Qualification Results of a New System for Rapid Transfer of Sterile Liquid through a Containment Wall

Manufacturers use various techniques to transfer sterile liquid. Some methods, however, cannot accommodate disposable equipment, and others cannot transfer through barriers. This article describes a new approach for aseptic fluid transfer that was developed to provide a high-quality aseptic connection and simplify passage through a wall. The authors discuss the product-qualification results for the approach, which show that the technology and its various components meet pharmacopeial product-qualification..
Apr 02, 2007
Volume 31, Issue 4

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 level.

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 materials.

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 containers.
  • 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.

Figure 1
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.

Figure 2
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.

Figure 3
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).

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