DRAFT FOR COMMENT

REPORTABLE CHANGES TO A WHO PREQUALIFIED MALE CIRCUMCISION DEVICE

PQMC _v1 DRAFT for comments - 27 June 2018 Reportable changes to a WHO Prequalified Male Circumcision Device

1 Contents 2 AUTHORIZATION ...... ERROR! BOOKMARK NOT DEFINED. 3 DOCUMENT REVISION HISTORY SHEET ...... ERROR! BOOKMARK NOT DEFINED. 4 CONTENTS ...... 2 5 1 PURPOSE OF THIS DOCUMENT ...... 3 6 1.1 INTENDED AUDIENCE ...... 3 7 1.2 SCOPE ...... 3 8 1.3 BACKGROUND ...... 3 9 2 REPORTING OF CHANGES TO WHO ...... 4 10 3 CHANGES REQUIRING A NEW PREQUALIFICATION APPLICATION ...... 5 11 4 REPORTABLE CHANGES ...... 6 12 4.1 REPORTABLE CHANGES TO THE MANUFACTURING PROCESS ...... 6 13 4.2 REPORTABLE CHANGES TO THE PRODUCT ...... 7 14 4.3 REGUALTORY STATUS AND OTHER CHANGES ...... 8 15 5 REPORTABLE ADMINISTRATIVE CHANGES ...... 9 16 6 NON-REPORTABLE CHANGES ...... 10 17 7 DETERMINING THE IMPACT OF A CHANGE ...... 10 18 8 REPORTING TO WHO ...... 11 19 9 ASSESSMENT OF SUBMITTED PQMC CHANGE REPORTING FORMS ...... 11 20 9.1 INITIAL SCREENING OF REPORTING FORM ...... 11 21 9.2 REVIEW OF REPORTING FORM ...... 12 22 10 OUTCOME OF ASSESSMENT OF THE CHANGE ...... 13 23 11 FAILURE TO REPORT A REPORTABLE CHANGE TO WHO ...... 13 24 12 MONITORING OF CHANGE REPORTING ...... 13 25 13 CHANGE ASSESSMENT FEE ...... 14 26 14 RELEVANT DOCUMENTS ...... 14 27 15 CONTACT INFORMATION ...... 15 28 ANNEX 1 – CHANGE PROCESS ...... 16 29 ANNEX 2: EXAMPLES OF REPORTABLE CHANGES TO PREQUALIFIED MALE CIRCUMCISION 30 DEVICES ...... 18 31 ANNEX 3: EXAMPLES OF NON-REPORTABLE CHANGES ...... 21 32 ANNEX 4: FORMATTING REQUIREMENTS FOR SUBMISSIONS ...... 21 33 REFERENCES ...... 23

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34 1 Purpose of this document

35 1.1 Intended audience 36 This document aims to provide manufacturers of WHO prequalified male 37 circumcision devices with information on when they must report to WHO 38 about: 39 • changes to the prequalified device or its manufacture; 40 • changes to the Quality (QMS) that the device is 41 designed and manufactured under; and/or 42 • other reportable administrative changes. 43 44 Manufacturers of WHO prequalified male circumcision devices should read 45 and understand this document so that they are aware of their duties and 46 responsibilities as a supplier of a prequalified male circumcision device as to 47 when to report to WHO applicable changes to the device, its manufacture 48 and other related activities. 49 50 Note: for the purpose of this document the following definition of 51 “manufacturer” applies: any natural or legal person with responsibility for 52 design and/or manufacture of a male circumcision device with the intention 53 of making the device available for use, under his/her name; whether or not 54 such a device is designed and/or manufactured by that person 55 himself/herself or on his/her behalf by another person(s) [1]. 56 57 This document does not address the required response to changes 58 made during the prequalification assessment. For changes 59 implemented during the assessment process, manufacturers should 60 contact WHO to seek guidance.

61 1.2 Scope 62 63 This document describes when and how a manufacturer will report to WHO 64 changes to a prequalified male circumcision device and its manufacture, the 65 QMS under which it is manufactured and certain administrative changes 66 associated with the device. To assist the understanding of when to report a 67 change to WHO, this document provides guidance and a non-exhaustive list 68 of generic examples. 69

70 1.3 Background 71 72 As part of the life cycle of a , changes to the product, and/or 73 its intended use, its manufacturing process or location or the QMS under 74 which it is produced may become necessary for technical or economic

