Validating Sterile Filtration: Overcome the Fear of Failure
Common practices, including the selection of model organism, reflect lack of process knowledge. Are they driven by science, irrational fear, or marketing?
By Maik W. Jornitz, Sartorius Stedim North America, and Theodore H. Meltzer, Capitola Consultancy
For a process as critical and sensitive as sterile filtration, it’s not surprising that many filter end-users experience some “fear of failure.” As risk management consultant Peter Sandman has said, people become fearful when they feel they are not in control . As a result, some may see established sterile filtration practices as inadequate. Compelled by fear to do more than necessary, they may overdesign their filtration systems, adding wasteful and costly procedures.
By embracing this fear, rather than studying the root causes of filter penetration and the specifics of each process, practitioners of sterile filtration impede the advancement of filtration science and its understanding within the industry and global regulatory agencies.
This article will examine several unnecessary practices that are burdened upon the industry today, using process validation principles to explain why they are inadequate. It will also touch on problems that result when “model organisms” used to evaluate sterile filters are seen as universal archetypes that can characterize all process situations and filter types.
First, let’s consider the concept of validation itself, which is designed to “establish documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes .
Validation is a global regulatory requirement for drug manufacturing, particularly for aseptic processes. As industry consultant Jim Agalloco has written , there is already a substantial body of knowledge on best validation practices for sterile injectable biotech products, including:
Fluid influences on the organisms, membrane polymer and retention mechanism
Process parameter influences on the membrane polymer, filter construction and retention mechanism
Validated processes are under control, yet their reliability continues to be questioned by regulators and those in the field, suggesting that many practitioners do not fully understand the validation concepts. This can often be traced to subjective fears rather than valid technical concerns.
Here are some examples of current concerns, requirements or practices, pulled directly from regulatory or company documents, that illustrate that fear:
“0.2-µm filters can be penetrated by microorganisms, so the industry must switch to 0.1-µm-rated filters.”
• “Increasingly, there are detectable but non-culturable organisms or L-forms or nano-bacteria in our processes.”
• “Redundant 0.2-µm filtration is necessary and should be used.”
• “I need an absolute 0.1- or 0.2-µm filter.”
• “Diffusive flow integrity testing is better than bubble point testing.” (Currently, there is a difference in preference between U.S. and European regulators)
• “Flawed filters will not be detected by a post-use test, as the pore will be plugged during filtration.”
• “The maximum bioburden in front of a sterilizing filter should be 10cfu/100mL.”
We will address many of these statements individually, later in this article.
First, however, let’s consider the industry’s current understanding of the role of the “model organism” in filter testing and validation practices. Obviously, the industry needs a model, since it would be impractical to test each and every microorganism, given the number and diversity of microbes in pharmaceutical settings. Furthermore, most of the organisms are not of concern, since their size offers no challenge to modern sterilizing grade filters.
The question is: does the most widely used model organism always reflect specific process and filter characteristics?
Beyond Size Exclusion: There Is No Universal Model Organism
Brevundimonas diminuta is typically used as the model for organisms that are expected to be found in pharmaceutical manufacturing environments. It was selected, based on its presence in pharmaceutical operations, and within native bioburden .
The organism has been found particularly suitable for validating sterilizing grade filters due to its size and ease of cultivation. However, it should only be used to model situations where its dimensions closely match the organisms of interest in a given application, relative to the filter pore size and shape.
Furthermore, in some cases, sieve retention may not be the mode of organism removal. For instance, in some cases, it may be adsorption, as the organism forms hydrogen bonds to the filter’s polymeric surface. This could account for the observation, 26 years ago, that Pseudomonas aeruginosa organisms are more strongly retained by polyamide membranes than by cellulose triacetate filters . It also explains the removal of latex particles from aqueous suspensions by polyamide membranes in the presence of surfactant, but not in its absence (Table 1) .
Table 1: Retention (%) of 0.198-µm spheres by various 0.2-µm-rated membranes
||In Water (% )
||In 0.05% Triton X-100 (%)