Downstream processing in the production of monoclonal antibodies (mAb) reduces the levels of virus by either removal or inactivation. Regardless of the technology, biomanufacturers must demonstrate the clearance capabilities of different downstream steps as part of the viral safety assessment process. Downstream processing typically includes:
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To reach viral clearance targets, most downstream processes include at least two chromatography operations. A typical solution is protein A capture, followed by ion exchange chromatography (IEX), comprised of cation exchange chromatography (CEX) to reduce antibody aggregate levels and anion exchange chromatography (AEX) to remove residual host cell proteins and DNA. Under select conditions, both CEX and AEX can contribute to viral safety.
Chemicals used for virus inactivation must meet the same high-quality standards as other raw materials. Selected chemicals should be manufactured or purified to GMP standards (based on the IPEC – PQG GMP guide for pharmaceutical excipients, 2006) for consistent high purity in order to assure process reliability. Chemicals with comprehensive testing and documentation packages simplify the compliance process.
Removal of virus by filtration is typically based on size, with most mAb production processes relying on filtration to provide high levels of both enveloped and non-enveloped virus reduction. Virus filtration is regarded as a robust step for virus removal and is relatively insensitive to process conditions. However, the presence of protein aggregates and other trace fouling species can negatively impact the throughput performance of virus filters, resulting in increased filtration area requirements. For greater filtration efficiency, a prefiltration step to remove fouling species may be incorporated, leading to significant improvements in virus filter capacity, flux, and overall viral filtration costs.
Manufacturers of biologics are required to evaluate their downstream manufacturing process for the ability of selected unit operations to inactivate or remove potential contaminants. Results of such clearance studies are required by regulatory authorities for investigational new drug (IND) submissions. Understanding these regulatory expectations is a key component of clearance study design, informing the manufacturer’s overall viral safety strategy.
Monoclonal antibody manufacturing is a highly templated approach used to produce mAb-based immunotherapies. Robust, scalable process solutions are required at every step to ensure high therapeutic concentration and process safety, while meeting speed-to-market and cost containment concerns.