reportable changes to a who prequalified in vitro diagnostic · reportable changes to a who...

REPORTABLE CHANGES TO A WHO

PREQUALIFIED IN VITRO DIAGNOSTIC

Draft for public comment 01 February 2016

Reportable changes to a WHO Prequalified IVD - Working document PQDx_121 v2 01 February 2016

Working document 20 January 2016 of 24

Contents 1

CONTENTS................................................................................................................................................ 2 2

PURPOSE OF THIS DOCUMENT ........................................................................................................ 3 13

1.1 INTENDED AUDIENCE............................................................................................................................3 4 1.2 SCOPE ...............................................................................................................................................3 5 1.3 BACKGROUND ....................................................................................................................................3 6

REPORTING OF CHANGES TO WHO .................................................................................................. 5 27

CHANGES REQUIRING A NEW PREQUALIFICATION APPLICATION .................................................... 5 38

REPORTABLE CHANGES .................................................................................................................... 6 49

4.1 REPORTABLE CHANGES TO THE MANUFACTURING PROCESS .........................................................................6 10 4.2 REPORTABLE CHANGES TO THE PRODUCT .................................................................................................7 11 4.3 OTHER CHANGES .................................................................................................................................9 12

REPORTABLE ADMINISTRATIVE CHANGES ..................................................................................... 10 513

NON-REPORTABLE CHANGES ......................................................................................................... 11 614

DETERMINING THE IMPACT OF A CHANGE .................................................................................... 11 715

7.1 PROCESS FOR CATEGORIZING AND REPORTING A CHANGE ..........................................................................13 16

REPORTING TO WHO ..................................................................................................................... 14 817

ASSESSMENT OF SUBMITTED PQDX CHANGE REPORT FORMS ....................................................... 14 918

OUTCOME OF ASSESSMENT OF THE CHANGE REPORT ................................................................... 15 1019

FAILURE TO REPORT A REPORTABLE CHANGE TO WHO ................................................................. 15 1120

MONITORING OF CHANGE REPORTING ......................................................................................... 15 1221

CHANGE ASSESSMENT FEE ............................................................................................................. 15 1322

RELEVANT DOCUMENTS ................................................................................................................ 16 1423

CONTACT INFORMATION ............................................................................................................... 17 1524

ANNEX 1: EXAMPLES OF REPORTABLE CHANGES TO PREQUALIFIED IVDS .............................................. 18 25

ANNEX 2: EXAMPLES OF NON-REPORTABLE CHANGES........................................................................... 21 26

ANNEX 3: FORMATTING REQUIREMENTS FOR SUBMISSIONS ................................................................ 22 27

REFERENCES ........................................................................................................................................... 24 28



Purpose of this document 129

1.1 Intended audience 30

This document aims to provide manufacturers of WHO prequalified in vitro 31 diagnostics (IVD) with information on when they must report to WHO on: 32

changes to the prequalified product or its manufacture; 33

changes to the Quality Management System (QMS) that the product was 34 designed and manufactured under; and/or 35

other reportable administrative changes. 36 37

Manufacturers of WHO prequalified IVDs should read this document to be 38 fully aware of their duties and responsibilities as a supplier of a prequalified 39 IVD to report applicable changes to the IVD, its manufacture and other 40 related activities. 41

42 Note: For the purpose of this document the following definition of “manufacturer” 43 applies: Any natural or legal person with responsibility for design and/or 44 manufacture of a diagnostic product with the intention of making the diagnostic 45 product available for use, under his/her name; whether or not such a diagnostic 46 product is designed and/or manufactured by that person himself/herself or on 47 his/her behalf by another person(s) [1]. 48 49 50 51 52

53

1.2 Scope 54

55 This document describes when and how a manufacturer will report to WHO 56 changes to a prequalified IVD and its manufacture, or to the QMS under 57 which it is manufactured. WHO also requires that certain other 58 administrative changes associated with the IVD are reported. As it is not 59 possible to describe all possible changes, this document provides guidance 60 and a non-exhaustive list of generic examples. The manufacturer should 61 contact WHO if in doubt. 62 63

1.3 Background 64

65 As part of the life cycle of an IVD, changes to the product, its manufacture 66 (the process and its location) and the QMS under which it is produced may 67

This document does not address the required response to changes made during the prequalification assessment. For changes implemented during the assessment process, manufacturers should contact WHO to seek guidance.



become necessary for technical or economic reasons. Such changesa to 68 prequalified IVDs range from minor (with little potential to impact the quality, 69 safety and/or performance of the IVD) to substantial (likely to affect the 70 quality, safety and/or performance). 71 72 A critical part of a manufacturer’s QMS is a process to design, review, verify, 73 validate (if appropriate), approve and implement changes. The next step is to 74 determine the significance of the change, on function, performance, usability, 75 safety and applicable WHO requirements for the IVD and its intended use. 76 Changes applied to an IVD must be made in compliance with the 77 requirements for control of design change according to ISO 13485:2003 [2]. 78

79

a Some regulatory authorities refer to changes as “variations”.



