PHARMACEUTICAL DEVELOPMENT OF MULTISOURCE (GENERIC) FINISHED PHARMACEUTICAL … · 134 biotechnological origin are covered by other guidelines. 135 1 WHO draft on Quality risk management

Working document QAS/08.251/Rev.3 May 2011 RESTRICTED

1 2

PHARMACEUTICAL DEVELOPMENT OF 3

MULTISOURCE (GENERIC) FINISHED PHARMACEUTICAL 4

PRODUCTS 5

– POINTS TO CONSIDER 6

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8 9 10 11 12 13 14 15 16 17 18 19 20 21

© World Health Organization 2011 22 23 All rights reserved. 24 25 This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The draft 26 may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in any 27 form or by any means outside these individuals and organizations (including the organizations' concerned staff and member 28 organizations) without the permission of the World Health Organization. The draft should not be displayed on any web site. 29 30 Please send any request for permission to: 31 Dr Sabine Kopp, Medicines Quality Assurance Programme, Quality Assurance and Safety: Medicines, Department of Essential 32 Medicines and Pharmaceutical Policies, World Health Organization, CH-1211 Geneva 27, Switzerland. Fax: (41-22) 791 4730; 33 e-mail: [email protected]. 34 35 The designations employed and the presentation of the material in this draft do not imply the expression of any opinion 36 whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its 37 authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines 38 for which there may not yet be full agreement. 39 40 The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended 41 by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions 42 excepted, the names of proprietary products are distinguished by initial capital letters. 43 44 All reasonable precautions have been taken by the World Health Organization to verify the information contained in this draft. 45 However, the printed material is being distributed without warranty of any kind, either expressed or implied. The responsibility 46 for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for 47 damages arising from its use. 48 49 This draft does not necessarily represent the decisions or the stated policy of the World Health Organization. 50

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Please address comments on this proposal, by 26 July 2011 to Dr S. Kopp, Medicines Quality Assurance Programme, World Health Organization, 1211 Geneva 27, Switzerland, fax: (+41 22) 791 4730 or e-mail: [email protected] with a copy to [email protected] and to [email protected].

During the past few years we have moved more towards an electronic system for sending out our working documents for comment, for convenience and in order to speed up the process. If you do not already receive our documents electronically, please let us have your e-mail address (to [email protected]) and we will add it to our electronic mailing list.

Working document QAS/08.251/Rev.3 page 2

Schedule for the proposed adoption process of working document QAS/08.251: 52

Pharmaceutical development of multisource (generic) finished pharmaceutical products 53

– points to consider 54

55 56

57

History Date

Preparation of a draft guideline which was endorsed by the WHO Expert Committee on Specifications for Pharmaceutical Preparations 15-18 October 2007

Mailing of draft for comments March 2008

Discussion of draft with collated comments by a WHO Expert Working Group June 2008

Mailing of revised draft for comments July 2008

Collation of comments received on revised draft September 2008

Presentation of revised draft with collated comments to WHO Expert Committee on Specifications for Pharmaceutical Preparations 13-17 October 2008

Collation of all comments received, including those arriving after the above-mentioned Expert Committee February 2009

Discussion at the WHO Expert Committee on Specifications for Pharmaceutical Preparations 12-16 October 2009

Discussion at the WHO consultation on paediatrics and generics guideline 29-30 April 2010

Mailing of revised draft for comments June 2010

Collation of comments received August 2010


Revised draft (Rev.2) transferred into CTD format March 2011

Mailing of revised draft for comments to the participants of the informal consultation March 2011

Discussion of revised draft (Rev.2) at the WHO consultation on paediatrics and generics guidelines 4-6 May 2011

Mailing of revised draft (Rev.3) for comments globally May 2011

Collation of comments received August 2011


Further action as necessary


CONTENTS 58 page 59

1. INTRODUCTION ......................................................................................................................... 4 60 1.1 General principles ......................................................................................................... 4 61 1.2 Scope............................................................................................................................... 4 62 2. PRE-DEVELOPMENT ACTIVITIES ............................................................................. 7 63 2.1 Desk research............................................................................................................ 7 64 2.1.1 Quality risk management ...................................................................................... 7 65 2.2 Additional considerations.....…………………………………………………..….. 9 66 2.2.1 Selection and characterization of comparator FPP(s)....................................... 9 67 2.2.2 Benchmarking for formulation experiments and stability studies…….… 9 68

2.2.3 Formulation selection experiments…………………………………………… 9 69 2.2.4 Bioequivalence and dissolution studies……………………………………… 10 70 3. PHARMACEUTICAL DEVELOPMENT ……………………………………..……. 10 71 3.2.P.2 Pharmaceutical development……………………………………………………. 1072 3.2.P.2.1 Components of the FPP……………………………………..………… 1173 3.2.P.2.1.1 Active pharmaceutical ingredient……………………………………. 1174 3.2.P.2.1.2 Excipients……………………………………………………………….. 1275 3.2.P.2.2 Finished pharmaceutical product……………………………………… 1276 3.2.P.2.2.1 Formulation development…………………………………………….. 1277 3.2.P.2.2.2 Overages……………………………………………………………….. 1478 3.2.P.2.2.3 Physicochemical and biological properties………………………….. 1479 3.2.P.2.3 Manufacturing process development………………………………….…. 1580 3.2.P.2.4 Container closure system……………………………………………..…… 1681 3.2.P.2.5 Microbiological attributes……………………………………………….… 1882 3.2.P.2.6 Compatibility……………………………………………………………….. 19 83 4. GLOSSARY....................................................................................................................... 18 84 5. REFERENCES …………………………………………………………………………. 20 85 APPENDIX 1. PUBLICLY AVAILABLE INFORMATION ON TENOFOVIR .......... 21 86 APPENDIX 2. INITIAL RISK ASSESSMENT OF CRITICAL QUALITY ATTRIBUTES 87 AND CRITICAL PROCESS PARAMETERS ..........................................................................25 88 APPENDIX 3. EXAMPLES OF PRESENTING ACTIVE PHARMACEUTICAL 89 INGREDIENT QUALITY ATTRIBUTES ................................................................................27 90 APPENDIX 4. INFORMATION ON DEVELOPMENT BATCHES .............................29 91 92 93

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1. INTRODUCTION 95 96 The aim of pharmaceutical development is to design a quality product and its manufacturing 97 process to consistently deliver the intended performance of the product. The information and 98 knowledge gained from pharmaceutical development studies provide scientific understanding to 99 support the establishment of specifications and manufacturing controls. 100 101 This guideline focuses on the development of multisource finished pharmaceutical products 102 (FPPs) which are intended to be bioequivalent to the relevant comparator product. Multisource 103 FPPs are usually required to be therapeutically equivalent to the comparator product. 104 105 This guideline provides a structured approach for industry, following International Conference 106 on Harmonisation (ICH) common technical document (CTD) format, for developing high-107 quality, multisource FPPs. The ICH CTD structure for pharmaceutical development information 108 allows for a logical, progressive description of the development process. 109 110 The guideline also intends to provide a good understanding of best practices in the development 111 of multisource FPPs and their manufacturing processes to assessors and inspectors. 112 113 Manufacturers who have chosen a more systematic approach to product development would 114 follow the development within the broader context of quality assurance principles, including the 115 use of quality risk management and pharmaceutical quality systems.1 116 117 This document is designed to be used in conjunction with other WHO guidelines and guidance 118 documents, including the WHO Guideline on submission of documentation for a multisource 119 (generic) finished pharmaceutical product: quality part. 120 121 1.1 General principles 122 123 The pharmaceutical development studies and the manufacture of primary batches are essential 124 elements for the science and risk-based approach to establish the critical quality attributes 125 (CQAs) of the FPP and the critical process parameters (CPPs) of the manufacturing process. 126 127 1.2 Scope 128 129 This guideline addresses the pharmaceutical development of multisource FPPs containing 130 existing active pharmaceutical ingredients (APIs) of synthetic or semi-synthetic origin. For the 131 purposes of this guideline, an existing API is one that has been previously authorized through a 132 finished product by a stringent regulatory authority (SRA).2 APIs from biological, or 133 biotechnological origin are covered by other guidelines. 134 135

1 WHO draft on Quality risk management (WHO/10.376) and ICH Q9: Quality risk management and Q10: Pharmaceutical quality system. 2 Stringent regulatory authority (SRA): a regulatory authority which is: a member of the International Conference on Harmonisation (ICH) (as specified on www.ich.org); or an ICH observer, being the European Free Trade Association (EFTA), as represented by Swiss Medic, and Health Canada (as may be updated from time to time); or a regulatory authority associated with an ICH member through a legally-binding, mutual recognition agreement including Australia, Iceland, Liechtenstein and Norway (as may be updated from time to time).


