Out-of-trend results

Thoroughly investigate complaints and out of specification and out of trend results. 

In the case of laboratory error or sample error, as defined by the Barr decision, there should be a formal mechanism for investigating these results. This investigation procedure should be defined in an SOP. This procedure can also be used to investigate out-of-trend results that look suspicious but are not OOS. This procedure should have the ability to evaluate the data collection procedures and, in the case of an error, identify the cause or likely cause of the error. The results of the investigation can be documented and included as a formal record in the stability study. It should prevent the studies from being... 

When the content deviations are too large this will result in an out of specification or at least an out of trend result and the whole preparation process will need to be investigated in a step by step manner to find the causes an example of such an investigation can be found in [7]. 

One assay falls out of trend by about 4% this could be a laboratory error (see Section 4.32) that, by chance, does not generate an OOS result and so goes undetected. This out-of-trend (OOT) result could... 

ASSAYl.dat As part of a cross-validation of a modification of a given analytical method, 20 samples were run on either method. There is at least one result that is out of trend (OOT), and another two to three are indicative of laboratory errors. 

Sample preparation (SP) is generally not given adequate attention in discussions of pharmaceutical analysis even though its proper execution is of paramount importance in achieving fast and accurate quantification (see Chapter 5). Non-robust SP procedures, poor techniques, or incomplete extraction are the major causes of out-of-trend and out-of-specification results. The common SP techniques have been reviewed with a strong focus on tablets or capsules, as they are the primary products of the pharmaceutical industry. Detailed descriptions of SP methods for assays and impurity testing are provided with selected case studies of single- and multi-component products. 

Procedure or forms for investigating, reporting, corrective action Out-of-trend (OOT) results Definition of OOT... 

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... 

PhRMA CMC Statistics and Stabdity Expert Teams (April 2003) Identification of out-of-trend stability results. Pharm Technol pp 38-52. 

The correctly designed, computer-based LIMS will offer a more robust and accurate means of identifying out-of-specification results than can be achieved by a human laboratory technician. With the additional ability to trend, collate and report results, the LIMS has become an important tool within the laboratory environment. The integrity of the data is frequently scrutinized by the regulatory authorities and is often found to be an area of weakness. 

All process deviations whether planned or unplanned, together with errors and out of specification results should be recorded with a controlled form or electronically onto a database system. Whether a paper system or an electronic system this needs to facilitate the management of the investigation stage, including root cause analysis where necessary, corrective and preventative actions and close out, as well as the data being available for trending (CAPA-system). This is an important part of any Pharmaceutical Quality System, see Sect. 35.6.15. 

The Quality Control (QC) department has to operate according to Go(xl Quality Control Laboratoiy Practice (GQCLP) standards [2]. All QC methods have to be validated and verified before application. The instruments used for QC are qualified and calibrated before QC testing is performed. There is a procedure in place for the investigation of Out Of Specification (OOS) and Out Of Trend (OOT) results. The reference standards used should be certified, qualified and verified. Documentation and traceability are important such as in production. All raw data should be retained. 

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. 

A second example is also informative. When samples are obtained from a normally distributed population, their values must be random. If results for several samples show a regular pattern or trend, then the samples cannot be normally distributed. This may reflect the fact that the underlying population is not normally distributed, or it may indicate the presence of a time-dependent determinate error. For example, if we randomly select 20 pennies and find that the mass of each penny exceeds that of the preceding penny, we might suspect that the balance on which the pennies are being weighed is drifting out of calibration. 

For adsorbates out of local equilibrium, an analytic approach to the kinetic lattice gas model is a powerful theoretical tool by which, in addition to numerical results, explicit formulas can be obtained to elucidate the underlying physics. This allows one to extract simplified pictures of and approximations to complicated processes, as shown above with precursor-mediated adsorption as an example. This task of theory is increasingly overlooked with the trend to using cheaper computer power for numerical simulations. Unfortunately, many of the simulations of adsorbate kinetics are based on unnecessarily oversimplified assumptions (for example, constant sticking coefficients, constant prefactors etc.) which rarely are spelled out because the physics has been introduced in terms of a set of computational instructions rather than formulating the theory rigorously, e.g., based on a master equation. 

The waste materials from the separation process are prepared for coprocessing by a contracted firm. Different tests are carried out on the waste material at the Lafarge laboratories to control the calorific power, ash production, and presence of chlorides. These characteristics are extremely important for successful coprocessing [6]. An example of the trends of the results of these tests is shown in Fig. 9. 

A newer trend in MS bom out of the need to adapt to requirements from clinicians and diagnostics is analyte profiling. There, tests have to be simple and reproducible, preferably on cmde samples such as semm or urine, and diagnostic results have to be absolutely correct. Another point is that the view that one disease can be associated with or... 

The order parameter is directly available from the calculations and the SCF results are given in Figure 17. The absolute values of the order parameter are a strong function of head-group area. Unlike in most SCF models, we do not use this as an input value it comes out as a result of the calculations. As such, it is somewhat of a function of the parameter choice. The qualitative trends of how the order distributes along the contour of the tails are rather more generic, i.e. independent of the exact values of the interaction parameters. The result in Figure 17 is consistent with the simulation results, as well as with the available experimental data. The order drops off to a low value at the very end of the tails. There is a semi-plateau in the order parameter for positions t = 6 — 14,... 

While comparisons of individual treated groups with the control group are important, a more powerful test of a possible effect of treatment will be to carry out a test for a dose-related trend. This is because most true effects of treatment tend to result in a response which increases (or decreases) with increasing dose, and because trend tests take into account all the data in a single analysis. In interpreting the results of trend tests, it should be noted that a significant trend does not necessarily imply an increased risk at lower doses. Nor, conversely, does a lack of increase at lower doses necessarily indicate evidence of a threshold (i.e., a dose below which no increase occurs). 

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