Liposome Drug
`Products
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`Chemistry, Manufacturing, and Controls; Human
`Pharmacokinetics and Bioavailability; and Labeling
`Documentation
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`Guidance for Industry
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`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
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`April 2018
`Pharmaceutical Quality/CMC
`
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`PROTIVA - EXHIBIT 2013
`Moderna Therapeutics, Inc. v. Protiva Biotherapeautics, Inc.
`IPR2018-00739
`
`

`

`Liposome Drug
`Products
`
`Chemistry, Manufacturing, and Controls; Human
`Pharmacokinetics and Bioavailability; and Labeling
`Documentation
`
`
`Guidance for Industry
`
`
`
`Additional copies are available from:
`Office of Communications, Division of Drug Information
`Center for Drug Evaluation and Research
`Food and Drug Administration
`10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
`Silver Spring, MD 20993-0002
`Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
`Email: druginfo@fda.hhs.gov
`http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
`
`
`
`
`
`
`
`
`
`
`
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`
`April 2018
`Pharmaceutical Quality/CMC
`
`
`
`
`
`
`
`

`

`Contains Nonbinding Recommendations
`
`TABLE OF CONTENTS
`
`
`
`
`I.
`INTRODUCTION............................................................................................................. 1
`BACKGROUND ............................................................................................................... 2
`II.
`III. DISCUSSION .................................................................................................................... 2
`A. Chemistry, Manufacturing, and Controls ................................................................................... 2
`1. Description and Composition .......................................................................................................... 2
`2. Physicochemical Properties ............................................................................................................. 3
`3. Critical Quality Attributes ............................................................................................................... 5
`4. Description of Manufacturing Process and Process Controls ........................................................ 5
`5. Control of Lipid Components ........................................................................................................... 5
`6. Drug Product Specification ............................................................................................................. 8
`7. Stability ............................................................................................................................................ 9
`8. Postapproval Changes in Manufacturing ...................................................................................... 10
`B. Human Pharmacokinetics: Bioavailability and Bioequivalence .............................................. 10
`1. Clinical Pharmacology Studies ...................................................................................................... 11
`2. Biopharmaceutics .......................................................................................................................... 12
`C. Labeling ........................................................................................................................................ 13
`IV. REFERENCES ................................................................................................................ 15
`
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`i
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`Contains Nonbinding Recommendations
`
`Liposome Drug Products
`Chemistry, Manufacturing, and Controls; Human
`Pharmacokinetics and Bioavailability; and Labeling Documentation
`Guidance for Industry1
`
`INTRODUCTION
`
`
`
`This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on
`this topic. It does not establish any rights for any person and is not binding on FDA or the public. You
`can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.
`To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the
`title page.
`
`
`
`
`I.
`
`This guidance discusses what types of information you, the applicant, should submit in your new
`drug application (NDA) or abbreviated new drug application (ANDA) for a liposome drug
`product reviewed by the Center for Drug Evaluation and Research (CDER). The discussion
`addresses the following topics for liposome drug products: (A) chemistry, manufacturing, and
`controls (CMC); (B) human pharmacokinetics and bioavailability or, in the case of an ANDA,
`bioequivalence; and (C) labeling in NDAs and ANDAs. It finalizes the revised draft guidance
`for industry Liposome Drug Products, Chemistry, Manufacturing, and Controls; Human
`Pharmacokinetics and Bioavailability; and Labeling Documentation that published in October
`2015.2 The recommendations in this guidance focus on the unique technical aspects of liposome
`drug products. This guidance does not provide recommendations on clinical efficacy and safety
`studies; nonclinical pharmacology/toxicology studies; or drug-lipid complexes.3
`
`Although this guidance does not provide recommendations specific to liposome drug products to
`be marketed under biologics license applications (BLAs), many scientific principles described in
`this guidance may also apply to these products.
`
`
`1 This guidance has been prepared by the Liposome Working Group in the Center for Drug Evaluation and Research
`(CDER) at the Food and Drug Administration.
`2 We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA
`Drugs guidance web page at
`http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
`3 Drug-lipid complexes are chemically and physically defined nonvesicular associations of drugs with certain lipids.
`Drug-lipid complexes are formed by mixing a drug with lipids in such a way that liposomes are not created. The
`CMC, pharmacokinetics, and bioavailability recommendations for drug-lipid complexes and liposomes can be
`similar. When the submission is for an NDA, contact the specific drug product’s review division with questions.
