cGMP (current Good Manufacturing Practice (cGMP))
This guidance document discusses selected issues and does not address all aspects of aseptic processing. For example, the guidance addresses primarily finished drug product CGMP issues while only limited information is provided regarding upstream bulk processing steps. This guidance updates the 1987 Aseptic Processing Guideline primarily with respect to personnel qualification, cleanroom design, process design, quality control, environmental monitoring, and review of production records. The use of isolators for aseptic processing is also discussed.
Although this guidance document discusses CGMP issues relating to the sterilization of components, containers, and closures, terminal sterilization of drug products is not addressed. It is a well-accepted principle that sterile drugs should be manufactured using aseptic processing only when terminal sterilization is not feasible. However, some final packaging may afford some unique and substantial advantage (e.g., some dual-chamber syringes) that would not be possible if terminal sterilization were employed. In such cases, a manufacturer can explore the option of adding adjunct processing steps to increase the level of sterility assurance.
BUILDINGS AND FACILITIES
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, in-process 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.
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 mm 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).
C. Clean Area Separation
An essential part of contamination prevention is the adequate separation of areas of operation. To maintain air quality, it is important to achieve a proper airflow from areas of higher cleanliness to adjacent less clean areas. It is vital for rooms of higher air cleanliness to have a substantial positive pressure differential relative to adjacent rooms of lower air cleanliness. For example, a positive pressure differential of at least 10-15 Pascals (Pa) should be maintained between adjacent rooms of differing classification (with doors closed). When doors are open, outward airflow should be sufficient to minimize ingress of contamination, and it is critical that the time a door can remain ajar be strictly controlled.
In some cases, the aseptic processing room and adjacent cleanrooms have the same classification. Maintaining a pressure differential (with doors closed) between the aseptic processing room and these adjacent rooms can provide beneficial separation. In any facility designed with an unclassified room adjacent to the aseptic processing room, a substantial overpressure (e.g., at least 12.5 Pa) from the aseptic processing room should be maintained at all times to prevent contamination. If this pressure differential drops below the minimum limit, it is important that the environmental quality of the aseptic processing room be restored and confirmed.
The Agency recommends that pressure differentials between cleanrooms be monitored continuously throughout each shift and frequently recorded. All alarms should be documented and deviations from established limits should be investigated.
Air change rate is another important cleanroom design parameter. For Class 100,000 (ISO 8 ) supporting rooms, airflow sufficient to achieve at least 20 air changes per hour is typically acceptable. Significantly higher air change rates are normally needed for Class 10,000 and Class 100 areas.
A suitable facility monitoring system will rapidly detect atypical changes that can compromise the facility’s environment. An effective system facilitates restoration of operating conditions to established, qualified levels before reaching action levels. For example, pressure differential specifications should enable prompt detection (i.e., alarms) of an emerging low pressure problem to preclude ingress of unclassified air into a classified room.
D. Air Filtration
A compressed gas should be of appropriate purity (e.g., free from oil) and its microbiological and particle quality after filtration should be equal to or better than that of the air in the environment into which the gas is introduced. Compressed gases such as air, nitrogen, and carbon dioxide are often used in cleanrooms and are frequently employed in purging or overlaying.
Membrane filters can be used to filter a compressed gas to meet an appropriate high-quality standard. These filters are often used to produce a sterile compressed gas to conduct operations involving sterile materials, such as components and equipment. For example, we recommend that sterile membrane filters be used for autoclave air lines, lyophilizer vacuum breaks, and tanks containing sterilized materials. Sterilized holding tanks and any contained liquids should be held under positive pressure or appropriately sealed to prevent microbial contamination. Safeguards should be in place to prevent a pressure change that can result in contamination due to back flow of nonsterile air or liquid.
Gas filters (including vent filters) should be dry. Condensate on a gas filter can cause blockage during use or allow for the growth of microorganisms. Use of hydrophobic filters, as well as application of heat to these filters where appropriate, prevents problematic moisture residues. We recommend that filters that serve as sterile boundaries or supply sterile gases that can affect product be integrity tested upon installation and periodically thereafter (e.g., end of use). Integrity tests are also recommended after activities that may damage the filter. Integrity test failures should be investigated, and filters should be replaced at appropriate, defined intervals.
2. High-Efficiency Particulate Air (HEPA)
HEPA filter integrity should be maintained to ensure aseptic conditions. Leak testing should be performed at installation to detect integrity breaches around the sealing gaskets, through the frames, or through various points on the filter media. Thereafter, leak tests should be performed at suitable time intervals for HEPA filters in the aseptic processing facility. For example, such testing should be performed twice a year for the aseptic processing room. Additional testing may be appropriate when air quality is found to be unacceptable, facility renovations might be the cause of disturbances to ceiling or wall structures, or as part of an investigation into a media fill or drug product sterility failure. Among the filters that should be leak tested are those installed in dry heat depyrogenation tunnels and ovens commonly used to depyrogenate glass vials. Where justified, alternate methods can be used to test HEPA filters in the hot zones of these tunnels and ovens.
Any aerosol used for challenging a HEPA filter should meet specifications for critical physicochemical attributes such as viscosity. Dioctylphthalate (DOP) and poly-alpha-olefin (PAO) are examples of appropriate leak testing aerosols. Some aerosols are problematic because they pose the risk of microbial contamination of the environment being tested. Accordingly, the evaluation of any alternative aerosol involves ensuring it does not promote microbial growth.
There is a major difference between filter leak testing and efficiency testing. An efficiency test is a general test used to determine the rating of the filter. An intact HEPA filter should be capable of retaining at least 99.97 percent of particulates greater than 0.3 mm in diameter.
The purpose of performing regularly scheduled leak tests, on the other hand, is to detect leaks from the filter media, filter frame, or seal. The challenge involves use of a polydispersed aerosol usually composed of particles with a light-scattering mean droplet diameter in the submicron size range, including a sufficient number of particles at approximately 0.3 mm. Performing a leak test without introducing a sufficient upstream challenge of particles of known size upstream of the filter is ineffective for detecting leaks. It is important to introduce an aerosol upstream of the filter in a concentration that is appropriate for the accuracy of the aerosol photometer. The leak test should be done in place, and the filter face scanned on the downstream side with an appropriate photometer probe, at a sampling rate of at least one cubic foot per minute. The downstream leakage measured by the probe should then be calculated as a percent of the upstream challenge. An appropriate scan should be conducted on the entire filter face and frame, at a position about one to two inches from the face of the filter. This comprehensive scanning of HEPA filters should be fully documented.
A single probe reading equivalent to 0.01 percent of the upstream challenge would be considered as indicative of a significant leak and calls for replacement of the HEPA filter or, when appropriate, repair in a limited area. A subsequent confirmatory retest should be performed in the area of any repair.
HEPA filter leak testing alone is insufficient to monitor filter performance. It is important to conduct periodic monitoring of filter attributes such as uniformity of velocity across the filter (and relative to adjacent filters). Variations in velocity can cause turbulence that increases the possibility of contamination. Velocities of unidirectional air should be measured 6 inches from the filter face and at a defined distance proximal to the work surface for HEPA filters in the critical area. Velocity monitoring at suitable intervals can provide useful data on the critical area in which aseptic processing is performed. The measurements should correlate to the velocity range established at the time of in situ air pattern analysis studies. HEPA filters should be replaced when nonuniformity of air velocity across an area of the filter is detected or airflow patterns may be adversely affected.
Although contractors often provide these services, drug manufacturers are responsible for ensuring that equipment specifications, test methods, and acceptance criteria are defined, and that these essential certification activities are conducted satisfactorily.