Sterile articles packaged in multi-dose containers must be free of microorganisms throughout their entire shelf-life. Due to the potential for the introduction of microorganisms through the repeated withdrawal of individual doses, sterile products that are packaged in multi-dose containers should contain an antimicrobial preservative. However, the concentration of an added antimicrobial preservative can be kept to a minimum if the ingredients of the compounded formulation possess an intrinsic antimicrobial activity. Antimicrobial effectiveness, whether inherent in the product or as a result of an antimicrobial preservative, must be demonstrated through USP <51> antimicrobial effectiveness testing. 

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As the presence of microorganisms in nonsterile preparations has the potential to reduce and/or inactivate therapeutic activity and adversely affect the health of patients, compounders are required to ensure that nonsterile preparations have a low bioburden that complies with established specifications for microbiological quality as outlined in USP <61>. USP <61> Microbial Enumeration tests provide a quantitative evaluation of a product’s microbial content to demonstrate compliance with established specifications.

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Table 1 in USP <1111> sets acceptance criteria for the presence of certain microorganisms in a nonsterile preparation based on its route of administration. The presence of these objectionable pathogens and microorganisms cannot exceed the acceptance criteria outlined in Table 1. USP <62> testing is designed to demonstrate compliance with these requirements by quantifying the presence of specified microorganisms.

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USP <71> outlines the compendial requirements for sterility testing that must be followed in order to be able to claim that the results of the test provide evidence that the product is sterile. 

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USP <71> Method Suitability Testing (MST) must be performed prior to being able to claim that the results of a USP <71> sterility test provide evidence of a preparation’s sterility. Method Suitability Testing only needs to be completed once for each compounded formulation, and consists of two parts: i) a suitability test that confirms that the growth media used for sterility testing supports the growth of certain microorganisms and ii) a validation test that demonstrates that no components of the compounded preparation inhibit microbial growth.

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 As bacterial endotoxins can pose health and safety hazards to patients, USP <85> requires bacterial endotoxin testing to detect and quantify the presence of endotoxins from Gram-negative bacteria in sterile compounds. To assure patient safety, the quantity of bacterial endotoxins may not exceed threshold limits defined in USP <85>. For each bacterial endotoxin test, inhibition validation testing is performed. This testing confirms that there are no components of the formulation that will interfere with the bacterial endotoxin test and that the testing used is sensitive enough to provide meaningful, accurate data.

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Endotoxin Oven Validation determines depyrogenation cycle effectiveness by detecting and quantifying the presence of endotoxins from Endotoxin Control Vials (ECVs). By using ECVs placed in different locations within the oven to mimic load configurations, the validation determines if the depyrogenation cycle parameters are effective at removing or inactivating the pyrogen. Endotoxin Oven Validation should be performed at a minimum yearly, ensuring proper function of the oven.

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Solutions must be essentially free from observable particulate matter. Due to the small amount of material and the heterogenous composition that particulate matter represents, it cannot be quantitated by chemical analysis alone.

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USP <1207> container-closure integrity testing demonstrates the ability of the container-closure system to maintain the integrity of its microbial barrier throughout the entire shelf-life of a product. Eagle utilizes a pressure decay to test container-closure integrity, which is one of the deterministic methods recommended by USP <1207>. As sterility is an event-related occurrence, container-closure integrity testing is performed to support the claim that the sterile containers in which the preparation is packaged are capable of maintaining the sterility of the product throughout its shelf life. 

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Identification by IR USP <197>: This test provides conclusive evidence of the identity of a substance using infrared absorption spectrums compared to a USP reference standard. Conformance with both IR absorption and UV absorption test specifications, as called for in a large proportion of compendial monographs, leaves little doubt, if any, regarding the identity of the specimen under examination.

Identification by UV USP <197>: This test provides the identity of a substance using ultraviolet absorption spectrums compared to a USP reference standard. Conformance with both IR absorption and UV absorption test specifications, as called for in a large proportion of compendial monographs, leaves little doubt, if any, regarding the identity of the specimen under examination.

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Total Organic Carbon (TOC) is an indirect measure of organic molecules present in pharmaceutical waters measured as carbon. Organic molecules are introduced into the water from the source water, purification and distribution system materials, biofilm growing in the system, and the packaging of sterile and nonsterile waters. TOC can also be used as a process control attribute to monitor the performance of unit operations comprising the purification and distribution system.

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USP <621> Chromatographic separation techniques are multistage separation methods in which the components of a sample are distributed between two phases, of which one is stationary and the other is mobile.  The analytical chromatography methods Eagle utilizes are designed to determine the concentration of the active ingredient(s) in a compounded preparation.  Testing protocols are developed based on guidelines delineated in USP <621> Chromatography and are validated according to USP <1225> Validation of Compendial Procedures and ICH Guidelines. The customer is notified immediately of any sample that does not test within acceptable limits.

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