Reporting of changes to WHO 280

81 For the purpose of this guidance, changes are defined either as reportable or 82 non-reportable. 83 84 All substantial changes and certain administrative changes associated with a 85 prequalified IVD are considered as reportable changes. These must be 86 reported via either a new prequalification application or submission of the 87 “Change Report Form for a WHO Prequalified In Vitro Diagnostic” (WHO 88 document PQDx_119) to WHO Prequalification Team – Diagnostics at 89 [email protected]. 90 91 Unless specified in this document, minor changes associated with a 92 prequalified IVD are considered as non-reportable and do not require the 93 submission of a PQDx Change Report Form to WHO. 94 95 A reportable change is one that is demonstrated, through risk analysis, to 96 have a potential impact on function, performance, usability, safety of a 97 prequalified IVD. 98 99 A reportable change may: 100

introduce a risk to the patient not previously identified; 101

change the probability of existing hazards occurring; and/or 102

alter the presentation of existing or new risks to the user (this can involve 103 labelling changes or new indications for use). 104

105 Reporting of reportable changes should occur prior to implementation of a 106 substantial change to allow WHO to assess the change. Manufacturers are 107 encouraged to contact WHO early in the process of designing and validating 108 the change, to allow sufficient time for assessment before the change is 109 implemented. 110

111

Changes requiring a new prequalification application 3112

113 In some cases, changes are of such a magnitude that they affect the safety 114 and performance of the product and a new application to the 115 Prequalification Programme is required. This will occur where it is deemed 116 that the changes have resulted in a product or application information of 117 substantial difference to that which was prequalified. In these cases, WHO 118 will notify the manufacturer that a new prequalification application is 119 required. This application will undergo prequalification assessment, 120 according to WHO guidance “Overview of the Prequalification of In Vitro 121 Diagnostics Assessment” (WHO document PQDx_007). WHO will also notify 122 the manufacturer on the impact of the planned change to the 123

mailto:[email protected]



prequalification status of the product subject to the change. 124 125 The changes listed below are examples of those which could require 126 submission of a new application for prequalification: 127

a change to what is detected (i.e. the analyte or measurand); 128

changes in antigens, antibodies, primers or solid phase; 129

a change to the specific disorder, condition or risk factor of interest that 130 it is intended to detect, define or differentiate; 131

a change in the test result format from a qualitative or quantitative or 132 vice versa; 133

a change in biological or chemical principle of the test; and/or 134

a change in design of test technology. 135 136 The combination of several changes can also result in the need for a new 137 prequalification application. Manufacturers should seek advice from WHO 138 when planning to introduce several changes at the same time. 139 140

Reportable changes 4141

142 The following sections provide more details on types of changes that require 143 submission of a “WHO Notification Form for Changes to a WHO Prequalified 144 In Vitro Diagnostic” (WHO document PQDx_119), hereafter referred to as a 145 PQDx Change Report Form. For a comprehensive list of documentation to 146 accompany the PQDx Change Report Form, please refer to Section 4 of the 147 form. 148

4.1 Reportable changes to the manufacturing process 149

A change to the prequalified IVD manufacturing process, facility or 150 equipment that could affect the IVD's quality, safety and/or performance is 151 considered a substantial change and therefore requires the submission of a 152 completed PQDx Change Report Form to WHO. 153 154

Reportable changes to a manufacturing process

Physical move/relocation of finished product manufacturing, assembling or other processing equipment from one location to a different location or; addition of a new facility (manufacturing facility, warehouse, etc.) within the same location.

Change in the manufacturing process such as the introduction of new equipment or change in workflow.

Changes to the manufacturing quality control procedures, such as the methods, tests or procedures used to control the quality of the materials or the product.



Removal of test acceptance criteria for incoming components, in-process and finished product. Removal of in-process inspections or final inspections without replacement of these activities.

Addition of in-process inspection steps in response to post-market product issues.

Change of a supplier, or sub-tier supplier, of reagents, antigens, antibodies, preservatives, anticoagulants, primers or solid phase.

Move of manufacturing, processing or packaging from a supplier to the manufacturer’s facility.

Move of manufacturing, processing or packaging from the manufacturer’s facility to a supplier.

