In-process monitoring

It is worth briefly pointing out the difference between in-line and online analysis. In-line analysis does not involve removal of the sample from the reaction vessel, for example in determining water or oxygen content. On-line analysis does involve removing a sample, usually as a side stream, which adds to the complexity of the plant since the sample off-take equipment will often need to be built to the same integrity as the plant. There are four common techniques employed  

Titration. This method obviously requires physical removal of a sample from the plant and results in the sample being thrown away. In modem equipment samples can be taken at specified intervals from a flowing sample stream using Flow Injection Analysis, enabling the analysis time to be shortened. 

The above principles will be exemplified through a brief discussion of near-inlrared spectroscopy. 

A similar approach using an isocratic method can be applied to in-process monitoring, where the goal is to monitor the disappearance of the starting material and appearance of the product. In-process methods will be discussed in greater detail in Section 14.6. 

Another approach is the use of monolithic columns consisting of silica based rods of bimodal pore structure. They contain macropores (-1-2 pm) and smaller mesopores ( 10-20nm) [38]. The macropores allow for low backpressure at high flow rates. The mesopores provide the needed surface area for interactions between the solute and stationary phase. The macropores result in higher total porosity as compared to porous silica particles. Flow rates of 5 mL/min can be tolerated on a 10-cm column without an appreciable loss in 

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Sample preparation is straightforward for a scattering process such as Raman spectroscopy. Sample containers can be of glass or quartz, which are weak Raman scatterers, and aqueous solutions pose no problems. Raman microprobes have a spatial resolution of - 1 //m, much better than the diffraction limit imposed on ir microscopes (213). Eiber-optic probes can be used in process monitoring (214). 

Controlled conditions include in-process monitoring and in-process inspection and test. All controls need a verification stage and a feedback loop. You cannot control production processes without performing some kind of verification. 

Analytical methodologies need to be further developed to allow for real-time, in-process monitoring and control prior to the formation of hazardous substances. 

Mass spectrometers must be regularly tuned or calibrated against a known standard, e.g. perfluorotributy-lamine (PFTBA). The trend is towards miniaturisation (10 x 24 x 14 in.). A concept for a micro mass spectrometer, with potential applications in process monitoring, has been presented [167]. Mass-spectrometry instrumentation (1997) has been reviewed [166]. 

Utility of 384-Well Plates for High-Throughput Applications and In-Process Monitoring of Cross Contamination... 

The Lab Chip instruments/methods currently commercially available generally have less resolution and are less sensitive compared to conventional CE-SDS methods. However, the high throughput of the Lab Chip technique makes it attractive for in-process monitoring during process development. The Lab Chip method is generally used for process development activities such as clone selection, cell culture process development, and optimization of the downstream purification process. 

Raman spectroscopy is particularly well suited for use in process monitoring and conttol. This chapter discusses Raman spectroscopy s attractive features as well as alerts the reader to aspects that may present ehallenges. The fundamental principles of the technique are reviewed. The reader will learn about instrumentation and options in order to make the most appropriate choices. Special aspects of performing quantitative Raman spectroscopy are discussed since these are required in many installations. Apphcations from many diverse fields are presented. The reader is encouraged to examine aU of the areas since there are good lessons and stimulating ideas in aU. 

S.E. Barnes, E.C. Brown, M.G. Sibley, H.G.M. Edwards and P.D. Coates, Vibrational spectroscopic and ultrasound analysis for the in-process monitoring of poly(ethylene vinyl acetate) copolymer composition during melt extrusion, Analyst, 130, 286-292 (2005). 

S. Barnes, J. Gillian, A. Diederich, D. Burton and D. Ertl, In process monitoring of polymorphic form conversion by Raman spectroscopy and turbidity measurements. Am. Pharm. Rev., 11, 80, 82-85 (2008). 

Finally, the use of PAT should not be limited to existing processes and products but is especially attractive in the R D and scale-up of new processes and products. PAT is especially effective in scale-up. As PAT involves consideration of all monitored variables and not only an empirical selection of some of those variables, and since in-process monitoring techniques are normally multiparametric (e.g., near-infrared spectra of a whole sample), they will be more suited to capture scale effects present in the sample s matrix that show up clearly in a consolidated multivariate analysis of quality and operating variables, thus helping the skillful engineer or scientist to pinpoint and solve scale-up problems thus resulting in a much faster process prototyping and scale-up. 

We gratefully acknowledge the support provided by the project team for sharing the analytical methods, in-process monitoring and process scale-up experience, and Engelhard Corporation for providing catalysts and characterization supports. We thank also Dr. W.L. Parker for fruitful discussions. 

In-process monitoring of the production process is usually a combination of on-line measurements and sampling. Any instrument used to make a measurement whose result either indicates the quality of the output of the production step or is used... 

In-Process Monitoring and Testing Controls for Tablet and Capsule Dosage Forms... 

Unit Operation In-Process Monitoring PAT Application In-Process Testing PAT Application... 

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. 

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