Friday, December 24, 2010

Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice

As provided for in the regulations, separate or defined areas of operation in an aseptic processing facility should be appropriately controlled to attain different degrees of air quality depending on the nature of the operation. Design of a given area involves satisfying microbiological and particle criteria as defined by the equipment, components, and products exposed, as well as the operational activities conducted in the area.

Clean area control parameters should be supported by microbiological and particle data obtained during qualification studies. Initial cleanroom qualification includes, in part, an assessment of air quality under as-built, static conditions. It is important for area qualification and classification to place most emphasis on data generated under dynamic conditions (i.e., with personnel present, equipment in place, and operations ongoing). An adequate aseptic processing facility monitoring program also will assess conformance with specified clean area classifications under dynamic conditions on a routine basis.

The following table summarizes clean area air classifications and recommended action levels of microbiological quality.

TABLE 1- Air Classifications (

Clean Area Classification
(0.5 um particles/ft3)
> 0.5 μm particles/m3
Microbiological Active Air Action Levels (c) (cfu/m3 )
Microbiological Settling Plates Action Levelsc (d)
(diam. 90mm;
cfu/4 hours)
1 (e)
1 (e)
a- All classifications based on data measured in the vicinity of exposed materials/articles during periods of activity.
b- ISO 14644-1 designations provide uniform particle concentration values for cleanrooms in multiple industries. An ISO 5 particle concentration is equal to Class 100 and approximately equals EU Grade A.
c- Values represent recommended levels of environmental quality. You may find it appropriate to establish alternate microbiological action levels due to the nature of the operation or method of analysis.
d- The additional use of settling plates is optional.
e- Samples from Class 100 (ISO 5) environments should normally yield no microbiological contaminants.
Two clean areas are of particular importance to sterile drug product quality: the critical area and the supporting clean areas associated with it.

A. Critical Area – Class 100 (ISO 5)

A critical area is one in which the sterilized drug product, containers, and closures are exposed to environmental conditions that must be designed to maintain product sterility. Activities conducted in such areas include manipulations (e.g., aseptic connections, sterile ingredient additions) of sterile materials prior to and during filling and closing operations.

This area is critical because an exposed product is vulnerable to contamination and will not be subsequently sterilized in its immediate container. To maintain product sterility, it is essential that the environment in which aseptic operations (e.g., equipment setup, filling) are conducted be controlled and maintained at an appropriate quality. One aspect of environmental quality is the particle content of the air. Particles are significant because they can enter a product as an extraneous contaminant, and can also contaminate it biologically by acting as a vehicle for microorganisms. Appropriately designed air handling systems minimize particle content of a critical area.

Air in the immediate proximity of exposed sterilized containers/closures and filling/closing operations would be of appropriate particle quality when it has a per-cubic-meter particle count of no more than 3520 in a size range of 0.5 μm and larger when counted at representative locations normally not more than 1 foot away from the work site, within the airflow, and during filling/closing operations. This level of air cleanliness is also known as Class 100 (ISO 5).

We recommend that measurements to confirm air cleanliness in critical areas be taken at sites where there is most potential risk to the exposed sterilized product, containers, and closures. The particle counting probe should be placed in an orientation demonstrated to obtain a meaningful sample. Regular monitoring should be performed during each production shift. We recommend conducting nonviable particle monitoring with a remote counting system. These systems are capable of collecting more comprehensive data and are generally less invasive than portable particle counters.

Some operations can generate high levels of product (e.g., powder) particles that, by their nature, do not pose a risk of product contamination. It may not, in these cases, be feasible to measure air quality within the one-foot distance and still differentiate background levels of particles from air contaminants. In these instances, air can be sampled in a manner that, to the extent possible, characterizes the true level of extrinsic particle contamination to which the product is exposed. Initial qualification of the area under dynamic conditions without the actual filling function provides some baseline information on the non-product particle generation of the operation.

HEPA-filtered air should be supplied in critical areas at a velocity sufficient to sweep particles away from the filling/closing area and maintain unidirectional airflow during operations. The velocity parameters established for each processing line should be justified and appropriate to maintain unidirectional airflow and air quality under dynamic conditions within the critical area.

Proper design and control prevents turbulence and stagnant air in the critical area. Once relevant parameters are established, it is crucial that airflow patterns be evaluated for turbulence or eddy currents that can act as a channel or reservoir for air contaminants (e.g., from an adjoining lower classified area). In situ air pattern analysis should be conducted at the critical area to demonstrate unidirectional airflow and sweeping action over and away from the product under dynamic conditions. The studies should be well documented with written conclusions, and include evaluation of the impact of aseptic manipulations (e.g., interventions) and equipment design. Videotape or other recording mechanisms have been found to be useful aides in assessing airflow initially as well as facilitating evaluation of subsequent equipment configuration changes. It is important to note that even successfully qualified systems can be compromised by poor operational, maintenance, or personnel practices.

Air monitoring samples of critical areas should normally yield no microbiological contaminants. We recommend affording appropriate investigative attention to contamination occurrences in this environment.
B. Supporting Clean Areas
Supporting clean areas can have various classifications and functions. Many support areas function as zones in which nonsterile components, formulated products, in-process materials, equipment, and container/closures are prepared, held, or transferred. These environments are soundly designed when they minimize the level of particle contaminants in the final product and control the microbiological content (bioburden) of articles and components that are subsequently sterilized.

The nature of the activities conducted in a supporting clean area determines its classification. FDA recommends that the area immediately adjacent to the aseptic processing line meet, at a minimum, Class 10,000 (ISO 7) standards (see Table 1) under dynamic conditions. Manufacturers can also classify this area as Class 1,000 (ISO 6) or maintain the entire aseptic filling room at Class 100 (ISO 5). An area classified at a Class 100,000 (ISO 8) air cleanliness level is appropriate for less critical activities (e.g., equipment cleaning).

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