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Top 10 Things to Consider when Purchasing an Isolator
Companies are beginning to understand the advantages of performing aseptic operations
within isolators. Regulators, as well, are promoting the technology primarily
for the separation of personnel from the processes that can occur within isolators.
However, many companies are purchasing isolated systems without considering all
of the issues involved in their operation.
There are a number of things to consider when purchasing an isolator including
initial and long-term operating costs, delivery timelines, mechanical quality
and customer support, among others. The following are ten often overlooked mechanical
and operational considerations that are also important to investigate when selecting
an isolator for purchase.
1. Chamber Leak Tightness
Example of an in-line isolator.
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Isolators are enclosures that are sealed to some standard of leak tightness. There
are a number of reasons to seal isolators. One reason is for operator safety during
the bio-decontamination process. The solutions used for chamber sanitization are
dangerous to personnel and need to be confined to the chamber and air handling
system. A second reason is for product or process safety. A sealed enclosure reduces
the opportunity for particles to enter the chamber and possibly contaminate the
process occurring in the isolated system. A third reason is for containment of
hazardous materials or products that are dangerous to personnel or the environment.
In this case, specific leak rate requirements should be set based on acceptable
exposure limits, keeping in mind factors such as the volume of the surrounding
room and the volume of fresh air exchange. Running the isolator at a negative
pressure compared to the surrounding room may be required.
A goal of isolator design should be to reduce the number and size of chamber penetrations.
Reducing the number of penetrations reduces the overall leak potential of the
system. The same is the case for the size of penetrations, as larger ones can
have a higher potential to leak. For penetrations like doors, an evolution of
seal types has developed over time. Simple mechanical-action passive seals have
evolved into seals with active action, such as inflatable seals, and advancements
such as monitoring systems. A further refinement is the vacuum door seal. The
vacuum serves both as an active seal, as the doors cannot be opened when it is
engaged, and as a smart seal, as the vacuum is continuously monitored to alert
operators when leaks occur. Because the seal is a vacuum, any leaks will be drawn
into the seal area, thus protecting both the internal and external environments.
2. Materials of Construction
There are several reasons why material type and finish are crucial to proper isolator
operations. The isolator and any equipment within it must be cleanable and not
degrade when cleaned. This is why low carbon stainless steel, polished to an appropriate
surface finish and passivated, and glass are the materials of choice for isolator
systems. Both are cleanable and handle all but the most corrosive cleaners. They,
and other common materials used in pharmaceutical operations, are compatible with
the sanitant solutions used for bio-decontamination. These material considerations
must be further expanded to include the air handling equipment. Air handling systems
with internal surfaces of painted steel and other incompatible materials should
be avoided.
All materials internal to the chamber, including process equipment like fillers,
must be tested to ensure that the sanitant used for bio-decontamination will effectively
reduce bioburden to appropriate levels. It has been shown in several studies that
both material type and material surface finish have an effect on surface bio-decontamination.
Problem materials should be avoided. Unique materials should be tested prior to
use.
Another critical aspect of materials internal to the chamber is the likelihood
of them absorbing and outgassing the sanitant solution used for bio-decontamination.
Excessive use of elastomers and plastics should be avoided, and Silicone in particular
should be eliminated from the chamber where possible.
3. Product Requirements
Example of a corner isolator.
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Certain products and other materials used in the processes that commonly occur
in isolators, particularly protein-containing solutions, are sensitive to the
solutions used for isolator bio-decontamination. There are several ways to mitigate
this issue. One method is to ensure that you reduce the opportunity for long-term
outgassing and contact with the process by avoiding the use of absorptive materials.
A second strategy is to modify or supplement sensitive materials in order to reduce
sensitivity to the sanitant. For example, special growth agars for use in isolators
exist that have been treated with chemicals that counteract the effect of peroxide.
This ensures that environmental monitoring results are not affected.
In regards to protecting product that is processed in isolators, two things should
be done. Firstly, the sensitivity of the product to residual sanitant should be
quantified. The best way to do this is to actually expose product to sanitant
in a controlled fashion. A test isolator can be used to expose filled product
containers, as this best mimics the actual exposure environment. This activity
will allow you to set an acceptable residual concentration and exposure time for
your process. Once this is accomplished, the chamber aeration process should be
optimized to ensure that sanitant concentration are lowered to acceptable levels
prior to the start of your process.
