Holistic, risk-based microbiological contamination control programs are being implemented throughout the industry as a means of increasing patient safety and improving the levels of overall process control and product quality. These multi-faceted programs integrate individual contamination control components such as cleaning and disinfection, environmental monitoring, gowning, facility design and maintenance etc. into a single comprehensive program that is tailored to the specific processes and products being manufactured. They also represent a change in the thought processes regarding how best to achieve and maintain an effective contamination control strategy. This paradigm shift in thought processes directly impacts microbiologists responsible for overseeing the efficacy of the facility’s contamination control program.
A contamination control program is like a puzzle. Each individual component, such as those mentioned above, represents a single piece of the puzzle. These pieces must fit together to form a whole in order to achieve the desired result. Strengths of one component can compensate for the shortcomings of another, and so the microbiologist must have a clear and in-depth understanding of each component in order to ensure that there are no missing pieces or gaps in the puzzle. However, once this understanding is acquired, a well-designed contamination control program can be a powerful tool in ensuring a robust and continuous state of microbiological control within the facility.
It all starts with an in-depth understanding of the manufacturing process itself as well as the processing environment.
The microbiologist must have a complete and thorough understanding of the process and the environment in which it is conducted in order to identify steps or locations where contamination is more likely to occur. Examples include:
- open processing steps or steps where transfers or aseptic connections are made
- points where operator intervention is required
- complex, multi-step processes
- processes occurring in older facilities where control strategies may be more limited due to facility design (e.g., a Grade A biological safety cabinet (BSC) or Laminar Flow Hood (LFH) with a Grade C background environment.)
- new processes, or recent processing changes
The microbiologist must also have a clear understanding of the risks associated with the process and be able to accurately assess the potential impacts of those risks on product quality and patient safety, and to identify and drive changes as necessary to mitigate the risks. The level of acceptable risk will vary with the type of process and/or product, the indication, and the target population.
For example, consider an advanced therapy medicinal product (ATMP) such as an autologous cell-therapy. At times, patient-specific needs demand that the product is manufactured, tested and administered to the patient within seven days or less. Typically, environmental monitoring results are not complete until after seven days of incubation have elapsed and therefore proper identification of recovered microorganisms are not available prior to product release. Similarly, depending on the method used (i.e., traditional vs. rapid), sterility testing results are usually not available for seven to fourteen days. Mycoplasma testing takes up to twenty-eight days before assay results are available. If any deviations occur during processing, they must be triaged and the risk to the patient determined before the investigation is fully completed.
With manufacturing timelines such as these, proactive measures to prevent the ingress of microorganisms are paramount. A truly superior, robust, effective and risk-based contamination control strategy is absolutely critical to ensuring patient safety and product quality. While a robust and effective contamination control program is also essential for more traditional production scenarios, most of these products can be held until all results and deviation investigations are completed and closed before they are dispensed to the patient.
The product indication can also influence how risk levels must be assessed. Does the product save or prolong life? Is it palliative in nature? Are there treatment alternatives or other options for the patients? Is the patient immunosuppressed or compromised based on their existing condition? Is the risk outweighed by patient need? There are often serious ethical issues that must be considered when making these risk assessments.
Microbiologists must spend more time observing operations on the manufacturing floor.
It is critical for the microbiologist to not only understand the process design and intended operations, but to personally experience how all of the process steps and interventions are conducted in real-time and how well each component of the contamination control program performs in conjunction. There are many minute operations or smaller-scale procedures that can have a major impact on the microbiological risk to the integrity of the process and product quality that cannot be sufficiently addressed in a classroom setting or written procedures. Visually observing how operations are actually performed can often be equally or more important than a written description of what is to be conducted. It is the “little things” that are often the most critical.
For example, how a manufacturing operator physically disinfects material(s) for subsequent entry into a clean room or BSC is critical to the efficacy of that decontamination step. Is enough agent being applied? Is the operator coating all surfaces adequately? Is the required wet contact time being maintained?
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A microbiologist possesses the technical knowledge and practical experience to fully and accurately assess the efficacy of the activity in a manner someone without this microbiological experience or background will not. Observations made when on the manufacturing floor are very important to continuous improvement of the contamination control program. They allow the microbiologist to suggest and drive improvements to each of the program components, thus making the larger, holistic program more robust and effective. In the previous example, if the cleaning and disinfection of items to be transferred into the cleanroom or BSC is found to be deficient in any way, the microbiologist can remediate the deficiency through improvements and/or clarifications in training and standard operating procedures, etc. and thusly increase the overall efficacy of the cleaning and disinfection component. In this way the microbiologist can assess and improve the other components of the contamination control program, including gowning practices, application of aseptic techniques, cleanroom behaviors, impact of operator interventions, etc.
