Technical Guidance Series (TGS)
for WHO Prequalification – Diagnostic
Assessment
Establishing component
stability for an IVD
Case study: single-use
buffer vials for rapid
diagnostic tests
Annex
to TGS–
2
Draft for comment
© World Health Organization 2017
All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World
Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791
4857; email: [email protected]). Requests for permission to reproduce or translate WHO publications –
whether for sale or for non-commercial distribution – should be addressed to WHO Press, at the above
address (fax: +41 22 791 4806; email: [email protected]).
The designations employed and the presentation of the material in this publication do not imply the
expression of any opinion whatsoever on the part of the World Health Organization concerning the legal
status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers
or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full
agreement.
The mention of specific companies or of certain manufacturers’ products does not imply that they are
endorsed or recommended by the World Health Organization in preference to others of a similar nature that
are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by
initial capital letters.
All reasonable precautions have been taken by the World Health Organization to verify the information
contained in this publication. However, the published material is being distributed without warranty of any
kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with
the reader. In no event shall the World Health Organization be liable for damages arising from its use.
Contact: Irena Prat, WHO Prequalification – Diagnostic Assessment, WHO - 20 Avenue Appia - 1211 Geneva
27 Switzerland.
Technical Guidance Series for WHO Prequalification – Diagnostic Assessment: Establishing component stability for an IVD - Case study: single-use buffer vials for rapid diagnostic tests
Annex to
TGS-2
Page 1 Draft for comment 19 September 2017
Contents
1 Definitions 3
2 Introduction 4
3 Summary of the stages of a stability study for components of IVD 4
4 Planning and risk management 5
5 Validation and verification of the stability of products and of changes to components 7
6 Product presentation for stability studies 7
7 Minimum number of lots 8
8 Stability of partly manufactured, bulk or stored components 8
9 Quantitative reporting of stability results 9
10 Monitoring specificity in stability studies 10
11 Zero time values and variance 10
12 Using data from accelerated studies 11
References 12
A 1 Summary 14
A 2 Health, safety and the environment 14
A 3 Training requirements 14
A 4 Responsibilities 15
A 5 Develop the risk management documentation 15
A 6 Develop the stability testing plan 17
A 7 Preparation of specific SOP required for the stability study 20
A 8 Selection and storage of stability panel members for the study 21
A 9 Selection and storage of ancillary components or accessories for the study 21
A 10 Storage of the components to be tested 22
A 11 Collection of the stability data 22
A 12 Establishment of the expiry dating of the component 24
WHO Prequalification – Diagnostic Assessment
Page 2 Draft for comment 19 September 2017
Acknowledgements
The draft document Technical Guidance Series for WHO Prequalification –
Diagnostic Assessment: Establishing component stability for an IVD - Case study:
single-use buffer vials for rapid diagnostic tests was developed with support from
the Bill & Melinda Gates Foundation and UNITAID. This draft was prepared in
collaboration with Dr J Duncan, London, United Kingdom; Ms D Healy; Ms R
Meurant and Ms A Sands, WHO, Geneva, Switzerland. This document was produced
under the coordination and supervision of Ms R Meurant and Ms I Prat,
Prequalification Team – Diagnostic Assessment, WHO, Geneva, Switzerland.
Technical Guidance Series for WHO Prequalification – Diagnostic Assessment: Establishing component stability for an IVD - Case study: single-use buffer vials for rapid diagnostic tests
Annex to
TGS-2
Page 3 Draft for comment 19 September 2017
Abbreviations 1
FMEA failure mode and effect analysis 2
IFU instructions for use 3
ISO International Organization for Standardization 4
IVD in vitro diagnostic medical device 5
QA quality assurance 6
QC quality control 7
QMS Quality Management System 8
R&D research and development 9
RDT rapid diagnostic test 10
SOP standard operating procedure 11
WHO World Health Organization 12
1 Definitions 13
1.1 For the purposes of this document, the terms and definitions given in 14
Technical Guidance Series for WHO Prequalification of in vitro diagnostic 15
medical devices: TGS-2 Establishing stability of in vitro diagnostic medical 16
devices (1) apply, with the additional definitions: 17
1.1.1 Component: Part of a finished, packaged and labelled IVD medical 18
device (2). 19
NOTE 1: Typical kit components include antibody solutions, buffer 20
solutions, calibrators and/or control materials (2) 21
1.1.2 Constituent: For the purpose of this document, constituent refers 22
to raw materials used to make a component. 23
1.1.3 A critical constituent has any of the following characteristics: 24
a new constituent i.e. a constituent not already issued as part 25
of a product already for sale 26
any constituent or accessory that has to be matched (titrated, 27
adjusted or verified for ongoing appropriateness, beyond 28
normal incoming goods inspection procedures) within an in 29
vitro diagnostic medical device (IVD) 30
any constituent containing a biological agent of a labile nature 31
(antibody, antigen, synthetic peptide, recombinant protein, 32
nucleic acid, biocide) 33
WHO Prequalification – Diagnostic Assessment
Page 4 Draft for comment 19 September 2017
any constituent or part thereof from a new supplier or from a 34
supplier without ISO 9001 certification or equivalent 35
