FDA对生物类似物的质量要求指南201202

Quality Considerations in

Demonstrating Biosimilarity to a Reference

Protein Product

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only. Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit comments to the Division of Dockets Management (HFA-305), Food and

Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments

should be identified with the docket number listed in the notice of availability that publishes in

the Federal Register.

For questions regarding this draft document contact (CDER) Sandra Benton at 301-796-2500.

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

Center for Biologics Evaluation and Research (CBER)

February 2012

Biosimilarity

Quality Considerations in

Demonstrating Biosimilarity to a Reference

Protein Product

Additional copies are available from:

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https://www.wendangku.net/doc/f39543063.html,/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

Center for Biologics Evaluation and Research (CBER)

February 2012

Biosimilarity

TABLE OF CONTENTS

I. INTRODUCTION (1)

II. BACKGROUND (2)

III. SCOPE (4)

IV. DEFINITIONS (5)

V. GENERAL PRINCIPLES (6)

VI. FACTORS FOR CONSIDERATION IN ASSESSING WHETHER PRODUCTS ARE HIGHLY SIMILAR (9)

A. Expression System (9)

B. Manufacturing Process (10)

C. Assessment of Physicochemical Properties (10)

D. Functional Activities (11)

E. Receptor Binding and Immunochemical Properties (12)

F. Impurities (12)

G. Reference Product and Reference Standards (13)

H. Finished Drug Product (14)

I. Stability (15)

VII. CONCLUSION (15)

VIII. RELEVANT GUIDANCES (16)

5 10 15 20 25 30 35 40 1 Guidance for Industry 1 2 Quality Considerations in Demonstrating Biosimilarity to a

3

Reference Protein Product

4 6 7 This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's) current 8 thinking on this topic. It does not create or confer any rights for or on any person and does not operate to 9 bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA 11 staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call 12 the appropriate number listed on the title page of this guidance. 13 14 16 I. INTRODUCTION 17 18 This guidance describes the Agency’s current thinking on factors to consider when

19 demonstrating that a proposed protein product is highly similar to a reference product licensed under section 351(a) of the Public Health Service Act (PHS Act) for purposes of submitting a 21 marketing application under section 351(k) of the PHS Act. Specifically, the guidance is

22 intended to provide recommendations to applicants on the scientific and technical information of 23 the chemistry, manufacturing, and controls (CMC) section of a marketing application for a 24 proposed biosimilar product submitted under section 351(k) of the PHS Act. 26 The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) amends the PHS Act 27 and other statutes to create an abbreviated licensure pathway in section 351(k) of the PHS Act 28 for biological products shown to be biosimilar to, or interchangeable with, an FDA-licensed 29 biological reference product (see sections 7001 through 7003 of the Patient Protection and

Affordable Care Act (Pub. L. 111-148) (Affordable Care Act)). The BPCI Act also amended the 31 definition of biological products to include “protein (except any chemically synthesized 32 polypeptide)” (see section 351(i)(1) of the PHS Act). A 351(k) application for a proposed

33 biosimilar product must include information demonstrating biosimilarity, based on data derived 34 from, among other things, “analytical studies that demonstrate that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive 36 components.”2 37 38 Although the 351(k) pathway applies generally to biological products, this guidance focuses on 39 therapeutic protein products and provides an overview of analytical factors to consider in demonstrating biosimilarity between a proposed protein product and the reference product. 41

1

This guidance has been prepared by the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration (FDA). 2

See section 351(k)(2)(A)(i)(I)(aa) of the PHS Act.

42 This guidance is one in a series of guidances that FDA is developing to implement the BPCI Act.

43 The guidances will address a broad range of issues, including:3

44

45 ?Quality Considerations in Demonstrating Biosimilarity to a Reference Protein

46 Product

47 ?Scientific Considerations in Demonstrating Biosimilarity to a Reference Product

48 ?Biosimilars: Questions and Answers Regarding Implementation of the Biologics

49 Price Competition and Innovation Act of 2009

50

51 When applicable, references to information in these guidances are included in this guidance.

52

53 FDA’s guidance documents, including this guidance, do not establish legally enforceable

54 responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should

55 be viewed only as recommendations, unless specific regulatory or statutory requirements are

56 cited. The use of the word should in Agency guidances means that something is suggested or

57 recommended, but not required.

58

59

60 II. BACKGROUND

61

62 In the 1980s, FDA began to receive marketing applications for biotechnology-derived protein

63 products, mostly for recombinant DNA-derived versions of a naturally sourced product. In light

64 of these applications, FDA established a regulatory approach for the approval of recombinant

65 DNA-derived protein products, which it announced in a policy document published on June 26,

66 1986 (51 FR 23309), in conjunction with a 1985 document titled Points to Consider in the

67 Production and Testing of New Drugs and Biologicals Produced by Recombinant DNA

68 Technology. The policy requires the submission of an investigational new drug application

69 (IND) to FDA for evaluation before initiation of clinical investigations in human subjects and

70 submission and approval of a new drug application (NDA) or biologics license application

71 (BLA) “before marketing products made with recombinant DNA technology, even if the active

72 ingredient in the product is thought to be identical to a naturally occurring substance or a

73 previously approved product” (51 FR 23309). The policy set forth in those documents was

74 developed in part because of the challenges in evaluating protein products solely by

75 physicochemical and functional testing and because the biological system in which a protein

76 product is produced can have a significant effect on the structure and function of the product

77 itself. Due to the complexities of protein products, FDA has, as a matter of policy, generally

78 required submission of an NDA in accordance with section 505(b)(1) of the FD&C Act or a BLA

79 in accordance with section 351(a) of the PHS Act containing product-specific full safety and

80 efficacy data for recombinant DNA-derived protein drugs. FDA has recognized, however, that

81 “[i]n some instances complete new applications may not be required.” (51 FR 23309).

