EXPERT COMMITTEE ON BIOLOGICAL STANDARDIZATION … · 133 Fund (UNICEF) and other United Nations...

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WHO/BS/10. 2155 4 ENGLISH ONLY 5

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EXPERT COMMITTEE ON BIOLOGICAL STANDARDIZATION 9 Geneva, 18 to 22 October 2010 10 11 Procedure for assessing the acceptability, in principle, of vaccines for 12

purchase by United Nations agencies 13 14 15

This document has been prepared for the purpose of inviting comments and 16 suggestions on the proposal contained therein, which will then be considered by the 17 Expert Committee on Biological Standardization (ECBS). The text in its present 18 form does not necessarily represent an agreed formulation of the Expert 19 Committee. Comments proposing modification to this text MUST be received by 20 8 October 2010 and should be addressed to the World Health Organization, 1211 21 Geneva 27, Switzerland, attention Quality Safety and Standards (QSS). Comments 22 may also be submitted electronically to the Responsible Officer: Ms Emma Uramis 23 Diaz at email:[email protected]. 24 25 The outcome of the deliberations of the Expert Committee will be published in the 26 WHO Technical Report Series. The final agreed formulation of the document will be 27 edited to be in conformity with the "WHO style guide"(WHO/KMS/WHP/09.1). 28

© World Health Organization 2010 29

All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World Health 30 Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: 31 [email protected]). Requests for permission to reproduce or translate WHO publications – whether for sale or for 32 noncommercial distribution – should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; e-33 mail: [email protected]). 34

The designations employed and the presentation of the material in this publication do not imply the expression of any 35 opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, 36 city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps 37 represent approximate border lines for which there may not yet be full agreement. 38 39 The mention of specific companies or of certain manufacturersʼ products does not imply that they are endorsed or 40 recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. 41 Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. 42

All reasonable precautions have been taken by the World Health Organization to verify the information contained in 43 this publication. However, the published material is being distributed without warranty of any kind, either expressed 44 or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the 45 World Health Organization be liable for damages arising from its use. The named authors alone are responsible for 46 the views expressed in this publication. 47

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48 Contents 49 CONTENTS .............................................................................................................................................2 50 ACRONYMS............................................................................................................................................3 51 1 INTRODUCTION..........................................................................................................................4 52 2 CONDITIONS FOR ACCEPTANCE OF APPLICATIONS....................................................6 53 3 STEPS OF THE PROCEDURE ...................................................................................................7 54

3.1 OFFICIAL REQUEST AND RESPONSE..................................................................................................7 55 3.2 MEETINGS WITH MANUFACTURERS .................................................................................................7 56 3.3 PRODUCT SUMMARY FILE (PSF) ......................................................................................................7 57 3.4 INITIAL TESTING OF VACCINE SAMPLES .........................................................................................10 58 3.5 WHO SITE AUDITS .........................................................................................................................11 59 3.6 REPORT AND OUTCOME OF THE ASSESSMENT ................................................................................13 60

4 CONSIDERATIONS FOR STREAMLINING THE PREQUALIFICATION PROCEDURE 61 BASED ON ENHANCED ASSISTANCE BY NRAS ........................................................................15 62

4.1 PROCEDURE FOR SELECTING ELIGIBLE NRAS................................................................................15 63 4.2 STREAMLINED PROCEDURE FOR VACCINES WITH MARKETING AUTHORIZATION/ LICENSING 64 GRANTED, BY ELIGIBLE NRAS.............................................................................................................15 65 4.3 VACCINES WITH POSITIVE SCIENTIFIC OPINION ISSUED BY EMA...................................................18 66

5 SPECIAL CONSIDERATIONS FOR FAST-TRACK PROCEDURE ..................................19 67 6 SPECIAL CONSIDERATIONS FOR ACCEPTING SUBMISSIONS OF VACCINES 68 MANUFACTURED IN MULTIPLE SITES OR COUNTRIES.......................................................20 69 7 OBLIGATIONS AFTER PREQUALIFICATION IS GRANTED.........................................22 70 8 ANNUAL REPORTING .............................................................................................................23 71 9 REASSESSMENTS .....................................................................................................................24 72 10 MONITORING CONTINUED COMPLIANCE WITH SPECIFICATIONS THROUGH 73 TARGETED TESTING PROGRAMME ...........................................................................................25 74 11 MONITORING VACCINE QUALITY COMPLAINTS OR AEFIS FROM THE FIELD.25 75 12 RECOMMENDATIONS FOR ACTION IN CASES OF NON COMPLIANCE..................26 76 13 HANDLING OF OUT-OF-SPECIFICATION (OOS)/INCONSISTENT RESULTS 77 BETWEEN LABORATORIES............................................................................................................26 78 14 COSTS ..........................................................................................................................................27 79 15 CONFIDENTIALITY .................................................................................................................27 80 16 NO CONFLICT OF INTEREST................................................................................................28 81 AUTHORS .............................................................................................................................................29 82 ACKNOWLEDGMENTS.....................................................................................................................32 83 APPENDIX 1 THE PRODUCT SUMMARY FILE...........................................................................33 84 APPENDIX 2 TESTING APPROACH FOR INITIAL EVALUATION FOR PQ.........................41 85 APPENDIX 3 PREQUALIFICATION PROCEDURE FOR VACCINES EVALUATED BY 86 EMA UNDER ARTICLE 58 OF REGULATION (EC) NO 726/2004 .............................................43 87 APPENDIX 4 CONFIDENTIALITY AGREEMENT .......................................................................46 88 APPENDIX 5 DECLARATION OF INTERESTS FOR WHO EXPERTS ....................................48 89

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Acronyms 91 The following acronyms are used in this document. 92 93 AEFI adverse event following immunization 94 AHU air-handling unit 95 AMC Advance Market Commitment 96 AR assessment reports 97 CHMP Committee for Medicinal Products for Human Use 98 CTD Common Technical Document 99 EMA European Medicines Agency 100 EU European Union 101 GAVI Global Alliance for Vaccines and Immunization 102 GCP good clinical practice 103 GMP good manufacturing practice 104 HIV human immunodeficiency virus 105 ICH International Conference on Harmonization 106 IVB Department of Immunization, Vaccines and Biologicals (WHO) 107 LSP lot summary protocols 108 MA marketing authorization 109 NRA national regulatory authority 110 NCL national control laboratory 111 OMCL Official Medicine Control Laboratories 112 OOS out of specification 113 PSF product summary file 114 PSPQ programmatic suitability of vaccines for prequalification 115 PSUR periodic safety updated report 116 QA quality assurance 117 QC quality control 118 QS quality system 119 QSS Quality, Safety and Standards (WHO) 120 SAGE Strategic Advisory Group of Experts 121 SOP standard operating procedure 122 TSE transmissible spongiform encephalopathy 123 TPP target product profile 124 UN United Nations 125 UNICEF United Nations Children’s Fund 126 USP United States Pharmacopoeia 127 VVM vaccine vial monitor 128 WHO World Health Organization 129

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1 Introduction 130 The World Health Organization (WHO), through its Department of Immunization, 131 Vaccines and Biologicals (IVB), provides advice to the United Nations Children’s 132 Fund (UNICEF) and other United Nations (UN) agencies on the acceptability, in 133 principle, of vaccines considered for purchase by such agencies. This service is called 134 prequalification. The purpose of the UN prequalification assessment is to provide 135 assurance that candidate vaccines: (a) meet the WHO recommendations on quality, 136 safety and efficacy, including compliance with WHO recommended Good 137 Manufacturing Practice (GMP) and Good Clinical Practice (GCP) standards; and (b) 138 meet the operational specifications for packaging and presentation of the relevant UN 139 agency. This is to ensure that vaccines provided through the UN for use in national 140 immunization services in different countries are safe and effective, and are suitable for 141 the target populations, at the recommended immunization schedules, and with 142 appropriate concomitant products. 143 144 The procedure in place at WHO to assess the acceptability of candidate vaccines for 145 the UN was published initially in the thirty-ninth report of the WHO Expert 146 Committee on Biological Standardization, Annex 1 (Technical Report Series, 147 No. 786, Geneva, WHO, 1989). Since then, a number of published revisions to the 148 procedure have been implemented (in 1996, 2002 and 2005). The last revision is 149 published in WHO/IVB/05.19. 150 151 The present document is a revision that takes into consideration challenges faced by 152 the vaccines prequalification programme, such as the increasing number of 153 submissions, the increasing diversity and complexity of the products submitted to 154 WHO for evaluation, as well as the on-going maintenance of the prequalified status 155 for those vaccines on the list. The latter includes reassessments and reviews of 156 variations, and investigation of quality and safety concerns reported by field workers, 157 which all translate into a growing workload for WHO. 158 159 This document addresses technical, communication and policy aspects of the 160 procedure and is based on the recommendations made by an ad hoc advisory 161 committee of experts on vaccines prequalification convened by WHO in May 2010 162 and on a series of supporting documents. These can be accessed at: 163 http://www.who.int/immunization_standards/vaccine_quality/pq_consultation_2010/e164 n/index.html 165 166 The document proposes an update of the current procedure (WHO/IVB/05.19). 167 168 The prequalification (PQ) procedure established by WHO for vaccines has been 169 effective in promoting confidence in the quality of the vaccines shipped to countries 170 through UN purchasing agencies and it is based on the following principles: 171 172

Reliance on the national regulatory authority (NRA) of the country of 173 manufacture which is required to be "functional", i.e. meeting the published 174 WHO NRA indicators for prequalification purposes. 175 http://www.who.int/immunization_standards/national_regulatory_authorities%176 20/vaccine_indicators/en/index.html/ 177

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General understanding of the product and presentations offered, 179 production process, quality control (QC) methods, quality system (QS) in 180 place and relevance for the target population of available clinical data. 181 182

Assurance of production consistency through compliance with GMP 183 requirements and monitoring of continued compliance with specifications 184 through testing of final product characteristics. 185

186 WHO can advise United Nations agencies whether vaccines effectively meet WHO-187 recommended requirements only if the responsible NRA exercises independent and 188 appropriate regulatory oversight of the vaccines in question and if the vaccines have 189 been assessed through the procedure described in this document. Since reliance upon 190 effective regulatory oversight by the NRA of the country of manufacture plays a 191 critical role in the system, manufacturers shall: (a) inform the NRA of their 192 application to WHO for the vaccine prequalification by sending to the NRA a copy of 193 the application letter sent to WHO; (b) request the NRA to participate/collaborate in 194 the process; and (c) provide the NRA with the necessary authorization to discuss the 195 relevant files with WHO representatives. 196 197 The update introduces a procedure for using, in some circumstances, enhanced 198 assistance from eligible National Regulatory Authorities (NRAs) (see section 4). 199 200 Under exceptional circumstances, extraordinary and temporary measures may be 201 applied in the situation where the NRA responsible for the regulatory oversight of a 202 product fails to sustain its functionality against WHO standards. This is done only 203 where it is necessary to ensure a global supply of vaccines of assured quality. As 204 recommended by the Strategic Advisory Group of Experts (SAGE), in emergency 205 situations, a process that enables WHO to obtain appropriate regulatory support to 206 maintain the prequalification status of vaccines may be applied. This procedure 207 applies to vaccines for which there is no immediate alternative source thus a removal 208 from the prequalified list would jeopardize the global supply. 209 210 As vaccines purchased by United Nations agencies need to meet WHO 211 recommendations or guidelines (whichever are available), novel vaccines for which 212 such recommendations are not available cannot be evaluated. In cases where a 213 vaccine is made available for a disease of public health importance, the development 214 of such guidelines will be prioritized by WHO and, as soon as a draft document 215 becomes available, this can be used for evaluation for prequalification purposes. 216 The fact that certain vaccines are not included in the list of prequalified vaccines 217 does not mean that, if evaluated, they would not be found to comply with the required 218 standards. 219 http://www.who.int/immunization_standards/vaccine_quality/PQ_vaccine_list_en/en/i220 ndex.html 221 222 WHO will define, in consultation with United Nations purchasing agencies, which 223 vaccines are a priority for prequalification and will make this information publicly 224 available. 225 http://www.who.int/immunization_standards/vaccine_quality/pq_priorities/en/index.h226 tml 227 228

WHO/BS/10.2155 This exercise is required in order to focus the use of resources. The priorities will be 229 redefined at regular intervals to ensure that efforts are put into evaluating those 230 available vaccines that are of highest public health importance and most needed in 231 developing countries. 232 233

2 Conditions for acceptance of applications 234 The following are the conditions for acceptance of applications: 235 236

a) The candidate vaccine is on the current list of priority products for UN 237 prequalification. 238

b) The candidate vaccine meets the mandatory characteristics for 239 programmatic suitability (as defined in the document "Assessing the 240 programmatic suitability of vaccine candidates for WHO 241 prequalification") 242 http://www.who.int/immunization_standards/vaccine_quality/ps_pq/en243 /index.html 244

245 Note: WHO encourages manufacturers to discuss with the prequalification secretariat, 246 early in the development process, any concerns over the programmatic suitability 247 characteristics for prequalification. 248

249 c) The NRA responsible for the regulatory oversight of the product has 250

been assessed by WHO as "functional" and has been found to meet all 251 the critical indicators defined for prequalification purposes. 252

253 Note: An applicant should check with its respective NRA if it has been assessed by 254 WHO. WHO will not be able to process any application until the WHO NRA 255 assessment is conducted and the outcome is satisfactory. 256 257

d) A marketing authorization (MA) has been granted by the relevant NRA 258 and the post-marketing regulatory oversight is under the responsibility 259 of the NRA of the country of manufacture (or the European Medicines 260 Agency (EMA) in the case of the centralized procedure for MA in 261 Europe) or that of the country of finishing and distribution. 262 Alternatively, if it is intended that the EMA Scientific Opinion1 should 263 serve as a basis to facilitate the MA of the vaccine, the Guideline on 264 Procedural Aspects regarding the Committee for Medicine Products 265 for Human Use (CHMP) should be used in the context of cooperation 266 with WHO for the evaluation of medicinal products intended 267 exclusively for markets “outside the community”. 268

269 Note: WHO encourages manufacturers to discuss with the prequalification secretariat, 270 early in the development process, on the product itself and the regulatory 271 requirements. 272

1 EMA Scientific Opinion in accordance with Article 58 of Regulation (EC) No726/2004 is exclusively restricted to medicinal product which are not authorized within the European Union. However the issuance of such Scientific Opinion does not prevent the possibility of submitting a future EU Marketing Authorization.

