Sterile Product Building, Facility and Clean Area Classification Guideline By USFDA

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Sterile Product Building, Facility and  Clean Area Classification Guideline By USFDA has clearly mentioned what conditions to be followed to maintain the Sterile Conditions in Sterile Product Manufacturing site.

21 CFR 211.42(b) states, in part, that “The flow of components, drug product containers, closures, labeling, in-process materials, and drug products through the building or buildings shall be designed to prevent contamination.”

21 CFR 211.42(c) states, in part, that “Operations shall be performed within specifically defined areas of adequate size.  There shall be separate or defined areas or such other control systems for the firm’s operations as are necessary to prevent contamination or mixups during the course of the following procedures: * * * (10)  Aseptic processing, which includes as appropriate:  (i)  Floors, walls, and ceilings of smooth, hard surfaces that are easily cleanable; (ii) Temperature and humidity controls;  (iii)  An air supply filtered through high-efficiency particulate air filters under positive pressure, regardless of whether flow is laminar or nonlaminar; (iv) A system for monitoring environmental conditions;   (v) A system for cleaning and disinfecting the room and equipment to produce aseptic conditions; (vi) A system for maintaining any equipment used to control the aseptic conditions.”

21 CFR 211.46(b) states that “Equipment for adequate control over air pressure, micro-organisms, dust, humidity, and temperature shall be provided when appropriate for the manufacture, processing, packing, or holding of a drug product.”   21 CFR 211.46(c) states, in part, that “Air filtration systems, including prefilters and particulate matter air filters, shall be used when appropriate on air supplies to production areas * * *.”

21 CFR 211.63 states that “Equipment used in the manufacture, processing, packing, or holding of a drug product shall be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance.”   21 CFR 211.65(a) states that “Equipment shall be constructed so that surfaces that contact components, inprocess materials, or drug products shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.” 21 CFR 211.67(a) states that “Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.” 21 CFR 211.113(b) states that “Appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed.  Such procedures shall include validation of any sterilization process.”

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 (Ref. 1).

TABLE 1- Air Classifications

 Clean Area Classification (0.5 um particles/ft3)ISO  Designationb> 0.5 µm particles/m3Microbiological Active Air Action Levelsc (cfu/m3 )Microbiological Settling Plates Action Levelsc,d (diam. 90mm; cfu/4 hours)
10053,5201e1e
1000635,20073
10,0007352,000105
100,00083,520,00010050

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.

  • The additional use of settling plates is optional.
  • 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 (§ 211.42(c)(10)).  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 (Ref. 2).  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.   See Section X.E. for additional guidance on particle monitoring.

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[1] 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 (Ref. 3).[2]  

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 situair 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.


[1] High Efficiency Particulate Air filter

[2] A velocity of 0.45 meters/second (90 feet per minute) has generally been established, with a range of plus or minus 20 percent around the setpoint.  Higher velocities may be appropriate in operations generating high levels of particulates.

Reference :-

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

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