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

Advanced aseptic technology

If the discussion shifts from manned cleanrooms to unmanned environments such as isolators and closed restricted access barriers (RABS), monitoring as a means of evaluating performance becomes even more marginalized. In other words, the industry's monitoring metrology is wholly inadequate for the dramatically improved contamination-control capability.** Studies using even advanced spectrophotometric methods targeting and detecting macromolecules associated with microbial life confirm that isolators are indeed exceptionally clean environments (6). Increasing monitoring intensity is therefore both unwarranted and unproductive. Increasingly, monitoring does nothing but confirm expectations; the methods are no longer sensitive enough to detect status changes. Status changes below the limit of detection in isolators and closed RABS (if they even exist) are, based upon the high level of safety attainable with products made in conventional cleanrooms, medically irrelevant.

Continuous and intensified monitoring

Recent years have seen an emphasis on continuous monitoring of environments, specifically as regards total particulate counting. Advocates of settle plates argue that because they can be exposed for 4–5 h, they are effectively a form of continuous monitoring. This notion, however, is exceedingly simplistic.

As previously noted, high air-exchange rates are the most effective means to dilute contaminants that are inevitably released into aseptic environments. Make no mistake, contamination release is unquestionably inevitable in manned environments. Modern cleanrooms routinely provide 500 or more air changes per hour. Assume that a large cleanroom has a total volume of 500 m3 and achieves a mean air-exchange rate of 500/h. The total volume of airflow passing through the room in an hour would be 500/h 500/m3, which equals 250,000/m3 of air per hour. If personnel placed 1000 monitoring devices in this room, each with the ability to sample 6 m3/h, they should be able to sample just 6000 m3 of the 250,000 m3 of air passing through this environment. This amounts to 0.24% of the air passing through the room in an hour.

The sampling probes could indeed be placed at critical locations, but they would still sample only a small fraction of the air moving through the critical zone. The cost of electronic particle samplers, which sample and report results in real time, is significant, and the modern microbial-detection systems are quite expensive. If such units cost $5000–10,000 and a company used such a vast number of them, the cost obviously would be prohibitive. In this admittedly extreme example of sampling intensity, the initial purchase cost would be $5–10 million. One could argue that two such units, one near the fill head and one near the closure application zone, would suffice. From a regulatory point of view, they might, but the amount of air actually sampled would be trivial. Such an exercise would be of little practical benefit. Passive sampling is even less likely to be of any real value in risk analysis, although it might help ensure a good inspectional experience.

Particulate excursions

If the above is true, why does industry observe nonviable particulate excursions? The confirmed reason is that processes inevitably generate particulates; most processing machinery is belt- or gear-driven and has moving parts. Process equipment generates nonviable particulates, and humans generate viable and nonviable particulates. Friction occurs on accumulation tables and bottom-drive conveyors between containers and equipment and between adjacent containers. Also, routine activities, such as opening a sterilized bag of closures and pouring them into a feed hopper, will generate transient levels of particulate that exceed the ISO 5 class limit (7).

Classifying cleanrooms under operational conditions is logical, or at least appears so. However, processes do generate particulates, and this effect cannot be eliminated. Powders and ointments are known particle generators, and even ordinary liquids can aspirate particles into the environment. Even in advanced aseptic processing in isolators, process-related excursions occur. In fact, if a probe is located too close to a point along the process line where particulate is generated, counts higher than the class level may be observed more or less continuously. This reality of aseptic processing is rarely discussed, which is unfortunate, and precisely why the authors chose to discuss it in this article. Realistically, the only way to ensure that any process with humans and machines is always within the ISO 5 class limit whenever sampled is to turn off the equipment and have the personnel limit their movement to levels significantly less than those required to perform their work. In other words, the conditions would no longer be dynamic.

Particulates are a functional reality in sterile drug manufacturing, whether the product is aseptically produced or terminally sterilized. This reality is why standards call for "essential" freedom from visible particles and why the compendial limits for total particulate are considerably higher than microbial expectations.

It follows, then, that requiring a firm to investigate any and all excursions is essentially pointless, because it would be investigating completely routine and normal conditions. A more appropriate expectation is that firms maintain their operations within a validated state of control and that in the interest of continuous process improvement they evaluate means of reducing particulate levels.

In the authors' experience in aseptic processing, periodic excursions do not routinely manifest themselves in high product-rejection rates or customer complaints. Periodic excursions above ISO 5 in the critical zone as a result of normal process operations do not increase risk to the patient. In fact, in the authors' experience, airborne particulate is less likely to correlate to visible particulate than is container cleaning or closure cleaning and feeding.

Performance expectations have to be realistic. Often excursions can be correlated to a routine activity such as restocking a parts hopper. It is not reasonable to expect a complete absence of airborne contamination in any manned ISO 5 environment, nor is it reasonable to consider that a minor, brief excursion violates classification requirements. It is reasonable to expect firms to design their manned facilities and closed RABS to handle personnel loads and production capacities, which means in general that these facilities must provide sufficient air-exchange rates. Isolators, given their relatively low enclosed volume and absence of personnel, operate perfectly satisfactorily at lower air-exchange rates. Pragmatic engineering and realistic appraisals of performance should carry the day.


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