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Environmental monitoring data can help keep sterile environments sterile.
Manufacture of medicines is most often required to be performed in a sterile environment to ensure the quality and safety of these products. Microorganisms lurking in the air or on surfaces may degrade APIs and impact their effectiveness, according to Anne-Grit Klees, PhD, BioMonitoring Portfolio Manager for The Life Science business of Merck KGaA, Darmstadt, Germany. “Furthermore, pathogenic and even many non-pathogenic microorganisms can cause serious and life-threatening infections in patients, especially if immunodeficient. For this reason, particularly injectable drugs must be sterile. This can be achieved by final sterilization of the drug or, if not possible, by aseptic manufacturing.”
It is recommended by regulators that microbial monitoring of cleanrooms and isolators is performed by a combination of methods, says Klees. “Air monitoring is performed with a combination of volumetric microbial air samplers (active air monitoring) and settle plates (continuous passive air monitoring). Surfaces and personnel should be monitored with contact plates or swabs. Using alternative methods is also permissible if these have been validated and show comparable or superior efficacies.”
Pharmaceutical Technology® spoke with Anne-Grit Klees to find out some environmental monitoring (EM) best practices manufacturers can follow to ensure the safety of their products.
PharmTech: What are the differences between environmental monitoring in aseptic versus non-aseptic manufacturing?
Anne-Grit Klees (The Life Science business of Merck KGaA, Darmstadt, Germany): The environmental monitoring methods are usually the same for both. The higher the cleanroom grade, the higher the monitoring frequency and number of sample locations. The monitoring equipment and culture media should possess features to match the cleanroom-grade requirements. For air samplers, features such as cleanability, resistance towards disinfectants, emission of particles, and disturbance of the unidirectional air flow are important to consider and should match the cleanroom concept. For culture media, there is a choice between single bagged ones for lower risk areas and irradiated, double, or triple bagged ones for the different manufacturing lines.
PharmTech: What are some best practices for air monitoring?
Anne-Grit Klees (The Life Science business of Merck KGaA, Darmstadt, Germany): When selecting an air sampler, important features to consider are sampling volume accuracy, a good efficiency of the method to collect small particles, and whether damage to microorganisms is avoided during the sampling process. The recovery efficiency should be validated by the supplier according to ISO [International Organization for Standardization] 14698. What also matters is ease-of-use to minimize the risk of human errors, low particle emissions to prevent contamination of the cleanroom, good cleanability, and minimal disturbances of the unidirectional air flow. If the air sampler can be integrated into external tracking software systems, all data can be handled. This helps to observe trends.
PharmTech: What are some best practices for surface monitoring?
Anne-Grit Klees (The Life Science business of Merck KGaA, Darmstadt, Germany): Surface monitoring is usually performed either with contact plates or swabs, depending on the accessibility of the sample location. Culture medium selection should be based on the ability over the complete shelf-life to detect a broad range of microorganisms. Furthermore, the media formulation should ensure that any potential growth-inhibiting substances such as disinfectant residues or antibiotics are inactivated. To maintain the cleanliness of the sampled surface any culture media residues should be removed after sampling.
PharmTech: What are some best practices for personnel monitoring?
Anne-Grit Klees (The Life Science business of Merck KGaA, Darmstadt, Germany): Personnel monitoring is always performed on the gloves, but also on gowning. The growth promotion properties of the selected media must [often] allow in-house skin flora of the personnel to grow. It is important that contact plate samples are taken of the personnel’s gowning or gloves before leaving the cleanroom. If glove tests are performed after critical interventions, the outer gloves should be replaced before continuing manual work.
PharmTech: What are the latest advancements in processes and workflows for environmental monitoring?
Anne-Grit Klees (The Life Science business of Merck KGaA, Darmstadt, Germany): These are stated in the current 2022 version of the EU [European Union] CGMP [current good manufacturing practice] Annex 1. While the well-established volumetric air samplers, settle plates, contact plates, and swabs are still recommended to be used frequently, a new focus is on the importance of a contamination control strategy of the pharmaceutical company. This should include a risk-based sample plan that states the frequency and sample locations for those methods. There are additions about using validated rapid or automated technologies, also for continuous volumetric air sampling. These need to be equal to or superior to the above-described methods.
PharmTech: What are some of the best tools for performing environmental monitoring of cleanrooms?
Anne-Grit Klees (The Life Science business of Merck KGaA, Darmstadt, Germany): Some portable microbial air samplers (e.g., the MAS-100 NT) offer high accuracy and excellent sampling efficiency. It is small enough to sample close to critical sample locations, can take up to 30 samples in one cleanroom, is easy to disinfect and available with an exhaust filter. It minimizes disturbance of the unidirectional air flow and is compatible with several EM software systems. Triple-bagged and gamma-irradiated ICR or ICR+ culture media for grade A and B cleanrooms reduce the contamination risk because outer bags can be removed in the material lock. Plate versions with locks allow safe transportation for incubation after sampling.
PharmTech: What are some of the best tools for performing environmental monitoring of a restricted-access barrier system (RABS)?
Anne-Grit Klees (The Life Science business of Merck KGaA, Darmstadt, Germany): In a RABS the same environmental monitoring tools can be used as in a cleanroom. However, if a RABS system is decontaminated with vaporized hydrogen peroxide (VHP), it must be ensured that the culture media within the RABS during decontamination are protected by VHP-impermeable bags. These can be hung up during decontamination. To prevent false negative results, all ICR settle plates, contact plates and ICR swabs are formulated to neutralize VHP residues. The MAS-100 NT can also withstand VHP decontamination if in switched-off mode. Alternatively, MAS-100 air samplers specially designed for isolators can be used.
PharmTech: What are some of the best tools for performing environmental monitoring of isolators?
Anne-Grit Klees (The Life Science business of Merck KGaA, Darmstadt, Germany): In isolators, space is limited, so the control unit of the dedicated air samplers (e.g., MAS-100 Iso line) for isolators are positioned on the outside, saving space inside. The distance can be up to 10 m. A double-valve system prevents cross-contamination and the air tubing can be decontaminated with VHP (e.g., with the MAS-100 Iso MH, one control unit can handle up to four sampling locations.)
Certain packaging designs (e.g., IsoBag rapid transfer bags) save space in isolators. They readily provide ICR settle or contact plates in a DPTE [differential pressure transmitter for air] beta bag. Plates can be safely transferred via rapid transfer alpha ports whenever needed.
PharmTech: How are data obtained from environmental monitoring? How are these data used in pharma manufacturing?
Anne-Grit Klees (The Life Science business of Merck KGaA, Darmstadt, Germany): The data are usually obtained as colony forming units from the culture media used in active and passive air sampling as well as surface and personnel sampling. The new EU GMP Annex 1 suggests using the data both for batch release decisions and for trending analyses. It is possible to detect adverse trends by increasing excursions from action limits or consecutive excursions from alert levels. Also, noticing changes in the microbial flora is important. This helps to maintain the level of cleanliness and address issues by corrective and preventive actions.
PharmTech: Are there specific analytical tools that work best for different types of environmental
Anne-Grit Klees (The Life Science business of Merck KGaA, Darmstadt, Germany): As the amount of data generated by environmental monitoring is huge, the PDA [Parenteral Drug Association] Technical Report No. 13 outlines computer-based tracking tools as essential. Specific software systems designed for environmental monitoring help to find adverse trends, and the stored data may allow conclusions as to what the root cause is. One important feature of the sampling equipment is that it should allow data transfer into such software systems, so that all tracked data are handled in a single database. This helps to stay compliant with the standard rules for data integrity.