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273 3 Steps of the procedure 274

For the evaluation of vaccines, WHO requires information related to the 275 manufacturing company and to the product itself. The manufacturer will provide 276 this information in the product summary file (PSF, see Annex 1) and during the site 277 audit if applicable. However, WHO reserves the right to terminate the assessment if, 278 at any time, it is considered that insufficient information has been provided to enable 279 effective completion of the assessment. 280 281 3.1 Official request and response 282 An application letter2 is to be sent to the Coordinator, Quality, Safety and Standards, 283 Department of Immunization, Vaccines and Biologicals (WHO/IVB/QSS) with 284 copies to the vaccines prequalification manager and the relevant NRA, with details of 285 country and sites of manufacture, licensing status and presentations put forward to 286 United Nations agencies for procurement. 287 288 Note: Application letters can be sent at any time and should provide the expected 289 date of file submission. 290 291 Manufacturers are encouraged to advise WHO as early as possible of their intention to 292 submit a specific vaccine for evaluation to facilitate planning. 293 294 WHO will acknowledge receipt and acceptance of application letter by email with 295 copy to the NRA and will only respond with an official letter in those cases where the 296 vaccine will not be accepted because it is not a priority. In such cases, the applicant, 297 and the NRA will be advised of the rejection of the application within two weeks of 298 receipt of the official request. 299 300 3.2 Meetings with manufacturers 301 If considered necessary or desirable by either party, before the actual evaluation 302 process starts, a discussion may be held between the manufacturer, the responsible 303 NRA (if willing to participate) and WHO. This pre-evaluation meeting should be 304 scheduled as early as possible with a predefined agenda to address questions sent in 305 advance to WHO by the manufacturer. 306 307 Such meetings are important to discuss programmatic suitability issues and can be 308 scheduled when requested by the manufacturer. 309 310 Additional meetings may be held during the evaluation process as required. 311 312 3.3 Product summary file (PSF) 313 A manufacturer for which the application letter is accepted will prepare and submit 314 one hard copy and five electronic versions (in CD), either in Microsoft Word, or pdf 315 format of a product summary file, fully up to date and written entirely in English 316 following the WHO format provided below: 317

2 The application letter's purpose is to communicate to WHO the manufacturer's intention of submitting a vaccine for evaluation.

WHO/BS/10.2155 318 Chapter 1: General information 319 Chapter 2: Personnel 320 Chapter 3: Premises and equipment 321 Chapter 4: Vaccine composition 322 Chapter 5: Production 323 Chapter 6: Quality control 324 Chapter 7: Stability 325 Chapter 8: Clinical experience 326 Chapter 9: Production/distribution data 327 Chapter 10: Update of regulatory actions 328 329 The WHO format is required; however, the Common Technical Document (CTD) 330 format can be accepted as long as a detailed cross-referencing of contents and those 331 aspects required by WHO but not included in the CTD requirements are presented. 332 Where PSF cross references to the Common Technical Document format, CTD 333 documentation can be e-copy only. E-copy documents should be searchable text 334 where possible. 335 336 The information to be provided in the file is specified in Annex 1 of this document. 337 338 WHO has established three deadlines a year for submission of product summary 339 files: 31 January, 31 May and 30 September. Two separate deadlines have been set 340 for the submission of applications of seasonal influenza vaccines to WHO, these are 1 341 July and 1 November of each year. 342 343 In each case, applications must arrive at WHO by the submission date to be 344 considered for the following review round. Applications received after the deadline 345 of submissions will not be considered for evaluation until the following review round. 346 347 Screening of the product summary file and payment 348 Upon receipt, the PSF will be screened for completeness and compliance with the 349 required format and contents. If the PSF is not in compliance with the format and 350 contents, the manufacturer will be informed through an official letter and required to 351 pay the screening fees. An improved PSF may be submitted to meet a subsequent 352 scheduled submission deadline without additional payment. In case of a second (final) 353 rejection, the manufacturer will be informed by official letter and an invoice will be 354 sent requesting payment of the screening fees. 355 356 In addition, an assessment of the suitability of the vaccine for the immunization 357 services where it is intended to be used will also be conducted at this stage. The 358 process for review of programmatic suitability of vaccine characteristics is described 359 in the document "Assessing the programmatic suitability of vaccine candidates for 360 prequalification." 361 http://www.who.int/immunization_standards/vaccine_quality/ps_pq/en/index.html) 362 363

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At the time of screening, vaccine candidates must be in compliance with the 364 mandatory programmatic characteristics.3 as defined by IPAC. If screening reveals 365 that mandatory characteristics are not met, then the PSF will be rejected. 366 If the PQ Secretariat identifies a deviation from the critical characteristics or a unique, 367 novel and innovative characteristic not otherwise specified as mandatory or critical, is 368 required. 369 370 The PSPQ Standing Committee is an advisory body to the PQ Secretariat and the 371 Director IVB constituted of experts on immunization programmes and vaccines 372 regulation . See PSPQ Standing Committee ToR in: 373 http://www.who.int/immunization_standards/vaccine_quality/ps_pq/en/index.html 374 375 The committee will review the documentation exclusively related to the specific 376 problem. During their review, and discussion leading to the formulation of 377 recommendations, the PSPQ Standing Committee may engage in confidential 378 discussion with manufacturers and additional technical experts that have been 379 approved by WHO and the manufacturer. All members of the PSPQ Standing 380 Committee will be required to sign a confidentiality agreement (see section 15 and 381 Appendix 4) and a declaration of interests form (see section 16 and Appendix 5) prior 382 to taking up their responsibilities for WHO. 383 384 Note: Under special circumstances, when there is limited access to a vaccine of public 385 health importance, exceptional considerations will be made regarding suitability of 386 vaccine candidates that are non-compliant with the critical characteristics or that 387 present with unique and innovative characteristics. This decision can be made by the 388 PQ secretariat and will take into consideration the recommendations of the PSPQ 389 Standing Committee as well as public health needs and issues related to access to 390 vaccines. 391 392 The screening process will be put on hold while the PSPQ Standing Committee is 393 conducting a review. The duration of the review time by the PSPQ Standing 394 Committee will be not longer than three months. In case of rejection following a 395 recommendation from the PSPQ SC, the reviewers may include a recommendation for 396 resubmission after validation by research of the acceptability of specific vaccine 397 characteristics. 398 399 When no review by the PSPQ Standing Committee is required, the manufacturer will 400 be informed within one month after the submission deadline if the PSF is accepted for 401 further review or rejected. In case of acceptance, the manufacturer will be informed 402 403 by letter of the acceptance of the file for evaluation and of the names of the experts4 404 proposed for the evaluation, together with a copy of their curricula vitae. At the same 405

3 'Mandatory' characteristics are those where compliance is compulsory at the time of application for WHO prequalification and must be unconditionally met prior to evaluation of the PSF. (see PSPQ paper) 4 NRA staff, independent consultants or staff from consulting companies can be appointed as external experts depending on the specific needs. The manufacturer has the right to reject one or more team members when justification is provided in which case WHO will find a replacement. All experts appointed by WHO to participate in the evaluation of a vaccine are required to sign a

WHO/BS/10.2155 time, an invoice will be sent by WHO requesting payment of the screening and 406 evaluation fees. Manufacturers will be expected to pay the fee and confirm 407 acceptability of the proposed experts within two weeks. Payment of the fees without 408 any further communication will be considered as a de facto agreement of the proposed 409 experts; the evaluation will then be initiated. 410 411 In case of rejection, for any reason, the manufacturer will be informed through an 412 official letter, an invoice will be sent by WHO requesting payment of the screening 413 fees, and with the agreement of the manufacturer the PSF will be destroyed at WHO. 414 415 Product summary file evaluation 416 The time frame for an initial review of a vaccine PSF will be three months. A 417 consolidated report will be provided to manufacturers who are expected to submit 418 responses to comments and any complementary information that may be requested. 419 There is no further action by WHO (the clock is stopped) until reception of the full 420 complementary information. 421 422 The complementary information must be submitted in one package in one hard copy 423 and five electronic copies with adequate cross referencing to the original file. If partial 424 responses are received at different times, the review will not start until all of the 425 outstanding items have been covered by the manufacturer. 426 427 WHO reserves the right to terminate this procedure for a specific vaccine if the 428 manufacturer is not able to provide the required response with acceptable action plan 429 within three months and the actual information within the agreed time period, or if the 430 information supplied is inadequate. 431 432 The time frame for review of complete complementary information will be three 433 months. 434 435 3.4 Initial testing of vaccine samples 436 As soon as the PSF is accepted and when the prequalification procedure described in 437 section 3 is applied, WHO will request the manufacturer to submit to WHO an 438 appropriate number of samples (between 25 and 200 depending on the vaccine type 439 and presentation offered) of three to five final lots, for independent testing. These lots 440 will have been formulated from consecutive bulk lots (in the case of combination 441 vaccines, consecutive bulks will be specified by WHO for one of the components). 442 443 The samples shall be accompanied by the respective lot-summary protocols fully 444 detailed as described in the WHO guideline for independent lot release of vaccines by 445 regulatory authorities (Ref WHO/BS/10.2128) and the detailed SOP for testing the 446 product characteristics (relevant tests). 447 Biological reagents and reference materials for the validation of the tests by WHO 448 contracted laboratories should be provided by the manufacturer. In some cases, 449 samples of bulk material may be requested. 450

confidentiality agreement (see section 15 and Annex 4) and a declaration of interests form (see section 16 and Annex 5) for that specific evaluation.

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WHO will send the vaccine samples to its contracted laboratories for the initial testing. 451 Tests undertaken will be the most relevant to reflect the quality, safety and efficacy of 452 the vaccine. Usually potency and toxicity are tested. However, depending on the 453 nature of the vaccines, other relevant tests may be performed. If applicable, the 454 relevant method should be transferred from the manufacturer to the contracted 455 laboratory through WHO. The performance of the contracted laboratories for the 456 relevant tests has been evaluated by WHO. 457 458 The samples subject to testing must comply in all respects with the information and 459 specifications stated in the PSF. They must have been produced under full-scale 460 production conditions, and be a representative sample of the product intended to be 461 marketed through United Nations agencies. The expected time frame for testing, from 462 the date of receipt of the samples by WHO to the finalization of testing by WHO, is 463 three months. 464 465 To promote the independence and impartiality of the testing, neither the manufacturer 466 nor any other party who may have requested that vaccines be tested through this 467 system will be informed where the testing is actually performed. Situations where the 468 manufacturer is asked by WHO to transfer the testing methodology to a National 469 Control Laboratory (NCL) will be the exception to this rule. Upon request, the 470 manufacturer and the relevant NRA will, however, receive a report of the test results. 471 472 Generally the selected contracted laboratories do not include the NCL of the NRA in 473 charge of the testing for lot release. Exceptions can be made in the case of 474 streamlined procedure. 475 476 3.5 WHO site audits 477 The main objectives of the site audits are to assess if the vaccine complies with 478 WHO recommendations for production and quality control, if it meets the United 479 Nations' tender specifications (which reflect the needs of the immunization 480 programmes at the country level), that the company has an adequate quality system 481 (QS) in place, and that the relevant vaccine/s is/are produced in compliance with 482 WHO-recommended GMP5. Other important aspects of the assessment include but 483 are not limited to: labelling, packaging and post-marketing surveillance system in 484 place, VVM implementation when required, stability programme, etc. 485 486 Site audits are required for those manufacturers applying for the prequalification of 487 new products to be evaluated for purchase by UN agencies. They are necessary as 488 part of the initial evaluation, as follow-up to corrective actions taken by the 489 manufacturer following WHO recommendations and for reassessment purposes. 490 They may also be deemed necessary as a result of complaints or reports of serious 491 adverse events following immunization (AEFIs) if a quality problem is suspected. 492 493 Site audits are part of the standard assessment performed to ensure that vaccine 494 candidates for purchase by UN agencies (or those that are already being purchased) 495 meet (or continue to meet) WHO recommendations and tender specifications. 496

5 In those aspects where GMP requirements are not detailed enough, other international Guidelines shall be followed by the manufacturer and appropriate justification for the choice provided. In such cases, WHO will assess against the standard used.

WHO/BS/10.2155 To the extent possible, they build on information gathered through inspections 497 performed by NRAs that meet the critical indicators established by WHO for vaccine 498 prequalification purposes. In such cases, if detailed reports of inspections are made 499 available for WHO review, WHO may decide, in agreement with the manufacturer, 500 to organize an abbreviated site audit. This would focus only on aspects relevant to the 501 product/s under evaluation that have not been addressed by the NRA that performed 502 the inspection, including all those aspects that are specific to the UN tender 503 specifications. 504 505 For a new application, when the review of the PSF and testing have been satisfactorily 506 completed, WHO may assemble a team to audit the manufacturing facility. The site 507 audit will take place as soon as possible after satisfactory test results are available, 508 usually within a time frame of two months. Technical staff from the relevant United 509 Nations agency may elect to join the team. Otherwise, the team will be composed, as 510 far as possible, of the same experts that have reviewed the file. Team members must 511 have expertise in the areas of production, quality control, quality assurance, quality 512 system and GMP. If additional members or replacement members are needed, the 513 curriculum vitae of the proposed new members will be submitted to the company for 514 clearance. The team will cover the range of expertise required to assess the vaccine in 515 question from the different perspectives. A WHO staff member will lead the audit 516 team and the members will act, on a temporary basis, as expert advisers to WHO. In 517 some circumstances, the leadership can be delegated to one of the external experts 518 who will act on behalf of WHO. 519 520 The NRA of the manufacturing country or the NRA for the regulatory oversight of 521 the product will be invited to assign one or two staff members to join the WHO team 522 as observers. 523 524 A bilateral consultation meeting will be held between WHO and the NRA, either at 525 the beginning or at the end of the mission. The purpose of this meeting is to discuss 526 regulatory aspects related to the vaccine/s in question and to lay the basis for the 527 letters of agreement. Topics addressed during such consultation meetings relate to 528 commitment for testing and release of vaccine lots for United Nations agencies, need 529 for feed back on findings during inspections, update on safety and efficacy data, 530 variations to the MA/licence that may have been requested, MA/ licence renewals, 531 recalls or withdrawal of lots, etc. WHO will establish letters of agreement with all the 532 NRAs responsible for the oversight of prequalified products. 533 534 WHO site audits to manufacturing facilities or results of consultations held with the 535 NRA may trigger a follow-up assessment of the NRA for one or more functions. 536 In such cases, these follow-up assessments should be performed within a maximum 537 time frame of six months. The outcome of these follow-up assessments may have an 538 impact on the final decision on the prequalification of the vaccines in question. 539 540 The findings and recommendations of the team will be discussed with the 541 company on a daily basis as required during the site audit. Where relevant, the team 542 may request the manufacturer to prepare a corrective action plan to address critical 543 recommendations and establish deadlines for receiving responses. The draft 544 report, which includes main findings, recommendations and closing remarks is 545

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prepared by the WHO team and left with the manufacturer. The findings and 546 recommendations will be also reported to the company and NRA representatives 547 during the closing meeting, which provides an opportunity for discussion, questions 548 and clarifications. 549 550 The final report providing findings, recommendations and conclusions is prepared by 551 the team and sent to the company within 30 days after completion of the visit with a 552 copy to the NRA. If corrective actions need to be taken by the manufacturer, WHO 553 will postpone its final recommendations to the United Nations agencies involved until 554 such actions are implemented and verified by WHO. 555 If the company does not comply with the agreed deadlines, the prequalification 556 process may be terminated. 557 558 3.6 Report and outcome of the assessment 559 When required, the final decision regarding the acceptability of the product for supply 560 to United Nations agencies may be taken in consultation with an ad hoc committee on 561 vaccines prequalification convened by WHO for this purpose. 562 563 Once WHO considers that the process is complete, and if the outcome is satisfactory, 564 WHO sends a letter to the United Nations agencies and also to the Global Alliance for 565 Vaccines and Immunization (GAVI) Alliance for Advance Market Commitment 566 (AMC)6 eligible products advising on (a) compliance of the vaccine with both the 567 WHO requirements and the specifications of the relevant United Nations agency, and 568 (b) the role of the NRA in certifying this. This letter will be copied to the 569 manufacturer, the NRA/NCL responsible for lot release, the relevant WHO Regional 570 and Country Offices, IVB department management and the approved VVM 571 manufacturer. 572 573 For AMC eligible products, WHO will send to the GAVI Alliance and the AMCs 574 Independent Assessment Committee (IAC) a report providing the rationale for 575 confirming or otherwise that the vaccine meets the Target Product Profile (TPP). 576 577 The vaccine will be included in the WHO list of prequalified vaccines immediately 578 after the letter to United Nations agencies is sent. A page providing the basis for the 579 acceptance of the prequalification of the specific vaccine will also be included in the 580 list of prequalified vaccines. The current list may be consulted at: 581 http://www.who.int/immunization_standards/vaccine_quality/PQ_vaccine_list_en/en/i582 ndex.html 583 584 IntheeventofanydisagreementbetweenthemanufacturerandWHO,anSOP585 forthehandlingof such disagreements will be followed to discuss andresolvethe586 issue.587 588

6 An AMC is a legally-binding agreement for an amount of funds to subsidize the purchase, at a given price, of an as yet unavailable vaccine against a specific disease causing high morbidity and mortality in developing countries. The establishment of AMCs should encourage the development of future generations of vaccines and in particular accelerate the development and availability of priority new vaccines to developing countries.

