Liposome Drug 
Products 
Chemistry, Manufacturing, and Controls; Human 
Pharmacokinetics and Bioavailability; and Labeling 
Documentation 
 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
April 2018 
Pharmaceutical Quality/CMC 
   
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 
II.  BACKGROUND ............................................................................................................... 2 
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 
i 
 
  Contains Nonbinding Recommendations 
 
Liposome Drug Products 
Chemistry, Manufacturing, and Controls; Human 
Pharmacokinetics and Bioavailability; and Labeling Documentation 
Guidance for Industry1 
 
 
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.  INTRODUCTION  
 
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 products 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. 
  1  Contains Nonbinding Recommendations 
 
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, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys 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.  BACKGROUND 
 
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. 
 
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. 
  2  Contains Nonbinding Recommendations 
 
iv. Nonliposome inactive ingredients (e.g., buffer components) 
 
b.  An expression of the amount of each lipid component used in the 
formulation based on the final form of the product:  
 
  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.   
 
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.  Ranges in the composition and/or attributes of components.  
 
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. 
 
2.  Physicochemical Properties 
 
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.    
 
a.  Morphology of the liposomes including, if applicable, lamellarity 
determination. 
 
  3  Contains Nonbinding Recommendations 
 
b.  Surface characteristics of the liposomes, as applicable, e.g., pegylation. 
 
c.  Net charge, typically measured as zeta potential of the liposomes. 
 
d.  Drug product viscosity. 
 
e.  Parameters of the contained drug. 
 
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. 
 
f.  Particle size (i.e., mean and distribution profile), preferably defined on the 
basis of volume or mass if particle density is known. 
 
g.  Liposome phase transition temperature. 
 
h.  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. 
 
i.  Leakage rate of drug from the liposomes throughout shelf life. 
 
j.  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. 
 
k.  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. 
  4  Contains Nonbinding Recommendations 
 
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. 
 
  5  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.   
 
  b.  Manufacture of Lipid Components 
 
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  Contains Nonbinding Recommendations 
 
 
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 FDAs current thinking on this topic. 
  7  Contains Nonbinding Recommendations 
 
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 manufacturers 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:  
 
a.  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) 
 
b.  Liposome contained and free drug substance 
 
c.  Total drug substance content, as labeled 
 
d.  Degradation products related to the lipids (e.g., lysolipids) or drug 
substance 
 
e.  Lipid content (to demonstrate consistency with the intended formulation) 
 
f.  Residual solvent(s), if any organic solvent(s) are used in the manufacture 
of the liposome product 
 
                                                 
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  Contains Nonbinding Recommendations 
 
  The residual solvents acceptance criteria should be based on the 
performance of the liposome drug product as well as safety concerns. 
 
g.  In vitro release of drug substance from the liposome drug products 
 
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  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 products 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. 
 
  10  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 
 
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 
 
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. 
 
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:  
 
i.  Multiple-dose study evaluating the drug pharmacokinetics after 
administration of the liposome drug product. 
ii.  Dose-proportionality study over the expected therapeutic dose 
range of the liposome drug product. 
iii.  Exposure-response studies if available. 
 
Depending on the target patient population and the proposed therapeutic indication for the drug, 
you should consider conducting drug interactions studies in specific populations. 
 
You should consult the appropriate CDER review division24 regarding the conduct and design of 
these studies if you have questions. 
 
                                                 
20 See 21 CFR 320.24(b)(1)(i). 
21 See 21 CFR 320.21. 
22 See footnote 16. 
23 See guidance for industry Population Pharmacokinetics. 
24 See footnote 16. 
  11  Contains Nonbinding Recommendations 
 
b.  Comparison Clinical Pharmacology Studies with Nonliposome Drug 
Product 
 
The drug disposition and pathways of elimination (including distribution, metabolism and 
excretion) as well as several important pharmacokinetic measures (Cmax, AUC) and parameters 
(e.g., clearance, volume of distribution, half-life) of a liposome formulation are likely to be 
different than those of a nonliposome formulation given by the same route of administration.  For 
example, a liposome drug formulation may exhibit extended-release characteristics in 
comparison to a non-liposome formulation with the same active pharmaceutical ingredient.   
 
If nonliposome formulations have been approved, we recommend comparing the proposed 
liposome to the corresponding approved nonliposome formulation to elucidate differences in 
absorption, distribution, metabolism, and excretion (ADME).  Conducting a mass balance study 
of a drug substance labeled with a radioactive isotope (e.g., 14C, 3H) in a liposome formulation 
and in a nonliposome formulation can be helpful in comparing drug distribution in organs of 
interest.   
 
You should conduct comparative studies to define and assess differences in ADME of the active 
ingredient between liposome and nonliposome drug products when the following apply:  
 
i.  Two products have the same active ingredient.  
ii.  Two products are given by the same route of administration.  
iii. The nonliposome drug product is approved and available for 
comparison. 
 
In a single dose pharmacokinetic study, you should compare the liposome and nonliposome drug 
products using either a crossover or parallel study design that employs an appropriate number of 
subjects considering the study drug, disease for which it is used, use in specific populations, and 
other factors that apply.  Depending on the drug substance under investigation, different doses of 
liposome and nonliposome drug products may be appropriate. 
 
