According to the new Annex 1, material pass-boxes must be designed to ensure physical separation and minimise microbial and particle contamination in different areas.
Annex 1: “4.10 The transfer of equipment and materials into and out of the cleanrooms and critical zones is one of the greatest potential sources of contamination. Any activities with the potential to compromise the cleanliness of cleanrooms or the critical zone should be assessed and if they cannot be eliminated, appropriate controls should be implemented.”
The key factor: systems integration
In AM's recent interview with Tim Sandle, microbiologist, science journalist and author, we focused on what is new in the new Annex 1 compared to previous versions:
“In the new Annex, microbiological contamination from materials entering the cleanroom is provided with a far greater emphasis. This has been identified as one of the major routes of contamination for items coming into the facility. The optimal means of transfer is via a double-ended autoclave and using moist heat. Where this is not possible, or where single-use sterile items are required, then a disinfection process is required. This can be automated (as with a decontamination chamber using hydrogen peroxide or chlorine dioxide) or a manual process using a transfer hatch equipped with a localised HEPA filter air supply.”
“The Annex 1 places emphasis upon both cleaning and disinfection. Most disinfectants are very poor at penetrating ‘soil’, and therefore items need to be cleaned prior to the application of a disinfectant.”
It is normal to carry out at least three simulations of worst-case load transfers
“The Annex 1 also indicates that the disinfectant should be ideally sporicidal and that a sporicidal is required for the transfer of materials from Grade C to Grade B. It is also important that items being transferred in are multi-wrapped and that a layer of wrapping can be removed at each stage of the transfer process as the item moves from the external area and through the cleanroom cascade.”
To carry out this task correctly, a quality risk assessment is required.
The risk assessment will need to address the following:
The packaging: Are there sufficient layers? Is the packing resistant to the disinfectant?
Detergent: Is the detergent suitable for cleaning? Is the detergent compatible with the disinfectant?
Disinfectants: Is the disinfectant sporicidal? Has the disinfectant been validated? Is there a risk of residuals?
Environmental monitoring: Has the transfer disinfection process been qualified? (It is normal to carry out at least three simulations of worst-case load transfers and conduct surface environmental monitoring). In addition, at what frequency will this be verified? Here any manual process is subject to variations in the technique, and there needs to be regular assessment in place. Furthermore, ongoing monitoring of the bioburden associated with incoming items should be undertaken and understood in terms of microbial numbers and species variation.
Non-routine items: How will atypical or non-routine items be handled? What is this risk assessment process in place for these?
Procedure: It is important that the entire process is documented and that the procedures are used to facilitate personnel training.
Annex 1: 4.11 The transfer of materials, equipment, and components into an aseptic processing area should be carried out via a unidirectional process. Where possible, items should be sterilised and passed into the area through double-ended sterilisers (e.g., through a double-door autoclave or depyrogenation oven/tunnel) sealed into the wall. Where sterilisation upon transfer of the items is not possible, a procedure that achieves the same objective of not introducing contaminant should be validated and implemented, (e.g., using an effective transfer disinfection, rapid transfer systems for isolators or, for gaseous or liquid materials, a bacteria-retentive filter).
With the disinfection step, the disinfection process must be carefully controlled because there is a high risk of contamination. Maintaining a wet contact time is critical for effective disinfection. If the validated time is not achieved, contamination may persist on the surface of the items.
The transfer into and out of the cleanrooms is one of the greatest potential sources of contamination
The optimal approach is to automate the decontamination process. This can be put in place using a biodecontamination chamber for multi-wrapped items. These items must have been sterilised using a proven technology (all items entering Grade A must be sterile). Typically, items are sterilised by radiation (such as gamma, X-rays or electron beam) or sometimes by a penetrative gas (such as ethylene oxide).
The most common technology for this is hydrogen peroxide, although there are alternatives. The advantage is that, through development, the process can be qualified and demonstrated to be consistent. In addition, the level of microbial inactivation is far greater than can be achieved with a manual process. To demonstrate this, biological indicators can be used. It is important that the biological indicators selected have proven resistance to the decontamination agent and are of a suitable population to demonstrate a 6-log reduction.
To carry out this task correctly, a quality risk assessment is required
With cycle development, controlling key parameters like temperature, humidity, the concentration of the biocide, and the contact time are essential. Attention should be paid to load configuration; for this, all items should be hung so that the decontamination agent can circulate around each item.
Items should also be multi-wrapped, enabling a layer of wrapping to be removed for the eventual transfer into Grade A.
Case study of MyBox: the integrated system for material transfer
AMTech by AM Instruments recently implemented a pass-through for a customer who needed the transfer stage upgraded to the new Annex 1 requirements.
Currently, critical materials such as sterile powders within the Grade B of an aseptic production department are introduced through a dynamic pass-box in which an operator externally decontaminates the materials by spraying a biocide and then wiping with a low-release wipe.
