer samples to a laboratory with 374

adequate capacity to perform the testing as described in this document. If no such laboratory is 375

available in the country NRAs should identify a competent and suitably equipped laboratory in 376

their region or elsewhere that can advise on designing a testing plan and/or do some or all of the 377

testing. The manufacturer of the genuine product may also be requested to provide information 378

or methods (including reference substances and a sample of the genuine product) that may be 379

used for the testing of suspect samples. 380

381


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7.1 Laboratory capacity 382

383

Best practices for QC laboratories and the minimum requirements for equipment are described in 384

WHO guidance (7), which focuses on QC using compendial or manufacturers’ methods, as 385

described in dossiers submitted for marketing authorization, to ensure compliance with the 386

requirements of compendial monograph or manufacturer’s specification. However, these 387

methods are designed to detect problems that may arise during the approved manufacturing 388

process and subsequent storage and distribution and may not necessarily be adequate to detect all 389

possible issues that could arise with medicines that have been deliberately falsified. 390

391

Laboratories, normally national medicine testing laboratories, that test suspected SFFC 392

medicines should preferably be ISO 17025 accredited by a recognized accreditation body (e.g. 393

International Laboratory Accreditation Cooperation, etc.) to perform the appropriate analytical 394

procedures that are listed in their scope of accreditation and/or be a WHO-prequalified 395

laboratory with the capability to test SFFC products with an appropriate array of analytical 396

techniques and sufficient expertise. Furthermore, they should be able to perform, interpret and 397

document the testing according to rigorous procedures to ensure that the results can withstand 398

legal scrutiny. The level of requirements may differ in different countries. 399

400

Beyond the requirements of good practices, described in general WHO guidance (7) and ISO 401

17025, some additional skills and capacity as outlined below are required for testing of suspected 402

SFFC medicines. 403

404

Expertise 405

Critical thinking. Laboratory staff should have the ability to critically appraise all that is 406

known about each case of a suspected SFFC product and not just accept pre-existing 407

standard testing procedures. This skill can be strengthened through discussions with peers 408

on specific cases and by learning from senior experts in the field. 409

410

Experience. Laboratories should have access to staff with experience in designing and 411

implementing science-based, tailor-made SFFC testing plans. Where this is not the case 412


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they should cooperate with other institutions and/or refer the testing request to an 413

institution where the required experience is available. 414

415

Knowledge. Laboratory staff should have up-to-date scientific expertise enabling them to 416

fully understand the scientific methods used in testing SFFC products, to apply them 417

correctly and to interpret the results adequately. 418

419

Equipment 420

Laboratories should take care that technical equipment for testing of suspected SFFC products 421

for which they have adequate knowledge and experience is qualified and maintained in good 422

condition. Investments should be planned so as to enable the basic functioning of the laboratory 423

for all its intended purposes and to maximize the benefits of any additional specialized 424

equipment purchased. The cost of the equipment should be considered together with that of 425

accessory products such as consumables, reagents, standards, databases and libraries, as well as 426

the costs of installation, maintenance and training. Sharing of equipment in regional cooperation 427

approaches can be considered to minimize the costs while maximizing the benefits. 428

429

Laboratories need also a secure storage place for the samples, when not being tested, to ensure 430

the chain of custody. 431

432

7.2 Standard operating procedure 433

434

Laboratories should develop, implement and maintain a standard operating procedure (SOP) for 435

testing of suspected SFFC products. Such an SOP cannot define each step in the testing, since 436

this will be determined on a case-by-case basis. Rather, it should ensure that the laboratory 437

follows good practice and internal quality management systems in planning, implementing and 438

documenting its actions with regard to each request for testing. 439

440

WHO guidance on good sampling practices (1) and Good practices for pharmaceutical quality 441

control laboratories (7), should be followed. 442

443


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Measures should be taken to minimize bias. Sampling should be separate from testing, except at 444

the stage of interpreting the final testing results where all that is known about the sample should 445

be taken into account. Staff performing each analysis of the testing plan should be blinded to the 446

results of the other analyses as far as possible. 447

448

The laboratory should ensure full traceability of samples and results as described in relevant 449

WHO guidelines (1, 7), and should follow rigorous procedures to preserve the integrity of 450

samples and documentation, with a chain of custody that will stand up to scrutiny in legal action. 451

