Process Analytical Technology

Gaining knowledge
An early application of the new software solution Sipat enables researchers to implement Process Analytical Technology in bioreactor processes.

Process Analytical Technology (PAT) offers pharmaceutical companies the prospect of gaining better control of processes, designing quality into the production process, and moving to real-time product release. However, in biopharmaceutical manufacturing, complex cell cultures and fermentation processes pose considerable challenges for the modeling and multivariate analysis that lie at the heart of PAT.

One inhibiting factor has been the absence of software that enables the full integration of PAT tools and all information flows during processing and online comparison of process data with previous or historical data. Therefore, Siemens has introduced and piloted a solution to this as part of a PAT project at the Process Development Laboratory of the Netherlands Vaccine Institute (NVI) in Bilthoven, the Netherlands. The software, known as Sipat, has been used to develop a real-time process verification tool for all critical process attributes of the cultivation process step of Bordetella pertussis bacteria, used for whooping cough vaccine.

Moving to direct release
The goal of the NVI project was to develop an alternative process development methodology and advanced process monitoring and control techniques that could lead to real-time release of the end product without final quality testing.

Siemens was chosen because of its specific knowl-edge in the area of bioprocess technology, process control, and advanced process monitoring techniques. Mathieu Streefland, PAT project leader and researcher at NVI, says, “The people at Siemens immediately stepped up to the challenge of designing and developing a manufacturing system that was capable of developing and executing a full PAT cultivation process step. They have a very clear and concise idea about PAT and what it takes to ‘PAT’ a process. Their ideas evolved and grew continuously during the project alongside our needs and requirements.”

Better bioreactor control strategies
The carefully designed feed and harvest strategies used in biopharmaceutical manufacturing rely on precise measurement and control of the main process parameters. With recent developments in instantaneous in-situ measurements, a whole picture of the fermentation process is available that produces not only information on individual parameters but also relative measurements, as a measure of change. Such developments afford better insight into what exactly is happening inside the bioreactor.

The NVI project is not only monitoring the changes in the known process parameters during the batch evolution but is actively searching for unknown parameters that have an impact on end-product quality and performance. Consequently, that will make it possible to define better control strategies and ultimately optimize the whole batch sequence for more product of a better quality, with lower costs.
Using PAT methods – which provide a structured, science-based approach for process development – allows the development of anticipatory process scenarios. These scenarios can be reevaluated at each moment during the batch run when corrections have to be made to obtain an end product of a desired quality (and/or purity) and performance in the shortest time and at the lowest costs. This eliminates off-spec production and leads to intrinsic right-the-first-time production.

How Sipat has helped
The new Sipat software enables the collection of data and the full integration of all information flows during processing and online prediction calculations as well as comparison of the actual batch trajectory with the “golden batch” trajectory. With Sipat, the NVI can integrate lab models with sophisticated near – infrared and mass spectroscopy measurements and data gathered by sampling to build a full process model.

NVI has built process understanding on all critical process attributes of the cultivation process step of Bordetella pertussis bacteria. The project has successfully proven the concept, and that success is being used to develop the process on a two-liter research-scale bioreactor. The knowledge gained will facilitate a fast upscaling of the process to commercial manufacturing scale. In this way, the NVI intends to implement PAT both in other cultivation processes and in other unit operations, such as freeze-drying or column chromatography.

Info              www.siemens.com/sipat
Contact         info.sipat@siemens.com

The new Sipat software enables the full integration of all information flows during processing as well as online prediction calculations and comparisons.