Bloomfield, Microbial Contamination: Spoilage and Hazard

A) Intended Use:
Bloomfield targets all manufactured pharmaceutical products that have the potential
to be contaminated in his chapter about spoilage and hazard. He outlines two main
dangers caused by the microbiological contamination of pharmaceuticals. The first
danger is product spoilage. Microorganisms can use the drug product as a substrate,
causing alterations to the chemical structure of the drug product itself (Denyer &
Baird, 2007, p. 30). This can decrease the efficacy of the drug. The second danger
is an immediate risk to a patient�s health. Contaminated products can lead to
disease and infections. Bloomfield suggests that an acceptable microbe level for
certain classes of drug products needs to be established (Denyer & Baird, 2007, p.
30). However, due to numerous variables, some predictable and others unpredictable,
it is difficult to set absolute standards. Instead, microbial contamination should
be reasonably controlled to the best of our current capabilities.
B) Microbiological Risk:
Due to the complex nature of pharmaceutical manufacturing, there are many sources
of contaminants that can make their way into the final drug product. Contaminations
can be present in raw source materials. Products of synthetic origins tend to have
less objectionable contaminates than those derived from natural sources (Denyer &
Baird, 2007, p. 32). For this reason it is important to consider the origin of each
component and evaluate the risk it can impart to the final finished product.
Microbial contamination can also be introduced during manufacturing from direct
contact between the drug product and equipment or personnel. Areas of particular
concern are dead spaces, which primarily occur in a water system�s dead legs,
joints or valves. Water along with product can stagnate in these areas, providing a
haven for bacteria to accumulate and reproduce. Once bacteria have colonized a
segment of a water system, removing the colony can be very difficult (Denyer &
Baird, 2007, p. 33). Is it therefore crucial to evaluate the design and
construction of the water system to eliminate or prevent as many of these problem
areas as possible. Another major source of contamination during manufacture are
personnel. It has been estimated that 104 particles are generated from personnel
every minute during normal processing activities (Denyer & Baird, 2007, p 33).
These skin particles serve as vectors to microbes allowing for indirect
contamination of the product to occur. Consequently, it is vital to stop the
ingress of these particles into the product. By using proper gowning techniques and
appropriate cleanroom behavior, contamination via personnel can be controlled and
eliminated. Some organisms are able to use the drug product as a substrate for
growth (Denyer & Baird, 2007, p. 35). This means that a very low level
contamination, which was initially able to pass microbial limit testing, can
eventually turn into a gross contamination which would fail the microbial limit
test and deem the product hazardous to patients. Low-level contaminations are of
greater concern to immunocompromised patients. For this patient group, a very low
dose can be infective due to patients� decreased resistance to infections.
Microbial growth in the product can cause many issues apart from the inherent risk
of disease or infection to the patient. Problems such as inefficient dosage
delivery, reduced bioavailability of the drug, a change in pigmentation, production
of odors, degradation of preservatives and buildup of harmful toxins can all be
resultant of microbial activity in the drug product (Denyer & Baird, 2007, p. 36).
An interesting phenomena Bloomfield discusses is the ability of certain gram-
negative bacteria to acquire resistance to disinfectants and surprisingly grow in
these types of solutions. These bacteria are able to do this by metabolizing
carbons found in antimicrobials (Denyer & Baird, 2007, p. 44). Consequently, it is
imperative to limit but ideally eliminate the microbial contamination of each and
every component utilized in the final drug product due to the immense risk
microorganisms can pose to the patient.
C) Limitations, Strengths, or Weaknesses:
Limitations to Bloomfield�s document mainly stem from the fact that most of the
studies cited were performed more than thirty years ago. Microbe biology has
remained relatively unchanged in that time period but there have been many advances
in technology for manufacturing and equipment design that are now implemented in
modern cleanrooms. It is for this reason that some of the studies and data used in
Bloomfield�s document may no longer be applicable today. I would not consider this
a weakness of the document however. I believe that many of the core concepts and
ideas discussed by Bloomfield are still relevant nonetheless.
D) Relevance to CGMP:
Bloomfield�s document on spoilage and hazard discusses many important issues vital
to CGMP. Microbes stemming from personnel can be a major source of contamination in
the finished drug product. Bloomfield states that a high percentage of skin
particles can be contaminated with normal skin flora (Denyer & Baird, 2007, p. 33).
These particles can make their way into the final drug product if pertinent
precautions are not taken. Contamination via personnel can be greatly reduced and
even eliminated by the appropriate education in gowning techniques, sanitation and
hygiene. The CFR Title 21 Part 211 has a section solely dedicated to qualifications
and responsibilities of operators in a production setting. The CFR specifies,
�personnel shall practice good sanitation and health habits� and in addition,
�(personnel) shall wear clean clothing appropriate for the duties they perform.
Protective apparel, such as head, face, hand, and arm coverings shall be worn as
necessary to protect drug products from contamination� (CFR, 2017). Bloomfield
refers to a few studies in his document where product containers and closures were
not properly cleaned and sterilized. This resulted in the contamination of the
final product when it was packaged into those compromised containers (Denyer &
Baird, 2001, p. 33). The CFR�s section on drug product containers and closures
states, �containers and closures shall be clean and, where indicated by the nature
of the drug, sterilized and processed to remove pyrogenic properties to assure that
they are suitable for their intended use� (CFR, 2017). Container and closure is
often the final step in the complex manufacturing process. Monitoring and testing
of this key step is crucial to prevent the presence of organisms in the final
product, which will ensure continued sterility.

References
Current Good Manufacturing Practice for Finished Pharmaceuticals. (2017, November
22). Retrieved November 25, 2017, from https://www.ecfr.gov/cgi-bin/text-idx?
node=pt21.4.211#se21.4.211_1165

Denyer, S. P., & Baird, R. M. (2007). Guide to microbiological control in

pharmaceuticals and medical devices. Boca Raton, FL: CRC Press - Taylor & Francis.