c10 IHBK069-Agalloco June 24, 2010 12:44 Trim: 10in× 7in

10 Aseptic processing transfer systems

Gary Partington

An important consideration when designing an enclosure is how to enter/exit items from the
enclosure. There are times when the integrity of the enclosure cannot be compromised and other
times when this is not important. This chapter reviews several transfer systems from the most
basic to the more complex, which can be used in aseptic and/or containment applications.

SIMPLE TRANSFER SYSTEMS

Hinged Doors
Hinged doors may be used in either aseptic or containment isolators as well as in restricted
access barriers (RABs). As shown in Figure 1, this door is a simple hinged door made of stainless
steel or plastic, which is opened to permit loading of the chamber prior to the task operation. It
can also be used to unload the chamber after task operation, as long as the containment isolator
has been thoroughly cleaned, and is safe to open or when the product is sealed in an aseptic
isolator.
Often these doors are equipped with safety interlocks to prohibit the door from being
opened during operations.
Similarly, the simple door in the right end (Fig. 2) is used in a RABs system to allow entry
of components such as empty vials and stoppers and to exit filled and stoppered vials.

Hatchback Windows
As is the case with hinged doors, hatchback windows provide another method of loading or
unloading an isolator or RABs, but provide a much larger opening to pass material or process
equipment through. This type of transfer system is popular in R&D isolators in which flexibility
may be required when using different types of process equipment. It is also useful in sterility
testing when loading an isolator with test materials, product, media, etc., and filling machine
isolators prior to operation. Hatchback windows are mainly used in aseptic isolators, but can
be used on containment isolators if contact surfaces are verified as cleaned before opening the
window. Hatchback windows can use inflatable and noninflatable gaskets to create the airtight
seal on the isolator or RABs body. The transfer isolator shown in Figure 3 uses a hatchback
window for easy loading.

Airlocks
Airlocks are typically small chambers attached to the end of the main enclosure. Airlocks use
pairs of simple hinged doors that are located between the airlock and the main isolator and
the airlock and the room. These doors can be interlocked such that one door cannot be opened
unless the other is closed. This will help prevent exposure from/to the main chamber and the
room. Airlocks are available in various sizes and often are equipped with a view window and
a glove port (Fig. 4).
Airlocks can also be equipped with a pressure equilibration HEPA (high-efficiency par-
ticulate arresting) filter or its own ventilation/HEPA filtration system. Airlocks are used to
enter/exit materials from the main chamber. These materials are generally larger than those
that can fit within a rapid transfer ports (RTP) system, which is discussed later. Before the
airlock door is opened to the outside room, the airlock must be completely cleaned of any
residual potent materials so as not to expose the operators. If used in an aseptic application,
the door between the chamber and the airlock cannot be opened until the airlock has been
decontaminated with a sporicidal agent.
c10 IHBK069-Agalloco June 24, 2010 12:44 Trim: 10in× 7in

ASEPTIC PROCESSING TRANSFER SYSTEMS 91

Figure 1 Hinged door. Source: Photo courtesy of Walker Barrier Systems.

Utility Panels
Often electrical cords for scales, mixers, stir plates, and other equipment can be passed out
of the isolator through a utility panel. Similarly, vacuum, liquid, air, or other process utilities
need to be brought inside the isolator. This can be done using a utility panel built into the
body of the isolator. The panel is customized for the process being performed inside the iso-
lator. The utility panel can consist of tri-clamp connections, bulkhead fittings, quick connects,
hose bards, compression fittings, etc. The utility panel shown in Figure 5 shows a number of
connections.

Figure 2 RABs door. Source: Photo courtesy of Walker Barrier Systems.

c10 IHBK069-Agalloco June 24, 2010 12:44 Trim: 10in× 7in

92 ADVANCED ASEPTIC PROCESSING TECHNOLOGY

Figure 3 Hatchback window. Source: Photo courtesy of Walker Barrier Systems.

Figure 4 Airlock. Source: Photo courtesy of Walker Barrier Systems.

c10 IHBK069-Agalloco June 24, 2010 12:44 Trim: 10in× 7in

ASEPTIC PROCESSING TRANSFER SYSTEMS 93

Figure 5 Utility panel. Source: Photo courtesy of Walker Barrier Systems.

Drum Doors and Bag Ports

A typical use for drum doors and bag ports is to connect large drums to an enclosure so that its
contents can be subdivided and dispensed, under negative pressure, into smaller containers to
protect the operator. As shown in Figure 6, the doors can be rather large, often 30 in. in diameter
to accommodate large drums. The door needs to pivot on a hinge so that the enclosure depth
can be minimized. This will allow the operator to reach the inner liner inside the drum, by using
glove ports.
Drums are presented to the outside of the enclosure using a drum lift device.