WHO/BS/10.2155 The prequalified status of a vaccine is valid until a new reassessment is scheduled by 589 WHO. (see section 9). 590 591 WHO reserves the right to revoke the prequalification status if fraud by the 592 manufacturer becomes evident. 593 594 For details on notification of changes or introduced variations, see section 7 595 Obligations after prequalification is granted. 596 597 Note: Communications, at any time, with the experts involved in a vaccine evaluation 598 should be done through the WHO focal person in charge of the product. 599

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600 4 Considerations for streamlining the prequalification 601

procedure based on enhanced assistance by NRAs 602 4.1 Procedure for selecting eligible NRAs 603 Experience gained with the evaluation of influenza H1N1 (2009) pandemic vaccines 604 showed that reliance upon effective regulatory oversight by the responsible NRA has 605 the potential to play a critical role in facilitating the prequalification procedure. It is 606 considered that the experience in the pandemic influenza context can be extrapolated 607 to other vaccines. 608 609 The proposed procedure envisages enhanced reliance on the oversight performed by 610 the responsible NRA, when the NRA exhibits a high level of performance of WHO’s 611 six recommended regulatory functions and exercises full regulatory oversight of any 612 given vaccine. 613 614 Full implementation of such an approach will require the development of a revised 615 NRA assessment tool with the additional performance indicators to supplement the 616 existing indicators. During the development and operational implementation of a 617 revised tool able to distinguish levels of functionality (maturity levels), an interim 618 selection process will be implemented with a limited number of NRAs with 619 established regulatory capacity to ensure standards for quality, safety and efficacy at 620 least equivalent to those recommended by WHO (eg Technical Report Series ). 621 622 The interim process to be used for selection of NRAs will be: 623

624 a)Acceptance of NRAs that have provided enhanced support to WHO for 625 pandemic H1N1 (2009) influenza vaccines 626

627 b)Case by case analysis of feasibility for other potential NRAs based on i) 628 review of the established procedures and practices for marketing 629 authorization/licensing of vaccines, ii) review and approval of variations/ 630 changes, iii) extent of the actual ongoing regulatory oversight exercised for 631 the vaccine of interest and iv) willingness of the agency to collaborate with 632 WHO in the evaluation and ongoing regulatory oversight of the vaccine of 633 interest. 634

635 Once the performance indicators have been developed, and the NRA assessment tool 636 is revised, allowing the establishment of functionality levels, a stepwise expansion to 637 include additional authorities can be carried out. 638 639 4.2 Streamlined procedure for vaccines with marketing 640 authorization/ licensing granted, by eligible NRAs 641 As an alternative to the WHO vaccine prequalification procedure described in section 642 3, the streamlined option can be applied to vaccine applications submitted for 643 evaluation by those selected NRAs who are eligible and willing to share regulatory 644 information with WHO through a collaboration agreement; 645 646 WHO will explicitly request the assistance of the NRA responsible for the regulatory 647 oversight of the candidate vaccine, and will engage in discussions for the 648

WHO/BS/10.2155 establishment of a formal collaboration agreement that will outline the shared 649 understanding of roles and responsibilities, and commitments of each party. 650 Provisions for confidentiality will be also included. 651 652 The scope of this agreement can be determined by both parties and could include one 653 or more of the following (each subject to agreement by the manufacturer): 654 655

Sharing of NRA reports relevant to product quality, non-clinical and clinical 656 evaluation 657

Sharing of NRA/ NCL test results (including the raw data) 658 Sharing of inspection reports 659 660

Once the collaboration agreement is formally established, depending on its nature and 661 scope, WHO may decide on a product by product basis to do one or more of the 662 following: 663 664

review the NRA assessment reports instead of reviewing the PSF; 665 review NRA/NCL testing results and their trending, if applicable, instead of 666

independently testing the final product characteristics; 667 review the NRA inspection reports and supplement with a short audit focused 668

on aspects related to United Nations' tender specifications instead of 669 conducting a full site audit. 670

671 Review NRA assessment reports instead of the PSF 672 In this instance WHO recognizes the assessment of the MA/licence dossier performed 673 by the selected NRAs responsible for the regulatory oversight of the candidate 674 vaccine as the basis for the decision on prequalification. WHO will review the NRA 675 assessment and inspection reports instead of reviewing the PSF and may follow-up on 676 queries, based on the available information provided by the responsible NRA for the 677 MA/licensing of the vaccine submitted for PQ. In case of additional questions related 678 to issues not addressed in the NRA reports, WHO will contact the manufacturer 679 directly and copy the NRA of such exchanges of additional information. 680 681 Typically, the responsible NRA would neither focus its review on aspects that are 682 specific to the national immunization schedules of countries that receive their 683 vaccines through the UN nor on the programme needs stated in the UN specifications. 684 These are to be assessed by WHO. In this respect the EMA Scientific Opinion 685 procedure (Article 58 of Regulation (EC) No. 726/2004) represents the exception 686 687 In view of the above, a review by WHO of the following aspects would remain 688 essential: 689 690

a) Review of mandatory and critical characteristics from the programmatic point 691 of view. 692

b) Eligibility, when required, for the AMC through review of the proposed 693 product characteristics against the target product profile criteria. 694

c) Confirmation that the vaccine meets WHO recommendations. 695 d) Review of stability data to ensure it meets the needs of immunization 696

programmes in developing countries (particularly those with weak cold chain 697

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systems) and assignment of a VVM category. 698 e) Review of clinical data to ensure that are applicable to the target population. 699 f) Review of recommended immunization schedules to ensure compatibility with 700

those existing in national immunization programmes. 701 g) Review of the suitability of samples, labels, inserts and packaging to meet the 702

United Nations agencies tender requirements. 703 h) Review of packaging for international shipment and its validation. 704

705 The applicant must provide a copy of the file submitted to the NRA and relevant 706 sections of the PSF to cover information required in items a to h above to WHO for its 707 perusal. 708 709 For those NRAs that do not require renewal of the licence on a regular basis, the NRA 710 should have an alternative mechanism in place to conduct an ongoing monitoring of 711 the quality, safety and efficacy of the vaccines over which they exercise the regulatory 712 oversight. Updated information on these vaccines should be conveyed to WHO by 713 the NRA at defined intervals. This information may be used in the reassessment 714 procedure. 715 716 Review of NRA testing results and their trend, if applicable, instead of 717 independently testing consistency of final product characteristics 718 Vaccines submitted for the initial evaluation for prequalification are categorized by 719 WHO into one out of four categories described in table 1 (see Annex 2). Vaccines 720 that meet the criteria described under categories I to III may be evaluated applying the 721 streamlined procedure. 722 723 In this case, WHO will recognize the lot release testing performed by the selected 724 NRA/NCL responsible for the regulatory oversight of the candidate vaccine. WHO 725 will review the available information e.g. testing results, raw data, trends -if 726 applicable-, and control charts. Based on the information provided by the NRA/NCL 727 responsible for the lot release and testing of the vaccine submitted for prequalification, 728 WHO will consider whether additional independent testing by WHO contracted 729 laboratories is required or if this information can be accepted by WHO for 730 prequalification purposes. 731 732 When the NRA/NCL responsible for the regulatory oversight does not perform the 733 critical tests, either for novel or traditional vaccines, testing by WHO contracted 734 laboratories needs to be conducted before the prequalification is granted. 735 736 Review of NRA inspection reports supplemented with a short audit 737 focused on aspects related to United Nations' tender specifications 738 instead of conducting a full site audit 739 This is based on WHO's recognition of the inspections conducted by the selected 740 NRAs responsible for the regulatory oversight of the candidate vaccine. The WHO 741 site audit as part of the initial evaluation, follow-up to corrective actions taken by the 742 manufacturer following WHO recommendations, or reassessment, will be replaced by 743 a review of inspection reports from the responsible NRA and a short audit by WHO 744 that will include verification of specific items relevant to UN tender specifications 745 746

WHO/BS/10.2155 If the review of inspection reports conducted by the responsible NRA is considered 747 sufficient to ensure that vaccine candidates (or those already being purchased) meet or 748 continue to meet the WHO requirements and specific conditions required for purchase 749 by United Nations agencies this information can be accepted by WHO for 750 prequalification purposes. 751 752 WHO will include, as part of the agreement with the relevant NRA an exchange of 753 information regarding results of national inspections, variations to the licence or 754 cancellations, rejection of lots, recalls and withdrawals, interruptions in production, 755 information on AEFIs reported or other matters that could affect the normal supply of 756 vaccine to United Nations agencies. 757 758 Other considerations 759 The implementation of the streamlined prequalification procedure as described above 760 requires an eligible authority and the willingness of this authority to engage in the 761 collaborative effort. Special attention should be given to authorities from countries 762 where English is not the mother tongue. In such cases, engagement in this exercise 763 would imply additional workload for the NRA to make their reports available in 764 English. Specificities of the collaboration (nature and extent) should be defined on a 765 case by case basis and reflected in the agreement. 766 767 Vaccines that are produced for export-only purposes require special consideration and 768 are not eligible for evaluation through the streamlined procedure described in section 769 4.2. 770 771 The report of the assessment is performed as per the standard prequalification 772 procedure. (see section 3). 773 774 4.3 Vaccines with positive scientific opinion issued by EMA 775 WHO is involved at different stages of the process of evaluation of vaccines by 776 EMA/CHMP under Article 58 (Regulation EC No. 726/2004). In this context, 777 EMA/CHMP issues a scientific opinion based on evidence of quality, safety and 778 efficacy, taking into consideration the benefit/risk assessment for the intended 779 population, which is consistent with the WHO's focus on developing countries. 780 781 All vaccine applications submitted for evaluation by EMA under Article 58, and 782 intended for immediate prequalification after a positive Scientific Opinion, will be 783 assessed through a streamlined procedure (see Annex 3) in such a way that the time 784 elapsed between a positive scientific opinion and prequalification will be minimized. 785

786

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5 Special considerations for fast-track procedure 786 The implementation of a fast-track procedure may be required under special 787 circumstances. This procedure is applicable to licensed vaccines (marketing 788 authorization available) that are part of the routine immunization programmes or those 789 that are used only as an emergency response, but not applicable in the case of novel 790 vaccines not yet introduced or recently introduced into the routine immunization 791 programmes. 792 793 In agreement with United Nations purchasing agencies or other partners, the fast-track 794 procedure can be considered in the following situations: 795 796

An acute shortage7 of a vaccine that puts at risk the global supply of routine 797 immunization programmes and/or an eradication effort. 798

799 An emergency situation , i.e outbreak or epidemic of a disease for which there 800

is no prequalified vaccine, or its availability is not sufficient and an additional 801 source of the same vaccine is required. 802

803 Exceptional situations such as: 804

805 Declaration of a pandemic of a disease for which production capacity needs to 806

be established. 807 808 Need of alternative to existing vaccines to be used during an eradication effort. 809

810 Any of the above exceptional situations may lead to acceptance of vaccines for 811 evaluation in parallel to the submission to the NRA for marketing authorization 812 purposes upon: 813 814 a) special request from the manufacturer, and 815 b) endorsement by senior management at WHO 816 817 818 In those cases where the fast-track procedure is followed, the established deadlines 819 for submission of PSFs do not apply. In addition, the site audit will take place (in 820 parallel with quality control tests of samples) while the results of tests are pending. 821 822 There should be maximum flexibility in this process. For example, review of the 823 dossier and testing of samples will be concomitantly performed and the site audit will 824 be conducted as soon as the dossier review is completed. Similarly to the streamlined 825 approach described under section 4, consideration should be given to reviewing 826 information provided by the relevant regulatory authority with the manufacturer’s 827 permission (including inspection reports), and to results of tests performed by the 828 relevant NRA/NCL to facilitate the evaluation process. 829 830

7 As agreed with UN purchasing agencies and other partners.

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6 Special considerations for accepting submissions of 831 vaccines manufactured in multiple sites or countries 832