An example of an SOP for testing of suspected SFFC products is provided in Annex 3. 452

453

7.3 Questions to be answered by testing 454

455

Upon receipt of a suspected SFFC sample the laboratory should communicate with the 456

regulatory authority, enforcement agencies and other relevant stakeholders as needed to clarify 457

the purpose and aims of testing, as well as the actions intended to be taken as a result of testing 458

and the means that will be available to take such action. Some examples of questions that 459

laboratories may be requested to answer are listed below. 460

461

Does the sampled product fall under the national legislation for pharmaceutical products? 462

Does the sample meet specifications defined as part of the stated product’s marketing 463

authorization? 464

Is the sample likely to have been falsified, not just poorly manufactured or degraded? 465

What specific substances should the testing be designed to detect? (Examples: specific 466

unexpected active ingredients or groups of active ingredients, specific impurities, any 467

substances that are consistent with reported adverse effects.) 468

What parameters should be tested to assess the health impact of the ingredients? 469

(Examples: content, dissolution or disintegration properties, sterility.) 470

Is there a forensic relationship between different fakes? If yes, on what aspects? 471

Are there any market authorization specifications and methods of analysis available for 472

the suspect samples? N.B. Check if there is a product monograph in the British 473


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Pharmacopoeia, The International Pharmacopoeia, United States Pharmacopeia or other 474

national or regional pharmacopoeias. 475

What are the expected excipients (if present) in the suspect samples? 476

N.B. As it is often not possible to answer that question, the testing should be arranged in 477

such a way that there is no (negative) interference of the excipients in the identification 478

and quantification of the substance that is expected to be contained in the sample. 479

480

The laboratory should communicate and cooperate with the regulatory authority at all stages of 481

testing as appropriate, enabling the regulators to adapt their initial risk assessment (section 6.1) if 482

needed, and enabling the laboratory to refine its testing plan in the context of latest available 483

information. 484

485

7.4 Testing plan and test procedures 486

487

All the available information about the samples should be provided to the laboratory in the form 488

of a request for analysis that would clearly indicate what is expected from experimental testing. 489

The inspector/enforcement officer who has collected the sample should inform the laboratory as 490

completely as possible and necessary for an efficient running of the testing. 491

492

An initial study should then be undertaken, having in mind the number of sampling units 493

available, to determine the substances to expect in the sample and parameters to be tested and to 494

design a science-based testing plan identifying the most efficient combination of methods to 495

provide the required answers. As a general rule, the less is known about a case, the more 496

complex the testing plan is likely to be. 497

498

A wide range of methods may be considered for inclusion in the testing plan, including simple 499

visual checks, the technologies listed in Annex 1 and other forensic analyses which may assist in 500

determining likely sources of suspected SFFC medicines. Each technique should be reappraised 501

to determine its most appropriate use in order to achieve the best possible performance in the 502

given context. 503

504


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More detail on combining technologies to identify SFFC products can be found in literature (e.g. 505

5). Various examples of flowcharts describing how one can proceed with testing are reproduced 506

in Annex 4 for illustrative purposes with kind permission of the authors, the European network 507

of official quality control laboratories. 508

509

7.5 Interpretation and reporting of results 510

511

General good practices in interpreting laboratory testing results are described in WHO guidance 512

(7). Specific points to document for testing of SFFC products include: 513

514

reasons for selecting the specific methods used in the testing plan; 515

measures taken to avoid bias in analysis and reporting; 516

traceability of the measurements, with links to all physical material and to the original 517

sample on which the test was done; 518

limitations of the selected methods as used in the testing plan, together with an 519

estimate of the measurement of uncertainty of a quantitative result, if performed, and the 520

conclusions. 521

522

8. REPORTING OF CONFIRMED SFFC PRODUCTS 523

524

A legal framework for reporting of SFFC products should be in place at national level. 525

The confirmed testing results should be reported to the regulatory authority of the country where 526

the SFFC product was found. It is the responsibility of the NRA, under the given circumstances, 527

to decide how the findings should be translated into appropriate action, in accordance with 528

national legislation and in cooperation with enforcement agencies and other stakeholders.5 The 529

affected manufacturer should be kept informed of the results of testing. Other regulatory 530

authorities should be informed as appropriate. A report should be submitted to the WHO Rapid 531

