Process optimization analytical methods

To automate all steps, it is important to use computer software tailored to conduct the analytical process, the data processing, and the optimization of the technological process automatically. The automated device for process control must only be constructed by a heterogeneous team. The team is composed of analysts, technologists, and electronic experts. The role of the team is to improve the quality and reliability of the automated device and, indirectly, of the product obtained through the technological process. The analytical method chosen for analysis of the components, as well as that... 

A pharmaceutical company has to adopt a proactive policy of validation for its facilities, production processes, production equipment and support systems, analytical methods, and computerized systems. A properly validated approach will help to assure drug product quality, optimize the processes, and reduce manufacturing cost. 

Analytical change control is the monitoring of any changes to analytical methodology, which has to be justified and evaluated for its performance and impact on the quality of the product. For process analytical methods, the change control approach requires significant documentation and can impede the efficient optimization of the method in the early phases of implementation if parameters have to be locked down based on an insufficient data set. 

The chapter is organized as follows. First, to establish a common language, we define some common terms from both a pharmaceutical and an engineering perspective. Subsequently, we review model-based design and optimization as a framework for product and process development and optimization, process scale-up, and continuous improvement activities. The role of process and analytical technology (PAT) methods and principles in this framework is discussed. Finally, the main areas requiring effort are identified. 

During the optimization of the drug substance synthetic process, significant changes were introduced into the process. To ensure that the analytical method will still be able to analyze the potentially different profile of the API, revalidation may be necessary. 

A pilot production is at about a lOOx level in general, the full scale-batch and the technology transfer at this stage should comprise preformulation information, product development report, and product stability and analytical methods reports. This is the time to finalize the batch production documentation for the lOOx level. The objectives of prevalidation trials at this stage are to qualify and optimize the process in full-scale production equipment and facilities. 

The surface of a solid sample interacts with its environment and can be changed, for instance by oxidation or due to corrosion, but surface changes can occur due to ion implantation, deposition of thick or thin films or epitaxially grown layers.91 There has been a tremendous growth in the application of surface analytical methods in the last decades. Powerful surface analysis procedures are required for the characterization of surface changes, of contamination of sample surfaces, characterization of layers and layered systems, grain boundaries, interfaces and diffusion processes, but also for process control and optimization of several film preparation procedures. 

Apart from establishing analytical validation parameters, other activities should include experimental optimization of each procedural step or method manipulation to determine the critical control steps that have a substantial impact on method performance. The ruggedness or process variability that may be employed in any particular method step, without reducing method performance, should be determined. It should be identified, for example, whether an analytical method may be stopped without adversely affecting the result. 

In order to optimize each embedding material property, complete cure of the material is essential. Various analytical methods are used to determine the complete cure of each material. Differential scanning calorimetry, Fourier transform-infrared (ftir), and micro dielectrometry provide quantitative curing processing of each material. Their methods are described below. 

In addition, sometimes a normal-phase HPLC method at subambient temperature must be applied for analytes that are extremely prone to hydrolysis. In the synthesis of leukotriene D4 antagonist, accurate quantitation of mesylate intermediate is essential for process optimization. Owing to its inherent instability, analysis of mesylate intermediate must be carried out under normal-phase conditions with nonprotic solvents however, significant cycliza-tion of mesylation was stiU observed in such condition at room temperature. The authors concluded that the on-column reaction of the mesylate was silica-catalyzed cyclization. By conducting the normal-phase HPLC analysis at -30 C, it was demonstrated that on-column cyclization was adequately inhibited [30]. 

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