Aseptic processing is one of the highest risk pharmaceutical operations, and thus requires a high level of control.
The pharmaceutical industry depends greatly on cleanroom standards to ensure the health and safety of patients, especially during aseptic processes for the production of drugs purporting to be sterile. At the recent 2021 PDA/FDA Joint Regulatory Conference, Brooke K. Higgins, MS, senior policy advisor, CDER, U.S. FDA presented on recurring deficiencies and safety failures found during FDA aseptic manufacturing inspections, both in the U.S. and globally, along with possible solutions.
Brooke K. Higgins, MS, senior policy advisor, CDER, U.S. FDAAs aseptic processing is one of the highest risk pharmaceutical operations, there are severe consequences to lack of control. FDA’s aseptic guidance, the European Annex, and a number of other valuable resources list principles to avoid contamination events, yet FDA continues to note inspectional trends surrounding aseptic technique and behaviors; facility, room, and process design; and the use of media fills.
“We know it takes a myriad of meticulous steps to ensure the quality of sterile drug products,” said Higgins. “This includes fastidious control over the sterile drug, container closures and components, and careful and attentive interactions in the processing and surrounding areas.”
FDA graph for assuring sterility of drug products.
Higgins emphasized that in control strategy, FDA rule requires manufacturers to run all processes by them to ensure proper protection from microbiological contamination of drug products purporting to be sterile. FDA also insists a current Good Manufacturing Practices (cGMP)-compliant firm must continually assess its systems and take action in a timely manner to ensure that it remains in a state of control—this includes the facility, equipment, and the process. FDA expects companies to assess the effectiveness of controls and measures in place to minimize the risk of contamination.
Causes of contamination
Main causes of contamination in the U.S. and internationally listed in the presentation were:
The personnel—Higgins said, “The major variable in the control of aseptic processing arises not from the sterilization processes, the cleanroom, or the filtration processes that are so often the subject of technical papers on regulatory guidelines, but rather from the workforce itself.” She noted that humans shed almost one billion particles a day, which may land on the aseptic processing line and even inside the sterile drug.
Incorrect actions commonly noted by FDA inspectors are:
operators placing head and upper torso into filling cabinet over open vials without clearing them;
operators inadvertently contacting the interior of doors used to access ISO 5 aseptic processing areas;
failure to disinfect materials before introducing them into ISO 5 aseptic processing area; and
sterile drug product leaks on the floor. Filling continues as operators attempt to clean spilled product by placing wipes and other materials over the area with their feet. Aseptic connections are made directly above spilled product.
Higgins asserted that personnel must be trained and frequently reminded of proper cleanroom procedures and behaviors. Further, a substantial part of environmental control includes management performing extensive observation of operator activities in the aseptic processing cleanroom and the surrounding areas to ensure that situations as noted above do not continue to occur.
Facility, room, and process design—Older facilities can often include “processing lines and facility layouts that are less effective at mitigating various operational variables that pose a risk to sterility,” as Higgins put it. “If equipment is not well designed, or is poorly maintained, repeated or extensive manual interventions often occur due to mechanical problems. When production line operators perform manual activities near an insufficiently protected product, they raise the risk of microbial contamination.”
Higgins explained that FDA has seen older facilities try to use a curtain or rigid plastic enclosures to separate the critical processing areas from the rest of the facility, but this is done oftentimes without proper risk evaluation. These platforms typically involve extensive manual interactions with the aseptic processing line and its exposed sterile drug product, containers, and closures. Such antiquated techniques often prove inefficient, with unstable lines, and they require frequent starts and stops to correct major problems and to make adjustments. This generates excessive opportunities for interaction between personnel and sterile material.
“I’d like to highlight that these lines that are considered traditional or conventional are not the modern choice. Given the technology available, these kinds of antiquated lines should not be the go-to for new facilities. These lines are at a heightened risk for quality and safety failures. It doesn’t make science or business sense to use these lines,” said Higgins.
