Critical process measurement

Monitoring by Electromechanical Instrumentation. According to basic engineering principles, no process can be conducted safely and effectively unless instantaneous information is available about its conditions. AH sterilizers are equipped with gauges, sensors (qv), and timers for the measurement of the various critical process parameters. More and more sterilizers are equipped with computerized control to eliminate the possibiUty of human error. However, electromechanical instmmentation is subject to random breakdowns or drifts from caUbrated settings and requires regular preventive maintenance procedures. 

Provide reliable and appropriate measurement of all critical process variables... 

The assessor should also find out whether an effective testing program is in place to help ensure the serviceability of process measurement equipment. The successful toller should have an established calibration program to address the accuracy of critical measurement equipment. Safety critical process parameters should be monitored and critical process equipment should automatically interlock when monitoring instrumentation detects safety critical deviations. Interlocks should either facilitate a remedy to the critical deviation or bring the process to the zero energy state. These instruments and interlocking devices should be routinely tested to ensure operational reliability. 

Measurement of performance. Quality Management requires that measures of performance be established for every activity. These measures include end-of-pipe measurement, such as amounts of material released into the environment or injury rates, and in-process measures of how efficiently you are managing, such as time to review safety improvement proposals or total resources expended on PSM. Each team should be required to identify potential performance measures for the processes they are developing and the activities these processes manage. Many of the end-of-pipe measures will already exist these should be critically examined to ensure that they truly measure performance and are not unduly influenced by other factors. For example, the number of accidents in a fleet of road vehicles is almost directly dependent on the number of miles driven with no improvement in performance, a reduction in miles driven would reduce the number of accidents. 

Confirm Measurement System > Baseline In-Process Product Parameters (Control, Capability) > Identify/Prioritize Process Steps > Identify Critical Process Parameters... 

Currently the main application of interest for parametric release is to replace the sterility test as a control method in appropriate cases (given the limited value of that test to predict sterility assurance due to statistical considerations, although it is also pointed out that a sterility test provides a final opportunity to identify a major failure, although other means should provide a more reliable way of detecting such failures). The concept is applicable to well-founded methods of sterilization where the product stability is known and development data have identified the critical process parameters. The measured parameters should be such as to ensure that correct processing of the batch provides sufficient assurance that the sterility assurance level intended has been achieved. 

A hazard evaluation is performed before assessing the technical feasibility of a new process. Chemical handling/storage criteria, critical process conditions, quality measurements, thermal hazards, and post-campaign cleanup are considered in the introduction of any new process/product. 

Granulation of urea [13] is a complex process that has to be controlled by experienced process operators in order to avoid critical shutdown situations. The parameters most often used for monitoring granulation processes are measured by classical univariate sensors, such as temperature, pressure and flow. However, these standard process measurements carry only little or no relevant information, or are only indirectly related to, for example particle size, clogging of the reactor, or the accumulation of a solids layer on the bottom plate. The response from these sensors often comes with quite a substantial delay time. 

Due to the complexity of bioprocesses, and the lack of direct in-process measurements of critical process variables, much work is being done on development of soft sensors and model predictive control of such systems. Soft sensors have long been used to estimate biomass concentration in fed-batch cultivations. The soft sensors can be integrated into automated control structures to control the biomass growth in the fermentation. 

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. 

Earlier I discussed a method of planning for PV, in particular the overall development function leading up to it. It appears that the development group has a number of avenues that will lead to the appropriate validation approach it takes. In one approach, the critical process parameters would be measured to monitor the process and document the fact that the process is validated. Many validation programs use this approach, but they are usually undertaken right after or as part of the technology transfer effort. 

Property prediction may be done using such routinely measured parameters as temperatures, pressures and flow rates when there is sufficient process knowledge to correlate these values with product quality. Sometimes process analyzers such as spectrometers are used to understand the process chemistry and kinetics, thus providing the ability to use soft sensors if the tool that helped elucidate the critical process variables is unavailable. 

Document Incorporate all critical process control parameters into a process control plan. Develop a long-term measurement matrix to monitor success and improved capabilities to meet or exceed customer expectations. Then reward the team ... 

The selection of instrumentation will be dependent on the chosen product characteristics being measured for the product form. Product characteristics can be categorized into physical structure, chemical identity, and homogeneity. The focus should be on critical process parameters affecting end product quality, although there may also be some process performance measurements. 

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