pmps
scenarios with ease, be that in emergency rooms, ambulances,
home care, hospitals or the Doctor’s surgery.
THE CHALLENGE
On the other hand, aseptic filling of syringes is especially
complex. The main challenge is gaining full microbiological
control of the environment, since the drugs are to be
administered straight into the patient’s body, bypassing the first
RABS: Injecting Change into Syringe Drug Delivery
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Joerg Zimmerman of Vetter reveals an innovative method of aseptic filling for syringes
Most people have witnessed the performance of the physician administeringan injection; screwing on the sterilised needle, sticking it into a vial, drawingthe medication, checking the level against the light, squirting a little bit out to make sure there was no air trapped in the needle and finally injecting thepatient. It all seems to be routine and yet the process involves several riskysteps. Was the needle really sterile? Is that drug really in order? Was thedosage accurate? And what happens to those few drops of costly drug thatremain at the bottom of the vial?
Joerg Zimmermann graduated in Pharmacy from Albert-Ludwigs University, Freiburg,Germany in 1994 and joined Vetter as Assistant Head of Production. Within Vetter, he has held various positions in process implementation, new product introduction and lyophilisation process development, and was Production Manager beforebecoming Head of Production of the Langenargen site, his current position, in 2000.As Head of Production, he is responsible for four production lines for asepticallyprefilled injection systems.
THE RISE OF THE PREFILLED SYRINGE
The one-way prefilled syringe answered these questions. It
greatly eased the process of administering many types of drugs,
and has definitely increased safety and reduced medical waste.
For one, the prefilled syringe allows exact dosing: all the
administrating personnel have to do is take it off the shelf and
inject. This, in turn, reduces the need for overfill volumes in the
vials, thus saving pharmaceutical companies bulk drug
substance. Secondly, the drug and its
packaging can be seamlessly traced from the
manufacturer to the patient thanks to
high-tech tracking and safety systems.
This prevents counterfeiting, mix-ups and
tampering, and ensures the
integrity of both the product
and the needle itself. And
finally, the prefilled syringe
can be used in all sorts of
defences. The world’s regulatory agencies, above all the FDA,
the EMEA and other authorities have therefore issued stringent
rules and regulations to monitor these high-risk processes. And
the regulations are becoming stricter. As a result, placing a drug
on the market in a prefilled syringe in large quantities requires
a fair investment in production facilities.
TECHNOLOGY AND EVOLUTION
The latest development is Restricted Access Barrier System
(RABS). RABS is not a single technology, in fact, but a
combination of ‘the best of ’ existing ones. To understand
how it works, we must take a look at older systems.
Originally, all the machinery used for the filling of sterile
products was placed in a cleanroom. The cleanroom was
equipped with a laminar flow system from ceiling to floor,
which prevented contaminants from getting into the
product during uninterrupted operation. The overpressure
created was considered sufficient to take care of separating
the unit from the outside world. High air exchange rates kept
the area as free of particles as possible. The problem,
however, was that operators were constantly in the direct
presence of the drug. In the case of an emergency, operators
had to access the critical filling zone and by doing so risk the
sterility of the product. While this can be done with care and
precaution, the risk still did not come close to zero. Thus,
innovation was required.
SEPARATING OPERATOR AND MACHINE WITH ISOLATORS
Cleanrooms do function well
and are still widely used, of
course. But analyses show
that most contamination
comes from the people who
perform interventions (1). To make the filling process even
safer, the industry developed the isolator. The idea was to
automate the entire filling process, thus reducing human
contact with the product to an absolute minimum. With the
isolator, the filling line itself is separated from the surrounding
environment, as the name indicates. Every part of the machine
is sterilised prior to the filling, usually with hydrogen peroxide
steam. Strategically placed glove ports allow operators to
perform standard or planned manipulations during the
process without ever coming into direct contact with any of the
critical surfaces.
At f irst, isolators seemed to be the answer to the
pharmaceutical industry’s challenges with aseptic filling.