This guideline provides guidance on the contents of a pharmaceutical development plan for 136 multisource pharmaceutical products for both the applicants for marketing authorizations and 137 national medicines regulatory authorities (NMRAs). 138 139 Pharmaceutical development issues depend on the API(s), the excipients, the dosage form, the 140 manufacturing process and the container closure system. Examples in the appendices are focused 141 on immediate release solid oral pharmaceutical dosage forms; however, the general principles 142 are applicable to all types of dosage forms, including injectables, modified release products and 143 respiratory products. 144 145 2. PRE-DEVELOPMENT ACTIVITIES 146 147 2.1 Desk research 148 149 Desk research includes all relevant documentation being collected and evaluated prior to 150 initiation of any laboratory activities. This documentation may include information such as is 151 detailed in: 152

– WHO, European Medicines Agency (EMA) and United States Food and Drug 153 Administration (US-FDA) web sites that contain regulatory information, for 154 example, the qualitative composition, mode of administration and the primary 155 packing materials of the innovator and multisource FPPs; and 156

– compendial monographs, scientific literature, patents, technical information typically 157 found in the applicant’s (open) part of the API master file, technical information on 158 excipients and prior company knowledge. 159

160 An example of the type of information that may be publicly available and how it may be used in 161 risk management (see below) is provided in Appendices 1 and 2. 162 163 2.1.1 Quality risk management 164 165 An essential part of desk research entails the identification of possible risks prior to the 166 development of a multisource product. 167 168 The applicant’s part of the API master file (APIMF)/drug master file (DMF) (if referenced) may 169 reveal risks associated with the API. For instance, reagents (e.g. dimethyl sulfate) or solvents (in 170 particular class 1) used in the process may each pose a risk. 171 172 Poor solubility is an important quality risk factor for APIs administered in the solid state as there 173 is a high risk that inter-batch variability in physical properties may translate into significant 174 differences in the in vivo performance. 175 176 It is recommended that polymorphism, pseudo-polymorphism and the implications of variability 177 in particle size be routinely considered. Variability in any of these key physical properties is 178 likely to be of particular significance for APIs that are of low solubility according to the 179 biopharmaceutics classification system (BCS). The requirement for routine control of 180 polymorphic form and particle size should be considered in accordance with advice in Decision 181 Trees 3 and 4 of ICH Q6A. When controls are necessary they should be established based on the 182 results obtained for the API lot(s) used in the biostudies. 183 184 For example The International Pharmacopoeia (Ph.Int.) restricts the polymorphic form of 185


mebendazole API to form C and furthermore states that the formulation, manufacturing process 186 and product packaging of chewable mebendazole tablets are designed and controlled so as to 187 minimize the conversion of the polymorphic form of mebendazole from C to A. 188 189 The reference source may contain information on other risk factors, such as the following 190 statement provided in the Ph.Int. monographs of saquinavir mesilate and nelfinavir mesilate 191 under Manufacture: “The production method must be evaluated to determine the potential for 192 formation of alkyl mesilates [genotoxic], which is particularly likely to occur if the reaction 193 medium contains lower alcohols. Where necessary, the production method is validated to 194 demonstrate that alkyl mesilates are not detectable in the final product.” Alternately, if present, 195 these impurities should be limited to a suitable justified level (refer to the Guideline on the 196 Limits of Genotoxic Impurities - EMEA/CHMP/QWP/251344/2006). 197 198 Prior knowledge of potential genotoxic impurities in an API is regarded as highly important. 199 Another example is provided in Appendix 1, where the publicly available assessment 200 information reveals that tenofovir disoproxil fumarate (TDF) may contain 9-propenyladenine, a 201 process-related impurity which is mutagenic. The Ph.Int. monograph for TDF includes a limit for 202 this impurity under Manufacture. The presence and control of this impurity should accordingly 203 be verified in the applicant’s part of the APIMF/DMF before selecting potential API 204 manufacturer(s). 205 206 The initial risk assessment of potential CQAs and CPPs of a multisource product should be based 207 on desk research and the applicant's own experience with the manufacture of the dosage form. 208 An example is provided in Appendix 2. 209 210 Literature, preferably peer-reviewed, may contain risk information essential for predevelopment. 211 For example, the presence of meso-ethambutol hydrochloride in commercial ethambutol 212 hydrochloride API material has been demonstrated in literature,1 though some pharmacopoeial 213 monographs do not clearly reveal the presence of this impurity. Recently a specific test was 214 included in the European Pharmacopoeia (PhEur.) for control of this impurity. 215 216 The least risky strategy for multisource product development is to use the same qualitative and, 217 where possible, quantitative formula as that of the comparator FPP – in the absence of the 218 possibility of patent infringement – in order to minimize the risks related to compatibility, 219 stability and bioequivalence. 220 221 Accompanying reconstitution diluents should also be included in the development strategy where 222 appropriate. This topic is discussed further in section 3. 223 224 2.2 Additional considerations 225 226 2.2.1 Selection and characterization of comparator FPP(s) 227 228 In many countries the NMRA provides a list of comparator products. Alternatively, references 229 are also available from WHO (Prequalification of Medicines Programme (PQ)), and international 230 lists of comparator products. Note that for a dossier to be submitted to PQ, the comparator must 231 be selected from its published lists. For guidance regarding PQ comparator products, reference 232 should be made to the information available under Guidance on Bioequivalence Studies on the 233 PQ web site. 234

1 Prasad B et al, Pharmacopeial Forum, 33, 326-333 (2007).


235 In the case of fixed-dose combination (FDC) FPPs, there will be instances when a combination 236 of APIs is recommended for clinical use but an innovator fixed-dose combination (FDC) 237 containing these APIs, whose approval was based on clinical trial data, will not be available as a 238 comparator product. FDCs approved based on data such as bioequivalence data are not typically 239 used as comparators, as the original safety and efficacy data is linked to the monocomponent 240 products and not the FDC FPP. For FDC FPPs, the development strategy should take into 241 account the formulae of the individual component comparator FPPs. If the innovator FDC exists 242 this should be the target product for the FDC multisource product development – even if the 243 individual comparator tablets may be used in the bioequivalence (BE) study (see also WHO 244 Guidelines for registration of fixed-dose combination medicinal products).1 245 246 The comparator product batch may be selected by dissolution profile testing.2 Ideally, a batch 247 which shows intermediate dissolution under the most discriminative condition (where the 248 difference in dissolution between the fastest and slowest batches studied is the largest), should be 249 selected as the reference product for pharmaceutical equivalence studies and bioequivalence 250 studies. 251 252 2.2.2 Benchmarking for formulation experiments and stability studies 253 254 The comparator sample should be thoroughly examined for parameters such as physical 255 properties, shelf-life, including in-use stability information, storage instructions and details of the 256 container closure system in comparison to the outcome of the desk research and the requirements 257 for marketing the new multisource product in the intended market. 258 259 All the relevant quality attributes of the dosage form should be analysed in the quality control 260 (QC) laboratory, e.g. assay, related substances, dissolution rate, pH, preservative concentrations, 261 water content, total mass, mass variation, resistance to crushing, friability and disintegration of 262 tablets. 263 264 The information obtained should be the basis for the development of the new multisource FPP. 265 266 2.2.3 Formulation selection experiments 267 268 Based on the outcome of the desk research and the national requirements for marketing 269 authorization, formulation experiments will be conducted to match the quality target product 270 profile (QTPP) of the comparator product. 271 272 This may include determining the qualitative and quantitative composition of the comparator 273 product. The qualitative information on the comparator product may be available in the public 274 domain, e.g. in its summary of product characteristics (SmPC) or package leaflet. Screening 275 different formulations to match the comparator dissolution profile is the best method to select the 276 final formula for scale up (typical ranges of excipients are illustrated in Appendix 5) from 277 laboratory to pilot batch. 278 279 Selected formulations may be stress-tested to challenge CQAs and to establish tentative 280 acceptance limits for their control. 281 1 WHO Technical Report Series, No. 929, 2005, Annex 5: Guidelines for registration of fixed-dose combination medicinal products. 2 WHO Technical Report Series, No. 937, 2006, Annex 7: Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability.


