Safety considerations for biopharmaceuticals are not only controlled during all steps of the upstream process, but the downstream process must also be able to add to the safety of the product.  It must be demonstrated that the downstream process is capable of inactivating agents that might bear a potential risk for the patient.  In addition, a virus removal step such as filtration must be integrated into the downstream process for biotech products to ensure their maximal viral safety.  The safety evaluation program for a specific manufacturing process depends on the product, the production system, the media additives and the intended application of the final product.

Virus safety studies

Process validation studies to determine the ability of the downstream process to remove and/or inactivate potential viral contamination must be performed prior to clinical trials. These studies use either specific or model viruses depending upon the cell substrate or the tissue used.  By spiking these viruses at known titers directly into a down-scaled version of the purification step to be studied, the effectiveness of its ability to inactivate or remove viruses is quantified by determining the log reductions factor.  Examples of specific or model viruses routinely used for such studies are shown in the following table:

Prior to the main viral safety study, cytotoxicity and interference tests must be performed to ensure that it is the process that is removing or inactivating the virus and not the matrix itself. Once these tests have been performed, the viral safety study is performed using end point titrations in a TCID50 assay.

With more than 10 years experience in viral safety studies, NewLab has conducted  more than 800 studies so far. The reports have been accepted by authorities worldwide including FDA, EMEA, PEI and the Japanese Ministry of Health.

Examples of some process steps which have been studied at NewLab BioQuality include:

TSE safety studies

The same basic principles used in viral safety studies also apply to TSE safety studies. The methods must preserve the functional and structural integrity of the product while removing or inactivating the TSE agent. The TSE protein is extremely resistant to inactivation conditions and, therefore, methods which remove the TSE proteins are preferred. These include such methods as precipitation, filtration, fractionation and chromatography.

NewLab BioQuality uses the Western blot method for the quantitation of TSE agents. This allows for the determination of TSE protein reduction of up to 4 logs. The Western blot is a quick and robust method for the determination of TSE clearance. Most clearance studies use the Western blot prior to initiating any in vivo testing. Those steps which appear to be most effective in removing TSE protein using the Western blot can then be tested using the animal models.