Process changes and their effect on process evaluation for viral clearance.

Abstract

The ability to remove and/or inactivate known and potential viral contaminants during the manufacturing process of a biological product has become an important parameter in assessing the safety of a biological product when it is produced from cell culture or from human or animal tissues. The combination of screening the starting material for infectious virus coupled with a process which will remove and/or inactivate significant levels of infectious virus has been demonstrated to be an effective way to assure product safety. A prime example of the application of this approach was in the manufacture of Factor VIII preparations which did not transmit HIV. Regulatory authorities have subsequently applied this model to a wide spectrum of tissue culture-derived products by requesting examination of the cell line for freedom from contamination with adventitious agents coupled with process evaluation. Difficult issues yet remain concerning agents which should be evaluated and what process changes should trigger a reassessment of the ability of the process to remove/inactivate virus. The broad issues of process changes and their potential effect on process evaluation will be discussed, including changes in the product, cell line, cell culture, manufacturing process, dosage and patient population. An initial process evaluation which is through and demonstrates robust removal and inactivation may obviate the need for re-evaluation of minor process changes.