By Agnes Shanley, Editor in Chief
Once a company introduces multivariate (MV) sensors and chemometrics and understand its processes, should it replace those MV sensors with simpler and cheaper sensors or timers? This was only one of the many relevant questions raised and discussed at the IFPAC summit meetings in San Juan on September 8 and 9. It also provides some insight into the tone of the event, which dispensed with the self-congratulations and PAT primers and went straight to the heart of the implementation challenges facing today’s pharmaceutical PAT teams.
The Summit, which brought together diverse lecturers from widely different backgrounds, was a group effort. It was organized by the International Foundation of Process Analytical Chemistry (IFPAC), the Puerto Rico Research Consortium of Pharmaceuticals and Academia (INDUNIV), the PAT systems integrator, IBS Caribe Inc., and Dr. R. Romañach from the University of Puerto Rico-Mayaguez.
Its program was carefully balanced to reflect both regulatory and corporate viewpoints. For example, a review from FDA on how its PAT team approached the task of reviewing Sanofi-Aventis’ PAT installation in Kansas City was followed by Sanofi-Aventis’ perspectives on the same project. Subsequent presentations covered a wide range of business strategies and technological PAT tools needed for a successful implementation.
Focus was also important, and aided by open discussion of practical issues, involving manufacturing specialists, researchers, vendors and “outsiders” experienced in applying PAT concepts outside of the pharma industry, who brought fresh perspectives. Although an introductory lecture was included for those new to PAT, most of the discussion was devoted to discussing the real-life challenges and problems that manufacturing professionals are encountering in their PAT programs.
For those of you who could not attend, this brief summary should provide some insights.
The program in a nutshell
Carlos Tollinche, PhD., Director of INDUNIV’s Scientific Affairs Board, kicked off the program, providing an overview of the pharma and biopharma industries, both globally and in Puerto Rico.
Rebeca Rodriguez, FDA’s National Investigator, discussed FDA’s approach to a PAT implementation inspection when she was part of the PATRIOT team reviewing the Sanofi-Aventis comparability protocol in Kansas City. She emphasized the Agency’s risk-based approach to inspections and its search for evidence of process knowledge and understanding. A critical part of implementing PAT, Rodriguez said, is taking a holistic view and understanding the ultimate goal, instead of focusing only on specific issues, such as designing, analyzing or controlling.
Following her presentation, Chan Cai, Ph.D., from Sanofi-Aventis, presented his view from “the other side.” His team implemented PAT throughout an entire production cycle, to better understand how the variability of the in-process measurements affected the downstream processes and final product quality. The measurements included:
- raw material attributes such as real-time ID, moisture content, and particle size;
- real-time granulation moisture level during drying;
- real-time material concentration profile during blending;
- content uniformity, moisture content, and hardness profile during tablet compression.
Sanofi’s ultimate goals were to:
- control the drying and blending time automatically;
- predict final tablet dissolution performance;
- feed forward the optimal settings for the compression equipment to reduce startup product loss and improve dissolution.
So far, Cai says, the projects are greatly increasing Sanofi-Aventis’ understanding of processes at the facility. In fact, just one of the PAT projects by itself has already improved dissolution results and reduced variation, he says.Perspectives from the chemical industry
Offering a fresh, non-pharma perspective, Walter Henslee, IFPAC consultant and Chief Editor of JPAC, discussed his extensive experience with multivariate analyzers at Dow and other companies. Dr. Henslee led groups that specified, installed and started up over 500 new process analyzers in more than a dozen sites worldwide, and provided technical support for 1500 PAT systems. He shared his experience and support to the PAT initiative. The good news? Implementation may be challenging, but once installed, the systems are easy to maintain.
From the vendor side, representatives from Curvaceous Software Ltd. discussed their company’s alternative to traditional MVA software. The programs are based on simple geometric forms and may be easier for non-mathematicians to use, they said.
Manuel Hormaza, CEO of IBS Caribe, a systems integrator based in San Juan, then outlined a roadmap to “real-time release,” which FDA has defined as “the ability to evaluate and ensure the acceptable quality of in-process and/or final product based on process data.” Synergistic technologies, standards and incentives now enable PAT implementations, he said, taking the industry closer to this goal. A systematic and gradual approach can only help ensure the desired result: added value, rather than simply more — or more complex — technologies.
Discussion of Near-Infrared (NIR) spectroscopy, currently the most widely used method in PAT, dominated the program. The technique permits chemical and physical material properties to be analyzed. Unlike the sampling thieves used in most QC operations today, NIR offers a scientific approach to powder sampling. Nevertheless, NIR spectra can be complex. Advanced chemometrics software can help ensure that they are analyzed and interpreted properly.
Chris McCready from Umetrics discussed chemometrics software packages available for multivariate (MV) data analysis, and how MV analysis can help the industry shift from its current paradigm of making each batch as good as the last one, to making each batch better than the one preceding it. However, before using MV analysis, he noted the importance of extracting, organizing and aligning data from all available sources (including LIMS, MES, SCADA, and ERP platforms).
Professor Carlos Velazquez, Ph.D., from UPR-Mayaguez presented the results of his team’s research work in granulation end points. The UPR team evaluated fluid bed dryers by monitoring the moisture content of the mix with NIR and concluded with a discussion of the mathematical modeling that best describes the operation.Comparing NIR and Raman
D.J. Strachan, Ph.D., from Kaiser Optical, then contrasted the usefulness of NIR vs. Raman spectroscopy for monitoring the physical and chemical properties of API forms during drug development.
Strachan recommends using Raman spectral analysis to follow chemical characteristics and thus, typical API processes such as syntheses and crystallizations. He observed that Raman analytical methods are continuing to improve and becoming widely available.First things last: Tracking raw material quality
Concluding the conference, Paul C. Entrop from Thermo Electron Corp. discussed how PAT can address raw material and product variability. NIR can be used to track raw materials’ physical and chemical throughout any process. He proposed a model that would use FT–NIR for raw materials identification, and to determine moisture, and physical parameters including particle size and polymorphism.
NIR can also be used in downstream processes for solid dosage forms, in processes such as blending and compression. In these processes, content uniformity demands physical measurements, and NIR can provides an easy and accurate assessment of process quality. He also discussed Thermo Electron’s APC software, which can be used to track lot history and monitoring.
Clearly, PAT efforts in Puerto Rico are well advanced, and the thirst for more technical PAT seminars has led to a follow-up event focused on hands-on NIR. It will be held in San Juan in December. Stay tuned to PharmaManufacturing.com and the PAT Insider
for more information.