It is a pre-condition to any submission of vaccines for prequalification evaluation that 833 the NRA responsible for the regulatory oversight of the product be assessed by a 834 WHO team with respect to its compliance with the six critical functions identified by 835 WHO. The functionality status of the NRA also needs to be sustained with time. 836 837 Due to the increasing diversity and complexity of the vaccines that can be 838 manufactured in multiple sites including different countries, WHO has to ensure that 839 the regulatory oversight is fully exercised and responsibilities are clearly defined at all 840 steps of production by the relevant functional NRAs. 841 842 The following criteria will be followed: 843 844 The assessment evaluation will be product specific, just as it is for vaccines produced 845 by one company in a single site and/or country. 846 847 If a company formulates and /or fills from bulks purchased from different sources 848 each of these final products is considered as a unique product and will be prequalified 849 separately. 850 851 If the formulation process used by a manufacturer of finished product of a vaccine is 852 different from that used by the manufacturer of the vaccine from seed (e.g. different 853 formulation procedures, different stabilizers, different adjuvants, different 854 preservatives and/or different excipients), these vaccines will be considered unique 855 products and may require preclinical and clinical evaluation. 856 857 Evidence will be required by WHO that the finished product manufacturer has 858 authorization from the vaccine manufacturer producing the bulk to export the final 859 product.. In the case where purchased bulk antigen A is used for combination with 860 antigens B and C from other sources, proper authorization by the bulk producer of 861 antigen A for combination (and possible limitations for distribution of the 862 combination vaccines) is required. 863 864 There must be a long-term contract between manufacturers although a minimum of 2 865 years can be acceptable, if justified. The technical terms and the duration of the 866 contract must be submitted to WHO for review as part of the assessment procedure 867 and whenever necessary additional information can be requested to the manufacturers. 868 869 For a manufacturer, with subsidiaries in different parts of the world that perform 870 different manufacturing steps, and if the bulk is not part of a licensed final product in 871 the country of manufacture, the NRA of the country where the finished product is 872 manufactured would need to exercise full regulatory oversight of the product. This 873 means this NRA is responsible for technical, non clinical and clinical review, and 874 regulatory inspections of the facilities in each country performing manufacturing 875 operations. This NRA would also grant the marketing authorization, perform lot 876 release, testing as necessary as well as post marketing surveillance. 877 878

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For finished product manufacturers of OPV vaccines to be eligible for the 879 prequalification process, the bulk material must have been evaluated as part of a 880 vaccine already prequalified by WHO for the UN market. 881 882 In those cases where the vaccine manufacture is conducted in more than one country 883 which may not be fully covered by the above provisions, the following aspects should 884 be considered to ensure the ongoing regulatory oversight of vaccines: 885 886

a) Responsibility for overseeing manufacturing of different production steps 887 should be shared between the relevant authorities (functionality being a 888 condition) with relevant agreements in place and MA/licensing and release is 889 under the responsibility of the authority from where the vaccine is distributed. 890

b) Consideration may be given to use article 58 of Regulation (EC) No 726/2004 891 if the applicant is based in the European Economic Area (EEA), or has a 892 contact point within the EEA. 893

c) Use of a production site in a country where the NRA has not been assessed as 894 functional requires that the NRA in country of manufacture of the final 895 product takes full responsibility for the oversight of the product. 896

d) If c) does not apply and/or article 58 of Regulation (EC) No 726/2004 897 alternative pathway can not be used for any reason, this site becomes 898 unacceptable for a product to be evaluated for purchase through United 899 Nations agencies. 900

901 The use of a totally unrelated (third party) NRA for the oversight of the product 902 (outside of the option of article 58 of Regulation (EC) No 726/2004) would not be 903 normally acceptable. However, if an agreement between NRAs is established for a 904 specific product, giving the third party authority full regulatory responsibility that 905 includes lot release for United Nations purposes, regular inspections, monitoring of 906 variations, and post-marketing surveillance, then WHO would review the terms of 907 agreement between the NRAs and make a case-by-case decision on it's acceptability. 908 909 WHO encourages the early discussions with the manufacturers and their respective 910 NRAs should they plan to embark in a project where multiple sites or countries are 911 involved in the production process, to discuss the proposed scheme and allocation of 912 responsibilities to the NRAs. 913

WHO/BS/10.2155

7 Obligations after prequalification is granted 914 All lots of prequalified vaccine shipped in response to orders placed by a United 915 Nation agency must have been released by the NRA in advance of shipping. A copy 916 of the lot release certificates will be kept by the manufacturer and sent, on request, 917 to the United Nations agencies or to the Coordinator, Quality, Safety and Standards, 918 Department of Immunization, Vaccines and Biologicals, World Health 919 Organization, Geneva (WHO/IVB/QSS). In addition, a suitable number of samples 920 (defined during the assessment process) of each vaccine lot supplied to the 921 UN agencies will be retained by the manufacturer, to be made available to 922 WHO/IVB/QSS on request for testing. 923 924 The manufacturer shall inform WHO/IVB/QSS of changes/variations that must be 925 notified or submitted to the NRA in the formulation, presentation, methods of 926 manufacturing or quality control and specifications, facilities, or for any other aspects 927 which might (a) result in a change of safety and/or efficacy of the vaccine, or (b) 928 change the basis of the regulatory approval by the NRA. 929 930 If the manufacturing country regulations do not require approval by the NRA of 931 changes/variations that fall under categories (a) and (b) stated above, WHO shall be 932 informed of the proposed changes before these are implemented on products supplied 933 to United Nations agencies. 934 935 When WHO relies on the oversight of changes/variations by the responsible NRA, an 936 annual summary of changes/variations (see section 8) would be sufficient. 937 938 When such reliance is not established, changes/variations that fall under categories (a) 939 and (b) stated above must be approved by WHO before implementation for UN 940 supply. All other changes/ variations can be reported to WHO on an annual basis as 941 detailed in Section 8. 942 943 If the labelling specifications are changed or model inserts are updated as part of 944 UN tender requirements manufacturers shall comply with the revised UN tender 945 specifications The updated versions of labels and package inserts must be reviewed 946 by WHO before implementation. 947 948 WHO reserves the right to take appropriate measures including "suspension of supply, 949 initiating a reassessment or withdrawal from the list " in case of non compliance with 950 post prequalification commitments and/or in case of misconduct. 951 952

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8 Annual Reporting 953 The following information should be provided in an annual report for each 954 prequalified vaccine: 955 956

A. The manufacturer should provide a summary of changes/variations to the 957 product(s) that have been implemented since the previous annual report (or for 958 the first annual report for a product, since initial prequalification). The table 959 below is provided as guidance. 960

961 Responsible NRA Description

of variation PSF Ch/section

CTD X-ref (where appropriate)

Prior approval date

Date of acknowledgement of notifiable change†

Self-assessable under national law or not applicable to national registration [ if required]

WHO prior approval date (where required) Or WHO notification date (as applicable)‡

962 For responsible NRA columns: manufacturer should complete one out of the three 963 columns which are relevant to change. 964 965 † Provide the date of the NRA letter acknowledging the notification or indicate if NRA has not 966 responded and hence give date change implemented under national law. 967 ‡ Ref to Points to consider "Variations to the vaccine prequalification file (in preparation) 968

969 B. The manufacturer should provide testing results from the ongoing stability 970

programme since the previous annual report (or for the first annual report for a 971 product, since initial prequalification). 972

973 C. Production and distribution data 974

• Summarytableshowingthequantityofbatchesanddosesoffinished975 productdistributedsincethepreviousannualreport.Thisshouldinclude976 productuseddomesticallyandproductexported.Thebatcheswhichhave977 beensuppliedtoUNagenciesshouldbeindicated.978

• Ifmorethanonepresentationismanufactured,theseshouldbelisted979 separately.980

981 D. GMPinspections(inwhichthePQproductwaswithinthescopeofinspection)982

performedsincethepreviousannualreport. 983 984 E. Asummaryupdateonimplementationofpost‐PQcommitmentsfromthe985

manufacturerwhentheseareindicatedintheapprovalletterorreassessment986 reportsuchas:987

988 • reportsofseriousadverseeventsfollowingimmunization;989 • reportsofqualitycomplaintsand/orrecallsfromthefieldforbatchesofthe990

prequalifiedvaccine;991 • notificationofanyproblem/constraintinproductionorqualitycontrol992

whichmightaffecttheinternationalsupplyofthisvaccine,bothinvolume993 and/orleadtimes.994

WHO/BS/10.2155 995

F. PeriodicSafetyUpdateReport(electronicdataonly)996 Followingreviewoftheannualreport,WHOmayrequestsupportingdata. 997 The timing for submission of annual reports should be established as the first 998 submission deadline one year after the date of prequalification. The manufacturer 999 may provide the latest annual report submitted to the NRA provided it contains the 1000 relevant information. The same established deadlines for PSFs submission will apply: 1001 31 January, 31 May and 30 September and for seasonal influenza vaccines: 1 July and 1002 1 November. 1003 1004

9 Reassessments 1005 Prequalification status is maintained until action is taken by WHO to revoke it. 1006 1007 However, periodic reassessment by WHO is required. The frequency, scope and need 1008 for reassessment will be based on quality risk management principles. 1009

1010 The following aspects will be taken into consideration by WHO: 1011

1012 stringency of oversight exercised by responsible NRA; 1013 prior experience with manufacturer and specific product; 1014 variations to the product indicated in annual reports since previous 1015

assessment; 1016 interruptions to production and/or supply to UN agencies; 1017 reported quality complaints and AEFIs; 1018 any failure to meet the WHO recommendations and/or the specifications 1019

of the offer to bid; 1020 results from targeted testing of batches supplied to UN agencies. 1021

1022 The above list is indicative but not exhaustive. 1023 1024 A letter to the manufacturer requesting submission of an updated PSF for 1025 reassessment should be made six months to one year prior to the proposed assessment 1026 time. Unless a paper copy is requested by WHO, the updated PSF should be in 1027 electronic form only. The updated PSF should contain a change control section which 1028 indicates the sections which have been changed from the previously submitted PSF. 1029 Items indicated in the change control section will be compared with summary tables 1030 of variations that have been submitted annually. The changed sections will also be 1031 compared to the initially submitted file. Only sections indicated as changed will be 1032 evaluated. If any changes are made that are not indicated in the change control 1033 section, they will not be considered as approved. 1034 1035 Testing of samples at reassessment is required only when there is insufficient 1036 evidence of continued compliance with specifications from the WHO annual targeted 1037 testing programme of batches supplied to UN agencies. 1038 1039 The need for and scope of a site audit at time of reassessment will take into 1040 consideration the demonstrated history of regulatory inspection of the facility by the 1041 NRA (including supply of reports of GMP inspections by the NRA). 1042 1043

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If,asaresultofthereassessment,itisfoundthatavaccinenolongercomplies1044 withtheWHO‐recommendedstandards,suchvaccineswillberemovedfromthe1045 list.Failureofamanufacturertoparticipateinthereassessmentprocedurewill1046 alsoleadtoremovalfromthelist.1047 1048

10 Monitoring continued compliance with specifications 1049 through targeted testing programme 1050

Samples of lots supplied through United Nations agencies will be selected, at least 1051 once a year, for testing of final product characteristics by WHO contracted 1052 laboratories. An appropriate number of samples (between 25 and 200 depending on 1053 the vaccine type and presentation offered) of three to five lots selected by WHO from 1054 a list of products supplied to UN agencies will be requested from the manufacturer. 1055 The manufacturer will provide lot summary protocols and the NRA/NCL release 1056 certificate as appropriate; will provide information on lot release for review. 1057 Manufacturers should commit to keep adequate number of retention samples for this 1058 testing programme. 1059 1060 Manufacturers will, in any case be contacted for follow-up actions in case of failure to 1061 meet specifications. 1062 1063 In the event of failure to meet the established criteria, WHO will investigate the 1064 problem and provide the United Nations agency with written information, copied to 1065 the manufacturer and the NRA, on the actions that need to be taken. 1066 1067

11 Monitoring vaccine quality complaints or AEFIs from 1068 the field 1069

Vaccine quality complaints 1070 In case of vaccine quality complaints, WHO will conduct an investigation and may 1071 perform independent testing after review of the relevant documentation including 1072 review of the temperature monitoring devices, review of the testing results and related 1073 data. 1074 1075 In case of complaints from the NCLs in the receiving countries, review of the testing 1076 results and related documentation (i.e. validation reports, SOPs and control charts) 1077 from the laboratory that puts forward the complaint is needed for WHO review before 1078 arbitration testing is commissioned. 1079 1080 1081 Adverse Events following immunization (AEFIs) 1082 In case of serious AEFIs or whenever WHO considers necessary, WHO will conduct 1083 an investigation according to established procedure. The review of the batch records 1084 by the manufacturer and the NRA exercising the regulatory oversight of the vaccine 1085 allows for detection of any potential deviation during the manufacturing process that 1086 may impact on the quality of the vaccine. 1087 1088 The targeted testing programme performed by WHO on a continuous basis supports 1089 the continued compliance of the vaccine with the established quality specifications. In 1090 addition, testing results gathered during the lot release process by the NRA/NCL are 1091

WHO/BS/10.2155 requested from the NRA/NCL exercising the regulatory oversight of the vaccine when 1092 the AEFIs are investigated. Further testing would be resource intensive and may not 1093 yield useful data. 1094 Therefore, the testing of a vaccine lot/batch would be recommended only if the 1095 clinical and/or epidemiological information about the AEFI case(s) indicates a 1096 potential vaccine quality problem and after review of the relevant manufacturing and 1097 control documentation. The investigation of AEFI cases would indicate if testing is 1098 required and in such case which specific type of test(s) is needed. 1099

Depending on the tests to be performed, the number of unopened containers (sampled 1100 from the field and from the manufacturer) required for testing needs to be calculated, 1101 so that it is powered enough to draw definitive conclusions about the relevant lot. In 1102 the event that testing is needed, WHO would contact one of the WHO contracted 1103 laboratories that could perform the test and subsequently inform the national 1104 authorities of the number of vaccine vials to be sent to WHO as well as other logistic 1105 arrangements. 1106 1107

12 Recommendations for action in cases of non 1108 compliance 1109

In the event of situations as described in sections 10 and 11 above and depending on 1110 the nature of the non compliance, WHO may recommend one or more of the 1111 following: 1112 1113

The manufacturers' lots of vaccines be more closely monitored through 1114 additional testing, visit to the manufacturing facilities together with the NRA 1115 responsible for the regulatory oversight of the product and/or review by WHO 1116 of the corrective/preventive actions during a probationary period that will 1117 depend on the failure. 1118

Purchase of the vaccine by UN agencies be suspended pending investigation 1119 and resolution of the problem. 1120

1121 The failures related to gaps in the manufacturing and/or quality system in place by the 1122 manufacturer may require a complete reassessment of the vaccine. 1123 1124 WHO will inform the relevant NRA responsible for the regulatory oversight about 1125 problems in the field or failure to meet established criteria. 1126 1127

13 Handling of Out-of-specification (OOS)/inconsistent 1128 results between laboratories 1129

1. Due to the increased complexity of the vaccines and new combinations 1130 currently available or in the pipeline for prequalification, the diversity 1131 of the methods applied for the quality control of the vaccines as well as 1132 the evaluation of results obtained through independent testing of such 1133 vaccines by WHO contracted laboratories, may pose challenges. 1134

2. In the case of inconsistent results by two WHO contracted laboratories, 1135 WHO may require testing of the vaccine by a third laboratory. 1136

WHO/BS/10.2155

3. WHO may convene an ad hoc committee of experts to assess the 1137 combined results and make a recommendation to WHO. 1138 Representatives from the WHO laboratories may take part in this 1139 committee. Recommendation from the committee will be then 1140 considered as final by the Prequalification Secretariat. 1141

