Virus Filtration: a key manufacturing step keeping medicines safe, including from emerging viruses like COVID-19
Virus retentive filters are filters used in biotechnology and plasma derived product drug substance manufacturing for the specific purpose of physically removing potential viruses from manufacturing process streams. Virus filters provide a key line of defense against introduction of adventitious viruses into this important class of medicines. With the insidious nature of the COVID-19 virus, which can infect healthy individuals for long periods asymptomatically, risk mitigation measures against inadvertent introduction of viruses into biotech process streams are more important than ever. Virus retentive filters are distinct from other filter types in that filter manufacturers have evaluated and optimized the robustness and efficiency of their virus removal performance and have developed integrity tests correlated to virus removal.
The imperative for developing virus filtration for biologics processing became evident in the 1980’s with the HIV epidemic which tainted the blood supply, and consequently the source material for the plasma products industry. This product class cannot be terminally sterilized, nor do absolute tests for viruses exist (i.e. all assays have a limit of detection). Thus, virus removal/inactivation measures during manufacturing like pasteurization, solvent/detergent inactivation or filtration were urgently needed to protect vulnerable patients. Shortly thereafter, the presence of retrovirus-like particles (RVLP) in bioreactor cell culture harvests, as well as facility contaminations with adventitious virus prompted the commercial biotechnology industry to adopt virus removal unit operations, like virus removal filtration.
Fortunately, a pharmaceutical filtration industry already existed targeting applications like terminal 0.2 μM filtration for parenteral dosage forms and protein concentration/buffer exchanges by ultrafiltration. In addition, the water treatment industry was also supplied by filter manufacturers as they were interested in ways to remove viruses and bacteriophage from municipal water supplies.
Many of the earliest virus filters leveraged technical knowledge gained from tangential flow ultrafilter applications, as many were already designed to have tight pore sizes. The new virus filters mostly targeted large viruses initially (i.e. HIV is 90-110 nm). Over time, the regulatory need for integrity testing and validation prompted both improvements in reliability and robustness (e.g. pin hole defects which may be acceptable in an ultrafilter at low levels would be unacceptable in a virus filter), as well as specific integrity testing offered by filter vendors. Because of concerns about cleanability and cleaning validation between use, regulators discouraged multiple use of virus retentive filters. This prompted industry to migrate away from TFF systems (originally conceived of as being able to be reused) to DFF systems (simpler and never claimed to be multiple use).
The next mega-trend was development of filters targeting small viruses, like parvoviruses (20-28 nm). Small virus retentive filtration was driven by Mouse Minute Virus (MMV) facility contaminations in the biotech sector. While such filters are highly desirable from a process virology standpoint, they pose a major technical challenge. The size difference between the product molecule (e.g. antibodies, other recombinant therapeutic proteins) and the target viruses (i.e. parvoviruses) is about 2-fold, making the molecular weight cut-off window very narrow. In some cases, virus breakthrough can occur when driven to process extremes. Since the initial parvofilters became available in the early 2000’s, more robust second-generation versions were developed by filter manufacturers as they designed around the technological gaps they identified in their filters.
The Parenteral Drug Association has taken an active role in educating end users of virus retentive filter products, as well as developing standards. The premier source of information for virus filtration since 2005 is “Technical Report 41: Virus Retentive Filtration”. This key document contains test methods for classifying large and small virus retentive filters based on relevant performance criteria, retention of bacteriophage models of viruses. Based on the nomenclature test methods, filters from at least four manufacturers (Pall Corp., Millipore, Asahi Kasei Planova Division and Sartorius) have been rated as able to clear substantial levels of either large or small batcteriophage (6 log10 of 64-83 nm PR772 and 4 log10 of 23-26 nm PP7, respectively). Currently, TR41 is being updated to reflect the latest advances in virus filtration technology, while PDA is also working on transitioning the nomenclature method into an official consensus standard.
Going forward, new applications and technology are being developed for biotech applications. For example, specialty high flow virus filters are now available as barriers against introduction of viruses via media supplements into biotech production cell cultures. New filter membrane construction materials are being prototyped by enterprising scientists and engineers, for example a lab at Uppsala University using natural sources like algae. All of these new concepts will expand the scope and practicality of virus filtration in biotechnology.
In summary, virus filtration has been evolving and improving over time, becoming more robust, moving from TFF to DFF, and targeting smaller viruses over time. We are quite fortunate, given the current COVID-19 situation, that virus filters are already in place in almost all biotech and plasma derived product drug substance manufacturing processes. Both large and small virus retentive filters are predicted to remove large Coronaviruses (100-160 nm), and buttress other safety measures in manufacturing.
Parexel’s consulting group can provide clients with expert advice when developing comprehensive virus risk mitigation strategies for biopharmaceuticals and biologics. Our recommendations are based on a deep knowledge and experience in viral clearance in bioprocessing. As mentioned above, regulators and the biologics industry are confronted with and have developed risk mitigation strategies against emerging viruses. Parexel stands ready to assist companies to develop tailored virus risk-mitigation strategies that are based on deep expertise and that consider a number of relevant criteria:
- What class is the product and are platform technologies available?
- What is the stage of product development (e.g. BLA vs. IND)?
- What specific unit operations will be used downstream?
- What cell substrates will be used for production?