FDA fleshes out models for safe continuous manufacture of therapeutic proteins

Regulatory NewsRegulatory News | 24 August 2021 |  By 

The US Food and Drug Administration (FDA) has issued a new paper to help shed light on how therapeutic proteins can be produced safely on a continuous manufacturing line.
Continuous manufacturing “is still a novel concept for therapeutic proteins” and more “tangible” examples are needed to implement the program, acknowledged FDA in the report. Further, there are “few published studies” addressing viral inactivation methods for these products.
However, it’s important to address safety issues in the use of continuous manufacturing for therapeutic protein production, said FDA, since it is “the next step in the evolution of therapeutic protein manufacturing and promises to increase efficiency through the immediate capture and purification of the target protein as it is produced in the bioreactor.”
The new report builds on two decades of research in which FDA collaborated with industry to understand how viral particles can be removed during the process of manufacturing biologic proteins.
The nature of the protein manufacturing process, which often involves mammalian cell lines, means that the possibility for viral contamination exists, and that host cells often contain endogenous sequences resembling retroviruses. These, in turn, can produce retrovirus-like particles (RVLPs) during the manufacturing process.
The report cites guidance documents and international standards that address the purification steps needed to achieve virus clearance during batch manufacturing; FDA’s efforts have contributed toward the development of these documents.
Still, as continuous manufacturing sees wider uptake, conventional viral clearance methods need to be revisited to make sure proteins can be safely produced in a continuous manufacturing environment.  For example, the International Council for Harmonisation’s ICH Q5A guidance addresses the viral safety of biotechnology produced through batch manufacturing and not continuous manufacturing.
Similarly, the agency’s February 2019 draft guidance laid out quality considerations for continuous manufacturing for small molecule products alone, excluding therapeutic proteins. (RELATED:  Continuous manufacturing: FDA drafts quality guidance, Regulatory Focus 26 February 2019)
In looking at how to adapt these standards to continuous manufacturing, FDA found that three process steps were “key.” These include capture chromatography, viral inactivation and viral filtration.
FDA developed a model that shows the viral clearance capabilities of continuous capture chromatography. In this experiment, researchers at FDA’s Center for Drug Evaluation and Research (CDER), in collaboration with an equipment manufacturer, performed a side-by-side viral clearance comparison of a continuous capture chromatography step with a batch capture chromatography step. The continuous capture setup uses smaller capture columns that can be moved through “simultaneously in a cyclical fashion.”
“The research found that although the initial cycle, or ‘start-up cycle,’ may affect variability in the log10 reduction value (LRV), the steady-state viral clearance capabilities were similar, with no difference seen between the columns within a cycle,” wrote FDA.
FDA then looked at a continuous viral filtration model that was shown effective in weeding out viral contamination. CDER researchers collaborated with a filter manufacturer and used a “well characterized” parvovirus surrogate, bacteriophage PP7, to purify human immunoglobulin. 
The model “was capable of operating virus filters for over four days without exceeding the recommended filter transmembrane pressure and with no loss in virus spike infectivity over the course of filtration time,” noted FDA, adding that “No virus was detected in the daily pooled effluent … indicating effective viral clearance.”
History has shown that if not properly controlled, viral contamination can have dangerous consequences, for both patients and manufacturers. In March 2012, a lawsuit filed by an Idaho woman claimed negligence on the part of Genzyme, now a subsidiary of Sanofi. The lawsuit was prompted by viral contamination discovered at the facility in 2009 in the manufacturing of Fabrazyme, used to treat Fabry disease. (RELATED: Lawsuit against Genzyme seeks damages for Fabrazyme shortages, Regulatory Focus 12 March 2012)
FDA continuous manufacturing models for therapeutic proteins


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