82

83 Improvements in manufacturing processes, process controls, materials and product testing, as

84 well as characterization tests and studies, have led to a gradual evolution in the regulation of

3 We update guidances periodically. To make sure you have the most recent version of a guidance, check the CDER

guidance page at https://www.wendangku.net/doc/f39543063.html,/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

85 protein products. For example, in 1996, FDA provided recommendations in its FDA Guidance

86 Concerning Demonstration of Comparability of Human Biological Products, Including

87 Therapeutic Biotechnology Products, which explains how an applicant may demonstrate,

88 through a combination of analytical testing, functional assays (in vitro and/or in vivo),

89 assessment of pharmacokinetics (PK) and/or pharmacodynamics (PD) and toxicity in animals,

90 and clinical testing (clinical pharmacology, safety, and/or efficacy) that a manufacturing change

91 does not adversely affect identity, purity, or potency of its FDA-approved product.

92

93 Since 1996, FDA has approved many manufacturing process changes for licensed biological

94 products, based on a demonstration of product comparability before and after the process change,

95 as supported by quality criteria and analytical testing and without the need for additional

96 nonclinical data and clinical safety and/or efficacy studies. In some cases, uncertainty about the

97 effect of the change and/or the results of the biochemical/functional comparability studies has

98 necessitated assessment of additional data, including nonclinical and/or clinical testing, to

99 demonstrate product comparability.

100

101 These concepts were further developed in the International Conference on Harmonisation of 102 Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and resulted 103 in the Q5E guidance on Comparability of Biotechnological/Biological Products Subject to

104 Changes in their Manufacturing Process. Although the scope of ICH Q5E is limited to an

105 assessment of the comparability of a biological product before and after a manufacturing process 106 change made by the same manufacturer, certain general scientific principles described in ICH 107 Q5E are applicable to an assessment of biosimilarity between a proposed biosimilar protein

108 product and its reference product. However, demonstrating that a proposed protein product is 109 biosimilar to an FDA-licensed reference product manufactured by a different manufacturer may 110 require more extensive and comprehensive data than assessing the comparability of a product 111 before and after a manufacturing process change made by the product’s sponsor. Unlike a

112 manufacturer who modifies its own manufacturing process with extensive knowledge and

113 information about the product and the existing process, including established controls and

114 acceptance parameters, the manufacturer of a proposed biosimilar product will likely have a

115 different manufacturing process (e.g., different cell line, raw materials, equipment, processes, 116 process controls, acceptance criteria) from that of the reference product and no direct knowledge 117 of the manufacturing process for the reference product.

118

119 In October 1999, FDA issued a draft guidance for industry on Applications Covered by Section 120 505(b)(2), which, among other things, stated that FDA may accept an application submitted

121 through the approval pathway described by section 505(b)(2) of the FD&C Act for a drug

122 product containing an active ingredient(s) derived from natural sources or recombinant DNA 123 technology. For example, FDA approved a 505(b)(2) application for a follow-on recombinant 124 DNA-derived human growth hormone product in May 2006. Greater knowledge due to

125 advances in science and technology, and improvements in manufacturing processes, process 126 controls, materials and product testing, as well as characterization tests and studies, facilitate the 127 use of an abbreviated pathway for the approval of a protein product.

128

129 The BPCI Act was enacted as part of the Affordable Care Act on March 23, 2010.4 The BPCI 130 Act creates an abbreviated licensure pathway for biological products demonstrated to be

131 biosimilar to, or interchangeable with, a reference product. Section 351(k) of the PHS Act (42 132 U.S.C. 262(k)), added by the BPCI Act, sets forth the requirements for an application for a

133 proposed biosimilar product and an application or a supplement for a proposed interchangeable 134 product.

135

136 Section 351(i) of the PHS Act defines biosimilarity to mean that the biological product is highly 137 similar to the reference product notwithstanding minor differences in clinically inactive

138 components and that there are no clinically meaningful differences between the biological

139 product and the reference product in terms of the safety, purity, and potency of the product (see 140 section 351(i)(2) of the PHS Act).

141

142 To meet the higher standard of “interchangeability,” an applicant must provide sufficient

143 information to demonstrate biosimilarity, and also to demonstrate that the biological product can 144 be expected to produce the same clinical result as the reference product in any given patient and, 145 if the biological product is administered more than once to an individual, the risk in terms of 146 safety or diminished efficacy of alternating or switching between the use of the biological

147 product and the reference product is not greater than the risk of using the reference product

148 without such alternation or switch (see section 351(k)(4) of the PHS Act).

149

150 Analytical studies provide the foundation for an assessment of the proposed protein product 151 intended for submission in a 351(k) application under the PHS Act and whether it is highly

152 similar to the reference product.

153

154

155 III. SCOPE

156

157 This document provides guidance on analytical studies that may be relevant to assessing whether 158 the proposed biosimilar protein product and a reference product are highly similar, which is part 159 of the biosimilarity assessment. This document is not intended to provide an overview of FDA’s 160 approach to determining interchangeability because FDA is continuing to consider the type of 161 information sufficient to enable FDA to determine that a biological product is interchangeable 162 with the reference product. Although this guidance applies specifically to therapeutic protein 163 products, the general scientific principles may be informative for the development of other

164 proteins, such as in vivo protein diagnostic products. If the reference product and the proposed 165 protein product cannot be adequately characterized with state of the art technology as

166 recommended by this guidance, FDA recommends that the sponsor consult FDA for guidance on 167 whether an application for the proposed protein product is appropriate for submission under 168 section 351(k) of the PHS Act.