Alert System (8). 532

5 See also reference (3), Section IV.1.3, containing the situation to prevent and reduce the risk to public health from the

action, activity or behaviour resulting in SSFFC medical products.


page 20

533

9. ARCHIVING OF SAMPLES AND REPORTS 534

535

The laboratory should store the samples appropriately and archive related documentation in 536

separate secure locations for future reference as required by legislation, documenting that the 537

integrity of samples and results has been preserved.7 538

539

10. REFERENCES 540

541

1. WHO Guidelines for the conduct of survey of quality of medicines. In: WHO Expert 542

Committee on Specifications on Pharmaceutical Preparations. Fiftieth report. Geneva, 543

World Health Organization. Technical Report Series, No. 996, 2016, Annex 7. 544

545

2. Combating unsafe medical products: outcomes of a survey on testing of suspect medicines. 546

WHO Drug Information 2013;27(2): 97-100. Available at: 547

http://www.who.int/medicines/publications/druginformation/issues/DrugInformation2014_548

Vol28-3/en/, accessed 13 October 2016. 549

550

3. Report of the Third meeting of the Member State Mechanism on 551

substandard/spurious/falsely-labelled/falsified/counterfeit medical products, Geneva, 29 to 552

31 October 2014. Annex. In: Sixty-Eighth World Health Assembly. Provisional agenda 553

item 17.3. Document A68/33. Substandard/spurious/falsely-labelled/ falsified/counterfeit 554

medical products. Report by the Director-General 555

http://www.who.int/gb/ssffc/, accessed 13 October 2016. 556

557

4. Resolution WHA67.20. Regulatory system strengthening for medical products. In: Sixty-558

seventh World Health Assembly, Geneva, 16–24 May 2011. Resolutions and decisions, 559

annexes. Geneva: World Health Organization; 2014:41-5 560

http://apps.who.int/gb/ebwha/pdf_files/WHA67-REC1/A67_2014_REC1-en.pdf , 561

accessed 13 October 2016. 562

563

http://www.who.int/medicines/publications/druginformation/issues/DrugInformation2014_Vol28-3/en/

http://www.who.int/medicines/publications/druginformation/issues/DrugInformation2014_Vol28-3/en/

http://www.who.int/gb/ssffc/

http://apps.who.int/gb/ebwha/pdf_files/WHA67-REC1/A67_2014_REC1-en.pdf


page 21

5. Buckley GJ and Gostin LO, Eds. Countering the Problem of Falsified and Substandard 564

Drugs. Committee on Understanding the Global Public Health Implications of 565

Substandard, Falsified, and Counterfeit Medical Products, Board on Global Health, 566

Institute of Medicine, National Academy of Sciences, Washington, D.C., 2013. Available 567

at: http://www.iom.edu/Reports/2013/Countering-the-Problem-of-Falsified-and-568

Substandard-Drugs.aspx. 569

570

6. Institute of Research Against Counterfeit medicines (IRACM). [Compilation of analytical 571

assays, covert or coded features, techniques, traceability and tracking technologies to 572

detect counterfeit medicines.] Available at: http://www.iracm.com/en/table/. 573

574

7. Good practices for pharmaceutical quality control laboratories. In: WHO Expert 575

Committee on Specifications on Pharmaceutical Preparations. Forty-fourth report. Geneva, 576

World Health Organization. Technical Report Series, No. 957, 2010, Annex 1. Available 577

at: 578

http://www.who.int/medicines/areas/quality_safety/quality_assurance/GoodpracticesPharm579

aceuticalQualityControlLaboratoriesTRS957Annex1.pdf. 580

581

8. WHO project for the surveillance and monitoring of SSFFC medical products. WHO Drug 582

Information 2013;27(2): 97-100. Available at: 583

http://www.who.int/medicines/publications/druginformation/issues/DI_27-584

2_SSFFC.pdf?ua=1 , accessed 13 October 2016. 585

586

http://www.iom.edu/Reports/2013/Countering-the-Problem-of-Falsified-and-Substandard-Drugs.aspx

http://www.iom.edu/Reports/2013/Countering-the-Problem-of-Falsified-and-Substandard-Drugs.aspx

http://www.iracm.com/en/table/

http://www.who.int/medicines/areas/quality_safety/quality_assurance/GoodpracticesPharmaceuticalQualityControlLaboratoriesTRS957Annex1.pdf