Figure 6 Drum door. Source: Courtesy of Walker Barrier Systems.

c10 IHBK069-Agalloco June 24, 2010 12:44 Trim: 10in× 7in

94 ADVANCED ASEPTIC PROCESSING TECHNOLOGY

ISOLATOR
SIDE BAGOUT RING RUBBER BAND
OR O–RING
PRODUCT DOUBLE BAG
WITH SLEEVE BAG

POLY CAP

STEP 1 STEP 2
WITH THE ISOLATOR SEALED POSITION THE SECURE THE OUTER BAG TO THE BAGGING
EMPTY BAG NEAR THE BAGOUT RING. RING WITH THE RUBBER BAND OR O–RING.

STEP 4
STEP 3 SECURE THE PRODUCT BAG LINER TO
REMOVE THE POLY CAP FROM THE INSIDE BAGGING RING ON THE INSIDE OF THE
OF THE ISOLATOR. ISOLATOR WITH RUBBER BAND OR O–RING.

SIDE BAGOUT PROCEDURE

Figure 7 Bag out process drawing. Source: Courtesy of Walker Barrier Systems. (Continued)

The drum can be placed in a bag and sealed to the bag port, as shown in Figure 7, or can
be sealed via an inflatable gasket inside the drum door, as shown in Figure 8.
When exiting smaller subdivided containers or product from an enclosure, smaller bag
ports can be used. The procedure shown in Figure 7 can be used to remove items as well. If a
drum is not used, the plastic bag can simply be sealed using a heat sealer or tie wrap method,
which will seal both the bag and the resulting cap on the bag port connected to the chamber.

INTERFACE SYSTEMS

Process Equipment Interface

Parts, media, and glassware need to be entered into an aseptic enclosure without breaking
the integrity of the environment. In this case, the vial tunnel, autoclave, or depyrogenation
oven is directly connected and sealed to the enclosure. The process equipment are equipped
with flange that is attached to the enclosure body with a gasket. Glassware is loaded into the
“dirty” side opening of an oven or tunnel. After washing and/or depyrogenation, the vials
enter the enclosure that has been decontaminated and is in the run mode. The door, shown in
Figure 9, raises up via an air cylinder to allow vials from a tunnel to enter the enclosure where
an accumulation table collects the vials. The door is sealed with an inflatable gasket during
decontamination.
Pass through autoclaves are used to enter media into isolators for sterility testing. Both lab
size (Fig. 10) and production size lyophilizers interface with aseptic enclosures so that loosely
stoppered vials filled inside can be placed into a lyophilizer, without exposure to the outside
room.
c10 IHBK069-Agalloco June 24, 2010 12:44 Trim: 10in× 7in

ASEPTIC PROCESSING TRANSFER SYSTEMS 95

PUSH THE BAG IN HERE

TO ASSIST IN CAP APPLICATION

STEP 6
TIE OFF BOTH INNER BAGS. TO REPLACE THE
POLY CAP ON THE INSIDE OF THE ISOLATOR, THE
ISOLATOR OPERATOR WILL START THE CAP ON
THE INSIDE OF THE BAGGING RING. THE SECOND
PERSON WILL PUSH THE EXCESS BAG INTO THE
STEP 5 ISOLATOR FROM THE OUTSIDE AND HOLD THE
OPEN INNER PRODUCT BAG AND FILL WITH CAP ON ONE SIDE WHILE THE ISOLATOR
PRODUCT PAKS. OPERATOR WILL FINISH APPLYING THE CAP TO
THE BAGOUT RING.

STEP 7 STEP 8
WITH THE POLY CAP SECURE ON THE RETURN TO STEP 1 AND REPEAT PROCESS.
INSIDE OF THE ISOLATOR, REMOVE THE
OUTER BAG FROM THE BAGOUT RING AND
TIE IT OFF.
SIDE BAGOUT PROCEDURE

Figure 7 (Continued )

Other equipment such as Fitzmills (Fig. 11) and tray dryers (Fig. 12) can be interfaced to
the isolator body. These are often used when processing potent powders. The mill motor and
dryer heating systems are outside the isolator to prevent contamination.

