USP 35General Information / ?1111? Microbiological Examination 691
20.Venables, H, and J Wells, Powder sampling. Drug Dev.
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抽丝on Good Manufacturing Practice during the manufacture,Ind. Pharm., 2002, 28(2): pp. 107–117.
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 prod-ucts 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 ?1111? MICROBIOLOGICAL individual results or on the average of replicate counts when replicate counts are performed (e.g., direct plating EXAMINATION OF NONSTERILE methods).
When an acceptance criterion for microbiological quality PRODUCTS: ACCEPTANCE is prescribed, it is interpreted as follows:
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功效与作用
—101 cfu: maximum acceptable count = 20;CRITERIA FOR PHARMACEUTICAL
—102 cfu: maximum acceptable count = 200;
—103 cfu: maximum acceptable count = 2000; and so PREPARATIONS AND forth.
Table 1 includes a list of specified microorganisms for SUBSTANCES FOR which acceptance criteria are set. The list is not necessarily exhaustive, and for a given preparation it may be necessary PHARMACEUTICAL USE
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 The presence of certain microorganisms in nonsterile
allow valid enumeration of microorganisms at the level pre-preparations may have the potential to reduce or even inac-scribed, a validated method with a limit of detection as tivate the therapeutic activity of the product and has a po-close as possible to the indicated acceptance criterion is tential to adversely affect the health of the patient. Manu-used.
facturers have therefore to ensure a low bioburden of
finished dosage forms by implementing current guidelines
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 103102Absence of Escherichia coli (1 g or 1 mL)Aqueous preparations for oral use 102101Absence of Escherichia coli (1 g or 1 mL)
Rectal use
103102—
Absence of Staphylococcus aureus (1 g or 1 mL)Oromucosal use
102
101
Absence of Pseudomonas aeruginosa (1 g or 1 mL)
Absence of Staphylococcus aureus (1 g or 1 mL)Gingival use 102101
Absence of Pseudomonas aeruginosa (1 g or 1 mL)
Absence of Staphylococcus aureus (1 g or 1 mL)Cutaneous use 102101
Absence of Pseudomonas aeruginosa (1 g or 1 mL)
自动皂液器Absence of Staphylococcus aureus (1 g or 1 mL)Nasal use 102101 Absence of Pseudomonas aeruginosa (1 g or 1 mL)
Absence of Staphylococcus aureus (1 g or 1 mL)Auricular use 102101
干墙Absence of Pseudomonas aeruginosa (1 g or 1 mL)
Absence of Pseudomonas aeruginosa (1 g or Vaginal use 102101
1 mL)
Absence of Staphylococcus aureus (1 g or 1 mL)Absence of Candida albicans (1 g or 1 mL)Absence of Staphylococcus aureus (1 patch)Transdermal patches (limits for one 102101
patch including adhesive layer and Absence of Pseudomonas aeruginosa (1 patch)backing)
Absence of Staphylococcus aureus (1 g or 1 mL)Inhalation use (special requirements ap-102101
ply to liquid preparations for nebuliza-Absence of Pseudomonas aeruginosa (1 g or tion)
1 mL)
Absence of bile-tolerant Gram-negative bacteria (1 g or 1 mL)
692?1111? Microbiological Examination / General Information USP 35
Table 2. Acceptance Criteria for Microbiological Quality of Non-Low water activity has traditionally been used to control sterile Substances for Pharmaceutical Use microbial deterioration of foodstuffs. Examples where the
available moisture is reduced are dried fruit, syrups, and
Total Combined pickled meats and vegetables. Low water activities make
Yeasts/Molds these materials self-preserved. Low water activity will also Total Aerobic Count prevent microbial growth within pharmaceutical drug prod-
Microbial Count (cfu/g or cfu/ucts. Other product attributes, for example, low or high pH,
(cfu/g or cfu/mL)mL)absence of nutrients, presence of surfactants, and addition Substances for103102of antimicrobial agents, as well as low water activity, help to pharmaceutical use prevent microbial growth. However, it should be noted that
more resistant microorganisms, including spore-forming
In addition to the microorganisms listed in Table 1, the Clostridium spp., Bacillus spp., Salmonella spp. and filamen-significance of other microorganisms recovered should be tous fungi, although they may not proliferate in a drug evaluated in terms of the following:product with a low water activity, may persist within the ?The use of the product: hazard varies according to the product.
