Quality attributes process optimization

This chapter will describe the use of nuclear magnetic resonance and magnetic resonance imaging to characterize the quality attributes of foods and for use in process optimization, shelf-life determination and component migration. 

Standardization of the milk fat and total solids contents of milk is accomplished by blending cream or skim milk with separated milk. Modern technology has developed continuous standardization processes that use turbidity or infrared absorption measuring devices to monitor and adjust the composition of the product as it leaves the separator. It is important that milk be accurately standardized to meet governmental legal requirements and to manufacture dairy products with optimal functional and quality attributes. 

Food processing operations can be optimized according lo the principles used for other chemical processes if the composition, Ihernio-phvsical properties, and structure of the food is known, However, the complex chemical composition and physical structures of most foods can make process optimization difficult. Moreover, the quality of a processed product may depend more on consumer sensory responses than on measurable chemical or physical attributes. Retention levels of ascorbic acid. CoHnO. or thiamine can often be used as an indicator of process conditions. 

The development of a qualified down-scale model of a process module is integral to the approach of process validation using bench-scale experiments, as described earlier. We have developed down-scale models of process steps ranging from various types of process chromatography for protein purification to separation by precipitation and filtration. These down-scale models have been utilized to evaluate the effects of relevant process parameters on product-quality attributes. The normal logical sequence of process development, of course, is bench scale to pilot scale to full scale. However, for many plasma protein purification processes, a reverse order needs to be followed. As licensed full-scale processes already exist, the full-scale process steps need to be scaled down to construct small process models in order to evaluate the robustness of process parameters on the product without impacting full-scale production. These models can also be utilized to evaluate process changes, improvements, and optimizations easily and economically. 

Prior to developing a drug product, a number of experiments need to be conducted that will fully characterize the API. This information will then be used to help guide formulation development efforts. Each of the critical pieces of information that are needed for formulation development will be discussed below. These include a screening process where an ideal soHd-state salt form is selected and the generation of a suite of analytical methods necessary to probe the critical quality attributes of the new chemical entity, to support synthetic optimization scale-up, stability studies, and the release of material for GLP and experimental use. 

API method development effort during dmg discovery is limited. In phase I, all impurities must be separated from a major peak to ensure peak purity. In phase n, a synthetic route needs to be selected and optimized. The method needs to be challenged when the route or process is changed. In phase III, the route is selected and the process is finalized. Critical Quality Attribute (CQA) impurities are defined and their references are typically prepared for method development. Method robustness and ruggedness must be demonstrated, and relative response factors of all impurities CQAs are determined before regulatory filing such as NDA and MAA. The validated definitive methods are transferred to manufacturing sites. 

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