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Guidance for Industry

Liposome Drug Products

Chemistry, Manufacturing, and Controls; Human

Pharmacokinetics and Bioavailability; and Labeling

Documentation

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only.

Comments and suggestions regarding this draft document should be submitted within 90 days of

publication in the Federal Register of the notice announcing the availability of the draft guidance.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 Liang Zhou, (301) 827-7471.

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

August 2002

CMC
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Guidance for Industry

Liposome Drug Products

Chemistry, Manufacturing, and Controls; Human

Pharmacokinetics and Bioavailability; and Labeling

Documentation

Additional copies are available from:

Office of Training and Communication

Division of Drug Information, HFD-240

Center for Drug Evaluation and Research

Food and Drug Administration

5600 Fishers Lane

Rockville, MD 20857

(Tel) 301-827-4573

 http://www.fda.gov/cder/guidance/index.htm

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

August 2002

CMC
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Table of Contents

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

II. CHEMISTRY, MANUFACTURING, AND CONTROLS...................................................................................2

A. Description and Composition...............................................................................................................................2

B. Physicochemical Properties.................................................................................................................................3

C. Description of Manufacturing Process and Process Controls..........................................................................3

D. Control of Excipients: Lipid Components..........................................................................................................4

E. Control of Drug Product: Specifications ............................................................................................................5

F. Stability...................................................................................................................................................................6

G. Changes in Manufacturing.....................................................................................................................................6

III. HUMAN PHARMACOKINETICS AND BIOAVAILABILITY.........................................................................7

A. Bioanalytical Methods...........................................................................................................................................7

B. In Vivo Integrity (Stability) Considerations ........................................................................................................8

C. Protein Binding......................................................................................................................................................8

D. In Vitro Stability.....................................................................................................................................................8

E. Pharmacokinetics and Bioavailability..................................................................................................................9

IV. LABELING............................................................................................................................................................. 11

A. Product Name...................................................................................................................................................... 11

B. Cautionary Notes and Warnings ........................................................................................................................ 11

C. Dosage and Administration................................................................................................................................ 12
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GUIDANCE FOR INDUSTRY11

2

3 Liposome Drug Products

4

5 Chemistry, Manufacturing, and Controls; Human Pharmacokinetics and

6 Bioavailability; and Labeling Documentation

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21 If you plan to submit comments on this draft guidance, to expedite FDA review of your comments, please:

22

23 • Clearly explain each issue and/or concern and, when appropriate, include a proposed revision and the

24 rationale or justification for the proposed change.

25 • Identify specific comments by line number or numbers; use the pdf version of the document, whenever

26 possible.

27 • If possible, send an electronic copy (Word or WordPerfect) of the comments you have submitted to the

28 docket by e-mail to coryj@cder.fda.gov.

29

30

31 I. INTRODUCTION

32

33 This guidance provides recommendations to applicants on the chemistry, manufacturing, and

34 controls (CMC); human pharmacokinetics and bioavailability; and labeling documentation for

liposome drug products submitted in new drug applications (NDAs).235 The recommendations in

36 this guidance focus on the unique technical aspects of liposome drug products. Applicants should

 

1

 This guidance was prepared by the Liposome Working Group of the Complex Drug Substances Coordinating

Committee (CDSCC) in the Center for Drug Evaluation and Research (CDER) at the FDA.

2

 A liposomal formulation of an active moiety that has already been approved or marketed in the United States is

not classified as a new molecular entity (Type 1 NDA). When submitted in an NDA, the drug is classified as a

Type 3 NDA unless it is a new ester, new salt, or other noncovalent derivative of the approved drug substance. In

that case, the NDA would be classified as a Type 2,3.

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

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

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

the applicable statutes and regulations.
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refer to the forthcoming drug product guidance337 for other recommendations on the CMC

38 documentation that should be submitted in original NDAs. Applicants can contact the appropriate

39 review division if they have questions on demonstrating bioequivalence and sameness of liposome

40 drug products. The recommendations in this guidance should be considered, to the extent

41 applicable, when a sponsor is submitting an investigational new drug application (IND).

