Robustness process

The Medicinal Chemistry route introduced the oxadiazole fragment prior to installation of the 4-FBA (Scheme 6.1). The overall yield for these two steps was only 37%. The oxadiazole required a two-step synthesis and was a much more expensive reagent than 4-FBA. In order to improve the chemical yield, reduce cost and improve the overall process robustness, we investigated the amidation with 4-FBA prior to installing the oxadiazole moiety. 

Technical and business rationales (increase process robustness, process efficiency, improved quality, cost reduction, etc.)... 

Finally, process analytics methods can be used in commercial manufacturing, either as temporary methods for gaining process information or troubleshooting, or as permanent installations for process monitoring and control. The scope of these applications is often more narrowly defined than those in development scenarios. It will be most relevant for manufacturing operations to maintain process robustness and/or reduce variability. Whereas the scientific scope is typically much more limited in permanent installations in production, the practical implementation aspects are typically much more complex than in an R D environment. The elements of safety, convenience, reliability, validation and maintenance are of equal importance for the success of the application in a permanent installation. Some typical attributes of process analytics applications and how they are applied differently in R D and manufacturing are listed in Table 2.1. 

Tables 2 and 3 show an antibody purification process scale-up from laboratory scale (1 mL) to intermediate scale (500 mL) to large scale of 10-85 L column volumes, maintaining the column bed height constant. Product quality and biocontaminant levels were maintained throughout the scale-up, though operational flow rates were significantly changed, demonstrating the consistency of the overall purification process. Thorough analysis of each coliunn performance is essential in order to sustain the process robustness at different scales of operation.

Including the key stakeholders in decisions affecting process design or changes ensures efforts by the process owner are applied correctly. Process robustness is dependent upon meeting business and customer needs, and the process owners require input and support from the stakeholder group. 

Assemble and document evidence of process robustness" and reproducibility. 

Examination of Figure 2, which illustrates pyramiding of parameter ranges, provides insight regarding the important relationships between process robustness and process validation. 

Establishing critical process parameter ranges and probable adverse consequences of exceeding range limits represents a better investment of resources and contributes more to process robustness and reliability. 

The idea behind this methodology is to apply a technique of experimental design with the goal of finding levels of the controlled factors that make the process robust to the presence of noise factors, which are uncontrolled. The controlled factors are process variables that are adjusted during the normal operation of a process. The noise factors are present in combination with controlled factors and have a significant influence on the response or quality of the product. Noise factors are either impossible... 

Borkowski, J. J. and Lucas, J. M. (1997). Designs of mixed resolution for process robustness studies. Technometrics, 39, 63-70. 

If lyophilizers of different types are used to lyophilize a drug product according to a same freeze-drying cycle, useful information about process robustness can sometimes be gained by comparing the values of the dependent parameters. The analytical properties, in particular the activity and the moisture of product batches manufactured in different lyophilizers, also deserve comparison. 

MicroChannel reactors have some significant drawbacks. The most troublesome is clogging of the channels via incoming particulate matter or from fouling during the reaction process. Robustness is another common problem with microreactors. Because the unit is made at such a small internal scale, the resistance to mechanical shock is low. These issues usually render the microchannel reactor unsuitable for reactions that have precipitates as a product. For the Prox reaction, microchannel reactors are suitable provided there is no water condensation and the incoming reformate is particulate free, especially from carbon. Since microchannel reactors are often made from substrates that include stainless steel, Hastelloy, glass, silicon, polymers, and ceramics, another issue that could arise is chemical compatibility. 

Kelly BD, Jennings P, Wright R, Briasco C. Demonstrating process robustness for chromatographic purification of a recombinant protein. BioPharm, October 1997. 

The determination of the property of interest in a simple solution will indicate to the analyst his working range in terms of sensitivity of the signal. The degree of trueness and precision are properties quantified in the validation process. Robustness or ruggedness concerns the ability of the method to remain unaffected by environmental changes (analyst, time, fluctuations in supplies, etc,). All six characteristics have to be established and quantified in the validation of the method (section 2.3). 

Toluene recovery process Maximization of economic benefit and minimization of environmental indicator. In addition to these two objectives, Kheawhom and Hirao (2002) considered process robustness measures (failure probability and deviation ratio) also. Normal boundary intersection method Sustainable process index was used as environmental indicator. Product revenue less capital and operating costs was the economic indicator Kheawhom and Hirao (2002)... 

Pharmaceutical Acceptable formulation/pack (meets customer needs Drug delivery/product performance acceptable Stable/acceptable shelf-life Clinical trial process robust and can be scaled up... 

During process optimisation, the capability and robustness of the manufacturing process is assessed (as described later in this chapter on process robustness), to confirm that the specifications can be met at the extremes of the limits. The capability of the test method, accuracy, precision and reproducibility will also affect the limits that can be achieved. 

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