Fast and flexible transfer technologies

The benefit of sporicidal gassing technology, typically hydrogen peroxide vapour for biological inactivation during aseptic processing, is well established. With a high level of control, producing repeatable and robust decontamination processes, the two key elements of a validatable process are achieved.

The long-standing issue of gassing cycles has been that the cycle time was too long to be included in the direct flow path for many aseptic processes. Instead, strategies of pre-use preparation, by biological decontamination of process areas and offline preparation of equipment and materials, have been employed Holding aseptic supplies for use or other batch processing systems are the current methods, together with other rapid transfer techniques. To enable rapid transfer of bio-decontaminated materials and products from one aseptic area to another, the complementary technology of Rapid Transfer Ports (RTP) Alpha–Beta double door system is used. Rapid gassing ports remove the need for off-line processing as the total decontamination cycle time is around 15 minutes. This is typically far less than the processing time of the delivered material/product load and enables just-in-time delivery of components to a process. The growth seen in the implementation of isolator barrier technology has highlighted a challenge with off-line batch gassing and isolator-to-isolator transfers. As numbers of isolators increase, the number of indirect process steps leads to significant logistical challenges, which will inevitably become a management headache. Having available and timely processing when using numbers of off-line batch processing steps together with the necessary RTP transfer isolator/pod-canisters, escalates not only the complexity but also the cost. Getting deliverables directly where and when they are needed in an aseptic process provides the ideal workflow and takes away the complication of having to complete excessive process steps. Rapid gassing ports become highly complementary to standard sterilisation transfer processes where 6-log reduction on surfaces, without the need for load penetration, is the process requirement. Critical product contact parts need sterilisation – for example by autoclaving or dry heat – before aseptic processing, but there are typically a number of deliverables that can be bio-decontaminated to a high level of microbial inactivation on external surfaces to support the critical processes. Such rapid gassing transfers can be qualified by use of biological indicators of the spore form type Geobacillus stearopthermophilus to a 6-log reduction. Direct delivery of materials to process isolators, with in-line sporicidal gassing using hydrogen peroxide vapour and through-the-wall process transfers of materials into an aseptic processing room, is a typical use of a rapid gassing port. Applications for compounding or sterility test are two good examples of rapid gassing port use, where various materials need to be conveyed into the processing isolator(s) without compromising sterility or asepsis during process transfers. With the Rapid Gassing Port (RGP) connected between two process isolators, both can be supplied from the same RGP. A rail loading system that slides left or right dramatically reduces the ergonomic challenge of unloading the materials into the isolator. The flexibility of use of the RGP method is such that 'through-the-wall' rapid gassing transfers can be completed. The high level of disinfection achieved on transfer reduces significantly the challenge in transfer of contamination on material surfaces into cleanrooms. The performance of combined surface biological inactivation and low absorption make it suitable for a wide range of materials, including paper, environmental monitoring test consumables, service tools/equipment and process supplies.