155

4.2 Reportable changes to the product 156

4.2.1 Design changes and changes to the intended use 157

Changes to a product may span from minor changes to the design of the 158 product to substantial changes in operating principles. All changes must be 159 evaluated, verified and validated according to the accepted procedures 160 recorded in the QMS documentation. Changes to the design specifications, 161 physical attributes, user interface, software or hardware may be substantial if 162 they potentially have an impact on the intended use, test procedure or 163 interpretation of results for the IVD. Additionally, changes to claims relating 164 to the intended use must be reported, even if they do not impact on design. 165 166 167

Reportable changes to the product design and intended use

A change to the reagent volume or specimen volume required to perform the test.

A change to the reading period (minimum or maximum).

The acceptability of new anticoagulants for plasma specimens.

A change to the automation process (including change to a new smaller/larger model if the IVD is an instrument) or the change from a manual procedure to an automated procedure for use.

A change to the operating principle.

Changes to materials/components supplied with the IVD (e.g. introduction of new ancillary reagents such as quality control reagents).

A change to the function of the product (e.g. screening, monitoring, diagnosis or aid to diagnosis, staging or aid to staging of disease, prediction, self-testing).

A change to the specific disorder, condition or risk factor of interest that it is intended to detect, define or differentiate.

A change in performance or design specifications.



Addition or removal of a specimen type (e.g. serum, plasma, whole blood, oral fluid, sputum, urine, dried blood spot).

A change to the intended testing population including any new or extended use (e.g. addition of neonates, antenatal women).

An addition or deletion of a contraindication for the device.

A change in the stability data resulting in a change to the period used to establish the expiry date of the IVD.

Changes to the materials supplied with the IVD (e.g. accessories such as lancets).

168

4.2.2 Changes in materials/components 169

170 Changes to critical raw materials/components used in the manufacturing 171 process of an IVD often affect its performance characteristics, for example 172 sensitivity and specificity. These changes should be assessed as to their 173 impact on the quality, safety and/or performance of the IVD. 174 175 Changes in materials/components that would typically be considered 176 reportable include: 177

Reportable changes in materials/components

Changes to the formulation of reagents in the assay that result in a change (either increase or decrease) to the stability/shelf-life claims.

Changes in the conjugate or substrates that do not change the intended use.

Changes in specimen preparation such as a change in nucleic acid extraction method.

The addition or change of a preservative to a reagent of the test kit.

Changes to the source (supplier) or processing of biological materials.

Changes from liquid to lyophilized reagents or vice versa.

Changes to materials/components that necessitate testing of additional clinical specimens, or retesting of original specimens, to determine performance characteristics of the IVD.

Changes to the materials/components of an IVD that result in a change to the operating principle of the product.

Changes to materials/components that potentially affect the operating procedure of an IVD include changes in reaction components or materials such as calibration materials, or changes in methods such as specimen pre-treatment, incubation times and operating temperatures.

Changes in energy supply requirements.

178 179



4.2.3 Changes to labelling 180

For the purposes of WHO Prequalification, labelling includes kit and kit 181 component labels and instructions for use. 182 183

Reportable changes to labelling

All changes to labelling should be reported unless the changes are made to : 1. Clarify labelling statement (clarifying instructions to make the device

easier or safer to use) without changing the procedure; 2. correct errors (typographical errors or numerical errors); and/or 3. include additional languages.

184

4.2.4 Changes to a product’s software 185

186

Reportable changes to the software

A software change that impacts the control of the product, and may alter the reporting result that is used in the diagnosis or other function.

A software change that modifies an algorithm impacting the test result.

A software change that impacts the way data are read or interpreted by the user, such that the diagnosis or other function may be altered when compared to the previous version of the software.

A software change that replaces previously required user input.

A software change to correct an error that presents a safety risk to the patient.

Addition of a new feature to the software that may affect the diagnosis or other software driven function.

A software change that incorporates a change to the operating system on which the software runs.

187

4.3 Other changes 188

189

Changes to QMS

Changes in the ISO 13485:2003 certification status of the manufacturer, of the prequalified IVD, such as suspension of the ISO 13485:2003 certificate, obtaining a new certification, or change in the scope of certification.

Change in Notified Body or certification body

Changes to the legal manufacturer including:

change of ownership;

change of legal entity status (Ltd, SA, etc.)

change of name and/or address.

190



Changes to the regulatory status

Change in the regulatory status of the prequalified IVD in any of the member nations or regions of the International Medical Device Regulators Forum (IMDRF). For example, licence suspension in Canada, receipt of a Warning Letter from the US FDA, suspension of ARTG registration in Australia, or suspension of a CE mark certification in the European Union.

