On April 04, 2018, the United States Food and Drug Administration (USFDA) finalized its Guidance for Industry on Liposome Drug Products - Chemistry, Manufacturing, and Controls; Human Pharmacokinetics and Bioavailability; and Labeling Documentation. The guidance provides unique aspects and the types of information sponsors should submit for new drug applications (NDAs) and abbreviated new drug applications (ANDAs) for liposome drug products48.
The 18-page guidance describes 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. Sections of the guidance also touch on descriptions and composition, physicochemical properties, critical quality attributes, description of manufacturing process and process controls, control of lipid components, drug product specification, stability and post-approval changes in manufacturing. The guidance does not provide recommendations on clinical efficacy and safety studies, nonclinical pharmacology and/or toxicology studies, liposome formulations of vaccine adjuvants or biologics or drug-lipid complexes.
Background
Liposomes are vesicles composed of a bilayer (uni-lamellar) and/or a concentric series of multiple bilayers (multilamellar) 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.
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
- an emulsion, which is a dispersed system of oil in water, or water in oil phases containing one or more surfactants,
- a microemulsion, which is a thermodynamically stable two-phase system containing oil or lipid, water and surfactants, and
- a drug-lipid complex.
A. Chemistry, Manufacturing, and Controls
The guidance recommends the following information should be included in the application:
- Description and Composition;
- Physicochemical Properties;
- Critical Quality Attributes;
- Description of Manufacturing Process and Process Controls;
- Control of Lipid Components;
- Drug Product Specification;
- Stability; and
- Post-approval Changes in Manufacturing
B. Human Pharmacokinetics: Bioavailability and Bioequivalence
The guidance says that for ANDA (Abbreviated New Drug Application) submissions for liposome drug products, the applicant should refer to applicable product-specific FDA guidance documents 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 an applicant is contemplating submitting an ANDA, it should consider contacting Office of Generic Drugs to request a pre- ANDA meeting.
The guidance further states that 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 plasma may not be reflective of bioavailability of the drug at the intended target organ (i.e., site of action). Therefore, for NDA submissions, the applicant should consult the appropriate Center for Drug Evaluation and Research (CDER) review division for advice concerning the determination of bioavailability of liposome drug products.
C. Labeling
The guidance provides specific recommendations regarding labeling content for liposome drug products.
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. The liposome drug product nonproprietary name should include terminology to express that the product is a liposome or a pegylated liposome.
2. Description Section
The applicant should include a cautionary note emphasizing that liposome drug products may behave differently from non-liposome drug products or other liposome products even though the active ingredient is the same. The applicant should specifically describe such differences. Note: It is not necessary for liposome drug products determined by FDA to be therapeutically equivalent.
3. Dosage & Administration
The applicant should include a statement recommending against substituting the liposome drug product for the non-liposome product or another liposome drug product that contains the same active ingredient unless FDA has determined that the products are therapeutically equivalent.
The guidance also recommends where appropriate, reconstitution instructions 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.
Footnote
48. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070570.pdf
The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.