169

170 All product applications should contain a complete and thorough chemistry, manufacturing and 171 controls (CMC) section that provides the necessary and appropriate information (e.g.,

172 characterization, adventitious agent safety, process controls, and specifications) for the product

4 The BPCI Act appears in title VII, subtitle A of the Affordable Care Act.

173 to be adequately reviewed. This guidance describes considerations for additional CMC 174 information that may be relevant to the assessment of biosimilarity between two protein

175 176 products. This guidance should be used as a companion to other guidances available from FDA that describe the CMC information appropriate for evaluation of protein products.5 We

177 encourage early interaction with FDA to discuss specific CMC issues that may arise for an

178 applicant’s proposed biosimilar product.

179

180 In addition to comparative analytical studies, an assessment of whether a proposed product is 181 biosimilar to a reference product generally will include animal studies (including the assessment

182 183 of toxicity) and a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics and/or pharmacodynamics).6

184

185 This guidance applies to applications submitted under section 351(k) of the PHS Act. However,

186 187 some scientific principles described in this guidance may be informative for the development of certain biological products under section 505(b)(2) of the FD&C Act.7 Section 505(b)(2) of the

188 FD&C Act and section 351(k) of the PHS Act are two separate statutory schemes. This guidance 189 is not intended to describe any relationship between the standards for approval under these

190 schemes.

191

192

193 IV. DEFINITIONS

194

195 For the purpose of this document, the following definitions are applicable:

196

197 Protein means any alpha amino acid polymer with a specific defined sequence that is 198 greater than 40 amino acids in size.

199

200 Chemically synthesized polypeptide means any alpha amino acid polymer that is (a) made 201 entirely by chemical synthesis, and (b) is less than 100 amino acids in size.

202

5 For CMC requirements for submission of a marketing application, applicants should consult current regulations,

the Guidance for Industry for the Submission on Chemistry, Manufacturing, and Controls Information for a

Therapeutic Recombinant DNA-Derived Product or a Monoclonal Antibody Product for In-vivo Use (issued jointly by CBER and CDER, August 1996) and other applicable FDA guidance documents.

6 For a discussion of the Agency’s current thinking on animal and clinical studies relevant to demonstrating

biosimilarity, see Draft Guidance for Industry on Scientific Considerations in Demonstrating Biosimilarity to a

Reference Product (issued jointly by CDER and CBER, February 2012).

7 A 505(b)(2) application is an NDA that contains full reports of investigations of safety and effectiveness, where at

least some of the information required for approval comes from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use (e.g., the Agency’s finding of safety and/or

effectiveness for a listed drug or published literature). A 505(b)(2) application that seeks to rely on a listed drug

(i.e., the reference product) must contain adequate data and information to demonstrate that the proposed product is

sufficiently similar to the listed drug to justify reliance, in part, on FDA’s finding of safety and/or effectiveness for the listed drug. Any aspects of the proposed product that differ from the listed drug must be supported by adequate data and information to show that the differences do not affect the safety and effectiveness of the proposed product.

203 Biosimilar or biosimilarity means that “the biological product is highly similar to the 204 reference product notwithstanding minor differences in clinically inactive components,”

205 206 and “there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.”8

207

208 Product, when used without modifiers, is intended to refer to intermediates, drug

209 substance, and/or drug product, as appropriate. The use of the term “product” is

210 consistent with the use of the term in ICH Q5E.

211

212 Reference product means the single biological product licensed under section 351(a) of 213 the PHS Act against which a biological product is evaluated in a 351(k) application. 214

215

216 V. GENERAL PRINCIPLES

217

218 Advances in analytical sciences (both physicochemical and biological) enable some protein 219 products to be characterized extensively in terms of their physicochemical and biological

220 properties. These analytical procedures have improved the ability to identify and characterize

221 222 not only the desired product but also product-related substances and product- and process-related impurities.9 Advances in manufacturing science and production methods may enhance the

223 likelihood that a product will be highly similar to another product by better targeting the original 224 product’s physiochemical and functional properties.

225

226 In addition to a complete CMC data submission as required under section 351(a) of the PHS Act, 227 the applicant should assess the analytical similarity to the reference product. The rationale for 228 the analytical similarity assessment should be clearly described with consideration for the known 229 quality attributes and performance characteristics of the specific reference product. Extensive, 230 robust comparative physicochemical and functional studies (these may include bioassays,

231 biological assays, binding assays, and enzyme kinetics) should be performed to evaluate whether 232 the proposed biosimilar product and the reference product are highly similar. A meaningful

233 assessment as to whether the proposed biosimilar product is highly similar to the reference

234 product depends on, among other things, the capabilities of available state-of-the-art analytical 235 assays to assess, for example, the molecular weight of the protein, complexity of the protein

236 (higher order structure and post-translational modifications), degree of heterogeneity, functional 237 properties, impurity profiles, and degradation profiles denoting stability. The capability of the 238 methods used in the analytical assessment, as well as their limitations should be described by the 239 applicant. Physicochemical and functional characterization studies should be sufficient to

240 establish relevant quality attributes including those that define a product’s identity, quantity, 241 purity, potency, and consistency. The product-related impurities, product-related substances, and 242 process-related impurities should be identified, characterized as appropriate, quantified, and

243 compared to those of the reference product to the extent feasible and relevant, as part of an

244 assessment of the potential impact on the safety, purity, and potency of the product.

