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While the multiple attributes method gains ground and traditional lab methods improve, broad efforts are underway to determine biopharmaceuticals’ most significant critical quality attributes and enable real-time release.
As the biopharmaceutical industry matures, manufacturers continue to embrace automation and more modern approaches to process design, development, and control. The reality, however, is that working with biologics is several orders of magnitude more complicated than it is for small molecules. As Jose Menezes, CEO of 4Tune Engineering, points out in a recent white paper (1), biologics can have a million times more critical quality attributes (CQAs) than small molecules, and many more of them are clinically relevant than is the case for small molecules.
Work is underway to bring greater understanding to how CQAs might be monitored to improve biopharmaceutical manufacturing. As part of the BioPhorum Operations Group’s Biomanufacturing Technology Roadmap, manufacturers and technology providers are focusing on how the industry might best approach in-line process monitoring and real-time release. Members of the group have refined a list of priority CQAs and required tests and will soon be publishing a white paper summarizing what they have learned so far. Michalle Adkins, director of life sciences consulting at Emerson Process Management, discussed the group’s progress at INTERPHEX on April 2, 2019 (2).
As she noted, biopharmaceutical manufacturers need to move from offline to real-time testing to reduce the complexity of multiple measurements and make quality control as noninvasive with as few connections as possible. “The goal,” she said, “is to push testing to the manufacturing floor.”
The working group has developed a list of CQAs and in-process controls for a monoclonal antibody (mAb) process, assuming use of a batch or fed-batch process, but in a way that would allow the basic principles to be extended to semi-continuous and continuous operation, Adkins explained. Aggregation and Protein A fragmentation were found to be among the most important cQA to monitor, Adkins said. Upstream, the most crucial CQAs include glucose concentration and cell mobility and downstream, they include turbidity, pH, and conductivity. In addition, monitoring virus and microbial control and endotoxin safety are crucial to assure product and patient safety, she said.
The process of determining the most important CQAs takes into account the type of testing that is done now (i.e., whether at-line, offsite, or in-line); whether the process has an in-process test or control; the approach used for release testing; and the approach take to continuous process verification.
So far, the list of attributes and user requirements specification have been developed, with the initial focus on glucose, aggregation, and amino acids. The group is also using return on investment analysis as well as internal rate of return, payback, and net present value to assess the business case.
Among other questions that this effort aims to address are whether a new method is needed or whether existing methods (mainly spectral measurement approaches) simply need to be improved and where measurements should take place. “We also need to share challenge data with suppliers,” Adkins noted.
In the end, the business case for in-line testing and real-time-release (RTR) will depend on the individual facility requirements, cost vs benefits analysis, and operating costs. So far, however, research has found that full-out production mode offers a better business case for embracing RTR, as does the potential for using a validated approach for another new product if yield and productivity improve. Adkins believes that the new approach will improve product yields and eliminate the need for sampling, sample management, storage, and investigations, which rely heavily on manual sampling and are subject to human error. Additional benefits will be providing a way to upskill the workforce and to focus on regulatory concerns, such as model validation and change management. Results and the white paper are due to be released later this year, and the group is looking for more insights and suggestions from industry professionals involved in this area.
1. J. Menezes et al., “Is the QbD Toolbox Ready for C&G Therapies? Patientt-Focused Predictive Outcomes: Integrating Patient Outcomes into Manufacturing of C> Bioproducts,” White Paper, April 2019.
2. M. Adkins, “In-Line Monitoring and Real-Time Release,” presented at INTERPHEX, New York City, April 2, 2019.
Volume 43, Number 5
When referring to this article, please cite it as A. Shanley, “Getting a Handle on Biopharm’s Most Critical Quality Attributes," Pharmaceutical Technology 43 (5) 2019.