1142 14 Costs 1143

The cost of the activities required to assess the acceptability, in principle, of candidate 1144 vaccines for UN agency purchase is covered by the manufacturers. It will be split 1145 into a screening fee and an evaluation fee. Both will be paid after the screening of the 1146 product summary file has been completed. If the screening process is not satisfactory, 1147 the manufacturer will be charged only the screening fee. 1148 1149 The expenses related to the site audit will be charged on a cost recovery basis. 1150 The evaluation of a vaccine will commence only after payment of the fee and receipt 1151 by WHO of the product summary file. 1152 1153 The cost of activities required to keep the WHO list updated or maintenance fee (i.e. 1154 review of annual reports, reassessments, handling of complaints and resolution of 1155 OOS results) is charged to the manufacturers on the basis of an annual fee. The 1156 expenses 1157 related to reassessment site audits are charged on a cost recovery basis. The 1158 maintenance fees will be charged to the manufacturers at the beginning of every 1159 calendar year. The reassessment process will not be initiated until the corresponding 1160 fee is paid to WHO. Failure to pay could ultimately lead to withdrawal of the 1161 vaccines from the list. 1162 1163 In all cases where follow-up site audits and other additional activities and resources 1164 are required for special reasons (e.g. failure to meet the criteria), these will be charged 1165 separately on a cost recovery basis. Fees will be updated on a regular basis. 1166 1167 Fees (screening, initial evaluation of candidate vaccines and annual maintenance fee) 1168 are kept on a separate list available on the website. 1169 http://www.who.int/immunization_standards/vaccine_quality/PQ_vaccine_manufactu1170 rers_guidance/en/index.html 1171 1172

15 Confidentiality 1173 Information to which WHO requires access for the purpose of assessing or reassessing 1174 the acceptability in principle of a vaccine for purchase by UN agencies may include 1175 confidential information. However, if, in the opinion of the manufacturer, 1176 any information to be submitted to WHO and its expert team members in the course 1177 of the (re)assessment procedure includes confidential information; the manufacturer 1178 must advise WHO thereof in writing, prior to or at the same time as the disclosure, 1179 duly identifying the confidential information in question. Notwithstanding the 1180 foregoing, WHO and its expert team members will treat all information submitted 1181 to them either as written documents or during site audits as confidential, in 1182 accordance with the terms set forth below. 1183 1184

WHO/BS/10.2155 WHO will treat information so identified contained in the product summary 1185 file (Annex 1) and information disclosed during site audits as confidential and 1186 proprietary to the manufacturer and, in this connection, take all reasonable measures 1187 to ensure (a) that such information (“the Confidential Information”) is not used for 1188 any other purpose than the (re)assessment procedure described in this document, 1189 and (b) that it is not disclosed or provided to any person who is not bound by similar 1190 obligations of confidentiality and non-use as contained herein. 1191 1192 WHO and/or its expert team members will not, however, be bound by any obligations 1193 of confidentiality and non-use to the extent they are clearly able to demonstrate that 1194 any part of the confidential information: 1195 a) was known to them prior to any disclosure by the manufacturer; or 1196 b) was in the public domain at the time of disclosure by the manufacturer; or 1197 c) has become part of the public domain through no fault of WHO and/or any of 1198 its expert team members; or 1199 d) has become available to WHO and/or any of its expert team members from a 1200 third party not in breach of any legal obligations of confidentiality to the 1201 manufacturer. 1202 1203 In connection with the above, WHO requires all experts to sign the confidentiality 1204 agreement attached as Annex 4, prior to taking up their responsibilities for WHO. 1205 1206

16 No conflict of interest 1207 The team of experts selected for a specific evaluation process includes experts in the 1208 fields of production, quality control/quality assurance, quality system, clinical 1209 evaluation and GMP. These experts are selected by WHO and act as WHO temporary 1210 advisers or consultants. Prior to formalizing arrangements with such experts, WHO 1211 will also require them to complete the WHO declaration of interests form attached as 1212 Annex 5. In addition, the confidentiality agreement referred to in section 15 above 1213 contains a conflict of interest undertaking, pursuant to which the experts agree to 1214 discharge their functions exclusively as advisers to WHO. They also confirm that 1215 they have no financial interest and/or other relationship with a party, which: 1216 1217 a) may have a vested commercial interest in obtaining access to any confidential 1218 information disclosed by the manufacturer in the course of the (re)assessment 1219 procedure described in this document; and/or 1220 1221 b) may have a vested interest in the outcome of the (re)assessment procedure, 1222 including, but not limited to, parties such as the manufacturer of the vaccine(s) 1223 that is (are) being assessed or manufacturers of competing vaccines. 1224 1225 WHO will advise the manufacturer in advance of the composition of the evaluation 1226 team, and provide curricula vitae of the experts included in the team. The 1227 manufacturer will then have the opportunity to express possible concerns regarding 1228 any of the expert team members to WHO. If such concerns cannot be resolved in 1229 consultation with WHO, the manufacturer may reject an expert team member, within, 1230 at the latest, 15 days of receipt of the proposed team composition. 1231 1232

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Authors 1233 1234 The proposals for the revision of the "Procedure for assessing the acceptability, in 1235 principle, of vaccines for purchase by United Nations Agencies" were prepared by: 1236 Working group 1: Programmatic suitability of vaccines for WHO prequalification 1237 (PSPQ) membership - Robin Biellik, Independent, Switzerland; Maria Cortes, PAHO 1238 Vaccine Quality Issues, U.S.A.; Nora Dellepiane, WHO, Immunization, Vaccines and 1239 Biologicals Department, Quality, Safety and Standards, Switzerland; Rudi Eggers, 1240 WHO, Immunization, Vaccines and Biologicals, Expanded Programme on 1241 Immunization; Mauricio Landaverde, PAHO Immunization Services, U.S.A.; Chris 1242 Nelson, Independent (Working Group Chair), U.S.A.; Ann Ottosen, UNICEF Supply 1243 Division, Denmark; Monica Pereira, PAHO Revolving Fund, U.S.A.; Piyanit 1244 Tharmaphornpilas, Department of Disease Control, Ministry of Public Health, 1245 Thailand; Emma Uramis, WHO, Immunization, Vaccines and Biologicals Department, 1246 Quality, Safety and Standards, Switzerland. Working group 2: Comparison of 1247 prequalification programmes membership - Drew Meek, WHO, Immunization, 1248 Vaccines and Biologicals Department, Quality, Safety and Standards, Switzerland; 1249 Anita Sands, WHO, Essential Health Technologies, Diagnostics and Laboratory 1250 Technology, Switzerland, Morteza Zaim, WHO, HIV/AIDS, TB, Malaria and Control 1251 of Neglected Tropical Diseases, Switzerland; André Van Zyl, WHO, Essential 1252 Medicines and Pharmaceutical Policies, Quality Assurance and Safety: Medicines, 1253 Switzerland. Working group 3: Revised approaches to testing final product 1254 characteristics membership - Teeranart Jivapaisarnpong, Department of Medical 1255 Sciences, Ministry of Public Health, Thailand; Carmen Rodriguez, WHO, 1256 Immunization, Vaccines and Biologicals Department, Quality, Safety and Standards, 1257 Switzerland; Ute Rosskopf, WHO, Immunization, Vaccines and Biologicals 1258 Department, Quality, Safety and Standards, Switzerland; Lorenzo Tesolin, Scientific 1259 Institute of Public Health, Belgium; Wilma Vergeer, National Control Laboratory, 1260 South Africa; Geneviève Waeterloos, Scientific Institute of Public Health, Belgium. 1261 Working group 4: Streamlining the prequalification procedures for products with 1262 EMA/CHMP positive scientific opinion membership - David Cockburn, Inspection 1263 sector, European Medicines Agency (EMA); Emer Cooke, Directorate, International 1264 Liaison Officer, European Medicines Agency (EMA); Liliana Chocarro, WHO, 1265 Immunization, Vaccines and Biologicals Department, Quality, Safety and Standards, 1266 Switzerland; Marie-Hélène Pinheiro, European Medicines Agency, United Kingdom; 1267 Lembit Rago, WHO, Essential Medicines and Pharmaceutical Policies, Quality and 1268 Safety: Medicines; Carmen Rodriguez, WHO, Immunization, Vaccines and 1269 Biologicals Department, Quality, Safety and Standards, Switzerland; Alessandro 1270 Spina - Legal sector, European Medicines Agency (EMA) 1271 Working group 5: WHO assessment of vaccines regulatory system: Proposal for 1272 establishment of maturity level concept membership - Norman Baylor, Center for 1273 Biologics Evaluation and Research, US Food and Drug Administration (USFDA), 1274 U.S.A.; Lahouari Belgharbi, WHO, Immunization, Vaccines and Biologicals 1275 Department, Quality, Safety and Standards, Switzerland (working group Chair); 1276 Pierre Henry Bertoye, Agence Française de Sécurité Sanitaire de Produits de Santé 1277 (AFSSAPS); Faten Fathalla and/or Heba Wali, Egyptian National Regulatory 1278 Authority (ENRA), Egypt; Stephane Guichard, WHO, Regional Office in Southeast 1279 Asia, India; Teeranart Jivapaisarnpong, Department of Medical Sciences, Ministry of 1280 Public of Health, (MoPH) Thailand; Youssou Ndao, Health Manager of Public Market 1281 Central Department, Ministry of Finance and Economy, Senegal; Jose Peña, 1282

WHO/BS/10.2155 PAHO/AMRO, U.S.A.; Franz Reigel, Independent, Switzerland; Christopher Rolls, 1283 Therapeutic Goods Administration (TGA), Australia; Celeste Sánchez, Centro para el 1284 Control Estatal de la Calidad de los Medicamentos (CECMED), Cuba; Surinder Singh, 1285 Central Drug Standard Control Organization (CDSCO), India; Lucky Slamet, 1286 National Agency of Food and Drug Control (NADFC), Indonesia. Working group 6: 1287 Requirements for product summary file submitted for prequalification. Initial 1288 evaluation and reassessment and requirements for annual report for prequalified 1289 vaccines membership - All from WHO, Immunization, Vaccines and Biologicals 1290 Department, Quality, Safety and Standards, Switzerland; Nora Dellepiane, Jackie 1291 Fournier-Caruana, Scott Lambert, Drew Meek (working group Chair), Sergio 1292 Nishioka, Carmen Rodriguez, Ute Rosskopf. Working group 7: Streamlining the 1293 prequalification procedure: Consideration of a risk-based approach membership - 1294 Joan Wilmarth Blair, M.A., Senior Advisor for International Affairs, Center for 1295 Biologics Evaluation and Research, U.S. Food and Drug Administration, U.S.A.; 1296 Nora Dellepiane, WHO, Immunization, Vaccines and Biologicals Department, 1297 Quality, Safety and Standards, Switzerland; Roland Dobbelaer, Consultant, Belgium; 1298 Rolando Domínguez Morales, Department for Biologicals and Vaccines, Centro 1299 Control Estatal de la Calidad de los Medicamentos (CECMED), National Regulatory 1300 Authority, Cuba; James Southern, WHO Temporary Adviser, Prequalification of 1301 Vaccines, South Africa; Emma Uramis Diaz, Consultant, WHO, Immunization, 1302 Vaccines and Biologicals Department, Quality, Safety and Standards, Switzerland; 1303 Huib van de Donk, WHO Temporary Adviser, Prequalification Influenza Vaccines, 1304 The Netherlands. Working group 8: Regulatory oversight of vaccines manufactured 1305 in multiple sites/countries membership - All from WHO, Immunization, Vaccines and 1306 Biologicals Department, Quality, Safety and Standards, Switzerland; Nora Dellepiane, 1307 Jackie Fournier-Caruana (working group Chair), Scott Lambert, Drew Meek, Sergio 1308 Nishioka, Carmen Rodriguez, Ute Rosskopf. 1309 1310 The proposals were discussed at the "Informal consultation with the ad hoc committee 1311 on vaccines prequalification for the revision of the procedure for assessing the 1312 acceptability, in principle, of vaccines for purchase by UN agencies"and 1313 recommendations were received from the Ad-hoc Committee Members (WHO 1314 Temporary Advisers) - Laura Gomes Castanheira, ANVISA, Brazil; Patrice Chagnaud, 1315 Agence Française de Sécurite Sanitaire de Produits de Santé (AFSSAPS), France; 1316 Xingyu Chen, Department of International Cooperation, State Food and Drug 1317 Administration (SFDA), People's Republic of China; Emer Cooke, European 1318 Medicines Agency, United Kingdom; Roland Dobbelaer, Vaccine Quality and 1319 Regulatory Expert, Belgium; Rolando Domínguez Morales, Department for 1320 Biologicals and Vaccines, Centro Control Estatal de la Calidad de los Medicamentos 1321 (CECMED), National Regulatory Authority, Cuba; Martin Eisenhawer, Swiss Agency 1322 for Therapeutic Products Inspectorates, Switzerland; Ian Feavers, National Institute 1323 for Biological Standards and Control (NIBSC), United Kingdom; Morag Ferguson, 1324 Independent, United Kingdom; Teeranart Jivapaisarnpong, Department of Medical 1325 Sciences, Ministry of Public Health, Thailand; Jeewon Joung, National Institute of 1326 Food and Drug Safety Evaluation, Korea Food and Drug Administration (KFDA), 1327 Republic of Korea; Ria Nibbeling, Centre for Biological Medicines and Medical 1328 Technology (BMT), National Institute of Public Health and Environment Protection 1329 (RIVM), The Netherlands; Marie-Hélène Pinheiro, European Medicines Agency, 1330 United Kingdom; Helen Rees, Reproductive Health and HIV Research Unit, 1331

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University of the Witwatersrand, South Africa; Christopher Rolls, Therapeutic Goods 1332 Administration (TGA), Australia; V.G. Somani, DGHS, Ministry of Health and F.W., 1333 Central Drugs Standard Control Organisation, India; Lucky Slamet, National Agency 1334 of Food and Drug Control (NADFC), Indonesia; James Southern, WHO Temporary 1335 Adviser, Prequalification of Vaccines, South Africa; Jean Marc Spieser, Biological 1336 Standardization/OMCL Network, European Department for the Quality of Medicines 1337 - Coucil of Europe, European Pharmacopoeia Commission Secretariat, France; 1338 Lorenzo Tesolin, Scientific Institute of Public Health, Belgium; Wilma Vergeer, 1339 National Control Laboratory, South Africa; Joan Wilmarth Blair, M.A., Senior 1340 Advisor for International Affairs, Center for Biologics Evaluation and Research, U.S. 1341 Food and Drug Administration, U.S.A.; Karen Midthun, Center for Biologics 1342 Evaluation and Research, U.S.A. and other meeting participants. 1343 1344 The first draft of the revised procedure was prepared by the drafting group: Emma 1345 Uramis Consultant, WHO, Immunization, Vaccines and Biologicals Department, 1346 Quality, Safety and Standards, Switzerland, Nora Dellepiane, Drew Meek, Carmen 1347 Rodriguez, Sergio Nishioka, Liliana Chocarro, Ute Rosskopf, all from WHO, 1348 Immunization, Vaccines and Biologicals Department, Quality, Safety and Standards, 1349 Switzerland and David Wood, Coordinator, WHO, Immunization, Vaccines and 1350 Biologicals Department, Quality, Safety and Standards, Switzerland taking into 1351 account the recommendations from the Ad-hoc Committee Members and posted on 1352 the WHO biologicals web site for public consultation. 1353 1354 Based on comments received from regulators, vaccine manufacturers and other 1355 experts the WHO/BS/10.2155 document was prepared by the drafting group and 1356 posted on the WHO biologicals web site for public consultation. 1357 1358 This final document was prepared based on comments received from regulators, 1359 vaccine manufacturers, other experts, and members and participants of Experts 1360 Committee on Biological Standardization meeting 2010. 1361

