Handling Process Deviations

Production, transport, and storage of products underlie several SOPs, which define the parameters and required results from tests at different stages. Since the world is not as perfect as described in an SOP, there are deviations from the expected outcomes, in which some of the results from testing do not conform to the specified parameters. The results are referred to as nonconformities or exceptions. 

Expert systems are ideally suited to support the handling of exceptions, particularly since rules are already available in the SOPs and final decisions have to be made in interaction with a domain expert. Exceptions are usually divided into different classes, each of which has a series of root causes. Table 8.1 shows examples of classes and their root causes in the laboratory. 

The quality control unit that is responsible for the release of a product has finally to decide whether or not the charge of the product can be released and sent to the customer. This decision requires all information about exceptions that occurred during the production process. An exception also requires a corrective measure to address 

Definition of Classes and Potential Root Causes for Exceptions in a Laboratory 

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Any investigation involving the process of manufacturing a batch of product must be included in the batch record. Part of the review process for release of the product should be to verify that there is an acceptable conclusion to any investigation. Refer to Chap. 13 for an extensive discussion for handling manufacturing deviations. 

Mass spectrometer precision was determined by making repeated measurements on a gas sample prepared by combustion of carbon isotope reference material NBS-22. The standard deviation of the mean derived from 10 consecutive measurements of this gas was 0.02 %o The error associated with the combustion and purification procedure was measured by replicate combustions of the NBS-22 reference material, which resulted in a standard deviation of 0 12 %o for five samples ITius, the overall precision associated with the mass spectrometric measurement of vs PDB was 0.12 %o, or in absolute terms, 1.3 ppm. Most of the error clearly was associated with the combustion and sample handling process. Since sealed-tube combustions have been shown to produce theoretical recoveries of carbon (33). these small errors most likely arise from handling the CO2 after it is released from the sample tube ... 

As with commercial manufacturing, product or process deviations, or the failure of any clinical batch or any of its components to meet any of its specifications must be handled by approved procedures and thoroughly investigated (21 CFR 211.192). The investigation report should include, among other things ... 

A common way of estimating benefits for regulatory control is to quantify how much closer a process constraint may be approached. Figure 13.1 shows the classic drawing. With poor control the process operator will enter a controller SP such that worst deviation does not violate the constraint. Improving the regulatory control and reducing the deviations increases operator confidence that the controller can better handle process upsets and so he will move the SP closer to the constraint. 

Handling of disturbance in the inlet process stream temperature is passive. Any changes in this load variable will affect the furnace temperature. The change in furnace temperature is measured by the outlet temperature transducer (TT) and sent to the feedback temperature controller (TC). The primary controller then acts accordingly to reduce the deviation in the furnace temperature. 

Regulatory authorities recognize that, in spite of all the control systems put in place, deviations and changes are sometimes inevitable. A robust GMP system includes procedures to handle, review, and approve changes in raw materials, specifications, analytical methods, facilities, equipment, processes, computer software, and labeling and packaging. All the changes have to be documented with references for traceability. 

With respect to compoimd management, the testing process, and assay and data validation, the BioPrint ADME assays are similar to the pharmacological assays. The test compounds are handled similarly with aliquots of prepared compounds set aside for the ADME screening. The only deviation... 

Therefore, in this approach, we develop Risk Model III as a reformulation of Risk Model II by employing the mean-absolute deviation (MAD), in place of variance, as the measure of operational risk imposed by the recourse costs to handle the same three factors of uncertainty (prices, demands, and yields). To the best of our knowledge, this is the first such application of MAD, a widely-used metric in the area of system identification and process control, for risk management in refinery planning. 

The interlaboratory results obtained from the analysis of defined standard solutions, but also from the analysis of sediment extracts prepared either by the coordinator of the study or by the participants themselves, also provide a measure of the variation between laboratories. The results show that the interlaboratory reproducibility ranges from 6.5% for the defined dioxin sample to 27.9% for the sediment sample extracted by the participants themselves. As was mentioned before, the reproducibility for this last sample is relatively high and most presumably due to the introduction of extra handlings (extraction and cleanup) to the total procedure. In addition, the fact that not all the participants had prior experience with the extraction protocol to be used could have added to the increase in variability of the process. Furthermore, the dilution factor was not dictated. This also introduces a certain degree of variation. For the reproducibility of the DR CALUX bioassay itself and not caused by differences in operating extraction conditions, the maximum variation between laboratories was observed to be 18.0%. The results for the sediment extract samples can also be used to estimate the method variability for extracts, that is, based on samples of unknown composition. Again, given the intra-as well as the interlaboratory variations observed in this study, it appears justified to conclude that the standard deviation of the means provides a reasonable estimate of the method variability, based on the overall aver-... 

It takes a lot more than just connecting an IR instrument to a pipe to make the instrument into a process analyzer. The system not only has to be constructed correctly and be capable of flawless operation 24 hours a day, but it also has to be packaged correctly, and be able to access the stream correctly and without any interference from process-related disturbances such as bubbles, water, particulates, etc. Finally, the data acquired from the instrument has to be collected and converted into a meaningful form and then transmitted to the process computer, where the information is used to assess the quality of the product and to report any deviations in the production. Beyond that point, the process computer, typically not the process analyzer, handles any decisions and control issues. There are a few exceptions where robotics are integrated with the analyzer, and good vs. bad product quality are assessed at the point of measurement. The use of... 

Instead, a wide variety of spectroscopic and electrochemical titration methods are often employed to determine the equilibrium constants for a molecular recognition process at several different temperatures, which are then analyzed by the van t Hoff equation to give the thermodynamic parameters for the process. However, there is a critical tradeoff between the accuracy of the value obtained and the convenience of the measurement since the thermodynamic parameters, evaluated through the van t Hoff treatment, do not take into account the possible temperature dependence of the enthalpy change, i.e. heat capacity, and are less accurate in principle. In fact, it has been demonstrated with some supramolecular systems that the van t Hoff treatment leads to a curved plot and therefore the thermodynamic parameters deviated considerably from those determined by calorimetry.3132 Hence one should be cautious in handling thermodynamic parameters determined by spectroscopic titration and particularly in comparing the values for distinct systems determined by different methods. 

Process design for continuous processes is carried out mostly using steady-state simulators. In steady-state process simulation, individual process units or entire floivsheets are calculated, such that there are no time deviations of variables and parameters. Most of the steady-state floivsheet simulators use a sequential modular approach in which the flowsheet is broken into small units. Since each unit is solved separately, the flowsheet is worked through sequentially and iteration is continued until the entire flowsheet is converged. Another way to solve the flowsheet is to use the equation oriented approach, where the flowsheet is handled as a large set of equations, which are solved simultaneously. 

Finally, management must cultivate a positive process safety culture that will inspire people to support process safety and metrics efforts. Perhaps the largest enticement to implementing new or revised process safety metrics is the knowledge that the results will be handled seriously and appropriately, with proper remedial action taken when necessary. A positive and mature safety culture promotes open dialogue on issues, discusses improvement strategies by engaging a broad array of employees, and will not tolerate deviation from established procedures. 

Written procedures are required to be established and followed for production and process controls as specified in 21 CFR Part 211.100. Because the specific requirements regarding handling of changes, deviations, and equipment identification are addressed in other sections of this article, and all other provisions of Subpart F are required in order to meet CGMP requirements for clinical supplies, this section will focus on the other aspects of Subpart F that provide unique challenges during clinical supply manufacture. 

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