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75 reasons. Such changesa to a prequalified male circumcision device range from 76 minor which have little potential to impact the quality, safety, performance , 77 performance or intended use of the device, to substantial which are likely to 78 affect the quality, safety, performance or intended use of the device. 79 80 A critical part of a manufacturer’s QMS is a documented, controlled and 81 approved process to design, review, verify, validate (if appropriate), approve 82 and implement changes. As part of this change process, a manufacturer 83 should also determine the significance of the change, on the quality, function, 84 performance, usability, safety, intended use, and applicable WHO 85 requirements for the prequalified male circumcision device and its intended 86 use. Manufacturers should also evaluate the effect of the change on 87 constituent parts of the of the device, on devices that are in-process or have 88 been delivered, and if the change has introduced new hazards that will alter 89 the initial risk analysis and risk control measures. Changes applied to a male 90 circumcision device must be made in conformance with the requirements for 91 control of design change according to ISO 13485:2016 [2]. 92 93 Annex 1 gives an overview of the Change Reporting process and associated 94 sub-processes. 95 96

97 2 Reporting of changes to WHO 98 99 For the purpose of this guidance, changes are defined either as reportable or 100 non-reportable. 101 102 All substantialb changes and certain administrative changes (information that 103 impacts the WHO public report) associated with a prequalified male 104 circumcision device are considered as reportable changes. These types of 105 changes must be reported to the WHO Prequalification Team – Diagnostics 106 Assessment at [email protected] by way of the “Change Reporting Form 107 for a WHO Prequalified Male Circumcision Device” (WHO document PQMC 108 REF to be added) and in some cases by way of a new prequalification 109 application. 110 111 Unless specified in this document, minor changes associated with a 112 prequalified male circumcision device are considered as non-reportable and 113 do not require the submission of a Change Reporting Form for a WHO 114 Prequalified Male Circumcision Device to WHO. These types of changes and

a Some regulatory authorities refer to changes as “variations”. b A substantial change is a change that could affect the quality, safety, performance or intended use of the prequalified male circumcision device.

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115 the manufacturer’s justification for not reporting the change are to be 116 documented and controlled in the manufacturer’s quality management 117 system. 118 119 A substantial change is one that is demonstrated, through risk analysis, to 120 have a potential impact on the quality, function, performance, usability, 121 intended use or safety of a prequalified male circumcision device. 122 123 It may: 124 • introduce new hazards that have not been previously addressed; 125 • adversely affect risks associated with existing hazards; and/or 126 • alter the presentation of existing or new risks to the user (this can involve 127 labelling changes or new indications for use). 128 129 Manufacturers should contact WHO early in the process of designing and 130 validating the change, to allow sufficient time for assessment before the 131 change is implemented. 132

133 3 Changes requiring a new prequalification application 134 135 In some cases, changes affect the safety, performance and/or intended use 136 of the device to such an extent that a new application for WHO 137 prequalification assessment is required. This will occur where it is deemed 138 that the changes have resulted in a product or application information of 139 substantial difference to that which was prequalified. In these cases, WHO 140 will notify the manufacturer that a new application to WHO prequalification 141 is required. This application will undergo prequalification assessment, 142 according to WHO guidance “Overview of the Prequalification of Male 143 Circumcision Devices Assessment Process” (WHO document PQMC_007). 144 WHO will also notify the manufacturer on the impact of the planned change 145 to the prequalification status of the product which is subject to the change. 146 147 The changes listed below are examples of those which could require 148 submission of a new application for prequalification: 149 • a change in design that influences the mode of operation of the device, 150 which would require additional clinical data to comply with the Essential 151 Principles of safety and performance of medical devices (4); 152 • Changes in packaging affecting the sterile barrier system or changes in 153 sterilization process; 154 • change to the legal manufacturer which involves the implementation of a 155 different Quality Management System. 156 • A change that affects the continued compliance of the QMS with the 157 relevant standards. 158

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159 160 The combination of several changes can also result in the need for a new 161 prequalification application. Manufacturers should seek advice from WHO 162 when planning to introduce several changes at the same time following the 163 procedure described in Section 8 below. 164

165 4 Reportable changes 166 167 The following sections provide more details on types of changes that require 168 submission to through the PQMC “Change Reporting Form Report Form for a 169 WHO Prequalified Male Circumcision Device” (WHO document PQMC REF to 170 be added). For a comprehensive list of documentation to accompany the 171 PQMC Change Reporting Form, please refer to Section 4 of the form. 172 173 For purposes of prequalification, reportable changes are divided in the 174 following categories: 175 4.1 Changes to the manufacturing process; 176 4.2 Changes to the product 177 4.2.1 Design changes and changes to the intended use; 178 4.2.2 Changes to labelling; 179 4.3 Regulatory status and other changes; and 180 5. Administrative changes. 181

182 4.1 Reportable changes to the manufacturing process 183 A change to the manufacturing process, facility or equipment that could 184 affect the quality, safety and/or performance of the prequalified male 185 circumcision device is considered a substantial change and thus reportable, 186 therefore requiring the submission of a completed PQMC Change Reporting 187 Form to WHO. 188 Examples of 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.