http://www.who.int/medicines/areas/quality_safety/quality_assurance/GoodpracticesPharmaceuticalQualityControlLaboratoriesTRS957Annex1.pdf

http://www.who.int/medicines/publications/druginformation/issues/DI_27-2_SSFFC.pdf?ua=1

http://www.who.int/medicines/publications/druginformation/issues/DI_27-2_SSFFC.pdf?ua=1


page 22

ANNEX 1 587

588

Examples of analytical techniques that may be used for package 589

identification, screening and testing of suspected SFFC products 590

591

The list shown below contains examples of analytical techniques that may be considered. These 592

include compendial methods as well as specific advanced techniques. Each technique should be 593

reappraised to determine its most appropriate use in order to achieve the best possible 594

performance in the given context. Laboratories may decide to outsource some of the analyses 595

necessitating specific advanced techniques to other suitably qualified laboratories. 596

597

Note: The list should not be considered to be complete or exhaustive. It is intended to provide 598

illustrative examples of commonly available technologies. Moreover, not all techniques are 599

required for a laboratory that undertakes such testing. 600

601

Main use Technique Full name Remark

Identification ATR/ FTIS

spectroscopy

Attenuated total

reflectance/Fourier

transform infrared

spectroscopy

–

Identification Melting point – –

Identity RI Refractive index –

Identification

assay

Spectrophotometry

(colorimetry) – –

Identification

assay

impurities

TLC Thin-layer

chromatography –


page 23

Assay

identification

impurites

GC/FID

Gas

chromatography

with flame

ionization

detection

–

Forensics

identification

assay

impurities

GC/MS

Gas

chromatography

with mass

spectrometric

detection

–

Assay

identification

impurites

LC/UV

Liquid

chromatography

with UV-detection

–

Residual

solvents

impurities

HS-GC/FID

Headspace gas

chromatography

with flame

ionization

detection

–

Forensics

residual

solvents

impurities

HS-GC/MS

Headspace gas

chromatography

with mass

spectrometric

detection

–

Inorganic

impurities ICP/OES

Inductively

coupled plasma

with optical

emission

spectroscopy

–


page 24

Inorganic

impurities ICP/MS

Inductively

coupled plasma

with mass

spectrometric

detection

–

Elemental and

chemical

analysis

XRF X-Ray

fluorescence –

Finished

pharmaceutical

product testing

Dissolution testing –

Bioavailability

of API and

quality of

finished

pharmaceutical

preparations

Finished

pharmaceutical

product testing

Disintegration

testing –

Finished

pharmaceutical

preparation and

indication on

bioavailability of

active

pharmaceutical

ingredient (API)

Specific

testing Sterility – –

Specific

Testing BET

Bacterial

endotoxins test –

Specific

testing

Osmolarity and

osmolality –

Characterization

of injections and

infusions

Finished

pharmaceutical

Light microscopy –

Particle

characterization


page 25

product testing

forensics

(size

distribution,

size, particulate

impurities)

Identification Raman

spectroscopy –

Characterization

of material

Forensics Photo scan/overlay

–

Documentation,

comparison (e.g.

packaging,

leaflets)

Forensic

FTIR/Raman

imaging

spectroscopy

–

Characterization

of material

composition

(distribution,

particulate

impurities)

Forensics TEM

Transmission

electron

microscopy

Characterization

of material

morphology

(tablet, particles)

Forensics SEM-EDX

Scanning electron

microscopy with

energy dispersive

X-Ray

spectroscopy

Characterization

of material

(surface,

distribution in

mixtures,

particulate

impurities)

Forensics

identification

impurities

LC-HRMS

Liquid

chromatography –

with high

resolution mass

spectrometric

Characterization

of unknowns

down to trace

levels


page 26

detection

Forensics

identification

assay

impurities

LC/MS

Liquid

chromatography –

with mass

spectrometric

detection

–

Forensics

impurities TDS-GC/MS

Thermodesorption

gas

chromatography

with mass

spectrometric

detection

Qualitative

analysis of

volatiles and

semi-volatiles in

solid samples

(direct analysis/

without sample

preparation)

Forensics LC/ELSD

Liquid

chromatography

with evaporative

light scattering

detection

–

Forensics

identification

assay

impurities

NMR, qNMR

Nuclear magnetic

resonance,

quantitative

nuclear magnetic

resonance

Characterization

of unknown

compounds and

mixtures –

qualitative and

quantitatively

602

603


page 27

ANNEX 2 604

Example of an information collection form 605

606

RECEIPT OF SUSPECT SFFC MEDICAL PRODUCT

Date on which the suspect product was received:

