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Based on a review of FDA Form 483’s issued to compounding facilities for inspections that occurred January to July 2017, 22 separate citations have been identified for critical airflow visualization. Critical airflow is a key element in the protection of sterile product from contamination. A summary of these citations include:
The design, construction, and operation of buildings and facilities are a key factor in minimizing product contamination. Key cGMP elements include:
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 * * *.”
Equipment design, size, location, cleaning and maintenance are also a factor in minimizing product contamination. Key cGMP elements include:
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.”
Last but not limited the production and process controls used to manage the manufacturing (or compounding) may have a significant impact to aseptic processing. Key cGMP elements include:
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 identified in the FDA Guidance Document Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing practice (p. 6)
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. [bold added by author]
Critical Airflow Visualization (smoke studies) are used to demonstrate proper airflow to protect the sterility of the product during aseptic operations. The studies should reflect actual practice i.e., what are the operations that the technicians will be performing in the ISO area. On review of the data (including the video recording) for acceptance if the data is inconclusive, shows turbulence, the time to intervene and correct the situation is now – not during an audit. The best systems can be invalidated through poor aseptic technique, improper gowning, poor maintenance, or failure to follow procedures.
Performance Validation has successfully performed critical airflow visualization or smoke testing in aseptic areas for many large pharmaceutical manufacturers. We can help you in designing the study to ensure the aseptic processing and interventions are identified and included in the testing. We can execute and document the study, and provide the documentation necessary to meet regulatory expectations.
Questions – please contact Dalton Pierson at Performance Validation.