42

43 Liposome drug products are defined as drug products containing drug substances (active

44 pharmaceutical ingredients) encapsulated in liposomes. A liposome is a microvesicle composed

45 of a bilayer of lipid amphipathic molecules enclosing an aqueous compartment. Liposome drug

46 products are formed when a liposome is used to encapsulate a drug substance within the lipid

47 bilayer or in the interior aqueous space of the liposome. A drug substance in a liposome

48 formulation is intended to exhibit a different pharmacokinetic and/or tissue distribution (PK/TD)

49 profile from the same drug substance (or active moiety) in a nonliposomal formulation given by the

50 same route of administration. The complete characterization of the PK/TD profile of a new

51 liposome drug product is essential to establish the safe and effective dosing regimen of the

52 product.

53

54 The guidance does not provide recommendations on:

55

56 • clinical efficacy and safety studies

57 • nonclinical pharmacology and/or toxicology studies

58 • bioequivalence studies or those to document sameness

59 • liposomal formulations of vaccine adjuvants or biologics

• drug-lipid complexes460

61

62

63 II. CHEMISTRY, MANUFACTURING, AND CONTROLS

64

65 The recommendations provided on CMC documentation focus on the information specific to

66 liposome drug products that should be submitted to CDER. An applicant should consult all

67 relevant regulations and guidances for information on the type of documentation that should be

68 submitted for drug substances and other aspects of documenting the identity, strength, quality,

69 purity, and potency of the drug product.

70

71 A. Description and Composition

72

 

3

 This guidance is under development and, when finalized, will replace the guidance for industry Submitting

Documentation for the Manufacturing of and Controls for Drug Products. CDER guidance documents can be

found on the Internet at http://www.fda.gov/cder/guidance/index.htm. We update guidances periodically. To make

sure you have the most recent version of a guidance, check the CDER guidance Web site.

4 Drug-lipid complexes are formed by mixing a drug with lipids in such a way that true liposomes are not created.

The CMC, pharmacokinetics, and bioavailability recommendations for drug-lipid complexes and liposomes can be

similar. Applicants intending to submit an NDA for a drug-lipid complex can consult the appropriate review

division in CDER for additional guidance if necessary.
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73 The components of liposome drug products are the drug substance, the lipids, and other

74 inactive ingredients. The quantity of lipid in the formulation should be expressed as the

75 molar ratio and percentage by weight of the lipid to the drug substance as well as on the

76 milligram (mg) per milliliter (mL) and per vial basis. The pharmacological and

77 toxicological properties and the quality of these drug products can vary significantly with

78 changes in the formulation, including the lipid composition. Therefore, any ranges in the

79 formulation components should be specified and be as narrow as feasible. The drug

80 product composition and any specified ranges for components should be justified.

81

82 B. Physicochemical Properties

83

84 The physicochemical properties of the liposome drug product are critical to ensuring drug

85 product quality. Therefore, a detailed evaluation of these properties should be provided.

86 Rigorous characterization of the physicochemical properties can also be beneficial in

87 evaluating subsequent changes in manufacturing (see section II.G. on Changes in

88 Manufacturing). The physicochemical characterization tests, which are critical to ensuring

89 product quality of each batch of liposome drug product, should be identified. However, all

90 the characterization tests need not be included in the specifications. Properties specific to

91 liposome drug products that may be useful to assess include:

92

93 • morphology of the liposome, including lamellarity determination, if applicable

94 • net charge

95 • volume of entrapment in liposomal vesicles

96 • particle size (mean and distribution profile)

97 • phase transition temperature

98 • spectroscopic data, as applicable

99 • in vitro release of the drug substance from the liposome drug product

100 • osmotic properties

101 • light scattering index

102

103 C. Description of Manufacturing Process and Process Controls

104

105 Liposome drug products are sensitive to changes in the manufacturing conditions, including

106 changes in scale. This should be considered during the development process, and critical

107 manufacturing parameters (e.g., scale, shear force, temperature) should be identified and

108 evaluated. If there are changes in critical manufacturing parameters, complete

109 characterization of the liposome drug product is recommended and in vivo studies may be

110 warranted (see section II.G. on Changes in Manufacturing).

