Using isolators for aseptic processing is fast becoming standard practice in the pharmaceutical industry. However, it is a well-known fact that the transfer of equipment and materials into and out of RABS and isolators is one of the greatest sources of contamination. This is why new regulations is being put into place to mitigate the risk. Anne Weeks and Kristian Siedler, two experts in environmental monitoring, discuss how manufacturers can reconcile contamination safety and processing efficiency.
How does the recently revised EU GMP Annex 1 approach the contamination challenge of transfers?
Kristian Siedler: Manufacturers have to implement a holistic contamination control strategy that helps them to understand their process. It has to cover the entire manufacturing chain in the facility and be based on a risk assessment. This includes preparing documentation that describes the contamination risk management strategy and how the demanded continuous improvements and investment plans to prevent contamination will be managed. Specifically, the risks of any activities that might compromise cleanliness must be assessed, and this includes the transfer of materials and equipment into and out of isolators.
Anne Weeks: Ideally, transfers into an isolator should be carried out in a one-way process and sterilization performed using a double-ended autoclave. Where this is not possible, a procedure that achieves the same objective of avoiding contamination must be validated and implemented. All airlocks should ensure physical separation and minimize microbial and particle contamination between areas. The final stage of an airlock must when at rest, be of the same cleanliness grade as the area to which it gives access. However, after decontamination and during processing, transfers of materials into isolators should be minimized and preferably supported by rapid transfer technologies or transfer isolators.
How can you reduce the transfer of materials when there is precious little storage space in your isolator?
Anne Weeks: It is possible to mount a transfer bag containing packs of contact or settle plates to the 190 mm alpha port of your isolator. There is no need to decontaminate the packs of plates, so the number of necessary decontamination cycles and the volume needed for surface contact is reduced. This enables longer periods of uninterrupted production and frees up valuable space, which is particularly useful for manufacturing campaigns lasting several days. These bags retain their integrity for multiple connections to the alpha port, so are highly flexible. Our gamma-irradiated IsoBag® DPTE rapid transfer bags can each hold up to 80 ready-to-use ICR settle or 100 contact plates for air and surface monitoring.
Kristian Siedler: It is also possible to use dedicated active air samplers like the MAS-100 Iso line of instruments where the control unit is positioned outside the isolator, with only the sampling heads needing to be inside. Integrated systems such as our MAS-100 Iso MH® sampler have multiple heads and can pull the gaseous VHP through the heads during a decontamination cycle, so there is no need to remove the heads for autoclaving. A single control unit can handle up to four sampling locations, and there are also various interfaces to allow direct control of the system via an isolator panel. If, instead, a portable sampler is used and moved from a lower-grade area to an isolator, it is important to address the risk of carrying over contaminants that remain within the instrument. An integrated exhaust HEPA filter can protect the processing environment against this risk.
Is the contamination risk of transfers reflected in the locations to be monitored?
Anne Weeks: Yes, this is usually the case. The monitoring areas result from the risk assessment that must be performed. For air monitoring, these locations are typically the entry and exit points of materials as well as the position where the product is filled and thus exposed to the environment. The surfaces to monitor are usually the gloves and other areas for which an elevated contamination risk has been established. This must take into account the operator’s ability to physically reach the surface to be sampled without contaminating the area.
Kristian Siedler: For difficult-to-access sampling locations such as equipment recesses and nooks, but also tubing and filling needles, swabs that generate a clear yes/no result have proved the ideal tool. To minimize false positives, they should be designed to avoid unnecessary handling steps before and after sampling. Our ICR swab carries its own sterile growth medium and therefore has to be opened only once. Only after it has been closed again does its medium come into contact with the pre-moistened swab tip. ICR swabs are triple-bagged to enable safe transfer into isolators.
What about taking materials out of the isolator?
Anne Weeks: The removal of materials, for example, environmental samples or waste, should be carried out in a unidirectional process that is separate from the entry route. If not possible, time-based separation of incoming and outgoing materials can be an option, along with controls applied to avoid isolator contamination. What sometimes gets too little consideration is the safe handling and removal of the culture media after sampling. Lockable plates as well as the sterile transfer bags included in our IsoBag® can help avoid external contamination and false-positive test results.
Find out how the IsoBag® rapid transfer bags containing packs of ICR/ICRplus contact and settle plates support safe and efficient aseptic processing in isolators. www.sigmaaldrich.com/isobags
Author Details
Anne Weeks, Commercial Applications Specialist BioMonitoring, MilliporeSigma; Burlington; MA; USA - An affiliate of Merck, KGaA Darmstadt, Germany;
Kristian Siedler, Global Product Manager, Commercial Excellence BioMonitoring- Merck KGaA, Darmstadt, Germany.
Publication Details
This article appeared in American Pharmaceutical Review:Vol. 27, No. 2March 2024Pages: 34-35
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