Article/carrier mixtures

A facility that conducts both GLP-regulated and non-GLP-regulated studies should think carefully about attempting to maintain a dual standard in any one laboratory or with any one group of laboratory workers. In the author s experience, such a dual standard is very difficult to maintain without carryover of non-GLP standards to GLP-regulated work. In such a case it may be far better to maintain a general GLP standard (e.g., data collection, record keeping) for all work in the laboratory, but perhaps allow exceptions for the non-GLP studies in areas such as quality assurance (QA) inspections and analytical requirements for test and control articles and article/carrier mixtures. 

If a testing facility is too small to handle the volume of work it has set out to do, there may be an inclination to mix incompatible functions. Examples might include the simultaneous conduct of studies with incompatible species (e.g., old world primates and new world primates) in the same room, setting up a small office in the corner of an animal housing area, housing an excessive number of animals in a room, or storing article/carrier mixtures in an animal room. 

The use of standard solutions, reference standards, and quality control samples, whether prepared by the laboratory or purchased commercially, is essential to valid analyses of test and control article/carrier mixtures and biological fluids (blood, serum, plasma, etc). 

The requirements of 58.113(a) substantially changed the state of the art for the conduct of nonchnical laboratory studies. Prior to the promulgation of GLP regulations, anal5di-cal tests to estabhsh the homogeneity and stabihty of article/ carrier mixtures were not routine, nor were tests to determine the concentration of test and control articles in the mixtures used to dehver test and control articles to test systems. 

StabUity of the article/carrier mixture can be established in conjimction with the homogeneity assays of nonsolutions. Separate stabdity tests will, of course, be required for solutions. Formal stability trials sufficient to show long-term sta-bdity of the mixtures are not required rather, stabdity shoidd be estabhshed for a period that encompasses the period of use of the article/carrier mixture. Period of use shoidd be defined as whichever of the foUowing two time periods is longer, the time between preparation of the mixture and final administration of that mixture to the test system, or the time between preparation of the mixture and the analysis of the mixture as required by 58.113(a)(2). Often the period between preparation and analysis may be longer than the period between preparation and last administration to the test system. 

There are no established guidelines with regard to the frequency of periodic concentration assays. Some laboratories randomly select a sample from one concentration of article/ carrier mixture per study per week. Other laboratories conduct an analysis of ad concentrations of article/carrier mixtures on a monthly or quarterly basis. 

When article/carrier mixtures are prepared by serial dilution of the highest concentration, FDA has suggested that it would be appropriate to perform an assay on the lowest concentration because this woidd confirm the accuracy of the ddution process. This is not a GLP requirement, however, and there is no prohibition on the analysis of any of the other concentrations. Anal5dical methods may not be sensitive enough for valid assays of the lowest concentration. 

Although some laboratories do not use any article/carrier mixture untd satisfactory anal5dical results are obtained from a concentration assay of the mixture, this is not a GLP... 

Tests to estabhsh the stabihty and homogeneity of article/carrier mixtures as well as the periodic concentration analyses of the mixtures must be conducted in full comph-ance with the GLP regulations. 

A reasonable interpretation of 58.113(c) should not require expiration dating of containers of article/carrier mixtures when the mixtures wiU be used on the date of preparation unless a component of the mixture has an extremely short (e.g., less than 8 hr) period of stability. This section does not require that an expiration date appear on feeders that are filled with article/ diet mixtures on the date the mixture is prepared and are presented to the test animals on that same day. 

The stability... under the conditions of administration will in most cases be the stability of the article/carrier mixtures determined under 58.113(a)(2). If a drug is administered as a powder (e.g., by capsule), the stabihty of the bulk drug determined under 58,105(b) will be reported. 

When article/carrier mixtures are prepared by serial dilution of the highest concentration, the FDA has suggested... 

Although some laboratories do not use any article/carrier mixture until satisfactory analytical results are obtained from a concentration assay of the mixture, this is not a GLP requirement. The concentration assays provide periodic assurance that test systems are being exposed to the amounts and types of test and control articles that are specified in the protocol, therefore the results of the periodic concentration assays must be reviewed critically and promptly. Analytical results outside a pre-established acceptable range (as defined by laboratory SOPs) will require follow-up. Followup should attempt to determine the cause of poor analytical results (e.g., improper pereparation of the article/carrier mixture, sample mix-up, poor analytical technique, equipment malfunction). Corrective action should then be provided as necessary. Usually analytical results in excess of 10% above or below expected values will require follow-up. 

Do any of the components of the test and control article carrier mixture has an expiration date Is that date clearly shown on the container ... 

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