Change to the sterilisation method and/or associated processes.

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Removal of test acceptance criteria for 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 materials used in the fabrication of the male circumcision device. 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. 189

190 4.2 Reportable changes to the product

191 4.2.1 Design changes and changes to the intended use 192 Changes to a product may span from minor changes to the design of the 193 product to substantial changes in intended use. All changes must be 194 evaluated, verified and validated according to the accepted procedures 195 recorded in the QMS documentation. Changes to the design specifications, 196 physical attributes, or instructions for use may be substantial if they 197 potentially have an impact on the intended use of the male circumcision 198 device. Additionally, changes to claims relating to the intended use must be 199 reported, even if they do not impact on design. 200 201 Examples of reportable changes to the product design and intended use A change to the target population or new indications for use, e.g. an expansion to the age range of males to be circumcised. A change to (or addition or removal of) a contraindication for use of the device. A change to the approved requirements and/or method for device use (e.g. change to training requirements, removal of requirements for client access to surgical facilities) which requires preclinical or clinical data to support the continuing safety and performance of the device. A change to the materials or material formulation, including changes to the device surface or coating, involving materials that contact body tissues or may be absorbed by the body. This includes addition of a colouring agent. A change to materials/components that necessitate testing to determine performance characteristics of the device, e.g. biocompatibility, tensile strength. A change to the operating principles not related to a new mechanism of action for the device. A change to the mode of operation or procedure for application or removal PQMC _ v01.4 DRAFT for comments - 27 June 2018 Page 7 of 23

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of the device. A change in performance or design specifications. A change to (or addition or removal of) a warning or limitation for use of the device. New data relating to stability impacting on the expiry date, transport or storage conditions of the device. Changes or deletions to the accessories supplied with the device (e.g. measuring devices, removal accessories, bandages), if not affecting performance and safety of the device; 202

203 4.2.2 Changes to labelling 204 205 For the purposes of WHO Prequalification, labelling includes labels and 206 instructions for use. All changes to labelling should be reported. 207 Reportable changes to labelling The following changes will not elicit an assessment/change fee. These changes should be reported to ensure that the WHO Public Reports contains the most current version of the labelling:

1. Clarify an existing labelling statement (e.g. or safety specification rewording in IFU without changing the meaning/instructions procedure; 2. Correct errors (e.g. typographical errors or numerical errors that do not change the interpretation of the procedure or safety specification); 3. Include additional languages; 4. Change the format of the labels and/or Instructions For Use without removal/addition of content or changing the presentation of risks to the user (e.g. to align with the requirements of international regulatory authorities); and/or 5. Replacing (or complementing) written text by internationally recognized symbols. 208

209 4.3 Regulatory status and Other changes 210 Changes to the regulatory status Change in the regulatory status of the prequalified male circumcision device in any of the member nations or regions of the International Medical Device Regulators Forum (IMDRF) (e.g. licence suspension in Canada, receipt of a Warning Letter from the US FDA, suspension from the Australian Register of Therapeutic Goods, or suspension of a CE mark certification in the European Union). PQMC _ v01.4 DRAFT for comments - 27 June 2018 Page 8 of 23

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Change to the classification of the device, such as up-classification by a regulatory authority. 211 212 Examples of changes to the QMS Changes in the ISO 13485 certification status of the manufacturer of the prequalified male circumcision device, such as suspension of the ISO 13485 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 (e.g. Ltd, SA, etc.); and • change of name and/or address. 213 214

215 5 Reportable administrative changes 216 217 Changes limited to the product name, product code(s) and/or manufacturer 218 name require reporting. 219 Reportable administrative changes Changes only to the product name. Changes only to the product code(s). Changes only to the manufacturer name. 220 221 For administrative changes, the following information should be provided 222 with the PQMC Change Reporting Form: 223 224 • a declaration that the change only affects the product name, product 225 code(s) and/or manufacturer name and has no impact on the quality, 226 safety, performance or intended use, as supported in the submitted 227 prequalification documentation and the reason(s) for making the 228 changes; and 229 • the new product labelling (labels, instructions for use, and any other 230 printed or electronic labelling material) reflecting the changes. 231 232 Changes to the WHO key authorized contact for the manufacturer do not 233 require submission of a PQMC Change Reporting Form but WHO should be 234 notified by email to [email protected] accompanied by a signed letter 235 from the manufacturer appointing new contacts as authorized to represent 236 the manufacturer for the purposes of prequalification. PQMC _ v01.4 DRAFT for comments - 27 June 2018 Page 9 of 23

