The future of aseptic processing
Dr Douglas Thorogood, Design and Development partner
of Isolators for Fabtech Technologies talks about the importance of cleanroom
In this presentation, I hope to demonstrate a major advancement
that has beneficially affected the future of aseptic processingthe advent
of isolator technology. Associated with this technology has been the emergence
of sterilisation techniques for the isolator and using the gas generators currently
available there has also developed gassing techniques for cleanrooms as well.
It is best at the start of this discussion to refer to some definitions that
are used today, some of which can be confusing. Historically processes performed
in cleanrooms used human operators who were gowned in sterile suits. The products
manufactured were defined as aseptic or aseptically produced.
In the field of pharmaceutical science, the words aseptic and sterile are sometimes
treated as being synonymous. In microbiological terms the words have different
meanings. Aseptic means the absence of pathogenic organisms whereas sterile
means the complete absence of life. It is probable that in early cleanroom processing
sterility would not be a reasonable expectation due to the presence of human
beings, however well trained and gowned the operators may be.
Why use isolator systems as opposed to cleanroom systems for aseptic processing?
Well-designed cleanrooms appear to work very well. The answer is complex and
is more to do with the culture of the pharmaceutical industry rather than science
and engineering. I hope that the following discussion may convince even the
most conservative among us that there is no longer any validation or regulatory
issue to stand in the way of using isolator technology for aseptic processing.
Isolators present us with the best opportunity to remove the presence of operators
from the critical processing field and it is possible to contemplate that product
assembled or filled under these circumstances are truly sterile. This is due
to the fact that the possibility of human borne contamination has been eliminated.
It is also possible to deliver reproducible biological decontamination to all
of the exposed surfaces inside the isolator and also to make aseptic transfers
into and out of the isolator.
Isolator use at present
Aseptic means the absence of pathogenic
organisms whereas sterile means the complete absence of life
Pharmaceutical uses for isolators started in 1975. Prior to
this time isolators had been used for some limited applications in this field
but were mainly focused upon maintaining germ free animals and also for housing
immune compromised human beings.
Much of the technical details stemmed from containment technology
in the nuclear industry. The aim here was to design isolators for containment.
For aseptic processing and sterility testing it was not a great leap of imagination
and design to propose systems to keep contamination from getting into the isolator.
Half suits as well as glove/sleeve fittings had been derived around this time
as well as an adaptation of a rapid transfer port used in the nuclear industry.
The main thrust of the use of the technology was in the field of sterility testing
and today there are more than 200 isolators or groups of isolators used for
The technology was mainly used
for sterility testing. Today there are more than 200 isolators used for
For aseptic processing (around 1975), the first use of the technology for the
filling of sterile powders into vials was in Italy. Other developments led to
the use of rigid wall isolators, consisting mainly of stainless steel, enclosing
a filling machine and also attached to a dry heat-sterilising tunnel. Advances
were also made in the field of sterilising the enclosure. Such systems were
used to fill cytotoxic products in vials, vaccines into syringes and also other
pharmaceutically active but heat labile products into vials, syringes and ampoules.
The two most common uses today are for vial filling or syringe filling aseptically
using high output filling lines.
The period of regulatory uncertainties regarding isolator
technology is nearing an end. There has been an increase in the number
of pre-approval inspections of isolator systems by the FDA and also an
increase in the number of approvals, although much lower than in Europe
Last year a survey was published where it was reported that there were 34 isolator-filling
lines in daily production around the world and that the FDA had approved six
of them. In Europe EU regulator approvals far exceeds this number. I believe
that various isolator manufacturers have delivered more than 95 filling lines
to customers around the world. Since the publication last year there have been
many additional pre-approval inspections by the FDA and I believe that the number
of FDA approved isolator filling systems will rise to around 10 to 15 in the
If we estimate the expansion of the technology, I believe
that the number of isolator filling systems purchased will increase by 15 to
20percent per annum over the next several years. My estimate is very conservative
but if these figures hold true then it is reasonable to expect isolators to
be cGMP by the year 2010.
The above estimates are for the high output filling lines
and represent only one application of isolators in aseptic processing. A very
large number of isolator systems are in use for investigational drug manufacture,
bioprocessing, complex device assembly and sterile implants with sterile adhesive.
Isolator use concerns
The current data on the expansion of isolator uses indicates that the technology
has been slow in being adopted for aseptic processing. Many concerns have been
expressed but the two major factors have been:
Regulatory approval: It is better to follow than to
lead. There still is a belief that it is far safer to follow the path set by
earlier users for aseptic processing and to wait until the regulators have approved
a number of facilities.
Validation: Lack of international guidelines or performance
specifications regarding a number of critical process control/validation issues.
This is largely due to the conservative nature of the pharmaceutical industry
in general. New manufacturing technology and systems are slow to be adopted
due to the highly regulated nature of the industry.