8 Section 7002(b)(3) of the Affordable Care Act, adding section 351(i)(2) of the PHS Act.

9 The use of the terms “product-related substances” and “product- and process-related impurities” is consistent with

their use and meaning in ICH Q6B.

245

246 Primary structure of some protein products can be highly heterogeneous and could affect the 247 expected clinical performance of a protein product. In addition to the typically low level of

248 replication errors in the DNA encoding the protein sequence and amino acid misincorporation 249 that occurs during translation, most protein products undergo some post-translational

250 modification that can alter the functions of the protein: by attaching it to other biochemical

251 groups such as a phosphate, various lipids and carbohydrates; by proteolytic cleavage following 252 translation; by changing the chemical nature of an amino acid (e.g., formylation); or by many 253 other mechanisms. Such modifications can result from intracellular activities during cell culture 254 or by deliberate modification of the protein, for example, PEGylation. Other post-translational 255 modifications can be a consequence of manufacturing process operations — for example,

256 glycation may occur with exposure of the product to reducing sugars. In other cases, storage 257 conditions may be permissive for certain degradation pathways such as oxidation, deamidation, 258 or aggregation. As all of these product-related variants may alter the biological properties of the 259 expressed recombinant protein, identification and determination of the relative levels of these 260 protein variants should be included in the comparative analytical characterization studies.

261

262 The three dimensional conformation of a protein is an important factor in its biological function. 263 Proteins generally exhibit complex three-dimensional conformations (tertiary structure and, in 264 some cases, quaternary structure) due to their large size and the rotational characteristics of

265 protein alpha carbons. The resulting flexibility enables dynamic, but subtle, changes in protein 266 conformation over time, some of which may be absolutely required for functional activity.

267 These rotations are often dependent on low-energy interactions, such as hydrogen bonds and van 268 der Waals forces, which may be very sensitive to environmental conditions. Current analytical 269 technology is capable of evaluating the three-dimensional structure of many proteins. Methods 270 such as X-ray crystallography and multi-dimensional nuclear magnetic resonance (NMR)

271 spectroscopy can help define tertiary protein structure and, to varying extents, quaternary

272 structure, and can add to the body of information supporting biosimilarity. At the same time, a 273 protein’s three-dimensional conformation can often be difficult to define precisely using current 274 physicochemical analytical technology. Any differences in higher order structure between a 275 proposed biosimilar and a reference product should be evaluated in terms of a potential effect on 276 protein function. Thus, functional assays are also critical tools for evaluating the integrity of the 277 higher order structures.

278

279 A scientifically sound characterization that provides a comprehensive understanding of the

280 chemical, physical, and biological characteristics of the proposed biosimilar product is essential 281 to the design of the manufacturing process and to the conduct of development studies. The body 282 of knowledge that emerges will serve to support product quality during development, at

283 approval, and over the postapproval life of the product. Manufacturers should perform in-depth 284 chemical, physical, and bioactivity comparisons with side-by-side analyses of an appropriate 285 number of lots of the proposed biosimilar product and the reference product and, where available 286 and appropriate, a comparison with the reference standard for specific suitable attributes (e.g., 287 potency). For a discussion of reference standards, see section VI.G of this guidance. The

288 evaluation of multiple lots of reference product and biosimilar product enables determination of 289 product variability across lots and/or range of heterogeneity within a lot of drug product.

290 Identification of the specific lots of the reference product used in the biosimilar studies together

291 with expiration dates and timeframes of actual use would also be of value. This information will 292 be useful in justifying acceptance criteria used for specifications to ensure product consistency, 293 in addition to assessing similarity. However, acceptance criteria should be based on the totality 294 of the analytical data and not simply the observed range of product attributes of the reference 295 product. For example, some product attributes act in combination to define a product’s safety, 296 purity, and potency profile and therefore their potential interaction should be considered when 297 evaluating similarity and setting specifications. Thus, for some glycoproteins, the content and 298 distribution of tetraantennary and N-acetyl lactosamine repeats can affect in vivo potency and 299 should not be evaluated totally independently of each other. Additionally, data obtained for lots 300 used in nonclinical and clinical studies and relevant information on the relationship between an 301 attribute and the performance of the drug product (see ICH Q8) can also be used to help establish 302 acceptance criteria.

303

304 An extensive analytical characterization may also reveal differences between the reference

305 product and the proposed biosimilar product, especially when using analytical techniques

306 capable of discriminating qualitative or quantitative differences in product attributes. Emphasis 307 should be placed on developing orthogonal, quantitative methods to more definitively distinguish 308 any differences in product attributes. If the results show highly similar functional and

309 physicochemical characteristics, including, for example, higher order structure, post-translational 310 modifications, and impurity and degradation profiles, the sponsor may have an appropriate

311 scientific basis for a selective and targeted approach to subsequent animal and/or clinical studies 312 to support a demonstration of biosimilarity. It may be useful to compare differences in the

313 quality attributes of the proposed protein product with those of the reference product using a 314 meaningful fingerprint-like analysis algorithm that covers a large number of additional product 315 attributes and their combinations with high sensitivity using orthogonal methods. Advances in

316 317 manufacturing science and Quality-by-Design approaches may facilitate production processes that can better match a reference product’s fingerprint.10 Such a strategy could further quantify

318 the overall similarity between two molecules and may lead to additional bases for a more

319 selective and targeted approach to subsequent animal and/or clinical studies.

