annex to tgs 2 - who · 54 and tgs-4: guidance on test method validation for in vitro diagnostic 55...

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

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Contact: Irena Prat, WHO Prequalification – Diagnostic Assessment, WHO - 20 Avenue Appia - 1211 Geneva

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mailto:[email protected]

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


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.


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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



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


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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.




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


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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.



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


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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 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


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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



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

https://www.iso.org/obp/ui/#iso:std:iso:18113:-1:ed-1:v1:en

https://www.iso.org/obp/ui/#iso:std:iso:18113:-1:ed-1:v1:en

https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=820.3

http://apps.who.int/iris/bitstream/10665/251915/1/WHO-EMP-RHT-PQT-2016.01-eng.pdf?ua=1

http://apps.who.int/iris/bitstream/10665/251915/1/WHO-EMP-RHT-PQT-2016.01-eng.pdf?ua=1

http://eur-lex.europa.eu/legal-content/EN/TXT/?uri=OJ:L:2017:117:TOC


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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

http://www.fda.gov/downloads/ICECI/Inspections/InspectionGuides/UCM085938.pdf%20accessed%2031%20May%202017

http://www.fda.gov/downloads/ICECI/Inspections/InspectionGuides/UCM085938.pdf%20accessed%2031%20May%202017

http://www.fda.gov/downloads/scienceresearch/fieldscience/laboratorymanual/ucm092179.pdf%20accessed%2031%20May%202017

http://www.fda.gov/downloads/scienceresearch/fieldscience/laboratorymanual/ucm092179.pdf%20accessed%2031%20May%202017



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


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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



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


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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



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


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TGS-2


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



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


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TGS-2


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



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


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TGS-2


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



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


Annex to

TGS-2


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

annex to tgs 2 - who · 54 and tgs-4: guidance on test method validation for in vitro diagnostic 55...

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