It’s a question of vital economic, environmental and political importance: How can the pharmaceutical industry best utilize new technologies for measurement in order to improve the speed and safety with which drugs are made? According to the Food and Drug Administration, by completely changing the way the industry approaches manufacturing according to a simple edict: “Quality cannot be tested into products; it should be built-in or should be by design.”

The FDA’s Process Analytical Technology (PAT) initiative stands as a crucial Agency response to the growing political issue of perceived high drug costs. It is also an important companion endeavor to its major August 2002 Pharmaceutical Current Good Manufacturing Practices (cGMPs) for the 21st Century: A Risk-Based Approach. Faced with a growing number of recalls and drug shortages, and emboldened by the emergence of measurement technologies that are able to monitor active and inactive ingredients, the FDA concluded that the pharmaceutical industry lags far behind similar industries when it comes to efficient, general practices in areas like measurement and quality assurance. Additionally, the Agency felt that a lack of innovation in the manufacturing sector was greatly due to regulatory uncertainties—manufacturers were slow to improve certain processes for fear of how the changes in their physical infrastructure would be treated by monitoring agencies.

The first inklings of the current PAT initiative arose from efforts in 2001-2002 by Dr. Ajaz Hussain, current deputy director of the Office of Pharmaceutical Science at the FDA, to point out how this climate meant relatively little was employed in the way of process control and monitoring. Further, it was asserted that even less of what real-time monitoring did exist was communicated to regulatory bodies. The industry was also locked into a process that was aimed at tests of product after it was manufactured.

Perhaps because of the perception issues, the FDA has been clear from the start that this new emphasis on process-by-process approach seeks to improve, rather than supplant, an already effective industry. To make use of a sports metaphor, the pharmaceutical manufacturers are the natural, gifted sprinter locked into a specific way of running a race. Through PAT, the FDA becomes a track and field coach, putting down his stopwatch and working with the runner on the physical mechanics of her stride, start and kick. Although there is some initial cost involved in terms of adjustment, the potential rewards for the bottom line are inevitable and enormous.

The PAT initiative directly targets manufacturing processes in a way that diminishes uncertainty by utilizing a battery of existing measurement tools during the process, in a way that meets specific, incremental goals determined to guarantee the best result. This facilitates a general philosophy of efficiency, in effect taking completely off the table batch production approaches with built-in waste or another strategy that might allow for multiple manufacturing runs. Repetition of individual applications also allows for improvements in efficiency throughout a single course of manufacture. The goal is never constant inspection—which would be designed to catch errors soon after they occurred, and is a drain on resources—but a built-in approach that eventually eliminates the variables and allows inspectors to notice a possible difference in the first place.

By examining process, increasing predictability of result, and making the manufacture more efficient, the Agency hopes to further mitigate the demand on extra resources through the application of need-based allocation, a mix of on-site, quality-assurance strategies, and even remote management options. It also should help more quickly distribute strategies on an industry-wide basis. Again, efficiency is the key. More information gathered by PAT efforts in monitoring leads to better use of existing resources; because the processes are beginning to be optimized in roughly the same manner throughout the industry, this makes improvements more easily and quickly adopted on a wider scale. What the FDA provides through PAT is a shared language of process, a language that can be boiled down to its grammatical essentials to help each individual producer get from point A to point B as quickly and smoothly as possible, and a common tongue to share any lessons learned without having to work backwards and figure out how it might apply.

The PAT initiative was formalized in August 2003. Its successes so far are built from a surprising storehouse of applicable technology and how the initiative itself has led to further breakthroughs on its behalf. Many companies already used some version of well-known risk management techniques that have proven fairly adaptable in service of meeting the FDA’s new requirements; risk management approaches are widespread enough that even those companies that didn’t make use of them have any number of resources on hand to help ease that transition. The tools—which are categorized by the FDA as follows;

• Multivariate data acquisition and analysis tools;
• Modern process analyzers or process analytical chemistry tools;
• Process and endpoint monitoring and control tools;
• Continuous improvement and knowledge management tools

—have enjoyed an expected marketplace boom because of the FDA’s well-communicated intentions. When PerkinElmer and Procognia teamed in mid-December to announce their method for analyzing glycosylation of proteins, they specifically targeted the PAT initiative. “Glycosylation analysis throughout the therapeutic protein discovery, development and manufacturing process will bring biopharmaceutical companies closer to satisfying the FDA’s PAT initiative. This technology is focused on reducing the time and cost of producing higher quality biopharmaceuticals,” the companies contended.

A non-content check-weighing system introduced to the market by BOC Edwards Pharmaceutical systems in July 2004 greatly emphasized its use during the manufacturing process. “Any problems with the process are identified virtually immediately and corrected via process feedback to the BOC Edwards filling equipment—a real-time approach that lies at the heart of the FDA’s recently unveiled PAT initiative,” the company’s announcement read.

Seattle’s Center for Process Analytical Chemistry is yet another company that envisions a definite use for its micro-analytical tools because of PAT guidelines, particularly in the area of product sampling. Because the FDA’s initiative depends on technology already widely applied in other industries, this facilitates market-driven partnerships between companies that make similar measurement and monitoring tools for those industries and pharmaceutical companies, in addition to providing an incentive for companies like BOC Edwards to come forward with their own useful processes.

There is also a new market for PAT information, with early adopters, university professors and experts in related fields of technology measurement and regulatory compliance currently in demand. There are two conferences planned for January 2005, following on the heels of a conference in November. The FDA has instituted a Journal club to discuss and keep track of pertinent publications on the matter, a sunrise school to quickly disseminate new information among its members, and a formal training program to take that knowledge into the field.

It might be easy to characterize some of this as exploitation of the FDA-instigated market for such information, but this actually has a place in the initiative itself, as a way of making information more widespread and uniform. The effect is a strange one, however, when it comes to placing new technology and differing levels of familiarity within a broad overview of how companies are proceeding with the precepts of the initiative. Ironically for a system of approaches designed to reduce variability within a series of processes, the differing levels of familiarity and compliance have given the PAT initiative (as it’s expressed by the policies of manufacturers) a definite, uneven quality.

To return to our sports metaphor of the gifted sprinter, individual members of the pharmaceutical industry’s track team are at different points when it comes to learning the precise techniques the FDA’s coach requires. The new year should see a continuation of improvements for the FDA’s general goals of understanding and control, an industry-wide settling-in process that will in turn lead to quick and wider improvements, particularly as emerging technologies sort themselves out in terms of effectiveness.