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237 6 Non-reportable changes 238 239 All other minor changes that are not required as part of a PQMC Change 240 Reporting Form and may include, but are not limited to: 241 • minor QMS changes such as increased post-market surveillance activity 242 or routine updates of controlled QMS procedures (such as control of 243 documents, management review etc.); not related to any reportable 244 changes as determined by the process in Section 4 above. 245 • minor manufacturing changes that would not have an effect on the 246 quality, safety or performance of the prequalified male circumcision 247 device; 248 • deletion or change of a provided accessory (e.g. bandages), if not 249 affecting performance and safety of the device; 250 • change to packaging design or to a container that is not in direct contact 251 with the device, and which does not impact the integrity of the device 252 during storage or transportation (not applicable if the packaging is 253 sterilized); and/or 254 • additional in-process quality control criteria or test methods for 255 manufacturing processes to provide equivalent or better assurances of 256 reliability, as determined by the manufacturer but which do not affect 257 safety or performance. 258

259 7 Determining the impact of a change 260 261 The requirement to report to WHO regarding a change depends on the 262 impact of the change on the quality, safety and/or performance of the male 263 circumcision device. The impact of a change should be determined for all 264 changes. The change to the overall residual risk evaluation for the device may 265 have arisen from: 266 • actions including field safety corrective actions (e.g. recalls or changes to 267 labelling) taken related to concerns arising from post-market surveillance 268 of complaints and adverse events; 269 • redevelopment including state of the art product improvements; 270 • changes to a manufacturing process, facility or equipment; 271 • changes to the design, components and/or accessories of the 272 prequalified male circumcision device; 273 • changes to the organization of the manufacturer; 274 • changes to the intended use and /or instructions for use; 275 • changes necessitating new pre-clinical and/or clinical data that raise new 276 issues of safety and performance; and/or 277 • published or unpublished literature raising new issues of safety and 278 performance with the device and/or procedure. 279 280 Consideration should be given to the impact of the change on the overall PQMC _ v01.4 DRAFT for comments - 27 June 2018 Page 10 of 23

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281 residual risk/benefit evaluation of the male circumcision device as per ISO 282 14971 [3]. This includes a determination of whether or not the change: 283 • introduces new hazards that have not been previously addressed; 284 • adversely affects the risk associated with existing hazards; 285 • alters the details of any of the information submitted for prequalification 286 (related to dossier, manufacturing site(s) inspection, technical or clinical 287 evaluation), such as the intended use and/or compliance with the 288 Essential Principles of safety and performance of medical devices [4]; 289 and/or 290 • affects the continued compliance of the QMS with the relevant 291 standards. 292 293 Where the change is considered substantial, as assessed through the above 294 process it should be reported to WHO. The steps in the risk analysis rationale 295 used for determining whether a change is reportable or not must be 296 documented. 297

298 8 Reporting to WHO 299 300 The manufacturer should inform WHO of the intention to report a change by 301 email to [email protected] and subsequently, complete and submit a 302 PQMC Change Report Form on a CD or DVD. For a comprehensive list of 303 documentation to accompany the PQMC Change Report Form, please refer to 304 Section 4 of the form. Formatting requirements are outlined in Annex 4 of 305 this document. 306 307 Manufacturers should communicate their intent to introduce a substantial 308 change in advance to allow sufficient time for assessing the change prior to 309 its implementation. WHO will not approve any changes without due 310 assessment. Depending on the type of change, the assessment may also 311 include a manufacturing site(s) inspection. 312

313 9 Assessment of submitted PQMC Change Report Forms

314 9.1 Initial Screening of Change Reporting Form and Supporting Documentation 315 316 Once WHO receives the PQMC Change Reporting Form, the change request 317 will be reviewed to determine the actions required to assess the change. 318 319 The report form and documentation (including project plan if appropriate) 320 will be screened for completeness. This screening does not take into 321 consideration the technical appropriateness of all the information provided

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322 within the change report. If the provided documentation is incomplete, the 323 manufacturer will be informed and requested to provide supplements within 324 a specified time period set by WHO. The manufacturer will be given one 325 opportunity to provide additional information prior to commencement of 326 the change documentation. 327

