Keys To Selecting Process Analytical Technology: Fit-For-Purpose, Form Factor, & Price
By Jason Dickens, Custom Sensors and Technology
The potential benefits of incorporating process analytical technologies (PAT) into a biopharmaceutical manufacturing process can prove transformative for a company’s overarching business strategy. From improved facility throughput to simplified resourcing and enhanced quality, these technologies, when employed correctly, offer optimized, streamlined solutions to manufacturing issues both complex and commonplace.
Employing these solutions correctly requires a comprehensive evaluation of the major factors that inform optimal PAT integration. PAT are real-time analytical devices and measurement tools that can be used to continuously monitor parts of a process to safeguard its quality or identify areas for improvement. PAT are among several tools that can help promote greater process knowledge and enable a quality by design (QbD) approach, which in turn helps facilitate improved product quality and mitigate risk. As such, many companies have begun incorporating these solutions more widely as part of their process validation approach; despite this, many have neglected the sort of holistic evaluation of their existing processes necessary to selecting PAT that is fit-for-purpose, easily integrated into their existing space, cost efficient, and suitable for deployment across pilot and manufacturing sites.
By examining existing processes and facilities, determining the goals of PAT incorporation, and establishing a PAT strategy that is tailored to an application, pharmaceutical companies can reap compounding rewards through improved monitoring and process control. Evaluating these technologies on three primary fronts – fit-for-purpose, form factor, and cost – can help companies identify the PAT best suited to their needs, avoiding both mismatch and overengineering as a result.
Process Control Vs. Real-Time Release
The first major consideration a pharma must make when selecting PAT is a fit-for-purpose evaluation. The rationale for PAT typically falls into one of two categories: process control and real-time release. PAT for process control enables rapid feedback to determine endpoints, inform feed strategy, or identify process excursions. Real-time release technologies, which often require a higher level of qualification when compared to process control solutions, are often more specific and selective than process control technologies, necessitating a higher degree of rigor that may be difficult for some companies. But for those trying to reduce their overarching analytical burden, particularly across multiple processes and manufacturing sites, this type of PAT mode can also prove transformative.
For a traditional manufacturing process, operators are often reliant on offline analytical tools, many of which take weeks to derive an output. Sampling a process, transferring that material to a lab, and awaiting an analytical result and review require additional time and resources; in contrast, process monitoring and control, as well as real-time release PAT, affords operators that data throughout a manufacturing process. Operators can utilize these two PAT approaches in tandem with off-line assays, which affords them an integrated analytical approach. The cost and complexity that typify introducing PAT can make it less appealing for companies married to traditional offline analyses alone, but their long-term return on investment in sufficient PAT adoption can create compounding efficiencies to enable product manufacture with sufficient quality and throughput. At a foundational level, process control technologies improve the overall quality of an application while reducing the operational burden from a logistical perspective, giving operators a new, distinct mode of control. The cost and logistical challenges inherent to offline analysis make process control and real-time release PAT an attractive tool for many applications.
Implementing varying levels of rigor to achieve specific ends is a relatively new concept for a marketplace that has been traditionally defined by a singularly conservative regulatory atmosphere. But understanding which PAT approaches can help augment an application’s existing processes, as well as how these can be adapted over time to accommodate growth, can help companies remain competitive in a rapidly changing healthcare landscape.
In-line, Online, And At-Line PAT
Many of the biggest challenges an organization can face in selecting a PAT or suite of technologies result from incorporating these new technologies prematurely, without performing the requisite benchmarking of their existing processes and needs. Some biopharmaceutical manufacturers, when faced with an issue regarding their existing analytical capabilities, may try to address the problem by emulating another company’s PAT approach. This strategy fails to account for the unique variables that attend their own processes, as well as those of another, likely disparate application. Additionally, because these technology solutions are part of an established process, they can represent an outmoded tool when compared to others on the market. This possibility, coupled with its antithesis – a solution overengineered for its purpose in a different application – can create a mismatch when integrated in a process without prior investigation.
Often, PAT for process control is sufficient to transform the monitoring paradigm of an existing application. These technologies typically fall into three categories: in-line, online, and at-line controls. In-line PAT, such as flow cells or probes, are integrated within the process, measuring material as it moves through equipment to generate data and meaningful results. Online analytical technologies, in contrast, require some form of integrated sampling, performed parallel to the process, that is scrapped or returned to the process once a measurement is made. Finally, at-line PAT allows operators to remove a sample from a process and take a measurement on-site adjacent to the process, either within the manufacturing suite or in close proximity; it is often used to perform more complex analyses via reagent additions that are unable to be integrated within a process, either via in-line or on-line due either to risks or unnecessary complexity. Plate readers, real-time material identification (spectroscopic and other methodologies) and rapid chromatography are a few examples of at-line PAT.
Choosing between an in-line, online, or at-line PAT is a question of timing – for applications that may require an analytical result within seconds or minutes, an in-line or online approach would be most useful, whereas those who can afford to wait to take a sample to an offline analytic may choose to incorporate an at-line technology. Moreover, certain samples may be too delicate for in-line approaches, necessitating either an online or at-line technology. Finally, certain PAT have space requirements that may prove difficult to manage for companies with existing facilities and processes that are difficult or expensive to reconfigure or expand. Method complexity and operator proficiency is also a consideration for the selection of an in-line, on-line, at-line or laboratory analytical approach.
Evaluating the form factor of a PAT is an integral part of understanding its value within a greater process or application. Often, an existing manufacturing train is space-limited; as a result, it can be difficult to reconfigure a process or process suite to accommodate certain in-line, on-line and at-line PAT technologies that require a significant amount of additional space. This challenge can often be resolved by collaborating with an several PAT suppliers to determine PAT suitability that balances fit-for-purpose, form factor and integration criteria (IT and mechanical), creating efficiencies for a process without engendering additional costs or constraints.
Concurrent with this evaluation is one that considers data integrity: For any system designed to transmit data, its configuration and control mechanisms serve to alter its outputs. As a result, operators must be prepared to demonstrate that they are maintaining a controlled system and that any changes made to it do not negatively impact the desired performance. Many companies may overlook this evaluation entirely, operating under the misapprehension that the FDA’s CFR Title 21 requirements are the responsibility of the equipment supplier. While this is true for a PAT’s parametric control and its performance output measurements, its integration into an existing process in a way that meets all of the requirements of CFR 21 are ultimately the responsibility of the biopharmaceutical manufacturer, in addition to sufficient PAT designs that enable traceable parametric control of the device. Understanding how to integrate a PAT into a process in a way that fulfills these requirements is an integral facet of a PAT evaluation; the right equipment supplier can help shepherd companies through this analysis to arrive at the right solution and IT integration plan for their needs.
Price As A Deciding Factor For PAT
The cost of incorporating a PAT into a process is the third primary consideration when evaluating technologies for a process. Much of this evaluation hinges on return on investment (ROI) – whether a technology is $20,000 or $200,000 arguably matters less than what its utility will mean for overall costs five or 10 years in the future. This evaluation can frequently result in the adoption of technologies that are less expensive and expansive than a company may have initially envisioned; often, once a goal has been identified for a PAT, further analysis will determine that a less complex technology solution than the one originally identified can serve the same purpose.
A company looking to incorporate a PAT into an existing manufacturing process must contend with validating its integration across several variables, from cleaning to performance checks to data integrity. Despite the rigor inherent to introducing these technologies to both traditional and novel manufacturing processes, the potential benefits of real-time release or process control PAT, including reduced batch losses, streamlined processes, and more predictable timelines, make them a valuable inclusion for even more valuable biologic production.