SubscribeThe past period has seen new initiatives and technologies developed in the Pharmaceutical industry. The Process Analytical Technology (PAT) initiative will lead to new in-process analytical technologies and techniques for a far more interactive qualification methodology, but this is not the only area of significant development.
Rapid and flexible technologies to improve operations and response / processing times are other key areas of development. Rapid microbiology will have a major impact on business operations. New techniques will provide more timely critical information on the state of microbial contamination in a product or process area for earlier product release and more responsive contamination control.
Complementary to such advances are new technologies that support rapid processing and in particular the age-old challenge of rapid aseptic transfer of products and materials during aseptic processing steps. This paper discusses the latest development in rapid bio-decontamination chambers and the operational opportunities presented in implementation.
Clarus PORT - Rapid gassing chamber
Gassing time shown in minutes to inactivate 15 No 6-log Geobacillus stearopthermophilus biological indicators.
Rapid gassing process transfers
The benefit of using sporicidal gassing technology, typically hydrogen peroxide vapour for biological inactivation during aseptic processing, has long been 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 the cycle time being too long to include 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 were used.
Holding aseptic supplies for use or other batch processing systems are currently used together with other rapid transfer techniques. To enable rapid transfer of bio-decontaminated materials and products from aseptic area to aseptic area, the complementary technology of Rapid Transfer Ports (RTP) Alpha -Beta double door system are used.
Rapid gassing ports remove the need for off line processing as the total decontamination cycle time is circa 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.
Challenges with existing technology
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 lead 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 complication of having to complete excessive process steps.
Rapid gassing ports become very 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 e.g. 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.
Implementation of the rapid gassing port technology
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 typical use of a rapid gassing port.
Rapid gassing PORT serving two process isolators
(picture courtesy of Baxter Healthcare)
Rapid gassing port and process isolators
Applications for compounding or sterility test are two good examples of rapid gassing port use various supplies / materials are needed 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 rapid gassing process
Rapid gassing has been made possible by the advances in scientific understanding of the hydrogen peroxide sporicidal gassing process. To optimize every single stage of the sporicidal gassing process an understanding of the critical process variables both to achieve surface bioburden inactivation and aeration (removal of gas residuals) was 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).
Optimization of the conditioning phase required an understanding on the impact of variation in starting %RH and critically the need for optimization of temperature variation in the system design. Gassing and dwell phases have required extensive studies on optimization of gas distribution and the achievement of saturated vapour concentration for minimum contact time.
The process of gas residual removal called 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 having to be concerned with typical dead-leg areas caused by gloves etc, has played a part in the success of achieving dramatically short aeration times.
Inherent technical advantages
Apart from the key advantages of direct in-line processing and rapid gassing cycles one other technical advantage that has become apparent is the significant reduction of gas absorption into loads or materials. As an example thin wall polythene bag containers that hold an aqueous solution, can cause absorption of hydrogen peroxide into the solution, but with rapid gassing 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 hence reduce the impact on aeration or further processing. From studies completed it is also been evident that the rapid gassing port solution provides much faster throughput using the same process isolators so there is an increase in production capability.
Fault or failure recovery
Using the rapid gassing technology has a significant impact on fault or failure recovery. If the process isolator(s) have an integrity breach e.g. glove tear, the recovery time to re-gas the isolator(s) is 1-2 hours, not 3-5 hours. If a bank storage isolator is used and it had a half suit tear then the recovery time to re-establish production could be reduced from 1-2 days down to a few hours by using an RGP in place of a bank isolator together with all its associated risks.
Qualification of the rapid gassing ports and associated isolators
It is not just the reduction in the process equipment used e.g. less isolators that provides a cost saving but also cost and time saving in qualification is made. With rapid gassing cycles many study cycles can be completed in a short time.
The following is 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 a 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 tables it is possible to assess the time and cost savings on a percentage basis. All quoted prices are in Euros for scale comparison only.
Qualification cost and time comparison
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.
Conclusion
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 (6 log reduction) 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 cost saving 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.