1.1.4 A critical component has the same definition as in the preceding 36
paragraphs with the term “constituent” replaced by “component”. 37
2 Introduction 38
This document was developed by the Prequalification Team – Diagnostic 39
Assessment group in WHO in response to stability concerns found during 40
post marketing surveillance of single-use buffer vials, which are used as a kit 41
component for RDT. The recommendations in the document may be 42
applicable to establishing the stability for any components for IVDs although 43
the examples and emphasis is on the change from establishing stability for 44
multiuse dropper bottles to that for single-use vials. The procedural steps for 45
stability studies are presented in Annex 1 as a policy (3) for illustrative 46
purposes. Precise standard instructions as would be expected in standard 47
operating procedures (SOP) are not provided but rather a listing what must 48
be done. 49
The WHO prequalification requirements and basic principles of TGS-2: 50
Establishing stability of an in vitro diagnostic medical devices for the WHO 51
Prequalification (1) apply equally to the validation of components, and this 52
document is to be read in conjunction with the aforementioned document 53
and TGS-4: Guidance on Test method validation for in vitro diagnostic 54
medical devices (4). 55
3 Summary of the stages of a stability study for components of 56
IVD 57
3.1 Prepare a risk evaluation based on the IVD design input documentation, the 58
instructions for use (IFU) and the manufacturing specifications. 59
3.2 Prepare the study plan based on the information in the risk evaluation. 60
3.3 Develop the protocols and any SOP required to fulfil the plan. 61
3.4 Select and store the materials (see page 21 to 22). 62
3.5 Initiate the stability study. 63
3.6 Obtain and analyse the data as it is generated. 64
3.7 Prepare the report. 65
Technical Guidance Series for WHO Prequalification – Diagnostic Assessment: Establishing component stability for an IVD - Case study: single-use buffer vials for rapid diagnostic tests
Annex to
TGS-2
Page 5 Draft for comment 19 September 2017
4 Planning and risk management 66
4.1 It is good practice to prepare, within the mechanisms of a quality 67
management system (QMS), a plan for the investigation of all aspects of IVD 68
stability. Planning is as important for components, and for changes to 69
components, as it is for studies of the complete product. A well-developed 70
study plan, with clearly defined objectives, responsibilities, and predefined 71
pass/fail acceptance criteria must be developed, reviewed and internally 72
approved in advance of testing. 73
4.2 Planning begins with defining the aims of the study, collecting all associated 74
information and developing a risk management plan. 75
4.2.1 Careful forward planning contributes to ensuring that sufficient 76
resources are made available, effective studies are performed and 77
that both experimental results and associated documentation are 78
recorded in an appropriate manner. 79
4.2.2 The risk assessment must cover all aspects of the IVD itself in 80
addition to considering the components concerned. 81
4.2.3 Information must, as a minimum, come from the design input 82
documentation for the IVD, the manufacturing specifications of 83
the component, the IFU and any claims made in submissions to 84
assessment bodies including the intended use, the intended users 85
and the intended environments of use. Manufacturing 86
specifications should include in-process and lot release1 quality 87
assurance (QA) parameters. 88
4.2.4 The final risk evaluation must define the parameters that require a 89
stability study and also those necessitating re-validation. 90
For evaluation of single-use buffer vials the factors in Table 1 91
can be important but will be different dependent on the 92
component, the intended use including regions of intended use 93
of the IVD 94
Table 1: 95
Source documents Factor
From the user inputs: Temperature range: at least 4 - 40°C, with cyclic changes
1 Lot release is the process of evaluation of an individual lot before giving approval for its release on
to the market.
WHO Prequalification – Diagnostic Assessment
Page 6 Draft for comment 19 September 2017
Source documents Factor
likely storage and
in-use environmental
conditions in
countries of use
Consideration: Many RDTs are stored in non-controlled
temperature environments where temperatures range from
cool temperatures overnight to hot temperatures during
the day
Humidity: a wide range
Consideration: 30% relative humidity to mimic desert
humidity and >85% to mimic tropical humidity
Pressure range: sea level to 3000 metres.
Consideration: air cargo-hold pressure, use on high
mountains
Degradation: in challenging environments of intended use
Consideration: aggressive fungi, bacteria and high light
intensity
Transportation: at least 4 - 50°C, with cyclic changes
Consideration: temperatures are expected to be even more
extreme than those experienced in storage by users,
possibility of freezing
From manufacturing
specification for
solution contained
within the vial
pH: as validated by research and development (R&D) department,
end of life value important
Viscosity: as validated by R&D department (depends on dropper
tips)
Conductivity: as validated by R&D department; good control of
manufacture and changes on storage
Biocide functionality: if required, biocides must remain potent.
Labelling: attachment and clarity
Residual fill-volume: dependent on plastic and leakage, humidity
and pressure the fill-volume can vary with time.
From QA/QC
specification
Delivered volume: when used as defined by IFU.
Drop volume: dependent on factors listed above, on plastic and on
the angle at which the vial held. Drop volume can vary
with dropper age.
Residual volume after use: can vary with time.