SOPHISTICATED TRANSFER SYSTEMS

Split Butterfly Valves

Split butterfly valves are used primarily in containment applications. Transfer of potent powders
from one area to another can be achieved using this technology. Split butterfly valves are
available in various sizes and styles, with the ability to achieve operator exposure level (OEL) of
<0.1 to 25 ␮g/m3 (1). This is a two-part system, an active part and a passive part, each of which
acts as an ordinary butterfly valve (Fig. 13). When these two parts are joined together, they form
a single valve preventing any surfaces from being exposed to potent powder during the transfer.
This technology can be integrated direct with process equipment. When used with an isolator,
the active valve is integrated into the isolator. The passive valve is part of a container, individual
bulk container (IBC), or other vessel. Product can be discharged either from the passive valve
container into the isolator for weighing, milling, etc., or from the isolator into the container after
it has been weighed, milled, etc.
c10 IHBK069-Agalloco June 24, 2010 12:44 Trim: 10in× 7in

96 ADVANCED ASEPTIC PROCESSING TECHNOLOGY

Figure 8 Inflatable drum seal. Source: Photo courtesy of Extract Technology.

Figure 9 Vial tunnel door. Source: Photo courtesy of Walker Barrier Systems.
c10 IHBK069-Agalloco June 24, 2010 12:44 Trim: 10in× 7in

ASEPTIC PROCESSING TRANSFER SYSTEMS 97

Figure 10 Lab lyophilizer isolator. Source: Photo courtesy of Walker Barrier Systems.

Figure 11 Mill isolator. Source: Photo courtesy of Walker Barrier Systems.

c10 IHBK069-Agalloco June 24, 2010 12:44 Trim: 10in× 7in

98 ADVANCED ASEPTIC PROCESSING TECHNOLOGY

Figure 12 Tray dryer isolator. Source: Photo courtesy of Walker Barrier Systems.

Rapid Transfer Ports (RTP)

RTP (Fig. 14) can be used to protect both product and personnel in aseptic and containment
applications. Air concentration of less than 1 ␮g/m3 has been recorded using the RTP transfer
system (2). The RTP system is made of the two parts typically called the alpha flange and beta
flange. Diameters of the most popular RTP are 105 mm, 190 mm, 270 mm, 350 mm and some at
460 mm. Materials of construction are polyethylene or polypropylene and stainless steel.
The alpha flange (Fig. 15) is generally mounted on the body of the enclosure.
Depending on the process being performed within the enclosure, the alpha flange can be
mounted in the floor, end wall, or ceiling. The beta flange (Fig. 16) can be connected to a transfer
isolator or a container or to a piece of process equipment such as an IBC or tank. The beta flange
is connected to the alpha flange by lining up the tabs in the beta flange to the slots in the alpha
flange (Fig. 17).

undocked & closed docked & closed docked & opened

Figure 13 Split butterfly valve. Source: Photo courtesy of GEA Pharma Systems.
c10 IHBK069-Agalloco June 24, 2010 12:44 Trim: 10in× 7in

ASEPTIC PROCESSING TRANSFER SYSTEMS 99

Figure 14 Rapid transfer ports. Source: Photo courtesy of Central Research Laboratories.

Figure 15 Alpha flange. Source: Photo courtesy of Walker Barrier Systems.

Figure 16 Beta flange. Source: Photo courtesy of Walker Barrier Systems.

c10 IHBK069-Agalloco June 24, 2010 12:44 Trim: 10in× 7in

100 ADVANCED ASEPTIC PROCESSING TECHNOLOGY

Figure 17 Container connected. Source: Photo courtesy of Walker Barrier Systems.

The beta flange is rotated at 60◦ clockwise, thus engaging both door halves together. The
operator will open the combined flanges inside the enclosure via the glove ports or half-suit.
The gaskets on the flanges seal the two door halves together and the beta flange to the alpha
flange. Potent material or microbes can neither get in/out of the chamber nor in/out of the two
door halves when they are “sandwiched” together (Fig. 18).
Items, product, parts, etc., can be transferred to and from the process enclosure without
breaking containment or “sterility.” While there is a line of contact when the RTP halves are
mated together, there are funnels and inserts that can be used to protect the gaskets as well
as eliminate possible product or component contact. There are also external gasket decontam-
ination devices available. Beta containers made of stainless steel can be steam sterilized with
components or supplies in an autoclave. It is then connected to a previously decontaminated
isolator for transfer of sterile supplies into the enclosure. Beta flanges are also available with or

Figure 18 Opened RTP. Source: Photo courtesy of Walker Barrier Systems.

c10 IHBK069-Agalloco June 24, 2010 12:44 Trim: 10in× 7in

ASEPTIC PROCESSING TRANSFER SYSTEMS 101

Figure 19 Document transfer isolator (front

view). Source: Photo courtesy of Walker Barrier
Systems.

for attachment of bags. Bags that can be sterilized can be used, for example, for stopper entry.
Others are used to bag out waste of potent materials.