`When the submission is for an ANDA, submit a Controlled Correspondence via email to
`GenericDrugs@fda.hhs.gov. For the definition of a controlled correspondence as well as the process to submit a
`controlled correspondence, see the final guidance for industry Controlled Correspondence Related to Generic Drug
`Development (September 2015) and the proposed revisions in the draft guidance issued in November 2017.
`
`
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`1
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`Contains Nonbinding Recommendations
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`In addition, you should consider recommendations in this guidance during drug development that
`may lead to the submission of an investigational new drug application (IND) for a liposome drug
`product. In connection with ANDA submissions, you should consider recommendations in any
`product-specific guidances, including bioequivalence and information necessary to demonstrate
`pharmaceutical equivalence to the reference listed drug (RLD).
`
`In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
`Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only
`as recommendations, unless specific regulatory or statutory requirements are cited. The use of
`the word should in Agency guidances means that something is suggested or recommended, but
`not required.
`
`
`II.
`
`Liposomes are vesicles composed of a bilayer (uni-lamellar) and/or a concentric series of
`multiple bilayers (multi-lamellar) separated by aqueous compartments formed by amphipathic
`molecules such as phospholipids that enclose a central aqueous compartment. In a liposome
`drug product, the drug substance is generally contained in liposomes.4 Typically, water soluble
`drugs are contained in the aqueous compartment(s) and hydrophobic drugs are contained in the
`lipid bilayer(s) of the liposomes. Release of drugs from liposome formulations, among other
`characteristics such as liposomal clearance and circulation half-life, can be modified by the
`presence of polyethylene glycol and/or cholesterol or other potential additives in the liposome.
`
`BACKGROUND
`
` A
`
` liposome drug formulation is different from (1) an emulsion, which is a dispersed system of
`oil in water, or water in oil phases containing one or more surfactants, (2) a microemulsion,
`which is a thermodynamically stable two phase system containing oil or lipid, water and
`surfactants, and (3) a drug-lipid complex.
`
`
`III. DISCUSSION
`
`
`A.
`
`Chemistry, Manufacturing, and Controls
`
`
`
`1.
`
`Description and Composition
`
`
`You should include the following information in your application:
`
`
`a.
`
`The drug product components listed by their established names, as
`follows:
`
`
`
`i. Drug substance
`ii. Lipids
`iii. Nonlipid components of the liposome
`
`4 The word contained includes both encapsulated and intercalated drug substance. Encapsulated refers to drug
`substance within an aqueous space and intercalated refers to incorporation of the drug substance within a bilayer.
`
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`2
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`Contains Nonbinding Recommendations
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`iv. Nonliposome inactive ingredients (e.g., buffer components)
`
`An expression of the amount of each lipid component used in the
`formulation based on the final form of the product:
`
`
`b.
`
`
`
`− For liquid – mg/ml and mg/vial
`− For dry powder for reconstitution – mg/ml after reconstitution and
`mg/vial
`− For semisolid – w/w (g/g)
`
`An expression of the molar ratio of each individual lipid to the drug substance is also
`recommended for each individual lipid in the finished formulation.
`
`c.
`
`An expression of the amount of drug substance in the formulation.
`
`Ranges in the composition and/or attributes of components.
`
`
`We recommend expressing the composition of the drug product as milligram of drug substance
`per milliliter of drug product and also milligram of drug substance per vial for liquid drug
`products. For dry powders, only the total amount of the drug should be listed.
`
`d.
`
`Because the pharmacological and toxicological properties and the quality of a liposome product
`can vary significantly with changes in the formulation, including the lipid composition, the
`ranges should be specified based on the following:
`
`
`i. Product development studies
`ii. How the ranges were selected
`iii. If and how the source of key excipients affects finished product
`quality
`
`These ranges should be linked to the factors that were analyzed during drug product development
`and supported by data.
`
`Physicochemical Properties
`
`2.
`
`
`Liposome structure and integrity are important physicochemical properties and they reflect the
`ability of the liposome drug formulation to contain the drug substance and to retain the drug
`substance within the appropriate liposome structure. The following properties are generally
`useful to characterize a liposome drug formulation. Variability in the following properties may
`lead to changes in the quality of the liposome drug product, including leakage of the drug from
`the liposomes. Properties that apply to your liposome drug product may vary from those listed
`below.
`
`
`Morphology of the liposomes including, if applicable, lamellarity
`determination.
`
`a.
`
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`3
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`Contains Nonbinding Recommendations
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`Surface characteristics of the liposomes, as applicable, e.g., pegylation.
