Masterstudiengang "Drug Regulatory Affairs"


Pathogen safety concepts for Biopharmaceuticals

Dr. Olaf Stamm (Abschlußjahr: 2009)

Language: English

A major concern for products derived from cell lines of human or animal origin, as well as those derived from human or animal plasma, is the potential risk of contamination with known or unknown viruses. Such contamination could have serious clinical consequences and can arise from the contamination of the source cell lines themselves (cell substrates) or from the adventitious introduction of viruses during production. To date, biotechnology products derived from cell lines have not been implicated in the transmission of viruses. However, regulatory bodies expect that the viral safety of these biopharmaceuticals is reasonably assured if a virus testing program is implemented. Such a program should comprise the assessment of virus removal and virus inactivation achieved during the manufacturing process. To prevent viral contamination, three principal and complementary approaches have been developed to fulfil regulatory expectations:

  • Selecting and testing cell lines and other raw materials, including media components, for the absence of detectable viruses which may be infectious and/or pathogenic to humans.
  • Assessing the capacity of the production processes to clear infectious viruses.
  • Testing the product during appropriate stages of production for the absence of detectable, contaminating viruses.

Overall virus safety is a function of implementing all three approaches, as the total absence of infectious viruses will not be achieved by analytical testing alone but by demonstrating that the purification regime during downstream processing will completely remove and/or inactivate viruses.

The overall principles of virus clearance studies apply to prion clearance studies as well. Currently, however, there is no cell culturebased assay available that can be used to determine a prion reduction factor. Within a prion clearance study, the infective prion material, produced in either hamster or mouse, can be used in two different assays:

  • Western blot analysis by detecting proteinase K resistant PrPSc
  • Animal studies using hamster or mice in in vivo studies.

Current regulatory guidance provides guidelines on how to evaluate the manufacturing process regarding its ability to remove/reduce infective prions. Driven by this guidance, manufacturers are required to estimate the potential of their manufacturing processes to reduce infectivity using a step-wise approach including theoretical considerations, biochemical assay (Western blot) and infectivity assay. Based on the outcome of this evaluation the addition of process steps that may increase the prion PrPSc reduction capacity may be considered.
The design of virus and prion clearance is driven by clear regulatory guidance and the work need to be performed in compliance with GLP. The entire pathogen safety concept is integral.

Pages: 49,
Annexes: 11 pages