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Why Perform a Viral/TSE/Microbial Clearance Study?

A major concern for many biologics is viral contamination. The ICH Q5A regulatory guideline indicates that a manufacturer of biological products for human use should demonstrate the capability of the manufacturing process to remove or inactivate known contaminants. One aspect of assessing the viral safety of a biopharmaceutical is to perform a viral clearance study.

A similar approach can be used to demonstrate the removal of other potential contaminants, e.g. TSE, DNA, mycoplasma, endotoxins and bacteria. In some chromatography processes, for example, the buffers used may result in virus inactivation. Although the inactivation kinetics of the buffer may be studied as an independent step, it may not be possible to demonstrate how the virus partitions during the chromatography process using infectivity assays. In other words, any physical removal of virus due to the chromatography process itself could not be evaluated. However, with the introduction of Q-PCR assays, many chromatography processes may now also be studied, at least with respect to removal or partitioning of viral genomes. Such studies may be performed in parallel with infectivity studies. At BioReliance we have validated Q-PCR assays for the majority of commonly used viruses.

For a viral clearance study of a product entering phase I/II clinical trials, a reduced number of viruses should be evaluated. In the US a minimum of a single study of a single virus should be performed. In Europe, a duplicate study with 2 viruses should be performed. For biologics derived from human blood products, the key virus chosen would be HIV. MLV would be the key virus chosen to study products derived from rodent cell lines at phase I/II. Increasingly, regulatory authorities have been asking for a second robust virus to be included in such early phase studies to show, at an early stage, the overall robustness of the process. We would therefore recommend  incorporation of a parvovirus model.

Where a product is due to enter phase III clinical trials a study should demonstrate the capacity of a process to reproducibly remove a range of viruses with different physico-chemical properties. Thus a study would typically be performed in duplicate, and include a panel of 4 (for recombinant proteins and monoclonal antibodies) or 5 (for human blood products) viruses.
Regulatory authorities are now also asking to see data on the robustness of a process, looking at extremes of conditions such as pH, temperature, and protein concentration. These data give an indication of the virus reduction capabilities of a manufacturing process under worst case conditions.

Examples of process steps studied for clearance include:

  • Heat Treatment
  • Pasteurisation
  • Lyophilisation/dry heat
  • Solvent Detergent
  • pH Treatment
  • Low pH (column elution)
  • High pH
  • Precipitation
  • Ethanol
  • Polyethylene Glycol
  • Chromatography
  • Ion Exchange
  • Affinity
  • Hydrophobic Interaction
  • Reverse Phase
  • Virus removal filtration

Examples of products for which clearance studies have been performed include:

  • Human and bovine blood products and coagulation factors
  • Equine and ovine blood products
  • Human and animal urine derived products
  • Tissue derived products
  • Monoclonal antibodies
  • Recombinant proteins
  • Medical devices (including collagen-derived products)
  • Enzymes