Kimberley Buytaert-Hoefen, PhD, Director of Regulatory Affairs, Azzur Group
When the FDA conducts inspections of aseptic drug manufacturers, they cover systems and areas within systems that present the greatest risk of product contamination and require strict control of processing parameters. Microbial controls and sterility assurance are the main focus of aseptic processing drug inspections. In an aseptic filling process, the drug product, containers, and closures are sterilized separately and then brought together under a high-quality environmental condition designed to reduce the possibility of a sterility breach. Any manual or mechanical manipulation of the sterilized drug, containers, or closures prior to or during aseptic filling and assembly poses the risk of microbial contamination. Humans are a significant source of contamination in aseptic processing, especially in production lines that require operators enter critical areas, Class 100/ ISO 5/Grade A, of the filling line.1,2
An FDA investigator will evaluate the design and layout of the facility including personnel and material flow and cleanroom design. Specifications for cleanroom areas such as layout, air filtration, appropriate air classification, pressure differentials between rooms and areas, temperature, and humidity should be established based on the risk of product contamination with particulate matter and microorganisms. The investigator will review the certification and qualification of the cleanroom areas to verify the areas meet design criteria and specifications. Cleanroom control parameters should be supported by microbiological and particle data obtained during qualification studies. Initial cleanroom qualification includes an assessment of air quality under as-built, static conditions. It is important for area qualification and classification to place an emphasis on data generated under dynamic conditions with personnel present, equipment in place, and during manufacturing. Certification and qualification typically includes data in support of the following: airflow pattern studies, High-Efficiency Particulate Air (HEPA) filter integrity testing, air velocity measurement, non-viable particles, and verification of appropriate pressure differentials, temperature, and humidity setpoints. The airflow pattern, smoke studies, conducted under dynamic conditions will be evaluated to verify the unidirectional airflow and air turbulence within the critical area where sterilized drug product, containers, and closures are exposed to environmental conditions. The investigator will request and review a diagram of pressure differentials. The pressure cascade should be clearly depicted in the diagram. Positive pressure is an essential operational feature of cleanrooms. To maintain air quality in a cleanroom, the pressure of a given room must be greater relative to a room of a lower grade. This is to ensure that air does not pass from ‘dirtier’ adjacent areas into the higher-grade cleanroom. Negative air pressure is used in cleanrooms where the goal is to keep any possible contamination from escaping the cleanroom. Windows and doors must be completely sealed, and by having a lower pressure, air outside the cleanroom is likely to flow into it, rather than out of it. Appropriate limits for pressure differentials should be established based on risk.1,3,4,5
Only personnel who are qualified and appropriately gowned should be permitted access to the aseptic manufacturing area. Gowning should provide a barrier between the body and exposed sterilized materials and prevent contamination from particles generated by and microorganisms shed from the body. It is recommended that gowns are sterilized and nonshedding and that with the addition of facemasks, hoods, beard covers, protective goggles, and elastic gloves that all skin and hair is covered. Written procedures should detail the methods used to don each gown component in an aseptic manner. An adequate barrier should be created by the overlapping of gown components for example gloves overlapping sleeves. If an element of a gown is found to be torn or defective, it should be changed immediately. Gloves should be sanitized frequently.1,2
Personnel monitoring should include a routine program for shift monitoring of operators gloves and an appropriate schedule for monitoring gowns. The establishment of limits should be based on the contamination risk to the product. Investigations of results that exceed the established levels or demonstrate an adverse trend should be performed. Personnel monitoring is critical in aseptic processing, and inspectional emphasis will be risk-based, focusing on those operations that require employees to enter the critical areas of the processing line. The investigator will watch personnel behaviors in the cleanroom. Personnel should not directly contact sterile products, containers, closures, or critical surfaces with any part of their gown or gloves. Personnel must avoid rapid movements that can create unacceptable turbulence in a critical area. Such movements disrupt the unidirectional airflow, presenting a challenge beyond intended cleanroom design and control parameters. The principle of slow, careful movement should be followed throughout the cleanroom. Personnel should keep the entire body out of the path of unidirectional airflow. Unidirectional airflow design is used to protect sterile equipment surfaces, container, closures, and product. Personnel should approach a necessary manipulation in a manner that does not compromise sterility of the product. To maintain sterility of nearby sterile materials, a proper aseptic manipulation should be to approach from the side and not from above the product. Also, operators should refrain from speaking when in direct proximity to the critical area.1,2
In order to define an appropriate environmental monitoring program, companies should use risk assessments to determine the appropriateness of sample locations, monitoring equipment and control levels, as well as in determining the types of organisms that should be considered objectionable to the process. Once these parameters have been defined, the process of developing an effective environmental monitoring program can be established. A well-defined written program for environmental monitoring should include all production shifts and should cover air, floors, walls, equipment surfaces, and in aseptic process operations, critical surfaces that come in contact with sterile product, containers, and closures. Appropriate alert and action levels should be established using data collected from contact plates, swabs, active air samplers and testing methods including media, plate exposure times, incubation times and temperatures that are designed to detect environmental isolates. Evaluations of the validity of the sampling locations and sampling methods should be performed periodically. An environmental monitoring program should be established that routinely ensures acceptable microbiological quality of air, surfaces, and gloves, as well as particle levels. Air quality should be monitored periodically during each shift. For example, monitoring the exit port for particles to detect any unusual results. Cleanroom monitoring programs should also be routinely reviewed to determine whether they reflect current best practices.3,4
