Protect them from viruses
Virus safety is a critical part of biopharmaceutical manufacturing. There are inherent risks associated with viral safety when handling animal cell culture. Chinese hamster ovary (CHO) cell lines are the most frequently found production platform for the expression of glycosylated proteins and monoclonal antibodies.
Image Credit: Pall Corporation
Due to their rodent origins, CHO cell lines can harbor endogenous retroviruses or retrovirus-like particles. Additional virus safety risks arise from the possibility that cell culture could be compromised by fortuitous viruses.
Therefore, the regulatory expectation of manufacturing platforms is to demonstrate the ability to remove or inactivate a wide range of viruses to limit the impact of viruses on patient safety.
Viral inactivation (VI) is one of the main elements of viral safety. It targets enveloped viruses that might be present in the feed of the product, usually the eluate from the protein A chromatography step.
A commonly accepted solution is exposure to low pH conditions (eg, pH 3 – 3.6) by acidifying the solution with acetic acid and keeping the pH low for a predetermined amount of time (usually 60 minutes) .
There are many approaches for the continuous VI; the one currently being explored in the field of bioprocesses relies on a plug-in flow contactor. Under this assumption, the pH of the eluted monoclonal antibody is reduced online as it flows through a tubular plug flow contactor.
The length of the tubular piston flow contactor is selected to provide the required residence time for the inactivation process. Some of the challenges facing the plug flow concept include managing concentration gradients in the process, validating downscaling, and dealing with disturbances and process disturbances.
In addition, the pre-processing usually requires homogeneous process conditions. Pall’s method for continuous VI depends on repetitive batch inactivation.
During the design and development of Pall’s CadenceÂ® System VI, Suggested Failure Mode and Effects Analysis (FMEA) approach suggests that product risks and process risks do not differ significantly with this approach relationship with the batch equivalent. .
Pall’s continuous VI concept relies on an approach equivalent to the well-known Batch VI process, and therefore the Key Process Parameters (KPCs) are also the same. This approach eliminates a large number of uncertainties in downscaling validation and provides homogeneous process conditions for downstream processing.
Pall CadenceÂ® The VI system has the potential to be used effectively for both low pH VI as well as solvent / detergent VI.
Virus retention filtration is the last step to ensure virus safety in downstream processing of monoclonal antibodies. It helps remove viruses by size and was developed to specifically target small viruses.
It is generally assumed that the virus filtration step has no impact on any other quality attribute, and therefore the vital parameters of the process are exclusively related to the removal of the virus.
In a continuous and fully integrated downstream processing platform, virus retention filtration is performed at constant rate, while running the process at constant pressure is the most frequently used procedure for batch virus filtration. .
Unlike batch processing, where the output from the previous step is pooled before virus filtration, there is a possibility that variabilities in protein concentration / pH / conductivity, etc., are present in the power supply of the virus filter in a virus filter. continuous process.
These variabilities are the result of the nature of the previous step (eg, chromatography column eluate). If an expansion tank is used between these unit operations, it could be sized to provide homogeneous feed to the virus filtration stage.
However, if an expansion tank is not used, the variability in protein concentration / pH / conductivity on virus removal performance should be appropriately risk assessed. If prior knowledge is not available, it may be necessary to conduct a viral clearance study to include these variables.
Throughout the process, the virus retention filter collects viruses and some proteins in the tortuous flow path. Accordingly, it is normal to observe a decrease in flux during the batch virus filtration step. This decrease in flux is due to the gradual increase in the resistance of the filter.
In continuous processing, this will correspond to an increase in the pressure difference across the filter. Therefore, as long as the virus validation studies are conducted in such a way that the minimum and maximum pressures are studied, the data will also relate to the continuous process.
The key process parameters for continuous virus filtration would then be the maximum volume to be processed (similar to batch virus filtration) and the maximum acceptable back pressure (equal to the decrease in flow in the filtration process of batch virus).
These CPPs can be studied using constant pressure, and – as long as the study design covers the entire operating range of the virus filtration step – the results can be applied to a constant flow process.
Another factor to consider when selecting a suitable virus filter and developing the virus filtration step is its ability to handle process downtime. This element needs to be considered at every step of the continuous downstream processing platform, but it could be increasingly crucial for virus filtration.
The reason is that not all virus retention filters can withstand process downtime in the same way. In some filters, the release of transmembrane pressure and / or process interruptions can influence the virus removal ability of the filter due to so-called backscattering.
About Pall Corporation
Pall Corporation is a global leader in high-tech filtration, separation and purification, serving the diverse needs of customers across the broad spectrum of life sciences and industry.
Pall Life Sciences provides cutting-edge solutions to customers who discover, develop and produce biotechnology drugs, vaccines, cell therapies and conventional pharmaceuticals.
Our advanced medical technologies are often the patient’s last line of defense against dangerous pathogens. And our food and beverage products provide essential protection against contaminants during the various stages of manufacturing.
Pall Industrial serves customers in the microelectronics, aerospace, fuels, petrochemicals, chemicals, automotive and power generation industries.
Our products play a key role in:
- Manufacture of innovative semiconductors and consumer electronics
- Filtration for commercial and military aerospace vehicles
- Maintain the reliability of essential industrial equipment
- Solve the growing problems of water quality, scarcity and demand
- Help energy companies maximize production and develop commercially successful next generation fuels
Based in Port Washington, New York, Pall has offices and factories around the world.
To learn more about how we are enabling a greener, safer future, visit Pall – Enabling A Greener, Safer Future.
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