320

321 The type, nature, and extent of any differences between the proposed biosimilar product and the 322 reference product, introduced by design or observed from comprehensive analytical

323 characterization of multiple manufacturing lots, should be clearly described and discussed. The 324 discussion should include identification and comparison of relevant quality attributes from

325 product characterization, as this is an important factor in assessing whether the proposed

326 biosimilar product is highly similar to the reference product. The potential effect of the

327 differences on safety, purity, and potency should be addressed and supported by appropriate data. 328

329 The type and extent of nonclinical or clinical studies that are needed to demonstrate biosimilarity 330 of the proposed biosimilar product can be influenced by several factors, especially the ability to 331 discern differences and their potential effect on safety, purity, and potency. For example, factors 332 such as the ability to robustly characterize the proposed biosimilar product or the reference

333 product (e.g., lack of suitable or sufficiently discriminative analytical techniques) or availability 334 of a relevant drug substance derived from the reference product could impact the nature of the 335 subsequent nonclinical or clinical studies. In addition, if the proposed biosimilar product or

10 See ICH Q8(R2) for guidance.

336 reference product cannot be adequately characterized, the sponsor should consult FDA for

337 guidance on whether an application for such a protein product is appropriate for submission 338 under section 351(k) of the PHS Act.

339

340 In general, a sponsor needs to provide information to demonstrate biosimilarity based on data 341 directly comparing the proposed protein product with the reference product. Analytical studies 342 intended to support a demonstration of biosimilarity for purposes of section 351(k) of the PHS 343 Act must as a scientific matter include an adequate comparison to the reference product licensed 344 under section 351(a). However, under certain circumstances, a sponsor may seek to use data 345 derived from animal or clinical studies comparing a proposed protein product with a non-U.S.-346 licensed product to address, in part, the requirements under section 351(k)(2)(A) of the PHS Act. 347 In such a case, the sponsor should provide adequate data or information to scientifically justify

348 349 the relevance of this comparative data to an assessment of biosimilarity and to establish an acceptable bridge to the U.S.-licensed reference product.11 The scientific bridge between the

350 non-U.S.-licensed product and the U.S.-licensed reference product is likely to include

351 comparative physico-chemical characterization, bioassays/functional assays, and comparative 352 clinical and/or nonclinical PK and/or PD data, as appropriate, and data to address any differences 353 in formulation or primary packaging. Sponsors are encouraged to discuss with FDA during the 354 development program the adequacy of the scientific justification and bridge to the U.S.-licensed 355 reference product; a final determination of the adequacy of the information will be made by FDA 356 during review of the 351(k) application.

357

358 VI. FACTORS FOR CONSIDERATION IN ASSESSING WHETHER PRODUCTS 359 ARE HIGHLY SIMILAR

360

361 When assessing whether products are highly similar, manufacturers should consider a number of 362 factors, including the following.

363

364 A. Expression

System

365

366 Therapeutic protein products can be produced by microbial cells (prokaryotic, eukaryotic), cell 367 lines of human or animal origin (e.g., mammalian, avian, insect), or tissues derived from animals 368 or plants. It is expected that the expression construct for a proposed biosimilar product will

369 encode the same primary amino acid sequence as its reference product. However, minor

370 modifications, such as N or C terminal truncations that will not have an effect on safety, purity, 371 or potency, may be justified by the applicant. Differences between the chosen expression system 372 of the proposed biosimilar product and that of the reference product should be carefully

373 considered because the type of expression system and host cell will significantly affect the types 374 of process- and product-related substances and impurities (including potential adventitious

375 agents) that may be present in the protein product. For example, the expression system can have 376 a significant effect on the types and extent of translational and post-translational modifications

11 Please refer to the Draft Guidance for Industry on Scientific Considerations in Demonstrating Biosimilarity to a

Reference Product (issued jointly by CDER and CBER, February 2012).

377 that are imparted to the proposed protein product, something that may complicate an effort to 378 demonstrate that the proposed biosimilar product is highly similar to the reference product (and 379 thus, for example, affecting the type and extent of nonclinical and clinical data that are needed 380 for demonstrating biosimilarity). Minimizing differences between the proposed and reference 381 expression systems to the extent possible can enhance the likelihood of producing a highly

382 similar protein product. The characterization of the expression construct, including its genetic 383 stability, should be demonstrated in accordance with principles recommended in ICH Q5B.

384

Process

385 B. Manufacturing

386

387 A comprehensive understanding of all steps in the manufacturing process for the proposed

388 biosimilar product should be established during product development. Characterization tests, 389 process controls, and specifications that will emerge from information gained during process 390 development must be specific for the proposed biosimilar product and manufacturing process. 391 The use of Quality-by-Design approaches to pharmaceutical development, along with quality 392 risk management and effective quality systems, will facilitate the consistent manufacturing of a 393 high-quality product. A type II Drug Master File (DMF) would not be acceptable for a 351(k) 394 application because, as with 351(a) BLAs, the license holder needs to have knowledge of and 395 control over the manufacturing process for the biological product.12 Other types of contract

396 manufacturing arrangements can be considered if the applicant does not intend to manufacture 397 the product for licensure.13

398

399 C. Assessment of Physicochemical Properties

400

401 Physicochemical assessment of the proposed biosimilar product and the reference product should 402 consider all relevant characteristics of the protein product (e.g., the primary, secondary, tertiary, 403 and quaternary structure, post-translational modifications, and functional activity(ies)). The 404 objective of this assessment is to maximize the potential for detecting differences in quality

405 attributes between the proposed biosimilar product and the reference product.

406

407 The applicant should address the concept of the desired product (and its variants) as defined in 408 ICH Q6B when designing and conducting the characterization studies. Thus, it will be important 409 to understand the heterogeneity of the proposed biosimilar product and the reference product 410 (e.g., the nature, location, and levels of glycosylation) and the ranges of variability of different 411 isoforms, including those that result from post-translational modifications.

