Process intensification and PAT essential for achieving real-time release

Development of complex methods enabling real-time release of therapeutics requires creativity and collaboration, say experts from NIIMBL and SCIEX.

Interest in real-time release (RTR) is driving the industry to think about process intensification in a coordinated manner. Process intensification offers the potential for increased efficiencies and thereby reduced cost and time for drug production. Workflows, capital and operating expenses, product quality, and waste production can all be positively impacted.

There is consequently a push in the industry to develop and coordinate the integration of analytical technologies that enable real-time process control and ultimately real-time release, according to Kelvin Lee, Gore Professor at University of Delaware and Director of the National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL).

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To develop intensified processes, analytical technologies are needed to assess how those processes are behaving in real-time, or close to real-time, to understand if the process is proceeding as intended and if the quality attributes of the product are within specifications. “Process analytical technologies (PAT) are a critical part of control strategies that ensure continuous operation within the design space,” Mark Lies, global business manager of Capillary Electrophoresis at SCIEX, told us.

The goal of many manufacturers is to minimize the number of technologies that human operators must manipulate by automating sample collection, preparation, method implementation and results analysis (inline or online), enabling automated and continuous process control. “Rapid inline or online methods that can provide results within seconds to minutes (versus hours, days, or weeks) are now a major focus of PAT and play a significant role in enabling process intensification and shortening development timeframes,” Lee said.

Commercially available PAT solutions performed in an inline/online/at-line manner are limited in number, however. Some sensors are currently used to monitor different parameters of cell-culture processes in near real-time, but more complex analyses are conducted completely offline.

Both sample and instrument challenges must be overcome if some of these offline methods are to be converted to rapid, at-line solutions. “PAT will need to be straightforward and ideally require only turnkey, push-button operation, thus reducing workforce development needs,” Lies noted.

“Sampling technologies must ensure that sample collection does not introduce contaminants into the bioreactor. Sample preparation, including both chemical and physical treatments must be simplified to the point where they can be automated,” he added.

Analytical instrumentation should be miniaturized to be suitable for minimal footprint and perhaps designed for remote operation, according to Lee. Standardized solutions for integration of PAT with process control equipment and data sharing between instruments will also be needed.

Reports in the literature of PAT solutions based on existing technologies and instrumentation applied in an inline manner indicate that some of these challenges can be addressed if sufficient tools are combined in a single process.

“This collective work has begun to establish the feasibility of potential inline processes, and we can expect initial model PAT solutions that provide rapid results in an online setting integrated with process control capabilities for more complex analyses to be developed in the next five to 10 years,” concluded Lee.

Of course, there is risk associated with the adoption and implementation of new technologies that might accelerate development timelines. Uncertainties exist regarding questions from health authorities on new analytical approaches. The incorporation of new technologies can lead to delays in approvals if there is not a shared understanding of the technologies with health authorities.

“Instrument vendors must get their new technologies into the hands of academic, industry, and regulatory science investigators to enable development of that shared understanding. Where possible, vendors should take advantage of recently introduced formal programs offered by regulatory agencies to discuss new technologies in development. More collaboration between biopharma companies and vendors early in the development process would be beneficial too,” Lies stated.

Increased communication between all stakeholders can enable greater information and data sharing that could facilitate the adoption and implementation of novel PAT solutions, Lee summarized. “Each group has a unique perspective. By creating additional avenues for dialogue and collaboration, we can drive more comprehensive discussions about new analytical technologies and their deployment,” he asserted.

The emergence of industry-led consortia to support the development of manufacturing innovations for the biopharma industry provides a foundation for de-risking some of these activities. The public-private partnership NIIMBL provides different stakeholders a forum for discussing strategy and executing manufacturing technology demonstration projects, thus advancing the development, implementation, and adoption of more efficient and rapid manufacturing capabilities, including PAT, according to Lee. NIIMBL is also working to ensure that a skilled workforce is available to help realize the vision of intensified processing and RTR of products.