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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

info@vetter-pharma.com

Reference

1. Friedman RL, Routes of contamination:

aseptic processing case studies CBER, in European Journal of Parenteral & Pharmaceutical Sciences, 10 (1): pp3-7, 2005