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Acknowledgments 1363 1364 Acknowledgements are due to the following experts and organizations for their 1365 comments on the draft of "Procedure for assessing the acceptability, in principle, of 1366 vaccines for purchase by United Nations Agencies, Revision 2010:" First draft - 1367 Agence Française de Sécurité Sanitaire de Produits de Santé (AFSSAPS), France; 1368 BioManguinhos, Oswaldo Cruz Foundation, Brazil; CBER, US Food and Drug 1369 Administration (FDA), U.S.A.; Rolando Domínguez Morales, Department for 1370 Biologicals and Vaccines, Centro Control Estatal de la Calidad de los Medicamentos 1371 (CECMED), National Regulatory Authority, Cuba; European Medicines Agency, 1372 United Kingdom; Martin Eisenhawer, Swiss Agency for Therapeutic Products 1373 Inspectorates, Switzerland; Ian Feavers, National Institute for Biological Standards 1374 and Control (NIBSC), United Kingdom; Morag Ferguson, Independent, United 1375 Kingdom; GlaxoSmithKline Biologicals, Belgium; International Federation of 1376 Pharmaceutical Manufacturers and Associations (IFPMA), Switzerland; Victor 1377 Maqueda, Independent, Argentina; John McEwen, Therapeutic Goods Administration 1378 (TGA), Australia; Julie Milstien, University of Maryland, U.S.A.; Agency of Food 1379 and Drug Control (NADFC), Indonesia; National Regulatory Authority, Iran; Chris 1380 Nelson, Independent, U.S.A.; Panacea Biotec Limited, India; Serum Institute of India, 1381 India;.UNICEF Supply Division, Denmark. Second draft - Agence Française de 1382 Sécurité Sanitaire de Produits de Santé (AFSSAPS), France; BioFarma, Indonesia; 1383 Biologicals E. Limited, India; BioManguinhos, Oswaldo Cruz Foundation, Brazil; 1384 Crucell, Switzerland; Federal State Unitary Enterprise of Chumakov Institute of 1385 Poliomyelitis and Viral Encephalitides, Russian Federation; GAVI Alliance, 1386 Switzerland; GlaxoSmithKline Biologicals, Belgium; GreenCross Corporation, 1387 Republic of Korea; Japan BCG Laboratory, Japan; Houda Langar, WHO Regional 1388 Office in the Eastern Mediterranean; Novartis, Italy; Panacea Biotec Limited, India; 1389 Dina Pfeifer, WHO Regional Office in Europe, Denmark; Sanofi Pasteur, France; 1390 Serum Institute of India, India; UNICEF Supply Division, Denmark. 1391 1392

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Appendix 1 The product summary file 1393 1394 The product summary file (PSF) is a summary dossier containing 1395 current information on the product to be supplied to UN agencies. It presents 1396 information on the product composition, manufacturing procedure, testing, stability, 1397 labelling, clinical experience and available post-marketing safety information. 1398 1399 For initial product assessments, a product summary file shall be submitted for each 1400 vaccine to be assessed. For combination vaccines, information shall be submitted on 1401 each of the component vaccines and on the combination itself. If a combination 1402 vaccine 1403 is being evaluated and the monovalent versions of the antigens contained in the 1404 combination are also being evaluated, the information provided for the monovalent 1405 vaccines (up to concentrated bulk) can be used for the assessment of the combinations, 1406 or conversely, the information on each antigen provided in the PSF of the 1407 combination 1408 vaccine can be used to assess the monovalent vaccines (up to concentrated bulk 1409 level). 1410 1411 The product summary file is expected to contain the following elements: 1412 1413 Chapter 1: General information 1414 1.1 Provide brief information on the company (including name and address of the site, 1415 including telephone, fax and 24-hour telephone numbers, and the principal contacts of 1416 the company), and relation to other sites where steps of the process or testing 1417 activities (for both the active and diluent) may be conducted. 1418 1.2 List pharmaceutical and non-pharmaceutical manufacturing activities carried out 1419 at the site as licensed by the national regulatory authority. This information shall also 1420 be provided for contracted manufacturers. 1421 1.3 Provide a short description of the site (size, location and immediate environment). 1422 List buildings on the site(s) or provide a site plan identifying the manufacturing, 1423 control, and storage activities in each building. 1424 1.4 State the number of employees engaged in the production, quality assurance, 1425 quality control, storage and distribution. 1426 1.5 List outside scientific, analytical or other technical assistance in relation to 1427 manufacture and analysis, including equipment and/or other facility maintenance and 1428 validation. In case of contract manufacturing and contract testing of part of the 1429 process, provide information on the way in which GMP compliance of the contract 1430 acceptor is assessed. 1431 1.6 Give a short description of the quality management system of the firm responsible 1432 for manufacture. 1433 1.7 Give a short description of the internal audit system and programme for qualifying 1434 suppliers of raw materials. 1435 1.8 List manufacturers supplying biological raw materials and adjuvants 1436 1437 Chapter 2: Personnel 1438 2.1 Provide an organizational chart showing the relationships between different areas, 1439 including quality assurance, production and quality control, with identification by 1440 name of key personnel (Head of Production, QA, QC, Warehousing and Engineering). 1441

WHO/BS/10.2155 2.2 Provide CVs for heads of production, quality assurance and quality control 1442 indicating educational and experience qualifications. 1443 2.3 Outline arrangements for basic and continuing training and how records are 1444 maintained. 1445 2.4 Describe requirements for personnel engaged in production, particularly relating 1446 to requirements for monitoring of health status (including immune status) for 1447 production personnel, and outside contract service personnel entering the 1448 manufacturing areas. 1449 1450 Chapter 3: Premises and equipment 1451 These will be examined in depth during the site audit. However, the following 1452 preliminary information shall be submitted: 1453 3.1 Provide simple, currently valid, floor plans and text description of manufacturing 1454 and QC areas. The floor plans should give an indication of scale, air flow and flows 1455 of materials, product, personnel and waste (architectural or engineering drawing are 1456 not required), room classification, air handling unit (AHU) identification by room. 1457 3.2 Describe the nature of construction and finishes, of manufacturing and QC areas. 1458 3.3 Describe ventilation systems in the manufacturing and QC areas. More details 1459 should be given for critical areas with potential risks of airborne contamination 1460 (schematic drawings of the systems are desirable). Classification of the clean rooms 1461 used for the manufacture of sterile products should be included. 1462 Description of the environmental monitoring programme is required. 1463 3.4 Provide information on special areas for the handling of highly toxic, hazardous 1464 and sensitizing materials. 1465 3.5 Describe water systems (schematic drawings of the systems are desirable showing 1466 storage tanks, loops, points of use, and sampling points) including sanitation 1467 procedures and schedules. Description of QC testing and schedules is required. 1468 3.6 Describe the maintenance system (description of planned preventive maintenance 1469 programmes and recording system). 1470 3.7 Complete a table, briefly describing major production and control laboratory 1471 equipment used for the production of the vaccine (including diluent). 1472 1473 1474 Room ID Major equipment in room Clean room class 1475 3.8 For products where a separate facility is required (e.g. tetanus, BCG), describe 1476 how separation is achieved. 1477 3.9 Describe qualification and validation procedures, including computerized 1478 recording and controller systems. Description of the validation master plan is 1479 required. 1480 3.10 Provide a brief description of the procedures for cleaning manufacturing areas 1481 and equipment, and for multipurpose areas, the system for cleaning and testing 1482 between campaigns. 1483 1484 Chapter 4: Vaccine composition, presentations and schedules 1485 4.1 State the composition of the product (including diluents). 1486 4.2 Describe the presentations made available to UN agencies, including diluents (if 1487 applicable), combination products, forms, dose sizes, type of containers, VVM type 1488

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used and descriptions of application devices (e.g. auto disable syringes) to be 1489 delivered with the vaccine, if applicable. 1490 4.3 Give the recommended schedule and route of administration. 1491 4.4 For both the final product and diluent, provide samples of primary container, 1492 labels, boxes and package inserts to be used for UN agency supply (in English). 1493 French, Spanish, Russian and Portuguese versions need to be made available before 1494 supply to UN agencies starts. Include the calculated volume per dose in cm3 of the 1495 secondary packaging. 1496 4.5 Include a sample of the lot-summary protocol to be provided to UN agencies (to 1497 follow the WHO-recommended format). 1498 1499 Chapter 5: Production8 1500 5.1 Provide the manufacturing formulae: 1501 a) for the production of each antigen in the vaccine (i.e. fermenter or culture volumes 1502 for each bulk batch size as applicable and typical bulk volumes per production run); 1503 b) the batching formula for each batch size of final formulated bulk product; 1504 c) the approximate number of vials and doses for each fill size and presentation; 1505 d) the lot numbering system for intermediates and final products. 1506 5.2 Provide a description of the manufacturing processes and the characterization of 1507 the product. This should include history or the master cell banks/virus seeds. 1508 Detailed flow charts should be provided to indicate: 1509 a) each manufacturing step; 1510 b) location (building/room) of each step, and transfers to other building/ sites, if 1511 applicable; 1512 c) in-process and quality control tests performed on all intermediates and final 1513 products; 1514 d) identification of any processes or tests performed by contract manufacturers or 1515 testers; 1516 e) storage times and temperatures of intermediates. 1517 For recombinant vaccines, a description of the construction and characterization of the 1518 recombinant vector as well as source of master cell bank/constructs shall be provided. 1519 Include details of the manufacture and QC of any adjuvant and diluents. 1520 5.3 Describe general policy for process validation. List process validation activities 1521 performed. 1522 5.4 Summarize arrangements for the handling of starting materials, packaging 1523 materials, bulk and finished products, including sampling, quarantine, release and 1524 storage. 1525 5.5 Summarize arrangements for the handling of rejected materials and products, and 1526 procedures for their destruction. 1527 1528 Chapter 6: Quality control 1529 6.1 Starting materials 1530 6.1.1 List control tests performed on raw materials, with appropriate characterization 1531 of starting materials: 1532 a) list of raw materials meeting compendia specifications, indicating the 1533 pharmacopoeia; 1534

8WHO recommendations or guidelines and UN agencies tender specifications must be met. For each specific test done the international standard met should be identified.

WHO/BS/10.2155 b) list of raw materials meeting in-house specifications including the tests performed 1535 and specifications; 1536 c) list of biological starting materials (human or animal origin) with information on 1537 the requirements to avoid risk of transmissible spongiform encephalopathies (TSEs) 1538 and human diseases (HIV, hepatitis, etc) in the final product; 1539 d) list of media with ingredients, tests performed and specifications. 1540 6.1.2 List control tests performed on labelling and packaging material(s), including 1541 primary and secondary packaging material. 1542 6.1.3 Describe qualification criteria for suppliers of raw material and relevant 1543 certificates. 1544 6.2 Intermediate products (as appropriate) 1545 6.2.1 List routine tests performed and specifications for intermediates. Include copies 1546 of standard operational procedures (SOPs) for critical QC tests (uncontrolled copies or 1547 concise description of the method and retest criteria are acceptable). 1548 6.2.2 List assay validation activities performed. 1549 6.3 Finished product (including diluent) 1550 6.3.1 List routine tests performed and specifications for final product. Concise 1551 description of the method and re-test criteria are acceptable but full SOPs in English 1552 should be made available on request. 1553 6.3.2 List assay validation activities performed. 1554 6.3.3 List final lots internally rejected in the previous two years and reasons for 1555 rejection. 1556 1557 Chapter 7: Stability 1558 Stability studies are expected to have been designed and conducted to meet WHO 1559 guidance WHO/BS/06.2049 Guideline on stability evaluation of vaccines or any 1560 update. 1561 http://www.who.int/biologicals/publications/trs/areas/vaccines/stability/en/ 1562 7.1 Provide information on stability tests on intermediates: 1563 a) information on containers for intermediate products; 1564 b) assigned shelf-life and storage conditions; 1565 c) QC methods and specifications, and rationale for the choice of tests for determining 1566 stability; 1567 d) identification of the dates of manufacture of the lots, the lot numbers, the vial and 1568 dose size, and the scale of production; 1569 Results of quantitative assays must be expressed as a numerical value with the 1570 appropriate limits and not as “pass” or “fail”. 1571 7.2 For each presentation provide information on stability testing of the finished 1572 product: 1573 a) assigned shelf-life and storage conditions; 1574 b) QC methods and specifications and rationale for the choice of tests for determining 1575 stability profile; 1576 c) identification of the dates of manufacture of the lots, the lot numbers, the vial and 1577 dose size, and the scale of production. 1578 Results of quantitative assays must be expressed as a numerical value with the 1579 appropriate limits and not as “pass” or “fail”. 1580 In addition to final product stability data at the recommended storage temperature, the 1581 accelerated stability data at elevated temperatures should be sufficient to justify the 1582

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choice of VVM for use with the product. [Vaccine Vial Monitor 1583 WHO/PQS/E06/IN05.1]. 1584 7.3 Provide information on stability testing of diluents and reconstituted vaccine in 1585 case of lyophilized vaccines. 1586 7.4 Describe the policy for assigning the date of manufacture of each component as 1587 well as the final product (e.g. combination vaccine) and diluents, as appropriate. 1588 1589 Chapter 8: Clinical experience 1590 Note 1: Clinical studies are expected to have been designed and conducted to meet 1591 WHO and international GCP principles. Applicants should consult the following 1592 three documents or any update in the WHO Technical Report Series (TRS): 1593 1) WHO TRS 924 (2004). Annex 1: WHO guidelines on clinical evaluation of 1594 vaccines: Regulatory expectations. 1595 2) WHO TRS 927 (2005) Annex 1: WHO guidelines on non-clinical evaluation of 1596 vaccines. 1597 3) WHO TRS 850 (1995). Annex 3: Guidelines for good clinical practice (GCP) for 1598 trials on pharmaceutical products. 1599 Other guidance documents: 1600 Points to consider for applicants - Clinical Considerations for Evaluation of vaccines 1601 for Prequalification 1602 http://www.who.int/immunization_standards/vaccine_quality/pq_vaccine_evaluation/1603 en/index.html 1604 International Conference on Harmonization (ICH) guidelines. 1605 Note 2: For vaccines whose licence was originally obtained many years before the 1606 application for WHO prequalification, it is possible that many or all of the clinical 1607 trials may not have been conducted or monitored to current international standards. 1608 For these vaccines all sections should be completed but additional emphasis should be 1609 given to information provided in sections 8.2.1, 8.2.5, 8.3.1 and 8.3.2 in order to 1610 sufficiently establish a history of safe and effective use. 1611 Note 3: In some cases, where the information received regarding the sections detailed 1612 below is not enough or not clear enough, or requires further scrutiny, WHO may 1613 request the applicant to submit the raw data. 1614 8.1 The applicant should provide a tabulated summary of the clinical development 1615 programme, in one or more tables, in which critical parameters that may have changed 1616 during the clinical development should be mentioned 1617 8.2 Clinical trials information 1618 8.2.1 Overview of clinical trials sponsored by the applicant 1619 The sponsor should provide a list of all clinical trials performed in all countries that 1620 are relevant to the application for WHO prequalification. These should include all 1621 studies sponsored by the applicant both before and at any time after initial licensure, 1622 whether or not submitted previously 1623 to the NRA(s) where the product is licensed. For each study on the list, the following 1624 information is required: 1625 • Final approved protocol, which should indicate date of protocol approval by the 1626