282 Any special design features of the pharmaceutical product (e.g. tablet score line, overfill, anti-283 counterfeiting measure) should be identified as it affects the pharmaceutical product and a 284 rationale for their use should be provided in the product dossier (PD). 285 286 2.2.4 Bioequivalence and dissolution studies 287 288 Bioequivalence and comparative dissolution studies should be conducted with samples from a 289 batch of the FPP of at least pilot size. The dissolution conditions and acceptance criteria should 290 be derived from the dissolution profiles obtained for the biobatch. 291 292 In the case where an in vivo bioequivalence study could be waived, similarity of the 293 formulations may be required, in particular with respect to excipients that may have an influence 294 on the extent and rate of absorption, e.g. sorbitol in liquid formulations or mannitol in solid 295 dosage forms. For instance, in the case of considering a biowaiver for an immediate release solid 296 oral dosage form containing a BCS Class 3 API, the risk of reaching an inappropriate biowaiver 297 decision needs to be critically evaluated, especially when the extent of absorption (fabs) is less 298 than 50%. As part of the risk assessment “the excipients used will also need to be scrutinized 299 carefully in terms of both qualitative and quantitative composition – the greater the deviation 300 from the comparator composition, the greater the risk of an inappropriate biowaiver decision.”1 301 302 Summaries of all bioequivalence (BE) studies (passed and failed) on the final formulation should 303 be discussed. 304 305 3. PHARMACEUTICAL DEVELOPMENT 306 307 It is recommended to use an internationally harmonized structure when submitting a dossier for obtaining 308 a marketing authorization. This section follows therefore the ICH CTD structure according to ICH M4. 309 310 The text of the M4Q (CTD-Q) guideline has been restated in this guideline in bold text, 311 verbatim, with minor modifications to accommodate WHO terminology and to include certain 312 text that would be appropriate for multisource pharmaceutical products, notably: 313 314

• “Drug substance” is replaced with “active pharmaceutical ingredient” or “API”; 315 • “Drug product” is replaced with “finished pharmaceutical product” or “FPP”; 316 • “application” is replaced with “product dossier” or “PD”; 317 • “combination product” is replaced with “fixed-dose combination” or “FDC”; 318 • “clinical batches” is replaced with “comparative bioavailability or biowaiver batches”. 319

320 Following the bold text of the M4Q (CTD-Q) guideline, additional guidance by WHO is 321 provided in plain text to easily distinguish from the ICH text and is included to provide further 322 clarity on WHO’s expectations and requirements. This approach is intended to facilitate the 323 identification and origin of the text in the guideline (i.e. from ICH or WHO). 324 325 3.2.P.2 Pharmaceutical development 326 327 The Pharmaceutical development section should contain information on the development 328 studies conducted to establish that the dosage form, formulation, manufacturing process, 329

1 WHO Technical Report Series, No. 937, 2006, Annex 7: Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability.


container closure system, microbiological attributes and usage instructions are appropriate 330 for the purpose specified in the product dossier. The studies described here are 331 distinguished from routine control tests conducted according to specifications. 332 Additionally, this section should identify and describe the formulation and process 333 attributes (critical parameters) that can influence batch reproducibility, product 334 performance and FPP quality. Supportive data and results from specific studies or 335 published literature can be included within or attached to the Pharmaceutical development 336 section. Additional supportive data can be referenced to the relevant nonclinical or clinical 337 sections of the product dossier. 338 339 Pharmaceutical development information usually includes, at a minimum: 340

341 • the definition of the QTPP as it relates to quality, safety and efficacy, considering for 342

example the route of administration, dosage form, bioavailability, strength and stability; 343 • identification of the potential CQAs of the FPP so as to adequately control the product 344

characteristics that could have an impact on quality; 345 • discussion of the potential CQAs of the API(s), excipients and container closure system(s) 346

including the selection of the type, grade and amount to deliver the product of the desired 347 quality; 348

• discussion of the selection criteria for the manufacturing process and the control strategy 349 required to manufacture commercial lots meeting the QTPP in a consistent manner. 350

351 These features are usually required to be discussed as part of the product development using the 352 principles of risk management over the entire life-cycle of the product (reference: ICH Q8). The 353 information gained through the pre-development activities may already have disclosed some of 354 these features and could form an integral part of pharmaceutical development. 355 356 For a discussion of additional pharmaceutical development issues specific to the development of 357 FDCs, reference can be made to WHO Technical Report Series, No. 929, Annex 5, Section 6.3.2. 358 359 Reference documents: ICH Q6A, Q8, Q9, Q10 360 361 3.2.P.2.1 Components of the FPP 362 363 The components of the FPP are the ingredients listed under 3.2.1.P.1 Description and 364 Composition of the FPP in the PD. The components thus include the API(s) and all the 365 excipients, as well as those excipients that may not be added to every batch (e.g. acid and alkali), 366 those that may be removed during processing (e.g. water for granulation) and any others (e.g. 367 nitrogen, silicone for stoppers). 368 369 3.2.P.2.1.1 Active pharmaceutical ingredient 370 371 The compatibility of the API with excipients listed in 3.2.P.1 is usually required to be 372 discussed. Additionally, key physicochemical characteristics (e.g. water content, solubility, 373 particle size distribution, polymorphic or solid state form) of the API that can influence the 374 performance of the FPP are usually required to be discussed. For FDCs the compatibility 375 of APIs with each other is usually required to be discussed. 376 377 Physicochemical characteristics of the API may influence both the manufacturing capability and 378 the performance of the FPP. 379 380


Information on the intrinsic physicochemical properties of the molecule, e.g. solubility, solid 381 state properties, including polymorphism and habit, melting range, pKa and hygroscopicity, are 382 needed for the development of the product to allow the FPP manufacturer to take full 383 responsibility for the quality and quality control of the API and the FPP. 384 385 Additionally, the manufacturer will need information (either from the API manufacturer, or 386 determined by another party, or by itself) on potentially critical properties of the API, together 387 with specifications, as applicable, e.g. solubility at 37 oC at relevant physiological pH values to 388 permit BCS classification of the API, partition coefficient (octanol/water) at 37 oC and particle 389 size distribution, etc., which may affect dissolution rate and bioavailability, as well as density, 390 bulk and tapped density, flowability, compressibility, etc., which may influence processibility. 391 The above API properties are usually required to be supported by experimental data (or by 392 information from peer-reviewed literature) and discussed regarding CQAs and CPPs. 393 394 The specifications of the API manufacturer and the retest period derived from formal regulatory 395 stability studies should also be available to the FPP manufacturer. 396 397 Guidance on compatibility studies is provided in Appendix 3 of the WHO Guidelines for 398 registration of fixed-dose combination medicinal products.1 In addition to visual examination, 399 chromatographic results (assay, purity) are required to demonstrate API-API and API-excipient 400 compatibility. In general, API-excipient compatibility is not required to be established for 401 specific excipients when evidence is provided (e.g. SmPC or product leaflet) that the excipients 402 are present in the comparator product. 403 404 Stress testing of the API should be designed to include simulation, as far as possible, of the 405 conditions that may be encountered during the manufacturing process of the FPP. An 406 example is illustrated in Appendix 3. 407 408 3.2.P.2.1.2 Excipients 409 410 The choice of excipients listed in 3.2.P.1, their concentration, their characteristics that can 411 influence the FPP performance is usually required to be discussed relative to their 412 respective functions. 413 414 When choosing excipients, those with a compendial monograph are generally preferred and may 415 be required in certain jurisdictions. Other resources are available for information on acceptable 416 excipients and their concentrations such as the FDA IIG list and the Handbook of 417 Pharmaceutical Excipients. Use of excipients in concentrations outside of established ranges is 418 discouraged and generally requires justification. In addition, available guidelines are usually 419 required to be referenced which address particular excipients to be avoided, for example azo 420 colourants as listed in EMA guideline CPMP/463/00 and Colorcon Regulatory Information Sheet 421 on azo and non-azo colourants. Other guidelines such as the WHO Points to consider for the 422 development of paediatric medicines may provide useful general guidance in this regard. 423 424 The characteristics and amounts of excipients that can influence the pharmaceutical product 425 performance or manufacturing capability are usually required to be discussed relative to the 426 respective function. The ability of functional excipients, e.g. pH-adjusting agents, buffers, 427 stabilizers (such as antioxidants and chelating agents), preservatives and dissolution modifiers 428 (such as surface active agents), to perform throughout the intended FPP shelf-life is usually 429