111

112 The chemical and physical complexity of liposome drug products can provide unique

113 challenges to the sterilizing filtration process. For example, constituents of the liposome

114 may block adsorptive interactions of organisms with the filter matrix, effectively allowing

115 organisms to pass through the sterilizing filter. Therefore, product-specific validation

116 studies should demonstrate the microbial retentivity of the intended sterilizing filters. 

117
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118 D. Control of Excipients: Lipid Components

119

120 The quality and purity of the lipid components can affect the quality of the liposome drug

121 product. Information concerning the CMC of the lipid components should be provided at

122 the same level of detail expected for a drug substance. For further information, refer to the

123 guidance for industry Submitting Supporting Documentation in Drug Applications for the

124 Manufacture of Drug Substances (the drug substance guidance). This information can be

125 provided in a Type IV Drug Master File (DMF). (See guidance for industry Guideline for

126 Drug Master Files).

127

128 In addition to the information recommended by the drug substance guidance,

129 recommendations specific to lipid components are provided below.

130

131 1. Description and Characterization

132

133 If the lipid is a well-defined synthetic or semisynthetic lipid, such as

134 dimyristoylphosphatidylcholine (DMPC), a structure proof based upon standard

135 spectroscopic techniques is usually sufficient. In the case of natural lipid mixtures

136 (e.g., egg lecithin), the lipid composition (i.e., percentage of each lipid) and the

137 fatty acid composition (i.e., the percentage of each fatty acid) should be provided.

138

139 2. Manufacture

140

141 For synthetic lipids, the source (e.g., manufacturer) and specifications for any

142 starting materials should be provided. For natural lipid mixtures and natural143 sourced materials that start the synthetic segment of a semisynthetic process, the

144 biological source (e.g., eggs), country of origin of the source material, supplier, and

145 specifications should be provided.

146

147 A complete description of the synthetic process, extraction, and purification

148 procedures should be provided, as applicable. Specifications should be provided

149 for starting materials, raw materials, solvents, and reagents. The controls for

150 critical steps and intermediates should be provided. Chromatographic purification

151 procedures should be described, including the collection of desired fractions, and a

152 sample chromatogram should be provided. For synthetic and semisynthetic lipids,

153 the manufacturing controls that ensure positional specificity of acyl side chains

154 should be provided, if applicable. (See the drug substance guidance for additional

155 information on the manufacturing information that should be provided.)

156

157 Procedures to ensure the removal of animal proteins and viruses should be

158 described, where applicable. Bovine-derived materials should not be imported

159 from countries that are defined as bovine spongiform encephalopathy countries by

160 the U.S. Department of Agriculture (see 9 CFR 94.11).

161

162 3. Specifications

163
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164 A full description of the tests, procedures, and acceptance criteria for the lipid

165 components should be provided. Reference standards should be established and

166 their preparation, qualifications, and storage conditions should be described. In

167 general, the analytical procedures should be validated and the specifications should

168 include a stability-indicating assay. Impurities, including possible synthetic by169 products, should be evaluated. The level that would warrant identification and

170 qualification will be determined on a case-by-case basis.

171

172 For synthetic lipids such as DMPC and semisynthetic lipids, the assay and impurity

173 tests can be done by comparison with the reference standard (e.g., thin-layer

174 chromatography (TLC)) when the analytical procedure can distinguish the desired

175 lipids from possible impurities. If the analytical procedure cannot distinguish the

176 desired lipids from impurities, then assays capable of confirming the fatty acid

177 composition and positional specificity should be used.

178

179 For natural lipid mixtures such as egg lecithin, the specifications should be

180 sufficient to ensure that the lipid can perform adequately in the liposome drug

181 product and conform to impurity limits. Based on the nature of lipid or lipid

182 mixtures, the lipid composition (e.g., percentage of each lipid and fatty acid,

183 positional specificity of acyl side chains, degree of fatty acid unsaturation) should

184 be specified in some circumstances. For instance, if the degree of unsaturation of

185 the fatty acid side chains is too high, stable liposomes might not be formed. If the

186 data indicate that this is a critical factor, acceptance criteria for the degree of fatty

187 acid unsaturation should be included in the specifications. Other examples of

188 parameters that can be critical to the performance of the lipid are the amount of

189 phosphatidylglycerol or phosphatidylserine in a lecithin preparation.

