Continuous bioprocessing, also known as next-generation bioprocessing, offers a route to significantly enhance the production of biopharmaceuticals. Potential benefits include increased product quality, improved batch-to-batch reproducibility, miniaturization of the manufacturing footprint, enhanced process understanding, greater efficiency and flexibility, and reductions in both capital expenditure and operating costs. However, there are gaps in the availability of process analytical technology (PAT) tools capable of supporting quality by design (QbD)-driven continuous bioprocessing.
As FDA has defined, PAT is a mechanism to design, analyze, and control pharmaceutical manufacturing processes through timely measurements of critical quality attributes (CQAs) and critical process parameters (CPPs) with the goal of ensuring consistent final product quality. The principles behind the PAT initiative is to enhance process and product understanding and control the process to ensure desired final product quality. Implementation of PAT systems has resulted from the regulatory authorities’ initiative to improve and modernize the pharmaceutical industry to enhance product quality with the adaptation of QbD/PAT concepts.
The PAT framework encompasses a series of tools designed to build quality into products while enhancing process understanding, increasing efficiency, and reducing costs.
The four building blocks of the PAT framework are:
Multivariate analysis (MVA): MVA statistics and design of experiments (DOEs) are the foundation for establishing QbD based Design Space involving the use of multidimensional interactions of input variables such as CPPs that are impacting CQAs. A scientific understanding of the multifactorial relationship between CPPs and CQAs require multivariate analysis for modelling multiple variables simultaneously.
Process analyzers: Process analyzers are automatic in-line or on-line tools for industrial process analytics, allowing samples to flow from the process equipment to the analyzers without human intervention. Process analyzers are intended to monitor real-time or near-real-time CQAs and keep the process within the design space to align with the guiding principles of QbD, building quality into the process and consequently into the products. Automatic process analyzers provide data to enhance process and product understanding such that CPPs can be controlled to achieve a set of desired CQAs
Process control: Control strategy is an important element of PAT to maintain the process within the design space. All the process parameters, raw materials, and intermediates that influence the CQAs must be monitored and controlled. Real-time and near real-time data from process analyzers allows timely control of CPPs and critical raw materials.
Continuous improvement: This is achieved through continued enhancement of product and process understanding, gained through product lifecycle experience. Automation and the implementation of knowledge management tools are recommended, with the collection of real-time CPPs and CQAs being essential for continuous improvement of the control strategy in response to data trends.
Agilent 2D-LC with SegFlow automated sampler has been demonstrated to be useful for online monitoring and control of titer and critical product quality attributes (CQA) of monoclonal antibodies and fusion proteins. Other applications include, but are not limited to, near-real-time amino acid quantitation and feedback control to maintain the homeostasis of cells in bioreactors. The integrated system is an enabling technology to fill the gap of current deficit in Process Analytical Technology (PAT) to support QbD driven continuous bioprocessing.
Access Webinar On Demand:
Process Analytical Technology: Online Monitoring and Control of Upstream Titer, Product Quality, and Amino Acid Content Using 2D-LC with SegFlow Interface
Featuring: Dr. Letha Chemmalil, Principal Scientist , Bristol Myers Squibb
