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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WHO DRAFT GUIDANCE ON TESTING OF “SUSPECT” 3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 kopps@who.int. 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
(kopps@who.int) with a copy to Ms Wendy Bonny (bonnyw@who.int) by 10 January 2017.
Our 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 already receive
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Working document QAS/15.634/Rev.2 Draft
page 2
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
Committee on Specifications for Pharmaceutical
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
Committee on Specifications for Pharmaceutical
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
Working document QAS/15.634/Rev.2 Draft
page 3
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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
Committee on Specifications for Pharmaceutical
Preparations
17–21 October 2016
Any follow-up action, as necessary
Working document QAS/15.634/Rev.2 Draft
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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
152
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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.
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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
Working document QAS/15.634/Rev.2 Draft
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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
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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 –
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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
–
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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
Working document QAS/15.634/Rev.2 Draft
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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
Working document QAS/15.634/Rev.2 Draft
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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
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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):
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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
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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
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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
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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
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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
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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
There should be a reporting form to be signed and dated on completion by the staff member 696
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
There should be a reporting form to be signed and dated on completion by the staff member 705
responsible. 706
6.2 Solid medicine (tablet) testing 707
6.2.1 Excipients 708
Use Subset 1 (see Chapter 4). 709
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
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719
There should be a reporting form to be signed and dated on completion by the staff member 720
responsible. 721
722
6.2.2 API 723
Use Subset 2 (see Chapter 4). 724
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
There should be a reporting form to be signed and dated on completion by the staff member 734
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
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7 Dissolution testing 746
Use Subset 1. 747
Perform dissolution testing in comparison to suitable reference sample. 748
Report results. 749
750
There should be a reporting form to be signed and dated on completion by the staff member 751
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
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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
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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
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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
Working document QAS/15.634/Rev.2 Draft
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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
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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
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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
Working document QAS/15.634/Rev.2 Draft
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START
Determine identity and/or content of labelled API(s) using suitable technique
(quantitation against reference standard)
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
(quantitation against reference standard)
LC-UV (single λ or DAD)LC-CADGC-FIDLC-MSGC-MSqNMR
CE
Yes
No
847
848
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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
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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
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