(T1230-08-51) Common Deficiencies with Spray Dried Dispersion Intermediates for Solid Oral Drug Products Assessed by the FDA

Purpose: Spray-dried dispersion (SDD) is a formulation technique that has gained popularity in recent years for enhancing the bioavailability of poorly water-soluble crystalline Active Pharmaceutical Ingredients (APIs). SDD is prepared by spray-drying a mixture of the API and a polymer dissolved in a common solvent. It has been used as an intermediate in many solid oral drug applications to improve the solubility of the API and, consequently, the bioavailability of the drug product. The FDA has received an increasing number of drug applications containing SDD over the past decade. Deficiencies related to the SDD may delay the review and approval process of these applications. Many of these deficiencies are commonly observed and can be avoided in the future drug application submissions.

Methods: We conducted a survey of new and abbreviated drug applications (NDAs and ANDAs) submitted over the years from 2008 to 2023 to the FDA to identify the most commonly occurring deficiencies for the SDD.

Results: The deficiencies were classified into four categories: manufacturing related deficiencies (e.g., process parameters, batch formula, batch records, yield, equipment, scale up, etc.), in-process controls deficiencies (e.g., in-process specification, in-process testing results, analytical method, sampling plan, etc.), storage and handling deficiencies (e.g., hold time, packaging, environmental controls, etc.), and formulation and drug product related deficiencies (e.g., quantities of the polymer and excipient, crystalline content monitoring of the drug product, etc.). For each category, additional sub-categories were defined to characterize the deficiencies. The highest occurring rate of 63% was observed for the in-process controls deficiencies for the SDD. The occurring rates of 50%, 50%, and 33% were observed for the manufacturing related deficiencies, storage and handling deficiencies, and formulation and drug product related deficiencies, respectively. Among the in-process controls deficiencies, the top three deficiencies were crystallinity control with analytical method and method validation report (27%), particle size distribution control (23%), and water content control (20%). Among the manufacturing related deficiencies, executed and master batch records (30%), SDD yield (27%), batch formula (23%), and spray drying process parameters (17%) related deficiencies were ranked as the top four deficiencies. For the storage and handling deficiencies, hold time (47%) was the most commonly occurring deficiency. For the formulation and drug product related deficiencies, crystallinity monitoring and control of the API in the drug product deficiency was found in 27% of the applications.

Conclusion: When reviewing NDAs and ANDAs containing SDD intermediates, certain common deficiencies have been observed that can slow down the approval process. To avoid these deficiencies in original submissions, it is crucial to provide robust and comprehensive supporting data that justifies the hold time for the SDD, ensure appropriate crystallinity control and analysis of the API in the SDD and final drug product, submit complete batch records, establish narrow yield limits with consistent yields for primary stability batches of the SDD, and implement effective particle size distribution and water content controls. By addressing these common deficiencies in the original submissions, the reviews and approval of solid oral NDAs and ANDAs containing SDD intermediates can be expedited, helping to bring important medicines to patients faster.