4. Environmental Monitoring
The methods, locations and frequency for environmental monitoring must be considered
in both the design of the isolator and for the process occurring within it. Particulate
monitoring, for example, requires either chamber penetrations to draw the air
to sample or portable equipment that can be bio-decontaminated and passed into
the chamber prior to use. Monitoring points often consist of isokinetic funnels
that are used to sample representative air with minimal disruption to its unidirectional
flow. Automated monitoring equipment can be integrated into the chamber design
and the isolator control system.
Viable monitoring can consist of both automated air sampling and manual sampling
methods like settling plates and swabs. Manual methods require a method for passing
sampling materials into and out of the isolator. One solution is to load enough
materials for one isolator campaign into the chamber and bio-decontaminating the
outer surface of the material bags during chamber sanitization. Another solution
is to use transfer isolators that dock with the main isolator chamber for transfer.
However, these chambers require development and validation of a separate, shorter
bio-decontamination cycle.
Sampling locations should be considered carefully. They should be immediately
adjacent to critical activities. This is not always easy to accomplish when activities
occur in areas that are difficult to reach or inaccessible. The location of glove
ports is often critical to successful, manual EM methods.
5. Glove Testing
It is evident that the FDA requires both visual inspection and automated testing
methods for isolator gloves and sleeves. That being said, there are important
considerations for both of these methods. Visual inspection requires training
and certification of personnel as well as a method for execution. When and where
visual methods are used is critical. Ideally, gloves should be inspected prior
to installation for ease of access. However, it is easier to do this with the
gloves installed in the ports, as repeated removal takes time and can harm the
gloves. The reliability of inspecting gloves through a thick glass door must be
considered, and opening the door will likely be required for this method.
There are several automated testing methods, some of which require removal of
the gloves. Yet this is not an ideal technique because the gloves can be damaged,
and connections and separate sleeves are not tested with these methods. On the
other hand, testing in place will take more time, as gloves cannot normally be
tested while other processes are occurring in the isolator. A solution to the
issue of time is to test many, if not all, of the isolator gloves simultaneously.
Glove age is often a factor in glove testing accuracy, particularly in regards
to the system’s ability to detect small holes. The latest generations of glove
testers precondition gloves using pressure pulses. This assures that all gloves
exhibit the same elastic properties prior to testing, regardless of age. It is
possible to quickly detect holes to a quantifiable level using this technique.
6. Controlling Particulate Generation
Particulates, whether viable or non-viable, must be controlled at all times inside
of the isolator. There are several ways to accomplish this. One is to ensure that
particles from the surrounding environment do not get into the chamber. A combination
of leak tightness and positive differential pressure will aid this effort. Items
that are located in the isolator or that enter the isolator during processing
should be designed to shed few if any particles. This includes equipment, parts,
tubing and disposable items and the isolator chamber, including elastomers used
for sealing penetrations. Items entering the isolator, as well as the isolator
itself, should be thoroughly cleaned to remove particles prior to bio-decontamination
or sterilization.
Processes that occur in isolators should be monitored during operation to determine
if excessive particle generation is an issue. Particular care should be taken
for processes that occur near areas of open manipulation. One process that can
be of concern is the opening of outer packaging for sterile items. Packaging held
together with adhesives or that is easily ripped during opening often generates
particles. Special care should be taken for processes that require repeated opening
of packaging, as this can cause a continuous generation of particles. Monitoring
processes in which the particles are eliminated from the environment via airflow
as well as those that require repeated opening of packaging to ensure particles
are not generated in excess is recommended.
7. Material Handling
One challenge of operating an isolator is getting materials in and out of the
isolator in an aseptic manner. In fact, material transfer is a major consideration
when deciding whether or not to perform processes within isolators. Certain processes
that involve handling large volumes of materials or that use very large equipment
may not function within isolators. Processes that involve the use of non-sterile
materials also may not seem sensible to operate within isolators.
Materials can be brought in an out of the isolator either in batches or in a continuous
stream, depending on process needs. Some processes require both types of transfer
to occur simultaneously. Batch transfers are commonly performed using sterile
transfer cans or bags that attach to specially-designed transfer port systems.
Continuous transfer, common for product filling operations, is accomplished via
mousehole penetrations designed to protect the isolator environment by controlling
the amount of air that flows out. Sliding mousehole partitions can also be used
so that the chamber is closed after each item enters into it.
Removing bad or broken items from the isolator can be performed using special
vacuum systems. These systems attach to sterile transfer ports normally located
on the bottom or lower portion of the chamber. Removal of items into a sterile
intermediary container is performed using a combination of valving and an automatic
vacuum system to ensure the chamber environment is not compromised.
