Liposome drug products frequently contain an already-approved drug, and can utilize the 505(b)(2) pathway to approval. Liposomal drug products are a sub-group of Non-biological Complex Drugs (NBCD) and contain greater complexity in characterization and approval than small-molecule drugs. Further, their generic follow-on products, ‘nanosimilars’ or complex generics, require more studies and/or more complicated studies to demonstrate bioequivalence and/or pharmaceutical equivalence to the innovator liposome product. Premier Consulting can guide sponsors of liposome-based products through regulatory strategy development and provide expert insight on the unique technical challenges for liposome products.
New Liposomal Drug Product Guidance
The FDA issued the first Guidance for Industry: Liposome Drug Products, Chemistry, Manufacturing, and Controls; Human Pharmacokinetics and Bioavailability; and Labeling Documentation in August 2002. A revised draft Guidance with the same title was issued in October 2015 to replace the original Guidance, and a final Guidance was issued in April 2018. The revised Guidance takes into account the transfer of review responsibility for some biologic products to CDER in 2003 and includes guidance on developing generic liposomal products.
Although the active component of a generic liposomal drug product is similar but not technically the same as the innovator product, they are regulated as generics if reviewed by CDER. However, like biosimilars, approval usually requires more than a bioequivalence study to demonstrate safety, efficacy, and pharmaceutical equivalence, making the regulatory strategy more complex than that required for straightforward small molecule drugs.
At the time of writing this blog, the FDA has issued 4 product-specific Guidances for developing generic versions of liposomal products (amphotericin B, daunorubicin citrate, doxorubicin hydrochloride, and verteporphin). Applicants of other generic liposome-drug products should use the new final Guidance for regulatory advice.
Advantages of Liposomal Products
The term liposome refers to a structure with a lipid bilayer or membrane enclosing an internal aqueous substance. However, the structure of the bilayer and the liposome can vary greatly including multiple layers, compartments, and other attributes. Liposomes can mimic cells and are typically highly biocompatible.
Liposomes can be used to reduce the systemic toxicity of a locally acting drug, target a site-specific antigen, deliver a drug payload intracellularly, and alter pharmacokinetic properties of a drug to effect release properties or increase circulation time.
Much of the difficulty in developing liposome products results from the variability between and within batches. Even changes in batch size can affect the variability, requiring an applicant to justify operating ranges for each batch size.
The new liposome Guidance provides a range of categories for which an applicant should provide liposome characterization data. Advice that not all categories will be applicable to all products is provided.
Due to the uniqueness of this these drug-lipid complexes, the developer is expected to devote considerable attention to 1) description and composition, 2) physicochemical properties, 3) critical quality attributes, 4) manufacturing process and process control, 5) control of lipid components, 6) drug product specifications, and 7) stability.
As expected, extensive characterization of the composition, variability, and stability of the liposomal component is required. Details regarding the preparation of the liposomes, and importantly, how unencapsulated drug is removed, are required. For injectable products, potential liposome-specific difficulties with the sterilization filtration process must be addressed.
Any new components in the liposome that are not listed in the FDA’s Inactive Ingredients Database or are outside of the limits provided in the database require extensive safety justification, similar to any non-liposomal inactive ingredients. This can be done in the application or by creating a Drug Master File, if the liposome component is to be made available commercially for use in other products.
Due to the complexity of liposome products, most changes made after product approval will require a prior approval supplement (PAS).
Human Pharmacokinetics: Bioavailability and Bioequivalence
Due to the complexity of the products and differing release profiles compared with other liposomal products and with non-liposomal liposomal products, the Guidance notes that measuring the amount of drug in plasma over time is unlikely to be sufficient to demonstrate bioequivalence. It may be necessary to determine the bioavailability of the drug at the site of action.
For ANDA applicants, a Pre-ANDA meeting is recommended prior to submission to determine an appropriate method for assessing bioavailability of drug at the site of action. For NDA applications, a Sponsor should consult with the appropriate CDER Review Division..
Comparison to Approved, Non-liposomal Drugs
If a non-liposomal product that contains the same active ingredient and is administered via the same route of administration, the FDA recommends that a Sponsor compare its proposed innovator liposomal product to the approved non-liposomal product.
Comparisons of the 2 products should be made via absorption, distribution, metabolism, and excretion (ADME) studies. Specifically, a mass balance study with radio-labeled drug substance may be needed to characterize differences in distribution between the liposomal and non-liposomal drug products.
A single-dose PK study in the appropriate patient population should also be performed, comparing the liposomal and non-liposomal products.
The Guidance indicates that studies should be performed to identify if the release characteristics between the products are similar. An attempt should be made to conduct in vitro/ in vivo correlation (IV/IVC) studies. Even if a complete correlation cannot be established, data on some relationships may be useful.
Liposome interaction with blood proteins should be investigated to determine the potential for ‘dose-dumping’ of drug in vivo.
The Guidance advises that the non-proprietary name of the drug product should indicate the formulation is liposomal. Although the first approval of a liposomal drug and dosage form will not be distinguished in product labeling, subsequent approvals with the same active ingredient and dosage form will include Type B, Type C, etc., in the labeling. This requirement relates to the complex nature of liposomal products.
The Guidance requests that Sponsors include in the Description section of the product labeling a cautionary statement informing that there may be potential differences in behavior between the product that is the subject of the application and other liposomal and non-liposomal products. However, this cautionary statement is not required for liposome drug products determined by FDA to be therapeutically equivalent.
The complex nature of both innovator and generic liposomal products requires customized development strategies in all cases. In Premier Consulting’s experience with liposomal products, a thorough CMC data review and novel bioequivalence / bioavailability study designs can go a long way in successfully navigating regulatory requirements.
Contact us to discuss how our CMC experts can help your liposomal products gain approval.
Angela Drew, PhD
Product Ideation Consultant
Robert Kessler, PhD
Senior Director of Analytical Development