Suspect product received by:

Signature of the

inspector/enforcement officer

and that of the owner of the

product collected/seized

Suspect product issued by:

Source of the suspect product:

Contact details of source of

suspect product:

Name and surname:

Physical address:

Email:

Telephone

number(s):

Other:

607

SUSPECT SFFC MEDICAL PRODUCT INFORMATION

1. Suspect product name(s):

2. Type of product (select the most appropriate box):

Innovator product ☐ Generic product ☐

Vaccine ☐ Blood product ☐

Diagnostic ☐ Herbal medicine ☐

Traditional medicine ☐ Other ☐

Additional comments (if applicable):

3. API(s) present in the product and declared strengths:

4. Description of the dosage form:

5. Description of product packaging (primary and secondary):

6. Does the packaging contain any holographic or SMS checkable label codes?

Yes ☐ No ☐

Provide description (if applicable):


page 28

SUSPECT SFFC MEDICAL PRODUCT INFORMATION (CONTINUED)

7. Is there a patient information leaflet available with the product?

Yes ☐ No ☐

8. Batch number/Lot number

(if available):

9. Manufacturing date

(if available):

10. Expiry date (if available):

11. Does this product fall under the national legislation for pharmaceutical products?

Yes ☐ No ☐

12. Market authorization holder

(if applicable):

13. Manufacturer(s) details:

14. Quantity of suspect product received:

15. Does the suspect product meet specifications defined as part of the stated product’s

marketing authorization? Yes ☐ No ☐

16. Is the sample likely to have been falsified, not just poorly manufactured or degraded? Falsified ☐ Other ☐

Additional information:

16. Any other information applicable:

608

609


page 29

610

TESTING REQUIREMENTS

1. Has the product been subjected to any preliminary testing?

Yes ☐ No ☐

If “Yes” provide a summary of results

2. What specific substances should the testing be designed to detect?

3. What parameters should be tested to assess the health impact?

4. What are the forensic relationships between different fakes?

5. Are the market authorization

specifications available? Yes ☐ No ☐

6. Are official testing methods

available? Yes ☐ No ☐

Description of methods

available:

7. Any specific testing

requests:

611

IMPACT ON PUBLIC HEALTH

1. Have any adverse reactions been

reported? Yes ☐ No ☐

If “Yes” provide more information:

2. Estimated number of patients adversely affected?

3. Estimated number of patients at risk?

4. Any other related information:

612

613

614

615

616


page 30

ANNEX 3 617

Example of a content of a standard operating procedure for testing 618

of suspected SFFC tablets 619

1 Purpose 620

The actual standard operating procedure (SOP) describes the workflow and the required test 621

procedures necessary to carry out a testing of suspected spurious/falsely-622

labelled/falsified/counterfeit (SFFC) tablets. 623

2 Scope 624

The actual SOP is only valid for the good laboratory practices/good manufacturing practices test 625

facility of YYYYY . 626

3 Sample receipt, documentation and storage 627

3.1 Sample receipt 628

When receiving a shipment of suspected SFFC tablets for analysis the receiving laboratory shall: 629

record 630

o name and signature of the person delivering the sample or courier company 631

waybill, 632

o date and time of receipt of the sample in the laboratory with signature of the staff 633

member, 634

o presence of accompanying documentation in the shipment; 635

check integrity (e.g. damages, broken sealing) of shipment packaging; 636

check completeness of shipment against shipping documents; 637

read out and check data logger (e.g. temperature control) – if applicable; 638

check and sign shipment documentation – if applicable; 639

archive all documents in the corresponding project files as per the corresponding SOP 640

xxx.xxx.xxx. 641


page 31

3.2 Sample documentation 642

After sample receipt and unpacking: 643

document packaging which contains the suspected SFFC tablets as received by 644

photographic image(s); 645

check contents using shipping documents and previously received information by sending 646

party; 647

document each sample: secondary packaging and primary packaging (e.g. blister) 648

including labels by photographic image(s); 649

archive all documents and photographic images in the corresponding project files as per 650

the corresponding SOP xxx.xxx.xxx; 651

store samples according to storage conditions according to SOP.xxx.xxx.xxx until testing, 652

record storage location; 653

prior to testing let samples equilibrate to ambient temperature. 654

655

3.3 All the above observations should be recorded on a checklist and signed and dated 656

on completion by the responsible staff member. There should be a checklist which should 657

be signed and dated by the staff member responsible for these duties. The time, date of 658

storage (identified) by whom (with signature) should be recorded. Who removed sample 659

from storage for equilibration to room temperature and when – signature required. 660