8. Bio-Decontamination Method Integration
Various methods exist for automatic bio-decontamination of isolators. The systems
on the market today can be grouped into two categories: stand-alone and integrated.
Stand alone systems are designed to bio-decontaminate a wide variety of chambers,
rooms and other enclosed spaces. They normally consist of a sanitant injection
system, a fan for moving air, tubing to connect to ports on the isolator, and
a descant system for controlling humidity. At times, they also have a heater for
heating the air stream and a catalyst for breaking down the sanitant after use.
Controls for the system are rarely integrated with the isolator controls except
for stop/start commands.
Integrated systems are typically installed in the isolator structure. Isolators
that are large enough to have an air handling unit often have a different type
of bio-decontamination system that is designed to work with the AHU. Operations
like sanitant injection and humidity control are performed by the bio-decontamination
system, whereas air flow and control is performed by the AHU. The bio-decontamination
system is sized for the chamber it services. Controls for the system are, at times,
integrated with the isolator controls.
Fully integrated bio-decontamination systems share the same control system, and
often the same human-machine interface, as the isolator. The bio-decontamination
system is still integrated as part of the AHU and sized according to the chamber.
Larger, state-of-the-art isolators are serviced by a full HVAC system, which performs
air handling, temperature control, humidity control and chamber aeration after
bio-decontamination is complete. In these systems, the bio-decontamination system
is greatly simplified and performs sanitant injection only.
9. Equipment in the Chamber
Equipment located in isolators must have certain attributes in order to successfully
perform their functions in this environment. The equipment must be designed to
be cleaned and bio-decontaminated. If the equipment must penetrate the enclosure
for mechanical connections or power supply, any interfaces must be designed to
be a seamless as possible. If the isolator is mounted to a machine plate, the
seam between the two must be sealed. Often, Silicone is used for this purpose.
The latest in technology for sealing isolators to machine plates includes multi-component
epoxy compounds that are rigid, do not absorb sterilant, and are resistant to
the harshest cleaning solutions.
Reliability is also a key attribute of equipment operated within isolators. Interventions
are limited, so frequent equipment breakdowns are not acceptable. It is important
to purchase high quality equipment designed for little direct input during use.
It is also recommended to operate the equipment before each bio-decontamination
cycle to ensure correct function.
Equipment within isolators must be designed for easy access during operation.
Any manipulations of the equipment after bio-decontamination must be performed
through gloveports. Therefore, adjustments to the equipment must not require a
high degree of tactile effort. Equipment for typical operations within isolators
has been specifically designed for isolator use. Making connections, changing
parts, correcting failures and other manipulations are often designed to be performed
with one gloved hand.
Another important activity is isolator mock-ups. Mock-ups assure all equipment
is located correctly within the chamber, glove ports are located to ensure correct
access and transfer ports and mouseholes are located to ensure correct supply
flow. Participation from the actual end-user groups is essential, as ergonomic
considerations need to be addressed. Part of mock-up testing should include insuring
that the gloves can be fully extended into the chamber for bio-decontamination.
10. Airflow
Recently, there has been much discussion on the topic of airflow within isolators.
Some have questioned the need for airflow altogether during processing. However,
one must consider the nature of the isolator itself when designing airflow requirements.
Two major types of isolators exist: closed isolators and open isolators. Whereas
closed isolators are fully sealed, open isolators have open, mousehole penetrations
for transfer of items in and out. Unidirectional airflow is required for correct
operation of open isolators, particularly when item transfers are occurring. It
is generally accepted that closed isolators can have unidirectional, turbulent
or no airflow depending on the process.
Airflow is also critical during bio-decontamination. Good airflow ensures thorough
distribution of sanitant, proper control of humidity and temperature and sufficient
aeration to remove sanitant to safe levels. Large isolators may require full HVAC
systems in order to assure good air flow and distribution because of the volume
of air that is involved. Sufficient airflow is also required at the end of each
cycle to ensure complete aeration of the sterilant from the chamber.
Conclusions
As can be seen, there are many mechanical and operational considerations that
need to be considered when selecting an isolator for purchase. It is important
to investigate these items during the acquisition process. Partnering with an
experienced isolator supplier who is able to implement state-of-the-art features
and processes will ensure the success of your isolator project.
Pharmaceutical Processing
Advantage Business Media
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