الجمعة، 29 أبريل، 2011

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 61 and Tests for Specified Microorganisms 62. 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.
Table 1. Acceptance Criteria for Microbiological Quality of Nonsterile Dosage Forms
Route of Administration Total Aerobic
Microbial Count
(cfu/g or
cfu/mL)
Total Combined
Yeasts/Molds
Count (cfu/g or
cfu/mL)
Specified Microorganism(s)
Nonaqueous preparations for oral use 103 102 Absence of Escherichia coli (1 g or 1 mL)
Aqueous preparations for oral use 102 101 Absence of Escherichia coli (1 g or 1 mL)
Rectal use 103 102
Oromucosal use 102 101 Absence of Staphylococcus aureus (1 g or 1 mL)
Absence of Pseudomonas aeruginosa (1 g or
1 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)
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 including adhesive layer and backing) 102 101 Absence of Staphylococcus aureus (1 patch)
Absence of Pseudomonas aeruginosa (1 patch)
Inhalation use (special requirements apply to liquid preparations for nebulization) 102 101 Absence of Staphylococcus aureus (1 g or 1 mL)
Absence of Pseudomonas aeruginosa (1 g or
1 mL)
Absence of bile-tolerant Gram-negative bacteria
(1 g or 1 mL)
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.
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.
Table 2. Acceptance Criteria for Microbiological Quality of Nonsterile Substances for Pharmaceutical Use

Total Aerobic
Microbial Count
(cfu/g or cfu/mL)
Total Combined
Yeasts/Molds Count
(cfu/g or cfu/mL)
Substances for
pharmaceutical use
103 102
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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