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Understanding how to identify, remediate, and prevent facility infection is crucial for product quality.
With the publicity surrounding the recovery of mold from pharmacy compounding facilities and formulated products connected to patient fungal infections and deaths, there has been a heightened awareness and concern for fungal recoveries in all manufacturing facilities. Humans cannot live in a world that contains at all times substantial concentrations of airborne mold, however, and not be expected to carry some mold along with them as they move from point to point. Mold will be present on clothes, skin, and human hair as a direct consequence of the level of airborne mold that typical individuals inevitably encounter on a daily basis. Reasonable precautions upon moving to sections of facilities where products are aseptically manufactured should include changing into captive shoes and clothing and donning of hair and shoe covers. These precautions, however, cannot be reasonably expected to completely obviate the possibility of random, low-level mold recovery during routine monitoring. There is no medical or toxicological evidence that a low-level environmental mold recovery in a production environment would result in greater risk to a product or end-user than low-level bacterial contamination. Certainly, airborne mold found intermittently and at low frequency is not indicative of mold colonization. Low-level mold likely finds its way into facility environments as a passenger on personnel entering facilities as well as on materials coming into and warehoused within facilities.
To reach spore levels, to say nothing of toxin levels relevant as health risks, mold proliferation (i.e., growth) is necessary. This condition would require a production facility to be infected by mold. Conditions that allow a production facility to become infected are always objectionable. A reasonable question is how would one diagnose the condition of facility infection?
Facility infection conditions
A facility is infected by the ongoing and consistent presence of mold. Given the microbiological assessments used in drug and biological production facilities, this means high viable recovery levels. There have been reports of building infection even in aseptic manufacturing areas, but fortunately these have occurred infrequently. Those that have been reported were due to water leaks from defective pipes or roofs that soiled wall materials made of sheetrock or drywall panels, which are an excellent food source for mold. The normal course of this type of facility infection is that high counts are recovered over a discrete period of time; the microbiological control team then recommends disinfection of the facility. Disinfection succeeds in a temporary diminution in frequency of recovery and count, but within typically 7–10 days a subsequent bloom is observed, manifested again by atypically frequent recoveries. Additional cycles of disinfection produce similar outcomes, with high counts again appearing within typically one to two weeks post disinfectant treatment. If a sheetrock wall is infected with mold, the only effective remediation is to demolish the walls and reconstruct them with a mold-inhibiting material, such as Plascore pharmaceutical cleanroom panels or fiberglass.
The recovery levels observed in residential and uncontrolled commercial building infection are unusually high and far exceed the total microbial recovery levels recommended in United States Pharmacopeia <1116> or EudraLex Volume 4, Annex 1 for classified manufacturing environments (1, 2). Should such conditions be observed in controlled pharmaceutical facilities, an extensive diagnostic program and further steps, including mold remediation, may be necessary. In the event that remediation is necessary, the work that must be done is often extensive, and may require considerable demolition and reconstruction. A mold remediation will be disruptive to operations and may have impact upon manufactured product or work in progress.
Limited facility infection
Mold infections within manufacturing facilities and laboratories may be limited to equipment such as refrigerators or incubators. Again, these are not transient low-level contamination recoveries, but instead are findings reflective of active mold growth. Mold infection of incubators and/or refrigerators has not been uncommon in microbiology laboratories. Fortunately, this is typically an easier condition to treat than wider-spread facility level mold infection.
A removal of all materials from the equipment followed by careful cleaning and disinfection will in most cases eliminate the infection. Preventive actions include avoiding spillage of organic materials such as media or test materials and where a spill does occur cleaning effectively and at a suitable frequency. Also, to prevent mold infection maintaining dry conditions is key, water spills should be removed quickly, and conditions that favor the formation of condensate should be avoided. In most cases, limited mold infection in support areas, such as laboratories, should not pose significant manufacturing risk, particularly when treated promptly and effectively.
The key risk factor regarding mold in drug and biological operations is proliferation-driven infection. Infection of facilities or equipment is easily distinguished from transient low-level contamination. Transient low-level contamination will occur infrequently and randomly. There will be no evidence of high-count levels being reached and no indication of persistence. Given the ubiquity of mold in nature and the levels with which they are present in outdoor air or in office complexes, the recovery of an occasional mold does not merit any particular concern.
On the other hand, evidence of mold proliferation indicative of infection of facilities or equipment must be taken seriously and requires the prompt implementation of corrective and preventive actions. In such cases, the potential effect of mold contamination on product should be carefully assessed.
In our experience, mold recoveries are typically occurring in industry at levels far lower than bacterial recovery. Certainly, microbiologists should keep a watchful eye on patterns to ensure that they have the means to take note of changes in pattern. It is important that significant microbial changes not be missed or ignored.
1. USP, General Chapter <1116>, “Microbiological Control and Monitoring of Aseptic Processing Environments,” (US Pharmacopeial Convention, Rockville, MD, 2012.)
2. Eudralex, Volume 4: EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use: Annex 1: Manufacture of Sterile Medicinal Products (Eudralex, March 2009 revision).
For further information, read the full article, Determining Facility Mold Infection, in the upcoming October issue of Pharmaceutical Technology.