药用辅料指南

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Guidance for Industry

工业指南

Nonclinical Studies for

非临床研究

Development of

发展于

Pharmaceutical Excipients

药用辅料

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only.

本指南文件只是为了征求意见

Comments and suggestions regarding this draft document should be submitted within 90 days of 关于这个草案的意见和建议应90天内提交

publication in the Federal Register of the notice announcing the availability of the draft

guidance. Submit comments to Dockets Management Branch (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) Robert E. Osterberg at 301-594- 5476, or (CBER) Martin Green at 301-827-5349.

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)

September 2002

Pharmacology/ToxicologyDraft — Not for Implementation

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Guidance for Industry

Nonclinical Studies for

Development of

Pharmaceutical Excipients

Additional copies are available from:

Office of Training and Communications

Division of Communications Management

Drug Information Branch, HFD-210

5600 Fishers Lane

Rockville, MD 20857

(Tel) 301-827-4573

(Internet) http://www.fda.gov/cder/guidance/index.htm

or

Office of Communication, Training and

Manufacturers Assistance, HFM-40

Center for Biologics Evaluation and Research

Food and Drug Administration

1401 Rockville Pike, Rockville, MD 20852-1448

Internet: http://www.fda.gov/cber/guidelines.htm.

Mail: the Voice Information System at 800-835-4709 or 301-827-1800

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)

September 2002

Pharmacology/ToxicologyDraft — Not for Implementation

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TABLE OF CONTENTS

I. INTRODUCTION................................................................................................................. 1

II. BACKGROUND ................................................................................................................... 1 III. RECOMMENDED DEVELOPMENT STRATEGIES TO SUPPORT MARKETING

OF NEW EXCIPIENTS IN DRUG PRODUCTS...................................................................... 3

A. Safety

Pharmacology .....................................................................................................................3

B. Potential Excipients Intended for a Maximum Duration of Clinical Use of 14 Consecutive

Days or Less....................................................................................................................................3

C. Potential Excipients Intended for a Maximum Duration of Clinical Use of More than 14

days but Less than or Equal to 90 Consecutive Days. ................................................................4

D. Potential Excipients Intended for a Maximum Duration of Clinical Use of More Than 3

Months. ...........................................................................................................................................5

E. Potential excipients for use in pulmonary or topical products. .................................................6

F. Photosafety data.............................................................................................................................7 IV . SUMMARY ........................................................................................................................... 7Draft — Not for Implementation

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Guidance for Industry

1

1

2 Nonclinical Studies for Development of

3 Pharmaceutical Excipients

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5

6

7

8

9 This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's) current

10 thinking on this topic. It does not create or confer any rights for or on any person and does not operate to

11 bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements

12 of the applicable statutes and regulations.

13

14

15

16

17

18 I. INTRODUCTION

19

20 This document provides guidance concerning development of safety profiles to support use of 21 new excipients as components of drug or biological products. It is intended for use by reviewers

22 within both the Center for Drug Evaluation and Research (CDER) and the Center for Biologics 23 Evaluation and Research (CBER) and by interested individuals in industry. This guidance is 24 intended to foster and expedite the development of new excipients, communicate to industry 25 current CDER and CBER thoughts pertaining to the safety data that should be generated to 26 support excipient development, and to increase uniformity within CDER and CBER as to 27 expectations for the nonclinical development of excipients.

28

29

30 II. BACKGROUND

31

32 In this guidance, the phrase new excipients means any ingredients that are intentionally added to

33 therapeutic and diagnostic products but which: (1) we believe are not intended to exert

34 therapeutic effects at the intended dosage (although they may act to improve product delivery, 35 e.g., enhancing absorption or controlling release of the drug substance); and (2) are not fully 36 qualified by existing safety data with respect to the currently proposed level of exposure, 37 duration of exposure, or route of administration. Examples of ingredients include fillers, 38 extenders, diluents, wetting agents, solvents, emulsifiers, preservatives, flavors, absorption 39 enhancers, sustained-release matrices, and coloring agents. Within the context of this guidance,

40 the term excipient does not apply to macromolecular compounds like albumin, or compounds 41 like amino acids and sugars that are used in biological products, nor does it apply to process or

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. Draft — Not for Implementation

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42 product-related impurities (e.g. degradation products, leachates, residual solvents), or extraneous

43 contaminants.

