Designed for rapid response
Dr Brian Bergin of Aseptic Technology & Design and Michael Greenbank of Baxter Healthcare UK describe the selection and evaluation of an isolator system for rapid response pharmaceutical compounding
Baxter Healthcare provides aseptic compounding services to the highest standards from four UK units. Chemotherapy, antibiotics, antivirals, and parenteral nutrition admixtures are prepared under aseptic conditions using specialist equipment, and delivered to hospital pharmacists. This service reduces the pressure on hospital pharmacies and increases potential patient throughput. Baxter has over 15 years’ expertise in aseptic manufacture and has recently invested in a new pharmacy compounding facility in the Northwest of England.
In commissioning this isolator system, Baxter Healthcare wanted to address a number of issues, common to anyone using isolators for aseptic compounding. Traditionally, peracetic acid has been used as the sanitizing agent for simple pharmacy isolators and Baxter wanted to move away from this. However, previous experience with hydrogen peroxide (H2O2) had led to very long gassing cycles, which in the event of equipment failure or breach of the aseptic environment meant long and expensive recovery times. Aseptic Technology & Design (ATD) was therefore commissioned to review Baxter’s existing processes and recommend improvements based on its extensive knowledge of isolator technology and aseptic manufacturing.
Existing process
The aseptic manipulations required in dispensing the pharmaceutical prescriptions were undertaken within the controlled environment of a sanitisable barrier system or isolator, designed to eliminate direct operator contact with the sanitised equipment and the dispensing process. Non-direct operator interaction with the process was through glove ports or half suits. The process flow is depicted in Figure 1.
Bulk prescription components were obtained from storage and loaded into one of three ‘sanitising’ isolators. A sanitisation cycle was then initiated to effect the surface decontamination of the components using peracetic acid or Vapour Phase Hydrogen Peroxide (VPHP). On completion of the cycle the components were transferred using sealed Rapid Transfer Port (RTP) canisters to one of two ‘bank’ isolators to be held as work-in-progress awaiting picking. It was also possible to transfer components direct to any one of the four dispensing isolators. Direct transfer to dispensing isolators was much less frequent, as it depended on the correct components being available from the sanitising isolator load, at the time they were needed in the dispensing isolator.
Components required for dispensing were selected from the bank isolator and transferred again using sealed RTP canisters into one of the four dispensing isolators where the prescription was made up. The completed prescription and any waste generated were passed out of the dispensing isolator via a Rapid Transfer Port (RTP) pass out sleeve, which was attached to the side (end wall) of the isolator.
While the existing ‘bank’ process enabled Baxter to provide a compounding service, this way of working proved to be unreliable and any breaches or compromise of the aseptic environment created extremely long and expensive recovery times. This was because the sanitising isolator/gas generator combination exhibited long cycle times, which meant it took about one week to completely re-stock the ‘bank’ isolators.
The weaknesses of such a process flow are many-fold, but crucially for the healthcare provider and patient, it is difficult to respond to emergencies and sudden changes in requirements. The process was very inflexible.
Value added analysis
A ‘value added’ analysis of the process highlighted the disproportionate level of support activities required to dispense prescriptions. Support activities were time consuming, required high maintenance and control, consumed additional resource and ultimately provided little flexibility. The key to radically improving the existing process was to eliminate as many support and non-value adding activities as possible. Attention was paid primarily to reducing the operational effort deployed in running the sanitising and bank isolators.
By carrying out this analysis ATD was able to propose several integrated isolator concepts that would significantly reduce the number of support activities involved and at the same time provide a more efficient and flexible operation.
ATD had successfully developed a rapid transfer chamber system with Metall + Plastic GmbH (M+P) of Germany for the aseptic transfer of syringe tubs into an isolator using H2O2. This system, installed at Solvay Pharmaceuticals in 2001, had a decontamination cycle capable of achieving a 6-log spore reduction in only 12 mins. It was realised that if prescription components could be sanitised in such a chamber, in sufficient quantity, in a similar time, the sanitising and bank isolators could be eliminated. The concept that was presented to Baxter is shown in Figure 2.
