SBIR-STTR Award

This project involves development of a low-power, compact and portable, reliable, safe, and easy-to- operate x-ray diffraction instrument for measurement of crystal concentration and phase composition for active pharmaceutical ingredients (API) in the stages of research, development, and production for the pharmaceutical industry and possibly extended to other industries. This could also be used online for primary measurement of drug quality in pilot production and manufacturing environments. The team of X-ray Optical Systems (XOS), a world leader in manufacturing advanced x-ray optics and optics enabled analyzers, and Bristol-Meyers-Squibb (BMS), a world leader in pharmaceutical research and development, has the expertise necessary to develop a successful instrument. The objective of this SBIR Phase I proposal is to demonstrate the feasibility of developing a compact analyzer capable of monitoring active pharmaceutical ingredients (API) online or at-line in the various stages of development and production. This will be accomplished by developing a novel, low-power, fully enclosed and shielded, parallel-beam x-ray diffraction (XRD) system to apply new analysis techniques. Specifically the powder XRD (PXRD) setup would use a 50 W x-ray Source coupled with a collimating polycapillary x-ray optic to determine the proper crystalline information and polymorphs in the API with a high degree of accuracy. This new technique will be non-destructive, rapid, and insensitive to sample position and roughness. In addition, the system equipment will be compact and portable, therefore, it will be easily integrated in an on-line production system. In order to demonstrate the applicability of this technique, XOS proposes to explore specific API's from the pharmaceutical industry that have been challenging to develop production models for, using existing PXRD technology. Parallel beam XRD has been used for characterization of pharmaceuticals (Yin 2007). This study has already demonstrated the feasibility on a standard laboratory system. Due to the extended footprint, power requirements and chilled-water cooling for high power x-ray source, the system is not suitable for a typical production environment. XOS can leverage the new source-optic coupled technologies to demonstrate the low- power, compact, easy-to-use, measurement method. In Phase I, XOS proposes to develop and demonstrate the performance of the PXRD setup via: 1) differentiation of particular sample characteristics, 2) correlation of new data with conventional laboratory data, 3) reproducibility, and 4) design a novel sample handling method. The proposed analyzer will have a positive impact to the general public by increasing drug development efficiency and shortening the turnaround times for manufacturing processes. The applicability for such a machine includes facilitating improved throughput of drug research with a more rapid and cost effective instrument, implementation of drug process analytical technology (PAT) using a primary measurement method, and improvements in drug quality by design (QbD).

Public Health Relevance:
This Public Health Relevance is not available.

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Current pharmaceutical manufacturing technologies and processes are highly regulated and based on decades of experience. The techniques start in a lab, are continued in a pilot campaign, and finally graduate to full-scale manufacturing. To improve drug quality and manufacturing, in 2001, the Food and Drug Administration (FDA) initiated Quality by Design (QbD) and Process Analytical Technology (PAT) Guidance for the pharmaceutical industry. This project will provide the ability to comply with that guidance and continuously monitor pharmaceutical quality during manufacturing. Crystallization of active pharmaceutical ingredients (API) involves achieving a specific crystalline phase, for which there can also be multiple polymorphic forms, a critical factor for drug effectiveness. Powder X-ray diffraction (PXRD) is the 'gold standard' analytical tool to determine API crystalline phase composition and polymorphic form. Unfortunately, PXRD is not currently used online real-time because of the configuration requirements for conventional PXRD. It is currently applied offline in the laboratory because of constraining sample presentation requirements and the system size, complexity, and operator-skill requirements of conventional PXRD systems. Recent developments at X-Ray Optical Systems (XOS) of collimating optics and detector systems provide an opportunity to overcome these problems and enable a wide range of online PXRD applications. The objective of the proposed project is development of a reliable, easy-to-use, compact, and safe PXRD system for continuous monitoring of crystalline characteristics of API real-time during drug development and manufacture. This will improve process control and, therefore, assurance of product quality by directly measuring the pharmaceutical critical quality attributes rather than reliance on monitoring process conditions supported by relatively infrequent sampling. The project focuses on online measurements during the API crystallization phase. This will be done with pharmaceutical industry collaborators at Bristol-Myers Squibb (BMS). Feasibility for such measurements has been demonstrated on the benchtop during Phase I studies. It will be demonstrated online at a BMS pharmaceutical research and manufacturing facility in Phase II. Phase II will include all of the necessary instrument development steps required to design, assemble, and test the prototype. This includes sample presentation, the fixed detector approach, and integrating the analyzer with an existing reactor at BMS. XOS has extensive experience with online optic-enabled XRD and X-ray fluorescence (XRF) applications. The proposed project is a match with the NIH Research Objectives for the Manufacturing Processes of Medical, Dental, and Biological Technologies topic as a systems-level technology. Improved drug quality, improved public health, reduced manufacturing costs, and reduced health-care costs are the ultimate goals.

Public Health Relevance:
The proposed analyzer will increase control over the quality of pharmaceuticals by providing the ability to measure the actual drug crystalline/molecular form during the process for the first time, compared to current practice of just monitoring the manufacturing parameters. The analyzer will be compact, inexpensive, and able to be set up and operated by operators and technicians. The ability to measure crystallinity in the drug directly online during development, pilot scale up, and full-scale manufacturing will impact public health by improving the consistency of pharmaceutical quality, reducing time to market by faster manufacturing ramp up, reducing manufacturing costs by increased process control, and improving manufacturing compliance through application of the FDA's Process Analytical Technology (PAT) drug certification guidelines.

Thesaurus Terms:
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