3.4 Remarks 661

When using photographic images for documentation purposes check image quality (e.g. 662

readability of text elements) before proceeding further. 663

Ideally sample documentation includes dimensions (e.g. primary and secondary 664

packaging, thickness and diameter of tablets). 665

Sending party should be informed on sample receipt – if applicable. 666


page 32

3.5 Observations 667

Any observations like damages of packaging, missing or additional samples shall be documented 668

and communicated to the sending party in order to decide how to proceed further. 669

4 Sampling and samples 670

Split each sample set into 2 to 3 subsets. 671

Keep Subset 1 and 2 for packaging inspection and documentation and for analytical 672

testing as described in the following chapters. 673

Keep Subset 3 as retained sample for any further investigation. 674

5 Overall aspect 675

5.1 Packaging 676

Consider Subset 1 (see Chapter 4). 677

Visually assess the aspect of the secondary and primary packaging. 678

Report observations of the external aspect of the packaging materials (including labels 679

and printing) like visible damages, holes, discoloration or stains. 680

Document observations by photographic images and archive them together with 681

corresponding notes in the project files as per the SOP xxx.xxx.xxx. 682

Report results. 683

684

There should be a reporting form to be signed and dated on completion by the staff member 685

responsible. 686

5.2 Samples 687

Consider Subset 2 (see Chapter 4). 688

Visually assess the aspect of the tablets. 689

Report observations of the external aspect of the tablets like visible fissures, holes, 690

inclusions, discoloration or stains. 691


page 33

Document observations by photographic images and archive them together with 692

corresponding notes in the project files as per the SOP xxx.xxx.xxx. 693

Report results. 694

695


responsible. 697

6 Analytical testing 698

6.1 Packaging testing 699

Use Subset 1 (see Chapter 4). 700

Record FTIR or Raman spectra according to the SOP xxx.xxx.xxx in order to confirm or 701

elucidate the identity of the primary packaging. 702

Report results. 703

704


responsible. 706

6.2 Solid medicine (tablet) testing 707

6.2.1 Excipients 708


Record FTIR or Raman spectra of a reference sample (i.e. certified medicine reference 710

sample) according to the SOP xxx.xxx.xxx. 711

Record FTIR or Raman spectra according to the SOP xxx.xxx.xxx of the tablet, which 712

was homogenized by mechanical grinding and compare against a reference sample in 713

order to confirm presence and relative concentration of expected excipients. 714

If differences to the data of the reference sample are observed perform in-depth analysis 715

of experimental data (e.g. presence of unexpected substances or lack of expected 716

substances). 717

Report results 718


page 34

719


responsible. 721

722

6.2.2 API 723


Homogenize at least one of the tablets of Subset 2 by mechanical grinding and use the 725

homogenized material for the next steps. 726

Confirm identity and concentration of the expected API in the suspect and reference 727

sample using the corresponding compendial method. Alternatively, an in-house method 728

can be used as long as the suspect tablet is tested against a suitable reference sample. The 729

suitability of the in-house method for intended use should be proven by means of 730

validation reports and should be a stability indicative method. 731

Report results. 732

733


responsible. 735

736

6.2.3 Additional tests 737

If tests as described in sections 6.2.1 and 6.2.2 do not deliver unambiguous results additional 738

screening tests can be performed on Subset 1 or Subset 3 after agreement with the sending party. 739

