CERSI Collaborators: Lex Schultheis, MD, PhD, Peter Zavalij Ph.D.

FDA Collaborators: Paresma Patel Ph.D., Yongming Lu Ph.D., Bimali Bandaranayake, PhD.

CERSI Subcontractors: Advanced Analyzer labs, Huapeng Huang, Ph.D

Project Start: February 8, 2023

Regulatory Science Challenge

Many drug substances are manufactured as small crystals. The structure of a crystalline drug substance varies depending on its precise manufacturing conditions. Differences in this crystalline structure can, in turn critically impact the drug’s physiochemical properties (e.g., solubility) ultimately affecting its safety and efficacy for patients. As such, careful control of the production of different crystal structures (polymorphs) is needed to ensure the safety and effectiveness of crystalline drug substances. The quality control of crystal structures in drug manufacturing is monitored using several conventional methods. The most reliable way to examine crystal structure is to shine x-rays onto them and measure how the x-rays bounce off the internal structure. Currently, this kind of x-ray analysis cannot be performed while a drug substance is being manufactured because the equipment needed is too large, slow to operate, too expensive, and the X-rays it uses are too powerful for worker safety. Consequently, samples from batches of drug substance are evaluated periodically during drug substance crystallization using testing methods that may not be as reliable as x-ray studies. This means that some batches of drug substance could be manufactured without knowing the crystal structure until after the drug substance manufacturing process is complete. If the drug substance has the wrong crystal structure, it cannot be released, meaning it must be reprocessed, leading to significant loss of material and increased time to produce important drugs.

This project is expected to advance the development of a technology to directly measure drug substance crystal structure continuously during the manufacturing process (crystallization process) using an X-ray based online probe. This way, drug substance abnormalities can be found and corrected rapidly as the drug substances are made - enabling automated quality control resulting in greater efficiencies and reduced costs.

Project Description and Goals

Investigators aim to develop a specialized technology that uses an X-ray based online probe to directly measure drug substance crystal structure during manufacturing. This technology will help investigators determine the extent to which continuous x-ray study of drug crystal structure can be relied upon for quality control.

The goals of this project are to: (1) compare the accuracy of the new technology (an X-ray based online probe) to traditional x-ray equipment in tests of the quality of drug substances; and (2) optimize the performance of the new technology to yield the best possible accuracy in the most efficient way.

The University of Maryland CERSI (M-CERSI) will prepare a report summarizing its findings, which will help inform FDA’s regulatory decision-making, specifically when the Agency is presented with new methods of drug substance manufacture that utilize x-ray analysis for continuous quality control.