190

191 4. Stability

192

193 Lipids used to manufacture liposomes should undergo stability studies to establish

194 the storage conditions and retest date or shelf life. Stress testing (i.e., high

195 temperature, light, pH, and oxygen), should be performed to determine the

196 degradation profile. The container and closure system for storage and shipment of

197 the lipids should be described, and relevant stability data should be provided.

198

199 E. Control of Drug Product: Specifications

200

201 For recommendations on specifications, applicants should consult the International

202 Conference on Harmonisation (ICH) guidance for industry Q6A Specifications: Test

203 Procedures and Acceptance Criteria for New Drug Substances and New Drug Products:

204 Chemical Substances, where appropriate. Additional testing specific to liposome drug

205 products is recommended over that which is typical of the nonliposomal dosage form.

206 Additional tests may include, for example:

207

208 • physicochemical parameters of the liposome determined to be critical to product

209 quality for each batch (see section II. B. on Physicochemical Characterization)
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210 • assay for encapsulated and unencapsulated (i.e., free) drug substance

211 • degradation products related to the lipids

212 • assay of lipid components

213 • in vitro test for release of drug substance from the liposome (see section III.D on In

214 Vitro Stability)

215

216 F. Stability

217

218 The concepts in the CDER guidance for industry Submitting Documentation for the

Stability of Human Drugs and Biologics 5219 and the ICH guidance Q1AR Stability Testing

220 of New Drug Substances and Products apply to the design of stability studies for liposome

221 drug products. In general, stability studies should address both physical and chemical

222 stability of the liposome drug product, including the liposome itself. Stability testing of

223 unloaded liposomes (i.e., liposomes to be combined with a drug substance before use)

224 should also be performed. Stress testing of liposome drug products and unloaded

225 liposomes may be warranted to demonstrate possible degradation or other reaction

226 processes unique to the liposomes.

227

228 The physical stability of liposome drug products is a function of the integrity and the size

229 distribution of the lipid vesicles. Liposomes are susceptible to fusion, aggregation, and

230 leakage of the encapsulated drug substance during storage. For instance, small unilamellar

231 vesicles are more susceptible to size changes than are multilamellar vesicles. Also, the

232 type of lipids in the bilayer or the encapsulated drug substance may affect fusion of the

233 liposomes or leakage of drug substance from the liposome. Therefore, tests for physical

234 parameters should be developed to assess the integrity and size of the liposomes.

235

236 Liposome drug products should be evaluated for stability of the encapsulated drug

237 substance as well as stability of the lipids that compose the liposomal bilayer. Lipids with

238 unsaturated fatty acids are subject to oxidative degradation, while both saturated and

239 unsaturated lipids are subject to hydrolysis to form lysolipids and free fatty acids.

240 Therefore, tests should be developed to evaluate the chemical stability of the lipids in the

241 liposome drug product.

242

243 G. Changes in Manufacturing

244

245 Manufacturing changes outside of the variations allowed in the approved application must

246 be reported to FDA, as described in section 506A of the Federal Food, Drug, and

247 Cosmetic Act (the Act) (21 U.S.C. 356a). CDER’s guidance for industry Changes to an

248 Approved NDA or ANDA should be consulted for recommended reporting mechanisms. All

249 changes should be performed in accordance with written change control procedures

250 established by the manufacturer.

251

 

5

 The 1987 stability guidance will be superseded by FDA’s draft guidance for industry Stability Testing of Drug

Substances and Drug Products (June 1998) once it is issued in final form.
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252 Because liposome drug products are a relatively new dosage form, it is not possible to

253 provide recommendations on the type of information that should be generated to

254 demonstrate that the change has not adversely affected the quality of the drug product. The

255 extent of the information and documentation to be developed and submitted to support a

256 change should depend on the types of manufacturing changes and the stage of manufacturing

257 at which the changes occur. In general, the information should include testing routinely

258 used for batch release of liposome drug products (see section II.E on Specifications) and

259 depending on the type of change, additional tests specifically directed at evaluating the

260 effect of the change on the liposome drug product (see section II.B. on Physicochemical

261 Properties). In vivo studies may be warranted to demonstrate that the changed product is

262 equivalent to the original product with respect to safety and efficacy.

