dose for API (active pharmaceutical ingredient) residue is
being challenged. Recent ISPE (International Society for
Pharmaceutical Engineering) and EMA (European Medicines
Agency) documents refer to toxicological-based determinations
for setting allowable API. This approach would enable manufacture of highly hazardous pharmaceuticals in a shared facility
in lieu of using dedicated equipment.
Sharnez opines that basing the criteria for bioburden on
0.001 of the dose is arbitrary. “The monoclonal antibody does
not survive the cleaning process or sterilization. The protein
would be denatured. A denatured protein may have different
issues. However, we need to understand and characterize the
residue to obtain meaningful acceptance limits for fragmented
and degraded protein.”
However, LeBlanc is concerned that these toxicological
limits could lead to allowable limits that were significantly
less stringent than limits based on the 0.001 dose criterion for
non-highly hazardous drugs. “While the toxicity of the API is
importance, other issues of residue removal are of concern.
This difference could be resolved by the FDA weighing in.”
LeBlanc expects that by 2020 we will know the direction to
be taken and will have implemented changes. “A reasonable
approach,” concludes LeBlanc, “would be to stay with 0.001
dose for traditional drugs, and use the toxicological approach
for highly hazardous ones.”
Paul Lopolito, Technical Service Manager at Steris Corp., St.
Louis, sees increasing emphasis on scientifically-based decisions in the cleaning process, in the impact of cleaning on
surfaces. “There will be increased monitoring. This includes
evaluating the cleaning agent chemistry, understanding rinsi-bility, assessing the toxicity risk of the API, and assuring that
the overall cleaning process is robust.
Requirements for quantitative consistency will increase.
“Not only will you have to be below the pass/fail,” explains
Forsyth, “you have to clean to the same level consistently all the
time. If pass/fail is 100, and you are usually at 1, you should be
getting to 1 consistently.”
Part of assuring a robust process includes monitoring.
Lopolito sees not only TOC (total organic carbon), conductivity,
and in-line UV monitoring but also routine use of advanced
techniques such as UHPLC (ultra high performance liquid chro-
matography). In contrast with current high performance liquid
chromatography, UHPLC analysis could be run in perhaps five
minutes, so in-line monitoring could be practical.
While some see cleanroom cleaning as completely separate
from product contact cleaning, others take a more integrated
approach. “Who cleans the floor?” asks Pluta. “The lowest one
on the totem pole. That should change. We have to say: ‘We will
train you. We will have competent personnel do the training.
We will pay you appropriately.’ That would be fantastic!”
Pluta adds that “one company combined site maintenance,
with equipment, with environmental (bacterial) monitoring.
They called it the Cleaning Science department. This was bril-
liant! That elevated it.” Pluta suggests that the pharmaceutical
industry consider combining cleaning product contact clean-
ing with microbial control and facility cleaning—all cleaning
should be approached by a scientific and technical approach.
He adds that personnel who do cleaning must understand the
importance of their responsibilities.
Lopolito favors on-site training. “There will be more SME
[subject matter expert] training to address CAPA [corrective
and preventative action] issues. The idea is to create site experts
through high-level training of a few individuals.” Lopolito
favors using outside experts because it is hard to benchmark
internally; you have to get the perspective of other companies.
He states that if there are too many people involved in training,
it becomes too general, that it is preferable to train the internal
trainers. In our own experience, we find that sometimes technicians need direct education. It depends on the application.
Perhaps, in 2020 we will see more customized training and
Catalysts and game-changers
Like many chemical reactions, change may require a push,
either a level of discomfort, or a positive opportunity. LeBlanc
notes that for pharmaceuticals, while some changes occur
slowly, blatant, well-publicized failures can result in more rapid
change, citing failures that prompted cleaning equipment vali-
dation. Pluta predicts that the great increase in organisms with
drug resistance will heighten awareness of cleaning. “Not a day
goes by without some report of contamination in industry,
hospitals, cruise ships, food packages, and so on—the world is
becoming more and more aware of the importance of clean-
ing.” Sharnez hopes for newer guidelines from the FDA. He sees
increasing synergy between industry and the regulatory com-
munity. “I predict that by 2020 regulations will be based more
on the potential impact to the patient, including the impact of
degraded protein on the patient.”
New developments could change the picture. Marc Madou,
Professor of Biomedical Engineering at the University of
California, Irvine suggests the potential for therapeutics and
diagnostics to come together on a single platform, a single
device, like a compact disc. If that happens, if we put desirable
biofilms onto a disc, “there will be an evolution. We will have
to look at different materials for cleaning, at different tech-
niques for cleaning; and manufacturing will have to be done in
a more well-defined, cleaner environment.”
Barbara Kanegsberg and Ed Kanegsberg (the Cleaning Lady
and the Rocket Scientist) are experienced consultants and educators in critical and precision cleaning, surface preparation, and
contamination control. Their diverse projects include medical
device manufacturing, microelectronics, optics, and aerospace.