Process quantitation

If reference materials of the suspected impurities are available, the drug substance or finished drug product should be spiked at an appropriate level to demonstrate that the result is unaffected by the addition of the impurity. Figure 2 shows examples of individual chromatograms of the API and three known process impurities. As shown here, none of the three process impurities interfere with the API peak, although peaks for impurities A and C appear to overlap and could co-elute if both were present in the sample. This specificity may be acceptable if the method was designated as an assay method for the quantitation of the API. For a method intended to quantitate process impurities, the overlap of these two components would in most cases be unacceptable due to the inability of the method to accurately measure the two individual components. 

However, the most significant practical issue for the implementation of an FT-NIR device suitable for quantitative process analytical applications arises from the need to maintain a very high degree of alignment at the point of recombination of the divided interferometer beam paths -at the exit of the interferometer. 

Arguably, the most important aspects of quality management for PAT are the concepts of quantitative process performance characterization using process capability indices as universal descriptors, which form the basis of the measure and analyze portions of the DMAIC model. Process capability indices consider simultaneously both process variability and process specifications to determine whether... 

Data are acquired and processed using a software for chromatographic and spectral interpretation, and for quantitative processing. 

Quantitative Processing. Plates or film with the diffraction patterns were scanned with a Joyce-Loebl microdensitometer. Radial (20) densitometric plots of the crystalline pattern (eventually three successive exposures of the crystalline pattern are analyzed) and of the corresponding amorphous pattern were recorded on the same curve. In this way, the plot of the amorphous pattern was used as a reference standard. The densitometric recording began with the optical density of the non-irradiated emulsion this allowed the evaluation and normalization of the optical density of the diffraction pattern. When the analytical slit passed through the image of the border of the 75 pm objective aperture, the densitometric curve showed a sudden density raise "A d". (Fig. 6) The plots of the amorphous and crystalline patterns were thus normalized to the same reference " A d". Crystallinity was determined on the normalized curves by measuring the areas "C + A" and "A" under the crystalline and amorphous plots respectively. 

Quantitative process approach High throughput analysis Sample volume Provide increased support when a go decision is made for development. Increased resources and/or improved methods of analysis. Independent of sample generation. Intralaboratory integration (i.e., automation). 

Figure 3.2 A quantitative process pipeline model, illustrating the transfer of successful drug candidates from one stage to the next. Quantitative increases in drug candidate sample-generation volume are complemented by proportional increases in resources for sample analysis. (Courtesy of Milestone Development Services, Newtown, Pa., USA.)...

Once the figures for an FTE are established, the cost corresponding to the number of samples that can be analyzed per day is calculated. Figure 3.6, illustrates a cost profile for LC/MS analyses up to 100 samples per day. This model indicates analysis throughput from a quantitative process approach and provides a fiscal illustration of the impact the analysis may have on drug development. For example, LC/MS-based strategies, which have been demonstrated to increase the rate of sample analysis by 2- to 10-fold in the pharmaceutical industry, can be expected to reduce the cost per analysis by a corresponding ratio. 

A 96-well SPE system for the simultaneous extraction of drugs and metabolites in biological matrices developed by Wu and coworkers (Simpson et al, 1998) is shown in Figure 6.39. In this approach, smaller elution volumes (75-200 FL) are used to improve SPE performance. This volume reduction allowed for the direct injection of samples without any evaporation and reconstitution. The collection plate that contains the elution fraction is loaded to an autosampler that is compatible with 96-well plates, thereby, eliminating the transfer to injection vials. This quantitative process improvement led to an improved analytical performance, considerable savings in time, and reduced cost. 

In response to off-line SPE assays in the 96-well plate format, LC/MS analyses that feature the direct injection of plasma with on-line extraction have been reported (Ayrton et al., 1997 Needham et al., 1998). This quantitative process approach eliminates the time-... 

Accelerated drug development schemes have shifted the need for analytical instrumentation to include criteria for high throughput (quantitative process approaches) and the capability to contribute to an application that produces information for accelerated decision making (qualitative process approaches). The value of sensitivity, selectivity, and detail are still significant however, new parameters dealing with efficiency, productivity, and information content have become the new watermarks for analytical instrumentation in the pharmaceutical industry. These factors have been affected by shorter timelines and the pharmaceutically relevant information required for decision making. 

