Improving Efficiency and Control in Biopharma Manufacturing With Process Analytical Technology

Read more about

• Considerations for Implementing PAT
• PAT and the Facility of the Future
• Examples of PAT in Biopharmaceutical Manufacturing
• Enhancing PAT Adoption: The Role of Analytical Instrument Suppliers
• References

The concept of process analytical technology (PAT) originated in a regulatory framework published by the United States Food and Drug Administration (FDA) in 2007.(1) An overarching goal of this framework is to encourage the use of more efficient strategies for development, manufacturing, and quality assurance by the biopharmaceutical industry. A key objective of PAT is to build quality into products rather than evaluating quality at the end of the process. This science-driven, risk-based, proactive approach introduces the concept of Quality by Design (QbD) and is endorsed by the International Council for Harmonization (ICH).(2-6)

When integrated into development and manufacturing workflows, PAT enables significant improvements in process understanding and optimization of product quality. It supports the development of dynamic manufacturing processes through real-time monitoring, accelerated control through feedback loops, real-time quality assurance, and real-time release.

This page describes key considerations for implementation of PAT, its role in enabling the facility of the future, and provides examples of this technology.

Considerations for Implementing PAT

Successful implementation of PAT requires identification of critical material attributes (CMAs) and critical process parameters (CPPs) that impact critical quality attributes (CQAs). It is also essential to select the right PAT technology and define the analytical methods that will be used to monitor sources of variability, allowing for real-time control of the process and maintaining the desired product quality within a defined design space.

The location of the monitoring depends on the process itself and the selected analysis method. Options for where the sample is monitored are listed in Table 1. In-line monitoring provides a more dynamic, real-time analysis and offers the fastest response times compared to off-line measurements that cause a significantly delayed response.

PAT and the Facility of the Future

By supporting a more detailed understanding and control of processes, use of PAT tools helps to facilitate the transition to Biopharma 4.0 and the facility of the future which includes fully automated, self-monitoring and autonomously regulated, continuous bioprocesses. PAT tools collect data in real time and make appropriate adjustments across the entire process.

The adoption of PAT in the biopharma sector has been relatively slow, however, mostly due to specific challenges that exist on the path toward the facility of the future. These challenges include transitioning current analytical technologies to in-line or on-line operations and developing fit-for-purpose solutions that are compatible with the PAT framework and complex biopharmaceutical processes. As an example, additional development in real-time product release and biosafety analysis is essential to reduce the lag times associated with cell-based assays as well as bioburden, mycoplasma, and endotoxin testing. Expanded adoption of PAT will be aided by a greater understanding the dynamic environment of biological reactions.

In addition, establishing appropriate analytical techniques, along with suitable methods and models for data evaluation, is critical. Challenges to implementation arise in situations where a limited process understanding exists and there is a lack of expertise in continuous processes or PAT models. These obstacles can lead to a hesitation to rely on PAT for integrity or release testing.

Examples of PAT in Biopharmaceutical Manufacturing

In the biopharmaceutical industry, PAT is mostly used to monitor CPPs in upstream cell culture or microbial fermentation processes. Sensor measurements in bioreactors typically include pH, dissolved oxygen (DO), carbon dioxide, temperature, pressure, and capacitance. More advanced spectroscopic or chromatographic methods have also been developed for in-line or at-line measurements. Additional parameters such as metabolites or intermediates, host cell proteins (HCPs), nutrients, cell density, cell viability, aggregates, particulates, and product concentration can be measured using these methods.

While used to monitor batch processes, PAT is also an increasingly important tool in process intensification of semi-continuous and continuous (perfusion) upstream processes.

Raman spectroscopy is an example of a PAT tool. (8) Using this technique, it is possible to identify molecules through a unique molecular fingerprint (9) with high molecular specificity and high reproducibility. This technique offers the ability to monitor and control bioprocesses in real-time and can be applied throughout the entire process, from material identification to upstream and downstream process steps to release testing. Because Raman spectroscopy can be performed in-line and in real time, changes and outliers can be identified quickly, triggering appropriate process control strategies, and resulting in a timely and more efficient process management. The ability of Raman spectroscopy to enable a highly specific quantitative analysis of complex, aqueous bioprocess solutions in-line and in real-time reinforces its value as a PAT tool in biopharmaceutical manufacturing.

Automated aseptic sampling is also an essential component of PAT implementation in biomanufacturing and supports advancement of the industry toward the digitally enabled facility of the future. Real-time, on-line measurements provide more rapid access to CPP and CQA data through streamlined analytical integrations. System variabilities can be detected sooner, allowing for more rapid corrective action.

The benefits of automated sampling to process development are significant, including elimination of the time and resources needed for off-line sample acquisition, processing, and analyses. The lengthy turnaround time between experimentation and data analysis is significantly compressed. This approach also minimizes the risk of contamination of both the sample and source due to handling, as well as the potential for inconsistencies in test results resulting from off-line sample hold times and testing.

Because they are readily scalable, automated aseptic sampling systems can also be implemented in manufacturing facilities. They can also be combined with other PAT technologies, such as Raman spectroscopy, for improved calibration and validation of data-driven models.

Enhancing PAT Adoption: The Role of Analytical Instrument Suppliers

Implementation of the PAT framework is the basis of a dynamic, future-ready, and more efficient manufacturing process. Suppliers of PAT analytical instruments, such as Raman spectroscopy and automated sampling, are invaluable partners to biopharmaceutical manufacturers as they begin their journey with PAT. With a deep understanding of process needs and analytical capabilities, these companies and their experts can offer support by providing or developing appropriate models, thereby guiding and expediting PAT adoption.