328 9.2 Review of Change Report Form and Supporting Documentation 329 Depending on the type of proposed change, Change Reporting Forms could 330 either undergo an “Administrative Review”, a “Technical Review”, or an 331 “Abbreviated Review” that considers the results of a stringent assessment 332 performed by a National Regulatory Authority (NRA). Stringent assessment 333 applies to the following regulatory assessments: CE: MDD certification, US 334 FDA: Premarket Approval (PMA), 510(k) Premarket Notification. The devices 335 for Voluntary Male Circumcision (VMC) which are in class II in the US, Health 336 Canada; Class III or IV device Licence, TGA; Conformity Assessment Certificate, 337 Japan; Minister's Approval. 338

339 9.2.1 Technical Reviews 340 A Technical Review is performed if the proposed change is not considered 341 “Administrative” or had not been previously stringently assessed by a 342 National Regulatory Authority. Technical reviews are performed if (i) the 343 change is likely to affect the intended use, quality, safety and/or performance 344 of the male circumcision device; or (ii) the change introduces new hazards 345 that have not been previously addressed, could adversely affect risks 346 associated with existing hazards, or could alter the presentation of existing or 347 new risks to the patient or user of the device. 348 349 Technical reviews are performed according to WHO document “Overview of 350 the prequalification of male circumcision devices assessment process” 351 (document PQMC_007). Manufacturers are given one opportunity to address 352 any deficiencies in the submitted documentation and/or data that have been 353 identified during the technical review. 354 355 If the submitted documentation supporting the change does not meet WHO 356 prequalification requirements or the requested information is not provided 357 by the manufacturer within the specified time period, WHO will reject the 358 change. 359 360

361 9.2.2 Abbreviated Reviews 362 If the manufacturer can provide proof that the proposed change has been 363 stringently assessed and accepted by an NRA, then WHO will perform an 364 Abbreviated Review and consider the conclusion of the NRA to make an PQMC _ v01.4 DRAFT for comments - 27 June 2018 Page 12 of 23

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365 informed decision of acceptance or rejection of the change. 366 367

368 10 Outcome of assessment of the change 369 370 WHO will inform the manufacturer of the outcome of the WHO assessment 371 of the change in writing. The manufacturer will be notified if WHO deems 372 that a manufacturing site inspection and/or a clinical evaluation is required. 373 The need to perform a manufacturing site(s) inspection and/or a clinical 374 evaluation will be established based on the nature of the change and its 375 potential impact on the quality, safety and/or performance. 376 377 Where a change is accepted by WHO, the manufacturer may implement the 378 proposed changes to the prequalified male circumcision device. As needed, 379 WHO may update the WHO prequalification public report and its list of 380 prequalified male circumcision devices to reflect the respective change. 381 382 If the submitted documentation supporting the change does not meet WHO 383 prequalification requirements or the requested information is not provided 384 by the manufacturer within the specified time period, WHO will reject the 385 change. The impact of such a decision on the prequalification status of the 386 prequalified device will be communicated to the manufacturer. 387

388 11 Failure to report a reportable change to WHO 389 390 Reporting of changes which meet the criteria for reportable changes, as 391 described in this guidance document, is mandatory for all prequalified male 392 circumcision devices. It is the manufacturer’s responsibility to notify WHO of 393 changes, as described in this guidance document, in order to keep the 394 prequalification status of the product up to date. Failure to report changes in 395 accordance with the requirements set in this document may result in the 396 delisting of the product from the list of prequalified male circumcision 397 devices. 398

399 12 Monitoring of change reporting 400 401 As part of routine post-prequalification activities, WHO re-inspections will 402 include a review of the compliance of the manufacturer to the requirements 403 of this document. Failure to comply may result in the assignment of a 404 nonconformity against the manufacturer’s QMS. 405 PQMC _ v01.4 DRAFT for comments - 27 June 2018 Page 13 of 23

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406 13 Change assessment fee 407 408 WHO will review the PQMC Change Report Form to determine the type and 409 level of assessment required. The cost of the activities required to assess the 410 change will be covered in part by the manufacturer. WHO charges a non- 411 refundable “Change Assessment Fee” of USD $3,000 for Technical and 412 Abbreviated Reviews. The fee must be paid on request by WHO and the 413 review will not begin until the payment has been verified. This fee will 414 contribute to the costs associated with change documentation review, 415 manufacturing site(s) inspection, and dissemination of change information. 416 417 WHO does not charge a “Change Assessment Fee” for Administrative 418 Reviews. 419 420 WHO reserves the right to decide, based on the change assessment findings, 421 whether a product continues to meet prequalification requirements. 422 Payment of the change assessment fee does not guarantee that the change 423 will be approved. WHO also reserves the right to reject the proposed 424 change(s) at any stage if the manufacturer is not able to, or fails to, provide 425 the required information in a specified time period, or when the information 426 supplied is inadequate to complete the change assessment effectively. 427 428 429

