Environmental Monitoring of Particle Counts is Easy

The manufacture of pharmaceutical and biotechnology productsrequires that the appropriate level of quality be designed andconstructed into the facility and systems that support theproduction process. Given that the FDA’s compliance focus, as aresult of 483 observations and warning letters, is on “inadequatefacility design” and “environmental and personnel monitoring,” onecan only conclude that the skill level, training, and attitude ofthe personnel involved were inadequate in the cases cited withrespect to the obvious requirement to minimize particulate,microbial, and pyrogen contamination.

How do these situations develop? While from time to time the EUmay provide some specific recommendations to meet cGMPs, the FDAnormally does not dictate how a specific outcome is to be achieved.In most of these situations, the aseptic fill application wastreated as if it were simply a Class 100 particle count requirementwithout regard for the critically important airflow patternsrequired to ensure that exposed products and components areprotected from contamination. Aseptic processing operations must beperformed within separate, defined areas to prevent microbialand/or cross-contamination.

Non-viable particulate and viable microbiological surveillanceis used to evaluate the design and control of thecGMP-manufacturing environment. The non-viable particulatemonitoring program is used to verify the maintenance of airclassifications called for in the facility design. Particulatemonitoring should be performed on a routine basis using statisticalsampling procedures that are appropriate for the individual room,equipment, and process.

In general, a comprehensive environmental monitoring programshould include scheduled monitoring of airborne viable andnon-viable particulates, pressure differentials, direction of airflow, temperature, humidity, and surface microbial contaminants onpersonnel and equipment, work tables, floors, and walls. Some firmsare beginning to monitor chemical contamination [airborne molecularcontamination, e.g., SOx, NOx, ozone, VOCs (volatile organiccompounds), and site-specific contaminants, such as chlorine,organophosphates, or ammonia] as well, when and where such aconcern exists.

A properly designed, controlled, and maintained HVAC system, aswell as an appropriate facility monitoring system, is crucial fordemonstrating and maintaining control. Facility monitoring systemsmust rapidly detect and record changes that might lead to acompromised environment and alert personnel of such changesimmediately.

Airborne non-viables should be monitored and controlled in allcritical and controlled environments. The monitoring of viablesshould be frequent and, in aseptic areas, the personnel should beroutinely monitored as well. Typical microbial flora should beidentified and records should be put into a historical database fortrend analysis. Alert and action levels are developed based onthese trends and product protection requirements. Definitiveprocedures for investigating contamination events must bedeveloped.

Allowable airborne viable counts vary with air classification aswell as with individual regulatory agencies. An environmentalmonitoring program should include routine testing of criticalprocess 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 forparticulate quality daily during all production shifts, as sheddingby personnel is typically the primary source of contamination andthere is generally no good correlation that can be made betweenairborne particulates and microorganisms.

A risk-adjusted approach to the design of environmentalmonitoring will often lead to more frequent sampling than theminimum recommendations. For example, many firms practicecontinuous particle monitoring in ISO 5 areas and USP <1116>recommends particulate monitoring each shift in ISO 7 areas andtwice per week in ISO 8 areas. When observing an operation, the FDAassesses whether the design creates potential contamination routes.

Additionally, some authorities may also require monitoring ofother parameters in conjunction with viables and non-viables; forexample, the EU requires continuous monitoring of pressuredifferentials under operational, dynamic conditions in Grade “A”areas.

Environmental Monitoring of Particle Counts is Easy EnvironmentalMonitoring of Particle Counts is Easy