1 WHO Technical Report Series, No. 929, Annex 5, 2005.


required to be demonstrated. 430 431 Antimicrobial preservatives are discussed in 3.2.P.2.5. 432 433 Many excipients such as povidone, microcrystalline cellulose and lactose are by nature 434 multifunctional. The chemically same excipients may have different grades (physical properties) 435 with different functional characteristics; therefore, conformance to pharmacopoeial 436 specifications does not always provide sufficient confidence that an excipient will perform 437 according to its intended purpose. 438 439 When an excipient is critical for manufacturing capability of the FPP, batch or supplier 440 variations should be minimized by including additional user requirements to those specified in 441 the pharmacopoeia, e.g. particle size distribution. 442 443 Ranges or alternates for excipients are normally not accepted, unless supported by appropriate 444 process validation data. Where relevant, compatibility study results (e.g. compatibility of a 445 primary or secondary amine API with lactose) should be included to justify the choice of 446 excipients. Specific details are usually required to be provided in the PD where necessary (e.g. 447 use of potato or corn starch). 448 449 3.2.P.2.2 Finished pharmaceutical product 450 451 3.2.P.2.2.1 Formulation development 452 453 A brief summary describing the development of the FPP is usually required to be provided, 454 taking into consideration the proposed route of administration and usage. The differences 455 between the comparative bioavailability or biowaiver formulations and the formulation 456 (i.e. composition) described in 3.2.P.1 are usually required to be discussed. Results from 457 comparative in vitro studies (e.g. dissolution) or comparative in vivo studies (e.g. 458 bioequivalence) should be discussed, when appropriate. 459 460 When preparing the PD for submission, the data requirements of the NMRA regarding 461 formulation development may depend on whether the multisource product has been newly 462 developed by the applicant or manufacturer, or whether it is an established multisource product. 463 464 The Prequalification Programme defines an established multisource product as one that has been 465 marketed by the applicant or manufacturer associated with the dossier for at least five years and 466 for which at least 10 production batches were produced over the previous year, or, if less than 10 467 batches were produced in the previous year, not less than 25 batches were produced in the 468 previous three years. For products that meet the criteria of an established multisource product, 469 all sections of P.2.2.1 of the dossier are usually required to be completed with the exception of 470 P.2.2.1 (a). In addition, a product quality review is usually required to be provided in the PD as 471 outlined in Appendix 2 of the WHO Guideline on submission of documentation for a 472 multisource (generic) finished pharmaceutical product: quality part. 473 474 The requirements for bioequivalence studies should be taken into consideration, for example, 475 when formulating multiple strengths and/or the product(s) may be eligible for a biowaiver. WHO 476 reference documents (e.g. the WHO guidelines on registration requirements to establish 477 interchangeability for multisource (generic) pharmaceutical products, WHO Technical Report 478 Series, No. 937, Annex 7) can be consulted. 479 480


Tablet scoring may be recommended or required in certain jurisdictions or, for example, when 481 scoring is indicated in the WHO invitation for expression of interest (EOI), or is specified for an 482 invited FPP in the listing of recommended comparator products, or when division into fractional 483 doses may be necessary according to approved posology. 484 485 If the proposed FPP is a functionally scored tablet, a study should be undertaken to ensure the 486 uniformity of dose in the tablet fragments. The data provided in the PD are usually required to 487 include a description of the test method, individual values, mean and relative standard deviation 488 (RSD) of the results. Uniformity testing (i.e. content uniformity or mass variation, depending on 489 the requirement for the whole tablet) should be performed on each split portion from a minimum 490 of 10 randomly selected whole tablets. As an illustrative example, the number of units (i.e. the 491 splits) would be 10 halves for bisected tablets (one half of each tablet is retained for the test) or 492 10 quarters for quadrisected tablets (one quarter of each tablet is retained for the test). At least 493 one batch of each strength should be tested. Ideally the study should cover a range of the 494 hardness values. The splitting of the tablets should be performed in a manner that would be 495 representative of that used by the consumer (e.g. manually split by hand). The uniformity test on 496 split portions can be demonstrated on a one-time basis and does not need to be added to the FPP 497 specification(s). The tablet description in the FPP specification and in the product information 498 (e.g. summary of product characteristics, labelling, package leaflet) is usually required to reflect 499 the presence of a score. 500 501 If splitting of a tablet is intended for a paediatric dose, a demonstration of content uniformity of 502 tablet fragments may be required. 503 504 Where relevant, labelling should state that the score line is only to facilitate breaking for ease of 505 swallowing and not to divide into equal doses. In this case a demonstration of uniformity is 506 unlikely to be required. 507 508 In vitro dissolution or drug release 509 510 A discussion is usually required to be included as to how the development of the formulation 511 relates to development of the dissolution method(s) and the generation of the dissolution profile. 512 513 The results of studies justifying the choice of in vitro dissolution or drug release conditions (e.g. 514 apparatus, rotation speed, medium) are usually required to be provided in the PD. Data are also 515 usually required to be submitted to demonstrate whether the method is sensitive to changes in 516 manufacturing processes and/or changes in grades and/or amounts of critical excipients and 517 particle size where relevant. The dissolution method should be sensitive to any changes in the 518 product that would result in a change in one or more of the pharmacokinetic parameters. 519 520 Recommendations for conducting and assessing comparative dissolution profiles can be found in 521 Appendix 1 of the WHO Guideline on submission of documentation for a multisource (generic) 522 finished pharmaceutical product: quality part. 523 524 In the case of rapidly dissolving FPPs containing highly-soluble APIs (BCS classes 1 and 3), a 525 single-point dissolution test limit of 80% in 30 minutes or less is considered sufficient as a 526 routine quality control test for batch-to-batch uniformity. For slowly dissolving or poorly water-527 soluble APIs (BCS classes 2 and4) in immediate-release products, a two-point dissolution range 528 (a dissolution window), one at an early time-point 45 minutes (e.g. Q=60% in 45 minutes) and 529 the other at a later point (e.g. Q=80% in 90 minutes) is recommended to characterize the quality 530 of the product. Note that in some cases the latter point may be lower than 80% if a plateau is 531


reached. 532 533 Modified-release FPPs are usually required to have a meaningful in vitro release rate 534 (dissolution) test that is used for routine quality control. Preferably this test should possess in 535 vitro-in vivo correlation. Results demonstrating the effect of pH on the dissolution profile are 536 usually required to be submitted if appropriate for the type of dosage form. 537 538 For extended-release FPPs, the testing conditions should be set to cover the entire time period of 539 expected release (e.g. at least three test intervals chosen for a 12-hour release and additional test 540 intervals for longer duration of release). One of the test points should be at the early stage of 541 drug release (e.g. within the first hour) to demonstrate absence of dose dumping. At each test 542 period, upper and lower limits should be set for individual units. Generally, the acceptance range 543 at each intermediate test point should not exceed 25% or ±12.5% of the targeted value. 544 Dissolution results are usually required to be submitted for several lots, including those lots used 545 for pharmacokinetic and bioavailability or biowaiver studies. 546 547 The dissolution acceptance limit(s) should also be incorporated into the stability programmes. 548 549 3.2.P.2.2.2 Overages 550 551 Any overages in the formulation(s) described in 3.2.P.1 are usually required to be justified. 552 553 Justification of an overage to compensate for loss during manufacture are usually required to be 554 provided in the PD, including the step(s) where the loss occurs, the reasons for the loss and batch 555 analysis release data (assay results). 556 557 Overages for the sole purpose of extending the shelf-life of the FPP are generally not acceptable. 558 559 3.2.P.2.2.3 Physicochemical and biological properties 560 561 Parameters relevant to the performance of the FPP, such as pH, ionic strength, dissolution, 562 redispersion, reconstitution, particle size distribution, aggregation, polymorphism, 563 rheological properties, biological activity or potency, should be addressed. 564 565 3.2.P.2.3 Manufacturing process development 566 567 The selection and optimization of the manufacturing process described in 3.2.P.3.3, in 568 particular its critical aspects, are usually required to be explained. Where relevant, the 569 method of sterilization should be explained and justified. 570 571 For products that meet the criteria of an established multisource product, in order to fulfil the 572 requirements of section P.2.3, section P.2.3 (b) of the dossier is usually required to be completed 573 and a product quality review is usually required to be submitted as outlined in Appendix 2 of the 574 WHO Guideline on submission of documentation for a multisource (generic) finished 575 pharmaceutical product: quality part. The guidance that follows applies to all other products, for 576 which section P.2.3 should be completed in its entirety. 577 578 The rationale for choosing the particular pharmaceutical product (e.g. dosage form, delivery 579 system) should be provided in the PD. The scientific rationale for the choice of the 580 manufacturing, filling and packaging processes that can influence FPP quality and performance 581 is usually required to be explained (e.g. wet granulation using high shear granulator). API stress 582


study results may be included in the rationale. Any developmental work undertaken to protect 583 the FPP from deterioration should also be included (e.g. protection from light or moisture). 584 585 The manufacturing process of the multisource FPP should be appropriate for the product that is in 586 development. It does not need to be the same as that of the comparator FPP. 587 588 Efforts should be primarily directed towards reducing variability in process and product quality. 589 In order to achieve this: 590