Sterile transfer The port can be fixed or mobile. In the mobile configuration the port wall door remains in place and interlocked, while the port is attached by an inflatable sealed flange with full interlocking controls (operational only when the port is connected). Fitting multiple interfacing port wall doors allows for even greater flexibility. For transfer of bio-decontaminated materials within the cleanroom, a simple mobile laminar airflow cart can be used to interface with the port, allowing movement to a workstation or isolator transfer hatch. The route of sterile transfer into cleanrooms has traditionally been double ended autoclaves; however, if only an aseptic transfer is required (6-log reduction of bioburden on surfaces - not porous load decontamination) then the RGP provides a complementary alternative. If RABs (Restricted Access Barriers) are to be used in traditional cleanrooms then the rapid transfer method greatly assists this technology. The stand-alone control and on-board catalyst ensures interface with the building is minimal (wall door interface only – no ducting) with only a power supply needed. The mobile gas generator (as used with the port) can also be utilised to independently bio-decontaminate isolators, incubators and other aseptic chamber applications. Multi-purpose use can provide significant advantages and cost savings. Rapid gassing has been made possible by the advances in scientific understanding of the hydrogen peroxide sporicidal gassing process. To optimise every single stage of the process an understanding of the critical process variables both to achieve surface bioburden inactivation and aeration (removal of gas residuals) is paramount. The gassing cycle stages are: conditioning (%Relative Humidity (RH) and temperature); gassing (charging to lethal concentrations); gassing dwell (contact time – allowance for variables and overkill security); and aeration (removal of gas residuals). Optimisation of the conditioning phase requires an understanding of the impact of variation in starting %RH and, critically, the need for optimisation of temperature variation in the system design. Gassing and dwell phases have required extensive studies on optimisation of gas distribution and the achievement of saturated vapour concentration for minimum contact time. The process of gas residual removal – aeration – is typically the longest part of traditional sporicidal gassing cycles and there was a significant challenge to reduce this phase to minutes rather than hours. The use of a highly efficient catalyst with considerably enhanced airflow without the need to be concerned with typical dead-leg areas caused by gloves etc., has played a part in the success of achieving dramatically shortened aeration times. Apart from the key benefits of direct in-line processing and rapid gassing cycles, another technical advantage that has become apparent is the significant reduction of gas absorption into loads or materials. Thin wall polyethylene bag containers that hold an aqueous solution, for example, can cause absorption of hydrogen peroxide into the solution; but with rapid gassing and the very short contact time, both in gassing and aeration stages, this type of absorption is virtually eliminated. Other packaging materials also have reduced absorption, and hence reduce the impact on aeration or further processing. Completed studies have also shown that the RGPP solution provides much faster throughput using the same process isolators, resulting in an increase in production capability. The use of the rapid gassing technology has a significant impact on fault or failure recovery. If the process isolator(s) have an integrity breach, such as a glove tear, the recovery time to re-gas the isolator(s) is 1-2 hours, rather than 3-5 hours. In the case of a half-suit tear in a bank storage isolator, the recovery time to re-establish production could be reduced from 1-2 days to a few hours by using an RGP in place of a bank isolator together with all its associated risks.

Lowering costs It is not just the reduction in the process equipment used – e.g. fewer isolators – that lowers the cost, but there are also cost and time savings to be made in qualification. With rapid gassing cycles many study cycles can be completed in a short time. Table 1 shows an example of two approaches to a compounding operation. The first example is the 'traditional' gassed isolator suite comprising a material-batch gassing isolator, bank-storage isolator and processing isolators, together with a transfer isolator for 'isolator-to-isolator' transfers fitted with Rapid Transfer Ports. The second is the use of an RGP simply connected between the two process isolators. Rapid transfer ports are still used on the process isolators but for material product pass out only, using heat-seal bag-out technology, to keep transfer out simple. From the table it is possible to assess the time and cost savings on a percentage basis. All quoted prices are in Euros for scale comparison only.

Cost and Time analysis • The traditional isolator equipment solution is 54% more expensive than the RGP equipment solution. • The qualification cost of the traditional isolator solution is 59% more expensive than the RGP solution. • The time saving in qualification of the rapid gassing solution is in the order of 43% with 40 days versus 70 days. • The qualification cost for both bank isolator solution and the RGP solution is 21% of total project costs respectively. The development of rapid gassing ports has been driven by user requirement to get back to direct in-line processing without excessive process steps but still maintaining a high level of disinfection in the process transfer task. With simplicity comes flexibility – a key requirement in today's market. Although the cost saving example in capital equipment purchase shown may be simplistic and not possible in all cases, the reduction through time saving in simplicity of operations can be very real. Rapid gassing technology provides another very useful tool in aseptic processing transfers and supports the development in other areas where rapid and flexible technology is needed to meet the competitive and changing nature of the drug development and delivery business.