In general, progress in drug development depends on data obtained from analytical instruments. Thus, how this information is derived and provided to decision makers is critical to the success of the pharmaceutical industry. LC/MS technologies have effectively and uniquely supported the productivity (quantitative processes) and efficiency (qualitative processes) needs of drug development. Future issues appear to be directed toward enhancement of the information-gathering process that focuses on the relationship between data and decision (Table 8.1). 

The heart of the pilot plant study normally involves varying the speed over two or three steps with a given impeller diameter. The analysis is done on a chart, shown in Fig. 36. The process result is plotted on a log-log curve as a function of the power applied by the impeller. This, of course, implies that a quantitative process result is available, such as a process yield, a mass transfer absorption rate, or some other type of quantitative measure. The slope of the line reveals much information about likely controlling factors. A relatively high slope (0.5-0.8) is most likely caused by a controlling gas-liquid mass transfer step. A slope of 0, is usually caused by a chemical reaction, and a further increase of power is not reflected in the process improvement. Point A indicates where blend time has been satisfied, and further reductions of blend time do not improve the process performance. Intermediate slopes on the order of 0.1-0.4, do not indicate exactly which mechanism is the major one. Possibilities are shear rate factors, blend time requirements, or other types of possibilities. 

A practically useful predictive method must provide quantitative process prediction from accessible physical property data. Such a method should be physically realistic and require a minimum number of assumptions. A method which is firmly based on the physics of the separation is likely to have the widest applicability. It is also an advantage if such a method does not involve mathematics which is tedious, complicated or difficult to follow. For the pressure driven processes of microfiltration, ultrafiltration and nanofiltration, such methods must be based on the microhydrodynamics and interfacial events occurring at the membrane surface and inside the membrane. This immediately points to the requirement for understanding the colloid science of such processes. Any such method must account properly for the electrostatic, dispersion, hydration and entropic interactions occurring between the solutes being separated and between such solutes and the membrane. 

QUANTITATIVE PROCESS STUDIES USING FACTORIAL DESIGNS... 

As important as are the three previously mentioned applications of chromatography (Table 1), it is accurate to observe that the primary use of chromatography is for the purpose of establishing the concentration of a known entity (analyte) in a specific sample. As few chromatographic detection strategies are absolute (i.e., their response function can be derived from first scientific principles), the quantitation process includes the characterization of the response function, where the response function is the mathematical relationship that exists between the concentration of an analyte in a standard and the response that is... 

Methods without models such as quantitative process history based methods (neural networks (Venkatasubramanian, et ah, 2003), statistical classifiers (Anderson, 1984)), or qualitative process history based methods (expert systems (Venkatasubramanian, et ah, 2003)),... 

A risk assessment is defined as a qualitative and quantitative process conducted by EPA to characterize the nature and magnitude of risks to public health from exposure to hazardous substances, pollutants, or contaminants released from specific sites. Risk assessments include the following components hazard identification, dose-response assessment, exposure assessment, and risk characterization. Statistical and biological models are used in quantitative risk... 

Upon this decomposition are based the quantitative processes of Knop, Hiifner, Yvon, Davy, Leconte, etc. 

For quantitative process calculations it is important to know what chemical species fomi in a given extraction system. The stoichiometry of the overall reactions affects the process material balance. Also, the number of different species fonnied determines the number of degrees of freedom required to specify the thermodynamic stale of a system. On the other hand, the detailed mechanism of a reaction, fiir example, whether amine extraction occurs by addition [reaction (8.2-5)] or ion exchange [reaction (8.2-7)], is of no direct concern unless slow reaction kinetics becoma an issue. 

When based on GC, the elemental analysis of organic compounds normally consists of the following steps (1) the preparation and introduction of a sample into the instrument (2) chemical conversion of the sample into simple volatile products (3) chromatographic separation of these products (4) detection of the separated products and quantitative processing of the results. 

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