Chemistry, Manufacturing, and Control of Ophthalmic Formulations - Ocular Pharmacology and Toxicology - page 69

Table 8
Reporting, identification, and qualification thresholds of impurities
in formulation

Maximum daily dose Threshold

Reporting thresholds

1 g 0.1 %

> 1 g 0.05 %

Identification thresholds
<

1 mg 1.0 % or 5 μ g TDI, whichever is lower

1-10 mg 0.5 % or 20 μ g TDI, whichever is lower

> 10 mg to 2 g

0.2 % or 2 mg TDI, whichever is lower

> 2 g

0.10 %

Qualification thresholds
<

10 mg 1.0 % or 50 μ g TDI, whichever is lower

10-100 mg 0.5 % or 200 μ g TDI, whichever is lower

> 100 mg to 2 g 0.2 % or 3 mg TDI, whichever is lower

> 2 g 0.15 %

TDI total daily intake

more of the following: gram-positive vegetative bacteria ( Staphylo-
coccus aureus ATCC 6538), gram-negative vegetative bacteria ( Pseu-
domonas aeruginosa ATCC 9027 and Escherichia coli ATCC 8739),
yeast ( Candida albicans ATCC 10231), and mold ( Aspergillus niger
ATCC 16404). The samples are then pulled at specified intervals to
determine if the antimicrobial preservative system is capable of
killing or inhibiting the propagation of organisms purposely intro-
duced into the formulation. The rate or the level of antimicrobial
activity determines compliance with the preservative efficacy stan-
dards for the cited categories of preparations. Preservative Standards
for multidose topical ophthalmic products (Log Reduction of
Organism Population at recommended test time) are presented as
in Table 9 .
The USP 36 Antimicrobial Effectiveness Test requires that
compositions containing category 1 products have sufficient anti-
bacterial activity to reduce an initial inoculum of approximately 10 5
to 10 6 bacteria by one log (i.e., a 90 % reduction in the micro-
organism population) over a period of 7 days and by three logs (i.e.,
a 99.9 % reduction in the microorganism population) over a period
of 14 days, and requires that there cannot be any increase in the
microorganism population following the conclusion of the 28-day
period. Relative to fungi, the USP standards require that the com-
positions maintain stasis (i.e., no growth) relative to the population
of the initial inoculum over the entire 28-day test period. Ophthal-
mic formulations are considered as a category 1 product.
The margin of error in calculating microorganism populations
is generally accepted to be

0.5 logs. The term “stasis” means that