The personnel who work in asepticmanufacturing areas continue to represent the greatest threat to drug production. Human beings
are prodigious bioreactors; by some accounts, 90% of the cells on the human body are microbiological in nature (5). Furthermore,
even with the most robust training programs, cleanroom personnel do not always adhere to good aseptic practices, generally
through thoughtlessness alone. Willful deviations from standard operating procedures may intend to mitigate the risk of failing
environmental monitoring data. Spraying sterile isopropyl alcohol on gloved hands or Tyvek suits immediately prior to plating,
for example, may reduce the risk of failing results, but is never condoned. Other deviations from standard operating procedures
and aseptic practices are more difficult to categorize. During a training event, an operator spoke of adding unapproved household
dish detergent to the validated disinfectant solution used in the classified cleanroom in order to produce more foam, which
was essential to good cleaning, they believed—a fallacy that can be dispelled through training. Though the intention was noble,
the behavior was still not compliant with cGMP practices and, at the very least, placed management in a poor regulatory situation.
In a worst-case scenario, it may have compromised the performance of the disinfectants putting the drug at risk.
There are hundreds of ways that an aseptic environment can be compromised through the well-meaning efforts of insufficiently
trained and monitored personnel. The key to reducing operating risk is to incorporate a solid cGMP platform in the training
program. This platform should draw on the evolving history of drug production, incorporating real-world examples of the damage
that adulterated drugs represent to human health. Everyone knows someone who uses pharmaceuticals at least periodically and
understanding what the risk of poor production control represents to a friend, loved one, or to oneself helps to personalize
the message and drive more thoughtful behavior. Basic training in microbiology, antimicrobial chemistry, and cleaning techniques
can ensure greater compliance by establishing a solid rationale for why certain products and conditions are used. In other
words, through education, a large complex system that requires the control of millions of invisible objects can be scaled
to a level that the cleanroom operator can understand and embrace. And once training is delivered, it must be reinforced through
frequent management interaction. However, as operation management spends more time away from the manufacturing floor, there
is less opportunity to observe behavior and a chance that oversight of problems may occur.
Cleaning is a cGMP requirement. The environment must be controlled to prevent particulate and microbial contamination of the
drug, packaging components, and product contact surfaces. The manner (e.g., products, application methods, and frequency)
in which cleaning and microbial control takes place varies from site to site, in part because of differences in facility design
and production needs. However, there are guidance documents and best practices that should be incorporated into the cleaning
and microbial control strategy (6, 7).
There are also practices that are not universally applied or sometimes well-understood. One such practice is disinfectant/sporicide
rotation. The term itself has undergone change over the past decade or so. In the past, rotation implied alternating use of
two broad-spectrum disinfectants of similar chemistry (e.g., two phenols or two quats). By rotating two different formulations
with similar active ingredients and different chemical or physical properties (e.g., pH, alkalinity), one might address a
broader spectrum of microorganisms (e.g., bacteria, fungi, viruses), while minimizing the development of problematic residues
that may occur from the interaction of two different, and potentially incompatible chemical species. At this time, the above
type of rotation is still prevalent as evidenced by recent FDA 483 observations, "The firm failed to follow written procedures
for cleaning and disinfection of Class 10,000 rooms, in that, production personnel do not alternate cleaning and disinfection
agents for sinks and flat surfaces, as dictated in SOP..." (8). However, as the need to control more resistant organisms,
such as fungal spores and bacterial endospores, becomes greater, rotation programs are often refined to include the use of
a sporicide. This model of alternating routine disinfectants, or one routine disinfectant, with a sporicidal agent, is fast
becoming a regulatory preference, and is noted in various regulatory and advisory documents, including USP <1072> "Disinfectants and Antiseptics," in USP 32–NF 27: "It is prudent to augment the daily use of a bactericidal disinfectant with weekly (or monthly) use of a sporicidal agent.
The daily application of sporicidal agents is not generally favored because of their tendency to corrode equipment and because
of the potential safety issues with chronic operator exposure. Other disinfection rotation schemes may be supported on the
basis of a review of the historical environmental monitoring data."
Selection of disinfectants and sporicides should be made based upon scientific evidence of efficacy against the target spectrum
of organisms, as well as other important considerations, such as substrate compatibility and operator safety. Sources that
provide information on the mechanisms by which different chemical entities work against the structures of various microorganisms
are too numerous to count and can certainly aid in the selection of disinfectants and sporicides (9). However, scientifically-based
references and conventional wisdom used to select these products does not alleviate drug manufacturers of the requirement
to validate disinfectants, sporicides, and even isopropyl alcohol for use in facilities under actual use conditions against
environmental isolates. According to FDA, "Disinfectant agents used to sanitize surfaces in the aseptic processing areas (APA)
have not been adequately qualified to assure that they provide the intended microbial decontamination when used in the manner
as specified in the standard operating procedures as follows: a. The qualification study only evaluated stainless steel and
not other surfaces in the APA such as glass, plastic and epoxy painted surfaces. b. The qualification study used a longer
exposure time to the sanitizing agent then that time specified in the cleaning SOPs. c. The qualification study immersed the
test surface in the disinfectant for ... Instead of wiping the surface as specified in the SOPs" (10).
In addition to microbial efficacy, the question of the role that disinfectant and cleaning agent residues play in environmental
control has become a more urgent concern (see Figure 3). Most disinfectants and cleaning agents contain ingredients that are
nonvolatile. In many cases, these are inert substances; however, the impact of these residues should be evaluated with regard
to subsequent cleaning and environmental monitoring activities: "No evaluation has been performed to ensure that cleaning
solution residues do not negatively impact environmental sampling or testing" (11). Therefore, it is prudent to incorporate
a rinsing strategy into your cleanroom contamination control procedures. This strategy should identify the rinsing agent,
frequency of rinsing and specific application procedures. Further, if a rinsing agent other than purified water or isopropyl
alcohol (or other product that leaves no residue) is to be used, then the nature of the residues being introduced must be
considered. Frequency of application needs to be assessed on the basis of "risk versus reward." Introduction of water or other
rinsing agents too frequently, especially immediately following disinfection, may lead to further microbial control challenges
through dilution of the disinfectant before sufficient contact time is achieved for optimum performance.
Figure 3: Disinfectant residue on epoxy flooring. (FIGURES 3 & 4: STERIS CORPORATION)
Environmental-monitoring data must demonstrate a state of sufficient control to prevent adulteration of product in an environment
where the facility design, the personnel, and the contamination-control practices employed may contribute to a variety control
challenges. A holistic approach, emphasizing the contribution of each part to the function of the entire complex system, enables
control that drug manufacturers require and that consumers deserve.
Figure 4: Disinfectant residue on vinyl flooring.
Elaine Kopis Sartain* is senior director of global marketing and technical service, and Jim Polarine is technical service specialist, both for STERIS Corporation, 5960 Heisley Road, Mentor, OH, 44060, tel: 314.290.4792, firstname.lastname@example.org
*To whom all correspondence should be addressed.