44

45 Excipients are potential toxicants. It is important to perform risk-benefit assessments on 46 proposed new excipients in drug products and to establish permissible and safe limits for these 47 compounds. Safety data should be submitted to support use of new excipients. As a result, there

48 is a perception that development of new excipients is resource intensive. With proper planning,

49 however, it is often possible to assess the toxicology of an excipient in a relatively efficient 50 manner. For example, sponsors may be able to develop new excipients concurrently with 51 development of new therapeutic substances by adding groups of animals that receive the

52 excipient to studies that would have been conducted anyway to develop a drug substance. We 53 recognize that existing human data for some excipients can substitute for nonclinical safety data,

54 and an excipient with documented prior human exposure under circumstances relevant to the 55 proposed use may not require evaluation in the full battery of toxicology studies outlined below.

56 For example, we will continue to consider factors such as use in previously approved products or

57 GRAS status as a food additive. Under some circumstances (e.g., similar route of

58 administration, level of exposure, patient population, and duration of exposure) other factors can

59 adequately qualify an excipient, although it may be important for the safety database associated 60 with that excipient to be brought up to current standards (e.g., submission of additional genetic 61 toxicology data). The applicable information that supported the prior use will be considered in

62 light of any proposed new use.

63

64 For products marketed under OTC drug monographs, 21 CFR 330.1(e) sets the criteria for 65 inactive ingredients: "The product contains only suitable inactive ingredients which are safe in 66 the amounts administered and do not interfere with the effectiveness of the preparation or with 67 suitable tests or assays to determine if the product meets its professed standards of identity, 68 strength, quality, and purity. Color additives may be used only in accordance with section 721 of

69 the act and subchapter A of this chapter." It is the manufacturer's responsibility to meet these 70 criteria and to have appropriate supporting data in its files. The provisions of section 330.1(e) do

71 not apply to OTC products marketed under new drug applications (NDAs) or abbreviated new 72 drug applications (ANDAs).

73

74 Requirements for submitting safety information on inactive ingredients in ANDAs for generic 75 products are stated in 21 CFR 314.94 (a)(9). Under this regulation, drug products intended for

76 parenteral, ophthalmic, or otic use should contain the same inactive ingredients in the same 77 concentrations as the reference listed drug product, with the exception of buffers, antioxidants, 78 and preservatives, provided that the applicant identifies and characterizes the differences and 79 provides information demonstrating that the differences do not affect the safety of the proposed 80 drug product. For other routes of administration (e.g., topical dermal, oral), there is no

81 requirement that the inactive ingredients in the final formulations be the same as those in the 82 reference listed drug product. However, the applicant is required to identify and characterize the

83 differences in inactive ingredients and provide information demonstrating that the differences do

84 not affect the safety of the proposed drug product. Consideration should be given to the prior 85 indication and patient population for which use of the excipient was previously deemed safe. 86 Alternatively, new or additional information to support the proposed new use should be 87 referenced.Draft — Not for Implementation

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88

89 A new or inadequately qualified inactive ingredient proposed for use in any product to be 90 marketed pursuant to an NDA, BLA, or ANDA should be supported by adequate data, which 91 may be placed in the application directly or in a drug master file (DMF). This guidance

92 describes what nonclinical data should be submitted to verify that a proposed excipient is safe in

93 the amounts administered if relevant prior human use cannot be adequately documented. 94

95 We may request additional safety data if we determine that the proposed conditions of use are 96 not fully supported by the available data. A pharmacokinetic profile could be requested for 97 excipients that are extensively absorbed or biotransformed. Where applicable, drug-excipient 98 interaction studies might also be requested. The proposed conditions of use of a new excipient

99 (e.g., use in pediatric patients) may affect the need for toxicology data.

100

101 We recognize that every compound is unique and that scientifically valid reasons may exist for

102 modifying and deleting certain of the studies listed below for a given combination of excipient

103 and proposed use. For example, it may be justifiable for the development of excipients deemed

104 necessary for the delivery of life saving therapies to be abbreviated (relative to development of

105 excipients for use in products for low morbidity indications) or completed postapproval. As 106 another example, excipients that are large polymers that differ from previously characterized 107 compounds only in molecular weight (chain length) may be adequate using less safety data, 108 provided that the new compound and the previously studied compound are sufficiently similar 109 with regard to physical state, pharmacokinetics, and levels of unreacted monomers and other 110 impurities. We will consider such exciptients on a case-by-case basis. All pivotal toxicology

111 studies should be performed in accordance with state-of-the-art protocols and good laboratory 112 practice regulations. The recommendations given below are primarily intended for compounds 113 for which adequate prior human exposure has not been documented.