263

264 Before distributing the product made with a change, applicants must assess the effect of

265 each manufacturing change (including site changes, changes to the lipid composition and

266 lipid component specifications) on the identity, strength, quality, purity, and potency of the

267 liposome drug product, as these factors relate to safety and efficacy (section 506A(b) of

268 the Act). The liposome drug product resulting from these changes (i.e., postchange

269 product) should usually be compared to the liposome drug product manufactured as

270 approved in the application (i.e., prechange product). Comparison testing of prechange

271 and postchange drug products should be performed to initially characterize the changed

272 product but is not necessary for routine testing after the change is implemented. An

273 applicant can contact the appropriate review division if it has questions on the type of

274 information to generate or the appropriate reporting mechanism for a postapproval change.

275

276

277 III. HUMAN PHARMACOKINETICS AND BIOAVAILABILITY

278

279 When an NDA is submitted for a liposome drug product, the requirements to provide human

280 pharmacokinetics and bioavailability data apply (see 21 CFR 314.50, 320.21, and 320.29). This

281 guidance does not provide information on clinical pharmacology and/or clinical efficacy and

282 safety studies that would be submitted in an NDA. Applicants should consult relevant guidance

283 documents for recommendations on the information to be provided for these topics, or they can

284 consult the appropriate CDER review division.

285

286 A. Bioanalytical Methods

287

288 Validated bioanalytical methods should be used when evaluating the pharmacokinetics and

bioavailablity of a drug substance.6289 For liposome drug products the bioanalytical method

290 should also be capable of measuring encapsulated and unencapsulated drug substance. If a

291 method that distinguishes between encapsulated and unencapsulated drug substance cannot

292 be developed, a justification as to why it is not feasible to develop such a method should

293 be provided.

294

 

6

 While the term drug substance is used throughout section III, it is recognized that the drug substance may exist

as the active moiety in vivo.
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295 Additional information on validation of methods can be found in CDER’s guidance for

296 industry Bioanalytical Method Validation.

297

298 B. In Vivo Integrity (Stability) Considerations

299

300 In addition to the general stability considerations of the drug substance in a biological

301 fluid, the stability of the liposome in vivo should be considered.

302

303 If the bioanalytical method can distinguish between encapsulated and unencapsulated drug

304 substance, the in vivo stability of the liposome should be determined. A single-dose study

305 is recommended to assess the in vivo stability of the liposome. The concentration-time

306 profile should be evaluated at multiple time points over an adequate period of time. The

307 concentration of encapsulated and unencapsulated drug substance should be determined at

308 each sampling time point.

309

310 The liposome is considered stable in vivo if, over the time course of the single-dose study,

311 the:

312

313 • drug substance, when in circulation, remains substantially in the encapsulated form

314 • ratio of unencapsulated to encapsulated drug substance remains constant

315

316 When the liposome is stable in vivo, the total drug substance concentration can be

317 measured to determine the pharmacokinetics and bioavailability. However, for an unstable

318 liposome drug product, the concentration of both encapsulated and unencapsulated drug

319 substance should be measured.

320

321 If an applicant uses a bioanalytical method that does not distinguish encapsulated and

322 unencapsulated drug substance, this method should be justified (see section III.A on

323 Bioanalytical Methods). When the applicant justifies the use of such a method, the total

324 drug substance concentration can be measured to determine pharmacokinetics and

325 bioavailability.

326

327 C. Protein Binding

328

329 The stability of liposomes in vivo can be affected by interactions with lipoproteins and

330 other proteins in the blood. Such interactions can have safety implications if dose dumping

331 occurs as a result of premature release of the drug substance from the liposomes.