Europe has a very large number of isolator installations and it is perceived
that regulatory bars there to implementation are less imposing. Whilst the FDA
offer strong general support for the technology implementation in the USA has
been generally slower than in Europe. It may be because the requirements for
isolator acceptance were not clear to many potential users. However I believe
the period of regulatory uncertainties regarding isolator technology is nearing
an end. There has been an increase in the number of pre-approval inspections
of isolator systems by the FDA and also an increase in the number of approvals,
although much lower than in Europe.
It is expected that the FDA will publish soon their long awaited Guideline for
the Production of Sterile Drug Products Produced by Aseptic Processing.
Other documentation to relieve some of the uncertainties
regarding isolator technology is as follows:
- The USP has already published a draft revision to the
general information chapter. One of the main changes is the inclusion of guidance
in the area of isolator design, validation and monitoring
- The PDA has developed a technical monograph on the design
and validation of isolators
- The draft ISO standard for the "Aseptic processing
of healthcare products" also includes a section on isolator technology
- In the UK there is published a "Guideline to the
use of isolator technology"
- In France the A3P group are drafting a French language
a practical Guideline for isolator implementers and users of isolator technology
- The Pharmaceutical Inspection Convention (PIC) has offered
two drafts of a guideline for the inspection of isolator systems, both for
testing and production.
Isolators continue to be installed and validated in Europe. Once Companies have
successfully demonstrated that approval of the new technology is achievable
other have followed to adopt the new technology. Coupled with these events and
also the success that numerous Companies have shown in the validation process
(IQ, OQ and PQ) it is apparent to me that the significant obstacles to using
isolation technology for aseptic processing is rapidly diminishing.
It is however important to understand the issues most significant
for the potential user. In my view the two technical issues for which there
are differences of opinion are:
- To preclude ingress of contamination - achieving isolation
- Chemical antimicrobial treatment given to an isolator
system to achieve a high level of sterility assurance - decontamination (sterilisation)
The most ideal condition to achieve absolute isolation is
complete leak tightness. To attain this ideal means in practice specialised,
dedicated technology. Generally there are two types of production or testing
- Batch production where the isolator is closed, sterilised
and the process completed without opening up the system.
- Continuous production in which materials are continually
entering and exiting the system through appropriate openings.
In a recent PDA publication James Agalloco proposed the following definition
for such isolators:
Open Isolators: are operated under positive pressure
to the external environment and have limited potential for exchange with contaminants
from the surrounding environment. Personnel do not directly access the critical
zone for set-up and use.
The environment on the inside of the isolator can be sterilised and is of substantially
higher microbial quality than the external environment.
Closed Isolators: are operated as a sealed system
and do not exchange contaminants with the surrounding environment. Personnel
do not access the critical zone during set-up and use.
The environment on the inside of the isolator can be sterilised and is of substantially
higher microbial quality than the surrounding environment.
The main difference between the two types of enclosures is that there is at
least one opening to the outside environment for the former whilst the latter
is sealed. For practical purposes the open isolator is sealed by over-pressure
with filtered air. In many cases now isolators are being manufactured with ULPA
filters instead of HEPA type filters and in some case with HEPA filters placed
before the ultimate ULPA filters.
Differential pressures have been used for many years to maintain
air quality zones within cleanrooms and the maintenance of a differential air
pressure in an isolator is simpler in that the openings into and out of the
isolator are small and they of a fixed size and location. This is not the same
picture for large cleanrooms where doors and pass throughs are opened and closed
and cause large shifts in pressure relationships that can be difficult to control.
In practice the situation for the open isolator is not complex or difficult
to control. It is relatively easy to maintain essentially static air pressure
conditions within an isolator. In practical terms it is maintenance of an adequate
airflow or velocity through the opening so that a reliable air seal results.
Note that it is important that the airflow rate through the opening is not the
same as that measured close to the filter face in the isolator. Velocities as
low as 0.1 to 0.3 meters per second have been shown to be effective. It is obviously
important to demonstrate that the airflow through the opening do not allow eddy
currents which may draw contamination into the isolator. It is also important
to demonstrate that in using gloves and half suits that air pressure changes
are within the acceptance criteria established for the system.
Unlike cleanrooms the small size and therefore volume of the isolator systems
in use today and which can be temporarily sealed are capable of being treated
frequently with chemical agents, usually in the form of a vapour or mist, which
are used to eliminate microbial contamination, see later in this paper.
Much of the methodology and agents used have been debated
regarding the removal of microbial contamination from an isolator system, be
it for aseptic processing or for sterility testing. One sees many reports which
use such terms as "sterilise the isolator", "sanitise the surfaces
exposed in the isolator", and "decontamination". Also some reports
add statements implying a sterility assurance level, which can only be attributed
to product, which are exposed to a terminal sterilisation process.
I think the industry tends to focus a great deal of attention to terminology
and semantics and not enough on the actual desired effect. The later is obviously
a reliably sterile and safe product.
