In-process sampling

Obtaining a representative sample from a process for on-line analysis is a huge challenge for chemists. The interface between the process stream and the analytical instrument is key, and no matter how sophisticated and sensitive the analyser, if the sampling section is not well thonght ont, the system will not be snccessful. Because processes vary and can have very extreme temperatures, pressures and other conditions, samples should be taken carefully. The sampling system shonld take into consideration that  

Analytical Instrumentation A Guide to Laboratory, Portable and Miniaturized Instruments G. McMahon 

In the past, analytical measurements during a process were always performed off-line or, at best, at-line. In recent years, the trend is towards on-line analysis. This has a significant impact on the way scientists use analytical instruments and how they can adapt existing equipment to work in the often harsh environments of processes in the pharmaceutical, food and other industries. 

Naturally, the sampling of solids, liquids and gases requires different approaches. Often, noncontact spectroscopic probes are used for powders, tablets and thick slurries. Gases can often be sampled in the same way as liquids but may require some preconcentration prior to analysis, especially if levels of the analyte being examined are low. An example of a commercially available system for sampling gases is available from ABB. It is called the DRS2170 Dynamic Reflux Sampler and is used to couple with GC instruments, photometers and other process analysers. It conditions samples in situ. The condensable components are removed and are used to support particulate removal. The unit 

Long throw immersion probe inserted into reactor 

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Due to the nature of the SMB process, in-process samples of the unwanted enantiomer and the enantiopure drug substance can be sampled at controlled times during the continuous process to assess the enantiomeric and chemical purity. One can monitor the process without system shutdown by diverting either the extract or the raffinate streams. Further monitoring of the receiving tanks can also be accomplished. 

Where trials are required to investigate the possible residue of test item in processed samples, e.g., juice, purde, etc., a larger quantity of the field sample must be collected. To collect this larger sample size, the size of the plots must often be increased at the... 

A final aspect of process analytical chemistry is the vulnerability of the sensitive detector components to the harsh conditions sometimes encountered in process sampling. It may be possible to physically separate sensitive components, especially the electronics, from the sampling site. Fiber optics... 

As described in the following chapter, there are many biopharmaceutical applications of protein assays. Assigning the protein concentration for the drug substance, drug product, or in-process sample is often the first task for subsequent analytical procedures because assays for purity, potency, or identity require that the protein concentration be known. Hence it is typical for several different methods to be employed under the umbrella of protein concentration measurement, depending on the requirements of speed, selectivity, or throughput. The protein concentration is valuable as a stand-alone measurement for QC and stability of a protein. However, protein concentration methods provide no valuable... 

Figure 12.9 Proton NMR spectra for an in-process sample of protein product with (bottom spectrum) and without (upper spectrum) a spike of 10 ag/ml Pluronic F-68. The Pluronic F-68 signal is clearly absent in the upper spectrum. This example demonstrates that if the Pluronic F-68 level was greater than 12.5 pg/ml, it would have been observed.

In-Process Sampling and Controls Blending Batches of Intermediates or APIs Contamination Control... 

Figure 3.2 Correct and incorrect increment delimitation in process sampling. Generic illustration (e.g. of a conveyor belt). The three examples to the left are all delineated correctly with parallel sampling implement boundaries, while the remaining three cannot deliver a correct (nonbiased) transverse cut of the l-D stream. Repeated sampling results in unbalanced transverse proportions of the flux of matter, the effect of which is IDE and IME.

Usnally IWE does not pose grave problems, if snitable countermeasures have been contemplated a priori. In process sampling obtaining a constant increment mass has many advantages, and is thus often given a high priority. For practical purposes, this can be considered effectuated if the relative variation between increment masses remains below, say, 20% [2,3,9,14]. In order not to confuse the process issues needlessly, below we shall assume that all IWE issues have been dealt with properly (i.e. eliminated). 

Practical interpretation of the experimental variogram is the first item to address. The variogram level and form provide valuable information on the process variation captured, as well as the quality of the sampling procedure employed. There are only three principal variogram types encountered in process sampling, but many more combinations hereof ... 

An in-process sample when examined by LC-MS on a single quadrupole showed three impurities, all with the same MH at the nominal mass of miz 402. This equated to an extra 14 Da higher than the parent mass. From the structure... 

The use of validated in-process sampling and testing methods in such a way that results prove that the process has done what it purports to do for the specific batch concerned, thus assuring that control parameters... 

Using aseptic technique, open the required number of vials, vor-texing each prior to removing an aliquot. Pool the samples aseptically in a sterile, pyrogen-free vial. Eor in-process sample, treat the bulk solution as a pooled sample. 

Correlation of Stratified In-Process Samples with Finished Product The following steps are recommended ... 

Prepare a summary of the data and analysis used to conclude that the stratified in-process sampling provides assurance of uniform content of the finished product. 

In-process sampling should be done in accordance with a written procedure. The Standard Operating Procedure (SOP) or production instruction should describe... 

The results of in-process sample testing are important to confirming the proper operation of the equipment. Therefore it is important to ensure the sampling device, wherever used, is clean. If cleaning after each use is not feasible or it is difficult to keep it clean until next used, then the sample device must be stored properly to protect it from environmental contamination. 

In-process samples are usually tested at-line or in the Quality Control laboratory. If the testing is performed by production personnel, the following requirements should be met ... 

There should be a sampling plan for finished excipient testing. The sampling plan should be in accordance with the in-process sampling requirements outlined above. It is important that if only one sample from the finished batch is taken, that it be representative of the excipient. This is usually not possible if the lot is not homogeneous. In that event, it is important to establish a sampling plan that assures sufficient samples are taken so that with all samples in conformance, the entire excipient batch is known to be conforming. 

Production and in-process controls (unit operations, time limits, in-process sampling, blending of intermediates or APIs, contamination control)... 

An extension of linear regression, MLR involves the use of more than one independent variable. Such a technique can be very effective if it is suspected that the information contained in a single independent variable (X) is insufficient to explain the variation in the dependent variable (Y). For example, it is suspected that a single integrated absorbance of the NIR water band at 1920 nm is insufficient to provide accurate concentrations of water contents in process samples. Such a situation can occur for several reasons, such as the presence of other varying chemical components in the sample that interfere with the 1920-nm band. In such cases, it is necessary to use more than one band in the spectrum to build an effective calibration model, so that the effects of such interferences can be compensated. 

The instructions embedded in computer program(s) either provide information on what the operators are supposed to do, or information on how the equipment or processes are intended to function. For example, for manufacturing operations, the batch production and control records may provide procedures, controls, instructions, specifications, and precautions to be followed when using computer systems. These programs may also contain control data for product formulation, batch size, yields, and automated in-process sampling/testing procedures. 

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