Documentation standards stability data

Tests have to be performed under standardized conditions with respect to temperature and humidity. Accelerated tests can be used to identify the weak points, but in the documentation submitted to the authorities long-term stability data vmder normal conditions are required. In these studies stability... 

For studies of more than four weeks in experimental duration, a reserve sample of each batch of the test, reference (analytical reference standard) and control substance must be retained. As this archive sample may be retained by either the sponsor or the contract facility, the responsibility should be addressed in the protocol. Additionally, a sample of the chemical should be collected prior to each application and immediately frozen for possible analysis for "storage stability of the test, reference and control substance at the test site". If the sponsor s storage stability data are inclusive of the storage conditions recorded at the test site, the GLP requirement will have been met and the above storage stability samples will not have to be analyzed (10). It should be noted that all test substance containers must be retained for the duration of the study i.e., until the study director signs the final report. A conditional exception for disposing of the containers may be obtained by writing to the OCM (11). OCM will set forth certain documentation requirements that will be required to account for the test substance containers. 

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. 

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. 

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. 

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. 

Documentation of preparation of stock and sub-stock solutions must start with receipt of the reference standard, its Certificate of Analysis, assigned purity (and possibly chiral purity) and its history of storage and use after receipt (Section 9.4.4). Procedures for preparation and subsequent dilution of stock solutions are described in Section 9.5.4 and stability testing for these solutions in Section 10.4.Ih. Some of the relevant documentation might be included in general laboratory SOPs but full documentation of all study-specific procedures and data regarding preparation, storage and validation of stock solutions is required. 

For study sample analysis the calibration curve and QC samples are evaluated separately, and run acceptance is based upon criteria estabhshed for both curves and QCs. For validation runs, however, only the standard curve and other factors such as carryover are considered for run acceptance and aU of the results for the various types of validation QCs, e.g., precision and accuracy, stability, etc., are reported and used for statistical analysis. It is important at this time to emphasize the distinction between a failed and rejected validation run. Runs may be rejected for specific assignable cause such as documented evidence that the method was run incorrectly or hardware failure (Section 10.5.2c). Data from failed runs on the other hand, such as those where an excessive number of calibrators are considered to be outhers or QCs used to assess precision and accuracy do not meet the... 

For situations where it appears that the system is running properly hut there is a brief interruption in the run, it may he possible to resume the injection sequence immediately provided that some procedure (preferably defined in a sample analysis SOP) is followed to assure that the system is equilibrated and running properly. For other circumstances where it is discovered that the system has been idle for an extended period but appeared to be tunning properly prior to stopping, a system re-start suitabihty test may be used to estabhsh that the instrument is equihbrated prior to restarting the mn at the point where it stopped. Solutions that are used for this purpose can be a cahbration curve standard or a QC sample. The back-calculated concentration of the standard or QC used for re-start suitability must meet the acceptance criteria stated in the method or SOP. The result obtained from a re-start suitabihty injection should not be used in the calibration curve or reported with the sample set QC s. In any event, the fact that there was an interruption in the run and the reason for a system re-start must be documented in the raw data and possibly flagged in the analytical results table. If the system re-start criteria that are specified in the laboratory SOPs are notmet, then the analytical run should be rejected (Section 10.5.3c) and the entire run should be re-injected provided that adequate extract stability has been estabhshed. Alternatively, the samples may be re-assayed (extraction and analysis of a new sample aliquot). 

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