Regulation of Aseptic Processing in the 21st Century - Pharmaceutical Technology

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Regulation of Aseptic Processing in the 21st Century
The authors question certain aspects of the industry's current regulatory-compliance strategy and suggest that aseptic-process control and evaluation should be revised.

Pharmaceutical Technology
Volume 35, pp. s46-s50

Smoke studies and airborne contamination

The last half dozen or so years have been marked by a dramatic increase in the emphasis on studies intended to visualize airflow. The origin of this movement is unclear, but perhaps people thought that smoke tests could somehow resolve things that monitoring no longer could. Over the past few years, regulatory comments have asserted that smoke studies indicated a "lack of sterility assurance." It is puzzling how someone could observe or review a recorded smoke-study test and draw from it far-reaching conclusions regarding sterility assurance. The lack of objective criteria in smoke studies suggests that definitive conclusions of that nature are highly suspect.

The air-movement story in most cleanrooms is the same. The vast majority of aseptic processing areas are designed with air entry above the work zone and with air returns mounted along the walls close to the floor. Thus, the air moves downward, generally at an initial rate > 0.45m/s. Generally at 1100–1200 mm above the floor, air in the critical zone comes into contact with a solid horizontal surface, encounters resistance, and, as a result, eddy currents develop. The air travels vertically downward in a unidirectional, but certainly not laminar flow, until it encounters the irregularly shaped, solid structure of the processing equipment oriented perpendicularly to the direction of airflow. Further disturbances to airflow arise from the movement of materials along the conveyor and the operation of such things as stopper-positioning arms, vibratory bowls, various feed mechanisms, and, of course, the filling pumps and related plumbing (8). Airflow in cleanrooms, RABS or isolator systems is still occasionally referred to as laminar flow, although in reality the airflow has significant turbulence and can best be described as "generally" or "mostly" unidirectional. References to "sweeping" movement of air convey the comforting notion of a cleansing effect, but realistically the sweep includes the movement of air over and across open containers and closures.

Airflow visualization or smoke studies can be informative, but only in a general sense. We do not believe that they enable an observer to draw far-reaching conclusions regarding sterility assurance. The studies may have value in assisting a firm in evaluating and tuning air movement in a general sense, but they don't have a major effect on environmental-monitoring results or on process-simulation studies. This fact is not surprising because smoke tests, environmental monitoring, and media-fill tests are not sensitive enough to discern minor differences in airflow, and as previously discussed, air-exchanges rate are more directly related to dilution and removal of contaminants.

The authors are not suggesting that firms curtail smoke studies, but they do caution against overinterpreting the results of such tests. Turbulence is unavoidable, and it is not reasonable to think that airflow can be evaluated precisely using visualization methods. Also, the visualization technique ideally should involve smoke generated in an isokinetic and isothermal manner. Obviously, when the smoke ordinarily used is colder or heavier than ambient air, it will move downward on its own, thus distorting the results. Regardless of how these tests are conducted, the authors see no way that these tests can provide an objective means to evaluate sterility assurance. Rather, they believe that where smoke studies are concerned, beauty is in the eye of the beholder.


The authors believe that the methods that industry has used to evaluate aseptic-processing environments, while of some value, cannot in and of themselves assess sterility. All manned environments are nonsterile, and the ability to prove objectively the sterility of aseptically filled products will remain elusive. To prove sterility in an environment would require a sample of infinite size to be analyzed with a method that has a limit of detection of zero. Such analytical methodology does not exist, and this article has shown that even with extreme sampling intensity, only a small fraction of air passing through an aseptic production environment would be sampled. The authors are concerned that the benefits of continuous total-particulate and microbiological monitoring are not technically significant. Environmental monitoring is a limited means to assess aseptic environments, and the industry has long since passed the point of diminishing returns.

Caution is also in order in the interpretation of nonviable particulate (i.e., total particulate) monitoring. The strict enforcement of class limits in every location within an ISO 5 area under dynamic conditions is unreasonable. Process-generated particulate is, at this point, inevitable, as are brief excursions at locations within the environment. The value of nonviable particulate monitoring is in ensuring that excursions are similar from day to day, in terms of frequency and amplitude, with reasonable allowances for inherent variability.

Smoke studies are another well-meaning initiative, but their value has been exaggerated. No objective parameters exist for smoke-test success, which means that acceptability is a subjective judgment call. No evidence demonstrates that smoke-test visualization can determine sterility assurance.

This article raises questions regarding elements that could be considered cornerstones of current regulatory-compliance strategy in aseptic processing, and thus challenges the status quo. The authors' justification is their belief that the current direction of aseptic processing process control and evaluation needs to be changed. Simply doing more of what the industry has been doing for years is not a good way forward.

Advanced aseptic technologies, including the interventionless systems already in use in some industrial aseptic applications, will require new approaches. Many physical parameters that can be measured may provide better assurance of quality in real time than conventional monitoring does. These parameters include air overpressure, humidity, temperature, air velocity across product entry or exit points, and nonviable particulate monitoring.

Given the cost of energy, the pharmaceutical industry will need to revisit air-supply systems, as other aseptic and clean industries have done already. Green aseptic processing is now possible, and high levels of automation and gloveless isolators promise to reduce costs and enable companies to manufacture products at competitive costs of goods produced in North America and Europe. Such systems are here today, and their use should be encouraged and incentivized by regulatory authorities.

Pharmaceutical aseptic processing sadly lags behind the technological level attained in other industries. This situation should not persist. Companies must embrace new technologies and appropriate process-control systems. To that end, meaningful dialogue between regulatory authorities and industry technology experts is required. The focus of these discussions must be on future technologies and control, rather than preservation of the status quo. The result should be safe, and low-cost aseptically produced medicines.

*The regulatory pressures and advent of validation in the 1970s fostered substantial improvement in many manned cleanrooms that plateaued some 20 years later. **Open restricted-access barrier systems where the enclosure must be opened during either setup or operation perform similarly to manned cleanrooms. †Other velocities would perhaps be even more effective, but regulators have fixed on this value. Its removal from Federal Standard 209C in 1987 suggests that it has little scientific validity, but regulators continue to enforce it.

James E. Akers* is the president of Akers Kennedy and Associates, PO Box 22562, Kansas City, MO 64113,
, and James P. Agalloco is president of Agalloco and Associates and a member of Pharmaceutical Technology's editorial advisory board.

*To whom all correspondence should be addressed.


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