The manufacture of pharmaceutical and biotechnology products requires that the appropriate level of quality be designed and constructed into the facility and systems that support the production process. Given that the FDA’s compliance focus, as a result of 483 observations and warning letters, is on “inadequate facility design” and “environmental and personnel monitoring,” one can only conclude that the skill level, training, and attitude of the personnel involved were inadequate in the cases cited with respect to the obvious requirement to minimize particulate, microbial, and pyrogen contamination.
How do these situations develop? While from time to time the EU may provide some specific recommendations to meet cGMPs, the FDA normally does not dictate how a specific outcome is to be achieved. In most of these situations, the aseptic fill application was treated as if it were simply a Class 100 particle count requirement without regard for the critically important airflow patterns required to ensure that exposed products and components are protected from contamination. Aseptic processing operations must be performed within separate, defined areas to prevent microbial and/or cross-contamination.
Non-viable particulate and viable microbiological surveillance is used to evaluate the design and control of the cGMP-manufacturing environment. The non-viable particulate monitoring program is used to verify the maintenance of air classifications called for in the facility design. Particulate monitoring should be performed on a routine basis using statistical sampling procedures that are appropriate for the individual room, equipment, and process.
In general, a comprehensive environmental monitoring program should include scheduled monitoring of airborne viable and non-viable particulates, pressure differentials, direction of air flow, temperature, humidity, and surface microbial contaminants on personnel and equipment, work tables, floors, and walls. Some firms are beginning to monitor chemical contamination [airborne molecular contamination, e.g., SOx, NOx, ozone, VOCs (volatile organic compounds), and site-specific contaminants, such as chlorine, organophosphates, or ammonia] as well, when and where such a concern exists.
A properly designed, controlled, and maintained HVAC system, as well as an appropriate facility monitoring system, is crucial for demonstrating and maintaining control. Facility monitoring systems must rapidly detect and record changes that might lead to a compromised environment and alert personnel of such changes immediately.
Airborne non-viables should be monitored and controlled in all critical and controlled environments. The monitoring of viables should be frequent and, in aseptic areas, the personnel should be routinely monitored as well. Typical microbial flora should be identified and records should be put into a historical database for trend analysis. Alert and action levels are developed based on these trends and product protection requirements. Definitive procedures for investigating contamination events must be developed.
Allowable airborne viable counts vary with air classification as well as with individual regulatory agencies. An environmental monitoring program should include routine testing of critical process support services, including clean dry compressed air, gases, and process water (RO/DI, USP water, and WFI).
Air and surfaces in critical areas should be monitored for particulate quality daily during all production shifts, as shedding by personnel is typically the primary source of contamination and there is generally no good correlation that can be made between airborne particulates and microorganisms.
A risk-adjusted approach to the design of environmental monitoring will often lead to more frequent sampling than the minimum recommendations. For example, many firms practice continuous particle monitoring in ISO 5 areas and USP <1116> recommends particulate monitoring each shift in ISO 7 areas and twice per week in ISO 8 areas. When observing an operation, the FDA assesses whether the design creates potential contamination routes.
Additionally, some authorities may also require monitoring of other parameters in conjunction with viables and non-viables; for example, the EU requires continuous monitoring of pressure differentials under operational, dynamic conditions in Grade “A” areas.