Flow time: from specimen or reagent addition to completion of
Technical Guidance Series for WHO Prequalification – Diagnostic Assessment: Establishing component stability for an IVD - Case study: single-use buffer vials for rapid diagnostic tests
Annex to
TGS-2
Page 7 Draft for comment 19 September 2017
Source documents Factor
flow across the nitrocellulose membrane of flow RDT
Functionality: with the stability testing panel2: all performance
claims must be met
5 Validation and verification of the stability of products and of 96
changes to components 97
5.1 Verification of the stability claims of a new IVD must follow the expectations 98
of “TGS2: Establishing stability of an in vitro diagnostic medical devices for 99
the WHO Prequalification” (1). 100
5.2 If a prequalified IVD is modified or new components are introduced as a 101
change (e.g. a change in configuration to single-use buffer vial from a 102
multiuse dropper bottle) then re-validation in addition to verification of 103
stability claims must be undertaken, subject to risk assessment, as part of 104
the change control (5, 6). 105
5.2.1 Changes to a prequalified IVD must be reported to WHO according 106
to WHO document "Reportable Changes to a WHO Prequalified In 107
Vitro Diagnostic Medical Device" (7) 108
6 Product presentation for stability studies 109
6.1 Stability and validation studies of components must be performed using 110
components made according to: 111
6.1.1 Validated manufacturing scales. 112
6.1.2 Finalized manufacturing specifications (8, 9, 10, 11): 113
in their final packaging (including all labelling) in which the 114
components will be made commercially available. If more than 115
one presentation (e.g. fill-volume, bottle size) is to be provided 116
each must be evaluated for stability. 117
manufactured on qualified manufacturing equipment. 118
meeting finalized and approved in-process quality control (QC) 119
specifications. 120
2 A panel is a collection of well characterised specimens and other materials that are used in quality
assurance and quality control to monitor aspects of device and component function during stability studies, for in-process control, for some aspects of design validation and at lot release.
WHO Prequalification – Diagnostic Assessment
Page 8 Draft for comment 19 September 2017
6.2 If components are not made to final validated and documented 121
manufacturing scale and specifications an attestation, with evidence, must 122
be presented to the assessment body (e.g. WHO prequalification) that 123
change of scale or documentation will not affect (11): 124
any parameters of the product 125
any of the manufacturer’s claims 126
6.3 Pre-production lots may only be used for stability and validation studies if 127
these conditions are met. 128
7 Minimum number of lots 129
7.1 The conclusions from stability studies must apply to every lot of component 130
and test device likely to be made during the commercial life of the product. 131
7.1.1 Sufficient numbers of different lots of component must be 132
evaluated to give assurance that every future lot of the IVD will 133
meet the stability claims. 134
“different lots” requires different batches of critical 135
constituents to be used in the components manufactured in 136
different production runs 137
7.1.2 Although standards (8, 9, 10) make reference to the testing of at 138
least three lots for shelf-life assignment and one lot for in-use 139
stability, these numbers represent the minimum numbers. Testing 140
of more lots may be necessary, depending on the lot-to-lot 141
variance observed when different batches of critical constituents 142
and components are used. 143
8 Stability of partly manufactured, bulk or stored components 144
8.1 Sometimes components of IVDs are prepared in bulk and stored for some 145
time before being used in several different lots of a complete product. Some 146
components are stored and then used in more than one product. Where 147
such products are used in multiple assays, the remaining shelf-life or in-use 148
life should be taken into consideration when being used as a component. 149
8.1.1 The design input documentation should define how long 150
components are likely to be stored and whether the component 151
will be stored partly manufactured or in its final configuration and 152
packaging. 153
8.1.2 An IVD cannot have a labelled shelf-life beyond that of any of its 154
components. Thus the shortest labelled shelf-life for any 155
Technical Guidance Series for WHO Prequalification – Diagnostic Assessment: Establishing component stability for an IVD - Case study: single-use buffer vials for rapid diagnostic tests
Annex to
TGS-2
Page 9 Draft for comment 19 September 2017
component within a lot of the IVD will determine the overall shelf-156
life of that lot and this must be reflected on the labelling. 157
8.2 Considerations for components used in more than one product 158
8.2.1 The risk assessment prior to stability and validation studies must 159
take into consideration each of the products in which the 160
component will be used. 161
the manufacturer must consider each factor and parameter for 162
each product validated during R&D work and then specified in 163
the manufacturing documentation; 164
if validated parameters are different between products in 165
which the component is to be used, the risk evaluation must 166
identify those differences and ensure that the study plan will 167
ensure proof of correct function in all products for all uses. 168
9 Quantitative reporting of stability results 169
9.1 Stability study results, like those for QA testing for lot release should be 170
numerically quantified. 171
9.1.1 It is important to be able to demonstrate whether or not a 172
parameter has changed during the course of a stability study and if 173
so by how much it has changed. Any quantitative change can then 174
be compared to the predetermined limits within which the IVD will 175
function. 176
predetermined limits will have been established in validation 177
studies. 178
the fact of a QC specimen being found reactive, or non-179
reactive, during stability studies is not informative unless there 180
is a validated relationship to the claims of the IVD. 181
WHO has observed that manufacturers use strong positive 182
specimens in the panel which are reactive at the beginning and 183
