A recent bestseller tackled the question of why an entire nation can be compelled to help one or a few people in life-threatening
situations (e.g., Chilean miners), but will do little to help millions who are at equal or greater risk (e.g., tsunami victims)
(1). This concept may be irrational, but it is an accurate portrayal of the difficulty in working toward abstract goals based
on concepts or proportions that are near impossible to grasp. Saving one nearby person is far easier to conceptualize than
saving millions who are suffering in a distant land. In situations such as these, the tendency is to turn away because we
cannot visualize how to effect change in something that we do not understand. This phenomenon also plays a role in environmental
control of drug-manufacturing spaces. We are asking personnel to exercise a great deal of caution and follow rigid protocols
designed to prevent contamination of the drug by invisible entities that number in the millions. To put it simply, those who
work in crucial manufacturing areas have an innate tendency to underestimate the impact they have on controlling a large complex
system, nevermind what subsequent effect that may have on public health, which really can be the outcome of poor manufacturing
control as evidenced by recent influenza vaccine shortages and product recalls (2,3).
Effective management of drug-manufacturing areas requires a holistic approach based on identifying and monitoring those components
that play the most critical roles: facility (design and conditions), personnel (training and management), and microbial control
programs (products and application). A holistic, multidisciplinary approach relies heavily on metrics to address and understand
the behaviors of complex systems.
The best defense is a good offense, especially when there are millions of dollars and the public health at stake—not hyperbole
when talking about vaccines and other biotechnology derived drugs. In these cases, where terminal sterilization is typically
not an option, a strong offensive position begins with a robust facility design that insulates the drug and packaging components
from sources of contamination. This design must include adequate barriers (e.g., interlocking doors, clear zone demarcation),
enough HVAC capacity to handle seasonal fluctuations in temperature and humidity, water control (e.g., placement of drains
and water-for-injection drops), cleanable design features (e.g., smooth coving, limited obstructions), and the selection of
chemical and moisture resistant materials of construction (e.g., 316L stainless steel, epoxy or polymeric flooring) to name
but a few considerations. When budget, time, and expertise is unlimited, design and construction of a drugmanufacturing facility
optimized to prevent product contamination can be easily achieved. However, in a less-than-optimized environment, the design
and facility condition are often contributing factors to microbial excursions, and in some cases, product contamination.
Figure 1: Water damaged wall covered with mold. (FIGURE 1: PHOTO BY JIM POLARINE)
Even stainless steel may suffer the effects of chemical exposure, or overexposure, resulting in rust. Rust and pitting present
challenges to effective microbial control in two ways: by providing shelter to microorganisms and residue, and by inhibiting
cleaning and decontamination agents from reaching microbes to achieve adequate contact time. Stainless steel is not the only
surface that can be damaged. Epoxy and polymeric floors can suffer significant damage from high foot traffic or the force
of moving heavy equipment—and are not immune to the effects of significant chemical exposure. Both scenarios may lead to pooling
water and associated microbial control problems, such as mold and Bacillus proliferation. Significant water damage to the structure can lead to endemic problems with molds and Bacillus (see Figure 1). Drainage issues can result in biofilm formation (see Figure 2), which cause significant, recurring problems
with Bacillus and other bacteria due to increased resistance to antimicrobial chemistries demonstrated by biofilms (4).
Figure 2: Biofilm formation in pipes. (FIGURE 2: ADAPTED WITH PERMISSION FROM MONTANA STATE U. CENTER FOR BIOFILM ENGINEERING)
Another necessity of good design is the inclusion of sufficient barriers to isolate the drug manufacturing process. Older
facilities or facilities that were not originally designed for this purpose may not have an ideal barrier design. The warehouse
or component staging areas, for example, may not be ideally located to prevent egress of undesirable particulate. It may not
be possible to establish one-way traffic because of structural limitations. In both cases, contamination control is more problematic
and, consequently, the drugmanufacturing process is more difficult to manage.
The most common approach to microbial control problems due to facility design flaws or damage is to increase the use of chemical
antimicrobial products by concentration, frequency, or both. Extremely aggressive chemical agents, such as acidified bleach,
may also be used on a short-term basis. While these measures may result in immediate improvements in environmental monitoring
data, in the long run, this approach may lead to even more damage and, thus, less ability to control the environment in the
future. The best solution to establish a high degree of control is to repair or retrofit the facility as required, which,
although costly, is perhaps less expensive than the alternative of chasing root causes of microbial excursions or product
contamination and rejection.