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Sep 15, 2008 (Vol. 28, No. 16)

FDA Backs PAT to Help Solve Manufacturing Woes

Process Analytical Technology Is a Key Part of Agency’s Plan for the 21st Century

  • Microextraction

    Finally, Dr. Colon-Rivera discussed microextraction as a means of sample enrichment using either small volumes of, or no organic solvents, with no need for further concentration. These techniques—such as solid-phase microextraction, liquid phase microextraction, and microextraction in packed syringe—are fast, simple, some of them disposable, and cost-effective, Dr. Colon-Rivera said.

    Bristol-Myers Squibb’s Gary McGeorge spoke in the conference on “Applications of chemical imaging,” a technique that has enjoyed rapid growth over the past decade as the required imaging and computer equipment has become widely available and robust computational software has been developed.

    The technique provides both chemical information (spectra) and spatial information. For example, when molecules of a drug crystallize from solution, Raman spectra may show differences due to crystal structure variations, indicating polymorphism that can change pharmaceutical activity. Bristol-Myers Squibb also looks at images of blends during the blending process to measure performance.

    A fundamental premise of chemical imaging, McGeorge told the conference, is that the relative location of components can be critical to pharmaceutical performance. Imaging of tablets can determine if aggregates of API influence the dissolution profile, measure the API particle size distribution, correlate laser line scan data with near infrared (NIR) image data, provide indices that can be used to describe spatial distribution and correlate these to dissolution characteristics, and determine why and how agglomerates influence the dissolution profile by imaging water uptake/ingress in situ.

  • Chemical Imaging

    The quantitative measures that result from chemical imaging can provide documented methods both in terms of processing and analysis, McGeorge noted, provide consistency across multiyear project timelines and provide numbers that can be utilized as specifications and in directed decision making. With a library of excipients and active ingredients, analysts could hypothetically evaluate what and how much is in a specific tablet, which would be useful for analyzing problems tablets, counterfeit analysis, and determination of homogeneity. With an archive of results, McGeorge pointed out, one can datamine and statistically compare variance across batches.

    Although chemical imaging is not yet a manufacturing technology, it is in relative terms, a high-throughput process, McGeorge observed. He noted that Raman mapping was quite slow requiring about an hour per tablet and that now, using chemical imaging, processing 20 tablets per hour is realistic. In terms of QbD studies of blending time, perhaps 100 samples per day could be tested, effectively replacing HPLC. The technique might also replace time-intensive dissolution testing to improve throughput of manufacturing facilities.

    As for the future development of chemical imaging, McGeorge identified three areas: continue exploring spatial distributions of components in drugs products, relate features of NIR images with those of other imaging and nonimaging methods, and relate performance metrics to images’ features across different product to develop formulation rules.

  • Goals of the FDA Guidance

    Economic Benefits

  • Reduced cycle times

  • Increased equipment utilization

  • Reduced warehousing requirements (quarantine)

  • Reduced time to market

  • Continuous operation

  • Reduced QA costs

    Quality Benefits

  • Higher production inspection rate

  • Reduced process errors

  • Decreased product exposure

  • Improved product consistency

  • Continuous process improvement

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