114

115

116 III. RECOMMENDED DEVELOPMENT STRATEGIES TO SUPPORT

117 MARKETING OF NEW EXCIPIENTS IN DRUG PRODUCTS

118

119 A. Safety Pharmacology

120

121 It is recommended that all potential new excipients be appropriately evaluated for

122 pharmacological activity using a battery of standard tests (see ICH S7 guidance). These 123 evaluations may be performed during the course of toxicology studies or as independent 124 safety pharmacology studies. It is useful for these data to be obtained at an early point 125 during the development of an excipient, since, if the excipient is found to be

126 pharmacologically active, this information may influence subsequent development. 127

128 B. Potential Excipients Intended for a Maximum Duration of Clinical Use of 14

129 Consecutive Days or Less.

130

131 It is recommended that the safety development of potential new excipients that are

132 intended for use in products that are limited by labeling to clinical use of 14 or fewerDraft — Not for Implementation

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133 consecutive days per treatment episode and are infrequently used include at least the 134 following:

135

136 1. Acute toxicology studies should be performed in both a rodent species and a

137 mammalian nonrodent species by the route(s) of administration intended for

138 clinical use (see CDER guidance for industry, Single Dose Acute Toxicity

139 Testing for Pharmaceuticals). It is not necessary to determine the LD50 of an

excipient.

2

140 It may be appropriate to omit acute toxicology studies from the

141 development of a new excipient under certain circumstances. For example, if

142 repeat-dose toxicology studies are performed in which the high dose is the

maximum feasible dose (MFD,

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143 e.g., 5 g/kg or 5% of the diet) and little or no

144 toxicity is observed at the MFD, it can be assumed that the acute toxicity has

145 been adequately evaluated.

146

147 2. It is highly recommended that the absorption, distribution, metabolism, and

148 excretion of the excipient be studied following administration by the clinically

149 relevant route(s) to the same species that are used in the nonclinical safety

150 studies (see the ICH S3A and S3B guidances). These data may be obtained in

151 separate (pharmacokinetic) studies or as toxicokinetic analyses associated

152 with toxicology studies.

153

154 3. Excipients should be evaluated in the standard battery of genetic toxicology

155 studies discussed in the ICH S2B guidance.

156

157 4. One-month repeat dose toxicology studies should be performed in both a

158 rodent species and a mammalian nonrodent species by the route(s) of

159 administration intended for clinical use. The studies should use state-of-the-

160 art protocols and include complete clinical pathology, histopathology, and

161 toxicokinetic analysis.

162

163 5. The reproductive toxicology of the excipient should be evaluated as discussed

164 in the ICH S5A and S5B guidances, including: (1) assessment of potential to

165 affect fertility or early embryonic development to implantation, (2) teratology

166 in both a rodent species and a mammalian nonrodent species, and (3) effects

167 on prenatal and postnatal development, including maternal function. It is

168 suggested that the most efficient way to address these different developmental

169 landmarks is use of a single-study rodent assay (as defined in the ICH S5A

170 guidance) to assess all phases of reproductive toxicity, in conjunction with a

171 teratology study in a nonrodent species provided that the available data predict

172 the excipient has minimal toxicity.

173

174 C. Potential Excipients Intended for a Maximum Duration of Clinical Use of

175 More than 14 days but Less than or Equal to 90 Consecutive Days.

176

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53 FR 39650 (October 11, 1988)

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Maximum feasible doseDraft — Not for Implementation

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177 It is recommended that the nonclinical development of potential new excipients that are 178 intended for use in drug products that are labeled for clinical use of more than 14 days 179 but less than or equal to 90 consecutive days per treatment episode include at least the 180 following:

181

182 1. All studies from sections A and B in this guidance, with the exception of the

183 1-month toxicology studies. Note: If toxicity or significant biological activity

184 is observed in short-term studies, one-month toxicology studies may be useful

185 for establishing dosages to be used in 3-month studies.

186

187 2. Three-month repeat dose toxicology studies should be performed in both a

188 rodent species and a mammalian nonrodent species by the appropriate route(s)

189 of administration. The studies should use state-of-the-art protocols and

190 include complete clinical pathology, histopathology, and toxicokinetic

191 analysis.

192

193 3. Other studies may be called for (e.g., studies involving parenteral

194 administration). Whether more data should be gathered is usually driven by

195 questions raised in the already completed studies.

196

197 D. Potential Excipients Intended for a Maximum Duration of Clinical Use of

198 More Than 3 Months.

199

200 It is recommended that the safety development of potential new excipients that are 201 intended for use in drug products labeled for clinical use of more than 3 months in a 202 given patient (either as a single treatment episode or as a result of multiple courses of 203 therapy to treat a chronic or recurrent condition) include at least the following:

204

205 1. All studies from sections A, B, and C of this guidance. Note that 28-day and

206 90-day toxicology studies are not essential, but may provide useful dosage

207 selection data.

