Microbial limits

United States Pharmacopeia (1995) 23rd revision. Rockville, MD US Pharmacopeial Convention. (Note the section dealing with microbial limit tests.)... 

Microbiological aspects will need to be discussed, but the amount of information will depend on the type of product. For nonsterile products there will need to be a description of the microbiological attributes of the product and, if appropriate, a rationale for not performing microbial limit tests. For preserved products the selection of the antimicrobial preservatives will need to be discussed and the effectiveness of the selected system demonstrated. For sterile products there will need to be appropriate process validation data and information on the integrity of the container-closure system. 

Microbial limits. Carry out the test according to the general procedure <61 >. The total count does not exceed 100 microorganisms per gram, and tests for Staphylococcus aureus, and Pseudomonas aeruginosa, are negative. 

TABLE 1 EU and USP Guidelines for Clean Room Microbial Limits... 

These tests would include compendial tests for Microbial Limits, Sterility, Bacterial Endotoxins, and Antimicrobial Effectiveness. 

The tests for microbial limits and recommendations for microbial quality criteria of raw materials, excipients, drug substances, and pharmaceutical products have been established in pharmacopoeial compendia for over 30 years. These tests are listed in the USP 24 Chapter (61) Microbial Limits Tests and in the Ph. Eur. 3rd ed.. Biological Tests 2.6.12 and 2.6.13, Microbial Contamination of Products Not Required to Comply with the Test for Sterility (total viable count, tests for specified microorganisms) and the JP XIII 30 Microbial Limit Test. 

The USP 24 General Notices state that alternative methods may be used to determine that products comply with the pharmacopoeial standards for the advantages in accuracy, sensitivity, precision, selectivity, adaptability to automation or computerized data reduction, or any other special circumstances. Such alternative or automated methods shall be validated However, when disputed, the compendial method is conclusive as it is the official or referee test. In addition, USP Chapter (61) Microbial Limit Tests states that automated methods may be substituted provided they are validated and give equivalent or better results, whereas USP Chapter (71) Sterility Tests states that alternative procedures may be employed to demonstrate that an article is sterile, provided the results obtained are at least of equivalent reliability. 

Tablets, powder- and liquid-filled capsules Microbial limit test, TAMC, TCYMC only Test development, scale-up and validation batches only 0, 6, 12, 24, 36 months...

Topical liquids, ointment, creams a. Microbial limit test, TAMC, TCYMC only b. USP AET for various use A < 0.75 test development, scale-up and validation batches only A > 0.75 all batches on stability for microbial limit first three batches for AET a. b. 0, 6, 12, 24, 36 months 0, middle of stability period and expiry... 

The following principles apply to microbial limit testing within a pre- and postmar-keted product stability program. 

The inclusion of the a routine microbial limit test in a marketed product stability protocol depends on the pharmaceutical dosage form. Typically, the test would be used only for nonsterile products, especially oral liquids, nasal sprays, and topical liquids, lotions, and creams that have sufficient water activity to support the growth of microorganisms. In contrast, tablets, powder- and liquid-filled capsules, topical ointments, vaginal and rectal suppositories, nonaqueous liquids and inhalation aerosols with a water activity too low to allow for the product to support the growth of microorganisms would not be routinely tested. 

To establish a microbial-limit testing history, all development, clinical, scale-up and process validation batches of new nonsterile dosage forms would be tested to verify that the pharmaceutical ingredients, manufacturing process, and packaging does not contribute to the bioburden of the product. After the testing history has been... 

Clontz, L., Microbial Limit and Bioburden Tests, Interpharm Press, Buffalo Grove, IL, 1998. 

USP 24 Testing Chapters (51) Antimicrobial Effectiveness Testing, (61) Microbial Limit Tests and (71) Sterility Tests, United States Pharmacopeial Convention, Inc., Rockville, MD, 2000. USP 24 Informational Chapters (1116) Microbiological Evaluation of Clean Rooms and other Controlled Environments, (1111) Microbiological Attributes of Pharmaceutical Articles, (1151) Pharmaceutical Dosage Forms, (1225) Validation of Compendial Methods, and (1231) Water for Pharmaceutical Purposes, United States Pharmacopeial Convention, Inc., Rockville, MD, 2000. 

Class B purified water is used for rinsing. This is the same as purified water class A, except that the microbial limit is 100 CEUs/100 ml. 

Tang, S. (1998), Microbial limits reviewed—Basis for unique Australian regulatory requirements for microbial quality of nonsterile pharmaceuticals, PDA, J. Pharm. Sci. Technol., 52,100-109. 

Important specifications for the manufacture of all solutions include assay and microbial limits. Additional important specifications for suspensions include particle size of the suspended drug, viscosity, pH, and in some cases, dissolution. Viscosity can be important, from a processing aspect, to minimize segregation. In addition, viscosity has also been shown to be associated with bioequivalency. pH may also have some meaning regarding effectiveness of preservative systems and may even have an effect on the amount of drug in solution. With regard to dissolution, there are at least three products that have dissolution specifications. These products include pheny-toin suspension, carbamazepine suspension, and sulfamethoxazole and trimethoprim suspension. Particle size is also important, and at this point it would seem that any... 

To address protection, use of tests (see Attachment A) for light transmission, moisture permeation, microbial limits, and sterility are generally considered sufficient. Testing for properties other than those described above (e.g., gas transmission, solvent leakage container integrity) may also be necessary. 

Compatibility and safety for topical delivery systems are addressed in the same manner as for topical drug products. Performance and quality control should be addressed for the rate-controlling membrane. Appropriate microbial limits should be established and justified for each delivery system. Microbiological standards are under development therefore, the review division for a specific application should be consulted. 

A microbial limit test was performed on a routine basis and the 20 consecutive batches each showed conformance to specifications. 

Solubility characteristics in suitable solvents, including color and clarity evaluation pH value if API is soluble in water Microbial limits testing... 

Inorganics Microbial control Microbial limit Particulate matter Endotoxin... 

Microbial tests are substantially less certain than chemical ones, especially when they entail quantification. Microbial limits must be looked at with some skepticism the real value might be something quite different—either higher or lower—than the reported one. Consider any absolute number with some caution the answers are never as clear as they might seem with microbiology. When it comes to enumeration, microbiology can be less than a pure science. 

The need for scientific versus arbitrary limits An approach based on therapeutic dose An approach based on toxicity Selection of the best approach Microbial limits... 

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