• all critical sources of variability should be identified and explained; 591 • the sources of variability should be minimized and controlled; and 592 • CQAs should be accurately and reliably predicted. 593 594

Process development studies should provide the basis for process improvement, process 595 validation and any process control requirements. All CPPs are usually required to be identified, 596 monitored or controlled to ensure that the product is of the desired quality. 597 598 For those products intended to be sterile an appropriate method of sterilization for the 599 pharmaceutical product and primary packaging material should be chosen. Where relevant, 600 justification for the selection of aseptic processing or other sterilization methods over terminal 601 sterilization is usually required to be provided in the PD. 602 603 Differences between the manufacturing process(es) used to produce comparative 604 bioavailability or biowaiver batches and the process described in 3.2.P.3.3 that can 605 influence the performance of the product are usually required to be discussed. 606 607 The scientific rationale for the selection, optimization and scale-up of the manufacturing process 608 described in 3.2.P.3.3 is usually required to be explained, in particular the critical aspects (e.g. 609 rate of addition of granulating fluid, massing time, granulation end-point). A discussion of the 610 CPPs, controls and robustness with respect to the QTPP and CQA of the product is usually 611 required to be included (ref: ICH Q8). 612 613 Based on closely monitoring the manufacturing process of pilot batches, provisional acceptance 614 ranges should be proposed for the CQAs of intermediates and CPPs that impact on downstream 615 processing. Interim acceptance criteria may be approved until enough knowledge is available to 616 finalize CQAs of intermediates and CPPs for production batches. 617 618 The manufacturing process used for pilot batches should be the same as the one proposed to be 619 applied to production batches and should provide product of the same quality and meeting the 620 same specification as that intended for marketing. 621 622 3.2.P.2.4 Container closure system 623 624 The suitability of the container closure system (described in 3.2.P.7) used for the storage, 625 transportation (shipping) and use of the FPP is usually required to be discussed. This 626 discussion should consider, e.g. choice of materials, protection from moisture and light, 627 compatibility of the materials of construction with the dosage form (including sorption to 628 container and leaching) safety of materials of construction and performance (such as 629 reproducibility of the dose delivery from the device when presented as part of the FPP). 630 631 The properties of the container closure systems should be defined by the characteristics of the 632


FPP and the conditions prevailing in the intended market (e.g. climatic zone IVb). 633 634 Stability testing of primary batches of the FPP is conducted on samples packaged in the container 635 closure system selected for marketing in order to confirm compatibility and product stability to 636 support PDs for marketing authorization. 637 638 When the container closure system is a critical factor of FPP stability, batch or supplier 639 variations should be minimized through tight specifications and extended sampling plans for 640 quality control (QC) testing. 641 642 To facilitate the visual identification of spurious/falsely-labelled/falsified/counterfeit medicines 643 (including by the public) the description is usually required to be completely detailed in the 644 product information. This may include information on the container-closure system, such as 645 "round, white opaque, high-density polyethylene (HDPE) bottles fitted with white opaque, 646 polypropylene continuous thread closures with induction sealing liner", or "a blister package 647 comprising clear transparent polyvinyl chloride (PVC) film with a backing of aluminium foil 648 coated with heat seal lacquer". 649 650 Primary packing materials, particularly plastics, are usually required to comply with relevant 651 pharmacopoeial and food contact regulations. 652 653 Testing requirements to verify the suitability of the container-closure system contact material(s) 654 depend on the dosage form and route of administration and, possibly, the manufacturing process. 655 The pharmacopoeias provide standards that are required for packaging materials; examples can 656 be found as follows: 657

Glass containers: USP <660> 658 PhEur 3.2.1 659

Plastic containers: PhEur 3.2.2, 3.2.2.1 660 USP <661> 661

Rubber/Elastomeric closures: USP <381> 662 PhEur 3.2.9 663

The following table outlines the general recommendations for the various dosage forms for one-664 time studies to establish the suitability of the container-closure system contact materials. 665

Solid oral products

Oral liquid and topical products

Sterile products (including ophthalmics)

Description of any additional treatments*

X X X (sterilization and depyrogenation of the components)

Extraction studies --- X X Interaction studies (Migration/sorption)

--- X X

Moisture permeability X (uptake)

X (usually loss)

X (usually loss)

Light transmission X** X X *e.g. coating of tubes, siliconization of rubber stoppers, sulfur treatment of ampoules/vials 666 X = information is usually required to be submitted 667 --- = information does not need to be submitted 668


**Not required if product has been shown to be photostable 669 670 The suitability of the container-closure system used for the storage, transportation (shipping) and 671 use of any intermediate/in-process products (e.g. premixes, bulk FPP) should also be discussed. 672 673 Devices 674 675 There are certain situations in which pharmaceutical dosage forms are developed in association 676 with specific devices. The device might be critical to enabling delivery of the medicine or it 677 might be included in order to facilitate administration. 678 679 Where the device is critical to drug delivery and fully integrated with the product formulation, 680 this product formulation-device combination should be considered as the primary product for the 681 purposes of regulatory submission. Examples of such products include metered dose inhalers 682 (MDIs), dry powder inhalers (DPIs), intranasal sprays and ready-made intravenous infusions. In 683 these cases the data necessary to support a regulatory submission would include: 684

• physical and chemical stability data for the product formulation-device combination in its 685 primary pack in order to support the claimed shelf-life and storage conditions; 686

• relevant data on extractables and leachables; 687 • for multidose products, demonstration of accurate dose delivery over the shelf-life of the 688

product under the registered storage conditions; 689 • for multidose products with a dose-counting mechanism, stability data to demonstrate 690

reliable performance of that mechanism over the shelf-life of the product under the 691 registered storage conditions; 692

• specification control and secure sourcing of all device components; and 693 • relevant information on any secondary device associated with the FPP, such as a spacer 694

device sometimes associated with inhaled products such as MDIs and nebulisers. This 695 device enables dose delivery in situations where the patient cannot easily use the primary 696 product to inhale the dose, particularly where paediatric administration is involved, acting 697 as a temporary reservoir for the dose which can then be inhaled more easily by the 698 patient. There will be some variability inherent with a spacer device but, nevertheless, an 699 acceptable accuracy of dose delivery when using this device needs to be demonstrated. 700 701

Alternatively, the codeveloped device may be intended to facilitate measurement of the 702 prescribed dose prior to administration; this is particularly important for paediatric products 703 where flexibility of dose may also be a requirement. Examples include spoons, cups, syringes or 704 droppers for oral delivery and droppers for nasal or aural delivery. A device is required to be 705 included with the container-closure system for oral liquids or solids (e.g. solutions, emulsions, 706 suspensions and powders/granules for such), any time the package provides for multiple doses. 707 708 In accordance with the Ph.Int. general chapter Liquid Preparations for Oral Use: 709 710 “Each dose from a multidose container is administered by means of a device suitable for 711 measuring the prescribed volume. The device is usually a spoon or a cup for volumes of 5 ml or 712 multiples thereof, or an oral syringe for other volumes or, for oral drops, a suitable dropper.” 713 714 In these cases the following data would be required to support a regulatory submission: 715

• for a device accompanying a multidose container, the results of a study should be 716 provided in the PD demonstrating the reproducibility of the device (e.g. consistent 717 delivery of the intended volume), generally at the lowest intended dose; and 718


• specifications for the device materials, including specific identification testing of the 719 material which will be in contact with the FPP. 720