These screening tests can include: 740

741

elemental analysis screening via ICP-OES or ICP/MS as per SOP.xxx.xxx.xxx; 742

screening for volatiles and semi-volatiles via TDS-GC/MS as per SOP.xxx.xxx.xxx; 743

screening for volatiles and semi-volatiles via GC/MS as per SOP.xxx.xxx.xxx; 744

screening for non-volatile, polar compounds via HPLC/MS as per SOP.xxx.xxx.xxx. 745


page 35

7 Dissolution testing 746

Use Subset 1. 747

Perform dissolution testing in comparison to suitable reference sample. 748

Report results. 749

750


responsible. 752

753

8 Abbreviations 754

SFFC Spurious/falsely-labelled/falsified/counterfeit 755

GC/MS Gas chromatography mass spectrometry 756

HPLC/MS High pressure liquid chromatography mass spectrometry 757

ICP/MS Inductively coupled plasma optical mass spectrometry 758

ICP/OES Inductively coupled plasma optical emission spectrometry 759

SOP Standard operating procedure 760

761


page 36

762

ANNEX 4 763

764

Examples of flowcharts for testing of suspected SFFC 765

medicines 766

767

Explanatory note to the Appendix 768

769

This Appendix includes the examples from an “Aide-Memoire for the Testing of Suspected 770

Illegal and Counterfeit Medicines” prepared by the European OMCL Network (Reference: 771

PA/PH/OMCL (06) 81 R6, Strasbourg, July 2016) which has been reproduced with the kind 772

permission from the Network members. 773

774

“The original version of this document was produced in response to many presentations given at a 775

number of Annual General Meetings of the OMCL Network (GEON). 776

777

The paper provides some practical and theoretical advice to OMCLs on the development of 778

protocols for the confirmation or determination of counterfeit medicinal products and was 779

adopted by the Network in 2007. 780

781

Subsequently, the testing of potentially illegal and counterfeit medicines throughout the 782

Network has expanded and many laboratories now have established processes and 783

expertise. 784

785

At the GEON annual meeting in June 2015, it was agreed that the “aide-memoire” document 786

should be revised and updated to provide an overview of the overall approaches that should be 787

taken for OMCLs analysing suspected illegal/counterfeit medicines. 788

789

This document has been prepared to include example high level process flows / decision 790

trees to assist OMCLs and promote a harmonised approach across the Network. It is 791


page 37

recognised that OMCLs will have existing processes in place and this document does not 792

supersede existing systems. This document is intended as an “aide memoire” only and 793

OMCLs are not expected to be audited for compliance with the document. 794

795

The techniques listed in this document are examples only and should not be seen as 796

exclusive or even preferred techniques. OMCLs should choose and use appropriate 797

equipment to meet their testing needs. 798

799

The individual OMCLs’ choice of specific analytical techniques and detailed testing SOPs are 800

outside the scope of this document and should be decided locally in accordance with local 801

legislation or policies (for example some OMCLs may routinely quantify APIs found but others 802

may not – either approach is acceptable), equipment availability and staff 803

expertise/preferences. 804

805

The final decision on what techniques to use and equipment to purchase and exactly what 806

testing to apply is left to individual OMCLs.” 807

808

809 810


page 38

Example 1. Decision tree to determine testing requirements 811

812

Are there any APIs declared?

Is it a suspected counterfeit?

Yes

No No

Yes

Sample Received

Use Medicine Protocol

Use Counterfeit protocol

Use Screening protocol

Manage sample as per laboratory quality system, and any additional evidence

continuity and reporting to court standard, if required

Is it presented as a medicine?

Yes

No

Register into laboratory quality

system

813

Note: 814

Where no APIs are declared, often the name or marketing of the item can indicate what 815

APIs may be present (for example, products may be marketed as weight loss or sexual 816

potency enhancers, or have suggestive pictures/branding that implies the product’s 817

intended effect). 818

Also internet searches using the product or producer name of the item can often provide 819

information on APIs, use and/or indication. 820

Further details of the protocols that may be applied are given in the following sections. 821


page 39

822

Example 2. Screening protocol (testing for “medicines in disguise”) 823

824

825

Samples may be presented as a food supplement, health tonic, “nutraceutical” or naturally 826

derived or herbal product. Usually there will be either no mention of API(s) in the product 827

or even a more positive statement such as “100 % natural extracts” or similar. Alternatively 828

samples may be presented in foreign language variants, or even unlabelled. 829

In these circumstances the priority of the testing is to establish whether there are any 830

APIs/potential pharmacologically active substances present and, if there is, at what level if 831

required). 832


page 40

Screen for presence of API/Potential pharmacologically active substance

using suitable technique(library search, confirm by comparison to reference

standard if possible)

GC-MSLC-MS, LC-DAD

XRPD

Substance present?

