The future of PAT

PharmTech: On an industry level, looking ahead five years, how do you see PAT evolving in the pharmaceutical industry, both in terms of adoption as well potential advancements in instrumentation, data analysis, and related testing in a PAT environment.

Freeman (Freeman Technology): While the use of PAT for information gathering and process monitoring, particularly in development, has grown substantially during the past five years, there is still some way to go in terms of optimizing its application across the whole manufacturing cycle and its utilization as a mechanism for process control. In the next five years, I expect PAT to penetrate further into commercial manufacture as confidence in its use and capabilities expand.

It is also my view that the extension of PAT into the manufacturing arena will prove valuable in terms of fully exploiting the processing experience that resides there. In our area, for example, the application of appropriate and relevant powder testing has unlocked real understanding about why certain plants behave as they do, providing information that can be used to further the development of more efficient processes. By closing this loop, and bringing formulation, process development, and manufacture closer together, PAT will be able to significantly accelerate progress.

Heil (Thermo Fisher Scientific): In the pharmaceutical industry, PAT is well adopted among the largest pharmaceutical companies, especially in the more developed countries. In the next five years, I see the evolution of PAT into smaller pharmaceutical companies, contract manufacturing organizations, dietary supplement manufacturers, and companies in the less-developed world. Companies in these regions and industries have seen the progress that the larger pharmaceutical companies have made and see the value of PAT tools, such as NIR spectroscopy, for monitoring and controlling their processes to improve quality and lower production costs.

Advances in data analysis and data management are critical to the future success of PAT. Managing the sheer volume of real-time, multivariate data generated from a production process so it can be used for real-time process adjustments or off-line production analysis is a challenge. During the last 10 years, significant knowledge has been gained on how to properly implement process instrumentation for on-line analysis.

For many companies, the starting point for implementing PAT tools was moving familiar laboratory spectroscopy techniques from laboratory to line. The value of PAT is built around real-time analysis of critical quality and performance attributes to improve process quality. For a pharmaceutical process, this means combining data from multiple sources to get a complete picture of the overall quality of raw, in-process, and final products. This approach requires advanced data-management systems capable of receiving information of various formats from multiple analyzers and production automation systems. Take for example, the data management required when applying PAT to the pharmaceutical hot-melt extrusion process. Real-time data of multiple formats and sources from a NIR analyzer, barrel temperature probe, pressure sensor, extruder-screw speed, and ingredient feed rates would need to be archived in a common location for real-time, multivariate data analysis as well as off-line post processing analysis.

Process analyzer software with automated archival and industry standard process communication protocols embedded into the process analysis workflow are critical attributes when implementing a PAT analyzer. Analyzer software that supports multiple data exchange formats, process communication protocols and the ability to execute external applications further simplifies the implementation process. Current gaps in data analysis and management have required pharmaceutical companies to write, implement, and validate custom software for their PAT applications. With future advances in data-analysis and data-management software, companies will be able to focus their PAT efforts on optimizing their sampling at point of analysis, chemometric models, and multivariate analysis tools, thereby allowing them to apply PAT to more challenging production processes.

Samojla (Waters): Real-time chromatographic analysis will increasingly enhance manufacturing processes—development, transfer, monitoring, and control. Integrating these enhancements within a unified information access model capable of very high-speed analytics will yield improved decision management, predictive analytics, and comprehensive analysis—without the paper. This integration can be achieved by deploying real-time analytics while eliminating the time delays, analytic, and process variability associated with traditional off-line analysis.

Aumiller (GE Analytical Instruments): In the next five years, the adoption of PAT will likely be very evolutionary in nature. Existing processes will be incrementally changed to provide for better efficiency. It is unlikely that a disruptive technology will be readily adopted that totally replaces an existing process.

Within the context of cleaning systems, we will likely see the development of better tools and analytics that allow for more optimal control of the processes. As indicated earlier, many cleaning processes currently employ the use of conductivity and TOC measurements as a check of equipment cleanliness. This testing is most often performed in the laboratory but also can be performed at-line to speed the time to result. With the use of robust and fast-responding on-line instrumentation, CIP cycles could be designed to run until contaminants drop below a predefined threshold rather than running for fixed periods of time. With the immediate feedback afforded by integrated conductivity and TOC monitors, processes could become quicker and require lower utility costs to achieve the same or better quality. This transition will require the use of instrumentation that can reliably detect the contaminants of interest within the complex matrix of a cleaning process.

Salamon (PerkinElmer): To consider the potential advancements in analytical instrumentation, I would look at other significant advances in pharmaceutical development and not just at PAT advances. Nanotechnology drug delivery is the biggest advancement in the past five years and will be the biggest advancement in the future five years. Currently proven scaled-up developed manufacturing practices and processes do not exist to consistently produce, on a large scale, nanopharmaceuticals. In the development laboratory, single particle – inductively coupled plasma–mass spectrometry (SP-ICP-MS) of nanomaterials is the most significant improvement. This is not in-line, on-line, or at-line testing, but is a significant advance in analytical testing.

References

1. FDA, Pharmaceutical cGMPs for the 21st Century—Risk-Based Approach: Final Report (Rockville, MD, 2004).

2. FDA, Guidance for Industry: PAT—A Framework for Innovative Pharmaceutical Development, Manufacturing and Quality Assurance (Rockville, MD, 2004).

3. FDA, Progress Report on Process Analytical Technology, http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/QuestionsandAnswersonCurrentGoodManufacturingPracticescGMPforDrugs/ucm072006.htm, accessed June 18, 2012.