332 Interactions of liposomes with serum proteins and lipoproteins can be dependent on the

333 type of lipids used in formulating the liposomes. The protein (including lipoprotein)

334 binding of the drug substance and liposome drug product should be determined over the

335 expected therapeutic concentration range. The major binding proteins should be identified.

336

337 D. In Vitro Stability

338

339 A validated in vitro test method should be established that uses an appropriate simulated

340 physiological medium and/or human plasma and acceptance criteria for the in vitro release
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341 of the drug substance from the liposome. An in vitro test that measures the release of the

342 drug substance from the liposome can be important for assessing the (1) quality of a

343 liposome drug product, (2) adequacy of the process controls, (3) release characteristics of

344 the product over time, and (4) the effect of CMC changes (e.g., minor manufacturing

345 process changes or change in site of manufacture). As experience is gained in the

346 manufacturing of a liposome drug product, an in vitro test, rather than an in vivo test, may

347 be useful in characterizing the liposome drug product when manufacturing changes are

348 made.

349

350 E. Pharmacokinetics and Bioavailability

351

352 To adequately characterize the pharmacokinetics and bioavailability of a drug substance

353 after administration of liposome drug product, the following studies should be performed:

354

355 1. Mass Balance Study

356

357 The Agency recommends a comparative mass-balance study be performed to define

358 and assess the differences in systemic exposure and pharmacokinetic measures or

359 parameters between liposome and nonliposome drug products when (1) the two

360 products have the same active moiety, (2) the two products are given by the same

361 route of administration, and (3) one of the products is already approved for

362 marketing. The disposition and pathways of elimination (including metabolism and

363 excretion) and several important pharmacokinetic measures (Cmax, AUC) and

364 parameters (clearance, volume, half-life) of a liposomal formulation administered

365 intravenously can be different from that of a nonliposomal formulation given by the

366 same route of administration. Although no examples currently exist, absorption

367 could also be altered for liposome drug product when given via non-intravenous

routes. For these reasons, if satisfactory7368 mass balance information is already

369 available for the approved drug product, a limited mass balance study can be

370 undertaken for the proposed drug product. In such a study, the quantity of the drug

371 substance excreted via the major route should be compared in sufficient subjects by

372 giving the liposomal and the nonliposomal formulations, using a crossover or a

373 parallel study design.

374

375 Comparison of the absorption, distribution, metabolism, and excretion (ADME) of

376 the liposome and nonliposome drug product form should be made, using a

377 crossover or noncrossover study design that employs an appropriate number of

378 subjects. Depending on the drug substance under investigation, the dose of the

379 liposome and nonliposome drug product may be different. The mass balance study

should be based on drug substance tagged with a radioactive label (e.g., 14C, 3380 H)

381 before its incorporation into liposomes to allow for sensitive monitoring of

 

7 Rarely, historical pharmacokinetic data for comparative purposes can be considered on a case-by-case basis in

lieu of formal comparative mass balance and/or pharmacokinetic study, taking into account the following factors:

(1) when and how the historical data was obtained, (2) similarities of study populations (e.g., disease condition),

(3) analytical procedures, and (4) data analysis. The appropriate CDER review division should be consulted to

determine whether historical data can be relied upon.
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382 radioactive label after administration. Blood (plasma or serum as appropriate),

383 urine, and fecal samples should be collected and assayed for radioactive label.

384 Other routes of elimination should be monitored as appropriate. Both parent drug

385 substances and any metabolites present should be quantitated. If feasible, mass

386 balance studies can use nonlabeled drug moieties and ingredients. However,

387 CDER recommends that a applicant contact the appropriate review division before

388 conducting studies using nonlabeled drug substance.

389

390 2 Pharmacokinetic Studies

391

392 When given by the same route of administration, the pharmacokinetics of a drug

393 substance in a liposomal formulation are expected to be different from the same

394 drug substance in a nonliposomal formulation. For this reason, the pharmacokinetic

395 studies should include a study to compare the ADME of a liposome and

396 nonliposome drug product when (1) the two products have the same active moiety,

397 (2) the two products are given by the same route of administration, and (3) one of

398 the products is already approved for marketing. This information can be useful in

399 establishing dosing regimens and in developing dose-concentration-response

400 relationships. The detailed design of the study should be based on the anticipated

401 dosing regimen in the intended patient population. These measures or parameters

402 should include area under the plasma concentration versus time curve, peak plasma

403 concentration, time to peak plasma concentration, elimination half-life, volume of

404 distribution, total clearance, renal clearance, and accumulation, as appropriate.

