(T1230-10-64) Scientific and Regulatory Considerations of Applying Morphologically Directed Raman Spectroscopy in Bioequivalence Assessment for Generic Orally Inhaled and Nasal Drug Products

Purpose: The demonstration of bioequivalence (BE) for locally acting drug products is challenging as the clinical efficacy depends on the drug reaching directly to the site of action when administrated at same molar dose under similar conditions. Bioavailability of orally inhaled and nasal drug products (OINDPs) is impacted by multiple factors, such as drug particle size distribution (PSD), release from formulation, absorption from nasal mucosa and availability at the site of action. Historically, the FDA recommended an in vivo comparative clinical endpoint/pharmacodynamic endpoint study to ensure equivalent local delivery of drug between test and reference products as the available analytical techniques lacked the ability of adequately characterizing PSD of active pharmaceutical ingredient (API) in the presence of excipients in the final formulation of OINDPs. With the emergence of advanced techniques such as morphology-directed Raman spectroscopy (MDRS), the FDA currently recommends that prospective applicants may submit drug PSD data using MDRS or other methodology as a component of weight-of-evidence approach to support BE of OINDPs in Abbreviated New Drug Applications (ANDAs). The FDA’s regulatory expectation for a pivotal MDRS study is that the comprehensive method validation should be submitted to demonstrate the adequacy of the selected MDRS method in identifying and measuring the drug particles without interference from the excipients present in the final formulation, and that the adequately validated method parameters should be used in the pivotal MDRS study. The purpose of this project is to delineate the commonly observed BE deficiencies related to a pivotal MDRS study in support of BE determination of generic OINDPs and to elaborate on the FDA’s expectations of the MDRS study recommendations.

Methods: Ten (10) ANDAs submitted between 2018 to 2022 containing a pivotal MDRS study to support BE determination of OINDPs were selected and evaluated in this project. The common BE deficiencies in the MDRS section related to method development, method validation and pivotal study were analyzed per the requirements as highlighted in the FDA guidance, literatures (including publications from FDA) and current BE assessment practices.

Results: From the identified ANDAs with a pivotal MDRS study, the results showed that all applications (100%) contained deficiencies related to method development, method validation and pivotal study. Specifically, the method development and validation data submitted were insufficient/inadequate to support the selected MDRS method. Under the method development, 100% of the ANDAs contained deficiencies related to MDRS sample preparation (e.g., sample dispersion technique, number and method of spray, batch-to-batch variability, sample volume and dilution, particle settling time, use of surfactants and sealants, composite sampling from multiple units). In all (100%) of the ANDAs, the deficiencies of inadequate selection of morphology filters (e.g., elongation, convexity, solidity and circularity) were noted. Other common deficiencies of MDRS imaging and size characterization related to the selections of optic magnification, threshold, Raman particle count, circular equivalent (CE) diameter and Raman correlation score were also observed. For the method validation, all ANDAs (100%) contained deficiencies related to MDRS reproducibility and robustness (e.g., scan area, sample volume, percent overlap). In addition, insufficient partial method validation upon method transfer across study sites was noted. Furthermore, in 30% of these ANDAs, deficiencies were identified in the pivotal MDRS study, such as non-use of validated parameters, non-use of proposed to-be-marketed or commercial batches, insufficient sample size (at least three batches of test and reference products with no fewer than 10 units from each batch), use of expired batches, statistical population BE analysis based on the pooled data from different pivotal studies. The other deficiencies such as missing data on polymorphic form of the test and reference Raman spectrum, missing of reference spectrum library, non-submission of relevant standard operation procedures (SOPs) and/or protocols for MDRS method development/validation were also identified. Additionally, deficiencies related to orthogonal methods were identified in 90% ANDAs, such as incomplete method development/validation (e.g., percent of particles for API and excipients below 1µ or 0.5µ).

Conclusion: The drug PSD data using a MDRS method is currently recommended as a component of weight-of-evidence approach and is becoming more common to support BE determination for generic OINDPs. With the increased number of ANDAs being submitted with a MDRS study, it is challenging but critical to adequately develop and validate a MDRS method before conducting the pivotal study. The outcome of this project helps the industry to understand the submission requirements for MDRS and emphasizes consideration of all the important aspects of MDRS method development, method validation and the use of validated parameters for the pivotal study. Most of the identified MDRS deficiencies could be preventable by providing additional supporting data on method development, method validation and pivotal studies. This will benefit industry in improving the overall quality of ANDA submissions by avoiding unnecessary deficiencies and reducing the number of review cycles which may lead to timely availability of the generic OINDPs to the American public