412

12 A type II DMF may, however, be used to support an Investigational New Drug Application (IND) for a biosimilar

product. Assurance of product quality should be provided on each lot of material produced by the DMF holder.

Procedures should also be in place to ensure that the IND sponsor is notified by the DMF holder of significant

changes to the DMF potentially affecting product quality. The sponsor is expected to provide notification to the

Agency of any relevant change in the IND in order to initiate a reevaluation of the DMF.

13 See FDA’s guidance on Cooperative Manufacturing Arrangements for Licensed Biologics (2008).

413 414 Particular analytical methodologies can be used to assess specific physicochemical characteristics of proteins. 14 These methodologies are described in published documents,

415 including scientific literature, regulatory guidelines, and pharmacopeial compendia. Some

416 techniques provide information on multiple characteristics. It is expected that appropriate

417 analytical test methods will be selected based on the nature of the protein being characterized 418 and knowledge regarding the structure and heterogeneity of the reference and the proposed

419 biosimilar product, as well as those characteristics that are critical to product performance. To 420 address the full range of physicochemical properties or biological activities adequately, it is often 421 necessary to apply more than one analytical procedure to evaluate the same quality attribute. 422 Methods that use different physicochemical or biological principles to assess the same attribute 423 are especially valuable because they provide independent data to support the quality of that

424 attribute (e.g., Size Exclusion Chromatography and Analytical Ultracentrifugation or Field Flow 425 Fractionation for the determination of aggregates). In addition, the use of complementary

426 analytical techniques in series, such as peptide mapping or capillary electrophoresis combined 427 with mass spectrometry of the separated molecules, should provide a meaningful and sensitive 428 method for comparing products.

429

430 Tests used to characterize the product do not necessarily need to be validated for routine quality 431 control purposes, but should be scientifically sound, fit for their intended use, and provide results 432 that are reproducible and reliable. In selecting these tests, it is important to consider the

433 characteristics of the protein product, including known and potential impurities. Information 434 regarding the ability of a method to discern relevant differences between a proposed biosimilar 435 product and a reference product should be submitted as part of the comparison.

436

437 Tests chosen to detect and characterize these post-translational protein modifications should be 438 demonstrated to be of appropriate sensitivity and specificity to provide meaningful information 439 as to whether the proposed biosimilar product and the reference product are highly similar.

440

441 D. Functional

Activities

442

443 Functional assays serve multiple purposes in the characterization of protein products. These tests 444 act to complement physicochemical analyses and are a quality measure of the function of the 445 protein product.

446

447 Depending on the structural complexity of the protein and available analytical technology, the 448 physicochemical analysis may be unable to confirm the integrity of the higher order structures. 449 Instead, the integrity of such structures can be inferred from the product’s biological activity. If 450 the clinically relevant mechanism(s) of action are known for the reference product or can

451 reasonably be determined, one or more of the functional assays should reflect these mechanisms 452 of action to the extent possible. The assessment of functional activity is also useful in providing 453 an estimate of the specific activity of a product, as an indicator of manufacturing process

454 consistency, as well as product purity and stability.

455

14 In some cases, in vivo immunogenicity studies may be able to detect subtle differences in structure or impurities

not detected by other methods.

456 If a reference product exhibits multiple functional activities, manufacturers should perform a set 457 of relevant assays designed to evaluate the range of activities. For example, with proteins that 458 possess multiple functional domains that express enzymatic and receptor-mediated activities, 459 manufacturers should evaluate both activities. For products where a single functional activity 460 can be measured by more than one, but related, parameter (e.g., enzyme kinetics or interactions 461 with blood clotting factors), comparative characterization of each parameter between products 462 should be used to provide additional valuable information.

463

464 The manufacturer should recognize the potential limitations of some types of functional assays, 465 such as high variability, that might preclude detection of small but significant differences

466 between the proposed biosimilar product and the reference product. As a highly variable assay 467 may not provide a meaningful assessment as to whether the proposed biosimilar product is

468 highly similar to the reference product, applicants are encouraged to develop assays that are

469 sensitive to changes in the functional activities of the product. In addition, in vitro bioactivity 470 assays may not fully reflect the clinical activity of the protein. For example, these assays

471 generally do not predict the bioavailability (PK and biodistribution) of the product. These

472 factors can impact PD and clinical performance. Also, bioavailability can be dramatically

473 altered by subtle differences in glycoform distribution or other post-translation modifications. 474 Thus, these limitations should be taken into account when assessing the robustness of the quality 475 of data supporting biosimilarity and the need for additional information. Finally, functional

476 assays are critical in assessing the occurrence of neutralizing antibodies in nonclinical and

477 clinical studies.

478

479 E. Receptor Binding and Immunochemical Properties

480

481 When binding or immunochemical properties are part of the activity attributed to the protein 482 product, analytical tests should be performed to characterize the product in terms of these

483 specific properties (e.g., if binding to a receptor is inherent in protein function, this property

484 should be measured and used in comparative studies, see ICH Q6B for additional details).

485 Various methods such as surface plasmon resonance, microcalorimetry, or classical Scatchard 486 analysis can provide information on the kinetics and thermodynamics of binding. Such

487 information can be related to the functional activity and characterization of the proposed

488 biosimilar product’s higher order structure.