191

Reportable administrative changes 5192

193 Changes limited to the product name, product code(s) and/or manufacturer 194 name require reporting. 195 196

Reportable administrative changes

Changes only to the product name.

Changes only to the product code(s).

Changes only to the manufacturer name.

197 For administrative changes, the following information should be provided 198 with the PQDx Change Report Form: 199 200

a declaration that the change only affects the product name, product 201 code(s) and/or manufacturer name and has no impact on the quality, 202 safety and/or performance, as supported in the submitted 203 prequalification documentation and the reason(s) for making the 204 changes; and 205

the new product labelling (labels, instructions for use, and any other 206 printed or electronic labelling material) reflecting the changes. 207

208 Changes to the WHO authorized contact for the manufacturer do not require 209 submission of a PQDx Change Report Form but WHO should be notified by 210 email to [email protected] accompanied by a signed letter from the 211 manufacturer appointing new contacts as authorized to represent the 212 manufacturer for the purposes of prequalification. 213

214




Non-reportable changes 6215

216 All other minor changes that are not required as part of a PQDx Change 217 Report Form and may include, but are not limited to: 218 Simple changes to the product labelling documentation, such as: 219

rewording or expanding for clarification; 220

translating from one language to another; 221

correcting typographical errors; and/or 222

replacing (or complementing) written text by internationally recognized 223 symbols; 224

minor software changes that do not impact the safety or performance of 225 the product; 226

minor QMS changes such as increased post-market surveillance activity 227 or regular updates of controlled QMS procedures (such as control of 228 documents, management review etc.); and/or 229

minor manufacturing, additional in-process quality control criteria or test 230 methods for manufacturing processes to provide equivalent or better 231 assurances of reliability, as determined by the manufacturer but which 232 do not affect safety or performance. 233 234

Determining the impact of a change 7235

The requirement to report to WHO regarding a change depends on the 236 impact of the change on the IVD's quality, safety and/or performance. The 237 impact of a change should be determined for all changes. The change to the 238 IVD overall residual risk evaluation may have arisen from: 239

actions taken related to concerns arising from post-market surveillance, 240 including adverse events, recalls or complaints; 241

redevelopment including state of the art product improvements; 242

changes to a manufacturing process, facility or equipment; 243

changes to the design or composition of the prequalified IVD; 244

changes to the organization of the manufacturer; 245

changes to the intended use and /or test procedure; and/or 246

changes necessitating new clinical and/or analytical data that raise new 247 issues of safety and performance. 248

249 Consideration should be given to the impact of the change on the overall 250 residual risk/benefit evaluation of the IVD as per ISO 14971:2007 [3]. This 251 includes a determination of whether or not the change: 252

introduces new hazards that have not been previously addressed; 253

adversely affects the risk associated with existing hazards; 254

alters the details of any of the information submitted for prequalification 255 (related to dossier, manufacturing site(s) inspection, or laboratory 256 evaluation), such as the intended use and/or compliance with the 257 Essential Principles of safety and performance of medical devices [4]; 258



and/or 259

affects the continued compliance of the QMS with the relevant 260 standards. 261

262 Where the change is considered substantial, as assessed through the above 263 process, it should be reported to WHO. The steps in the risk analysis rationale 264 used for determining whether a change is reportable or not must be 265 documented. 266

267



7.1 Process for categorizing and reporting a change 268

269

270 271

Figure 1. Flow diagram for categorizing and reporting change. 272

Identify the change and document reasons

for change

Conduct a risk analysis for the change and determine the

potential impact of the change

Define the information needed to assess the impact

of the change

Review the risk assessment after evaluating the results of the

change assessment and before introducing hazard reduction

steps

Categorize the change as

substantial or minor

Report if applicable using PQDx Change

Report Form

Start



Reporting to WHO 8273

274 The manufacturer should inform WHO of the intention to report a change by 275 email to [email protected] and subsequently, complete and submit a 276 PQDx Change Report Form on a CD or DVD. For a comprehensive list of 277 documentation to accompany the PQDx Change Report Form, please refer to 278 Section 4 of the form. Formatting requirements are outlined in Annex 3 of 279 this document. 280 281 Manufacturers are encouraged to communicate their intent to introduce a 282 substantial change in advance to allow sufficient time for assessing the 283 change prior to its implementation. WHO will not approve any changes 284 without due assessment. Depending on the type of change, the assessment 285 may also include a manufacturing site(s) inspection. 286 287

