A Review of Four Technologies Used to Reduce Operator Interventions in Aseptic Manufacturing
The pharmaceutical industry has never
been an early adopter in taking on new
technologies, preferring instead to evolve
slowly and consciously.
Recently, due to increasing demand for
high-quality, affordable medicines combined
with regulatory concerns over patient
safety regarding aseptically produced
sterile products, manufacturers have been
adopting new technologies. These technologies
are making aseptic manufacturing
more robust and sustainable.
To understand this transformation, it
helps to look back over a decade. In a
2006 article in Pharmaceutical Manufacturing,
James Agalloco, James Akers and
Russell Madsen used the term “advanced
aseptic technology” (1). They defined an
advanced aseptic technology as “one in
which direct intervention with open product
containers or exposed product contact
surfaces by operators wearing conventional
cleanroom garments is not required
and never permitted” (1).
But why is “advanced aseptic technology”
necessary? Research shows the typical
person sheds 1,000,000,000 skin cells per
day of a size 33 μm × 44 μm × 4 μm—
equivalent to a rate of 30,000 to 40,000
dead skin cells shed from the surface of
the skin every minute. Of these, approximately
10% carry microorganisms. There
are, on average, four microorganisms per
skin cell. One term commonly used to
describe skin flakes with adhered microorganisms
is “microbial carrying particles.”
Advanced aseptic processing technology
focuses on eliminating human interventions
in aseptic operations to mitigate the
aforementioned risk to sterile products
during manufacturing. This requires
a risk-based system design for robust
controls during operation. Below is a look
at some of the preferred advanced aseptic
processing techniques in current use.
Isolators and RABS
In conventional cleanrooms, the aseptic
core is protected with unidirectional
downward or sidewise airflow of HEPAfiltered
air. This core is separated by
flexible curtains or rigid partitions from
its surrounding environment, with air
spilling over from the aseptic core into the
surrounding environment downstream of
the critical area. Operators interfere with
the aseptic core via their sterile gloved
hands. Sanitization of internal surfaces
occurs through periodic disinfection.
Now, this type of design has its inherent
shortcomings with respect to protection
of Grade A critical environments due to
operator intervention and material movement
from Grade B to Grade A zones.
Performance of such a system is totally
dependent on operators’ skills in terms
of aseptic practice and the procedural
design for machine setup, operation and
environment monitoring. This is driving
the industry to substitute conventional
cleanroom technology with isolators and
restricted access barrier systems (RABS) technology (Table 1). Both these technologies
offer a significantly higher sterility
assurance level (SAL) over conventional
cleanroom technologies.
Table 1 Comparison Between Aseptic Isolators and RABS
Isolators were initially used to protect
operators from highly potent drug substances
(2). Isolation technology began to
be introduced to pharma manufacturing
in the early 1980s, but has only recently
become popular in aseptic processing.
RABS, on the other hand, emerged
more recently, around the mid-1990s.
This technology was introduced to
deal with the shortcomings of isolators
when it comes to operational feasibility
and operator access to critical areas for
setup and maintenance. RABS are typically
unsealed barriers, supplying HEPA
filtered air to the RABS interior before
exhausting the air through a gap between
the system’s walls and equipment. This
requires a Grade B environment. In addition,
a RABS may need a better quality
of air supply adjacent to its doors, with
appropriate procedural controls if open door interventions are considered as part
of the manufacturing process.
Robots Replace Operators
Use of robotics in cleanrooms remains at
a nascent stage; however, the technology
is quickly gaining acceptance due to its
advantages over other advanced aseptic
technologies for isolating operators from
critical zones. In the past, robots were
used only in mass production processes.
As robotic systems have become more accessible
in terms of cost and customization
in recent years, they are now widely employed
in small production processes such
as drug discovery. Robots are used inside
isolators to eliminate operator intervention
and control external contamination.
The gloveless robotic isolator for aseptic
manufacturing has a strong legacy based
on its use in the semiconductor industries,
where manufacturers have realized
tremendous gains in productivity and
quality by using robotic “workcells.” These
are closed robotic systems that can operate
at extremely low particle levels. These
isolators are called “gloveless” because they
do not have glove ports to allow operator
intervention during the production
process. In pharma, these robots perform
all operations within a system. Vial filling
and stoppering can occur without
the need for external intervention by an
operator. Plus, the robot self-adjusts and
aligns the machine based on need. A
gloveless isolator can be installed in Grade
C or D cleanrooms, depending on regulatory
requirements.
By integrating filling and handling robotics
within a gloveless isolator, the risk to
the product from particulate generation
and microbial contamination due to
human interventions is far lower. Vision
systems and automated environmental
monitoring support a repeatable, error-free process with strong assurance that
the product is safe. These types of systems
provide clear benefits over conventional
isolators or RABs with a high degree of
SALs. This, along with single-use technology
(see below), addresses cleaning
validation challenges for some difficult-to-clean
products and can reduce downtime
during changeovers.
A Word About Single-Use Tech
Single-use systems refer to a wide range
components that replace conventional reusable
stainless steel vessels and processing
lines. This technology dates back to the
early 1980s when it began to be used to
manufacture capsule filters and presterilized
syringe filters for laboratory use (3).
In aseptic processing, single-use systems
offer closed connections to avoid aseptic
manipulations in classified environments.
Thus, in combination with the barrier
technologies outlined previously, this provides
a higher degree of SAL, but only if
implemented using a thorough, risk-based
system design.
Moving into the Future
As new technological offerings for aseptic
manufacturers surge and regulators gain
ever greater levels of confidence in these
technologies, more legacy facilities will be
forced to modernize.
To fully embrace the advantages of these
technologies, manufacturers will need to
switch to a risk-based approach that suits
the needs of each specific technology,
be it an isolator, RABS, robotic system
or single-use technology. To respond to
such changes will call for a paradigm shift
throughout the entire industry.
References
- Agalloco, J., Akers, J., and Madsen, R. “What is Advanced Aseptic Processing?” Pharmaceutical
Manufacturing 4 (2006): 25—27.
- Weston, F. “Debating the Role of RABS and Isolators in Aseptic Manufacturing.” Pharmaceutical
Technology August 2016.
- Martin, J. “A Brief History of Single-Use Manufacturing.” BioPharm International (Nov. 2,
2011).
About the Author
Subrata Chakraborty is Senior
Director and Sterile Cluster
Head with Cipla. He has more
than 23 years of experience
in various capacities in
handling multiple sterile
dosage forms.