at the end of the stability study. However, this does not 184
provide any indication of whether the specimen has lost 185
activity and whether the potential decrease in activity is 186
significant. 187
9.1.2 Although many IVD are not intended to produce quantitative test 188
results it is generally possible to make the reading of results 189
objective by use of a scoring system. 190
WHO Prequalification – Diagnostic Assessment
Page 10 Draft for comment 19 September 2017
WHO recommends the use of scoring cards where intensity of 191
the colour reaction (as noted on the scoring card) is scored 192
either semi-quantitatively (e.g. –, +, ++, +++, ++++) or 193
quantitatively (e.g., a score of 0 to 5). 194
some IVDs for antibody detection might stipulate that the 195
strength of test result is not correlated with the antibody titre, 196
although for any particular antibody the signal strength 197
normally correlates with dilution of the antibody solution and 198
with the relative activity of the device 199
10 Monitoring specificity in stability studies 200
10.1 Control of specificity is important because the specificity is among the most 201
significant performance claims for an IVD with diagnosis as the intended use. 202
10.1.1 Specificity is influenced by the additives in solutions and diluents 203
(detergents, chaotropic agents, cell constituents, masking 204
proteins) thus monitoring the stability of these is an important 205
function of the stability testing panels. 206
it is usual to collect a set of false reactive specimens and 207
interfering specimen types (12) during the R&D phase of 208
product design and to monitor and control lot-to-lot variation 209
and stability using them in the panels. Changes in results for 210
the stability testing panel members chosen to monitor stability 211
should be investigated 212
11 Zero time values and variance 213
11.1 The value of each measured characteristic at the beginning of the stability 214
study and its variability over the study are important pieces of information. 215
11.1.1 Characteristics should be measured independently for each lot of 216
material in the stability study to provide a time zero or benchmark 217
value. 218
subsequent analysis of the stability data will indicate whether a 219
statistically significant change has occurred to any measured 220
parameter for any lot during the course of the study. Although 221
relevant practical allowable changes should have been 222
predetermined in product or process validation, all statistically 223
significant changes should be evaluated stringently to decide 224
whether they may be representative of some otherwise 225
undetected important change 226
Technical Guidance Series for WHO Prequalification – Diagnostic Assessment: Establishing component stability for an IVD - Case study: single-use buffer vials for rapid diagnostic tests
Annex to
TGS-2
Page 11 Draft for comment 19 September 2017
12 Using data from accelerated studies 227
12.1 For the purposes of WHO prequalification, labelling should be based on real-228
time stability studies. 229
12.1.1 Accelerated shelf-life studies can be used in submissions to WHO 230
prequalification, however, real-time studies must be initiated and 231
ongoing. Labelling with respect to stability at the time of 232
prequalification will be based on the findings of the real-time 233
studies. 234
12.1.2 Accelerated studies may sometimes be acceptable and may be of 235
use in providing inputs to real-time studies. 236
whenever accelerated data is used in the submission, real-time 237
data must always be supplied to WHO prequalification as it 238
becomes available. 239
Appendix B in reference (8) exemplifies the minimum 240
requirements and methods of calculation of a predicted shelf-241
life from accelerated stability testing data 242
243
WHO Prequalification – Diagnostic Assessment
Page 12 Draft for comment 19 September 2017
References 244
1. WHO Prequalification – Diagnostic Assessment. Technical Guidance Series (TGS). 245
Establishing stability of an in vitro diagnostic medical device for WHO Prequalification 246
TGS–2. Geneva: World Health Organization. 2016. 247
http://www.who.int/diagnostics_laboratory/guidance/technical_guidance_series/en/, 248
accessed 15 July 2016. 249
2. ISO 18113-1:2009. In vitro diagnostic medical IVDs – Information supplied by the 250
manufacturer (labelling) – Part 1: Terms, definitions and general requirements. 251
Geneva, Switzerland: International Organization for Standardization; 2009. 252
3. CLSI. Quality management system: development and management of laboratory 253
documents; approved guideline Sixth edition. CLSI document QMS02-A6. Wayne, PA: 254
Clinical and Laboratory Standards Institute (CLSI); 2013. 255
4. WHO Prequalification – Diagnostic Assessment. Technical Guidance Series (TGS). 256
Guidance on test method validation for in vitro diagnostic medical devices TGS–4. 257
Geneva: World Health Organization. 2016. 258
http://www.who.int/diagnostics_laboratory/guidance/technical_guidance_series/en/, 259
accessed 01 January 2017. 260
5. ISO 13485:2003. Medical IVDs - Quality management systems - Requirements for 261
regulatory purposes. International Organization for Standardization (ISO); Geneva: 262
2003. 263
6. United States CFR - Code of Federal Regulations Title 21. Sec. 820.3 Definitions, 264
Washington DC; 2016. 265
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=820.3 266
accessed 10 August 2017. 267
7. Reportable changes to a WHO prequalified in vitro diagnostic medical device. WHO 268
Prequalification Team: Diagnostics Assessment. Geneva; 2016. 269
http://apps.who.int/iris/bitstream/10665/251915/1/WHO-EMP-RHT-PQT-2016.01-270
eng.pdf?ua=1 accessed 31 May 2017 271
8. CLSI. Evaluation of Stability of In Vitro Diagnostic Reagents; Approved Guideline. CLSI 272
document EP25-A. Wayne, PA: Clinical and Laboratory Standards Institute; 2009. 273
9. ISO 23640:2011. In vitro diagnostic medical IVDs - Evaluation of stability of in vitro 274
diagnostic reagents. International Organization for Standardization (ISO); Geneva, 275
Switzerland: 2011. 276
10. Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 277
2017 on in vitro diagnostic medical devices. OJ L 117, 5.5.2017, p. 176–332 278
http://eur-lex.europa.eu/legal-content/EN/TXT/?uri=OJ:L:2017:117:TOC 279
accessed 31 May 2017 280
