Monitoring Processing Steps

If a compound is known to have chemical stability issues and is going to be administered in low dose, the best prevention is to ensure the highest degree of crystallinity of the bulk active ingredient delivered to the formulation and maintain it in the state with the highest ratio of drug to excipient possible. 

TABLE 12.1 Physical Factors Considered in Unit Operations of Solid Oral Dosage Forms 

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Analytical accuracy. The mixture of all deuterium-labeled internal standards is added to each water sample before extraction. This does not prevent the loss of the unlabeled herbicides from the sample in subsequent processing steps, but a proportional loss of the deuterated internal standard precludes the need to correct for recovery. Although referring to recovery in this type of analysis is inappropriate, the accuracy of this method should be monitored. 

The reactor pressure is reduced to 0 psig to flash off any remaining water after a desired temperature is reached. Simultaneous ramp up of the heat source to a new setpoint is also carried out. The duration spent at this second setpoint is monitored using CUSUM plots to ensure the batch reaches a desired final reactor temperature within the prescribed batch time. The heat source subsequently is removed and the material is allowed to continue reacting until the final desired temperature is reached. The last stage involves the removal of the finished polymer as evidenced by the rise in the reactor pressure. Each reactor is equipped with sensors that measure the relevant temperature, pressure, and the heat source variable values. These sensors are interfaced to a distributed control system that monitors and controls the processing steps. 

The IHC stain procedure is a multistep staining protocol, the various steps intended to provide amplification of stain results. Therefore, a control system must include elements to control each step of the stain process. Such a control should also include a range of reactivities, and that range ideally would encompass the total expression range expected for the measured component. The control should also monitor each step of the multistep protocol. This author has devoted a number of years to this concept, resulting in a patented control for multistep staining processes.14 Such a control provides sufficient information to monitor every IHC stain run, and when the control is evaluated quantitatively, normalization of data from one stain run to another within the same laboratory, and even between laboratories. A process control is a measure of the stain protocol and does not take the place of a control for the primary antibody. While the primary antibody control should include range of expression level detection, a different primary control must be present for every primary antibody used in a stain run (Fig. 10.4). 

Figure 10.4 Schematic concept for a process control slide. The number of rows of analytes printed onto the slide depend on the number of process steps which need to be monitored.

The results described here demonstrate the importance of appropriate treatment and monitoring in actual drinking water processing plants, with attention to the specific requirements of the raw water matrix in use. In particular, the adverse effect of certain processes, namely pre-chlorination, which has been implicated in the inhibition of biodegradation in subsequent steps, and in the formation of alternative metabolites, is highlighted. Furthermore, the variable efficiency of GAC filtration in practice, emphasises the need for regular monitoring and quality control. The duration of specific process steps has also been shown to influence the efficacy of the technique, and should be addressed in application. 

The BioView sensor includes a software package (CAMO ASA, Norway) for data analysis and on-Une estimation of different bioprocess variables simultaneously. Thus, the instrument is able to predict the trends of the concentration courses of different variables during a cultivation and is used to give information about important process steps (e.g., feeding time, harvesting time, etc.). The instrument is able to monitor on-line several fluorophores in situ and non-invasively during cultivation processes and permits an estimation of different bioprocess variables simultaneously. The increasing of cell mass concentration and the product formation as well as the actual metabolic state of the cells is simultaneously detectable by this fluorescence technique. 

The 60-percent design specifies the detailed design basis, primary process steps, process flow diagrams, major equipment components, monitoring requirements, facility requirements (e.g., building layouts, electrical and ventilation requirements), and preliminary operational strategies. Detailed final specifications of all process components, facilities, and operations are not complete. 

In-process monitoring of critical processing steps and end-product testing of current production can provide documented evidence to show that the manufacturing process is in a state of control. Such validation documentation can be provided from the test parameter and data sources disclosed in the section on retrospective validation. 

Critical process steps are usually determined by analyzing process parameters (factors in a process that are controllable and measurable) and their respective outcomes. Not all process parameters affect the quality and purity of APIs namely its impurity profile and physical characteristics. For validation purposes, manufacturers should identify, control, and monitor critical process parameters that may influence the critical quality attributes of the API. Process parameters unrelated to quality, such as variables controlled to minimize energy consumption or equipment use, need not be included in process validation. 

Define which process variable will be used as the monitoring device of each process step. 

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