QbD and PAT in Upstream and Downstream Processing - BioPharm International talks to industry experts about the implementation of QbD and PAT tools in biopharmaceutical manufacturing - BioPharm


QbD and PAT in Upstream and Downstream Processing
BioPharm International talks to industry experts about the implementation of QbD and PAT tools in biopharmaceutical manufacturing

BioPharm International
pp. 28-37

BioPharm: What are some recent advances in PAT or other analytical tools that better enable product characterization and the increased process understanding desired in a QbD paradigm? How is QbD applied to equipment design and implementation in biologic API manufacturing?

Girard (Spinnovation): FDA identified the use of new analytical methods, such as nuclear magnetic resonance (NMR), to monitor and control processes as important in increasing manufacturing quality through QbD. NMR could change the face of bioprocess development and monitoring because it provides access to component identity, plus quantitative data, rapidly and easily from a single analysis. NMR profiling can provide full visibility of the presence and concentration of feed components, contaminants, and metabolites. The technique is capable of providing access to accurate concentration data for media components. NMR-based methods can provide rapid and accurate quantitative monitoring of more than 50 media components, contaminants, and metabolites within a culture at any stage in the process to meet QbD requirements.

The use of NMR, combined with statistical approaches, provides rapid solutions to performance inconsistencies in simple and complex raw materials within upstream processes of virtually any bioprocess, offering the ability to characterize chemically complex media. NMR techniques have the potential to contribute significantly to an understanding of process-critical parameters, helping to reduce performance variability and minimize the risk of process failure in large-scale biopharma production.

Johanning (QAtor): Before (traditional) installation, test and qualification of equipment a QbD approach involves a design qualification, where the user requirement specification (URS), which includes the basic CQAs from the master and manufacturing production files, is reviewed and qualified against the proposed equipment design. This, of course, involves specialists from R&D, manufacturing, and quality assurance. The design qualification and review is challenging the equipment design with special attention on CQAs such as contamination with germ and fibrillation.

Vanden Boom (Hospira): In the case of biosimilar products, the bioanalytical characterization of originator products over the approved shelf life provides a powerful input for use of a QbD paradigm in process development. Biosimilar developers also have the opportunity to employ modern manufacturing technologies, including PAT tools, to enhance process control. The enhanced monitoring of potential CPPs on current buffer dilution and chromatography skids represent one example of improved equipment design contributing to the improved process control of biopharmaceutical manufacturing processes.

Weber (CMC Biologics): PAT implies an online monitoring system that can determine if a process is trending negatively in 'real time.' The essentials of PAT have been in the industry nearly from the beginning: data historian. Although PAT allows for maximal design space control and understanding, whether one has real-time information and automated response capability is not essential to the QbD paradigm. However, having a well-understood and robust historian is. As long as processing trends and capabilities are assessed on a per-run basis, there is an opportunity to monitor and adjust to ensure that the process performs optimally within the design space. Many unit operations within cell-culture manufacturing processes have control capabilities built into the equipment; as long as the assessment is performed, the equipment can repeatedly perform within the required space. Couple that with strong operator training and having real-time process adjustments is already inherent in a process without PAT. Generating dynamic and static control charts on a per-run basis of the process allows for trend analysis, and adjustments can be made should a negative trend be detected. This can all be accomplished without a formal PAT system.

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