APR January/February 2022 - 14

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MICROBIOLOGY
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* The method of application.
* The intended recipient: risk may differ for neonates, infants, and
the debilitated.
* Use of immunosuppressive agents, corticosteroids.
* The presence of disease, wounds, organ damage.
Analysis of the USP <1111>
Risk Factors
In this section of the article, the author will discuss the implication
of these risk factors as cited in <1111> and whether they should
be extended.
Hazard According to the Route of Administration
Drug product administered into the eye and sometimes the lower
respiratory tract, but not the nose, are marketed as sterile products.
For instance, USP <771> Ophthalmic Products - Quality Tests states that
sterility testing is mandatory for ophthalmic products making them
sterile products. The U.S. Good Manufacturing Practice Regulations
21 CFR 200.50 Ophthalmic Preparations and Dispensers require
ophthalmic products be sterile. Inhalation suspensions, solutions
and aerosols being aqueous were in 2000 re-classified by the FDA as
sterile products in response to serious infection outbreaks due to the
bacterial contamination of some generic inhalation solutions (21 CFR
200.51 Aqueous-based drug products for oral inhalation). Otic products
administered into the inner ear or when the eardrum is perforated are
usually sterile (see Mucosal Drug Products-Product Quality Tests <4>).
What generalizations may be made about microbial risk by the route
of administration? Do oral dosage forms have the least risk and
inhalants the greatest risk of microbial infection to the recipient? What
is the hierarchy of microbial contamination for non-sterile products?
USP <1115> Bioburden Control of Non-sterile Drug Substances and
Products lists these dosage forms in descending order based on the
invasiveness of the route of administration only. The risk hierarchy of a
partial list of dosage forms is as follows:
* Metered-dose and dry powder inhalants
* Nasal sprays
* Otics
* Vaginal suppositories
* Topicals
* Rectal suppositories
* Oral liquids (aqueous)
*
Liquid-filled capsules
* Oral tablets and powder-filled capsules
This generalization may be adjusted based on a risk-based assessment
of the physicochemical attributes and intended use of an individual
drug product.
14 |
| January/February 2022
The Nature of the Product
Questions asked in USP <1111> include does the product support
growth and does it have adequate antimicrobial preservation? Product
attributes like water activity, pH, osmolality, salt content, redox potential,
presence of chelating agents, single-use or multiple-use packaging,
storage temperature, and antimicrobial preservative effectiveness
will mitigate the microbial contamination risk. The measurement of
the effectiveness of an antimicrobial preservative system is described
in USP <51>. Some pharmaceutical microbiologists have noted the
absence of Burkholderia cepacia from the list of challenge organisms.
However, the chapter does recommend adding additional challenge
organisms, stating " The standard battery of challenge organisms described
in this test need not prevent the inclusion of other species of
microorganisms if deemed useful to measure the biological activity of
the preservative system for a specific product " .
Aqueous, multiple-use non-sterile drugs must be either inherently antimicrobial
or contain a preservative system that meets the product category
requirements of USP <51> Antimicrobial Preservative Effectiveness.
The USP has official test chapters for measurement of water activity
<922>, pH < 791> and osmolality <785 > but not redox potential. As
a non-sterile product never has a single physico-chemical attribute,
what is the relative effectiveness of each of these attributes versus a
combination of two or more attributes? Adding the concept of hurdle
technology derived from the food industry in Bioburden Control of
Non-sterile Drug Substances and Product <1115> would be worthwhile
(Leistner, 2000).
The Method of Application
The role of the method of application is largely unexplored. For
example, do leave-on versus wash-off non-sterile products have
different risk levels for specific routes of administration? One would
expect so. Is there a different microbial risk associated with a topical
ointment, cream, gel, lotion, wipe, or spray? Would the difference be
related to drug penetration, skin barrier disruption, or retention on the
surface? The answers to these questions are largely unknown.
The Intended Recipient: Risk May Differ for
Neonates, Infants, and the Debilitated
Immunological efficacy and bio-genomic development varies with
age, disease, and medical intervention. It is well known that newborns
have an undeveloped microbiome making them more susceptible
to invasive pathogens. For example, the strict anaerobe Clostridium
botulinum can colonize the intestinal tract of infants between 3 and
6 months old that have poorly developed intestinal microbiome,
producing the neurotoxin that results in infant botulism (Brook, 2007).
The progress of the colonization of the intestine of a newborn differs
as to whether the infant was delivered vaginally or by Caesarean
section as lactobacilli derived from the birth canal colonizes the
infant intestine (Houghteling and Walker, 2015). Currently, Purified
Honey, NF is the only pharmaceutical ingredient with an absence of
Clostridium spp. requirement when the ingredient is used in products
administered to infants less than I year of age. Also, patients treated

APR January/February 2022

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