Promoting Patient Safety
ASTM Test Method Helps Ensure Drug Sterility
To assess whether a filter can remove contaminant microorganisms from liquid drugs, filter manufacturers and government agencies alike turn to an ASTM standard to check product quality — a step that protects patients every day.
Pharmaceutical manufacturers sterilize many drugs by heat treatment, but a number of liquid medicines produced for patient injection would be damaged under such conditions. To ensure that such liquid solutions are sterile and free of microorganisms that could hamper patient health, pharmaceutical companies use sterilizing grade filters. An ASTM International standard, F 838, Test Method for Determining Bacterial Retention of Membrane Filters Utilized for Liquid Filtration, provides a method to assess filter efficiency.
Traditionally, sterilizing means killing microorganisms, which can be done by multiple physical methods, as for example with heat. However, in the case of a number of pharmaceutical drug solutions, heating does not work; it may alter the solution or drug component.
“Simple, chemical entity solutions like saline solutions can be heat sterilized. However, most biological drug products would be altered, if not destroyed, by heat treatment. These solutions require cold sterilization methods, such as sterilization by membrane filtration,” says Maik Jornitz, group vice president, marketing and product management, for Sartorius Stedim Biotech in Edgewood, N.Y.
That’s where sterilizing filters come into service. These filters, by their design and construction, separate microorganisms from the pharmaceutical liquid stream. And, to determine whether a filter performs as expected and required, laboratories use the bacterial challenge test standardized in F 838.
Laboratories or filter manufacturers, either to test their own products or under contract with pharmaceutical companies, will test and confirm filtrate sterility according to the standard. Medical device and diagnostic test kit companies also use F 838.
When contracted by a pharmaceutical company or other firm to validate filtrate sterility, a laboratory checks whether a fluid put through a specific filter would be considered to be sterile under predetermined production conditions. To do so, laboratories begin by growing microorganisms under controlled conditions so that they reach a very specific, very small size. The filter to be tested is subjected to a high concentration challenge, usually ten million organisms per square centimeter, to determine whether any penetrate it.
Following the initial filtration, the liquid filtrate is run through a so-called analytical filter, one used to check on the sterilizing filter’s effectiveness. Afterward, the lab places the analytical filter in a petri dish with specific added nutrients and incubates the dish for up to 72 hours. If, when inspecting the filter, there is no growth found, the filtrate is indeed sterile and the filter is confirmed as being effective.
Filter and F 838 Development
Microporous membrane filters, an early 20th century invention, first came into use in the early 1930s, and manufacturers used the first sterilizing grade filters, rated 0.45 microns for the rate of fluid flow through the membrane, to remove yeasts, molds and bacteria from beverages and pharmaceutical fluids. However, membranes could not easily be compared.
In 1967, F.W. Bowman, M.P. Calhoun and M. White announced the discovery of a smaller organism that penetrated the 0.45 micron-rated filters, and as a result industry needed a new filter that would be considered sterilizing. The development and use of 0.2 micron membrane filters to separate the smaller organism, Pseudomonas diminuta, now reclassified as Brevundimonas diminuta, from a liquid, came about to meet that need.
The Health Industry Manufacturing Association, in concert with filter manufacturers, originally undertook the development of a microbial challenge test, completed in 1982, to compare these membrane filters. A test was needed that would describe:
The following year, ASTM International published the test as standard F 838.
This milestone created a solid foundation on which the filter manufacturers could build their 0.2 micron retention rating, and the industry could trust that the filters classified as such all passed the same standard challenge test. With the standard, the pharmaceutical industry became purchasers of commercial filters and users of selected filtration devices designed and assembled in accord with specific scientific principles. A solid scientific benchmark was established. This benchmark was reviewed in 2005 by ASTM International Committee D19 on Water and reissued that year.
The Impact of F 838
The impact of this standard on filtration processing applications has been exceptionally broad and influential, particularly in the field of pharmaceuticals, and its publication made possible an industry-wide adherence to a basic measurement. ASTM standard F 838 is the basis for, among other applications, the integrity test limits indispensable to nondestructively test micro-porous filters. In addition, the F 838 challenge conditions are also used for other pore size ratings, although with different challenge organisms.
“Post bulk filtration for removal of microorganisms is a cost-effective means of removing any organisms that may have entered the sterile pharmaceutical bulk during manufacturing,” notes Nancy Tomoney, senior validation scientist for CSSC, Inc., Morristown, N.J. “F 838 allows validation of a filter system to prove removal of high levels of microorganisms greater than 0.2 microns in size.”
Dr. David Hussong, associate director for new drug microbiology, Office of Pharmaceutical Science Center for Drug Evaluation and Research, U.S. Food and Drug Association, affirms the usefulness of the standard as well. “When a product is filtered to remove microorganisms, some method has to be described,” he says. “The standard, F 838, has a lineage that goes back many years so we’re quite familiar with the method, and it can be used as a reference so that the reviewers understand just how it was done in the laboratory.”
Since the publication of ASTM F 838, sterility assurance by filtration gained a tremendous enhancement: filtration with 0.2 micron rated filters became dependable instead of remaining a gamble on whether such rated filters truly work as claimed.
“For filter manufacturers and filter users, the standard is absolutely vital. You have to see that beforehand you just had house numbers for filters. Everybody could call a filter of 0.2 micron sterilizing grade but there was no standard challenge test,” Jornitz says. F 838 changed that situation for the better, particularly to the benefit of people receiving injections.
As Jornitz and Theodore Meltzer, principal of Capitola Consultance, say, “It can be said that the ASTM standard F 838 test empowered nondestructive filter integrity tests, routinely used in pharmaceutical production processes, with their present authority.”