While this procedure has always provided an adequate level of decontamination, it can no longer be considered appropriate when compared to the risk of introducing microbial contamination into a sterile department.
Another critical issue, no less important, lies in the different conformation of loads that contemplate not only standard loads.
The demand for automation of this process, releasing it from the manual dexterity of the operator to make the procedure "validatable" and "repeatable," led to a feasibility study for the installation of a biodecontaminant pass-box with an integrated ionised hydrogen peroxide system-HPE technology.
Specifically, the AMTech department of AM Instruments focused its efforts on the following:
Design of an L-shaped pass-box to allow a large loading area
Integration of HPE technology for biodecontamination
Machine construction and testing
Disassembly at AM Instruments
Assembly at the customer’s premise
In fact, the current design of the premises and the restricted manoeuvring space in the material loading/unloading area necessitated an in-depth engineering study that presents innovative solutions to create a stand-alone pass-box that can easily replace the existing one without having to change the premises' volumes substantially.
The final solution has the following features:
- Dynamic pass-box with integrated biodecontamination with HPE technology
- Repeatability of operations with standardised sterilisation cycles for defined item groups
- Repeatability of operations for non-standardised sterilisation cycles for specific materials
- Ability to save and manage several different sterilisation recipes
- Traceability and data integrity (compliance with CFR 21 Part 11 and Annex 11)
- Proper backup and restore process
- Access control through named user IDs
- Readable electronic records
- Identification of altered and invalid records
- Complete audit trail file and report
- Unalterable time reference
As reiterated earlier, a final essential step is, cycle validation with a thorough study of loads and their standardisation, not to mention the testing phase of sterilisation cycles for all required load types.
Another important step is the transfer of materials between two Grade A areas, passing through a Grade B area.
AMTech by AM Instruments designed Cart2Count that allows this transfer without the need to connect to the mains electrical supply and with continuous, on-board particle monitoring.
With Cart2Count, AMTech by AM Instruments has made full use of its experience in building laminar flow systems as well as monitoring systems.
Another critical issue, no less important, lies in the different conformation of loads that contemplate not only standard loads
The LAF trolley has been developed to allow the completely safe handling and transfer of materials between Grade A areas, passing through a Grade B area, without the need for an electrical supply (battery life of up to one hour).
The LAF trolley is commonly used to transfer partially stoppered vials from the filling line to the freeze-dryers, and then from the freeze-dryers to the vial-capping machines.
Air is drawn from the environment through pre-filters located at the sides, filtered by the HEPA filter, forced horizontally into the working area, and recirculated through a dedicated plenum opposite the filter. The recirculation avoids turbulence in the grade B zone.
One of the most common deviations in aseptic processes is the absence of continuous monitoring during material transfer.
An example of deviation found during an inspection is: “No continuous monitoring of particles is carried out throughout the critical process for A class areas. Transportation of not finally stoppered vials with products through B class area is carried out in portable untight carts with horizontal class A LAF, no continuous particle monitoring is carried out in the carts. The particles are checked only before transportation beginning and after product unloading.”
During the design phase, the most critical aspects were examined
During the design phase, the most critical aspects were examined, for which highly satisfactory solutions were reached: minimising stagnation and turbulence zones in the area where the trays are loaded using sealed doors and a recirculating airflow system; carrying out a risk assessment to install the isokinetic probe at the most relevant point; making data transmission “secure” and “compliant” by installing dedicated access points; making changes to the Wi-Fi system to ensure a constant connection that allows for continuity of data monitoring and integrity. In the event of a server connection error, the PLC on the trolley guarantees data storage. Once the connection is re-established, the system automatically downloads the data to the server. In the event of a failure to communicate with SCADA or full memory (during local storage), a special alarm triggers. The trolley features a control panel for self-diagnostics, displaying the battery status and checking the status of sampling and the particle counter. The trolley was designed and built, and all the verification tests necessary for its release were carried out within the short time frame imposed by the inspection request.
Depending on the needs of the client, Cart2Count can be fitted with a continuous particle monitoring system depending on the client’s needs.
With Lighthouse APEX R5P - Ethernet with built-in pump, particles are counted through a classic Light Scattering system, and the light source for the counting is a laser diode with a threshold of 0.5 microns for the first channel and 5.0 microns for the second in the standard model.
- Compatible with Hydrogen Peroxide (H2O2) vapour up to 1000 ppm concentrations. The appliance features buffer storage capable of holding up to 3,000 samples if communication with the data acquisition system is interrupted.
- 0.5 - 5.0 μm standard
- Flow rate: 1.0 CFM (28.3 LPM)
- Data storage: 3,000 records
- H2O2 vapour decontamination compatible
- Self-diagnostics for laser, flow and detector
- NIST traceable meets ISO 21501 - 4 and JJF 1190
- View real-time data from your Mac, PC, tablet or smartphone
- Communication modes: RS-485, Ethernet, POE, Modbus TCP, ASCII, RTU
- Smart-port for configuration, remote display and environmental sensors