Process-scale considerations validation

Gross-Butler equation is that the reactant is in isotopic equilibrium with the solvent. Given that the process under consideration occurs on an exceptionally short time scale, the assumption is not necessarily valid. A very thorough analysis of the isotopic possibilities was used to show that the interpretation presented here is nonetheless correct.25... 

While tailoring the process to suit available equipment is a major factor during process development, once the process is developed and validated, selection of appropriate equipment that is than qualified for the process under consideration is very critical for smooth scale-up. Many a good process comes to naught due to poor equipment selection, leading to rework and avoidable waste of that most precious resource time. Two major activities are done at this stage ... 

To gain FDA approval or license for marketing, a pharmaceutical product must be shown to be safe and effective for its proposed or intended use. The drug company or sponsor must also provide evidence to show that the processes and control procedures used for synthesis, manufacture, and packaging are independently validated to ensure that the pharmaceutical product meets established standards of quality. The overall effort from the inception of a new molecular entity and the establishment of analytical, scale-up, and quality control procedures, to the collection of safety and efficacy data for consideration by the FDA as part of an NDA or BLA, is called the drug development process. 

For purification, scale-up considerations are important even in the earliest phases of development. It is important to avoid the use of purification techniques of limited scale-up potential even for early clinical production because thorough justification of process changes and demonstration of biochemical comparability are necessary prior to product licensure. For successful scale-up, it is important to understand the critical parameters affecting the performance of each purification step at each scale. Conversely, it is important to verify that the scaled-down process is an accurate representation of the scaled-up process, so that process validation studies, such as viral clearance and column lifetime studies, can be performed at the laboratory scale. 

Studies of thermal oxidation of polymers are usually carried out as accelerated by raising temperature of the sample so that the oxidation can take place in a considerably short time scale. This makes any extrapolation to lower temperatures unreliable since many processes are involved in degradation and several of these may become rate-limiting as the temperature is changed. This is particularly valid when such extrapolation is performed through the melting range. 

Process validation is documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-deter-mined specifications and quality attributes [48]. For cell culture-derived biopharmaceuticals, important quality attributes to establish include structural integrity and potency of the API and freedom from impurities. Thus, the demonstration of removal of cell culture and process impurities is a key part of process validation. Often, due to practical considerations, some studies are performed at small scale. In these cases, periodic concurrent monitoring of impurities during large-scale production can confirm the results from small-scale studies. 

As well as the nitration-specihc advantages, the time, the amount of materials necessary for the process validation, and the risk of scaling-up are all reduced considerably. 

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