2.  Biopharmaceutics 
 
a.  Drug Release Characteristics 
 
You should demonstrate that the release characteristics of the liposome product meet the label 
claim, and describe any release differences between the liposome product and nonliposome 
product with the same active ingredient. 
 
b.  In Vitro/In Vivo Correlation (IVIVC)  
 
Although it is challenging to establish IVIVC for liposome products, we encourage you to 
attempt it for your liposome product.  Some in vitro/in vivo relationships (IVIVRs) may be 
established even if a complete IVIVC is not feasible. 
  12  Contains Nonbinding Recommendations 
 
 
c.  Bioanalytical Methods 
 
You should use validated bioanalytical methods when evaluating the pharmacokinetics and 
bioavailability of the liposome-contained and free drug substance (drug released from the 
liposome).25   
 
d.  Liposome-Protein Interaction 
 
Depending on the types of lipids used in formulating liposomes, interactions between liposome 
surface and blood proteins may affect the drug release and pharmacological properties of a 
liposome drug product in vivo.  Such interactions can have safety implications because of dose 
dumping.  Submission of information from prior studies of protein-liposome interactions may 
suffice for a new liposome drug product if the following apply: 
 
i.  Lipid composition of the formulation ingredients is the same as in the 
previously studied liposome drug product. 
ii.  Physicochemical characteristics of the two liposome drug products are 
similar. 
 
C.  Labeling 
 
Specific recommendations regarding labeling content for liposome drug products are provided 
below.  Additional guidance on current labeling requirements is available on the CDER guidance 
Web site.  In particular, the guidance on Safety Considerations for Container Labels and Carton 
Labeling Designs to Minimize Medication Errors provides general labeling recommendations.  
 
1.  Nonproprietary Names of Drug Products Approved under the Federal Food, 
Drug, and Cosmetic Act 
 
The nonproprietary name of a drug product approved under the Federal Food, Drug, and 
Cosmetic Act is its established name, which, in most instances, will be the United States 
Pharmacopeia (USP) drug product monograph title for that product.  If there is no USP 
monograph for the liposome drug product, refer to 21 CFR 299.4, USP General Chapter <1121> 
Nomenclature,26 and the USP Nomenclature Guidelines.27  The liposome drug product 
nonproprietary name should include terminology to express that the product is a liposome or a 
pegylated liposome. 
 
Examples: 
 
  [DRUG] Liposome Type X [DOSAGE FORM] 
  [DRUG] Pegylated Liposome Type X [DOSAGE FORM] 
                                                 
25 See draft guidance for industry Bioanalytical Method Validation. 
26 United States Pharmacopeia-National Formulary (USP 40-NF 35, supplement 2 <1121> NOMENCLATURE.   
27 Refer to USP Nomenclature Guidelines on the USP website at http://www.usp.org/health-quality-
safety/compendial-nomenclature.  
  13  Contains Nonbinding Recommendations 
 
 
The first liposome product approved for a particular drug and dosage form will be type A, but the 
type should not be given (i.e., Type A should not be included in the labeling).  For subsequent 
drug products of the same drug and dosage form, you should list the type and replace X 
sequentially with B, C, D, . . . Z.28 
 
2.  Description Section 
 
You should include a cautionary note emphasizing that liposome drug products may behave 
differently from nonliposome drug products or other liposome products even though the active 
ingredient is the same.  The applicant should specifically describe such differences.  Note: this is 
not necessary for liposome drug products determined by FDA to be therapeutically equivalent. 
 
3.  Dosage and Administration 
 
You should include a statement recommending against substituting the liposome drug product 
for the nonliposome product or another liposome drug product that contains the same active 
ingredient unless FDA has determined that the products are therapeutically equivalent. 
 
Where appropriate, reconstitution instructions29 and a statement regarding the appropriate in-use 
period should be provided.  This information should be provided for both unloaded liposomes 
that are reconstituted with a drug substance-containing solution at the time of use and for 
products in which the drug substance is loaded into the liposomes during manufacturing.  For 
liposome drug products that are labeled for use after mixing with other approved drug products 
(e.g., large volume injectable solutions), admixing instructions and a statement regarding the 
appropriate in-use period of the admixed product should be included.  As warranted, include 
storage conditions for the reconstituted drug, robustness of the liposome drug product under 
varied reconstitution conditions (e.g., degree of shaking), and use of in-line filters. 
 
 
   
                                                 
28 Note that with respect to ANDA submissions, the product name is the same as the nonproprietary or established 
name of the RLD. 
29 See 21 CFR 201.57(c)(3)(i)(J)(iv). 
  14  Contains Nonbinding Recommendations 
 
IV.  REFERENCES 
 
Guidance for Industry30 
 
Bioanalytical Method Validation  
 
Changes to an Approved NDA or ANDA 
 
Controlled Correspondence Related to Generic Drug Development 
 
Drug Master Files Guidelines 
  
Formal Meetings Between FDA and ANDA Applicants of Complex Products Under GDUFA 
 
Genotoxic and Carcinogenic Impurities in Drug Substances and Products: Recommended 
Approaches 
 
PAT  A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality 
Assurance 
 
Population Pharmacokinetics 
 
Process Validation:  General Principles and Practices 
 
ICH, Q1A(R2) Stability Testing of New Drug Substances and Products 
 
ICH, Q2(R1) Validation of Analytical Procedures:  Text and Methodology 
 
ICH, Q6A Specifications:  Test Procedures and Acceptance Criteria for New Drug Substances and 
New Drug Products:  Chemical Substances  
 
ICH, Q8(R2) Pharmaceutical Development  
 
ICH, Q11 Development and Manufacture of Drug Substances  
  
                                                 
30 The guidances listed in the References are available on the FDA Drugs guidance web page at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
  15