Media fill procedures and data will be reviewed during an FDA inspection. An aseptic processing operation should be validated with a media fill that uses a microbiological growth medium in place of the product. The process simulation includes exposing the microbiological growth medium to product contact surfaces of equipment, container closure systems, critical environments, and process manipulations to closely simulate the same exposure that the product itself would undergo. The sealed containers filled with the medium are then incubated to detect microbial contamination. Results are interpreted to assess the potential for a unit of product to become contaminated during actual operations for example start-up, sterile ingredient additions, aseptic connections, filling, and closing. Non-viable monitoring should occur during operations and include sites where there is the most risk to exposed product, container, and closures. Non-viable monitoring, pressure differentials, temperature, and humidity should be continuously monitored during routine production and should be alarmed to alert operators of excursions. The investigator will check if excursions from acceptable ranges are investigated to determine impact on product and if needed, corrective actions were taken. An evaluation of the program for periodic recertification of the HEPA filters in critical areas to maintain appropriate airflow will be performed by the Investigator. The HEPA recertification typically includes integrity testing of the HEPA filters and air velocity checks.1,2
Efficacy of disinfectants, including assessment of the suitability, efficacy, and limitations of the disinfecting agents used in the controlled area, production equipment and laboratories should be performed and documented. The assessment includes laboratory studies that test the effectiveness of agents on different surface materials. Material coupons should be used with surface types as found in production. The studies should be done with the same disinfecting agents and contact times, which should be defined in written procedures. It is also important to understand that disinfectants have limitations, and most are not effective against every type of microorganism. For this reason, manufacturers should use more than one type of disinfectant. It is recommended that the disinfectant active substances are changed, in rotation, for the aseptic areas. At least one disinfectant with efficacy against bacterial spores is required for a cleanroom. Biocides, such as alcohols, quaternary ammonium compounds, phenols, and amphoteric surfactants are effective against bacteria in their vegetative phase but ineffective against bacterial spores. Products containing hydrogen peroxide, peracetic acid, hypochlorite, chlorine dioxide, or formaldehyde as an active substance are effective against spores. The FDA investigator will review the sanitization procedures for cleanroom areas, processing lines, and non-autoclavable equipment, materials, and components. They will focus on the areas where the sterile product is exposed up to and including sealing operations. These critical areas represent the highest risk to the product. The suitability, efficacy, and limitations of disinfecting agents and adequacy of procedures will be reviewed, including the data that establishes the expiry of the disinfection solution. For multi-use facilities and non-dedicated equipment, an evaluation of the adequacy of the changeover procedures and cleaning to prevent cross-contamination between products will be reviewed by the investigator.1,3,4,5
For aseptic processing, using isolation systems to separate the external cleanroom environment from the aseptic processing line and to minimize its exposure to personnel is recommended. A positive pressure isolator, supported by adequate procedures for its maintenance, monitoring, and control is preferred over traditional aseptic processing because it includes fewer opportunities for microbial contamination during processing. Operators should remain vigilant to potential sources of operational risk. A leak in certain components of the system can constitute a significant breach of integrity. The integrity of gloves, half-suits, and seams should receive integrity assessments and have a comprehensive preventative maintenance program. Replacement frequencies should be established in written procedures that ensures parts will be changed before they breakdown. Transfer systems, gaskets, and seals are among the other parts that should be covered by the maintenance program. The decontamination method should render the inner surfaces of the isolator free of viable microorganisms. Multiple available vaporized agents are suitable for achieving decontamination. Process development and validation studies should include a thorough determination of cycle capability. An appropriate, quantified Biological Indicator (BI) challenge should be placed on various materials and in many locations throughout the isolator, including difficult-to-reach areas. Cycles should be developed with an appropriate margin of extra kill to provide confidence in the robustness of the decontamination processes. The specific BI spore titer used, and the selection of BI placement sites should be justified. The uniform distribution of a defined concentration of decontaminating agent should be evaluated as part of these studies. Chemical indicators may also be useful as a qualitative tool to show that the decontaminating agent reached a given location.4
To ensure regulatory compliance during an FDA inspection, companies should review the design features of their cleanroom on a regular basis and take appropriate corrective actions to ensure that both airflow and laminarity are maintained, especially when personnel are operating in the area. Maintenance issues could be mitigated by conducting routine and frequent checks of both the condition of the area and the equipment, ensuring that concerns are quickly repaired. A strong and comprehensive cleanroom design, qualification, and monitoring program strengthens the company’s regulatory compliance, enhances product quality, and ensures patient safety.
References
1. Cleanroom Technology Auditing Page. Available at https://www.cleanroomtechnology.com/news/ article_page/Auditing_cleanrooms/105618. Accessed February 9, 2015.
2. Pharmaceutical Technology Europe, Pharmaceutical Technology Europe-12-01-Moldenhauer, J., (2010). Passing Cleanroom Inspections, Pharmaceutical Technology Europe 22(12).
3. FDA Compliance Program 7356.002A (2015) Sterile Drug Process Inspections.
4. FDA Guidance for Industry, (2004) Sterile Drug Products Produced by Aseptic Processing-Current God Manufacturing Practice. ISO 14644-1:2015
Author Biography
Dr. Kimberley Buytaert-Hoefen obtained a Bachelor’s de- gree in Psychology at SUNY at Binghamton and then went on to complete her Master’s and Doctorate degrees in Neuroscience at the University of Colorado at Boulder. She completed two post-doctoral fellowships at the University of Colorado Health Sciences Center where she specialized in embryonic and adult stem cell research. In 2005, she entered private industry with a position as a Lead Scientist at Navigant Biotechnologies. In 2009, she accepted a position as a Consumer Safety Officer at the FDA, where she specialized in pharmaceutical inspections with an emphasis on biotechnology, sterile processing, and medical device. Since 2016, as a Consultant, Dr. Buytaert-Hoefen specializes in Biologics, Gene and Cellular therapies. She assists companies with the authoring of regulatory documents, interactions with regulatory agencies, and GLP, GCP, and GMP regulatory compliance.
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