Assessment of submitted PQDx Change Report Forms 9288

289 Once WHO receives the PQDx Change Report Form, the change report will be 290 reviewed to determine the actions required to assess the change. 291 292 The report form and documentation (including project plan if appropriate) 293 will be screened for completeness by WHO staff. This screening does not take 294 into consideration the technical appropriateness of all the information 295 provided within the change report. If the provided documentation is 296 incomplete, the manufacturer will be informed and requested to provide 297 supplements within a specified time period set by WHO. The manufacturer 298 will be given one opportunity to provide additional information prior to the 299 full technical review. 300 301 The information submitted in the PQDx Change Report Form will then 302 undergo a full technical review by external experts appointed by WHO and 303 performed as per the WHO document “Overview of the prequalification of in 304 vitro diagnostics assessment” (document PQDx_007). Assessors must have 305 the qualifications and expertise in the relevant fields and must comply with 306 the confidentiality and WHO conflict of interest rules. The manufacturer will 307 be given one opportunity to address any deficiencies in the submitted 308 documentation and/or data that has been identified during full technical 309 review. 310 If the submitted documentation supporting the change does not meet WHO 311 prequalification requirements or the requested information is not provided 312 by the manufacturer within the specified time period, WHO will reject the 313 change. 314 315



http://www.who.int/diagnostics_laboratory/evaluations/140530_pqdx_overview_doc_007.pdf?ua=1

http://www.who.int/diagnostics_laboratory/evaluations/140530_pqdx_overview_doc_007.pdf?ua=1



Outcome of assessment of the change report 10316

317 WHO will inform the manufacturer of the outcome of the WHO assessment 318 of the change in writing. The manufacturer will be notified if WHO deems 319 that a manufacturing site inspection and/or a laboratory evaluation is 320 required. The need to perform a manufacturing site(s) inspection and/or a 321 laboratory evaluation will be established based on the nature of the change 322 and its potential impact on the quality, safety and/or performance. 323 324 Where a change is accepted by WHO, the manufacturer may implement the 325 proposed changes to the prequalified product. As needed, WHO may update 326 the public report and its list of prequalified products to reflect the respective 327 change. Information on the change may be included in the updated WHO 328 prequalification public report. 329 330 If the submitted documentation supporting the change does not meet WHO 331 prequalification requirements or the requested information is not provided 332 by the manufacturer within the specified time period, WHO will reject the 333 change. The impact of such a decision on the prequalification status of the 334 prequalified IVD will be communicated to the manufacturer. 335 336

Failure to report a reportable change to WHO 11337

338 Reporting of changes which meet the criteria for reportable changes, as 339 described in this guidance document, is mandatory for all prequalified IVDs. It 340 is the manufacturer’s responsibility to notify WHO of changes, as described in 341 this guidance document, in order to keep the prequalification status of the 342 product up to date. Failure to report changes in accordance with the 343 requirements set in this document may result in the delisting of the product 344 from the list of prequalified IVDs. 345 346

Monitoring of change reporting 12347

348 As part of routine post-prequalification activities, WHO re-inspections will 349 include a review of the compliance of the manufacturer to the requirements 350 of this document. Failure to comply may result in the assignment of a non-351 conformity against the manufacturer’s QMS. 352 353

Change assessment fee 13354

355 WHO will review the PQDx Change Report Form to determine the level of 356



assessment required. The cost of the activities required to assess the change 357 will be covered in part by the manufacturer. The non-refundable change fee 358 of 3,000 USD will contribute to the costs associated with change 359 documentation review, manufacturing site(s) inspection, and dissemination 360 of change information. On payment of this fee, WHO assessment of the 361 change will commence. 362 363 WHO reserves the right to decide, based on the change assessment findings, 364 whether a product meets the prequalification change requirements. 365 Therefore, payment of the change assessment fee does not guarantee that 366 the change will be approved. WHO also reserves the right to reject the 367 proposed change(s) at any stage if the manufacturer is not able to, or fails to, 368 provide the required information in a specified time period, or when the 369 information supplied is inadequate to complete the change assessment 370 effectively. 371 372

Relevant documents 14373

374

WHO. Overview of the prequalification of in vitro diagnostics assessment. PQDx_007. 375 Geneva, Switzerland. World Health Organisation; 2014 376

377

ISO 13485:2003. Medical devices – Quality management systems – Requirements for 378 regulatory purposes. Geneva, Switzerland: International Organization for Standardization; 379 2003. 380

381

ISO 14971:2007. Medical devices – Application of risk management to medical IVDs. 382 International Organization for Standardization; Geneva, Switzerland: 2007. 383

384

GHTF/SG1/N41R9:2005 Essential Principles of Safety and Performance of Medical Devices. 385 Global Harmonization Task Force (GHTF) Steering Committee; 2005 386

387

CLSI. Evaluation of Stability of In Vitro Diagnostic Reagents; Approved Guideline. CLSI 388 document EP25-A.Clinical and Laboratory Standards Institute; Wayne, PA; 2009. 389