Further design issues noted during inspections include:
aseptic filling equipment design, room space, protection of the area and filling equipment where connections are made, and the number of personnel present during filling operations are deficient;
stopper hopper leans diagonally across the filling line during stopper loading thereby blocking first air; and
interventions require a large door to be opened. When opened, the door is exposed to the ISO 7 area, and when being closed, there is a significant risk of the lower quality room air sweeping into the ISO 5 filling cabinet. Empty, open sterile vials are located extremely close to the door.
Smoke studies—FDA is increasing emphasis on line design review during inspections as well as case review. One means of review that is being continuously emphasized is smoke studies, which verify the sterility of a line effectively by illuminating design weaknesses that pose contamination hazards when performed properly.
“We observed through smoke studies that when some doors open the airflow changes profoundly. It causes excessive turbulence within the ISO 5 closure,” Higgins explained. “Whether it’s an isolator or an open system, you must take time to understand the risks associated with your processing. Assess what can go wrong within each area, watch operations, compare what’s being done to what your procedure is saying, compare what you see to what is being simulated in your smoke studies, evaluate the ergonomics of the line in the processing areas and how operators interact with the line itself. These areas and others can help identify your gaps.
Issues surrounding smoke studies that are commonly found in FDA inspections include:
Smoke studies not being dynamic
Smoke studies lacking simulation of multiple critical interventions
Non-unidirectional airflow being seen in smoke studies
Inadequate visualization of airflow due to either lack of smoke or the view of the aseptic processing zone being obstructed
“Studies must include dynamic operations and sufficient smoke to visualize airflow as interventions are simulated,” said Higgins. “Non-unidirectional airflow must be identified and addressed. Some of the better studies that I’ve seen have captured the activities and airflow from various angles. This truly helps prevent obstructive views.”
Media fills—FDA inspections are continuing to find issues with media fills and needing to perform investigations into media fill failures. The inspections often find that process simulations do not always represent actual aseptic manufacturing operations. To ensure appropriate simulations, Higgins explained that a company could incorporate a retrospective review of inherent critical interventions performed during production and a risk assessment of new interventions that have been performed from previous media fill studies. She further noted that FDA inspections document poor investigations and a lack of understanding of the media fill failures which do not identify root cause or CAPAs.
“Continuous observation of operations and well-documented batch records are critical to developing a robust media fill program,” said Higgins.
Common FDA inspection observations are:
Interventions not being appropriately simulated
Additional cleaning performed prior to media fills
Rejection of integral vials without sufficient justification
Not all operators included in media fills
Poor investigations into failing media fills which lack scientifically supported conclusions and CAPAs, and fail to address all potentially compromised lots
The future of aseptic processing
Along with solutions to these issues such as employee training and improving the quality of smoke studies, Higgins highlighted technologies that can better protect product from contamination during aseptic processing. These technologies either improve the separation between personnel and sterile product or eliminate it altogether.
The first solution Higgins noted was gloveless robotic isolators. Isolators already greatly reduce major hazards from personnel activity but gloveless robotic isolators provide the next step which, according to Higgins, profoundly reduces contamination risks. Robotics perform all operation within the system without glove ports that would allow personnel to intervene.
The second solution listed is advanced environmental monitoring technology. In lieu of, or along with, traditional monitoring, this can include technologies such as biofluorescent particle counting systems. As operators do not need to handle the monitoring equipment for such systems or perform certain other tasks, like switching out plates, fewer manual manipulations are needed within the ISO 5 area.
“These systems provide continuous, real-time monitoring and feedback as soon as a potential microbe is collected from the ISO 5 area. However, firms must still ensure these systems are appropriately qualified and that particle limits are still appropriately established. While using this advanced technology, ISO 5 isolate identification still remains essential,” said Higgins.
She further highlights that the amount of investment a company makes into newer technologies, such as automation and isolators, shows how dedicated the company is to sterility and having a strong quality culture. This culture extends beyond the philosophy to the manufacturing infrastructure; investment in properly designed processes, facilities, and equipment; and capable personnel.
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Brooke K. Higgins, MS, senior policy advisor, CDER, U.S. FDA
FDA graph for assuring sterility of drug products.