Technical Guidance Series for WHO Prequalification – Diagnostic Assessment: Establishing component stability for an IVD - Case study: single-use buffer vials for rapid diagnostic tests
Annex to
TGS-2
Page 13 Draft for comment 19 September 2017
11. US FDA Guide to inspections of quality systems: ORA, Food and Drug Administration , 281
Centre for devices and radiological health (CDRH), Silver Spring, MD; 1999 282
http://www.fda.gov/downloads/ICECI/Inspections/InspectionGuides/UCM085938.pdf 283
accessed 31 May 2017 284
12. CLSI Interference Testing in Clinical Chemistry; Approved Guideline - Second Edition. 285
CLSI document EP07- A2. Wayne, PA: Clinical and Laboratory Standards Institute 286
(CLSI); 2005. 287
13. ASTM International. ASTM D4169-14. Standard Practice for Performance Testing of 288
Shipping Containers and Systems. ASTM International, West Conshohocken, PA; 2014. 289
14. US FDA: ORA Lab Manual, Volume III, Section 4-Basic Statistics and Data Presentation 290
paragraph 4.5.3. FDA Office of Regulatory Affairs, Silver Spring, MD. 291
www.fda.gov/downloads/scienceresearch/fieldscience/laboratorymanual/ucm092179.292
pdf accessed 31 May 2017 293
294
WHO Prequalification – Diagnostic Assessment
Page 14 Draft for comment 19 September 2017
Annex 1: Example policy: stability studies for components of RDT 295
Introduction 296
The following is written for illustrative purposes as an example of a policy (3). 297
As a policy, it explains what steps are to be taken to generate acceptable 298
stability data for components of IVD. It does not give precise, standard 299
instructions as would be expected in SOP. As a result the process outlined in 300
this policy could be completed in different ways as required for different 301
components and different IVD. A manufacture is expected to have SOPs 302
covering all the activities with precise instructions for performing risk 303
assessments, for preparing testing plans, for operation of all the instruments 304
and facilities involved, for document control and change control, for selection 305
and use of statistical methodology, and for all aspects of stability work: for 306
example choice of test devices, conditions for storage of components, reagents 307
to be used, methods for linking design input requirements to the predefined 308
outcomes of stability studies, and so forth. For the purposes of this guidance 309
and to illustrate this expectation, the planning described here will make 310
reference to such specific SOPs. Although this is an example of a policy 311
controlling stability studies on components of IVD the examples are all related 312
to a change from multiuse dropper bottles to single-use dropper vials, in 313
agreement with the previous sections 314
A 1 Summary 315
A 1.1 This example of a stability policy has been written in line with the 316
requirements of ISO 23640:2011 (9) and CLSI EP25-A2 (8). . 317
A 1.2 The policy outlines the procedures necessary for collecting the data 318
required before a component shelf-life can be assigned but does not 319
provide detailed guidance on how to assign that shelf-life. 320
A 2 Health, safety and the environment 321
A 2.1 No specific requirements for the use of this documentary policy but see 322
paragraphs A 5.1.1, A 6.3 and A 7.2. 323
A 3 Training requirements 324
A 3.1 Technical staff must been trained on all the instrumentation to be used, on 325
the specific assays to be performed, and on the conduct and reporting of 326
stability studies. Specific training is required before: 327
data analysis 328
temperature monitoring and recording for incubators, fridges, 329
freezers and cold rooms. 330
Technical Guidance Series for WHO Prequalification – Diagnostic Assessment: Establishing component stability for an IVD - Case study: single-use buffer vials for rapid diagnostic tests
Annex to
TGS-2
Page 15 Draft for comment 19 September 2017
A 4 Responsibilities 331
A 4.1 The R&D department is responsible for the development and 332
documentation of a testing plan, including pre-determination of the 333
requirements (required test outcomes) used for defining stability and the 334
selection of materials and specimens to be tested. 335
A 4.2 The R&D department is responsible for obtaining the materials, putting 336
them into the correct environments, the subsequent testing and 337
equipment validation and monitoring, unless agreed otherwise. 338
A 4.3 The R&D Project Leader is responsible for assigning the allowable 339
component life from data generated in the study. 340
A 4.4 The R&D Project Leader, along with the QA manager, is responsible for 341
investigating any excursion/deviation from expectation. 342
A 5 Develop the risk management documentation 343
A 5.1 Prepare a risk management document, normally as a failure mode and 344
effect analysis (FMEA), with supporting documents to cover all the 345
technical aspects of the component under evaluation. This would include at 346
least the technical specifications, supplier details and acceptance criteria 347
for the component, specifications for the manufacturing processes 348
involving or leading to the component and the related QA and QC 349
processes. 350
A 5.1.1 Evaluate all health, safety and environmental aspects of the 351
potential studies. 352
A 5.1.2 Obtain and consider the input documentation of the product 353
particularly the intended use (environment of use and intended 354
user), and the requirements from the manufacturing department 355
provided as part of the design input requirements 356
evaluate the overall conditions in which the product, and 357
hence the component, will be required to operate and the 358
extremes of conditions to be used in the stability study 359
(e.g. temperature, pressure, humidity, microbiological 360
contaminants, vibration) (1). 361
A 5.1.3 Consider the claims for the IVD and evaluate which must be 362
proven to be met at the end of the IVD’s assigned life, for 363
example: 364
detection of critical specimens, ranges, analytical sensitivity, 365
precision 366
WHO Prequalification – Diagnostic Assessment
Page 16 Draft for comment 19 September 2017
specificity claims, analytical and diagnostic 367
time at which results must be read, flow times, drop volumes, 368
stability of output reading 369
A 5.1.4 Obtain the list of the constituents (“bill of materials”) of the 370
component and consider the physics and chemistry of each in 371