430 14 Relevant documents 431 432 • WHO Prequalification – Diagnostic Assessment: Overview of the Prequalification of Male 433 Circumcision Devices Assessment Process. WHO PQMC_007, v1, dd mm yyyy. Geneva: 434 World Health Organization; 2011. 435 436 • ISO 13485:2003 and 2016. Medical devices – Quality management systems – Requirements 437 for regulatory purposes. Geneva: International Organization for Standardization; 2003, 2016. 438 439 • ISO 14971:2007. Medical devices – Application of to medical IVDs. Geneva: 440 International Organization for Standardization; 2007. 441 442 • GHTF/SG1/N41R9:2005 Essential Principles of Safety and Performance of Medical Devices. 443 Global Harmonization Task Force (GHTF) Steering Committee; 2005. 444 445 • FDA: Deciding When to Submit a 510(k) for a Change to an Existing Device (K97-1). Center 446 for Devices and Radiological Health, FDA. Deciding When to Submit a 510(k) for a Change to 447 an Existing Device (K97-1) and Center for Biologics Evaluation and Research (CBER), Silver 448 Spring, MD: Food and Drug Administration; 1997. 449

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450 • Guidance for Industry and Food and Drug Administration Staff. 30 Day Notices, 135 Day 451 Premarket Approval (PMA) Supplements and 75 Day Humanitarian Device Exemption (HDE) 452 Supplements for Manufacturing Method or Process Change. Center for Devices and 453 Radiological Health (CDRH) and Center for Biologics Evaluation and Research (CBER), MD, 454 USA; 2011. 455 456 • Guidance for Industry and Food and Drug Administration Staff. Modifications to Devices 457 Subject to Premarket Approval (PMA) – The PMA Supplement Decision. Center for Devices 458 and Radiological Health (CDRH) and Center for Biologics Evaluation and Research (CBER), 459 MD, USA; 2008. 460 461 • Guidance for Industry and Food and Drug Administration Staff. Manufacturing Site Change 462 Supplements: Content and Submission. Center for Devices and Radiological Health (CDRH) 463 and Center for Biologics Evaluation and Research (CBER), MD, USA; 2015. 464 465 • PMA Supplements and Amendments. Available 466 at http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourD 467 evice/PremarketSubmissions/PremarketApprovalPMA/ucm050467.htm Accessed 08 468 January 2016. 469 470 • Real-Time Premarket Approval Application (PMA) Supplements. Center for Devices and 471 Radiological Health (CDRH) and Center for Biologics Evaluation and Research (CBER), MD, 472 USA; 2006. 473 474 • NBOG BPG 2014-3 Guidance for manufacturers and Notified Bodies on reporting of Design 475 Changes and Changes of the Quality System. Notified Body Operations Group (NBOG), Bonn, 476 Germany; 2014. 477 478 • Health Sciences Authority of Singapore. Medical device Guidance GN-21: Guidance on 479 change notification for registered medical devices. Revision 4. Singapore; 2015 480 481 • Changes or variations to therapeutic devices in the ARTG. Therapeutic Goods Administration 482 (TGA). ACT, Australia; 1998. 483 484 • Health Canada: Guidance for the Interpretation of Significant Change of a Medical Device. 485 Health Products and Food Branch, Ottawa, Ontario; 2011. 486

487 15 Contact information 488 Any inquiries regarding changes to prequalified male circumcisions devices 489 should be addressed to: [email protected] 490

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491

492

493 Annex 1 - Change Process 494 495

496 WHO Manufacturer Description 497 Manufacturer Manufacturer determines information needed to 498 proposes change assess impact of the change. to prequalified MC 499 device Manufacturer determines impact of the change on the prequalified device. 500 Manufacturer retains: Result of risk analysis. 501 Manufacturer reviews change Review of risk assessment.