Ethics Committee and the NRA. 1627 • Evidence for registration in a clinical trial registry that is included in the WHO 1628

International Clinical Trials Registry platform. 1629 • Indication of whether the study complied with GCP. 1630 • For each such study, provide in a tabulation or a brief summary, the following 1631

information: 1632

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• the type of study 1633 • the rationale for its conduct 1634 • the location(s) of study sites 1635 • the dates of the study 1636 • numbers and ages of subjects 1637 • statement of final conclusions on safety and immunogenicity 1638

Copies of all publications and abstracts about these trials should accompany the 1639 submission in section 8.2.1. 1640 In addition, the applicant should list any trials that are known to be currently ongoing 1641 with summary of details of the study plan and expected date of results. 1642 8.2.2 Other studies with the applicant’s product 1643 The applicant should make every effort to provide a list of all trials and, when 1644 applicable, observational studies, relevant to the application that were not sponsored 1645 by the applicant but in which the product was evaluated. 1646 This list should be compiled from publications identified using an extensive literature 1647 search (details of which should be provided) and, in the case of co-licensure 1648 agreements, from any other company that holds a licence for or a right to market the 1649 same product. 1650 8.2.3 Clinical summary 1651 Provide a detailed summary and interpretation of the safety and efficacy data obtained 1652 from the pre-licensure clinical studies and all studies performed in the post-licensure 1653 period that support the current prescribing information. The summary should pay 1654 particular attention to any data that are relevant to the use of the product worldwide in 1655 WHO recommended schedules, for instance co-administration of other vaccines. In 1656 the absence of such data, the summary should provide a preclinical and/or clinical 1657 justification for the extrapolation of the existing data to the likely circumstances of 1658 use after prequalification, should the vaccine be prequalified. This summary should 1659 complement, and not replace, the summary written by an independent clinical expert 1660 described in 8.2.5. 1661 8.2.4 Assessment reports (AR) 1662 Whenever possible the applicant should provide the clinical sections of the NRA 1663 assessment reports from the country of origin and/or country where initially licensed. 1664 Assessment reports for both initial licensure and for any subsequent variations to the 1665 licence for changes relevant to clinical data are requested. 1666 1667 8.2.5 Clinical expert report 1668 Provide an independent clinical expert report on the clinical studies (evidence of 1669 expertise and independence should be provided). If the application for 1670 prequalification is based on the extrapolation of the existing clinical data to the likely 1671 circumstances of use after prequalification and if the data are old or there is a doubt 1672 regarding the ethical or regulatory oversight of the trial, the report should discuss the 1673 degree of compliance with WHO GCP recommendations and current guidance 1674 regarding preclinical and clinical trials with vaccines. 1675 8.2.6 Preclinical studies sponsored by the applicant 1676 Provide a simple list of all preclinical studies that were sponsored by the applicant in 1677 support of use in clinical trials in humans, or for significant changes to manufacture or 1678 use. Include in the list any important conclusions. For preclinical studies performed 1679 after initial licensure, indicate the reasons for these studies. Any other particularly 1680

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relevant reports regarding safety aspects, whether or not generated by the applicant, 1681 should be provided. 1682 8.3 Documentation of safety 1683 Safety data should be submitted both in the case of the initial application for 1684 prequalification evaluation and for reassessment purposes. 1685 8.3.1 Provide an outline of the post marketing pharmacovigilance plan for the product 1686 8.3.2 Initial evaluation of vaccines that have been in the market for a long time or 1687 reassessment of already prequalified vaccines. 1688 Provide an outline of the applicant’s procedures for the collection, onward notification 1689 and assessment of adverse events. 1690 Provide a listing of all reported AEFIs for the vaccine in question in the last five years 1691 or since the last WHO reassessment. As far as is possible from the reports received, 1692 applicants should list the type of reaction, lot number, date and place of immunization, 1693 patients’ initials and age and, for immunization series, the dose number. A judgment 1694 of seriousness and whether or not the event was expected (in the light of the 1695 prescribing information) should be provided where this was possible from the 1696 information. An assessment of the relationship to the vaccine made by a clinician and, 1697 where relevant, by the applicant company, or its independent clinical expert, should 1698 be included. 1699 Whenever periodic safety updated reports (PSURs) are available, these shall be 1700 submitted. The PSURs should include information from all geographical areas where 1701 the vaccine is used or the absence of such information defended and should follow the 1702 ICH format. 1703 8.3.3 Recently licensed vaccines 1704 In the case of vaccines that have been recently licensed, provide information on any 1705 ongoing phase IV studies or on any active monitoring of the safety profile that is 1706 taking place. 1707 8.3.4 Documentation of serious adverse events 1708 For serious adverse events reported in the last five years, or as long as the vaccine has 1709 been marketed (when shorter than five years), provide fullest possible description of 1710 each case, including any information there may be on investigations, actions, patient 1711 treatment and outcome. This information shall be provided as part of the PSUR. 1712 1713 1714 Chapter 9: Production and distribution data 1715 9.1 Provide information on the quantity of finished product distributed domestically 1716 and exported in the previous three years. List the different presentations separately, 1717 and indicate whether the list gives the numbers of vials or the numbers of doses 1718 distributed. When the product is a combination vaccine, information should also be 1719 provided on the history of distribution of component vaccine(s), when applicable. 1720 9.2 Provide a list of countries where the product is licensed (marketing authorization) 1721 and supplied. 1722 9.3 Summarize the arrangements and recording system for distribution, including the 1723 release process performed by the manufacturer and the NRA. 1724 9.4 Summarize the packaging procedures for international shipments (including box 1725 sizes, packing volumes, etc.). Provide the validation protocols and reports of the 1726 shipping boxes used for UN supply. Recommendations provided in the most recent 1727 version of the WHO Guidelines on the international packaging and shipping of 1728 vaccines shall be followed. 1729

WHO/BS/10.2155 9.5 Describe the arrangements for handling complaints and product recalls. Include 1730 description of the recall investigation system, procedures for corrective actions, and 1731 description of regulatory requirements in case of recalls. Include provisions to inform 1732 WHO/UN. 1733 9.6 Give the quantity of bulk vaccine destined for UN agencies, supplied to contract 1734 fillers/packagers for finalization (list individually). 1735 1736 Chapter 10: Update of regulatory actions 1737 10.1 Provide a copy of regulatory documentation: 1738 a) marketing authorizations for all formulations; 1739 b) information on refusals, withdrawals, or suspensions including those 1740 that are manufacturer initiated; 1741 c) GMP certificate or equivalent. 1742 10.2 Provide a list of lots rejected by the NRA, if applicable. 1743 10.3 Describe restrictions on distribution or recalls, including manufacturer-initiated 1744 recalls. 1745 10.4 Name clinical trial suspensions, including manufacturer-initiated suspensions. 1746 10.5 Describe dosage or schedule modifications since initial licensure granted. 1747 10.6 Provide information on changes in target populations or indications since initial 1748 licensure granted. 1749 10.7 List inspections conducted by NRAs within the previous two years, including the 1750 scope of each inspection. 1751 10.8 List inspections conducted by foreign authorities within the previous two years, 1752 including the scope of each inspection. 1753 1754

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Appendix 2 Testing approach for initial evaluation for PQ 1755 1756 Table 1: 1757

Category Criteria WHO requirements/testing approach Requirements from the manufacturer before PQ is granted

Requirements post PQ

I Novel vaccine or new combination released by a competent NRA/NCL responsible for the regulatory oversight. NCL is performing the critical tests on a regular basis

• Review of UN tender aspects through samples of the vaccine in the final packaging presentation (to be submitted with the PSF)

• Review of the testing results by the manufacturer and the NCL (raw data) of minimum 3 lots formulated from consecutive bulk lots

• Review of the trends of the testing results of both NCL and manufacturer (if applicable)

• Review the control chart of the reference used in manufacturer's and NCL's assays.

• Review of the method validation of manufacturer and NCL may be required

• Detailed SOP for testing the product characteristics (relevant tests)

• Biological reagents and reference materials for the validation of the tests by WHO contracted laboratories

• Transfer of the relevant method by the manufacturer to the relevant laboratories through WHO

II Novel vaccine released by a competent NRA/NCL responsible for the regulatory oversight Validation of the critical tests is in progress.


• Review of the testing results by the manufacturer (raw data) of minimum 3 lots formulated from consecutive bulk lots

• Review of the trends of the testing results of the manufacturer (if applicable)

• Agreement with the NCL to validate the tests during the PQ evaluation

• Review of the method validation of manufacturer and the control chart of the reference used in manufacturer's assays may be required

• Agreement to perform and provide results to WHO before PQ is granted



• Transfer of the relevant method by the manufacturer to the relevant laboratories through WHO

• Commitment from the manufacturer to keep retention samples for testing by WHO contracted laboratories

• Testing of the vaccine through the targeted testing programme

1758 1759

WHO/BS/10.2155 Table 1(continued): 1760 1761

Category Criteria WHO requirements/testing approach Requirements from the manufacturer before PQ is granted

Requirements post_PQ

III Traditional vaccine released by a competent NRA/NCL responsible for the regulatory oversight. NCL is performing the critical tests on a regular basis


• Review of the testing results by the manufacturer and the NCL (raw data) of minimum 3 lots formulated from consecutive bulk lots

• Review of the trends of the testing results of both NCL and manufacturer

• Review the control chart of the reference used in manufacturer’s and NCL’s assays


• Biological reagents and reference materials for the tests by WHO contracted laboratories

IV Novel or traditional vaccine NRA/NCL responsible for the regulatory oversight does not perform the critical tests


• Testing by WHO contracted laboratories before the PQ is granted

• Agreement with the NCL to validate the tests • Review of the testing results by the manufacturer

(raw data) of minimum 3 lots formulated from consecutive bulks lots

• Review the control chart of the reference used in manufacturer’s assays

• For novel vaccines, review of the method validation of manufacturer



• Transfer of the relevant method (if applicable) by the manufacturer to the relevant laboratories through WHO

• Commitment from the manufacturer to keep retention samples for testing by WHO contracted laboratories

• Testing of the vaccine through the targeted testing programme

1762

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Appendix 3 Prequalification procedure for vaccines evaluated by 1763 EMA under Article 58 of Regulation (EC) No 726/2004 1764 1765 Background 1766 WHO provides a service to UNICEF and other UN agencies that purchase vaccines, to determine 1767 the acceptability in principle of vaccines from different sources for supply to these agencies. 1768 1769 The purpose of the prequalification assessment is to verify that the vaccines meet the 1770 specifications of the relevant UN agency, and are produced and overseen in accordance with the 1771 principles and specifications recommended by WHO for good manufacturing practice (GMP), 1772 and for good clinical practice (GCP). This is to ensure that vaccines used in national 1773 immunization services in different countries are safe and effective for the target population at the 1774 recommended schedules, and that they meet particular operational specifications for packaging 1775 and presentation. 1776 1777 For vaccines (and all medicines) manufactured by European manufacturers (or at least with a 1778 legal presence in the European Community) intended for exclusive use in markets outside the 1779 European Community, EMA established a mechanism (Article 58 of Regulation (EC) No 1780 726/2004 ) whereby the European Medicines Agency (EMA) may give a scientific opinion, in 1781 the context of cooperation with the World Health Organization (WHO). 1782 WHO recognizes that the evaluation by EMA under “Article 58” is done according to the 1783 principles applied by the prequalification process, in terms of assurance of quality, safety and 1784 efficacy for the intended population (i.e. developing countries). WHO provides input at different 1785 stages of the process, including the determination of eligibility of the product for evaluation 1786 under Article 58 and involvement in the assessment of the dossier. 1787 Therefore, in order to align the EMA evaluation under Article 58 and the WHO evaluation for 1788 prequalification purposes, a simplified procedure has been developed. 1789 1790 Application process to WHO/QSS 1791 The applicant must submit the following: 1792 1) An application letter is to be sent to the Coordinator, Quality, Safety and Standards, 1793 Department of Immunization, Vaccines and Biologicals (WHO/IVB/QSS) with a 1794 copy to the vaccines prequalification manager and EMA, with details of country and sites of 1795 manufacture and presentations offered. 1796 1797 Note: Application letters can be sent at any time after the submission of the dossier to 1798 EMA .Manufacturers are encouraged to advise WHO as early as possible of their intention to 1799 submit a specific vaccine application to facilitate planning. 1800 2) A statement that the applicant acknowledges and agrees to the fact that EMA will share with 1801 WHO the report of the CHMP evaluators, inspection reports (manufacturing facilities and 1802 clinical trial sites), and test results if available with the WHO Prequalification team , as well as 1803 mutual immediate notification of quality or safety concerns of the product. 1804 3) Electronic copy of the dossier submitted to EMA for evaluation under “Article 58”. 1805 4) Technical information relevant to UN specifications, including information relevant to the 1806 programmatic suitability of the vaccine. 1807 5) Notification about the OMCL laboratory selected for any testing required by EMA for 1808 evaluation under article 58 or for prequalification by WHO/QSS. 1809 6) Fees (see section 14) 1810 1811