OTHER TRANSFER SYSTEMS

Document Transfer Systems

Document Transfer systems are being considered more in containment applications. Rather than
risk passing contaminated paperwork into office areas or placing a fax machine in a highly potent
process area, document transfer boxes are being employed. This is a small isolator with a RTP
system, as shown in Figures 19 and 20. The alpha flange is mounted into the facility wall between
the contained process room and the “uncontained” area. The beta flange of the document
box is connected to the alpha flange. Paperwork can be passed through the connected RTP,
allowing the operator to complete the paperwork via glove ports. The paperwork is not exposed
to the potent materials in the process room and can be safely returned to the noncontained
area.

Tray Transfer Systems

Tray transfer systems are often employed inside transfer isolators and airlocks. To facilitate
passing materials through an airlock or through a RTP beta sleeve, a sliding tray can be provided.
Material is placed on the tray, which is then slid through the airlock or beta sleeve on telescoping
rails to the next position. Other tray handling devices include a lift system, which rises to various
shelf heights where an operator can slide a tray of product to or from a shelf minimizing the
risk of dropping the tray.
c10 IHBK069-Agalloco June 24, 2010 12:44 Trim: 10in× 7in

102 ADVANCED ASEPTIC PROCESSING TECHNOLOGY

Figure 20 Document transfer isolator (rear view).

Source: Photo courtesy of Walker Barrier Systems.

Sterile Liquid Transfer

During aseptic fill processes, a sterile liquid transfer container may be used to make an aseptic
connection inside the enclosure. The container is made of 316 L stainless steel and is fixed with
a RTP beta flange. Inside the container is a coil of tubing (Fig. 21).
This arrangement can be steamed in place. Once the RTP halves have been connected
together and the filling isolator has been decontaminated, the RTP is opened. The coil of tubing
is pulled from the container and connected to the filling nozzle.

AUTOCLAVABLE
FILTER

FERRULE

105mm. BETA
CLAMP
FLANGE
HOSE

105mm. X 500mm. LG.

LIQUID TRANSFER CONTAINER

Figure 21 Sterile liquid transfer container drawing. Source: Courtesy of Walker Barrier Systems.
c10 IHBK069-Agalloco June 24, 2010 12:44 Trim: 10in× 7in

ASEPTIC PROCESSING TRANSFER SYSTEMS 103

Figure 22 Sterile liquid transfer port. Source: Photo courtesy of Central Research Laboratories.

The sterile liquid transfer port (SLPT) (Fig. 22) uses a 190-mm RTP beta flange in 316 L
stainless steel, which is equipped with tri-clamp fittings for product connection and condensate
drain. The product tank in connected to the SLTP with flex tubing. The product tank and the
SLTP are steamed in place together. Upon completion, the 190-mm beta flange is connected to
the alpha flange in the wall of the enclosure. The door is opened and sterile tubing inside the
enclosure is connected to the fill machine and to the SLTP. The product may now be delivered
from the product tank to the fill machine through a sterile connection.
Another system uses plastic connectors that are made up of a male and female coupling
that are compatible with gamma and autoclave. Once the single use, single actuation com-
ponents are assembled together, a sterile fluid path is enabled. The components cannot be
disassembled, reducing the risk of a sterility breach.

Pack-off Heads
Finally, pack-off heads are used to seal against drums, IBCs, and drum liners to provide contain-
ment when transferring potent powders from process equipment into containers. For highly
potent powders, an outward inflating sealing head (Fig. 23) is incorporated inside an isolator.
A drum with a liner is brought inside the isolator. The liner is connected to the pack-off
head. The seal is inflated and expands to seal against the liner in an airtight manner. Potent

Figure 23 Pack-off head. Source: Photo courtesy of Extract Technology.

c10 IHBK069-Agalloco June 24, 2010 12:44 Trim: 10in× 7in

104 ADVANCED ASEPTIC PROCESSING TECHNOLOGY

powder is discharged through the pack-off head and safely into the drum. The liner is tied off
and the drum closed. Use of the pack-off head inside the isolator eliminates plumes of powder
being scattered inside the isolator and keeps the drum clean.

CONCLUSION
Many solutions are available for transferring materials in/out of an enclosure. It is important to
determine the criticality of maintaining the enclosure environment when selecting the transfer
approach. It is also important to have a process plan in place along with sizes of materials to be
transferred, frequency of transfer, weight, and duration. This will help chose the correct transfer
system(s) as well as the design of the enclosure.

REFERENCES
1. GEA Pharma Systems. http://www.gea-ps.com. Accessed April 3, 2009.
2. Lahti C. 35097 Isolator surrogate test protocol and report. New Lisbon, WI: Walker Barrier Systems.
2009.