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Technological Advances Address Biocontamination Control Challenges
By Chris Mach
Control over microbiological contamination has never been more critical to the
pharmaceutical processing industry. Recently a major pharmaceutical manufacturer’s
plant was closed by regulatory authorities because of contamination issues, resulting
in a severe hit to the company’s earnings and stock price. Bioaerosol sampling,
designed to detect contamination so it can be quickly corrected, is limited by
the trade off of particle collection efficiency, which is promoted by rapid movement
of organisms, against the need to avoid stressing microorganisms during sampling.
This tradeoff has become even more critical with the release of the International
Standards Organization’s 14698-1 2003 standard which establishes tougher than
ever bioaerosol sampling requirements. Developers of bioaerosol sampling technology
have responded with new technology that has the potential to help pharmaceutical
manufacturers overcome these challenges.
The closure of Chiron’s Liverpool England plant for five months in 2004 and 2005
and its impact upon the flu vaccine supply highlighted the growing importance
of biocontamination control in pharmaceutical manufacturing. This episode demonstrated
how a single contamination incident could not only endanger patients but also
have an enormous financial impact on manufacturers. The importance of biocontamination
control has been validated by the Food and Drug Administration’s (FDA’s) Process
Analytical Technology (PAT) initiative which is encouraging manufacturers to move
from reliance on final product microbiological quality control towards in-process
control at key points in the manufacturing process. The new ISO standard further
highlights the limitations of existing sampling methodologies by specifically
stating that traditional settle plates should not be used to measure the total
number of viable particles in the air. Rather, they should be limited to measuring
the rate at which particles settle on surfaces.
Trends towards active sampling technology
With settle plates clearly on their way out, there has been a steady trend in
the industry towards the use of a variety of active sampling technologies, such
as centrifugal, filtration and impaction samplers. These technologies all have
in common the use of some method for impelling organisms towards the media. Using
active methods to move the microorganisms towards the media increases the sensitivity
of an active sampler. On other hand, active methods also run the risk of over-stressing
microorganisms to the point that it will become more difficult or impossible to
detect them.
The ISO standard establishes the principle and methodology for assessing and controlling
biocontamination in a cleanroom. It also provides methods for evaluating and qualifying
air samplers. The new standard also states that a formal risk analysis procedure
should be implemented to evaluate the area at risk and identify appropriate mechanisms
of control as well as establish initial control levels. Improvements are clearly
needed since the vast majority of even active air samplers do not meet the specific
requirements set out in the ISO standards. These requirements include factors
such as the effective sampling rate, duration of sample acquisition and physical
attributes of the sampling device.
Most of the technological advances of the last few years have focused on inertial
impact samplers. This type of sampler is based upon the principle that when a
stream of gas undergoes a sharp change in direction the particles it is transporting
will tend to continue in the original direction. This type of sampler captures
particles by using a nozzle to accelerate a jet of air against the media. The
air is forced into a sharp turn when it hits the media. The particles are unable
to negotiate the turn, so they impact onto the media. The probability that the
particle will be captured by the media depends on the particles’ linear dimensions,
particle speed at the nozzle output, air viscosity, impactor geometry, and adhesion
of the particle to the impaction plane. In designing a sampler, it’s important
to consider both the adhesion of the particle to the agar surface and the ability
of this surface to absorb the particle’s kinetic energy to minimize the chance
that the particle will bounce off the media and escape.
Laser-Enhanced Rectangular nozzles identify contamination from controlled environment
One approach that has been developed to meet these requirements involves the use
of laser technology to form precision rectangular nozzles, which directs the microorganisms
to a recognizable pattern on the assay media surface. This approach enables interception
of organisms that might normally escape observation because they lack sufficient
sedimentation speed. It also makes it easy to distinguish random contamination
on the media surface from the actual microbial contamination in the cleanroom.
The air is pulled downward through the nozzles using a vacuum. An internal gas
filter scrubs the air prior to leaving the system in order to avoid introducing
microbial contamination back into the controlled environment. Only colonies within
the radial impaction pattern generated by the sample head are considered to be
contamination from within the controlled environment, while others represent adventitious
contamination of the sample.
Figure 2: BioCapt Impactor on the
Pall-Ascotec* Microbiological Remote Air Monitoring System.
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Recently this technology was tested for physical and biological efficiency using
the methods set out in ISO 14698 along with a conventional slit sampler which
was used as a baseline. Inertial impact samplers operating at 25 and 50 liters
per minute were tested according to the ISO 14698 methods. These inertial impact
samples as well as a conventional slit sampler were tested for their ability to
collect various sizes of samples and for the survival and growth of the microorganisms
that are collected. An aerostable bacterial spore was aerosolized into a 28 cubic
meter clean room supplied with a horizontal flow of clean air through HEPA filter
banks. A spinning top aerosol generator (STAG) was used to generate aerosol drops.
The microbial aerosol was generated in 10 second on/off pulses while the samplers
were operated.
Test results show improvements in particle collection efficiency
The testing demonstrated that the 50-liter per minute sampler setting can capture
more than half of particles that are less than one micron in size. The 25-liter
setting is somewhat less efficient, capturing over half of particles that are
less than two microns in size. Still, these values are considerably higher than
values reported with conventional samplers in the past. The biological efficiency
of the 50-liter per minute setting was measured at 95.3% higher than a conventional
slit sampler for one minute testing period and 82.4% higher for a 20-minute testing
period. The new sampler technology also has a net impact surface of less than
1% of the total plate surface which implies that false positives can be excluded
with a statistical probability of better than 99%. These results easily meet the
requirements set forth in ISO 14698. They demonstrate that new sampling technology
can help drug manufacturers minimize the risk of non-compliance resulting for
inefficient contamination analysis.
Figure 3: Pall-Ascotec MiniCapt portable
instrument |
Reliable microbial monitoring of air quality is required to ensure quality of
pharmaceutical production and meet Good Manufacturing Practice (GMP) requirements
for the United States and Europe. A single contamination incident could have enormous
customer safety and financial implications. The ability to identify contamination
events during production is essential in making it possible to take appropriate
actions in time to prevent any danger to the public. The selection of air samplers
plays an important role in the ability to detect and monitor microbial contamination.
Passive sampling devices such as settle plates make it difficult to comply with
regulatory requirements because they do not meet ISO 14698 standards. Newer active
sampling technology has demonstrated substantial improvements in physical and
biological sampling efficiency. Advanced air monitoring technologies can help
biotechnology and pharmaceutical companies gain better quality control of manufacturing
processes and provide greater assurance of product safety.
About the author: Chris Mach is Marketing Manager, Biotechnology, Pall
Life Sciences. Figure 1: Impacted media plate with colonies defined in the impaction
plane. The circled colony represents false positive growth outside the impaction
area Figure 2: BioCapt Impactor on the Pall-Ascotec? Microbiological Remote Air
Monitoring System Figure 3: Pall-Ascotec MiniCapt portable instrument ? The Ascotec
brand is owned by Biotrace International Plc ? The Ascotec brand is owned by Biotrace
International Plc
Pharmaceutical Processing
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