Isolators are environments and not product contact surfaces and that the treatment
of the environment of an isolator is performed with chemical steriliants periodically.
Therefore the microbiological quality of the enclosure is determined by many
factors of which sterilisation (or decontamination) is only one. Also remember
that the values used to define the performance of a sterilising effect, an S.A.L
of 10-6, are really only an assessment of risk.
The guidelines offered at the moment mentioned earlier suggests a "kill"
of three to six logs of an appropriate biological monitor. In the choice of
the monitor there is much still to be defined, for guideline purposes, as to
the characteristics and resistance of the species chosen, currently Geobacillus
stearothermophilus or Bacillus subtilis var. globigii (niger).
In my experience decontaminating the isolator environment within this range
of "kill" will result in a product that has a very safe level of sterility
assurance. This has been borne out many times as shown by data derived from
the decontamination of sterility test isolators.
Equally important my experience has taught me that even the
most demanding of these requirements can be readily met by way of a well-designed
Sterilising dry-heat oven tunnels. These are now used to
introduce sterile containers into the isolator at the start of the filling process.
There are many variations on the same theme but in essence the junction of the
two parts of the system tunnel and isolator can be engineered easily and securely.
Airflow generally tends to be adjusted to flow from the isolator into the "clean"
end of the tunnel. Doors are now available to close off the entrance to the
tunnel when sterilising or decontaminating the isolator.
They are commonly referred to as
Rapid Transfer Systems, usually a door on the isolator and a matching
"door" on the transfer isolator or container
In many cases of designing an isolator system for high speed filling lines
(30,000 to 40,000 vials per hour, as an example) there is the problem of the
safe transfer of stoppers, plugs and caps as well as getting sterile containers
into the isolator. This also applies to access of the sterile product to be
Components include product contact parts that are conventionally
sterilised by team or dry heat. Stoppers, plugs and caps are radiation, gas
or steam sterilised. In may cases they are introduced via another isolator attached
to an autoclave or dry heat oven and can be passed into the working isolator
through the use of a transfer isolator or a dedicated container.
All of the transfers into the environment of the process
isolator can be conducted by the use of a double door system, which maintains
the sterility of both isolators and isolator/container. They are commonly referred
to as Rapid Transfer Systems, usually a door on the isolator and a matching
"door" on the transfer isolator or container. A recent introduction
has been a dedicated "door" which is used to accept a dedicated container.
This container (bag) is disposable. On docking the container but before opening
the face of the container is exposed to ultra violet light decontamination There
are other variants on the UV theme to gain access to the isolator without compromising
the sterility of the enclosure, etc. For pre-packed tubs of sterile syringes
there is also now a low power electron beam system that can be attached to the
isolator that effectively decontaminates the outside of each tub at a rate of
6 tubs per minute.
In many cases a dedicated steam in place line is connected
into the isolator and is sterilised as part of the tank and pipework for the
product. Once sterilised the line is opened inside the isolator and connected
to the filling line pumps. This avoids making an aseptic connection outside
of the isolator environment. Alternatively a modified rapid transfer container
is attached to the product tank and steam sterilised in place. The container
is then attached to the isolator, the door opened and the filling tube (sterile)
attached to the filling line pumps, etc.
The use of the above techniques is expanding and we are gaining more validated
data as to the efficacy of the systems in use at present. Again the transfer
systems used eliminates the presence of the operator and also ensures sterile
connections without fear of extraneous contamination.
Chemical sterilisation or decontamination
Another additional aspect of isolator technology is the ability to be able to
decontaminate the isolator environment by using a gaseous or aerosolled chemical
agent. These agents are usually powerful oxidising agents such as peracetic
acid or hydrogen peroxide although recently there have been tests made using
chlorine dioxide and ozone. There have been advances too in the method of delivering
these agents and there are now available gas generators, which can be validated
to deliver reproducible cycles. In this field there are also devices used to
measure the gas concentration, mainly for hydrogen peroxide, with some degree
of accuracy and reproducibility, which enables the monitoring of a sterilisation
cycle to be more reliable when used in conjunction with biological monitors
during the sterilisation cycle validation phase.
At this point in time there are no significant regulatory issues regarding the
validation and use of an isolator system to manufacture aseptically filled product.
These facts should persuade a pharmaceutical manufacturer to use the technology.
Some standards issues need to be resolved but this is equally true with regard
to conventional aseptic processing technology. With the latter and using conventional
clean room technology could the "clean room" be considered an "endangered"
species when compared to the advantages isolator technology can bring to the
field of aseptic processing. It is interesting to consider that delayed implementation
of isolator techniques may bring about a greater regulatory risk.
Companies that are left behind in the moves to implement isolator techniques
for aseptic filling may find that their current processes are no longer cGMP
because they will not provide the level of product safety and security that
is possible in isolators.