No

Yes

START

Determine content of substance using suitable technique

(quantitation against reference standard)

LC-UV (single λ or DAD), LC-MS, LC-CADGC-FID, GC-MS

qNMRCE

REPORT DATA

Is/are there any API(s) present?If so, at what level?

How does the API content compare to authorised products?

Is there more or less than the lowest authorised dose with significant pharmacological effects?

Is quantitation needed?

Yes

No

Note: screening methods may not detect every possible substance and OMCLs may operate more than one method (e.g. for different drug classes).

Methods will need to be updated to include new molecules as they are discovered.

For unknown or new molecules, advanced techniques may be needed to provide structure elucidation.

833

834 835


page 41

Example 3. Medicine protocol (testing of “unapproved products”) 836

837

Samples may be legal, licensed medicines in other countries, but not necessarily in the 838

country where they have been found, or they may be legal medicines sold outside of the 839

correct, legal supply chain. They might also contain drug substances that are not licensed 840

or legally authorized for sale or treatment. Usually the API(s) in the product will be listed 841

on the label and the product will be packaged and presented as a medicine. In some cases, 842

the samples may be presented in foreign language variants, so the API(s) present may be 843

unclear. 844

The priority of the testing is to establish that the labelled API is present, and (if required) at 845

what level. 846


page 42

START

Determine identity and/or content of labelled API(s) using suitable technique


LC-UV (single λ or DAD)LC-CADGC-FIDLC-MSGC-MSqNMR

CEXRPD

Screen for presence of API using suitable technique(library search, confirm by comparison to reference

standard if possible)

GC-MSLC-MSXRPD

Is the product labelled as containing API(s)?

Yes

No

REPORT DATA

Are the labelled API(s) present?How do they compare to labelled content?

Are any other APIs present (aside from any labelled API)?

If so, at what level?

Is the labelled API(s) present?

If required, determine content of detected API(s) using suitable technique


LC-UV (single λ or DAD)LC-CADGC-FIDLC-MSGC-MSqNMR

CE

Yes

No

847

848


page 43

Example 4. Counterfeit protocol 849

For samples that are presented as licensed medicines but are suspected of being falsified, or 850

counterfeit, it is essential that the OMCL is able to make contact with the market 851

authorization holder (MAH) of the genuine product. This may either be directly or through 852

the competent authority, inspectorate or enforcement group. Genuine comparator batches 853

(ideally 3 batches including the suspicious lot) should be obtained. If the product is 854

manufactured at a variety of production sites samples should be obtained from each. It is 855

not usually possible for a laboratory to determine conclusively that a sample of product is 856

counterfeit based on testing alone. The priority of the testing can only be to say whether the 857

suspect sample is consistent with the genuine product or not. 858

859


page 44

Contact MAHRequest comparatorRequest information

Sufficient sample for both OMCL and MAH to test?

Yes

Test in OMCL

No

Send portion of sample to MAH

START

Information and/or

comparator samples

from MAH

AUTHENTICITY TESTING

Compare the suspect with comparator/artwork using suitable technique

(visual examination; microscopy, physical, colour, packaging including covert features)

Compare spectral fingerprint of product with authentic comparator

(FT-IR, NIR, Raman, XRF, XRPD)

Determine identity and content of labelled API(LC-MS, GC-MS, LC-UV, GC-FID)

Compare impurity/solvent profile of suspect with comparator (LC-MS, GC-MS, LC-UV, GC-FID)

Compare excipients in suspect with comparator (FT-IR, Raman, XRPD)

REPORT DATA

Is the suspect sample similar to or different from the comparator?

Is the OMCL data and MAH data concordant?

Test in MAH Lab

Testing results from

MAH

Comparator samples and/or artwork to be provided to the OMCL

Are the batch/lot No. and expiry details concordant with a genuine batch?

What is the complete formulation of the product?

Is the product produced on more than one site of manufacture?

Is the batch disposition (if a genuine batch number) available? Does this correlate with where the sample was found?

If possible/allowed

Note: when a suspect sample is found not to contain labelled API, the OMCL may wish to apply the screening protocol to determine what, if anything is present

860

861

*** 862

Documents

WHO DRAFT GUIDANCE ON TESTING OF “SUSPECT” SPURIOUS ...€¦ · Working document QAS/15.634/Rev.2 Draft page 7 3.153 GLOSSARY 154 155 chain of custody. A chronological record