Azaya Therapeutics – Meeting FDA Standards Requires Accurate Size, Charge and Concentration for Bioequivalence Testing

Azaya Therapeutics is an oncology company, based in San Antonio, Texas, focused on developing more effective treatments through its nanotechnology platform.

Azaya manufacturers a generic form of the drug Doxil/Caelyx, and uses the qNano to verify that particle size and characterization are within the definition of bioequivalence as set forth by the US FDA and European Medicines Agency (EMA). Doxil is a pegylated (polyethylene glycol coated) liposome-encapsulated form of doxorubicin, used to treat a wide range of cancers.

“Since there are relatively few liposomal products in the US and EU market, regulatory bodies are very conservative and cautious in their assessments. In particular, there is significant scrutiny within the chemistry, manufacturing, and control (CMC) requirements for liposomal products,” says Don Kruppa, Vice President, Operations at Azaya Therapeutics.”

In fact, both the EMA and the US FDA view this liposomal nanotechnology within the same paradigm as “biosimilars” with respect to regulatory requirements and characterization.

Click here to View Izon Science Presentation on FDA Website:   “Assurance of physical equivalence (size, charge, concentration, aggregation, interactions) of complex nanomedicine substances”

How does accurate particle characterization fit into the process?

The accuracy of particle characterization is one of the key elements to support any marketing application as all regulatory agencies expect manufacturers to have consistency, between batches, of particle size, concentration, charge and particle size distribution.

TRPS characterization using the qNano overcomes the limitations of long-standing but dated bulk-analysis technologies, such as dynamic light scattering (DLS), which are not capable of reliably measuring polydisperse samples. (Previous article: “Study compares low versus high resolution techniques”)

“The typical DLS characterization is flawed with respect to accuracy in characterizing the particle size and distribution. While there may be distinctly a bi-modal distribution, the DLS method will report an average particle size and the actual distribution will not be identified. With the qNano, the actual particles are measured, a true and accurate distribution is reported and both concentration and charge are also measured,”

Concentration is another property of key importance to nanomedicine manufacturers and regulators. The typical DLS instrument does not measure charge or concentration. This is significant as concentration of liposomes is critical since other physicochemical testing and their results are dependent on liposome concentration. One example would be total sulfate in our liposomal ATI-0918, a generic Doxil/Caelyx. Total sulfate is key to the release characteristics of this product and is directly correlated to concentration of liposomes.

What is the risk of not providing accurate detailed characterization?

Without a detailed, validated and robust analytical method, which characterizes the entire liposome including size, distribution and charge, regulatory agencies will not have confidence that manufacturers can replicate the product batch to batch.

Kruppa explains, “Their main concern is that the nanoparticles release the drug too quickly or inconsistently causing toxicity issues in the patient. The entire argument for a liposome delivery system, is extended release, higher AUC, and higher dosing,”

“If the particles are of different sizes and have a bimodal or trimodal distribution, there is increased concern for consistency of delivery, targeting of tumor tissues and other safety issues. Furthermore, your entire application and process validation may be questioned. Using the qNano and a validated method, one can display and scientifically argue that the data accurately represents the batches being produced.”

How can high resolution characterization help nanomedicine manufacturers provide better data to meet regulatory standards?

Since Azaya Therapeutics is making a generic to Doxil/Caelyx, the qNano is being used to verify that particle size and characterization are within the definition of bioequivalence as set forth by the US FDA and EMA.

The comparison of Azaya’s product to the Reference Listed Drug (RLD) is critical and the more accurate the data, the better chance of approval.

“Using the qNano, we are demonstrating the accuracy and robustness of our data when it is compared to the RLD. We are at 98% equivalence in particle size and distribution. These data will be a vital element in our application indicating that indeed our process and batch data truly indicates equivalence to the RLD, Doxil/Caelyx,” says Kruppa.

Azaya plans to use a variety of physicochemical data to support their marketing applications and filings. Specific to particle size, distribution, charge and concentration, the qNano will be an invaluable instrument because the data is more accurate since it does measure each particle and reports it, not just an average as the DLS method.

“The science and technology have evolved which will stipulate the qNano as the industry standard in accurately measuring particle size and distribution and conversely making the DLS system obsolete with respect to liposomal and nanoparticle characterization.”