Controlling and monitoring particles is important for every type of cleanroom, be it semiconductor, pharmaceutical, food and beverage manufacturing, or biotech. This is accomplished through the use of technology such as filtration and proper pressurization, as well as through the use of operating procedures that reduce the risk of particulates being introduced to the clean environment … but what happens when these procedures or technology fail or prove insufficient? Investigating and correcting the problem can prove costly and result in ruined product and lengthy downtimes, especially when viable particles (i.e. microbes) are involved.
Non-viable, or inorganic particles, can cause a company significant inconvenience and potential loss of profits and product, but when a breach occurs in the environment these nonviables can be tracked down in realtime using a particle counter. An experienced cleanroom certifier, in most cases, will be able to track down the problem in a matter of hours or days. Corrective action can be implemented and the effects of corrective or preventive actions can be measured immediately with a particle counter. This ability to investigate and check corrective actions in real-time is much more difficult when dealing with viable particles. Traditional methods for monitoring viable particles are time-consuming and don’t always yield concrete evidence that can be acted on in confidence. These methods include the use of plates which are placed in high-risk or areas of interest around the cleanroom. The plates are then left in place for several hours during which time particles in the air, including any microorganisms, will settle on them. The plates then must be collected, incubated, and then identified and counted after colonization, based on the surface area of the plate. This process can take anywhere from 3 to 7 days before a problem is identified during which time the problem, in the case of microorganisms, is only going to (literally) grow.
Another traditional method which offers some improvement in the collection method is the use of air samplers. Particles are collected on a contact plate, filter membrane, or agar strip via impaction in a manner that does not disrupt the normal airflow and does not render the biological particles non-viable. This more active collection method results in a better sample, but the viable must still be incubated and colonized before they can be counted and identified which takes time.
Consider the following: if a breach in the environment occurs and viable particles are introduced it will take 3 to 7 days to realize there was a breach. After that an investigation must be started to locate the source of the breach, which can be challenging since the viable particles may have been introduced up to a week prior. Even if the source can be pinpointed quickly and remediation implemented, it will take another 3 to 7 days to verify the effectiveness of the corrective action using traditional methods. All of this can quickly add up to weeks of lost manufacturing time.
So what else can be done to secure a controlled environment against viable particles? There are a number of solutions on the market that offer real-time detection of microbes, but each has some limitations and drawbacks that it’s important to be aware of. There are a number of particle counters on the market that can detect the presence of viable particles. These particle counters are similar to traditional particle counter, but they use a special laser that causes biological particles to fluoresce as they pass through the beam. The light from the fluorescing organisms is then detected via photo-sensitive optics and the counts can be separated into viable and non-viable.
These instruments can be expensive and do not identify the microorganisms. Traditional lab analysis is still required to determine the nature of the viable particles which may be necessary before a source can be determined and controls implemented. Some of these instruments double as a sampling method, allowing you to collect a sample directly from the instrument after counting.
The advantage to using these instruments for monitoring is that they provide real-time monitoring. Instead of finding the presence of biological a week after the fact, it’s possible to catch them immediately. This greatly speeds and simplifies investigation as the introduction of the particles is more easily pinpointed or traced to a particular event in the timeline. Corrective action can be taken immediately to contain or eliminate the breach even as a sample is sent to the lab for analysis. It’s also possible to measure the effectiveness of such remediation efforts immediately after they are implemented rather than having to wait for slower traditional methods. Early detection can also lead to prevention of an incident if the viable are detected soon enough, before they have time to spread.
Another method for early detection is a portable microbe sensor. They work by first sampling air through a cyclone which filters out larger particles. The particles are then attracted to a capture plate via electrostatic force and are then heated until they fluoresce. Photo-sensitive optics then measure the volume of fluorescing particles and report it more-or-less in real time. There is a brief delay while the organisms heat up before they fluoresce, but this process typically only takes 10 minutes. Disadvantages of this method include an inability to identify the viables, and there is no actual particle count. These instruments are cheaper than viable-detecting particle counters and, when used for spot checking or as a first line of defense, can provide the important early warning of a problem before it grows.
Manufacturers of these devices are usually willing to discuss the various options and provide technical information to aid end users in finding an optimal solution for their specific needs. In the end it is largely a cost vs. risk assessment as many of these solutions are expensive, but not nearly so much as weeks of lost manufacturing time due to an incident – or worse yet, a product recall and potential legal complications.
References
1. FDA: Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice
2. European Community, Guide to GMP for Medicinal Products and Active Pharmaceutical Ingredients, Annex 1
3. The Japanese Pharmacopoeia, Fifteenth Edition
Bob Casale is with Kanomax USA Inc., Andover, N.J.; www.kanomax-usa.com
This article appeared in the January/February 2015 issue of Controlled Environments.