721 When the intention is to submit a PD in CTD format, a sample of the device is usually required 722 to be provided with Module 1 of the PD. 723 724 3.2.P.2.5 Microbiological attributes 725 726 Where appropriate, the microbiological attributes of the dosage form are usually required 727 to be discussed, including, for example, the rationale for not performing microbial limits 728 testing for non-sterile products and the selection and effectiveness of preservative systems 729 in products containing antimicrobial preservatives. For sterile products, the integrity of the 730 container-closure system to prevent microbial contamination should be addressed. 731 732 Where an antimicrobial preservative is included in the formulation, the amount used should be 733 justified by submission of results of the product formulated with different concentrations of the 734 preservative(s) to demonstrate the least necessary but still effective concentration. The 735 effectiveness of the agent should be justified and verified by appropriate studies (e.g. USP or 736 PhEur. general chapters on antimicrobial preservatives) using a batch of the FPP. If the lower 737 limit for the proposed acceptance criterion for the assay of the preservative is less than 90.0%, 738 the effectiveness of the agent should be established with a batch of the FPP containing a 739 concentration of the antimicrobial preservative corresponding to the lower proposed acceptance 740 criteria. 741 742 As outlined in the WHO guidelines on Stability testing of active pharmaceutical ingredients and 743 finished pharmaceutical products ,1 a single primary stability batch of the FPP should be tested 744 for effectiveness of the antimicrobial preservative (in addition to preservative content) at the 745 proposed shelf-life for verification purposes, regardless of whether there is a difference between 746 the release and shelf-life acceptance criteria for preservative content. 747 748 3.2.P.2.6 Compatibility 749 750 The compatibility of the FPP with reconstitution diluent(s) or dosage devices (e.g. 751 precipitation of API in solution, sorption on injection vessels, stability) is usually required 752 to be addressed to provide appropriate and supportive information for the labelling. 753 754 Where a device is required for oral liquids or solids (e.g. solutions, emulsions, suspensions and 755 powders/granules for reconstitution) that are intended to be administered immediately after being 756 added to the device, the compatibility studies mentioned in the following paragraphs are not 757 required. 758 759 Where sterile, reconstituted products are to be further diluted, compatibility should be 760 demonstrated with all diluents over the range of dilution proposed in the labelling. These studies 761 should preferably be conducted on aged samples. Where the labelling does not specify the type 762 of containers, compatibility (with respect to parameters such as appearance, pH, assay, levels of 763 individual and total degradation products, subvisible particulate matter and extractables from the 764 packaging components) should be demonstrated in glass, PVC and polyolefin containers. 765 However, if one or more containers are identified in the labelling, compatibility of admixtures 766 needs to be demonstrated only in the specified containers. 767 1 WHO Technical Report Series, No. 953, Annex 2, 2009.


768 In the case of infusion sets where a product formulation is added to an infusion vehicle in an 769 intravenous administration set (giving set) immediately prior to administration, the following 770 data would be required: 771

• physical and chemical stability data for the prepared infusion to support the claimed in-772 use shelf-life and storage conditions; 773

• compatibility data to support the claimed in-use shelf-life and storage conditions; and 774 • specification control and secure sourcing of all giving set contact materials. 775

776 Studies are usually required to cover the duration of storage reported in the labelling (e.g. 24 777 hours under controlled room temperature and 72 hours under refrigeration). Where the labelling 778 specifies coadministration with other FPPs, compatibility should be demonstrated with respect to 779 the principal FPP as well as the coadministered FPP (i.e. in addition to other, aforementioned 780 parameters for the mixture, the assay and degradation levels of each coadministered FPP should 781 be reported). 782 783 In some cases when a pharmaceutical product is developed for global marketing, there may also 784 be a need to consider alternative diluents or liquids for dispersion and/or in-use reconstitution for 785 a product, and compatibility with these diluents or liquids may be required to be established. 786 787 4. GLOSSARY 788 789 active pharmaceutical ingredient 790 A substance or compound intended to be used in the manufacture of a finished pharmaceutical 791 product as therapeutically active compound (ingredient). 792 793 comparator product (source: WHO Technical Report Series, No. 937, Annex 7, 2006) 794 The comparator product is a pharmaceutical product with which the multisource product is 795 intended to be interchangeable in clinical practice. The comparator product will normally be the 796 innovator product for which efficacy, safety and quality have been established. The selection of 797 the comparator product is usually made at the national level by the drug regulatory authority. 798 For the Prequalification Programme, the selection of the comparator product is based on the 799 information presented under Guidance on Bioequivalence Studies available on the 800 Prequalification web site. 801 802 control strategy (source: ICH Q8) 803 A planned set of controls, derived from current product and process understanding that ensures 804 process performance and product quality. The controls can include parameters and attributes 805 related to active pharmaceutical ingredient and finished pharmaceutical product materials and 806 components, facility and equipment operating conditions, in-process controls, finished product 807 specifications, and the associated methods and frequency of monitoring and control (ICH Q10). 808 809 critical process parameter (CPP) (source: ICH Q8) 810 A process parameter whose variability has an impact on a critical quality attribute and, therefore, 811 should be monitored or controlled to ensure the process produces the desired quality. 812 813 critical quality attribute (CQA) (source: ICH Q8) 814 A physical, chemical, biological or microbiological property or characteristic that should be 815 within an appropriate limit, range or distribution to ensure the desired product quality. 816 817


finished pharmaceutical product (FPP) (source: WHO Technical Report Series, No. 953, 818 Annex 3, 2009) 819 A finished dosage form of a pharmaceutical product, which has undergone all stages of 820 manufacture, including packaging in its final container and labelling. 821 822 fixed-dose combination finished pharmaceutical product (FDC-FPP) (source: WHO Technical 823 Report Series, No. 937, Annex 7) 824 A finished pharmaceutical product that contains two or more active pharmaceutical ingredients. 825 826 formal experimental design (source: ICH Q8) 827 A structured, organized method for determining the relationship between factors affecting a 828 process and the output of that process. Also known as “design of experiments”. 829 830 generic product 831 See multisource (generic) pharmaceutical products. 832 833 life-cycle (new) 834 Development of a product from introduction, through various development stages to marketing 835 and discontinuation. 836 837 multisource (generic) pharmaceutical products (source: WHO Technical Report Series, No. 937, 838 Annex 7) 839 Multisource pharmaceutical products are pharmaceutically equivalent or pharmaceutically 840 alternative products that may or may not be therapeutically equivalent. Multisource 841 pharmaceutical products that are therapeutically equivalent are interchangeable. 842 843 pharmaceutical alternatives (source: WHO Technical Report Series, No. 937) 844 Products are pharmaceutical alternative(s) if they contain the same molar amount of the same 845 active pharmaceutical moiety(s) but differ in dosage form (e.g. tablets versus capsules), and/or 846 chemical form (e.g. different salts, different esters). Pharmaceutical alternatives deliver the same 847 active moiety by the same route of administration but are otherwise not pharmaceutically 848 equivalent. They may or may not be bioequivalent or therapeutically equivalent to the 849 comparator product. 850 851 pharmaceutical development (source: ICH Q8) 852 Pharmaceutical development is the set of studies performed to design a quality product and its 853 manufacturing process to produce a product that consistently delivers as intended. 854 855 pharmaceutical equivalence (source: WHO Technical Report Series, No. 937, Annex 7) 856 Products are pharmaceutical equivalents if they contain the same molar amount of the same 857 API(s) in the same dosage form, if they meet comparable standards, and if they are intended to 858 be administered by the same route. Pharmaceutical equivalence does not necessarily imply 859 therapeutic equivalence, as differences in the excipients and/or the manufacturing process and 860 some other variables can lead to differences in product performance. 861 862 pharmaceutical equivalents (source: WHO Technical Report Series, No. 937) 863 Products are pharmaceutical equivalents if they contain the same amount of the same actives in 864 the same dosage form, if they meet comparable standards, and if they are intended to be 865 administered by the same route. Pharmaceutical equivalence does not necessarily imply 866 therapeutic equivalence, as differences in the excipients and/or manufacturing process and some 867 other variables can lead to differences in product performance. 868


869 pharmaceutical product (source: Marketing Authorization of Pharmaceutical Products with 870 Special Reference to Multisource (Generic) Products: A Manual for Drug Regulatory Authorities 871 – Regulatory Support Series No. 005, 1998) 872 Any preparation for human or veterinary use that is intended to modify or explore physiological 873 systems or pathological states for the benefit of the recipient. 874 875 pilot-scale batch (source: WHO Technical Report Series, No. 953, Annex 2) 876 A batch of an API or FPP manufactured by a procedure fully representative of and simulating 877 that to be applied to a full production-scale batch. For example, for solid oral dosage forms, a 878 pilot scale is generally, at a minimum, one-tenth that of a full production scale or 100 000 tablets 879 or capsules, whichever is the larger; unless otherwise adequately justified. 880 881 primary batch (source: WHO Technical Report Series, No. 953, Annex 2) 882 A batch of an API or FPP used in a stability study, from which stability data are submitted in a 883 registration application for the purpose of establishing a retest period or shelf-life, as the case 884 may be. 885 886 process robustness (source: ICH Q8) 887 Ability of a process to tolerate variability of materials and changes of the process and equipment 888 without negative impact on quality. 889 890 production batch (source: WHO Technical Report Series, No. 953, Annex 2) 891 A batch of an API or FPP manufactured at production scale by using production equipment in a 892 production facility as specified in the application. 893 894 quality (source: ICH Q8) 895 The suitability of either an API or a pharmaceutical product for its intended use. This term 896 includes such attributes as the identity, strength and purity (ICH Q6A). 897 898 quality target product profile (QTPP) (source: ICH Q8) 899 A prospective summary of the quality characteristics of a finished pharmaceutical product that 900 ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of 901 the finished pharmaceutical product. 902 903 therapeutic equivalence (source: WHO Technical Report Series, No. 937, Annex 7) 904 Two pharmaceutical products are considered to be therapeutically equivalent if they are 905 pharmaceutically equivalent or pharmaceutical alternatives and after administration in the same 906 molar dose, their effects, with respect to both efficacy and safety, are essentially the same when 907 administered to patients by the same route under the conditions specified in the labelling. 908 This can be demonstrated by appropriate bioequivalence studies, such as pharmacokinetic, 909 pharmacodynamic, clinical or in vitro studies. 910 911 5. REFERENCES 912 913 [Note from the Secretariat: 914 The references will be added here when the document has been finalized.]915