502 Manufacturer categorizes change as substantial (reportable) or minor (non-reportable). 503

504

505 Manufacturer documents the answers to the following questions. 506 Decision to Y report changes 1) Is the change a simple administrative 507 WHO performs change to just the product name, product Administrative, Technical or code(s), or the manufacturer’s name? 508 Abbreviated review of 2) Does the change: change • Introduce new hazards that have not 509 been previously addressed? • Adversely affect risks associated with 510 N existing hazards? and/or • Alter the presentation of existing or new risks to the user? 511 If the manufacturer answers No to all of the 512 questions above then the change is non- reportable and manufacturer is required to 513 document and control the change according to its QMS procedures. 514 If the manufacturer answers Yes to any of the questions above, then the change is reportable 515 and Manufacturer is required to submit via courier an electronic copy of a completed PQMC 516 Change Form (PQMC REF to be added) and any supporting information to WHO on a CD or DVD. 517

518 For reportable Administrative changes WHO does not charge a change assessment fee. 519 For reportable changes that require a Technical Review or an Abbreviated Review, WHO charges 520 a non-refundable change assessment fee of USD $3,000 that must be paid before WHO begins 521 either type of review.

Continued 522 Continued

523

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524

525 526 527 528 529 530

531 532 Manufacturer WHO Description 533

534 Continued 535 Continued

536

537

538 Manufacturer If the change affects the safety and/or Does change prepares new performance of the device, as per section 3, 539 then the Manufacturer must submit a new affect device PQMC “Prequalification Application” to WHO for review. safety +/- Y submission 540 performance? WHO’s review process follows guidance according to document WHO PQMC_007 WHO PQMC_007 541 542 N 543 If WHO considers that the change could have a potential impact on the quality, safety and/or WHO performs performance of the device, then WHO may 544 Site inspection site inspection perform a site inspection prior to making a final required? Y according to decision to accept the reported change. 545 WHO PQMC Site inspection follows guidance document WHO REF to be added PQMC REF to be added 546

547 N Manufacturer answers specific questions about 548 Manufacturer the change and submits them to WHO within the specified time period. Additional responds to 549 Questions about Y request for change additional 550 information

551 552 N 553

554 WHO accepts or rejects the change and informs the manufacturer of Manufacturer documents change in 555 the decision QMS or stops change process

556 557 558 If WHO accepts the change, the manufacturer implements it then supplies the changed device. 559 Manufacturer WHO updates the public record and list of 560 implements change prequalified products and verifies implementation and supplies device or at its next site inspection. consults with WHO on next steps If WHO rejects the change, the manufacturer PQMC _ v01.4 DRAFT for comments - 27 June 2018 stops the change process and consults with WHO Page 17 of 23 on next steps.

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561 Annex 2: Examples of reportable changes to prequalified male 562 circumcision devices 563 564 The following list is intended as an aid to manufacturers to help determine 565 the significance of particular changes. The list is not exhaustive and should be 566 considered in conjunction with the guidance provided in this document.

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 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 device materials used in the fabrication of the male circumcision device. 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. Change that affects the microbial quality by increasing the bioburden alert or action levels or introducing an organism that is more difficult to kill. Device design and/or material changes that introduce a feature that makes the device more difficult to sterilize. Change to the sterilisation method and/or associated processes.

Change in the density or configuration of the sterilization load.

Change to the quality control verification and validation process for sterilization such as introducing parametric release.

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Change in the packaging of medical devices subject to sterilization.

Changes to the product design and intended use A change to the target population or new indications for use, e.g. an expansion to the age range of males to be circumcised. A change to (or addition or removal of) a contraindication for use of the device. A change to the approved requirements and/or method for device use (e.g. change to training requirements, removal of requirements for client access to surgical facilities) which requires preclinical or clinical data to support the continuing safety and performance of the device. A change to the materials or material formulation, including changes to the device surface or coating, involving materials that contact body tissues or may be absorbed by the body. This includes addition of a colouring agent. A change to materials/components that necessitate testing to determine performance characteristics of the device, e.g. biocompatibility, tensile strength. A change to the operating principles not related to a new mechanism of action for the device. A change to the mode of operation or procedure for application or removal of the device. A change in performance or design specifications. A change to (or addition or removal of) a warning or limitation for use of the device. New data relating to stability impacting on the expiry date, transport or storage conditions of the device. Changes or deletions to the accessories supplied with the device (e.g. measuring devices, removal accessories, bandages), if not affecting performance and safety of the device; Changes in materials/components Changes to materials/components that necessitate testing to determine performance characteristics of the device, e.g. biocompatibility, tensile strength. Changes to the materials/components of the device that result in a change to the operating principle of the product. Addition of a colouring agent to materials that are in contact with the patient’s body.

