Stability data trending

Stability Data Trending. Stability testing provides information about the quality of a drug product under the influence of a variety of environmental factors such as temperature, humidity, and light varying with time... 

Out-of-trend (OOT) value A measured result obtained from a sample that does not appear consistent with the stability data trend. When an OOT value is identified, an investigation of the sample is made to determine the validity of the OOT result and the impact on the overall stability study. 

Once a product gains FDA approval for marketing, the sponsor should maintain a readily retrievable profile of commercial batches. This includes individual batch release data and stability data. These data should be compiled throughout the year and tabulated prior to the anniversary of NDA approval for submission in the annual product report to FDA. By maintaining an ongoing database, which is reviewed as new information is added, changing trends in the data can be observed and management notified if any of these trends are unfavorable. 

As part of a multi-technique investigation (see also discussion under mid-infrared spectroscopy later), Corrales et al. [13] plotted the carbonyl index for films prepared from three grades of polyethylenes a high-density PE (HDPE), a linear low-density PE (LLDPE) and a metallocene PE (mPE) (see Figure 5). In this study, the data trend shown in Figure 5 correlated well with activation energies derived from the thermal analysis, which showed that the thermal-oxidative stability followed the order LLDPE > mPE > HDPE, whereas the trend... 

Where stability data show a trend toward potency loss or degradant increase under accelerated conditions, it is recommended that historical accelerated stability data from a representative prechange batch be sub-... 

Where stability data show a trend towards potency loss or degradant increase under accelerated conditions, it is recommended that historical accelerated stability data from a representative prechange batch be submitted for comparison. It is also recommended that under these circumstances, all available long-term data on test batches from ongoing studies be provided in the supplement. Submission of historical accelerated and available long-term data would facilitate review and approval of the supplement. 

Qualification and maintenance Temperature and humidity records Investigation and reporting of excursions Stability reports Impurities profiles Test points used for data evaluation Selective reporting of data Data trends... 

Alternately, should a review of the product quality data show that there have been no significant changes in any analytical test results, stability profiles, SPC data trends, etc., the APR may confirm that these changes did not require revalidation individually or collectively. 

If the accelerated stability data show a trend toward a significant failure, the test protocol should be amended to include more frequent testing to determine the time period where the actual failure occurs. 

The details of the assessment of stability data are under intense discussion within the scientific community. A majority of laboratories evaluate data with acceptance criteria relative to the nominal concentration of the spiked sample. The rationale for this is that it is not feasible to introduce more stringent criteria for stability evaluations than that of the assay acceptance criterion. Another common approach is to compare data against a baseline concentration (or day zero concentration) of a bulk preparation of stability samples established by repeated analysis, either during the accuracy and precision evaluations, or by other means. This evaluation then eliminates any systematic errors that may have occurred in the preparation of the stability samples. A more statistically acceptable method of stability data evaluations would be to use confidence intervals or perform trend analysis on the data [24]. In this case, when the observed concentration or response of the stability sample is beyond the lower confidence interval (as set a priori), the data indicate a lack of analyte stability under the conditions evaluated. 

Abstract This chapter discusses the evaluation of stability data. It follows the stability study information from the point that raw data is generated in the lab, calculations are performed to give test results, and test results are entered in the stability summary sheets, until data is finally entered into a stability report for submission purposes. This chapter also includes a summary of data evaluation addressed in ICH QIE and a discussion of Out-of-Speciflcation (OOS) and Out-of-Trend... 

The trend identification can be qualitative and performed by graphing the stability data or could be performed by statistical analysis of the collated data. In both cases, the site OOT Standard Operating Procedure (SOP) defines criteria for designating a data deviation from the norm as an OOT incident. The OOT criteria must be set in such a way that all significant OOT incidences are identified, ideally without false positives. 

The Limit of Quantitation (LOQ) and the reportable limit for impurities also impact impurity test OOT procedures. It is common practice to report impurity peaks below the Limit of Quantitation as < LOQ, which is set to the reporting limit for that impurity per ICH Q3A(R2). Therefore, the purity result for peaks just below the LOQ cannot be used for trending although the analytical method variance may be satisfactory at that level. This reporting practice again decreases the information presented in the stability data tables, limits the QQT tools for impurities close to the... 

Once the study is started, any change to the stability protocol needs to be made with appropriate approvals. Justitication must be recorded. The Stability administrator must also check to assure that there are enough samples to test the changes. An example of a study amendment could be an addition of testing time points to more completely monitor out-of-trend stability data. 

Chapter 13 discusses the collection and presentation of stability data. Evaluation of data (ICH QIE) is also discussed as well as Out-of-Specification (OOS) and Out-of-Trend (OOT) investigations. In addition, it also introduces the stability report and data trending. 

Answer No, temperature maps and individual tube outlet temperature read-out are considered as the final authority and what the absolute flux distribution is and what the tube temperatures are. Supplemented, instruments such as the corn popper, zone temperature monitor, and tube temperature deviation recorders are designed to provide crude data on temperature stability or trends. Since most supplemental instrumentation can be adjusted or biased to fit a particiilar operating period, this type of equipment cannot be relied upon until adjustment is made for existing pile conditions. In other words, strict adherence to a single false or biased indication from any one instrument c m lead to severe control difficulties. 

The above data are correct to about 20 kJ mole but it will be seen that the general trend among these more covalent bonds does appear to be a decrease in stability from carbon to silicon, i.e. the same way as was found for more ionic bonds in the halides. Thermodynamic data for metallorganic methyl compounds used in the produchon of semiconductor systems are shown in Table 2.3. 

Interesting stabilization and structural trends have been noted using MP2/6-31G calculations on the effect of substituents on imines. The data below give AE for the isodesmic reaction and show that stabilization tends to increase with Xbe 1 gi (>up electronegativity of the substituent. The X—N=CH2 bond angle decreases with Xbe-... 

Carbanion-stabilizing effects have been calculated at several levels of theory. Table 7.6 gives some gas-phase data. The AMI and PM3 semiempirical calculations have also been done in water. The order NO2 > CH=0 > CN > Ph > CH2=CH is in accord with the experimental trends and reflects charge delocalization. The electronegative substituents F, OH, and NH2 are stabilizing by virtue of polar effects. The small stabilization provided by CH3 is presumabfy a polarization effect. 

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