`
`Net charge, typically measured as zeta potential of the liposomes.
`
`b.
`
`c.
`
`d.
`
`e.
`
`For example, drug encapsulation efficiency (the amount of drug contained inside liposomes
`compared with total amount of drug) and liposome drug loading (the amount of drug contained
`relative to the amount of the lipid used, which is the drug-to-lipid ratio).5 This information
`should be supported by development data, including test results on batches of liposome drug
`used in pivotal clinical trials or bioequivalence studies.
`
`Drug product viscosity.
`
`Parameters of the contained drug.
`
`
`
`f.
`
`
`g.
`
`h.
`
`
`i.
`
`j.
`
`
`k.
`
`
`
`Particle size (i.e., mean and distribution profile), preferably defined on the
`basis of volume or mass if particle density is known.
`
`Liposome phase transition temperature.
`
`In vitro release of the drug substance from the liposome drug product
`under the stated/described experimental conditions with supportive data
`and information regarding the choice of those conditions.
`
`Leakage rate of drug from the liposomes throughout shelf life.
`
`Liposome integrity changes (e.g., drug release, drug encapsulation
`efficiency, liposome drug loading, size) in response to changes in factors
`such as salt concentration, pH, temperature, or addition of other
`excipients, as applicable.
`
`Liposome structure supported by spectroscopic or other analytical
`method(s).
`
`
`
`
`
`
`5 Xu, X, Khan, M, and Burgess, D, 2012, A Quality by Design (QbD) Case Study on Liposomes Containing
`Hydrophilic API: II. Screening of Critical Variables, and Establishment of Design Space at Laboratory Scale,
`International Journal of Pharmaceutics, 423: 543-553; and Liposomes as Carriers for Controlled Drug Delivery,
`Long Acting Injections and Implants, chapter 11, pages 195 to 220, ISBN 978-1-4614-0553-5, Publisher: Springer.
`
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`4
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`Contains Nonbinding Recommendations
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`
`3.
`
`Critical Quality Attributes
`
`
`Critical quality attributes (CQAs) particular to liposome drug products include some of the
`physicochemical properties described above including vesicle/particle size and size distribution,
`and morphology. For general information on drug product development, see the International
`Council for Harmonisation (ICH) guidance for industry, Q8(R2) Pharmaceutical Development.
`
`
`4.
`
`Description of Manufacturing Process and Process Controls
`
`
`We recommend including a detailed process flow diagram and a description of unit operations
`with ranges for the process parameters and process controls. These ranges should be supported
`by pharmaceutical development studies. The process and mechanism of liposomal drug loading,
`as well as the removal of free (un-incorporated) drug from the liposome formulation via
`purification should be described in detail. The manufacturing process should be validated to
`demonstrate manufacturing process consistency and reproducibility before commercial
`distribution.6
`
`Liposome drug products are sensitive to changes in the manufacturing conditions, including
`changes in scale (size of the batches). Appropriate process controls should be established during
`product development. Prior knowledge can be leveraged and risk assessment techniques can be
`used to identify manufacturing process parameters that potentially affect finished product
`quality.
`
`Some examples of manufacturing process parameters that may affect liposome drug performance
`are shear force, pressure, pH, temperature, batch-size-related hold times, lyophilization
`parameters, etc. You should provide adequate justification for the selection of the operating
`ranges for different batch sizes.
`
`The physical and chemical complexity of liposome drug products present unique challenges to
`the sterilizing filtration process. For example, components of liposomes could interact with the
`filter matrix and clog it. Therefore, validated product-specific purification and sterilization
`methods should demonstrate the ability of the microbial sterilizing filters to function correctly,
`without compromising the integrity and structure of liposomes.
`
`
`5.
`
`Control of Lipid Components
`
`
`The quality of lipid components, including modified lipids (e.g., polyethylene glycol (PEG)
`modified lipids), can affect the quality and performance of the liposome drug product. In case of
`a novel lipid component, i.e., any lipid component not listed in the Inactive Ingredient Database
`(IID),7 or a component that exceeds the amount listed in the IID for the intended route of
`administration, the level of detail provided in the submission should be comparable to that for a
`
`
`6 See guidance for industry Process Validation: General Principles and Practices.
`7 See http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm.
`
`
`
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`5
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`

`
`
`b.
`
`Manufacture of Lipid Components
`
`Contains Nonbinding Recommendations
`
`drug substance.8 This information should be provided in the application or in a Type IV Drug
`Master File (DMF).9
`
`In addition, you should provide the following information specific to lipid components:
`
`
`a.