Changes to labelling The following changes will not elicit an assessment/change fee. These changes should be reported to ensure that the WHO Public Reports contains the most current version of the labelling:

1. Clarify an existing labelling statement (e.g. or safety specification rewording in IFU without changing the meaning/instructions PQMC _ v01.4 DRAFT for comments - 27 June 2018 Page 19 of 23

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procedure; 2. Correct errors (e.g. typographical errors or numerical errors that do not change the interpretation of the procedure or safety specification); 3. Include additional languages; 4. Change the format of the labels and/or Instructions For Use without removal/addition of content or changing the presentation of risks to the user (e.g. to align with the requirements of international regulatory authorities); and/or Replacing (or complementing) written text by internationally recognized symbols. Changes to the QMS Changes in the ISO 13485 certification status of the manufacturer of the prequalified male circumcision device, such as suspension of the ISO 13485 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 (e.g. Ltd, SA, etc.); and change of name and/or address. Change in the regulatory status Change in the regulatory status of the prequalified male circumcision device in any of the member nations or regions of the International Medical Device Regulators Forum (IMDRF) (e.g. licence suspension in Canada, receipt of a Warning Letter from the US FDA, suspension from the Australian Register of Therapeutic Goods, or suspension of a CE mark certification in the European Union). Change to the classification of the device, such as up-classification by a regulatory authority. Administrative changes Changes only to the product name. Changes only to the product code(s). Changes only to the manufacturer name. 567 568

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Annex 3: Examples of non-reportable changes

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

Minor changes include the following changes

1. Translating the label and/or IFU from one language to another. 2. Addition of languages to labelling 3. Replacing (or complementing) written text by internationally recognized hazard symbols. 4. Minor QMS changes such as increased post-market surveillance activity or routine updates of controlled QMS procedures (such as control of documents, management review etc.); not related to any reportable changes as determined by the process in Section 4 above. 5. Minor manufacturing changes that would not have an effect on the quality, safety or performance of the prequalified male circumcision device; 6. Deletion or change of a provided accessory (e.g. bandages), if not affecting performance and safety of the device; 7. Change to packaging design or to a container that is not in direct contact with the device, and which does not impact the integrity of the device during storage or transportation (not applicable if the packaging is sterilized); and/or 8. 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.

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Annex 4: Formatting requirements for submissions

• The electronic copy must be submitted on a CD or DVD. Submissions by email will be rejected. Hardcopies are not required. • The layout and order must be easy to follow and appropriately identified. The attachments must be clearly identified and divided into sections as listed in Section 4 of the PQMC Change Report Form. PQMC _ v01.4 DRAFT for comments - 27 June 2018 Page 21 of 23

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• The cover of the CD or DVD should indicate “Change Report Form” and include detailed information such as the name of the product, PQMC number, name of the manufacturer and date of submission. • PDF is the primary file format used for the electronic copy. However, you must not include any PDF that requires a password to open it. • The electronic copy must be organized as per the format prescribed for the printed copy. • The name of the file name should be descriptive of its content and meaningful to the reviewers. The name can be up to 125 characters and can have spaces, dashes (not elongated dashes), underscores, and periods. However, the name of the file must not contain any of the following special characters or it will fail the loading process:

• 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), please consider when using Adobe®plug-ins to create PDF files and/or capture or display data, there is a risk that information may not display correctly because reviewers may not have access to certain plug-ins to review content being displayed by a plug-in. • All PDF files should be created directly from the source documents whenever feasible rather than creating them by scanning. PDF documents produced by scanning paper documents are far inferior to those produced directly from the source document, such as a Microsoft Word document, and, thus should be avoided if at all possible. Scanned documents, particularly tables and graphs, are more difficult to read. • For any scanned document, we highly recommend that you perform optical character recognition (OCR) so that the text is searchable. Check to see that the content has been correctly converted by: (i) highlighting an area of text and (ii) searching for a word or phrase. If the word or phrase is not returned in the search, then the OCR did not recognize the text. • Submit all documents presented in the change report in English (unless other arrangements have been made with WHO prior to submission of the documentation). • Any translations of documents must be carried out by a certified translator. Provide an official document attesting to the accuracy of the translation and details on the credentials of the translator. • Provide both the original and the translated documents. • All measurement units used must be expressed in the International System of Units (SI).

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References

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 and 2016. Medical devices – Quality management systems – Requirements for regulatory purposes. Geneva, Switzerland: International Organization for Standardization; 2003, 2006. 3 ISO 14971:2007. Medical devices – Application of risk management to medical devices. Geneva: International Organization for Standardization. Geneva, Switzerland; 2007.

4 GHTF/SG1/N68:2012N41R9:2005 Essential Principles of Safety and Performance of Medical Devices. Global Harmonization Task Force (GHTF) Steering Committee; 2012.2005

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