Current Thinking in Viral Safety: Risk Management Protects Patients

BPI’s editor in chief S. Anne Montgomery recently caught up with long-time editorial advisor Hazel Aranha (purification technologies technology expert for Sartorius Stedim Biotech, North America). They discussed a number of topics related to viral safety.

Montgomery: What is the current thinking regarding virus-safety assurance in biopharmaceutical manufacturing? How is the industry preventing viral contamination?

Aranha: The “holy grail” of viral safety — absolute freedom from extraneous agents or residual pathogenicity — is a myth. That said, biopharmaceutical products have had an excellent safety record, and we have not had iatrogenic transmission of pathogenic viruses associated with their administration. Our risk mitigation and management approaches for virus-safety assurance — appropriate sourcing, demonstrating process ability to clear viruses, and using in-process controls — have delivered products with excellent safety profiles (from a virological standpoint).

Risk mitigation is at the forefront of every quality paradigm. In addition to incorporating orthogonal virus-clearance unit operations downstream, manufacturers are paying closer attention to upstream risk mitigation. Ensuring that adventitious agents do not end up in bioreactors or any upstream processes is not a regulatory requirement, but it makes business sense in view of the catastrophic consequences that would follow a contamination incident. Inactivation methods such as heat and irradiation have been used upstream. And recently, filter manufacturers have introduced economical virus-removal filters that provide good retention of bacteria, mycoplasma, and adventitious viruses. With those pragmatic approaches, I anticipate an increasing demand for upstream risk mitigation.

Montgomery: What recent changes have you seen specific to virus validation studies?

Aranha: Our general approach to virus-clearance evaluation (or virus validation studies) has proved to be effective and stood the test of time. There are no prescriptive regulatory requirements for log reduction of viruses. In view of the considerable heterogeneity and diversity of biopharmaceuticals as a class, manufacturers are required to document that their processes provide an adequate safety margin over and above any potential virus load. Log virus reduction is commonly expressed as “greater-than a specific log reduction value” for a given test virus: e.g., parvoviruses such as mouse minute virus (MMV) and porcine parvovirus (PPV).

Another issue on our radar is the introduction of novel cell substrates. Their use brings concomitant risks of unknown viruses, unexpected viruses, and novel viruses. These systems will require better understanding and evaluation of issues such as what constitutes an appropriate virus testing panel for validation studies.

Montgomery: We hear about virus breakthrough with filters for small viruses. Can you comment on that?

Aranha: Virus-removal filtration based on size exclusion has become a relatively standard industry practice. But we need to acknowledge that virus-retentive filtration using 20-nm rated virus filters does not provide absolute retention of small viruses. Precise contributing factors to virus recovery in fractions downstream of the filter in virus validation studies (breakthrough) are not well understood. However, they probably depend on a combination of factors: virus filter characteristics (membrane chemistry/structural configuration), product matrix conditions (pH, ionic strength), and process operating conditions (sustained pressure excursions, process interruptions, depressurization, and flow decay). Our understanding of virus filtration has increased significantly in recent decades. Remaining gaps in our knowledge are being addressed through both data generation and statistical approaches.

Montgomery: Another area of interest to our readers is increased use of prefilters with virus filters. Why use them?

Aranha: Prefilters are commonly used to remove process or product-related impurities, thus optimizing the viral filtration step. With increasing pressures on cost containment, the requirement is to optimize process economics (without compromising safety). Virus filters are among the most costly consumables in biomanufacturing. Any approach that maximizes their capacity to capture viruses, improves throughput, and provides significant cost savings needs to be investigated.

Zero risk is a myth. Risk assessment, mitigation, and management are key components of a quality risk-management paradigm. Knowledge management is an enabler of quality systems. Our ultimate goals are safety and patient access. Both goals are furthered by applying preventative strategies such as virus inactivation and virus-removal filtration. A virus-safety management program based on sound scientific reasoning, benefit–risk assessment and risk management/mitigation, and knowledge development is imperative to maintain a high level of virus safety assurance. We all must recognize that the weakest link in a chain is also the strongest: It can break the chain.

Alison Center is editorial assistant ([email protected]) for BioProcess International, PO Box 70, Dexter, OR 97431. S. Anne Montgomery is editor in chief of BioProcess International, and Hazel Aranha, PhD, RAC, is a technology expert at Sartorius Stedim Biotech North America in Bohemia, NY.