`
`Description and Characterization of Lipid Components
`
`
`If the lipid is synthetic (e.g., a lipid manufactured by chemical synthesis from specified starting
`materials) or semi-synthetic (e.g., a lipid manufactured by modification of naturally occurring
`precursors such as dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine
`(DSPC), or dimyristoylphosphatidylcholine (DMPC)), you should provide proof of structure,
`including fatty acid composition and positional specificity. You should specify the lipid
`composition (e.g., percentage of each lipid and fatty acid, positional specificity of acyl side
`chains, and degree of fatty acid unsaturation).
`
`In the case of naturally-sourced lipid mixtures, (e.g., egg lecithin), you should provide the lipid
`composition as a range of percentages for each stated lipid present in the mixture and its fatty
`acid composition.
`
`
`
`The information provided on the manufacture of lipid components depends on whether the lipid
`is synthetic, semi-synthetic, or naturally sourced.
`
`For synthetic and semi-synthetic lipids, we recommend you provide the following information:
`
`
`i. A complete description of the synthetic process and purification
`procedures, as applicable
`ii. Specifications for starting materials,10 raw materials, solvents, and
`reagents
`iii. Controls for critical steps and intermediates, including the
`manufacturing controls that ensure positional specificity of acyl
`side chains, if applicable
`
`
`For naturally-sourced lipid mixtures, and any naturally-sourced materials that start the synthetic
`segment of a semi-synthetic process, you should provide the following information:
`
`
`i. Biological source (e.g., eggs)
`ii. Country of origin for animal-sourced material
`iii. Supplier
`iv. A description of extraction and purification procedures, as
`applicable11
`
`8 For further information, see ICH Q11 Development and Manufacture of Drug Substances (ICH Q11).
`9 See guidance for industry Drug Master Files: Guidelines.
`10 See ICH Q11 for recommendations about the selection of starting materials.
`11 Ibid.
`
`
`
`6
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`Contains Nonbinding Recommendations
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`
`
`Procedures to ensure the avoidance, removal, and/or inactivation of animal proteins and viruses
`and any other infectious agents should be described, where applicable.
`
`You should address the avoidance and/or removal of pyrogenic material and bacterial endotoxins
`by establishing appropriate controls during the manufacturing process, and include this
`information in the application.
`
`
`c.
`
`Specifications for Lipid Components
`
`
`You should provide the following specification information for each lipid component used to
`manufacture the drug product.
`
`
`i. The identity test capable of distinguishing the intended lipid
`component from lipids with similar structures.
`ii. The assay based on a stability-indicating analytical procedure.
`iii. The validated analytical procedures accompanied by the validation
`data.
`iv. Impurity testing:
`1. Trans-fatty acid
`2. Free-fatty acid
`3. Peroxides (associated with unsaturated fatty acids)
`4. Lysophospholipids
`5. Solvents and catalysts used in the synthesis or purification
`processes
`v. Other testing:
`1. Counterion content and limits on divalent cations, when
`appropriate
`2. The degree of unsaturation of the fatty acid side chains (for
`lipid mixtures)
`
`
`Information about impurities, including synthetic by-products, where applicable, should be
`provided. Impurities may warrant identification and qualification, depending on the following:
`
`
`i. The amount of the impurity in the final liposome drug product
`ii. Known toxicities of the impurity
`iii. Structural alerts12
`
`
`For synthetic lipids and semi-synthetic lipids, compare the lipid under test with the reference
`standard or material using an analytical procedure that is capable of distinguishing the desired
`lipids from their impurities (e.g., HPLC, TLC).
`
`
`12 Ashby, J, Paton, D, March 1993, The Influence of Chemical-Structure on the Extent and Sites of Carcinogenesis
`for 522 Rodent Carcinogens and 55 Different Human Carcinogen Exposures, Mutation Research, Volume 286, Issue
`1, Pages 3-74; and guidance to industry Genotoxic and Carcinogenic Impurities in Drug Substances and Products:
`Recommended Approaches. When final, this guidance will represent the FDA’s current thinking on this topic.
`
`
`
`7
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`

`Contains Nonbinding Recommendations
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`Information about the preparation, qualification, and storage conditions for each reference
`standard or material used in testing lipid components should be provided.
`
`
`d.