An in-depth working knowledge is critical to ensuring successful root cause analyses and practical, effective corrective and preventative action (CAPA).
Microbiological deviations and/or investigations, particularly those related to environmental monitoring excursions, are notoriously difficult to conduct. The abnormalities are discovered several days, even up to a week, after the causal event has occurred. Frequently, the microorganisms identified are typical human skin flora, or common environmental organisms that can be easily transferred by operators to manufacturing materials or vice-versa. As a result, there is usually a myriad of possible root causes for the event and the resulting investigation often contains a fair amount of speculation as to how the contaminating organism might have entered the processing train or surrounding environment. However, if the microbiologist possesses the in-depth knowledge of how the process is actually conducted and where potential contamination risks exist or may be elevated (e.g., steps that require a greater degree of human intervention, especially those that are more intricate or difficult to perform or the presence of a brand new, inexperienced operator, etc.), not only will the correct investigative path become more clear, but the ascertained root cause will be better supported with data and science-based rationale. This is simply because the microbiologist will know exactly where to focus the investigation and “point the compass” in the appropriate direction.
In-depth knowledge of the process, the contamination control program and how they integrate in real-time is essential for successful trending data analysis.
A solid, well-designed and useful trending program is an invaluable tool for the microbiologist. Such a trending program includes robust and thoughtful data analysis. However, to develop such a trending program, one first needs to know what specific information is required. A thorough understanding of the interaction between the process and the contamination control program is essential for proper data analysis.
Have excursions in microbial counts been increasing in a given area? Has there been an increase in recoveries of a particular organism type, such as a spore-former? Are new microorganisms/floras being recovered? If so, was the applied CAPA effective? Is the same pattern occurring in areas of similar activity or room classification? Has anything changed?
A well-designed trending program that includes critical data analysis not only aids the microbiologist in identifying issues. It can also help to indicate why a problem is occurring through the elucidation of patterns throughout the facility. This in turn allows for the application of meaningful and effective CAPA that will actually resolve the underlying issue as opposed to simply addressing individual incidents or “firefighting” (e.g.; simply addressing repeated increases in microbial excursions with repeated sanitizations).
Most importantly, appropriate trending data analysis will provide the microbiologist with the data and science-based rationale required to make and support any risk-based cGMP decisions. For example, trending data analysis can be used to determine the appropriate type and level of contamination controls required for higher-risk processing steps, and then how to monitor and modify those controls to achieve maximum efficacy.
It is critical that this knowledge be shared throughout the entire microbiology team, and not be possessed by a single individual.
Some firms are addressing this issue by hiring microbiologists who spend all of their time on the manufacturing floor. They are responsible for monitoring the manufacturing process and environmental conditions for potential contamination risks on a daily basis. These individuals can utilize their microbiological expertise to identify and provide suggestions for CAPA or mitigations in real time, which can result in important improvements in overall process control and microbiological integrity as previously discussed.
However, it is important that all members of the Microbiology team gain this knowledge and experience, and not just a single individual. It is extremely helpful to analysts dealing with any type of microbiological issue. Examples include, but are not limited to, investigating EM excursions, troubleshooting erroneous lab assays, and developing qualification or validation protocols. An analyst lacking this deeper knowledge is likely to overlook details or fail to ask the right questions. Consider an analyst tasked with selecting a rapid microbiological method (RMM) for implementation in the laboratory. Understanding the full detail of the process and how the product is made, including any intermediates that will need to be tested is critical in ensuring the proper alternative method is selected. For example, if a material that is intended to be tested contains a high concentration of cells, an assay that utilizes membrane filtration for sample processing may not be the best option. Will the samples likely require little neutralization or rinsing, or a lot of neutralization or rinsing? What are the microorganisms of greatest concern with regard to the process train? Can these be recovered or detected? Is this test result required before processing can resume? The same applies to the selection of appropriate facility sanitization agents and application frequencies, gowning materials and levels of required gowning, personnel and material flow patterns etc.
Conclusion
Part of ensuring patient safety and end-to-end process and product quality requires the implementation of robust, risk-based, comprehensive facility contamination control programs. In order to design, implement and support these programs, microbiologists throughout the industry must broaden and deepen their base of knowledge and experience. To accomplish this, microbiologists must expand the scope of their workplace outside of the laboratory environment and onto the manufacturing floor. Gaining a practical, in-depth working knowledge of the manufacturing process as it is conducted in real time and how it interacts with all of the components of contamination control program is critical to understanding where vulnerabilities to microbial contamination actually exist. It is the first step to ensuring sound, risk-based cGMP decision-making, continuous process improvement and an efficient, effective facility contamination control program in a continually changing industry landscape.