terms of potential effects on stability, for example: 372
plastics and stoppers from some manufacturers contain mould 373
release agents remnants from the mould which can affecting 374
the product function. 375
some adhesives (e.g. gum) from labels diffuse through plastic 376
into the contents of containers. 377
some plastics are porous to water vapour and to atmospheric 378
gases 379
some antimicrobial agents are unstable under some conditions 380
of pH and ionic composition 381
assess photostability for compounds whose photostability is 382
not known and which are not to be stored in lightproof 383
containers 384
A 5.1.5 Obtain the manufacturing documentation for the component. 385
Evaluate the importance of each of the parameters in the 386
manufacturing specification, evaluate each of the specification 387
requirements and consider which parameter might affect 388
product function and which might change over time, for 389
example: 390
“pH 6.7 – 7.1” 391
“required drop size = 30 ±4µL” 392
“fill-volume = 120 ±10µL” 393
A 5.1.6 Consider whether components made from new raw materials 394
(detergents, biologicals, biocides) will have the same stability as 395
those made from stored raw materials. 396
some detergents generate peroxides on standing 397
some proteins change conformation on ageing 398
A 5.1.7 Consider the minimum number of lots of components required, 399
composed of different lots of constituents, based on knowledge 400
Technical Guidance Series for WHO Prequalification – Diagnostic Assessment: Establishing component stability for an IVD - Case study: single-use buffer vials for rapid diagnostic tests
Annex to
TGS-2
Page 17 Draft for comment 19 September 2017
of likely interlot variability over the commercial life of the 401
product. (See Minimum number of lots, page 8.) 402
A 5.2 Consider the applicability of accelerated stability studies, and if found 403
appropriate the methods for obtaining the Arrhenius constants and 404
subsequent proof of validity (See Using data from accelerated studies, page 405
11). 406
A 6 Develop the stability testing plan 407
A 6.1 Write a complete, detailed plan, before starting any practical work, 408
according to which everything to be done will be fully documented and 409
then approved. 410
A 6.2 Prepare the plan, based on the risk assessment, including at least each of 411
the following: 412
The work environment 413
A 6.3 Consideration of health and safety issues from the use of the new 414
components and any planned test methods. 415
A 6.4 The management structure including competencies and training 416
requirements of technical staff performing the work. 417
A 6.5 The precise schedule of testing. 418
A 6.6 The precise instrumentation to be used, including storage facilities and 419
validation, calibration, monitoring and servicing. 420
A 6.7 The precise ranges of storage conditions to be used (A 5.1.2) 421
“room temperature” is inadequate: the precise temperatures 422
to be used must be defined and subsequently recorded. 423
the extremes of conditions used will define the extent of 424
permissible claims. 425
simulated transport stress conditions will almost always be 426
required before setting those same components onto long-427
term real-time stability studies. Simulated transportation 428
challenge should not be replaced by actual transportation 429
challenge. Actual transportation challenges often do not 430
explore the full range of transportation conditions that could 431
be encountered, including extreme values ( 1, 8) 432
WHO Prequalification – Diagnostic Assessment
Page 18 Draft for comment 19 September 2017
The items to be tested 433
A 6.8 The lot numbers of components to be tested with justification for any 434
manufacturing anomalies or excursions from finalized documented 435
procedures. 436
A 6.9 The lot numbers of components not under investigation (ancillary reagents) 437
but which are essential for the testing (all the other components of the 438
product), see A 9 Selection and storage of ancillary components or 439
accessories for the study, page 21 440
A 6.10 The storage conditions of the ancillary reagents to ensure that any changes 441
found in the tested component are not caused by changes in the ancillary 442
reagents. 443
A 6.11 The number of units (bottles, devices) of each component to be stored 444
under each condition. 445
The testing methods 446
A 6.12 The numerical criteria by which components will be judged satisfactory to 447
be used, given the required shelf-life of the product. 448
Define and justify the expected value for each characteristic at 449
the beginning and end (if different) of the component’s 450
proposed shelf-life. 451
A 6.13 Any physical or chemical measurements to be performed on the 452
components, separate from the test procedure according to the IFU. For 453
example: 454
pH 455
viscosity 456
component initial and final weights 457
drop volumes, residual volumes 458
colour, turbidity 459
resilience of labelling 460
long-term efficacy of seals and thermal sealing 461
A 6.14 The test for overall functionality of the new component. This is usually that 462
the product will meet all its claims for the intended use at the end of the 463
assigned shelf-life, with the component at the end of its to be assigned 464
shelf-life. 465
Technical Guidance Series for WHO Prequalification – Diagnostic Assessment: Establishing component stability for an IVD - Case study: single-use buffer vials for rapid diagnostic tests
Annex to
TGS-2
Page 19 Draft for comment 19 September 2017
Some components might have longer shelf-lives than the 466
entire product but it is important to ensure that, while a lot of 467
the product cannot have a later expiration date than the 468
shortest dated component, the product will function as 469
claimed with all components at the end of their stated shelf-470
lives 471
A 6.15 The stability testing panel to be used (A 8 Selection and storage of stability 472
panel members for the study, page 21), justifying each panel member’s 473
inclusion and defining: 474
the volume and characterization of the bulk material to be 475
used 476
the numbers and volumes of aliquots to be stored 477
the storage conditions for the panel members, or the method 478
of obtaining, characterizing and validation of labile panel 479
members such as whole blood for cell counts 480
