How to Determine if an Organism is “Objectionable”
Scott Sutton,
Ph.D.
Vectech
Pharmaceutical Consultants
This article first appeared in the
PMF Newsletter
of July, 2006 and is protected by copyright to PMF. It
appears here with permission.
Previous articles in this series (1, 2, 3) have examined the
difference in focus between the USP/NF requirements for the
absence of specific microorganisms in monograph products and
that the USP Microbial Limits Tests does not address the legal
requirement that non-sterile products be free of “objectionable
organisms” as set forth in 21CFR 211.113 and 21 CFR 211.165.
So, since the microbial limits tests do not address
themselves to “objectionable” microorganisms, how is the
manufacturer to determine if there are “objectionables” in a lot
of product awaiting release? One approach is suggested by FDA -
once all organisms grown in the total count studies (total
aerobic as well as total yeast and mold) are identified, a
qualified microbiologist would conduct a risk analysis on the
presence of that organism in that medication (4). This risk
analysis should incorporate a minimum of four separate analyses:
Absolute numbers of organisms seen Microorganism’s
Characteristics Product Characteristics Potential Impact on
Patients
Absolute Number of Organisms Seen
Although high numbers of non-pathogenic organisms may not
pose a health hazard, they may affect product efficacy and/or
physical /chemical stability. An unusually high number of
organisms seen in the product may also indicate a problem during
the manufacturing process, or an issue with a raw material. The
high bacterial counts may indicate that the microorganisms are
thriving in the product. If a preserved product this could
indicate that the product’s preservative system is not
functioning or worse, the preservative was missing or
incorrectly formulated.
The Characteristics of the Microorganism
The characteristics of the microorganism can be determined by
a search of textbooks, or library work, by internet searches, or
a combination of all of these. It is always a good idea to
remember that you are interested in the microbiology of the
situation – do not restrict the search to pharmaceutical sources
as most of the best information will come from food,
environmental, clinical and perhaps cosmetic microbiology
sources in addition to the pharmaceutical field.
During this search look for synonyms of the organisms current
name. With the widespread use of genetic techniques in taxonomy
the names of some organisms have undergone multiple changes. The
national culture collections are a good source of synonyms and
all name variants should be researched.
First of all, determine if the organism is a known pathogen.
A good place to start on this search is the FDA web site the
“Bad Bug Book.” This is only a guide, but a good one (5). One
approach is to do a preliminary evaluation for any organism that
appears on the FDA/CFSAN list and immediately classify that
organism as “objectionable.” However, it is also important to
consider the route of administration and the susceptible
population in this evaluation.
A second characteristic of the microorganism that must be
taken into account is the potential for the organism to cause
spoilage of the product. Make a list of substances used by the
microorganism for growth. This can be from the literature, or
from the identification equipment. For example, the Vitek 2
Compact will provide an extensive list of compounds the
microorganism can metabolize, the Biolog a list of carbohydrates
utilized, etc. Use the information gained during the
identification of the organism. Compare these to the product
formulation for potential issues. A microorganism is also
objectionable if it has the potential to degrade the product on
stability. Evaluate the microorganism’s tolerance to unusual
conditions: low or high pH high salt concentration high sugar
concentration (osmotic conditions) Low water activity Growth
temperature, etc. It can also be useful to determine if the
microorganism has a recognized proclivity for harboring
plasmid-mediated antibiotic resistance. This is a special
concern in regards to horizontal transmission of the trait
within an vulnerable patient population.
Product Characteristics
The dosage form is important to consider. Is the product
anhydrous or water based? This can have an effect on the ability
of microorganisms to proliferate. Does it have sufficient free
water to support microbial growth (6, 7). Is the container
designed to minimize contamination and subsequent spoilage?
Closure design can have a major effect on in-use stability of a
product. Is the container adequately designed to retard access
to the environment, and to prevent contamination from the
environment. Give special consideration to the likelihood of an
anhydrous medication’s exposure to water, providing the
potential for microbial proliferation. The route of
administration is also important. A medication orally
administered can tolerate some microorganisms that would be
disastrous in a medication meant to be applied topically to
abraded skin or to rashes. Similarly, some microorganisms that
could be tolerated in a topical would cause severe distress to a
patient if taken orally. Inhalants, although not required to be
sterile, are a particularly sensitive area and great care should
be taken in classifying any contaminate as “non-objectionable.”
Other product-related considerations should include a review of
the production records and the environmental monitoring trends,
A review of field complaints is also useful (is this contaminant
one that causes eventual returns?).
Patient Population
Finally, a consideration of the targeted patient population
is in order. The manufacturer cannot control, and should be held
accountable, for patient abuse of a product or off-label use of
the product by physicians. However, reasonable use of the
product should be considered and part of the risk analysis. Are
patient populations that are likely to use this product at
increased risk if exposed to the particular microorganism?
Summary
The FDA’s concern with non-sterile dosage format is that the
product not contain “objectionable” organisms. This FDA concern
has been made clear since the 1970’s. However, many companies
continue to mistakenly believe that if their non-sterile product
meets the requirements in USP, it will be safe from FDA dispute.
This not the case. The manufacturer is responsible for all
contents of his drug product. Should question arise over the
appropriateness of a particular organism, the manufacturer is
expected to have a justification for the presence of that
organism, preferably as part of the batch release document.
Presented here is a brief description of some factors to
consider in determining if an organism is objectionable. These
considerations include: Absolute number of organisms present
Microorganism characteristics Product characteristics Patient
Population These are not meant to be a comprehensive listing of
all issues, but rather a starting point for the non-sterile
manufacturer to use in establishing their program to qualify
finished product bioburden.
References
-
Sutton, S. 2006. The
Harmonization of the Microbial Limits Tests; Enumeration.
PMF
Newsletter
12(3):2-3
PDF Copy
-
Sutton, S. 2006. The
Harmonization of the Microbial Limits Tests; Absence of
Specified Microorganisms.
PMF Newsletter
12(4):2-8
PDF Copy
-
Sutton,
S. 2006. Microbial Limits Tests: The Difference Between
“Absence of Objectionable Microorganisms” and “Absence of
Specified Microorganisms”
PMF Newsletter
12(6):3-9
PDF Copy
-
Guide
to Inspections of Microbiological Pharmaceutical Quality Control
Laboratories. 1993
http://www.fda.gov/ora/inspect_ref/igs/micro.html FDA
-
http://vm.cfsan.fda.gov/~mow/intro.html
-
USP.
2004. <1112> Application of Water Activity Determination to
Nonsterile Pharmaceutical Products
Pharm Forum.
30(5):1709-1713
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Werner,
D. 2000. Water Activity: An Underestimated Parameter in
Pharmaceutical Quaity Control.
Pharmeuropa.
12(3):373-375
Consulting with Scott Sutton
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