International Pharmacopoeial Guide Limits

In setting the limits for guides appropriate to particular pharmaceutical preparations, both USP and PhEur take account of

• The significance of microorganisms to different types of product

• The way in which the product is used

• The potential hazard to the patient.

Although the pharmacopoeias describe tests for counting two different groups of microorganisms, and tests for detecting the presence or absence of four different selected indicator microorganisms, there is only one single guide in USP XXVI to which all these restrictions apply (Silver Sulfadiazine Cream).

The USP XXVI has 18 guides for oral liquids containing microbiological specifications, 40 for creams and lotions, 17 for ointments and gels, and only three for aqueous inhalations. Table 4.2 makes it clear that "typical" USP microbiological limits applying to oral liquids are for quantitative limits and restrictions on the absence of E. coli and Salmonella spp. "Typical" USP microbiological limits applying to topical preparations are for absence of Staphylococcus aureus and Pseudomonas aeruginosa.

The distinction between the two groups of limits for pharmaceutical preparations is that enteropathogenic microorganisms such as E. coli, Salmonella and other similar types are infective through ingestion in the way that oral liquids are taken, but are not typically infective through the skin. Staphylococcus aureus and Pseudomonas aeruginosa and other similar types of microorganism are infective when applied to broken or damaged skin, where topical preparations are likely to be applied.

PhEur has a broadly similar approach to its categorization of products versus microbiological limits. In Section 5.1.4 it recommends (but does not mandate) limits that should be applied if necessary for broad "categories" of pharmaceutical preparation. For aqueous-based nonsterile preparations, inhalations, topicals and

Contamination of Aqueous-Based Nonsterile Pharmaceuticals

91

Table 4.2 Microbiological Limits in USP XXVI.

Numbers of Guides With/without

With/without limits

With/without limits

quantitative limits

for absence of

for absence of E. coli

Staphylococcus aureus

or Salmonella spp.

or P. aeruginosa

Oral solutions, 15/3

5/13

17/1

Suspensions and syrups

Topical creams and lotions 2/38

40/0

6/34

Topical ointments and gels 0/17

17/0

2/15

Aqueous inhalations and

nasal solutions 0/3

3/0

0/3

transdermal patches belong in category 2; oral solutions, suspensions and liquids in Category 3A.

Category 2 preparations require absence of Staphylococcus aureus, Pseudomonas aeruginosa and compliance with a quantitative limit. Category 3A preparations should comply with a quantitative limit and be free from E. coli.

The "typical" quantitative limit in USP for oral liquids is not more than 100 cfu/g or ml (aerobic bacteria). This applies to 14 of the 15 guides specifying quantitative limits in USP XXVI. One guide (Aciclovir Oral Suspension) has a tighter limit of not more than 10 cfu/ml, which is understandable considering that patients using this preparation are likely to have weakened immune systems. Four of the guides with limits on bacteria also have limits on yeasts and molds (not more than 10/g or ml).

PhEur applies weaker limits than USP to bacterial numbers in oral liquids. Category 3A, for preparations for oral administration applies a quantitative limit of not more than 103 aerobic bacteria/g or ml. On the other hand, PhEur applies a quantitative limit of not more than 102 fungi/g or ml to all products for oral administration — USP rarely applies limits to yeasts and molds.

Restrictions on particular microorganisms in USP are intended to apply to absence in 10 g or 10 ml. The restrictions in PhEur apply only to absence in 1 g or 1 ml.

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