The revision to EU GMP Annex 1, in August 2022, updated the requirement for Grade A environments used during sterile manufacturing. This was the change in acceptance criteria to ‘no growth’ (from the previous value of 1 CFU). This change not only paves the way for alternative microbiological methods it signalled the shift in regulatory thinking towards the detection of any contamination within the aseptic core being atypical and problematic.
One of the dilemmas faced by microbiologists, on the recovery of contamination at Grade A, is whether the contamination derived from the aseptic operation or from the activity of transfer in to or out of the aseptic environment. If adventitious contamination cannot be verified, the recovery could lead to a batch rejection.
A potential microbial contamination transfer risk exists with both RABS (restricted access barrier systems) and isolators, given the need to introduce materials from outside of the protective barrier. While isolators afford greater protection by virtue of providing a complete barrier and an environment that can be subjected to an automated decontamination cycle, the transfer issue still presents a concern.
This article looks at the problem of transferring materials to the aseptic core from lower controlled environments and describes a solution from Merck that significantly improves the environmental monitoring workflow through the use of the IsoBag® solution.
Contamination transfer risks
One of the primary routes by which contamination enters the aseptic core is through material transfer, either on items or from personnel interacting with the transferred materials. Sources of microbial contamination represent hazards, and the level of risk depends on the likelihood of contamination being transferred from the source to the critical area. Assessing such risks and designing them out of the process is a central part of the Contamination Control Strategy (CCS). The CCS is an important component of Annex 1 (1).
This requires hazard analysis and risk assessment, as represented by figure 1:
Figure 1: Hazard analysis and assessment
With figure 1, risk is lowered through controls. Examples of controls required to reduce the risks include (1, 2):
- Assessment of the vendor’s suitability to supply consumables.
- Elimination of items unsuitable for introduction into a cleanroom. Need for incoming consumables to be multi-wrapped (minimum of three layers in addition to outer packaging).
- Need for sporicidal disinfection when transferring between areas of different cleanliness levels (such as cleanrooms of different grades).
- The avoidance of items that generate fibres.
- Using airlocks and transfer hatches between cleanrooms of different grades.
- Having appropriate pressure differentials.
- Ensuring airlocks and transfer hatches areas are interlocked and that alarms must be in place. Controlling the time of transfer so that disinfected items are subjected to the required contact time.
- For transfer between Grade C and B, in ensuring that items are flushed with HEPA filtered air.
- Adopting ‘no touch’ solutions to transfer items into Grade A.
With each step, contamination can be transferred and any weakness leading to contamination being detected in the aseptic core may have arisen from the external packaging if decontamination steps were inadequate or if the execution of controls was performed inadequately. The CCS helps to drive consideration of the ‘bigger picture’.
Importantly the emphasis should always be on control. Achieving control is achieved by identifying hazards and then risk assessing these hazards for their severity (should they occur) and their likelihood of occurring. One aspect of control is with design improvement and the IsoBag® solution is an example of such an improvement.
IsoBag® solution
The IsoBag® solution enables bagged culture media and exposed plates to be successfully transferred into and out of an isolator, eliminating the opportunity for cross-contamination from personnel or from the environment. This transfer mechanism means that, post-incubation, any contamination detected is reflective of the Grade A environment.
Improving asepsis
Where plates are pre-loaded into an isolator ahead of decontamination, the process of packs of plates reaching the isolator requires a layer to be removed as the plates move from a preparation area to the surrounding isolator environment (typically EU GMP Grade C) and then into the isolator. This means that the plates presented to the isolator are only single wrapped. Whilst steps will be taken by personnel to minimise contamination transfer from the unwrapping process as plates transition through the facility this is a manual disinfection process. A reliance on manual disinfection will occasionally lead to contamination, given the intricacies of manual disinfection. Furthermore, no isolator decontamination process is 100% efficient, especially when endospore forming bacteria are transferred into the isolator and where there is the potential for occluded surfaces.
Reducing transfer risks
The design of the IsoBag® solution avoids contamination transfer through the use of an alpha-beta port system (where the alpha port is the port designed within the isolator and the beta port is the basis of the IsoBag®). The alpha-beta design is based on DPTE® technology.
DPTE® is a rapid transfer port technology, developed by Getinge, enabling a reliable and leak tight transfer. With the process, the alpha part and the beta part are connected by a manual 60° rotation which detaches the doors from their supports and then joins them together. Once these are secured, the doors can now be opened without breaking sterility or containment and items transferred.
Tightness is secured by the lip seals of the new assembly.
Enhancing sterility
IsoBag® are prepared prepacked with environmental monitoring plates. These plates, together with the complete bag assembly, are sterilised by radiation, which is a proven method of decontamination and effective against endospore forming bacteria.. The irradiation process is also demonstrated not to affect the growth promoting properties of the culture medium (with or without the addition of a disinfectant neutraliser).
Improving decontamination cycle robustness
Another advantage of the IsoBag® is that microbiological culture media, in the form of contact and settle plates, does not need to be placed inside the isolator to be decontaminated before use. When decontamination cycles are run, using methods like vapour hydrogen peroxide, the decontamination process is achieved through surface contact. The more items that are pre-loaded into the isolator then the greater the chance of insufficient surface contact occurring, or with surface occlusion arising, and hence inadequate decontamination.
The IsoBag® eliminates this step, thereby reducing the number of items that need to be placed inside the isolator in advance of decontamination and enabling culture media to be used as required.
Flexibility and space
The IsoBag® concept also increases the available space within the isolator and avoids it from becoming cluttered with too many plates. The IsoBag® enables only those plates that are required to be seamlessly transferred in. This creates more working space.
The concept also adds flexibility in that should more environmental monitoring media than was originally anticipated be needed, then additional plates can be rapidly transferred. The alpha-beta port system enables up to 10 connections and disconnections
in the process and keeping those plates available for use at any time. Unlike traditional methods, where single-bagged plates are decontaminated and stored in the isolator, limiting space and often interrupting workflow, with our IsoBag®, plates are mounted to the isolator’s port and used directly since they are already gamma-irradiated (ready-to-use). In addition to safety and efficiency, the process also frees up time and saves money.
Meeting data integrity expectations
The culture media transported via the IsoBag® is presented in a format that reduces cross-contamination through the plates having lockable lids, thereby ensuring that post-sampling contamination is unlikely. Data integrity is further enhanced through the use of 2D-datamatrix codes, which ensure sample traceability.
Summary
The activity of transferring materials in and out of the aseptic core requires planning and a highly-developed workflow. This is necessary to avoid introducing microorganisms into the critical area and for protecting samples from adventitious contamination after sampling. Failure to do so is problematic – either putting sterile products at risk or creating false negatives. The IsoBag® concept provides a mechanism to avoid these problems – both for transfer in and out of the isolator.
References
1. Sandle, T. (2023) Biocontamination Control for Pharmaceuticals and Healthcare, 2nd edition, Academic Press, London, UK
2. Strategy/Program: From Global Development to Site Implementation, American Pharmaceutical Review, at: https://www.americanpharmaceuticalreview.com/Featured-Articles/564173-Establishing-a-Contamination-Control-Strategy-Program-From-Global-Development-to-Site-Implementation/
Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)
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