Nevertheless, some danger zones remained; namely the point
of entry of the material and the point of exit of the finished,
filled syringe. In addition, the integrity of the gloves became
an issue. In the early 1990s, other drawbacks became
apparent. While the isolator did promise a high degree of
sterility, installing it in a controlled – though not necessarily
classified – area was thought to reduce operating costs
dramatically. This in turn meant that any breach of the
isolator’s integrity represented a risk to the product, so the
surrounding rooms at most sites have since been upgraded
cutting sharply into anticipated f inancial benefits.
Furthermore, the extensive sterilisation involving hydrogen
peroxide or other gasses, reduces the operating time of the
isolators considerably.
SEPARATING OPERATOR AND MACHINE WITH RESTRICTED ACCESS BARRIER SYSTEMS
A further evolutionary step was thus needed to improve the
functionality of the aseptic operations. The outcome was
RABS, which was conceived as a way to build a safe bridge
between the sterility assurance of the isolator and the
flexibility of the classical cleanroom. The problem with the
isolators is the actual time needed to open up the machine,
install parts, close it and then sterilise it with VHP. This
also cuts down on a company’s flexibility. Isolators are
excellent for filling toxic substances, since the employees
also have to be protected from the product, or for mono-lines,
where a single product is filled, thus requiring fewer changes
in parts.
The concept involved placing a filling line in an ISO 5/ Class
100/ Class A cleanroom equipped with a laminar flow cover
and a barrier between operator and machine. All interventions
were to be done through gloveports installed in the machine
cover. This permitted quick and safe manipulations of the
filling machine. This was coupled with a high degree of
automation eliminating direct human interference with the
product. A mock-up of the RABS-equipped filling line was
even built for the purpose of testing all possible scenarios.This
was followed by optimisation of the machine cover and
gloveport positioning to make the line as ergonomical
as possible.
STATE OF CONTROL
Once the RABS has been properly set up, filling per se becomes
a very well controlled process that needs supervision and the
occasional intervention via gloveport. The type of pump used is
decided well in advance. Experience has shown that applying
inline filtration of the product on the filling line as close as
possible to the point of fill does reduce the critical area within
the cleanroom to a minimum. What is important is the
microbiological monitoring. The final step in qualification of a
line is always the media fill: by filling growth-promoting media
such as tryptic soy broth, the aseptic process can be tested by
simulating all likely interventions. Operators have to take part in
the media fill as part of their qualification at least once per
year. These fills are monitored by quality assurance personnel at
all times.
RABS: FURTHER PREREQUISITES FOR SUCCESSFUL OPERATION
Overall, RABS are more than just a happy convergence of
filling equipment, gloveports and cleanroom classification.
Properly designed equipment is imperative from the beginning,
in other words, it has to be specifically designed and built. The
surrounding room must be able to maintain ISO 5 classification
in the critical zone at all times. Personnel must be instructed in
proper gowning practice and specially trained to handle the
machinery expertly. The room must also be kept under
management supervision and a separate quality system
installed. In terms of direct operations, the operator must ensure
an initial high level of disinfection with a sporicidal agent.
Overall, RABS are more than just a happy convergence of fillingequipment, gloveports and cleanroom classification. Properly designedequipment is imperative from the beginning, in other words, it has to bespecifically designed and built. The surrounding room must be able tomaintain ISO 5 classification in the critical zone at all times. Personnelmust be instructed in proper gowning practice and specially trained to handle the machinery expertly.
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Furthermore, proper SOPs must be written up for rare
interventions, disinfection, appropriate line clearance and
documentation of events during the filling process. In short,
RABS requires considerable investment. But for a company
filling different products and requiring automation, flexibility
and safety, it is well worth the time and effort.
DEFINING RABS
Until now, however, many companies have been calling any
enclosure RABS. In order to establish clear specifications, the
FDA asked if ISPE could help devise a definition for RABS to
assist the industry, the agency itself and overall healthcare. A
committee comprised of RABS users, agency representatives
and equipment manufacturers was formed. The members
discussed the views and implementations of RABS. The team
was led by Jack Lysfjord from Bosch Packaging. Members
included Joe Shabushnig of Pfizer; Michael Porter of Merck;
Ian Symonds of GSK, Joerg Zimmermann of Vetter and Rick
Friedman from the FDA. Five months later, a draft of the
definition went out to the industry for comment shortly after the
presentation at the ISPE conference in Arlington, VA in early
June 2005. Comments from the industry were gathered,
examined and worked into the draft if found to be relevant and
valid. The definition was added to the ISPE glossary and will be
included in the investigator guidelines of the FDA. The final
definition was presented at the ISPE Annual Meeting in
November 2005.