208

209 2. A 6-month repeat-dose toxicology study should be performed in a rodent

210 species by the appropriate route(s). The study should use state-of-the-art

211 protocols and include complete clinical pathology, histopathology, and

212 toxicokinetic analysis. Studies involving excipients of low toxicity should, in

213 general, use the MFD as the upper limit for testing.

214

215 3. A chronic toxicology study should be performed in a mammalian nonrodent

216 species by the appropriate route(s). If toxicity and pharmacologic effect were

217 absent in state-of-the-art subchronic studies, a 6-month study may be

218 sufficient. When toxicity is detected in shorter duration studies, or in rodents,

the chronic study in nonrodents should be extended to 1 year.

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219

220

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A 9 month study may be adequate in cases in which substantial human experience exists with closely related

excipients or when long-term clinical testing will provide a substantial portion of the safety database.Draft — Not for Implementation

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221 4. If appropriate (see ICH S1A guidance), one of the following approaches

222 should be used to evaluate carcinogenic potential:

223

224 a. Two-year carcinogenicity bioassays in two appropriate species by the

relevant route(s).

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225

226

227 b. A two-year carcinogenicity study in one rodent species plus an

228 alternative study (e.g., appropriate use of neonatal or transgenic

229 animals) in a different rodent species. The usual choice for that

230 alternative, absent evidence of genotoxicity, should be a model

231 sensitive to nongenotoxic carcinogenic events.

232

233 c. Submission of documentation providing scientific justification that

234 carcinogenicity data are not necessary. For example, based on

235 negative genetic toxicology data (see ICH S2B guidance for

236 recommended assays), limited systemic exposure, absence of

237 accumulation based on nonclinical and clinical pharmacokinetic data,

238 negative histopathology data from chronic toxicology studies

239 performed at the MFD (absence of preneoplastic lesions and other

240 toxicologic effects), and knowledge of other compounds in the same

241 class, it may be reasonable to forego carcinogenicity testing.

242 Decisions concerning the adequacy of this approach would be made on

243 a case-by-case basis, using a weight-of-evidence approach. In other

244 cases, adequately performed cell transformation assays or one 2-year

245 bioassay in the rat or one transgenic assay, if negative, may be

246 sufficient to contribute to the weight of evidence assessment to address

247 the carcinogenic potential of the excipient. It is strongly encouraged

248 that application of the above approach be undertaken in consultation

249 with appropriate CDER or CBER staff.

250

251 E. Potential excipients for use in pulmonary or topical products.

252

253 It is recommended that the safety development of potential new excipients that are

254 intended for use in topical (dermal, intranasal, intraoral, ophthalmic, rectal, or vaginal) or pulmonary drug products include the following

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255 :

256

257 1. All studies from sections A, B, C, or D, as appropriate, using the appropriate

258 route of administration. Studies that include the to-be-marketed formulation of

5

When possible, it may be most cost-effective for excipients to be evaluated for carcinogenicity through inclusion in

bioassays that are conducted in support of active ingredients. In such cases, it may be appropriate for the

carcinogenicity assessment of an excipient to be limited to administration of a single dosage of the excipient per

species (addition of a single arm to each bioassay), provided that the dosage was either the maximum tolerated dose

(MTD) or the MFD.

6

For cases in which a new excipient is being developed in relation to a specific product, sponsors are encouraged to

consult with the appropriate division to determine if additional guidance is available.Draft — Not for Implementation

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259 the drug product are preferred, if this information is available at the time of

260 excipient development.

261

262 2. Sensitization study (e.g., guinea pig maximization study or murine local

263 lymph node assay).

264

265 3. Excipients intended for topical use may require support from toxicology

266 studies by both the intended clinical route and by the oral or parenteral route if

267 clinical pharmacokinetic studies conducted under conditions of maximum

268 exposure show patients would experience systemic exposure to the excipient

269 or its metabolite, particularly if limited systemic exposure were observed in

270 nonclinical studies conducted by the clinical route of administration. The

271 developer of a potential new excipient is invited to contact the appropriate

272 center to discuss whether or not this is appropriate for a specific compound.

273

274 4. For topical dermal products and ophthalmic products, it may be appropriate to

275 conduct an ocular irritation study.

276

277 F. Photosafety data.

278

279 It is recommended that excipients be evaluated for photosafety as described in the CDER 280 guidance for industry entitled Photosafety Testing.

281

282

283 IV. SUMMARY

284

285 In summary, acknowledging the need to develop new excipients, CDER and CBER have 286 proposed a flexible approach that attempts to consider both the type of use the excipient will 287 have in approved products and the biological activity and physical properties of the molecular 288 entity. It is recognized that during the course of data evaluation, the reasons for additional data

289 or the potential to eliminate some studies may become apparent. In such cases, consultation with

290 appropriate center staff is recommended to avoid development delays

291