WHO/BS/10.2155 The evaluation process 1812 WHO will base the evaluation on the following: 1813 a) EMA “Art. 58” Scientific Opinion and its annexed Assessment report from EMA/CHMP 1814 b) Certificate of analysis of consistency lots by a qualified (OMCL) laboratory 1815 c) Reports from relevant inspections (GMP, GLP and GCP) jointly agreed upon between 1816 WHO/QSS and EMA and performed during the EMA/ CHMP “Article 58” Scientific Opinion 1817 evaluation procedure. 1818 1819 Although the EMA/CHMP procedure under Article 58 of Regulation (EC) No 726/2004, is done 1820 by rapporteur/co-rapporteur in collaboration with WHO/QSS and its experts/expert groups and 1821 the evaluation ensuring that the clinical data provided by the applicant is relevant to the UN 1822 target population at the intended schedules, other programmatic aspects reflected in the tender 1823 specifications of the UN purchasing agencies will not be part of the review process under 1824 “Article 58” evaluation and will therefore remain to be reviewed by WHO during the 1825 streamlined prequalification evaluation. 1826 1827 In view of the above, a review by WHO of the aspects listed below would remain essential: 1828 1829

a) Confirmation that the vaccine meets the WHO recommendations and UN tender 1830 specifications; 1831

b) Review of stability data to ensure it meets the needs of immunization programmes in 1832 developing countries (particularly those with weak cold chain systems) and to assign a 1833 VVM category; 1834

c) Review of recommended immunization schedules to ensure compatibility with those 1835 existing in national immunization programmes and non interference with co-administered 1836 vaccines; 1837

d) Review of samples, labels, inserts and packaging to suit the UN Agency tender 1838 requirements; 1839

e) Review of mandatory, critical and innovative product characteristics from the 1840 programmatic point of view; 1841

f) Review of packaging for international shipment and its validation; 1842 g) If applicable, recommendation that the vaccine would be eligible for the AMC through 1843

review of the proposed product characteristics against the target product profile criteria. 1844

Note: items b, c, d, and e are expected to be included in the EMA/CHMP evaluation done in 1845 collaboration with WHO under Article 58 of Regulation (EC) No 726/2004. If such assessment 1846 and supportive data are available, the applicant should state so and indicate specifically where 1847 this have been addressed in EMA/CHMP Art. 58 Scientific Opinion documents. 1848 1849 Report and outcome of the assessment 1850 Once WHO considers that the process is complete, and if the outcome is satisfactory, 1851 WHO sends a letter to UNICEF and other UN agencies, advising on the compliance 1852 of the vaccine with both the WHO recommendations and the specifications of the relevant UN 1853 agency. The vaccine will then be included in the WHO list of prequalified vaccines immediately 1854 after the letter to United nations agencies is sent. The current list may be consulted at: 1855 http://www.who.int/immunization_standards/vaccine_quality/pq_suppliers/en/index.html 1856 1857 The prequalified status of a vaccine is valid until revoked by WHO. 1858 1859 1860

WHO/BS/10.2155

Assurance of continued acceptability 1861 After the prequalification of the product has been granted, follow up activities to ensure 1862 continued acceptability of the vaccine for supply through UN agencies will be performed 1863 according to the general prequalification procedure, as follows: 1864

reassessments 1865 evaluation of variations submitted by the applicant 1866 targeted testing of lots supplied to UN agencies 1867 monitoring of continued compliance with specifications 1868 follow up of complaints and reports of adverse events following immunization 1869

(AEFIs). 1870

The above list is indicative but not exhaustive. 1871 1872 Failure from manufacturers to submit variations through EMA may lead to withdrawal of the 1873 scientific opinion and the prequalification status. 1874 1875 Note: These activities will be done, whenever applicable, in collaboration with EMA within the 1876 context/basis of Article 58 of Regulation (EC) No 726/2004. 1877

1878

WHO/BS/10.2155 Appendix 4 Confidentiality agreement 1878 Provisions for team members participating in WHO missions to assess/ 1879 reassess the acceptability, in principle, of vaccines for purchase by United 1880 Nations agencies 1881 1882 In the course of discharging your functions as an expert adviser under this Agreement, 1883 you will gain access to certain information, which is proprietary to WHO or to the 1884 manufacturer(s) of the vaccine(s) which need(s) to be assessed for purchase by 1885 UN agencies. You undertake to treat such information (hereinafter referred to as 1886 “the Information”) as confidential and proprietary to WHO or the aforesaid 1887 manufacturer(s). In this connection, you agree to: 1888 1889 1) not use the Information for any other purpose than discharging your obligations 1890 under this agreement; and 1891 2) not disclose or provide the Information to any person who is not bound by 1892 similar obligations of confidentiality and non-use as contained herein. 1893 1894 However, you will not be bound by any obligations of confidentiality and non-use to 1895 the extent that you are clearly able to demonstrate that any part of the Information: 1896 1897 1) was known to you prior to any disclosure by WHO and/or the manufacturer(s); 1898 or 1899 2) was in the public domain at the time of disclosure by WHO and/or the 1900 manufacturer(s); or 1901 3) has become part of the public domain through no fault of your own; or 1902 4) has become available to you from a third party not in breach of any legal 1903 obligations of confidentiality to WHO and/or the manufacturer(s). 1904 1905 You also undertake not to communicate the deliberations and findings of the team(s) 1906 of experts in which you will participate, as well as any resulting recommendations 1907 and/or decisions of WHO, to any third party, except as explicitly agreed by WHO. 1908 1909 You will discharge your responsibilities hereunder exclusively in your capacity as an 1910 expert adviser to WHO. By signing this Agreement, you furthermore confirm that 1911 you have no financial interest and/or other relationship with a party, which: 1912 1913 1) may have a vested commercial interest in obtaining access to any part of the 1914 Information referred to above; and/or 1915 2) may have a vested interest in the outcome of the assessment of the vaccine(s), 1916 in which you will participate, including but not limited to parties, such as the 1917 manufacturer(s) of the vaccine(s) that is (are) being assessed or manufacturers 1918 of competing vaccines. 1919 1920 In this regard, it should be noted that the manufacturer(s) of the vaccine(s) under 1921 evaluation have the right to object to your participation in the team(s) of experts 1922 which will evaluate (its) (their) vaccine(s). If such objection cannot be resolved in 1923 consultation with the manufacturer(s), WHO shall be entitled to terminate this 1924 Agreement or cancel part of the activities to be undertaken by you hereunder. 1925 The travel and per diem allowances payable to you under this Agreement will in 1926 such event be adjusted accordingly. 1927

WHO/BS/10.2155

1928 I hereby agree to the conditions and provisions contained in this document. 1929 1930 Signed: _________________________________________________ 1931 Name (typewritten): ______________________________________ 1932 Institute: _______________________________________________ 1933 Place: __________________________________________________ 1934 Date: __________________________________________________ 1935 1936

1937

WHO/BS/10.2155 Appendix 5 Declaration of interests for WHO experts 1937

WHO's work on global health issues requires the assistance of external experts who may 1938 have interests related to their expertise. To ensure the highest integrity and public confidence 1939 in its activities, WHO requires that experts serving in an advisory role disclose any 1940 circumstances that could give rise to a potential conflict of interest related to the subject of the 1941 activity in which they will be involved. 1942

All experts serving in an advisory role must disclose any circumstances that could 1943 represent a potential conflict of interest (i.e., any interest that may affect, or may reasonably be 1944 perceived to affect, the expert's objectivity and independence). You must disclose on this 1945 Declaration of Interest (DOI) form any financial, professional or other interest relevant to the 1946 subject of the work or meeting in which you have been asked to participate in or contribute 1947 towards and any interest that could be affected by the outcome of the meeting or work. You 1948 must also declare relevant interests of your immediate family members (see definition below) 1949 and, if you are aware of it, relevant interests of other parties with whom you have substantial 1950 common interests and which may be perceived as unduly influencing your judgement (e.g. 1951 employer, close professional associates, administrative unit or department). 1952

Please complete this form and submit it to WHO Secretariat if possible at least 4 weeks 1953 but no later than 2 weeks before the meeting or work. You must also promptly inform the 1954 Secretariat if there is any change in this information prior to, or during the course of, the meeting 1955 or work. All experts must complete this form before participation in a WHO activity can be 1956 confirmed. 1957

Answering "Yes" to a question on this form does not automatically disqualify you or 1958 limit your participation in a WHO activity. Your answers will be reviewed by the Secretariat to 1959 determine whether you have a conflict of interest relevant to the subject at hand. One of the 1960 outcomes listed in the next paragraph can occur depending on the circumstances (e.g, nature and 1961 magnitude of the interest, timeframe and duration of the interest). 1962

The Secretariat may conclude that no potential conflict exists or that the interest is 1963 irrelevant or insignificant. If, however, a declared interest is determined to be potentially or 1964 clearly significant, one or more of the following three measures for managing the conflict of 1965 interest may be applied. The Secretariat (i) allows full participation, with public disclosure of 1966 your interest; (ii) mandates partial exclusion (i.e., you will be excluded from that portion of the 1967 meeting or work related to the declared interest and from the corresponding decision making 1968 process); or (iii) mandates total exclusion (i.e., you will not be able to participate in any part of 1969 the meeting or work). 1970

All potentially significant interests will be disclosed to the other participants at the start 1971 of the activity and you will be asked if there have been any changes. A summary of all 1972 declarations and actions taken to manage any declared interests will be published in resulting 1973 reports and work products. Furthermore, if the objectivity of the work or meeting in which you 1974 are involved is subsequently questioned, the contents of your DOI form may be made available 1975 by the Secretariat to persons outside WHO if the Director-General considers such disclosure to 1976 be in the best interest of the Organization, after consulting with you. Completing this DOI form 1977 means that you agree to these conditions. 1978

If you are unable or unwilling to disclose the details of an interest that may pose a real or 1979 perceived conflict, you must disclose that a conflict of interest may exist and the Secretariat may 1980

WHO/BS/10.2155

decide that you be totally recused from the meeting or work concerned, after consulting with you. 1981

Name:________________________________________ 1982 Institution: ____________________________________ 1983 Email:________________________________________ 1984 Date and title of meeting or work, including description of subject matter to be considered 1985 (if a number of substances or processes are to be evaluated, a list should be attached by the 1986 organizer of the activity): 1987

_____________________________________________________________________________1988 ___________________________________________________________________ 1989

1990

Please answer each of the questions below. If the answer to any of the questions is "yes", briefly 1991 describe the circumstances on the last page of the form. 1992

The term "you" refers to yourself and your immediate family members (i.e., spouse (or partner 1993 with whom you have a similar close personal relationship) and your children). "Commercial entity" 1994 includes any commercial business, an industry association, research institution or other enterprise whose 1995 funding is significantly derived from commercial sources with an interest related to the subject of the 1996 meeting or work. "Organization" includes a governmental, international or non-profit organization. 1997 "Meeting" includes a series or cycle of meetings. 1998 1999 EMPLOYMENT AND CONSULTING 2000 Within the past 4 years, have you received remuneration from a commercial entity or other 2001 organization with an interest related to the subject of the meeting or work? 2002

1a Employment Yes/No 2003 1b Consulting, including service as a technical or other advisor Yes/No 2004 2005 RESEARCH SUPPORT 2006 Within the past 4 years, have you or has your research unit received support from a 2007 commercial entity or other organization with an interest related to the subject of the 2008 meeting or work? 2009 2010 2a Research support, including grants, collaborations, sponsorships, and other funding Yes/No 2011 2b Non-monetary support valued at more than US $1000 overall (include equipment, 2012

facilities, research assistants, paid travel to meetings, etc. Support (including honoraria) for being on a 2013 speakers bureau, giving speeches or training for a commercial entity or other organization with an 2014 interest related to the subject of the meeting or work? Yes/No 2015

2016 INVESTMENT INTERESTS 2017 Do you have current investments (valued at more than US $10 000 overall) in a 2018 commercial entity with an interest related to the subject of the meeting or work? Please 2019 also include indirect investments such as a trust or holding company. You may 2020 exclude mutual funds, pension funds or similar investments that are broadly diversified 2021 and on which you exercise no control. 2022 2023 3a Stocks, bonds, stock options, other securities (e.g., short sales) Yes/No 2024 3b Commercial business interests (e.g., proprietorships, partnerships, joint ventures, board memberships, 2025

WHO/BS/10.2155

controlling interest in a company) Yes/No 2026

2027 INTELLECTUAL PROPERTY 2028 Do you have any intellectual property rights that might be enhanced or diminished by the outcome of 2029 the meeting or work? 2030 2031 4a Patents, trademarks, or copyrights (including pending applications) Yes/No 2032 4b Proprietary know-how in a substance, technology or process Yes/No 2033 2034 PUBLIC STATEMENTS AND POSITIONS (during the past 3 years) 2035 2036 5a As part of a regulatory, legislative or judicial process, have you provided an expert opinion or 2037

testimony, related to the subject of the meeting or work, for a commercial entity or other organization? 2038 Yes/No 2039

5b Have you held an office or other position, paid or unpaid, where you represented interests or defended 2040 a position related to the subject of the meeting or work? Yes/No 2041

2042 ADDITIONAL INFORMATION 2043 2044 6a If not already disclosed above, have you worked for the competitor of a product that is the subject of 2045

the meeting or work, or will your participation in the meeting or work enable you to obtain access to a 2046 competitor's confidential proprietary information, or create for you a personal, professional, financial 2047 or business competitive advantage? Yes/No 2048

6b To your knowledge, would the outcome of the meeting or work benefit or adversely affect interests of 2049 others with whom you have substantial common personal, professional, financial or business interests 2050 (such as your adult children or siblings, close professional colleagues, administrative unit or 2051 department)? Yes/No 2052

6c Excluding WHO, has any person or entity paid or contributed towards your travel costs in connection 2053 with this WHO meeting or work? Yes/No 2054

6d Have your received any payments (other then for travel costs) or honoraria for speaking publicly on 2055 the subject of this WHO meeting or work? Yes/No 2056

6e Is there any other aspect of your background or present circumstances not addressed above that might 2057 be perceived as affecting your objectivity or independence? Yes/No 2058

2059 7. TOBACCO OR TOBACCO PRODUCTS (answer without regard to relevance to the 2060

subject of the meeting or work) 2061 2062 Within the past 4 years, have you had employment or received research support or other 2063 funding from, or had any other professional relationship with, an entity directly involved 2064 in the production, manufacture, distribution or sale of tobacco or tobacco products or 2065 representing the interests of any such entity? Yes/No 2066

EXPLANATION OF "YES" RESPONSES: If the answer to any of the above 2067 questions is "yes", check above and briefly describe the circumstances on this page. If you 2068 do not describe the nature of an interest or if you do not provide the amount or value 2069 involved where relevant, the conflict will be assumed to be significant. 2070

Nos. 1 -4: 7 Type of interest, question number and category (e.g., Intellectual Property 4.a copyrights) and basic descriptive details.

Name of company, organization, or institution

Belongs to you, a family member, employer, research unit or other?

Amount of income or value of interest (if not disclosed, is assumed to be significant)

Current interest (or year ceased)

WHO/BS/10.2155

2071 CONSENT TO DISCLOSURE. By completing and signing this form, you consent to the 2072 disclosure of any relevant conflicts to other meeting participants and in the resulting report or 2073 work product 2074 2075

DECLARATION. I hereby declare on my honour that the disclosed information is 2076 true and complete to the best of my knowledge. 2077

Should there be any change to the above information, I will promptly notify the 2078 responsible staff of WHO and complete a new declaration of interest form that describes 2079 the changes. This includes any change that occurs before or during the meeting or work 2080 itself and through the period up to the publication of the final results or completion of the 2081 activity concerned. 2082

Date: ________________ Signature________________________________ 2083 2084

2085

EXPERT COMMITTEE ON BIOLOGICAL STANDARDIZATION … · 133 Fund (UNICEF) and other United Nations...

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