405 (See section III.B on In Vivo Integrity Considerations for recommendations on

406 whether the pharmacokinetic measures or parameters should be based on total drug

407 substance or both encapsulated and unencapsulated drug substance.) Major

408 metabolites associated with the therapeutic or toxic effects of the drug substance

409 should be determined. The following pharmacokinetic studies should be

410 conducted:

411

412 • a single-dose pharmacokinetic study; this should be a comparative study

413 between the liposome and nonliposome drug product, when appropriate (see

414 above)

415 • a multiple-dose study evaluating the pharmacokinetics of the drug substance

416 after administration of the liposome drug product

417 • a dose-proportionality study over the expected therapeutic dose range after

418 administration of the liposome drug product

419

420 A population-pharmacokinetics approach can be used where appropriate. See

421 CDER’s guidance for industry Population Pharmacokinetics.

422

423 3. Additional Pharmacokinetic Studies

424

425 The following pharmacokinetic studies should be considered:

426

427 a. Food-Effect Studies
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428

429 Food intake can affect the lipid composition of plasma, which may affect

430 the disposition of liposome drug products. The applicant should consult

431 with the Agency if there are questions regarding the conduct and design of

432 food studies.

433

434 b. Drug Interactions and/or Special Populations

435

436 Depending on the results of the mass balance and the pharmacokinetic

437 studies, investigation of drug-drug interactions and/or pharmacokinetics in

438 special populations may be warranted. The applicant should consult with

439 the Agency if there are questions regarding the conduct and design of these

440 studies.

441

442 c. Exposure-Response Studies

443

444 Exposure-response studies should be provided when available.

445

446

447 IV. LABELING

448

449 Information on labeling requirements can be found in sections 502(e)(3) and 508(a) of the Act (21

450 U.S.C. 352(e)(3) and 358(a)) and in parts 201 and 299 (21 CFR parts 201 and 299). Guidance

451 specific to liposome drug products is provided below

452

453 A. Product Name

454

455 The product name should include the established name, dosage form, terminology to

456 describe that it is a liposome drug product, and, if desired, a proprietary (i.e., brand) name.

457 The descriptive terminology should include the term liposome and, when appropriate, such

458 terms as Type A, Type B, and Type C, to distinguish one liposome product from other

459 liposomal formulations of the same drug substance that are not therapeutically equivalent.

460 For example:

461

462 BrandX (Acetaminophen) Liposome-Type A For Injection

463

464 B. Cautionary Notes and Warnings

465

466 Liposome encapsulation can substantially affect a drug product's functional properties

467 relative to those of the unencapsulated or nonlipid-associated drug substance. In addition,

468 different liposome products with a common drug substance can vary from one another in

469 the chemical composition and physical form of the lipid component. Such differences may

470 affect the functional properties of these drug products. CDER recommends that when

471 warranted:

472

473 • A cautionary note should be included in the description section of the labeling
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474 regarding the fact that liposome drug products may behave differently from

475 nonliposome drug products.

476 • A warning should be included in the labeling that the liposome drug product is not

477 equivalent to or cannot be substituted for other drug products containing the same drug

478 substance.

479

480 C. Dosage and Administration

481

482 Under § 201.57(j), reconstitution instructions with supporting data are required for

483 lyophilized liposome drug products (21 CFR 201.57(j)). This information should be

484 provided for both unloaded lyophilized liposomes that are reconstituted with a drug

485 substance-containing solution at the time of use, as well as products in which the drug

486 substance is loaded into the liposome by the manufacturer and then lyophilized. Other

487 issues that should be addressed, as warranted, include storage conditions for the

488 reconstituted drug, robustness of the liposome drug product under varied reconstitution

489 conditions (e.g., degree of shaking), and appropriateness of using in-line filters.

490