for buffer solutions: ensure that borderline reactive and false 481
reactive specimens are included in the stability testing panel. 482
(See Monitoring specificity in stability studies page 10) 483
A 6.16 The time points over the study duration at which each of the stability 484
testing panel members will be tested 485
Perhaps not every panel member needs to be tested at each 486
time point 487
A 6.17 The replication (at least in duplicate) of each stability testing panel member 488
at the times at which it will be tested. 489
Methods for data evaluation 490
A 6.18 If the product itself does not give a quantitative result consider how to 491
quantitate stability data (see Quantitative reporting of stability results, 492
page 9). 493
stating a criterion without a numeric value (e.g. “must be 494
positive”) is rarely acceptable since unrecorded changes might 495
then occur 496
A 6.19 Define and justify the statistical techniques to be used in data analysis, in 497
assessing variance and in assigning shelf-life. 498
A 6.20 Define methods for detecting and disposing outlying values 499
outliers must always be recorded and must never be omitted, 500
even if repeat testing is within specification 501
WHO Prequalification – Diagnostic Assessment
Page 20 Draft for comment 19 September 2017
A 6.21 Develop and validate (14) any spreadsheets to be used in data collection 502
and calculation. 503
A 6.22 Prepare the graphs (paper or electronic) to visualize the performance of 504
each parameter, physical, chemical or stability testing panel related over 505
the course of the testing time 506
A 6.23 Define the expected and allowable variance of time zero values. 507
A 6.24 Define and document methods to ensure that any change apparently found 508
in the component under test is not caused by changes in other components 509
of the assay system. 510
A 6.25 Define methods for approval of proposed deviations from the plan and for 511
evaluation of any unexpected events during practical work 512
Approval for the plans 513
A 6.26 Justify any planned deviations from this policy 514
A 6.27 Obtain authorization of the plan before starting any work. 515
A 6.28 Establish managerial control and review of the progression of the planned 516
study 517
A 7 Preparation of specific SOP required for the stability study 518
A 7.1 Prepare protocols and any specific SOP for the testing 519
A 7.2 The outcome of the risk management and planning (outlined in the 520
previous paragraphs) will be a set of test methods that the manufacturer 521
will perform to collect the stability data. The following points should be 522
considered for all procedures: 523
ensure and document that technical staff are aware of any 524
hazards involved in the planned study 525
ensure that SOPs are in place for each of the testing methods 526
to be used (4) 527
ensure that any new test methods or panel members are valid 528
for the intended purpose; 529
ensure that any instruments to be used are validated for that 530
specific purpose 531
ensure that protocols are in place to be assured that sufficient 532
numbers of all reagents, stability testing panels, ancillary 533
components and other supplies are collected, labelled and 534
stored appropriately for the whole of the study. (Generally a 535
25 % excess over that actually required is accumulated.) 536
Technical Guidance Series for WHO Prequalification – Diagnostic Assessment: Establishing component stability for an IVD - Case study: single-use buffer vials for rapid diagnostic tests
Annex to
TGS-2
Page 21 Draft for comment 19 September 2017
A 8 Selection and storage of stability panel members for the study 537
A 8.1 Use only well characterized specimens from which to prepare the stability 538
testing panels. 539
A 8.2 Select stability testing panel members or physical methods to test all the 540
functionalities of the component (4) identified in the risk assessments. 541
for stability or changes to buffer solutions known false reactive 542
and potentially interfering specimens and borderline 543
specimens must always be included unless there is clear 544
evidence that they are not needed 545
A 8.3 Set aside sufficient volume in aliquots to allow for the testing on each 546
occasion specified in the plan (but not so large of volume as to waste 547
materials). 548
use the same lot of panel members throughout the testing 549
period 550
A 8.4 For panel members known to be stable over the planned period of the 551
study: 552
store the stability panel member so as to prevent loss of 553
activity, for example in aliquots below the eutectic point, at -554
80 °C if antigen or nucleic acid 555
Do not repeatedly freeze and thaw aliquots of stability testing 556
panel specimens 557
A 8.5 Ensure that a complete set of panel members is kept at <-80°C or other 558
conditions under which it is known to be stable so that 559
the panel can be life extended: if that is found necessary 560
unexpected results can be checked against a separately stored, 561
unused panel 562
A 8.6 For panel members known to be labile ensure that replacement specimens 563
will be available to monitor the critical claims and that such specimens are 564
fully characterized by acceptable methods. 565
A 9 Selection and storage of ancillary components or accessories 566
for the study 567
A 9.1 Set aside sufficient components or accessories so that the study can be 568
completed using the same “match” at each testing point. 569
WHO Prequalification – Diagnostic Assessment
Page 22 Draft for comment 19 September 2017
non-critical or interchangeable components and accessories 570
(as defined by the risk assessment) need not be designated in 571
advance although it is prudent to do so. 572
bear in mind that several lots of the component being tested 573
will be used and the objective is to obtain data not only on 574
stability of the component but on any variability in stability 575
between lots (A 5.1.7) 576
A 9.2 Store such ancillary materials under conditions known to provide maximum 577
stability as defined in the stability plan. 578
A 9.2.1 Store the selected items securely 579
A 9.2.2 Do not allow the selected ancillary components and accessories 580
set aside for stability studies to be used for any other purpose. 581
A 10 Storage of the components to be tested 582
A 10.1 Store the component so that liquid constituents are in contact with all the 583