`
`Stability of Lipid Components
`
`
`For each lipid used to manufacture the liposome, you should provide results from stability
`studies and stress testing (e.g., after exposure to high (e.g., 50 ºC) and low (e.g., -20 ºC)
`temperatures, light, pH, and oxygen) that were used to determine the degradation profile, to
`develop an appropriate stability-indicating analytical procedure, and to establish appropriate
`storage conditions and retest period(s). Reference to a DMF is acceptable when the stability
`studies referenced in the DMF used the same lipids (source, grade, supplier) as proposed to be
`used in the drug product. Stability studies and validation of analytical procedures should be
`conducted according to ICH guidelines.13
`
`You should retest the lipid component after its storage beyond the lipid manufacturer’s stated
`“retest period” or when the lipid component is exposed to temperatures other than its labeled
`storage temperature to ensure conformance to its specification prior to use in a drug product. For
`example, if unusual conditions occur during shipping or transit leading to exposure of the lipid
`component to elevated temperatures for a significant time period, you should retest the lipid
`component to ensure conformity with specification.
`
`
`6.
`
`Drug Product Specification
`
`
`You should provide a drug product specification that accounts for specific attributes for your
`liposome products. The following are examples of characteristics or attributes specific to the
`liposome formulation that should be included in the specification:
`
`
`Physicochemical parameters of the liposome determined to be the CQAs
`of the product (e.g., mean particle size and size distribution of liposomes,
`osmolality, zeta-potential and physical stability)
`
`Liposome contained and free drug substance
`
`Total drug substance content, as labeled
`
`Degradation products related to the lipids (e.g., lysolipids) or drug
`substance
`
`Lipid content (to demonstrate consistency with the intended formulation)
`
`Residual solvent(s), if any organic solvent(s) are used in the manufacture
`of the liposome product
`
`a.
`
`
`b.
`
`c.
`
`d.
`
`
`e.
`
`f.
`
`
`
`
`13 See guidances for industry Q1A(R2) Stability Testing of New Drug Substances and Products; Q2(R1) Validation
`of Analytical Procedures: Text and Methodolology.
`
`
`
`8
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`

`Contains Nonbinding Recommendations
`
`The residual solvents acceptance criteria should be based on the
`performance of the liposome drug product as well as safety concerns.
`
`
`
`In vitro release of drug substance from the liposome drug products
`
`
`g.
`
`A validated analytical procedure for in vitro release should be established, preferably using an
`appropriate physiological medium (e.g., simulated physiological medium or human plasma) with
`suitable agitation. When a liposome drug product is extremely stable under physiological
`conditions, an in vitro quality control (QC) release test can be performed under nonphysiological
`conditions to accelerate the release of drug substance from the liposomes. For all drug products,
`information about any relationship or correlation between the in vitro quality control release test
`and the in vivo pharmacokinetic profile should be provided to justify the use of such a QC test,
`as established through analytical method development studies. In some cases, a test using cell
`culture or animal models may be appropriate.
`
`h.
`
`For injectable liposome drug products, sterility and the absence of
`pyrogens or bacterial endotoxins
`
`
`
`7.
`
`Stability
`
`
`Stability studies should address the microbiological, physical, and chemical stability of the
`liposome drug product, including the integrity of the liposomes in the drug product.14
`
`The physical stability of liposome drug products can be affected by a number of factors (e.g., the
`liposome integrity,15 the size distribution of the lipid vesicles, unsaturation of the fatty acid
`groups). Some liposomes are susceptible to fusion (i.e., irreversible coalition of smaller
`liposomes to form larger liposomes), aggregation (i.e., reversible conglomeration or pooling of
`two or more liposomes without fusion), and leakage of the contained drug substance during
`storage. Fusion, aggregation, or leakage can be affected by the lipid components in the liposome
`or by the contained drug substance. Stability testing should include tests to assess liposome size
`distribution and integrity.
`
`You should evaluate the chemical stability of the lipid components in the liposome as well as the
`chemical stability of the contained drug substance. Lipids with unsaturated fatty acids are
`subject to oxidative degradation, while both saturated and unsaturated lipids are subject to
`hydrolysis to form lysolipids and free fatty acids. It may be appropriate to conduct stress testing
`of unloaded liposomes to assess possible degradation or other reaction processes unique to the
`liposomes.
`
`When designing stress and accelerated stability testing studies, you should recognize that
`liposome drug products behave differently near or above the phase transition temperature(s).
`
`
`
`14 See ICH Q1A(R2) Stability Testing of New Drug Substances and Products.
`15 See section III.A.2.
