Continuous process validation

An example of CQV of the batch cultivation of a vaccine has been demonstrated, where univariate (temperature, dissolved oxygen, pH) as well as spectroscopic tools were used to develop process models. The measurements were used for a consistency analysis of the batch process, providing better process understanding which includes the understanding of the variations in the data. MSPC analysis of four batches of data was performed to monitor the batch trajectories, and indicated that one batch had a deviation in the pH. From the MSPC information, combined with calibration models for the composition of the process based on NIR spectral data, improved monitoring and control systems can be developed for the process, consistent with concept of CQV. The data from the univariate sensors and NIR were also fused for a global analysis of the process with a model comprised of all the measurements. 

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Process validation is the procedure that allows one to establish the critical operating parameters of a manufacturing process. Hence, the constraints imposed by the FDA as part of process control and validation of an SMB process. The total industrial SMB system, as described, is a continuous closed-loop chromatographic process, from the chromatographic to recycling unit and, with the use of numerical simulation software allows the pharmaceutical manufacturer rapidly to design and develop worst-case studies. 

Step (6) can be broken down as given in Table 2.7. If the hardware and its operation is under control, and some experience with similar problems is available, experiments need only be carried out late in the selection process to prove/disprove the viability of a tentative protocol. Laboratory work will earnestly begin with the optimization of instrumental parameters, and will continue with validation. In following such a simulation procedure, days and weeks of costly lab work can be replaced by hours or days of desk work. 

Process validation is intended to show and document that the process described, when operating within the designated parameters, will produce product of the appropriate quality and demonstrate that the manufacturing process is under full control. Process validation should extend from laboratory-scale and preformulation studies (say to of production scale) to formulation to pilot-scale manufacture (say production scale) to full industrial-scale manufacture, with a clear, logical, and continuous path between these stages. The magnitude of scale-up at each stage should not normally exceed a factor of 10. 

The validity of the Poisson distribution for silver nucleation is demonstrated in Fig. 5.48B. The assumption for this kind of treatment is that the nucleus formation is irreversible and that the event is binary consisting of a discontinuous process (nucleus formation) and a continuous process (flow of... 

Summing up, a robust and easy to handle SMB-design uses 4 zones, a recycling pump fixed in respect to the columns and two pumps for the control of the outlet flow rates. Extremely high precision of all technical components of the SMB is needed. All pumps and valves have to be exactly synchronized. The flow rates should not vary by more thanl % from the preset value. All connections between the different parts of the system must be carefully optimized in order to minimize the dead volume. All columns should be stable and nearly identical in performance. If the SMB-technology is to be used in Biotechnology, GMP issues (cleaning, process and software validation) also have to be considered. In addition and as with any continuous process in that particular area, the definition of a batch could be a problem. 

In Other words, the assurance of quality by measurement of process impurities in the end product has been replaced by assurance of quality by the removal of variance in the process (by continuous monitoring of a continuous process). Naturally, whether online process analysis is being used as a surrogate for an alternative off-line technique to measure specific analytes or as a monitor to reduce process variance it needs calibration and validation. These stages require measurement of process analytes by a reference off-line technique, usually HPLC, and subsequent demonstration that the resulting calibration model has reliable predictive power. 

The formal validation is often completed after the PAI, where three-batch process validation will be conducted in accordance with the protocol approved during the preapproval inspection. The primary objective of the formal process validation exercise is to establish process reproducibility and consistency. Such validation must be completed before entering the market. The formal validation studies continue through packaging and labeling operations (in whole or in part), so that machinability and stability of the finished product can be established and documented in the primary container-closure system. 

Most pharmaceutical manufacturers now put substantial resources into process validation for both regulatory and economic reasons, but despite continued educational efforts by both the agency and the pharmaceutical industry, FDA inspections (both domestically and internationally) continue to find some firms manufacturing drug products using unvalidated or inadequately validated processes. Evidently there is still room for improvement, and continued discussion, education, and occasional regulatory action appears warranted. 

Some current publications address process validation from an almost exclusively statistical approach. The effect of such articles on nonstatisticians usually ranges from dismay to panic and, unfortunately drives them away, instead of toward use of statistics. Statistical process control (SPC) can be especially valuable when applied to process validation, both before and after the validated process enters commercial use. By statistically analyzing critical process parameter data throughout a batch or continuous process, SPC provides the opportunity to predict problems (trend analysis) and even take corrective action (trend control), before the problems occur, yet relatively few firms appear to be actually implementing SPC universally across all processing today, probably because SPC... 

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