route of administration (eye, nose, respiratory tract).When formulating an aqueous oral or topical dosage ?The nature of the product: does the product support form, candidate formulations should be
evaluated for water growth? does it have adequate antimicrobial activity so that the drug product may be self-preserving, if preservation?possible. For example, small changes in the concentration of ?The method of application.sodium chloride, sucrose, alcohol, propylene glycol, or glyc-?The intended recipient: risk may differ for neonates, in-erin in a formulation may result in the creation of a drug fants, the debilitated.product with a lower water activity that can discourage the ?Use of immunosuppressive agents, corticosteroids.proliferation of microorganisms in the product. This is par-?The presence of disease, wounds, organ damage.ticularly valuable with a multiple-use product that may be Where warranted, a risk-based assessment of the relevant contaminated by the user. Packaging studies should be con-factors is conducted by personnel with specialized training ducted to test product stability and to determine that the
in microbiology and in the interpretation of microbiological container–closure system protects the product from mois-data. For raw materials, the assessment takes account of the ture gains that would increase the water activity during processing to which the product is subjected, the current storage.
technology of testing, and the availability of materials of the Reduced microbial limits testing may be justified through desired quality.risk assessment. This reduction in testing, when justified,
may entail forgoing full microbial limits testing, implement-
ing skip-lot testing, or eliminating routine testing.
Nonaqueous liquids or dry solid dosage forms will not
support spore germination or microbial growth due to their
low water activity. The frequency of their microbial monitor-
ing can be determined by a review of the historic testing ?1112? APPLICATION OF WATER database of the product and the demonstrated effectiveness横向线性马达
of microbial contamination control of the raw materials, in-ACTIVITY DETERMINATION TO gredient water, manufacturing process, formulation, and
packaging system. The testing history would include micro-NONSTERILE PHARMACEUTICAL bial monitoring during product development, scale-up, pro-
cess validation, and routine testing of sufficient marketed PRODUCTS product lots (e.g., up to 20 lots) to ensure that the product
has little or no potential for microbial contamination. Be-
cause the water activity requirements for different Gram-re-
active bacteria, bacterial spores, yeasts, and molds are well The determination of the water activity of nonsterile phar-described in the literature,1 the appropriate microbial limit maceutical dosage forms aids in the decisions relating to the testing program for products of differing water activities can following:
be established. For example, Gram-negative bacteria includ-(a)optimizing product formulations to improve antimi-
ing the specific objectionable microorganisms, Pseudomonas crobial effectiveness of preservative systems, aeruginosa, Escherichia coli, and Salmonella species will not (b)reducing the degradation of active pharmaceutical in-proliferate or survive in preserved products with water activi-gredients within product formulations susceptible to
ties below 0.91, while Gram-positive bacteria such as Staph-chemical hydrolysis,
ylococcus aureus will not proliferate below 0.86, and Aspergil-(c)reducing the susceptibility of formul
ations (especially
lus niger will not proliferate below 0.77. Furthermore, even liquids, ointments, lotions, and creams) to microbial
the most osmophilic yeast and xerophilic fungi will not pro-contamination, and
liferate below 0.60, and they cannot be isolated on com-(d)providing a tool for the rationale for reducing the fre-
pendial microbiological media.1 The water activity require-quency of microbial limit testing and screening for
ments measured at 25° for the growth of a range of objectionable microorganisms for product release and representative microorganisms are presented in Table 1.
stability testing using methods contained in the gen-
eral test chapter Microbial Enumeration Tests ?61? and1J. A. Troller, D. T. Bernard, and V. W. Scott. Measurement of Water Activity.
Tests for Specified Microorganisms ?62?.In: Compendium of Methods for the Microbiological Examination of Foods. Amer-ican Public Health Association, Washington, DC, 1984 pp.124–134. Reduced water activity (a W) will greatly assist in the pre-
vention of microbial proliferation in pharmaceutical prod-ucts; and the formulation, manufacturing steps, and testing of nonsterile dosage forms should reflect this parameter.
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