Stability documentation standards

The application of PSA measurements for clinical monitoring of prostatic carcinoma requires fine tuning of PSA assays. One important aspect of this tuning is to have well-defined standards (primary calibrators). Calibrators or primary reference materials consisting of PSA complexed with ACT have been prepared and are available to sponsors of commercial immunoassays. As a result of this, some sponsors have studied calibration stability and have shown that calibration did not change within 14 to 90 days. Primary references of 90 percent PSA-ACT and 10 percent f-PS A have been shown to minimize differences in PSA measurements between different assays [NCCLS Document—Primary Reference Preparations Used to Standardize Calibration of Immunochemical Assays for Serum Prostate... 

QA requires the efficient analysis of many samples to support routine production release and stability programs. Methods are typically established in the analytical development group. Efficiency and convenience issues, including the speed of media preparation and the relative convenience of data handling and documentation, are important here. While compliance is important in all aspects of the pharmaceutical industry, QA functions must approach compliance perfection. Depending upon the facility, the automated apparatus may be tailored to specific methods with fixed configurations. Dissolution methods may be routine enough that a custom system, optimized for productivity, may be justified. Compliance of USP and use of industry standard apparatus is important to maintain compatibility with other company laboratories or in the case contract laboratory services are required. 

ECT should be considered for more severe forms of depression (e.g., those associated with melancholic and psychotic features, particularly when the patient exhibits an increased risk for self-injurious behavior) or when there is a past, well-documented history of nonresponse or intolerance to pharmacological intervention. Limited data indicate that bipolar depressed patients may be at risk for a switch to mania when given a standard TCA. A mood stabilizer alone (i.e., lithium, valproate, carbamazepine, lamotrigine), or in combination with an antidepressant, may be the strategy of choice in these patients. Some elderly patients and those with acquired immunodeficiency syndrome may also benefit from low doses of a psychostimulant only (e.g., methylphenidate) (see also Chapter 14, The HIV-Infected Patient ). Fig. 7-1 summarizes the strategy for a patient whose depressive episode is insufficiently responsive to standard therapies. 

Stock Solution Stability. The stability of stock solutions of drug and the internal standard should be evaluated at room temperature for at least 6 h. If the stock solutions are refrigerated or frozen for the relevant period, the stability should be documented. After completion of the desired storage time, the stability should be tested by comparing the instrument response with that of freshly prepared solutions. 

Adolescents. Documentation of the safety and efficacy of antidepressants and mood stabilizers is better for adolescents than for children, although not at the standard for adults. That is unfortunate, because mood disorders often have their onset in adolescence, especially in girls. Not only do mood disorders frequently begin after puberty, but children with onset of a mood disorder prior to puberty often experience an exacerbation in adolescence. Synaptic restructuring dramatically increases after age 6 and throughout adolescence. Onset of puberty also occurs at this time of the life cycle. Such events may explain the dramatic rise in the incidence of the onset of mood disorders, as well as the exacerbation of preexisting mood disorders, during adolescence. 

All stability studies on clinical trial materials must be carried out in full accordance with cGMPs, even if a research department carries out the studies. All studies must be carried out by adequately trained personnel under adequate work conditions. The personnel must use properly qualified and calibrated stability chambers, instruments, reagents, and standards. They must follow validated analytical methods and approved written procedures, and they must properly document all work. There must be proper sample and data traceability, change control, and go on. 

Analytical measurements should be made with properly tested and documented procedures. These procedures should utilise controls and calibration steps to minimise random and systematic errors. There are basically two types of controls (a) those used to determine whether or not an analytical procedure is in statistical control, and (b) those used to determine whether or not an analyte of interest is present in a studied population but not in a similar control population. The purpose of calibration is to minimise bias in the measurement process. Calibration or standardisation critically depends upon the quality of the chemicals in the standard solutions and the care exercised in their preparation. Another important factor is the stability of these standards once they are prepared. Calibration check standards should be freshly prepared frequently, depending on their stability (Keith, 1991). No data should be reported beyond the range of calibration of the methodology. Appropriate quality control samples and experiments must be included to verify that interferences are not present with the analytes of interest, or, if they are, that they be removed or accommodated. 

Although the importance of environmental factors (temperature, rela-- -tive humidity, airborne contaminants, and oxygen) that affect the fading of dyed textiles exposed to artificial and natural light indoors is well documented (1,2), relatively little information exists on the effectiveness of UV stabilizers incorporated into plastic films to minimize or retard such fading. To obtain this information, light-sensitive blue wool fabric (AATCC L-4 standard) was exposed to light from a xenon-arc source, with and without protection by clear cellulose acetate films... 

Documentation and the same type of procedures are important for mixtures of articles with carriers. In addition, procedures for each test or control article that is mixed with a carrier, appropriate analytical methods shall be conducted to determine the uniformity and stability of the mixture and the concentration of the test or control article in the mixture. In GLP studies, these assays should incorporate validated methods. SOPs need to define general ranges for standard parameters used for analytical acceptability. 

The testing and qualification of reference standards should continue such that the necessary documentation (internal and external reports, certificates of analysis, stability reports, supporting raw data) is complete from both a regulatory and scientific standpoint at the time of the NDA filing. 

Product characterization Sponsors of prescription products must document information about the chemical purity of the active ingredient as well as product formulation and stability. An OTC drag product must meet the OTC monograph standards. DSHEA does not require ary chemical characterization or standardization. 

Quality Control Data. Data obtained from assays of blood gas and pH control materials may be handled in the same way as data from other clinical chemistry determinations (i.e., mean, SD, and coefficient of variation, and control and confidence limits for construction of Levey-Jennings plots). As stability of commercial aqueous control materials is generally several months, vendors often provide data reduction programs that standardize and simplify documentation. However, the resulting reports are temporally delayed and are most useful for meeting accreditation requirements as opposed to real-time corrective or preventive action. They are however useful to compare long-term performances with other laboratories. Equally important features of quality assurance to an active blood gas service are the sixth sense of practiced operators for detecting subtle manifestations of deterioration of instrument performance and the suspicion of trouble expressed by clinicians. 

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