(166e) Establishing Appropriate Particle Size Specifications for Solid Oral Dosage Forms

Sun, Z., Office of Generic Drugs, OPS, CDER, FDA

Control of particle size distribution of pharmaceutical powders is critical in the manufacture of solid oral dosage forms due to significant impact of particle size on the safety and efficacy of the drug product. As shown in many publications, particle sizes of powders have profound influences on not only drug product performance (e.g., dissolution, content uniformity, and stability etc.) but also drug product manufacturability (e.g., flowability, blend uniformity, compactibility etc.). Therefore, establishing appropriate particle size specifications is necessary for control of drug product quality and manufacturing consistency.

Traditionally, in the manufacture of solid oral dosage forms, control of particle sizes is only considered for the drug substance with low solubility. However, for the Quality by Design (QbD) approach, the effects of particle sizes of the drug substance, excipients, and in-process materials on critical product attributes (CQA) of the drug product should be assessed based upon drug formulation and manufacturing process. If particle sizes of some of raw or in-process materials are identified as the critical material attributes (CMA) during manufacturing processes (e.g., mixing, granulation, milling, blending, coating etc.), the particle size specification is required for each of these materials, which may include not only the drug substance but also excipients and in-process materials. In this presentation, some examples will be discussed to demonstrate when the particle size specification needs to be established based upon the QbD approach.

Once a particle size specification of pharmaceutical powders is required, the next question is how to establish an appropriate particle size specifcation. In many new drug applications (NDAs) and abbreviated new drug applications (ANDAs), it is common to see that the particle size specifications submitted are not complete, not really meaningful, or not adequate to control the particle size distribution of pharmaceutical powders. Therefore, it is important to know what information should be included in the particle size specification to meet the regulatory requirement. In this presentation, for each component of particle size specifications (analytical procedures, method validation, and acceptance criteria), recommendations will be discussed regarding establishment of an appropriate particle size specification.