A ‘value added’ analysis of the proposed rapid gassing process clearly demonstrated that a significant reduction in the number of support activities and associated equipment could be achieved. The rapid gassing concept was thus identified as the preferred option for the new equipment.
Prototype evaluation
While the advantages of the rapid gassing process were very attractive, the performance of such a system in terms of decontamination time for compounding components had not been proven. This was new technology to Baxter and in order to reduce business risk and build confidence in the feasibility of the system, ATD suggested the inclusion of two distinct phases in the user requirement specification (URS). Phase one involved the design, fabrication and development of a prototype Component Transfer Chamber (CTC) system (approx 0.5m3 internal vol.) that would be used to assess performance before moving to phase two. Phase two was the project proper including the supply of a number of compounding isolator systems.
Evaluation criteria for the prototype CTC were determined by collating details of the range of components and materials that would need to be accommodated by the chamber. The existing product mix delivered to customers was analysed in order to establish trends and similarities of workload. The mix and quantity of components required to make up 1-2hrs dispensing was determined in order to define the capacity of the racking system required to support the components and materials being transferred. This data was then used to define a number of different loads for the testing and validation of the prototype CTC and incorporated into the URS. The test loads would have to be surface decontaminated and the CTC aerated to less than 1ppm H2O2 in less than 15 mins. In order to prove this, the decontamination process would be challenged with Tyvek-wrapped biological indicators each loaded with greater than 6-logs of Geobacillus stearothermophilus.
The URS was distributed to several isolator manufacturers and two VHP Generator suppliers. After the initial tender phase, two suppliers were chosen to proceed with the manufacture of a prototype CTC system for evaluation. Following discussions with Baxter and ATD the chosen suppliers designed and fabricated the prototype chamber and provided all the necessary equipment to enable the suitability and effectiveness to be tested as well as the sanitisation cycle.
Evaluation criteria
In addition to satisfactory completion of the prototype testing, the choice of supplier progressing to phase two depended on a detailed assessment of the proposed equipment. Phase two required 4-glove dispensing isolators with the option to integrate or connect the chosen CTC. It was a requirement that the sanitisation cycle of the isolators would be complete in < 4 hours (including aeration to <1ppm). M+P was the only manufacturer to meet the evaluation criteria for phase one and was chosen as the preferred supplier. The final as built system is shown in figure 3.
Capital & operational costs
An important factor when considering capital costs is to also include an estimate of operating and maintenance costs over the anticipated lifetime of the equipment. The capacity of the M+P chamber meant it could accommodate up to 3hrs workload and thus minimise the actual number of transfers required. This was an important factor when considering liquid H2O2 consumption which over several years can provide a significant cost saving. There was no significant difference between the capital costs of the M+P equipment compared with the other equipment under evaluation. The adoption of the rapid gassing concept meant that capital costs were significantly lower than would have been the case using the ‘bank’ system.
Production requirements
The requirements for production considered not only the performance of the CTC in providing rapid gassing of components but also the various procedures involved in operating the chamber in an easy and safe manner that would provide a validatable, robust and reliable process.
The prototype chamber had enough capacity to supply two dispensing isolators and sufficient capacity for the dispensing of Total Parenteral Nutrition (TPN) components.
The requirement was for the chamber to achieve a minimum 6-log reduction of bio-burden of all surfaces within 20 mins. It was demonstrated that the 6-log cycle including aeration to less than 1ppm of H2O2 was achievable in less than 12 mins. The data gathered was consistent for nine different load configurations.
The dimensions of the prototype rack were 600mm (l) x 600mm (h) x 600mm(w) giving a load space capacity of 0.22 m3, 60% of the overall chamber capacity. The rack was made from stainless steel and built onto four bi-directional wheels, making it a free-standing structure and easily manoeuvrable back-and-forth and side-to-side. There were several operational advantages to this approach:
As the rack was free-standing, it could be loaded away from the isolators and dispensers in a loading area within the cleanroom or in a separate ‘prep’ room. Having the prepping and loading away from the isolators and other operators also reduced the health and safety risks to staff. Loading in the prep area also eliminates double handling of components making the process more efficient.
