New FDA Guidance on Liposomes

The U.S. Food and Drug Administration, FDA, published its final guidance for industry on liposome drug products in April 2018. It finalizes the revised draft guidance for industry Liposome Drug Products, Chemistry, Manufacturing, and Controls; Human Pharmacokinetics and Bioavailability; and Labeling Documentation that has been published in October 2015.

According to the guidance "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."

Liposome drug products exist as injectable liposome drug products (for example long acting injections). For those, sterility and the absence of pyrogens or bacterial endotoxins has to be shown. Furthermore they occur in form of topical products /cosmetics and oral products (e.g. as a carrier of dietary and nutritional supplements). The use of liposomes is primarily directed at targeted drug delivery. In case of topical application, for example, they release both lipophilic and hydrophilic active substances specifically into the epidermis.

Liposome formulations are different from

• emulsions (dispersed systems of oil in water, or water in oil phases containing one or more surfactants),
• microemulsions (thermodynamically stable two phase systems containing oil or lipid, water and surfactants), and
• drug-lipid complexes (chemically and physically defined nonvesicular associations of drugs with certain lipids).

The new guidance discusses what types of information should be submitted to FDA in new drug applications (NDAs) or abbreviated new drug applications (ANDAs). It does not cover recommendations specific to liposome drug products to be marketed under biologics license applications (BLAs). However, many scientific principles described in this guidance may also apply to these products. The provided recommendations focus on the unique technical aspects of liposome drug products. The document addresses the following topics:

• Chemistry, manufacturing, and controls (CMC);
• Human pharmacokinetics and bioavailability / bioequivalence;
• Labeling in NDAs and ANDAs.

The guidance refers to Quality by Design (QbD) principles according to ICH Q8(R2) Pharmaceutical Development including screening of critical variables (Critical Quality Attributes, CQAs) and establishment of a Design Space. The inclusion of a detailed process flow diagram and a description of unit operations with ranges for the process parameters and process controls is recommended. The ranges should be supported by pharmaceutical development studies. Liposome drug products are sensitive to changes in the manufacturing conditions, including changes in scale (batch sizes). Appropriate process controls should be established during product development. 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, sterilizing filtration, etc.

Postapproval Changes in Manufacturing (see also ICH Q12 draft)
According to FDA, "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." FDA emphasizes to contact the appropriate review division associated with the application to discuss questions regarding the type of information to generate or the appropriate reporting mechanism for a postapproval change.

For more Information please see FDA´s Guidance for Industry: Liposome Drug Products, Chemistry, Manufacturing, and Controls; Human Pharmacokinetics and Bioavailability; and Labeling Documentation.