390

NB-MED/2.5.2/Rec2. Reporting of design changes and changes to the quality system. Co-391 ordination of Notified Bodies Medical devices (NB-MED) on Council Directives 90/385/EEC, 392 93/42/EEC and 98/79/EC; 2000 393

394

FDA: Deciding When to Submit a 510(k) for a Change to an Existing Device (K97-1). Center 395 for Devices and Radiological Health (CDRH) and Center for Biologics Evaluation and 396 Research (CBER), MD, USA; 1997 397

398

FDA: Guidance for Industry and Food and Drug Administration Staff. 30 Day Notices, 135 Day 399 Premarket Approval (PMA) Supplements and 75 Day Humanitarian Device Exemption (HDE) 400 Supplements for Manufacturing Method or Process Change. Center for Devices and 401

http://www.who.int/entity/diagnostics_laboratory/evaluations/140530_pqdx_overview_doc_007.pdf?ua=1

http://www.iso.org/iso/catalogue_detail?csnumber=36786


https://www.iso.org/obp/ui/#iso:std:iso:14971:ed-2:v2:en

http://www.imdrf.org/docs/ghtf/final/sg1/technical-docs/ghtf-sg1-n41r9-2008-principles-safety-performance-050520.pdf

http://shop.clsi.org/method-evaluation-documents/EP25.html

http://shop.clsi.org/method-evaluation-documents/EP25.html

http://www.meddev.info/_documents/R2_5_2-2_rev7.pdf

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm080235.htm

http://www.fda.gov/RegulatoryInformation/Guidances/ucm080192.htm





Radiological Health (CDRH) and Center for Biologics Evaluation and Research (CBER), MD, 402 USA; 2011 403

404

FDA: Guidance for Industry and Food and Drug Administration Staff. Modifications to 405 Devices Subject to Premarket Approval (PMA) – The PMA Supplement Decision. Center for 406 Devices and Radiological Health (CDRH) and Center for Biologics Evaluation and Research 407 (CBER), MD, USA; 2008 408

409

FDA: Guidance for Industry and Food and Drug Administration Staff. Manufacturing Site 410 Change Supplements: Content and Submission. Center for Devices and Radiological Health 411 (CDRH) and Center for Biologics Evaluation and Research (CBER), MD, USA; 2015 412

413

FDA: General Principles of Software Validation; Final Guidance for Industry and FDA Staff. 414 Center for Devices and Radiological Health (CDRH) and Center for Biologics Evaluation and 415 Research (CBER), MD, USA; USA; 2002 416

417

FDA: PMA Supplements and Amendments. Available at 418 http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevi419 ce/PremarketSubmissions/PremarketApprovalPMA/ucm050467.htm Accessed 08 January 420 2016 421

422

FDA: Real-Time Premarket Approval Application (PMA) Supplements. Center for Devices and 423 Radiological Health (CDRH) and Center for Biologics Evaluation and Research (CBER), MD, 424 USA; 2006 425

426

NBOG BPG 2014-3 Guidance for manufacturers and Notified Bodies on reporting of Design 427 Changes and Changes of the Quality System. Notified Body Operations Group (NBOG), Bonn, 428 Germany; 2014 429 430

Health Sciences Authority of Singapore. Medical device Guidance GN-21: Guidance on 431 change notification for registered medical devices. Revision 4. Singapore; 2015 432

433

TGA: Changes or variations to therapeutic devices in the ARTG. Therapeutic Goods 434 Administration (TGA). ACT, Australia; 1998 435

436

Health Canada: Guidance for the Interpretation of Significant Change of a Medical Device. 437 Health Products and Food Branch, Ottawa, Ontario; 2011 438

439

Contact information 15440

Any inquiries regarding changes to prequalified in vitro diagnostics should be 441 addressed to: [email protected] 442 443



http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM467414.pdf

http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM467414.pdf


http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/PremarketSubmissions/PremarketApprovalPMA/ucm050467.htm

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/PremarketSubmissions/PremarketApprovalPMA/ucm050467.htm


http://www.nbog.eu/resources/NBOG_BPG_2014_3.pdf

http://www.nbog.eu/resources/NBOG_BPG_2014_3.pdf

https://www.tga.gov.au/sites/default/files/dr4-appendix-03.pdf

http://www.hc-sc.gc.ca/dhp-mps/md-im/applic-demande/guide-ld/signchng_modimportante-eng.php




Annex 1: Examples of reportable changes to prequalified IVDs 444

445 The following list is intended as an aid to manufacturers to help determine 446 the significance of particular changes. The list is not exhaustive and should be 447 considered in conjunction with the guidance provided in this document. 448

Types of reportable changes

Changes to a manufacturing process

Physical move/relocation of finished product manufacturing, assembling or other processing equipment from one location to a different location or; addition of a new facility (manufacturing facility, warehouse, etc.) within the same location.

