Particle Size Specifications for Solid Oral Dosage Forms: A Regulatory Perspective
Particle Size/Oral Dosage
Zhigang Sun, Ph.D., Naiqi Ya, Ph.D., Richard C. Adams, & Florence S. Fang Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration
The views and opinions expressed in this article are only of the authors and do not necessarily reflect the views or policies of the FDA.
Introduction
In the pharmaceutical industry, particle characterization of powder materials has become one of the crucial aspects in drug product development and quality control of solid oral dosage forms. The particle size distribution (PSD) of the drug substance may have significant effects on final drug product performance (e.g., dissolution, bioavailability, content uniformity, stability, etc.). Furthermore, the PSDs of both drug substance and excipients can affect drug product manufacturability (e.g., flowability, blend uniformity, compactibility, etc.), which, ultimately, can impact safety, efficacy, and quality of the drug product. Many publications have shown that the PSDs of pharmaceutical powders have profound influence on almost every step of manufacturing processes for solid oral dosage forms, including pre-mixing/mixing, granulation, drying, milling, blending, coating, encapsulation, and compression [1-3]. Therefore, the impact of particle sizes of pharmaceutical powders on drug product manufacturability and performance should be evaluated at different pharmaceutical development phases for each specific drug application [4]. Once these particle size effects have been determined in the final development phase, the target PSDs of pharmaceutical powders can be selected and the appropriate particle size specifications should be established for control of drug product quality and ensuring manufacturing consistency. In this paper, we will discuss several important aspects of the particle size specification for solid oral dosage forms from a regulatory perspective. Discussion will include the relevance of a particle size specification as a part of the critical material attributes of formulation components and product intermediates as well as key considerations in the establishment of a particle size specification.
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