SETTING UP THE RABS
A company opting for RABS to fill syringes must take a
number of precautionary steps before starting. Even personnel
must be considered in the equation: the use of such
sophisticated, highly automated filling lines also means that
highly qualified operators are needed.
Daily operations begin with the gloves: the RABS definition
clearly states that sterile gloves are required and should
be sanitised or changed as appropriate. This, in fact,
would allow gloves to remain in place for several days and
only be sanitised using an alcoholic disinfectant. It is
recommended that sterilised gloves are used, and that they are
changed on a daily basis. All machine parts are then installed
using these sterilised gloves. During the production process
the gloves are used to perform the necessary interventions,
including refill operations for packaging components.
Microbiological monitoring is performed throughout the fill
and after.
Another key step is the disinfecting and cleaning of the
cleanroom. The draft RABS definition calls for disinfection
using a sporicidal agent as one of the design features. Multiple
day operations are possible only under certain circumstances.
One option is to use a sporicidal agent based on a peroxide,
which is easy to use, non-corrosive and allows complete and
safe daily disinfection.
The next stage is to make sure the syringes are sterile, a process
requiring several steps. The first is to wash the syringe barrels,
rubber stoppers and closure parts prior to sterilisation. This is
usually done with washing machines using purified water for
first washing steps, followed by a final rinse with water for
injection. The second step is lubrication of the parts with, in
general, medical grade silicone oil. Just enough silicone is
applied to allow movement of the stopper in the syringe. The
third and final step is the sterilisation itself. This is generally
done using dry heat tunnels, since this removes pyrogens, which
could cause fever in the patient, and fixes the silicone oil to the
glass surface (creating what is called ‘baked-on silicone’). Dry
heat will not work in the case of syringes with staked needles,
however, so in those cases steam sterilisation is used. This, in
turn, requires a more sophisticated washing process to reduce
pyrogens on the glass.
The syringes are now ready to be delivered automatically – that
is, without manual intervention – to the filling machine. Filling
is carried out using rotary piston, rolling diaphragm or
peristaltic pumps. The solution to be filled is inline-filtered as
close to the point of fill as possible. Next, the stopper is then
introduced into the syringe using a stopper placement tube with
a slightly smaller diameter than the syringe. The stopper is
compressed through the tube with a placement pin. When the
stopper has reached its final position, the tube is retracted first,
letting the stopper expand and ensuring that no overpressure
has been created in the syringe. At the end of the fill, the
machines are dismantled, cleaned and sterilised. Gloves are
removed, checked for integrity and then sterilised.
THE ADVANTAGES OF RABS
There is no single universal answer to the challenges in
aseptic filling. Isolators are ideal when filling cytotoxic
products, for example, or antibiotics. A company with single
product lines will also be well served with the classic
isolator. However, a contract manufacturer working under the
pressure of having to fill quickly and safely, whilst providing
full capacity including back-up lines, will f ind the
investment worthwhile. The RABS principles outlined
above provide the manufacturer with a very flexible
schedule. The downtime of the line between batches for
cleaning, including the cleaning-up phase for the room, are
kept to a minimum. Products and syringe formats can be
shifted around to optimise deployment of filling lines
without compromising the product quality. In retrofitting
lines, space restrictions often mean that the laminar flow
covers have to be modified, as well as the handling features
of the machine. The benefits, however, do outweigh the
drawbacks and the expense. �
The author can be contacted at
Reference
1. Friedman RL, Routes of contamination:
aseptic processing case studies CBER, in European Journal of Parenteral & Pharmaceutical Sciences, 10 (1): pp3-7, 2005
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