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By Otilia Koo, Rao Mantri, and John R. Crison

Otilia KooRao Mantri-finalJohn Crison-finalMany of us, as pharmaceutical scientists, have encountered challenges in developing appropriate active pharmaceutical ingredient (API) particle size specifications that are relevant to in vivo performance and manufacturing controls. API particle size specifications, one element of total control strategy for oral drug products and corresponding drugs substances, are chosen to ensure product quality and consistency is maintained. Specifications are chosen to confirm the quality of the drug substance and drug product rather than to establish full characterization, and should focus on those characteristics found to be useful in ensuring in vivo performance of the drug substance and drug product.

For oral solids and suspensions, ICH Q6, Decision Tree #3 (PDF) provides guidance that API particle size specifications should be based on whether the particle size is critical to dissolution/bioavailability, processability, stability, content uniformity, and product appearance. The most challenging aspect of following the guidance continues to be the determination and demonstration of particle size specifications that are meaningful from a clinical performance perspective.

In recent years, the use of physiologically-based pharmacokinetic in silico tools to predict the impact of the particle size on the in vivo dissolution, absorption, and bioavailability has become widespread and an important part of the formulation development decision process. Nevertheless, when it comes to setting or defining API particle specifications, the default position is to use the boundaries of API properties (batch data) that have been used clinically. Additionally, it is difficult to know which method is best to use as input to the PBPK models as well as for specifications.

In the upcoming AAPS webinar on June 25, Challenges in Setting API Particle Specifications to Meet Both Manufacturing and Bioavailability Needs, attendees will review the link between particle size and dissolution/in vivo performance, get current thinking on the applications of dissolution/absorption and other PBPK models, and discuss practical considerations towards setting “physiologically meaningful” particle specifications.

The objectives of the webinar are:

  • Demonstrate that API particle size specification is one element of the overall control strategy.
  • Review challenges and approaches to determine API particle size that may be relevant to dissolution.
  • Illustrate the use of PBPK modeling to assess the potential impact of particle size on in vivo dissolution, and perspective on setting particle size specifications.

Hopefully, you can get a deeper understanding into characterization of API particles and how to approach particle specifications that can better predict in vivo performance!

Otilia Koo, Ph.D., is currently a principal scientist at Bristol-Myers Squibb Company in New Brunswick, N.J., and is responsible for the pharmaceutical development of commercial solid dosage formulations. She received her doctorate in pharmaceutics from the University of Illinois at Chicago and master’s in pharmaceutics from the National University of Singapore.
Rao Mantri, Ph.D., is currently working as director and head of Materials Science & Engineering at Bristol-Myers Squibb Company. He received his B.Tech. in chemical engineering from Osmania University, India, M.S. in chemical engineering, and Ph.D. in pharmaceutical chemistry with honors from the University of Kansas.
John R. Crison, R.Ph., Ph.D. has over 34 years of experience in pharmacy practice, pharmaceutical research and development, and teaching, as is evidenced by a strong publication record, particularly in the area of BCS and modeling of in vitro data to predict in vivo performance. Crison received his B.S., M.S., and Ph.D. from the University of Michigan.