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 requirementto minimize particulate, microbial, and pyrogen contamination.

A sampling of FDA observations on environmental monitoring violations culled from warning letters available to the public on the FDA website includes thefollowing:

• Monitoring is not conducted routinely nor concurrently with manufacturing. Sampling should be done daily during both shifts, both inside and outside of the LAF (laminar air flow) areas, and sample times should be varied to cover all parts of the production period. Sampling frequencies and locations must be defined.
• Microbial air samples under laminar flow modules are collected only understatic conditions.
• Less than 10% of the microbial air samples were collected after noon,although production routinely continues until 3:00 p.m.
• Room air microbial samples are collected with the RCS (rotary centrifugal sampler) on a tripodat a height of 5 feet, which does not represent working level in these rooms.There is no trending of data.
• There has been no daily monitoring of aseptic areas and LAF modules for non-viable particulates on a day-of-productionbasis.
• HEPA filters have been certified with DOP (di-octyl phthalate) and aparticle counter and not with a photometer.
• Air velocities have been reported as an average and do not show the individual readings.
• HEPA filters need to be DOP tested at least twice a year, not once ayear as is currently being done.
• Some of the validations of air quality in rooms were done only under static conditions without personnel. Also,no smoke pattern studies on the LAF have been performed to show effects of curtainmovements on laminar air flows.
• The firm has not set alert and action limits for most environmental samples; it needs to identify all organisms isolated from aseptic area untila database is established for normal flora found in the production environment(with frequency distribution) for use in evaluating sterility test results.
• Failure to eliminate objectionable organisms from interior surfaces of transfer carts in which sterilized unsealed containers of drug product are exposed.
• No validation studies have been conducted to assure the microbial settle plates are capable of supporting microbial growth after the stated 3-hour exposure time in Class 100 rooms.
• The quality control unit did not assure that adequate systems and controls were in place to monitor the functioning, and to detect malfunctions, of the air handling systems used to control and assure aseptic conditions in aseptic manufacturing areas.

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. A classic example comes to mind when recalling a number of unidirectional flow aseptic fill cleanrooms that, once built, have proven unable to meet validation requirements. 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 performedwithin 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 maintainingcontrol. Facility monitoring systems must rapidly detect and record changes that might lead to a compromised environment and alert personnel of such changesimmediately.