Change in the manufacturing process such as the introduction of new equipment or change in workflow.

Changes to the manufacturing quality control procedures, such as the methods, tests or procedures used to control the quality of the materials or the product.

Removal of test acceptance criteria for incoming components, in-process and finished product. Removal of in-process inspections or final inspections without replacement of these activities.

Addition of in-process inspection steps in response to post-market product issues.

Change of a supplier, or sub-tier supplier, of reagents, antigens, antibodies, preservatives, anticoagulants, primers or solid phase.

Move of manufacturing, processing or packaging from a supplier to the manufacturer’s facility.

Move of manufacturing, processing or packaging from the manufacturer’s facility to a supplier.

Changes to the product design and intended use

A change to the reagent volume or specimen volume required to perform the test.

A change to the reading period (minimum or maximum).

The acceptability of new anticoagulants for plasma specimens.

A change to the automation process (including change to a new smaller/larger model if the IVD is an instrument) or the change from a manual procedure to an automated procedure for use.

A change to the operating principle.

Changes to materials/components supplied with the IVD (e.g. introduction of new ancillary reagents such as quality control reagents).

A change to the function of the product (e.g. screening, monitoring, diagnosis or aid to diagnosis, staging or aid to staging of disease, prediction,



self-testing).

A change to the specific disorder, condition or risk factor of interest that it is intended to detect, define or differentiate.

A change in performance or design specifications.

Whether the test is qualitative or quantitative.

Addition or removal of a specimen type (e.g. serum, plasma, whole blood, oral fluid, sputum, urine, dried blood spot)

A change to the intended testing population including any new or extended use (e.g. addition of neonates, antenatal women).

An addition or deletion of a contraindication for the device.

A change in the stability data resulting in a change to the period used to establish the expiry date of the IVD.

Changes to the materials supplied with the IVD e.g. accessories such as lancets.

Changes in materials/components

Changes to the formulation of reagents in the assay that result in a change (either increase or decrease) to the stability /shelf-life claims.

Changes in the conjugate or substrates that do not change the intended use.

Changes in specimen preparation such as a change in nucleic acid extraction method.

The addition or change of a preservative to a reagent of the test kit.

Changes to the source (supplier) or processing of biological materials.

Changes from liquid to lyophilized reagents or vice versa.

Changes to materials/components that necessitate testing of additional clinical specimens, or retesting of original specimens, to determine performance characteristics of the IVD.

Changes to the materials/components of an IVD that result in a change to the operating principle of the product.

Changes to materials/components that potentially affect the operating procedure of an IVD include changes in reaction components or materials such as calibration materials, or changes in methods such as specimen pre-treatment, incubation times and operating temperatures.

Changes in energy supply requirements.

Changes to labelling

All changes to labelling with exception of those listed in Annex 2: Examples of non-reportable changes are those made to:

clarify labelling statement (clarifying instructions to make the device easier or safer to use) without changing the procedure;

correct errors (typographical errors or numerical errors); and/or

include additional languages.

Changes to a product’s software

A software change that impacts the control of the product, and may alter the reporting result that is used in the diagnosis or other function.



A software change that modifies an algorithm impacting the test result.

A software change that impacts the way data are read or interpreted by the user, such that the diagnosis or other function may be altered when compared to the previous version of the software.

A software change that replaces previously required user input.

A software change to correct an error that presents a safety risk to the patient.

Addition of a new feature to the software that may affect the diagnosis or other software driven function.

A software change that incorporates a change to the operating system on which the software runs.

Changes to the QMS

Changes in the ISO 13485:2003 certification status of the manufacturer, of the prequalified IVD, such as suspension of the ISO 13485:2003 certificate, obtaining a new certification, or change in the scope of certification.

Change in Notified Body or certification body.

Changes to the legal manufacturer including:

change of ownership

change of legal entity status (Ltd, SA, etc.)

change of name and/or address.

Change in the regulatory status

Change in the regulatory status of the prequalified IVD in any of the member nations or regions of the International Medical Device Regulators Forum (IMDRF). For example, licence suspension in Canada, receipt of a Warning Letter from the US FDA, suspension of ARTG registration in Australia, or suspension of a CE mark certification in the European Union.

Administrative changes

Changes only to the product name.

Changes only to the product code(s).

Changes only to the manufacturer name.

