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

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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..


Pharmaceutical Technology


The connector can be closed and reused as many as five times within one week. This feature is useful for multiple transfers (e.g., a single bag containing five volumes of a formulation component to be transferred in five different batches) or in the exceptional cases of major operational troubles. For example, a major breakdown on a liquid-filling line would risk the destruction of connected bulk material. The Gammasart ATD connector safely allows the bulk to be removed from the line, stored, and reused within a few days. When the connector cover is screwed an additional 9 ° beyond its initial position, the seal is recompressed, and good closure integrity is maintained.

Application of Gammasart ATD

The connector can be used to cross any type of separation between two areas with different containments. The most common application in the pharmaceutical industry is the transfer of formulated bulk product to the aseptic filling line. The transfer may be from a cleanroom to a protected environment (e.g., an isolator or restricted-access barrier system [RABS]) or from a corridor to the class A–ISO 5 cleanroom.

Other possible applications include transfer during formulation, which can be accomplished in two ways:
  • by transfering the different components to the formulation container;
  • by transfering the formulated bulk product to the different storage units.

In the latter application, Gammasart ATD will be used in a reverse direction. The flow will move from inside the contained area to the sterile container.

Because the connector resists both gamma-irradiation and steam sterilization, various kinds of containers may be selected. Both sterilization procedures can be combined. Therefore, two possibilities for the sterilization of the container–connector assembly can be envisaged:

  • In containers that can be sterilized by gamma irradiation (e.g., flexible pouches), the connector should be preassembled, and the full assembly should be irradiated.
  • For containers that can only be steam-sterilized (e.g., stainless steel containers), the preirradiated connector should be assembled before steam sterilization.

Qualification of the Gammasart ATD connector


Table I: Overview of tests performed on connector and results obtained.
The connector was validated completely (see Table I). The tests were conducted on connectors subjected to 45 kGy of irradiation and a cycle of steam sterilization.

Leak test. The leak test is critical to ensure that the seal effectively preserves the sterile environment of the Gammasart ATD connector and to eliminate the risk of viable-particle penetration inside the connector during storage. The leak limit was fixed at 0.9 cm3 /min at 350 mbar or 35,000 Pa, corresponding to the closure integrity of the attached container.

Leak test after multiple opening–closure cycles. This test was performed to validate the fact that a connector can be opened and reclosed as many as five times within one week. The relatively short period of time results from the fact that the connector seal is overcompressed upon its first reclosure to obtain new closure integrity. Nevertheless, because over-compression can occur only once, the closure integrity cannot be maintained for a long time period thereafter, especially after subsequent openings.

Aging conditions. The connector was tested with various aging times to verify that the connector specifications such as closure integrity are maintained. The various aging periods were as follows:

  • one month aging at room temperature;
  • accelerated aging for 74 days at 60 °C, corresponding to roughly two years of aging in normal conditions;
  • one year of aging at room temperature.

Low temperature. The connectors were stored at –20 °C and –60 °C for 15 days before use. After being unfrozen, the connectors showed a behavior similar to that of connectors that were not frozen.

Fitting and traction test. This tested the ease of installing the tubing when the connector was open and verified the connection's resistance to rapid flow.

Burst-pressure test. The connector's resistance to high pressure was tested to eliminate the risk of operator injury if the connector accidentally came unscrewed after pressure increases occurred inside the container attached to the connector (e.g., in the case of liquid transfer inside a container with a defective vent filter). The test was conducted at 6.5 bar for 30 s. Roughly half of the connectors showed seal deformation, but none of them became disassembled.

Particle test. Because the pharmacopeia allows the presence of a limited amount of particle from the container and filling process, particle presence was recorded in various volumes collected over time. The objective was not to exceed a count of 600 particles bigger than 10 μm and 60 particles bigger than 25 μm per 50-mL volume. These data correspond to 10% of the pharmacopoeia limits for a single injection, independent of volume.

USP cytotoxicity and biocompatibility. These tests confirmed that the polybutylene terephthalate material meets the most stringent safety criteria (USP class VI). No sign of toxicity was recorded on the cell or when the material was administered to animals using three different methods.

Extractable profiles. Connector bodies were placed in a worst case-situation. They were immersed in water for injection for 24 h at 80 °C or in ethanol for 24 h at 50 °C. Analyses showed a release of material that always was less than 50 μg/connector and usually less than a few μg/connector. To extrapolate the amount of release from the internal tubing surface, the data must be divided by a factor of 10.

Endotoxin detection. Preliminary tests showed an undetectable level of endotoxin inside the connector tubing where the liquid passes through. This test will be repeated when the final connector packaging is available.


Table II: Media fill results.
Media-transfer simulation. Media-fill simulations were performed in a workshop using closed-vial technology to validate the quality of the connection. Three lots of ~6300 vials were filled in the assembly workshop (i.e., a nonclassified area). Two connectors were used for each lot to create a circulation loop. Seven, 1-m3 samples of air were collected inside the RABS to record the presence of colony-forming units (see Table II). The recorded samples show no presence of contaminant in the vial or in the environment.

Conclusions

The SART connection technology performs aseptic transfers through any type of separation between areas with different containments. The Gammasart ATD connector provides several advantages for users. The major advantage is the robustness of the connection system that prevents contamination of the area and provides the highest sterility assurance level. These results are achieved through the use of the precise alpha-beta system that has been used extensively for several models of connections (such as the RTP container or beta-bag) to bring autoclaved material inside the protected environment.

The second key advantage is the technology's ease of use, which includes simple manipulation and a setup time of less than one minute. In addition, the container is kept outside the critical area. Ease of use combined with security features such as interlock prevents operator mistakes and, therefore, reduces the risk of contaminating the transferred product.

The third advantage is the possibility of reversing the connection in the event of problems during the process. Most systems do not allow reversing the connection and saving the transferred product. This characteristic creates the potential risk of product loss. It also may force operators to fix problems in suboptimal conditions, leading to an increased contamination risk.

Finally, the solution is inexpensive and flexible, allowing users to adapt it to various situations.

The connector's qualification plan confirmed that the materials used, the port design, and the connector device meet the most stringent criteria. Therefore, the SART connection system is a suitable candidate for multiple-transfer applications in the pharmaceutical industry.

Acknowledgments

The authors would like to thank Thomas Paust, Paul Priebe, and Patrick Balériaux for their recommendations on this article. Aseptic Technologies benefits from grants from the Walloon Region and from the Agence Wallone à Exportation.

Benoît Verjans* is the commercial director, Jacques Thilly is the technology director, and Christian Vandecasserie is a consultant at Aseptic Technologies, tel. +32 81 409 417, fax +32 81 409 411,
Hartmut Hennig is the head of new technologies in the quality assurance and research and development departments at Sartorius. Patrick Evrard is the manager of TS biotech devices at GSK Biologicals.

*To whom all correspondence should be addressed.

Submitted: Feb. 18, 2007. Accepted: Mar. 6, 2007.

Keywords: aseptic transfer, barrier–isolator, containment, sterile connections


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