489

490 F. Impurities

491

492 The applicant should characterize, identify, and quantify impurities (product- and process-related 493 as defined in ICH Q6B) in the proposed biosimilar product and the reference product. If

494 comparative physicochemical analysis reveals comparable product-related impurities at similar 495 levels between the two products, pharmacological/toxicological studies to characterize potential 496 biological effects of specific impurities may not be necessary. However, if the manufacturing 497 process used to produce the proposed biosimilar product introduces different impurities or higher 498 levels of impurities than those present in the reference product, additional

499 pharmacological/toxicological or other studies may be necessary. As discussed in ICH S6, “[i]t

500 501 is preferable to rely on purification processes to remove impurities . . . rather than to establish a preclinical testing program for their qualification.”15

502

503 Process-related impurities arising from cell substrates (e.g., host cell DNA, host cell proteins), 504 cell culture components (e.g., antibiotics, media components), and downstream processing steps 505 (e.g., reagents, residual solvents, leachables, endotoxin, bioburden) should be evaluated. The 506 potential impact of differences in the impurity profile upon safety should be addressed and

507 supported by appropriate data. In all cases, the chosen analytical procedures should be adequate 508 to detect, identify, and accurately quantify biologically significant levels of impurities (see ICH 509 Q2B). In particular, the results of the immunological methods used to detect host cell proteins 510 depend on the assay reagents and the cell substrate used. Such assays should be validated using

511 512 the product cell substrate and orthogonal methodologies to ensure accuracy and sensitivity. This should be done across both products to the extent relevant and feasible.16

513

514 The safety of the proposed biosimilar product, as with any biological product, with regard to 515 adventitious agents or endogenous viral contamination should be ensured by screening critical 516 raw materials and confirmation of robust virus removal and inactivation achieved by the

517 manufacturing process (see ICH Q5A for guidance).

518

519 G. Reference Product and Reference Standards

520

521 A thorough physicochemical and biological assessment of the reference product should provide a 522 base of information from which to develop the proposed biosimilar product and justify reliance 523 on certain existing scientific knowledge about the reference product. Sufficient evidence that the 524 proposed biosimilar product is highly similar to the reference product must be demonstrated in

525 526 an appropriate time frame to support a selective and targeted approach in early product development (e.g., reduced nonclinical studies, and/or dose-finding clinical studies).17 To justify

527 a selective and targeted approach to a clinical program, a comprehensive physicochemical and 528 functional comparison to the reference product should be performed during early product

529 development and discussed with the appropriate FDA staff. An analytical similarity assessment 530 should support the use of lots that demonstrate the biosimilarity of the proposed biosimilar

531 product used in the principal clinical trial to the reference product and the proposed commercial 532 product. The biosimilar application should include a thorough analytical comparison between 533 the proposed biosimilar product and the reference product. In addition, even when multiple 534 approved products are on the market, a sponsor must demonstrate that the proposed product is 535 biosimilar to a single reference product that previously has been licensed by FDA.

536

537 If the drug substance has been extracted from the reference product in order to assess analytical 538 similarity, the applicant should describe the extraction procedure and provide support that the 539 procedure itself does not alter product quality. This undertaking would include consideration for

15 See ICH S6, page 2.

16 This may be limited by the availability of high levels of reference product host cell proteins or differences in

product and reference substrate.

17 See 21 CFR 312.23 for Investigational New Drug (IND) application content and format.

540 alteration or loss of the desired products and impurities and relevant product-related substances, 541 and it should include appropriate controls that ensure the relevant product characteristics of the 542 reference product are not significantly altered by the extraction procedure.

543

544 If there is a suitable, publicly available and well-established reference standard for the protein, 545 then a physicochemical and/or functional comparison of the proposed biosimilar product with 546 this standard should also be performed. For example, if an international standard for calibration 547 of potency is available, a comparison of the relative potency of the proposed biosimilar product 548 with this potency standard should be performed. As is recommended in ICH Q6B, an in-house 549 reference standard(s) should always be qualified and used for control of the manufacturing

550 process and product.

551

552 In summary, analytical studies carried out to support the approval of a proposed biosimilar

553 product should not focus solely on the characterization of the proposed biosimilar product in 554 isolation. Rather, these studies should be part of a broad comparison that includes, but is not 555 limited to, the proposed biosimilar product, the reference product, applicable reference standards, 556 and consideration of relevant publicly available information.

557

558 H. Finished Drug Product

559

560 Product characterization studies should be performed on the most downstream intermediate best 561 suited for the analytical procedures used. The attributes evaluated should be stable through any

562 563 further processing steps. For these reasons, characterization studies are often performed on bulk drug substance.18 However if bulk drug substance is reformulated and/or exposed to new

564 materials in the finished dosage form, the impact of these changes should be considered.

565

566 If the finished drug product is best suited for a particular analysis, the characterization should 567 compare the proposed finished biosimilar product and the finished reference product. If an

568 analytical method more sensitively detects specific attributes in the drug substance, but the

569 attributes it measures are critical and/or may change during manufacture of the finished drug 570 product, comparative characterization may be called for on both the isolated drug substance and 571 the finished drug product.

572

573 The acceptability of the type, nature, and extent of any differences between the proposed finished 574 biosimilar product and the finished reference product should be evaluated and supported by

575 appropriate data and rationale. Additionally, different excipients in the proposed product should 576 be supported by existing toxicology data for the excipient or by additional toxicity studies with 577 the formulation of the proposed biosimilar product. Excipient interactions as well as direct

578 toxicities should be considered. Proteins are very sensitive to their environment. Therefore, 579 differences in excipients or primary packaging may affect product degradation and/or clinical 580 performance. Differences in formulation between the proposed biosimilar product and the

581 reference product are among the factors that may affect whether subsequent clinical studies may 582 take a selective and targeted approach.