449 450

451



Annex 2: Examples of non-reportable changes 452

453 The following list is intended as an aid to manufacturers to determine the 454 significance of particular changes. The list is not exhaustive and should be 455 considered in conjunction with the guidance provided in this document. 456 457 458

Minor changes include the following changes

1. Changes that are made to clarify labelling statements or correct errors (typographical errors or numerical errors) without changing the procedure.

2. Rewording or expanding for clarification.

3. Translating from one language to another.

4. Addition of languages to labelling

5. Replacing (or complementing) written text by internationally recognized hazard symbols.

6. Minor software changes that do not impact the safety or performance of the product.

7. Minor QMS changes such as increased post market surveillance activity or regular updates of controlled QMS procedures (such as control of documents, management review etc.).

8. Minor manufacturing, additional in-process quality control criteria or test methods for manufacturing processes to provide equivalent or better assurances of reliability, as determined by the manufacturer but which do not affect safety or performance.

459



Annex 3: Formatting requirements for submissions 460

461

The electronic copy must be submitted on a CD or DVD. Submissions by email will be 462 rejected. Hardcopies are not required. 463

The layout and order must be easy to follow and appropriately identified. The 464 attachments must be clearly identified and divided into sections as listed in Section 4 of 465 the PQDx Change Report Form. 466

The cover of the CD or DVD should indicate “Change Report Form” and include detailed 467 information such as the name of the product, PQDx number, name of the manufacturer 468 and date of submission. 469

PDF is the primary file format used for the electronic copy. However, you must not 470 include any PDF that requires a password to open it. 471

The electronic copy must be organized as per the format prescribed for the 472 printed copy. 473

The name of the file name should be descriptive of its content and meaningful to the 474 reviewers. The name can be up to 125 characters and can have spaces, dashes 475 (not elongated dashes), underscores, and periods. However, the name of the file must 476 not contain any of the following special characters or it will fail the loading process: 477

478 tilde (~) single quotation mark (‘)

vertical bar (|) less than sign (<)

asterisk (*) double quotation marks (“)

forward slash (/) question mark (?)

elongated dash (–) colon (:)

backward slash (\) pound sign (#)

apostrophe (’) various other symbols (e.g.→,*,β,α,∞,±,™)

greater than sign (>)

When creating a PDF from the source document (e.g. Microsoft Word document), 479 please consider when using Adobe®plug-ins to create PDF files and/or capture or 480 display data, there is a risk that information may not display correctly because 481 reviewers may not have access to certain plug-ins to review content being displayed by 482 a plug-in. 483

All PDF files should be created directly from the source documents whenever feasible 484 rather than creating them by scanning. PDF documents produced by scanning paper 485 documents are far inferior to those produced directly from the source document, 486 such as a Microsoft Word document, and, thus should be avoided if at all 487 possible. Scanned documents, particularly tables and graphs, are more difficult to 488 read. 489

For any scanned document, we highly recommend that you perform optical 490 character recognition (OCR) so that the text is searchable. Check to see that the 491 content has been correctly converted by: (1) highlighting an area of text and (2) 492 searching for a word or phrase. If the word or phrase is not returned in the search, 493 then the OCR did not recognize the text. 494

WHO recognizes that use of OCR may not be feasible in some cases for documents with 495 figures and images. Hence, there may be cases in which it is appropriate to include 496



scanned documents in the electronic copy. 497

Submit all documents presented in the change report in English (unless other 498 arrangements have been made with WHO prior to submission of the documentation). 499

Any translations of documents must be carried out by a certified translator. Provide an 500 official document attesting to the accuracy of the translation and details on the 501 credentials of the translator. 502

Provide both the original and the translated documents. 503

All measurement units used must be expressed in the International System of Units (SI). 504 505

506



References 507

1 GHTF/SG1/N071:2012 Definition of the Terms ‘Medical Device’ and ‘In Vitro Diagnostic (IVD) Medical Device’. Global Harmonization Task Force (GHTF) Steering Committee; 2012 . 2 ISO 13485:2003. Medical devices – Quality management systems – Requirements for regulatory purposes. Geneva, Switzerland: International Organization for Standardization; 2003. 3 ISO 14971:2007. Medical devices – Application of risk management to medical IVDs. International Organization for Standardization; Geneva, Switzerland: 2007. 4 GHTF/SG1/N41R9:2005 Essential Principles of Safety and Performance of Medical Devices. Global Harmonization Task Force (GHTF) Steering Committee; 2005



https://www.iso.org/obp/ui/#iso:std:iso:14971:ed-2:v2:en

http://www.imdrf.org/docs/ghtf/final/sg1/technical-docs/ghtf-sg1-n41r9-2008-principles-safety-performance-050520.pdf