(8e) Process Development, Characterization, and Understanding in an Integrated Continuous Monoclonal Antibody Manufacturing Testbed

Process and product understanding is at the root of manufacturers’ efforts to produce safe and effective medicines. The 2009 ICH and FDA Guidance for Industry Q8(R2) Pharmaceutical Development describes a quality-by-design (QbD) approach that “emphasizes product and process understanding and process control, based on sound science and quality risk management” (1). During the product development stage, the critical quality attributes (CQAs) required to ensure product quality are defined, and the relationship of these CQAs to the critical process parameters (CPPs) that impact them are determined. Manufacturers can use a risk-based approach to define a design space in which the combination of process inputs and process parameters are demonstrated to provide assurance of product quality(2,3). Development of a control strategy that maintains the process within the bounds of the design space will ensure consistent product quality.

Researchers in our group at MIT are building novel first-principles- and data analytics-based mathematical modeling tools for the manufacturing of biopharmaceuticals. To experimentally validate these modeling tools and to fully understand the impact of model choice on product quality, a fully instrumented and integrated continuous testbed for the manufacturing of monoclonal antibodies (mAbs) was constructed. The testbed consists of 4 parallel upstream systems including 4 perfusion devices, with one reactor assembly integrated with a fully continuous downstream system including Protein A chromatography, in-house designed viral inactivation, and ion exchange chromatography. The testbed is equipped with instrumentation to fully characterize the process, including in-reactor probes for Raman spectroscopy (Kaiser RamanRXN2), viable cell density (Aber Futura), and optical density (Optek). To provide further at-line process and product characterization, each upstream assembly is equipped with two MAST Sample Pilots for automated sampling of both the reactor contents and the perfusate. The MAST system delivers samples to a Nova FLEX2 cell culture analyzer for key metabolite quantification as well as verification of in-reactor sensors including pH. For at-line characterization of CQAs, the cell-free perfusate samples are collected in a Gilson GX-271 liquid handler, purified using at-line purification using Protein A chromatography, and delivered automatically via MAST to either an Agilent 1260 Bio-Inert HPLC for assessment of aggregation and titer or to an Agilent 6545XT LC/QTOF for characterization of glycosylation profiles using mass spectrometry.

This presentation describes the instrumentation and discusses data collection and process integration within the testbed. The experimental data generated by this highly instrumented integrated continuous biomanufacturing testbed enable the evaluation, development, and validation of modeling methods and control strategies, and ultimately contribute to improved process understanding for better informed risk-based decisions during manufacturing campaigns.

References:

1. Pharmaceutical development Q8(R2). International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline (2009).
2. Anurag S. Rathore and Helen Winkle. Quality by design for biopharmaceuticals. Nature Biotechnology 27(1):26-34 (2009).
3. Mo Jiang, Kristen Severson, J. Christopher Love, Helena Madden, Patrick Swan, Li Zang, and Richard D. Braatz. Opportunities and challenges of real-time release testing for biopharmaceutical manufacturing. Biotechnology and Bioengineering, 114(11):2445-2456 (2017).