916 APPENDIX 1 917

PUBLICLY AVAILABLE INFORMATION ON TENOFOVIR 918 919 920 General note: Example includes specific references to a regional authority regulation.1 921 922 For general requirements refer to the WHO Prequalification web site 923 924 Tenofovir disoproxil fumarate has a molecular formula of C19H30N5O10P • C4H4O4 and a 925 molecular weight of 635.52. It has the following structural formula: 926

927 Tenofovir disoproxil fumarate is a salt of an oral prodrug of tenofovir. Because tenofovir was not 928 well absorbed from the intestine, the prodrug, tenofovir disoproxil, was developed to increase 929 bioavailability. 930 931 The recommended dose is one 245 mg tablet (245 mg tenofovir disoproxil (as fumarate)) daily 932 taken orally with a meal. 933 934 Active pharmaceutical ingredient 935 936 Tenofovir disoproxil fumarate (tenofovir DF) is a diester prodrug of the purine-based nucleotide 937 analogue, tenofovir. Tenofovir DF is obtained by introduction of labile esters on the phosphonate 938 group of tenofovir. This (isopropoxycarbonyloxy)methoxy ester is utilized as a promoiety in 939 order to increase lipophilicity and enhance the oral bioavailability of the parent compound. 940 941 The physicochemical characteristics of tenofovir DF with respect to salt selection, hygroscopicity, 942 dissociation constant, partition coefficient, solubility, solution and solid state have been studied. 943 Tenofovir disoproxil fumarate is manufactured as an anhydrous crystalline form using a linear 944 synthesis. Following isolation the product is dried at not more than 45 °C to a solvent content 945 (LOD or GC) of not more than 0.5%. The dry product is milled to break up any aggregates. 946 947 Tenofovir DF contains a single chiral centre at the C-11 position (C-2 of the propyl side-chain) 948 and the defined method of synthesis routinely produces the R-enantiomer. 949 950 Two polymorphic forms have been identified by X-ray powder diffraction and DSC, a "high" 951 melting polymorph (115–118 °C) and a "low" melting polymorph (112–114 °C). The melting 952 enthalpies, intrinsic dissolution rates and solubility of these crystal forms are indistinguishable 953 and, therefore, these solid-state differences are unlikely to result in clinical consequences. 954 1 European Medicines Agency. European Public Assessment Reports: Viread, Scientific discussion. WHO Public Assessment Reports. Scientific dicussion: Tenoforvir DF tablets.


955 The proposed specification for the API includes relevant tests for: appearance; identity (IR & 956 HPLC); assay by HPLC (97–101% tenofovir DF, non-chiral); enantiomeric purity by HPLC (not 957 less than 98% of the R-isomer); 14 potential related impurities are described of which eight are 958 controlled in the specification by HPLC; organic volatile impurities; and heavy metals. Physical 959 tests include: clarity of solution; water content; DSC (main endotherm characterization); and 960 particle size. 961 962 9-propenyladenine (9-PA) is a process-related impurity which is mutagenic. Although the 963 amounts found in batches of the API have been monitored and limited throughout development, 964 a routine test and limits for this impurity should be included in the API specification. 965 966 Analytical validation data for all analytical methods are provided and take into account current 967 guidelines. Details of the reference standards are provided. 968 969 Batch analyses data are presented for a total of 39 batches of tenofovir DF used in toxicological, 970 clinical and stability studies, with precise impurity profile. However, some further clarification is 971 required. 972 973 Tenofovir DF shows excellent physicochemical stability when stored at 5 ºC for up to 36 months 974 (three lots, packaged in polyethylene bags, sealed and then placed into tightly-capped HDPE 975 bottles), the primary route of chemical degradation being hydrolysis. There was no significant loss 976 in purity or increase in total impurity and degradation product content after storage under 977 accelerated storage conditions (same packaging, at 25 ºC/60%RH and 30 ºC/60%RH) for up to six 978 months. 979 980 Tenofovir DF API is specified to be stored under refrigeration at 2–8 ºC. Tenofovir DF is to be 981 stored in polyethylene bags, which are placed into tightly-closed HDPE containers and the 982 proposed retest period of 24 months is supported. 983 984 Finished pharmaceutical product 985 986 Viread is formulated as immediate-release, film-coated tablets containing 245 mg of tenofovir 987 disoproxil (as fumarate), equivalent to 136 mg of tenofovir. The excipients are those commonly 988 used in this type of product: pregelatinized starch (binder); croscarmellose sodium (disintegrant); 989 lactose monohydrate (filler); microcrystalline cellulose (filler); magnesium stearate (lubricant); 990 and a proprietary hypromellose-based film-coating (lactose monohydrate, glycerol triacetate, 991 hypromellose, titanium dioxide [E171], indigo carmine lake [E132]). 992 993 The tablets are presented in high density polyethylene (HDPE) bottles with aluminium foil 994 induction seals and polypropylene child-resistant caps. Each bottle contains 30 tablets and 995 includes a canister of silica gel as a desiccant to reduce the headspace moisture and polyester 996 fibre to prevent tablet chipping in transit. 997 998 The fumarate salt of the diester prodrug of tenofovir is chosen to increase intestinal permeability 999 and to improve the bioavailability of the active substance. The choice for a tablet presentation 1000 and the rationale for both the proposed qualitative and quantitative composition of the 1001 formulation has been presented. 1002 1003 1004 1005


The processing parameters, including those for the film coating, have been investigated and 1006 optimized. The free moisture in the tablets is minimized both during the manufacturing process 1007 and in the packaging. 1008 1009 The HDPE resin used for the primary packaging (bottles) is thick and was selected based upon 1010 moisture vapour transmission data, as the product must be protected from extended periods of 1011 exposure to high moisture conditions. The use of 1 gram of silica gel (in a canister) per bottle 1012 was established based upon stability data. Induction sealing of the bottle (with aluminium foil) 1013 also reduces the available moisture. 1014 1015 Film-coated tablets of different strengths have been used in clinical trials and the formulations 1016 for these have been presented. 1017 1018 The manufacturing processes have all been well described. Manufacture commences with a 1019 conventional wet granulation process, followed by a drying of the granules (to LOD ≤ 3%) to 1020 reduce the intragranular moisture content. After compression, the bulk uncoated tablets are tested 1021 for hardness and friability. Finally the film coating (aqueous-based) is applied. 1022 1023 The industrial batch size has been stated to be up to 1000 kg. The frequency of in-process control 1024 testing remains to be fully clarified. 1025 1026 Nine lots of up to 230 kg in size have been manufactured and used for validation studies and 1027 although the process has been shown to be robust and to result in consistent product some points 1028 for clarification remain and some further validation data are also required. 1029 1030 The product specification contains the relevant tests and limits for a product of this type. Tests 1031 include appearance, identification of the API (HPLC and UV), assay (96–105% at release, 90–1032 105% during shelf-life, by HPLC), and limits for 10 named related impurities/degradates. 1033 Unspecified impurities are limited to not more than 0.2% each. In addition, there are also 1034 pharmacopoeial tests for content uniformity, dissolution, water content and microbial limits. 1035 1036 The proposed specification limits for total impurities and degradation products in both the release 1037 and shelf-life specifications are very high and remain to be tightened or further justified by 1038 reference to the original toxicological studies. 1039 1040 The analytical methods are described and suitably validated in accordance with current 1041 guidelines. Batch analyses results on 10 batches are provided. 1042 1043 Long-term and accelerated stability studies were conducted on nine batches of tenofovir DF 1044 tablets, 245 mg. The stability batches were produced at a scale that is greater than one-tenth of the 1045 intended commercial scale, were identical in the composition, used the same manufacturing 1046 process, and were packaged into the same container-closure system as the intended commercial 1047 product. 1048 1049 Long-term stability studies were conducted at 25 ºC/60%RH and 12 months data are available 1050 for two batches and nine months data for three batches. 1051 1052 The results indicate an acceptable long-term stability. The tablets remained within the product 1053 specifications when stored for up to 12 months at 25 ºC/60%RH. A statistical analysis was 1054 performed to estimate the total impurity and degradation product content at the proposed 1055 expiration dating period of 24 months. However, the stability data provided do not yet support 1056


