The transfer of sterile liquid is an operation performed frequently during the development of sterile-liquid drugs such as
injectables or ophthalmic drops. To achieve such transfers, operators should set up a connection after preparing the sterile
liquid. Several types of transfer can be performed, each requiring a validated technology to ensure the sterility-assurance
Transfer between two containers usually is achieved with a valve-to-valve connection, followed by steam sterilization of the
space between the two valves. This procedure is well established, mostly in the context of large stainless steel equipment,
and takes at least two hours, including a cooling down period. In addition, it requires clean steam, the evacuation of condensates,
and a system of recording the sensed parameters.
This technique is not especially attractive for applications that involve disposable equipment or more-frequent connections
of multiple, smaller containers. Blood banks typically perform these types of transfers. In the early 1980s, the technique
of flame-sterilizing the tubing ends under laminar flow was replaced by hot-plate welding (also called "tube fusion"). This
technique is suitable for small-diameter thermoplastic tubing made of polyvinyl chloride, thermoplastic elastomer, or other
Disposable connection devices have been introduced for applications requiring connections between two tubes. Kleenpak from
Pall (East Hills, NY), DAC from BioQuate (Clearwater, FL), and Lynx S2S from Millipore (Billerica, MA) are presterilized disposable
systems that reportedly are safe for low-classification or unclassified environments.
The addition of barriers and isolators around critical aseptic processes created a new environment for aseptic transfer. In
such systems, it clearly is preferable to leave containers such as bulk containers outside the protected environment. Sterile
liquid must then cross the wall through a connection mechanism. It is quite difficult to introduce the container in the protected
environment because the container's exterior cannot be thoroughly sterilized.
The first transfer system also originated in the context of large, infrequent transfers involving the well known rapid-transfer
port (RTP) transfer container from La Calhène (Vendôme, France). It consists of steam-sterilizing tubing in a stainless steel
transfer container docked to the barrier wall, unfolding the tubing, and introducing it into the barrier or isolator. In some
cases, it is possible to sterilize the preassembled system (e.g., the RTP container and the empty tank), but in many cases, the classic valve-to-valve steam sterilization is still necessary.
Because of the increased use of flexible pouches, Stedim (Aubagne, France) introduced its rapid aseptic fluid transfer (RAFT)
system, which connects to pouches using a Biosafe port. The stainless steel container described previously is replaced by
a plastic bag equipped with a disposable flange that is docked to an RTP port. The disposable part is attached beforehand
to the flexible pouch and gamma sterilized with it as a closed system. Unfortunately, the docking system does not allow multiple
uses because reclosing and reopening is not feasible unless multiple flanges are attached to the bag.
This article describes a new approach for aseptic fluid transfer: the Sartorius Aseptic Rapid Transfer (SART) connection technology.
The system incorporates a SART port and a disposable Gammasart aseptic transfer device (ATD) connector and was developed to
provide a high-quality aseptic connection and simplify passage through a wall. The authors will discuss SART's product-qualification
results to show that this technology and its various components meet the stringent pharmacopeial product-qualification requirements.
Principle of the technology
The SART technology was developed for the aseptic transfer of liquid through a barrier or any separating wall. The system
has the following features:
- a port of minimal size that is fixed on the separation (in many isolators, wall space is restricted);
- an RTP system comprising four matching "V-shaped profiles," two of which have seals at the tip. The four components' small
size enables accurate matching of the shaped profiles.
- an incoming-liquid tube that does not rotate or twist during docking in the port;
- a mechanical-interlock system that prevents accidental opening of the port when the connector is absent;
- a disposable connector to be attached to the external container's tubing. The connector should be small to accommodate small
- rigid plastic not subject to pinholes that provides sterility protection for the connecting inner tubing;
- a leak-test limit that meets standards comparable with those in place for the closure integrity of the attached container.
All connectors are tested individually during the manufacturing process.
- a maximum of five reclosing and reopening cycles to withstand the partial emptying of a container and to provide flexibility
if operation is interrupted;
- compatibility with rigid liquid containers (e.g., stainless steel, glass, plastic) and flexible container (e.g., pouches);
- simplicity and low cost that enable multiple volumes or a small volume of liquid to be transferred.
The Gammasart ATD connector consists of two parts: the connector body that contains the rigid tubing and the connector cover
(see Figure 1). To open the docked connector, an operator locks the cover into the SART port and removes it by unscrewing
it. Thus, the rigid tubing is released into the aseptic area.
Both the connector body and the connector cover are made of polybutylene terephthalate and molded in a classified environment.
A seal made of Santoprene (Advanced Elastomer System, Newport, UK) thermoplastic elastomer is overmolded on the connector
cover. This seal ensures the quality of the system's closure integrity.
The principle of the SART connection is based on the alpha-beta concept of four V-shaped profiles that are in contact at the
tips. This alpha-beta concept initially was developed for the nuclear industry in the 1960s. The concept has been approved
by pharmaceutical industry authorities and used widely since La Calhène introduced it in the 1970s. As illustrated in Figure
2, the four V-shaped profiles of the SART system are the connector body, the connector cover, the internal part of the port,
and the seal of the port. Two of them are rigid (the connector body is made of polybutylene terephthalate, and the internal
port is made of stainless steel) and two are flexible (the connector-cover seal is made of Santoprene, and the external port
seal is made of silicone).
The connector device must be subjected to at least 25 kGy of gamma irradiation to ensure its sterility. The device was validated
at 45 kGy to ensure that the entire radiation range was validated. The connector should be irradiated alone if it will be
attached to a nonirradiated container such as a stainless steel vessel. If it will be used with a stainless steel vessel,
the connector can be sterilized by autoclaving. High- and low-pressure cycles should be used to push water vapor into the
connector and dry it. Preliminary tests performed with 106 biological indicators located in the assembled connector have shown total kill. If the connector will be used with containers
such as plastic pouches, it should be irradiated after assembly.
The connection process includes the following steps (see Figure 3):
- The Gammasart ATD disposable connector is introduced into the port and secured with two clamping devices on the external port
(see Figure 3a).
- The internal port's clamping system firmly holds the connector cover inside. The objective is to contain all the connector
cover's exposed outer parts inside the port (see Figure 3b). The internal port is sanitized in a clean environment in parallel
with the rest of the main equipment (e.g., with a vaporized hydrogen peroxide cycle).
- The port is opened by rotating the internal port (see Figure 3c).
- The tubing (e.g., silicone) is placed in the contained area on the connector's sterile tubing (see Figure 3d).