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Assuring sterility with ASTM F 838-83

Article  in  Pharmaceutical Technology Europe · December 2008

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ASTM International - Standards Worldwide Page 1 of 3

March/April 2008
Feature

Promoting Patient Safety

ASTM Test Method Helps Ensure Drug Sterility

based on a paper by Maik W. Jornitz and Theodore H. Meltzer

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.

Sterilizing Filters

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

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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:

z Organism type to be used;

z Organism growth conditions and media composition;
z Challenge conditions; and
z Test and sampling setup.

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.

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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.”

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