`
`
`
`9
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`

`Contains Nonbinding Recommendations
`
`If the liposome drug product is marketed as an approved kit containing unloaded liposomes and
`drug substance in separate containers, your stability program should include testing of the
`unloaded liposomes and the drug substance in their commercial container-closure systems.
`
`If the liposome product is labeled for use after reconstitution with a co-packaged or other
`specified diluent, or is labeled for use after mixing it with other approved drug products (e.g.,
`large volume injectable solutions), supporting stability data on the product under the in-use
`conditions of its storage and use should be submitted in the application. This should include
`physical, chemical, and microbiological studies to support the in-use period. A specified in-use
`or storage interval, after which an admixed and/or unused liposome product must be discarded,
`should be determined through an in-use stability study. A statement regarding the appropriate
`in-use period(s) for the reconstituted/admixed drug product should be included in the labeling,
`together with instructions for reconstitution or mixing.
`
`
`8.
`
`Postapproval Changes in Manufacturing
`
`
`Liposome drug products are complex and sensitive formulations and response to CMC changes
`is less predictable than with more conventional formulations. Therefore, changes to the
`formulation, container closure, site of manufacture, or manufacturing process (including
`substantive equipment and scale changes) will usually require a prior approval supplement. In
`vivo studies may be needed to assess changes that can affect the performance of the drug
`product. You can contact the appropriate review division16 associated with your application if
`you have questions regarding the type of information to generate or the appropriate reporting
`mechanism for a postapproval change.17
`
`B.
`
`Human Pharmacokinetics: Bioavailability and Bioequivalence
`
`
`For ANDA submissions for liposome drug products, please refer to applicable product-specific
`FDA guidance documents18 that outline recommendations regarding human pharmacokinetic and
`other bioequivalence studies for generic liposome drug products. These guidance documents
`also discuss additional characterization studies and information (e.g., drug product composition
`and active ingredient loading) necessary to demonstrate pharmaceutical equivalence to the RLD.
`When no product-specific guidance exists for a generic product, this guidance applies. If you are
`contemplating submitting an ANDA, you should consider contacting OGD19 to request a pre-
`ANDA meeting.
`
`
`16 When the submission is for an NDA, contact the specific drug product’s review division with questions. When
`the submission is for an ANDA, submit a Controlled Correspondence via email to GenericDrugs@fda.hhs.gov. For
`the definition of a controlled correspondence as well as the process to submit a controlled correspondence, see the
`final guidance for industry Controlled Correspondence Related to Generic Drug Development (September 2015)
`and the proposed revisions in the draft guidance issued in November 2017.
`17 See 21 CFR 314.70 and FDA guidances related to submission of postapproval changes to the chemistry,
`manufacturing, and controls section of drug applications.
`18 See http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm075207.htm.
`19 See draft guidance for industry Formal Meetings Between FDA and ANDA Applicants of Complex Products
`Under GDUFA.
`
`
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`

`Contains Nonbinding Recommendations
`
`Because of the complex interaction between drug release from the liposome drug product and the
`tissue and/or cellular uptake of the drug substance and/or the liposome, a simple measurement of
`total drug substance concentration in plasma20 may not be reflective of bioavailability of the drug
`at the intended target organ (i.e., site of action).21 Therefore, for NDA submissions, you should
`consult the appropriate CDER review division22 for advice concerning the determination of
`bioavailability of liposome drug products.
`
`
`1.
`
`Clinical Pharmacology Studies
`
`
`
`a.
`
`Pharmacokinetic and Mass Balance Studies for Liposome Drug Products
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`Information from pharmacokinetic studies is useful for establishing dosing regimens and
`developing dose-concentration-response relationships. The study design should be based on the
`anticipated dosing regimen in the intended patient population. We recommend using a
`population pharmacokinetics approach, where appropriate.23
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`The pharmacokinetic measures or parameters should include area under the plasma concentration
`versus time curve (AUC), peak plasma concentration, time to peak plasma concentration,
`elimination half-life, volume of distribution, total clearance, renal clearance, and accumulation
`for both free and total drug, as appropriate. For mass balance studies, you should collect and
`assay blood (i.e., plasma or serum, as appropriate), urine, and fecal samples for the radiolabeled
`moiety. For these studies, you should monitor and quantify both parent drug and any metabolites
`present, as appropriate.
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`You should determine major metabolites associated with the therapeutic and toxic effects of the
`drug substance. We also recommend conducting the following in vivo studies:
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`i.
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`ii.
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`Multiple-dose study evaluating the drug pharmacokinetics after
`administration of the liposome drug product.
`Dose-proportionality stu