Other advantages are that the chamber and rack is not loaded through a door or opening which could restrict operator access and the loaded racks can simply be wheeled from the prep area straight to the relevant chamber.
Different racks can be designed to suit the product type and mix for each workstation. This allows maximisation of the capacity of the chamber for TPN, chemotherapy, etc. Also, the entire rack can be unloaded into the dispensing isolators after gassing making unloading easier. During times of high demand and peak activity where a series of rapid response doses are required, the rack can be pulled into one isolator freeing up the chamber immediately for loading with the next rack.
Removing the rack also makes the actual chamber more accessible for cleaning and maintenance. The racks themselves were easy to clean.
Operator Interface
It was a requirement to minimise operator input in operation of the equipment. The M+P system was controlled from a single operating panel at which all aspects of operation, including sanitisation, were initiated. It was specified that there should be no manual connections prior to gassing cycles. As the gas generator was fully integrated with the system, no manual connections were required and the number of manual checks and documentation in operation was thus reduced. Another important feature was the absence of the requirement to manually handle and weigh the liquid H2O2.
Cleaning
Full access to all areas of the chamber for cleaning was required without compromising the sterile status of the attached isolators. The component rack was not a permanent feature of the chamber and could be completely removed for cleaning of both. All doors could be interlocked and linked to the “sterile/non-sterile” status of the attached isolators. There were no occluded areas or “telescopic” components that might harbour a build-up of debris or toxic powders. Unlike a telescopic system, cleaning of the chamber and rack could take place whilst both attached isolator systems remained “sterile”.
In the event of generator breakdown it was a requirement that the system must have built in contingency. The prototype chamber was capable of providing unidirectional down flow at a flow rate of 0.45m/s. This enabled the chamber to be used as an ISO 5 pass-through hatch. The M+P equipment is also provided with a built in modem for remote diagnosis and fault clearing thus minimising downtime.
In the event of a compromise of the aseptic environment it was a requirement that the complete isolator system could be opened, cleaned and gas sanitised ready for production in less than 4 hrs. M+P provided evidence that isolators of a similar size could be sanitised in 2-3 hrs.
After careful consideration and detailed evaluations of the available systems, Baxter invested in three fully integrated Isolator Modules manufactured and installed by M+P initially. The modules were fully tested at a Factory Acceptance Test (FAT) in order to ensure that before the equipment left the factory there were no outstanding issues.To date it has invested in 10 of the modules. The importance of the FAT should not be under estimated. All aspects of the sanitisation cycles were tested to ensure that the performance of the module was equivalent to the performance of the evaluated prototype.
Equipment performance
The CTC achieves a 10-log reduction of G. stearothermophilus at all locations with a cycle time (including aeration to <1ppm) of <15 mins. The system guarantees a high level of sterility assurance for dispensed products with processing times that are significantly faster than those achieved by using traditional ‘spray and pray’ techniques. Variable load configurations have been tested and have no effect on cycle times or capability. This allows greater flexibility as the process is not restricted by fixed load configurations.
The attached dispensing isolators may be sanitised together or independently with a cycle time of < 1 hr (including aeration to <1ppm). This is a major process improvement and allows for rapid recovery in the event of a compromise of the aseptic environment.
This project was delivered on time and under budget and was a major success for Baxter Healthcare. Careful definition of customer requirements up front, allows the equipment to be designed to deliver the optimum process. The building and testing of prototypes and independent evaluation of the sanitisation capabilities of the equipment, before buying, allowed Baxter to make an informed equipment choice and drastically reduced the potential business risk of investing in a new technology. Rapid gassing technology developed by ATD in association with M+P has revolutionised the compounding pharmacy operation.