immediate packaging materials. 584
if a liquid can come into contact with more than one type of 585
material (e.g. a solution in a polystyrene vial with a neoprene 586
stopper) then orientation of the component during storage i.e. 587
upright versus inverted or horizontal should be such that the 588
liquid comes into contact with all types of material. 589
vibration of the stored components might be necessary on 590
occasion 591
A 10.2 Record the temperature and humidity of each storage location daily. 592
nominate a member of staff to do this as a critical part of their 593
job 594
ensure warnings are disseminated if storage conditions are 595
outside the designated ranges or are showing unacceptable 596
trends 597
A 11 Collection of the stability data 598
A 11.1 General expectations of data collection 599
A 11.1.1 Data collection methodology must be defined in the plan for each 600
specific study. 601
A 11.1.2 Raw data must be collected and stored in a secure and traceable 602
manner. 603
Technical Guidance Series for WHO Prequalification – Diagnostic Assessment: Establishing component stability for an IVD - Case study: single-use buffer vials for rapid diagnostic tests
Annex to
TGS-2
Page 23 Draft for comment 19 September 2017
traceability of the data to date, operator (by name and 604
signature), equipment 605
any spreadsheets used for collecting, calculating or presenting 606
results must be formally validated, or verified by an 607
independent methods 608
A 11.1.3 Testing is not done before the defined times 609
Additional testing is permitted but the rest of the original 610
schedule must always be followed 611
A 11.1.4 Recording of the lot and item numbers of each component and 612
test device tested. 613
A 11.1.5 Recording of any unexpected events noticed while the test is being 614
performed, for example: 615
change in the physical state of the component, packaging or 616
labelling 617
change in smell or turbidity, which could indicate microbial 618
growth 619
change in viscosity or formation of precipitates 620
change in colour 621
leakage 622
A 11.1.6 Approval of pre-determined deviations from schedule. The 623
following have proven appropriate in practice but must be 624
evaluated for each study 625
test at the specified time for scheduled intervals of less than 626
three weeks 627
test no more than three days after the scheduled date when 628
the intervals between testing dates are three weeks to two 629
months 630
test no more than 14 days after the scheduled date when the 631
intervals between testing dates are greater than two months 632
A 11.2 Specific technical expectations of data collection 633
A 11.2.1 Establishment and recording of a time zero value (the value when 634
the study is started: when the component is moved from optimal 635
storage to the conditions under study, see Zero time values and 636
variance, page 10) 637
WHO Prequalification – Diagnostic Assessment
Page 24 Draft for comment 19 September 2017
for each lot separately 638
for all the parameters being evaluated 639
on sufficient occasions to establish a time zero value with its 640
variance 641
An “occasion” must be defined in the risk assessment but some 642
factors to consider are the work environment, operator and 643
equipment so as to cover all the variation that might be expected 644
during the study 645
A 11.3 Specific expectations of data review during collection 646
A 11.3.1 The results are compared with the criteria in the stability plan 647
immediately after the test procedure is completed. 648
A 11.3.2 The testing is immediately repeated if any criteria are not met. 649
a method to investigate a first failure is documented and 650
followed but not necessarily before the repeat testing 651
the original data is kept along with a record that repeat testing 652
was done 653
if the repeat assay also fails to meet criteria the project leader 654
is alerted but a third repeat is not performed without prior 655
investigation 656
A 12 Establishment of the expiry dating of the component 657
A 12.1 Establish the expiry dating for the component from real-time data only 658
unless the relationship between accelerated data and real-time has been 659
established. 660
A 12.1.1 Subject to prior risk evaluation it is usually safer to launch a 661
product with a restricted life, which can be extended as real-time 662
data is collected, than to use accelerated data. (See Using data 663
from accelerated studies, page 11) 664
A 12.1.2 For the purposes of WHO prequalification, labelling should be 665
based on real-time stability studies. 666
A 12.1.3 Consider lot–to-lot, user to user and test-to-test variation when 667
setting the expiry dating. 668
A 12.2 Set the expiry date as the last date, minus a safety factor (usually one or 669
two months for products with lives greater than 12 months and as agreed 670
via risk evaluation for test devices and components with shorter lives or for 671
in-use, opened or “on-board” stabilities), at which the component meets all 672
Technical Guidance Series for WHO Prequalification – Diagnostic Assessment: Establishing component stability for an IVD - Case study: single-use buffer vials for rapid diagnostic tests
Annex to
TGS-2
Page 25 Draft for comment 19 September 2017
the end of life criteria necessary for the claimed functionalities with at least 673
95 % confidence. 674
A 12.3 Ensure that real-time stability data is collected to support any dating from 675
accelerated stability data. 676
A 12.3.1 Ensure that QA, manufacturing and marketing departments are 677
made aware of any discrepancy between real-time and 678
accelerated stability data as soon as possible. 679
A 12.4 Prepare the stability report 680
A 12.4.1 Prepare the report in accord with the QMS and document control 681
but include at least the following in the report: 682
an executive summary 683
the testing plan 684
lot numbers involved and the location of the manufacturing 685
documentation 686
criteria for all the testing, including physical, chemical and the 687
stability testing panels at start and end of the assigned life of 688
the components 689
location of the records of all original testing data and storage 690
conditions 691
results obtained - present data in tabular and in graphical form 692
summary and conclusions regarding stability 693
an authorized statement of the component shelf-life 694