Process development factor levels

Often the decision to select a batch or continuous processing mode involves a determination of the relative contributions of capital and operating expenses to total process costs for the proposed level of capacity. As Denbigh (1) points out, what is best for a highly industrialized country with high labor costs is not necessarily best for a lesser developed country. In many cases selectivity considerations determine the processing mode, particularly when the reaction under study is accompanied by undesirable side reactions. The yield of the desired product may differ considerably between batch and continuous operation and between the two primary types of continuous processes. When the yield is lower for a continuous process, this factor may be so important in the... 

All process development starts with chemistry. The selection criteria for the most suitable chemistry for a continuous process do not suffer from the same constraints as those for a large-scale batch process. For example, highly exothermic reactions are not only possible in a flow reactor, but are in fact preferred [47]. As operator exposure will be low and so will stock levels, different safety considerations come into play that may allow utilisation of otherwise intolerably toxic reagents. Process telescoping is a necessity to minimise the number of intermediate isolations. Examination of all these factors is facilitated by online analysis because of its speed and maintenance of experimental integrity (i.e. no requirement for sampling). 

It is critical, during initial process development, to give serious consideration to the amount of material that will be applied (especially for processes involving drug layering or those involved with the application of modified-release coatings to fine particle products, where required coating levels in excess of 50% are not uncommon). Key factors to be established are ... 

As shown in this chapter, formulating HPMC matrices can be a complex process critical factors being drug solubility, dosage level, rate-controlling polymer and excipient choice. In order to help the pharmaceutical scientists with a starting formula for hydrophilic matrix tablets, Colorcon, hic. has developed a predictive formulation service called HyperStart [97]. This system is based on mathematical models and relationships, validated with extensive experimental data. Use of the HyperStart formulation service may help to simplify the formulation and development process and reduce the time to market. 

Detailed experimental designs are undertaken at all levels of process development—discovery, scouting, product and process development and improvement, qualification, prove-outs, even start-up. With respect to startup in an industrial environment, not only will DOE quantify the relationship between operating conditions and product specifications, it can also help develop standard operating procedures as well as optimize stand-by conditions (conditions at which the plant runs at reduced capacity due to poor market conditions or problems downstream). DOE is an efficient means to assess the effect and interaction of factors. The effect is defined as the variation of the response variable with respect to a change in a factor while interactions assess the relative change in the response variable with respect to two or more factors. 

The optimal combination of the EMM process parameters and their combined effect on MRR and accuracy is found out based on the developed second-order mathematical models, i.e., Eqns (8.2) and (8.3) for correlating the various process parameters effects with MRR and machining accuracy. Optimum factor levels that will maximize the MRR and minimize the accuracy related responses, i.e., WOCs are calculated and are listed in Table 8.4 for single optimization along with its predicted responses. MRR... 

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