the claimed limit of 8.0% for impurities/degradation products in the shelf-life specification. 1057 1058 No significant change in physicochemical stability was observed for tenofovir DF tablets stored 1059 for six months at 40 ºC/75%RH. The pharmaceutical product remained within the product 1060 specifications over the six-month study duration. No significant change in physicochemical 1061 stability was observed for tenofovir DF tablets exposed to artificial daylight fluorescent lamps. 1062 1063 On the basis of the long-term and accelerated stability data and the statistical analyses, the 1064 proposed shelf-life, i.e. 24 months with no specific storage condition, is acceptable. However, 1065 clarification of some of the stability data and some additional data are required. 1066 1067 All the excipients in the product comply with current pharmacopoeial specifications and 1068 monographs and are widely used for the manufacture of solid oral dosage forms. 1069 1070 Information has been provided to demonstrate that the CPMP is satisfied that the materials, 1071 lactose monohydrate, magnesium stearate (vegetable source) and the proprietary film coating 1072 (Opadry II Y-30-10671-A) are in compliance with the latest EU guidance on Minimizing the 1073 Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary 1074 Medicinal Products.1 1075 1076 Satisfactory control specifications and certificates are provided for the packaging materials. 1077 The bottles and closures are controlled according to the general pharmacopoeial requirements for 1078 plastic containers and closures. 1079

1 WHO guidelines on transmissible spongiform encephalopathies in relation to biological and pharmaceutical products (www.who.int/bloodproducts/tse).


APPENDIX 2 1080

INITIAL RISK ASSESSMENT OF CRITICAL QUALITY ATTRIBUTES AND 1081

CRITICAL PROCESS PARAMETERS 1082

1083 1084 Using Appendix 1 as the source of information the following risk statements can be made: 1085 1086 Active pharmaceutical ingredient (Tenofovir DF): 1087

• The publicly available QC and stability information does not suggest racemization during 1088 storage. 1089

• Polymorphism is unlikely to be a CQA. 1090 • Potentially critical physical attributes include clarity of solution, water content and 1091

particle size. 1092 • 9-propenyladenine (9-PA) is a process-related impurity, which is mutagenic. 1093 • Tenofovir DF shows excellent physicochemical stability when stored at 5 ºC for up to 36 1094

months. (Note: unusual storage conditions which deserve special attention.) 1095 • The primary route of chemical degradation is hydrolysis. 1096 • There was no significant loss in purity or increase in total impurity and degradation 1097

product content after storage under accelerated storage conditions (same packaging, at 1098 25 ºC/60%RH and 30 ºC/60%RH) for up to 6 months. (Note: the packing materials 1099 protect the API from environmental humidity.) 1100

1101 Finished pharmaceutical product 1102

• The FPP is formulated as immediate-release film-coated tablets containing 245 mg of 1103 tenofovir disoproxil (as fumarate), equivalent to 136 mg of tenofovir. 1104

• The excipients are those commonly used in this type of product. 1105 • The tablets are presented in high density polyethylene (HDPE) bottles with aluminium 1106

foil induction seals and polypropylene child-resistant caps. Each bottle contains 30 1107 tablets and includes a canister of silica gel as a desiccant. 1108

• The free moisture in the tablets is minimized both during the manufacturing process and 1109 in the packaging. 1110

• The HDPE resin used for the primary packaging (bottles) is thick and was selected based 1111 upon moisture vapour transmission data, as the product must be protected from extended 1112 periods of exposure to high-moisture conditions. 1113

• Manufacture commences with a conventional wet granulation process, followed by a 1114 drying step to dry the granules (to LOD ≤ 3%) to reduce the intragranular moisture 1115 content. 1116

• Finally the film coating (aqueous-based) is applied. 1117 • The product specification contains the relevant tests and limits for a product of this type. 1118

The proposed specification limits for total impurities and degradation products in both 1119 the release and shelf-life specifications are very high and remain to be tightened or 1120 further justified by reference to the original toxicological studies. 1121

• Long-term stability studies were conducted at 25 ºC/60%RH and 12 months data are 1122 available for two batches and nine months data for three batches. The results indicate an 1123 acceptable long-term stability. The stability data provided, however, do not yet support 1124 the claimed limit of 8.0% for impurities/degradation products in the shelf-life 1125 specification. 1126


The following table* exemplifies the initial risk assessment of critical quality attributes of a 1127 multisource company based on experience with the manufacture of film-coated tablets. 1128 1129

Unit operations Quality attributes Weighing Granulation Drying Blending Compression Coating PackingAppearance Identity test NNNIIIRRR Uniformity of mass

Uniformity of content

Disintegration Dissolution Resistance to crushing

Friability Water content Degradants Assay Microbial limits

Control strategy Monitoring strategy Prior knowledge 1130 * This table is based on ICH Q9 Quality risk management, Annex II – Potential applications: 1131 “Risk Management approach to focus on critical attributes” and has been modified to comply 1132 with multisource pharmaceutical products. 1133 1134


APPENDIX 3 1135

EXAMPLES OF PRESENTING ACTIVE PHARMACEUTICAL INGREDIENT 1136

QUALITY ATTRIBUTES 1137

[Note from the Secretariat: 1138 Comments are being sought as to whether this information would be useful here, or should 1139 rather be given as practical advice, e.g. on the web site of the Prequalification Programme.] 1140 1141 Physicochemical characteristics of the API (not described under 3.2.S.1.3 General properties) 1142 that can influence manufacturing capability and the performance of the FPP should be tabulated 1143 and discussed, for example: 1144 1145

Method (compendial): 1146

Particle size of API used in relevant laboratory and pilot-scale batches Batch number (and use)

Measured data (µm)

<API batch No.> <FPP batch No.> (design)

<API batch No.> <FPP batch No.> (final laboratory)

<API batch No.> <FPP batch No.> (stability)

<API batch No.> <FPP batch No.> (bioequivalence)

Proposed acceptance range (µm)

D 10 D 50 D 90 Add rows, as needed Change data range, as relevant

1147 1148


Apparent density of API used in relevant laboratory and pilot-scale batches

<API batch No.> <FPP batch No.> (design)

<API batch No.> <FPP batch No.> (final laboratory)

<API batch No.> <FPP batch No.> (stability)

<API batch No.> <FPP batch No.> (bioequivalence)

Proposed acceptance range (g/ml)

Bulk Tapped



Stress Treatment Observations Assay: S1: Insert as many rows as necessary D1: Insert as many rows as necessary Total unspecified:

None Initial values of the API

Total impurities: Assay: S1: D1: Total unspecified:

Temperature A thin layer of the API is kept at 80°C for 4 weeks in a Petri dish (open system) with sampling once a week


Humidity A thin layer of the API is kept at 40 °C /100% RH for four (4) weeks in a Petri dish (open system) with sampling once a fortnight


Oxidation

Oxygen is bubbled slowly through the oxygen-saturated aqueous solution/suspension (under constant mixing) of the API for 24 hours with sampling every eight (8) hours

Total impurities: 1151 S1, S2, etc., are synthesis impurities (as in API specifications). 1152 D1, D2, etc., are degradation products. 1153


APPENDIX 4 1154

INFORMATION ON DEVELOPMENT BATCHES 1155 1156

[Note from the Secretariat: 1157 Comments are being sought as to whether this information would be useful here, or should 1158 rather be given as practical advice, e.g. on the web site of the Prequalification Programme.] 1159 1160

1161 Screening laboratory batches with different proportions of excipients to match comparator 1162 dissolution. 1163 1164

Composition of formulation development experiments Lab01 Lab02 Lab03 Lab04 Ingredients g % G % g % G %

API 1 API 2 API 3 Excipient 1 Excipient 2 Excipient 3 Excipient 4 Excipient 5 Dissolution, % at pH …

1165 1166 Comparator product – bench mark (Hypothetical example - Ph.Int., paddle, 75 rpm, 900ml) 1167 1168

% API dissolved % API dissolved % API dissolved

pH 6.8 buffer pH 4.5 buffer pH 1.2 buffer Time (min)

22 15 27 5

27 25 42 10

35 36 55 15

42 42 65 20

49 48 76 30

57 49 88 45

65 49 92 60

76 50 100 90 1169 Graphical presentation and summary evaluation of the results of comparative dissolution studies 1170 of the test (samples taken from the bioequivalence batch No. …) and comparator products: 1171 1172 1173

*** 1174

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PHARMACEUTICAL DEVELOPMENT OF MULTISOURCE (GENERIC) FINISHED PHARMACEUTICAL … · 134 biotechnological origin are covered by other guidelines. 135 1 WHO draft on Quality risk management