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Printed by: Trifena Lokajaya Official Date: Official Prior to 2013 Document Type: GENERAL CHAPTER @2023 USPC
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á1111ñ MICROBIOLOGICAL EXAMINATION OF NONSTERILE
PRODUCTS: ACCEPTANCE CRITERIA FOR PHARMACEUTICAL
PREPARATIONS AND SUBSTANCES FOR PHARMACEUTICAL USE
The presence of certain microorganisms in nonsterile preparations may have the potential to reduce or even inactivate the
therapeutic activity of the product and has a potential to adversely affect the health of the patient. Manufacturers have therefore
to ensure a low bioburden of finished dosage forms by implementing current guidelines on Good Manufacturing Practice during
the manufacture, storage, and distribution of pharmaceutical preparations.
Microbial examination of nonsterile products is performed according to the methods given in the texts on Microbial
Enumeration Tests á61ñ and Tests for Specified Microorganisms á62ñ. Acceptance criteria for nonsterile pharmaceutical products
based upon the total aerobic microbial count (TAMC) and the total combined yeasts and molds count (TYMC) are given in
Tables 1 and 2. Acceptance criteria are based on individual results or on the average of replicate counts when replicate counts
are performed (e.g., direct plating methods).
When an acceptance criterion for microbiological quality is prescribed, it is interpreted as follows:
• 101 cfu: maximum acceptable count = 20;
• 102 cfu: maximum acceptable count = 200;
• 103 cfu: maximum acceptable count = 2000; and so forth.
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Table 1. Acceptance Criteria for Microbiological Quality of Nonsterile Dosage Forms
Total Aerobic Total Combined
Microbial Count Yeasts/Molds
(cfu/g or Count (cfu/g or
Route of Administration cfu/mL) cfu/mL) Specified Microorganism(s)
Nonaqueous preparations for oral use
Aqueous preparations for oral use
Rectal use
10
102
10
3
3
ci 10
101
10
2
2
Absence of Escherichia coli (1 g or 1 mL)
Absence of Escherichia coli (1 g or 1 mL)
Oromucosal use 102 101 Absence of Staphylococcus aureus (1 g or 1 mL)
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Absence of Pseudomonas aeruginosa (1 g or1 mL)
Gingival use 102 101 Absence of Staphylococcus aureus (1 g or 1 mL)
Absence of Pseudomonas aeruginosa (1 g or 1 mL)
Cutaneous use 102 101 Absence of Staphylococcus aureus (1 g or 1 mL)
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Absence of Pseudomonas aeruginosa (1 g or 1 mL)
Nasal use 102 101 Absence of Staphylococcus aureus (1 g or 1 mL)
Absence of Pseudomonas aeruginosa (1 g or 1 mL)
Auricular use 102 101 Absence of Staphylococcus aureus (1 g or 1 mL)
Absence of Pseudomonas aeruginosa (1 g or 1 mL)
Vaginal use 102 101 Absence of Pseudomonas aeruginosa (1 g or 1 mL)
Absence of Staphylococcus aureus (1 g or 1 mL)
Absence of Candida albicans (1 g or 1 mL)
Transdermal patches (limits for one patch in- 10 2
10 1
Absence of Staphylococcus aureus (1 patch)
cluding adhesive layer and backing)
Absence of Pseudomonas aeruginosa (1 patch)
Inhalation use (special requirements apply to 10 2
10 1
Absence of Staphylococcus aureus (1 g or 1 mL)
liquid preparations for nebulization)
Absence of Pseudomonas aeruginosa (1 g or 1 mL)
Absence of bile-tolerant Gram-negative bacteria (1 g or 1 mL)
Table 2. Acceptance Criteria for Microbiological Quality of Nonsterile Substances for Pharmaceutical Use
Total Aerobic Total Combined
Microbial Count Yeasts/Molds Count
(cfu/g or cfu/mL) (cfu/g or cfu/mL)
Substances for pharmaceutical use 103 102
Table 1 includes a list of specified microorganisms for which acceptance criteria are set. The list is not necessarily exhaustive,
and for a given preparation it may be necessary to test for other microorganisms depending on the nature of the starting
materials and the manufacturing process.
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Printed by: Trifena Lokajaya Official Date: Official Prior to 2013 Document Type: GENERAL CHAPTER @2023 USPC
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If it has been shown that none of the prescribed tests will allow valid enumeration of microorganisms at the level prescribed, a
validated method with a limit of detection as close as possible to the indicated acceptance criterion is used.
In addition to the microorganisms listed in Table 1, the significance of other microorganisms recovered should be evaluated
in terms of the following:
• The use of the product: hazard varies according to the route of administration (eye, nose, respiratory tract).
• The nature of the product: does the product support growth? does it have adequate antimicrobial preservation?
• The method of application.
• The intended recipient: risk may differ for neonates, infants, the debilitated.
• Use of immunosuppressive agents, corticosteroids.
• The presence of disease, wounds, organ damage.
Where warranted, a risk-based assessment of the relevant factors is conducted by personnel with specialized training in
microbiology and in the interpretation of microbiological data. For raw materials, the assessment takes account of the processing
to which the product is subjected, the current technology of testing, and the availability of materials of the desired quality.
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