583

18 See 21 CFR 207.3.

584 I. Stability

585

586 An appropriate physicochemical and functional comparison of the stability of the proposed

587 biosimilar product with that of the reference product should be initiated. Accelerated and stress 588 stability studies, or forced degradation studies, should be used to establish degradation profiles 589 and provide direct comparison of the proposed biosimilar product with the reference product. 590 These comparative studies should be conducted under multiple stress conditions (e.g., high

591 temperature, freeze thaw, light exposure, and agitation) that can cause incremental product

592 degradation over a defined time period. Results of these studies may reveal product differences 593 that warrant additional evaluation and also identify conditions under which additional controls 594 should be employed in manufacturing and storage (see ICH Q5C and Q1A(R) for guidance). 595 Sufficient real time, real condition stability data should be provided to support the proposed 596 dating period.

597

598

599 VII. CONCLUSION

600

601 The foundation for an assessment of biosimilarity between a proposed biosimilar product and its 602 reference product involves the robust characterization of the proposed biosimilar product,

603 including comparative physicochemical and functional studies. The information gained from 604 these studies is critical to the overall product assessment that as a scientific matter is necessary 605 for the development of a proposed biosimilar product. In addition, a 351(k) application for a 606 proposed biosimilar product must contain, among other things, information demonstrating

607 biosimilarity based upon data derived from animal studies (including the assessment of toxicity) 608 and a clinical study or studies (including the assessment of immunogenicity and

609 pharmacokinetics or pharmacodynamics), unless the Agency determines that an element is

610 unnecessary in a particular 351(k) application. The ability to discern relevant differences

611 between the proposed product and its reference product will depend on the available analytical 612 technology and complexity of the product. Any information regarding differences between the 613 proposed product and the reference product should be considered to determine whether the

614 statutory standard for biosimilarity can be met.

615

616

617 VIII. RELEVANT GUIDANCES

618

619 The following guidance documents may be relevant to sponsors developing or considering

620 development of a biosimilar product candidate. All Agency guidance documents are available 621 on FDA’s Web page (https://www.wendangku.net/doc/f39543063.html,/RegulatoryInformation/Guidances/default.htm).

622

623

624 1. Draft Guidance for Industry on Scientific Considerations in Demonstrating Biosimilarity 625 to a Reference Product (issued jointly by CDER and CBER, February 2012)

626

627 2. Draft Guidance for Industry, Biosimilars: Questions and Answers Regarding

628 Implementation of the Biologics Price Competition and Innovation Act of 2009 (issued 629 jointly by CDER and CBER, February 2012)

630

631 3. FDA Guidance Concerning Demonstration of Comparability of Human Biological

632 Products, Including Therapeutic Biotechnology-Derived Products (issued jointly by 633 CDER and CBER, April 1996)

634

635 4. Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for 636 Human Use (issued by CBER, February 1997)

637

638 5. Guidance for Industry for the Submission of Chemistry, Manufacturing, and Controls 639 Information for a Therapeutic Recombinant DNA-Derived Product or a Monoclonal 640 Antibody Product for In Vivo Use (issued jointly by CDER and CBER, August 1996) 641

642 6. FDA Guidance on Cooperative Manufacturing Arrangements for Licensed Biologics 643 (issued jointly by CDER and CBER, November 2008).

644

645 7. ICH M4Q The Common Technical Document

646

647 8. ICH Q2 Text on Validation of Analytical Procedures

648

649 9. ICH Q2B Validation of Analytical Procedures: Methodology

650

651 10. ICH Q3A Impurities in New Drug Substances

652

653 11. ICH Q5A Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of 654 Human or Animal Origi n

655

656 12. ICH Q5B Quality of Biotechnological Products: Analysis of the Expression Construct in 657 Cells Used for Production of r-DNA Derived Protein Products

658

659 13. ICH Q5C Stability Testing of Biotechnological/Biological Products

660

661 14. ICH Q5D Quality of Biotechnological/Biological Products: Derivation and

662 Characterization of Cell Substrates Used for Production of Biotechnological/Biological 663 Products

664

665 15. ICH Q5E Comparability of Biotechnological/Biological Products Subject to Changes in 666 Their Manufacturing Process

667

668 16. ICH Q6B Specifications: Test Procedures and Acceptance Criteria for

669 Biotechnological/Biological Products

670

671 17. ICH Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients 672

673 18. ICH Q8 Pharmaceutical Development

674

675 19. ICH Q9 Quality Risk Management

676

677 20. ICH Q10 Pharmaceutical Quality System

678

679 21. ICH S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals

药品经营的质量风险管理规程

编号：SY-AQ-04294 ( 安全管理) 单位：_____________________ 审批：_____________________ 日期：_____________________ WORD文档/ A4打印/ 可编辑 药品经营的质量风险管理规程Regulations on quality risk management of pharmaceutical trade

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1.目的： 为保证公司能适当的应对质量风险，提高质量风险应对的效率和效果，增强行动 的合理性，有效的配置资源——利用有限的资源，最大化的减小风险，特制定本 规程。本规程规定了药品质量风险管理的原理、过程、工具及其应用范围。 2.范围： 本标准适用于公司所有药品生命周期内的质量风险管理的全过程。 3.责任： 质管科长、质量受权人、公司各相关职能部门对本规程的实施负责。

4.内容： 4.1 质量风险管理流程图 不 可 接 受沟通

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Guide operators to deal with the process of things, and require them to be familiar with the details of safety technology and be able to complete things after special training.药品经营的质量风险管理 规程正式版

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