Scales timeline

With a tight production timeline, we chose to move forward with Silicycle Thiourea, which offered good Pd removal and filterability, albeit at a higher cost. In subsequent process development work the progress of Pd removal versus time was evaluated at both room temperature and 65°C. Results are shown in Figure 5.3 for 3 g scale reactions with 30% w/w Silicycle Thiourea. Pd removal was not only faster at elevated temperature but also more Pd was removed. 

The Medicinal Chemistry route suffered from several shortcomings that prohibited implementation on a kilogram scale while meeting the project timeline requirements ... 

Initial scale-up of microbial biotransformation is conveniently run with multiple flasks without extensive reaction optimization. A typical flask fermentation is performed at 28 °C, 250 rpm with 100 mL culture in a 500 mL Erlenmeyer flask, although other settings will work fine too. Three parameters need to be investigated before scale-up the time for adding the substrate, the optimal substrate concentration and the time course of product formation. Optimization of other factors, such as medium composition and pH, growing cells versus resting cells [74], is helpful, if the timeline allows and if there is a sufficient amount of the substrate to support the screening. 

This decision to scale-up is usually made two to three years before the projected regulatory filing date for the approval of the product, which in turn means about three to four years before the launch of the product. This is why the decision to scale-up is in direct opposition to the process development timeline, and special care has to be taken when developing a process for biologies in order for manufacturing not to be limitation on product approval. 

Shorter discovery timelines and accelerated development expectations have hindered the traditional approaches for natural products research. Furthermore, emphasis on chemical diversity presents a great challenge in this area, particularly because traditional natural products screening programs focus on one source of chemical diversity such as microorganisms or plants. Still, the primary issue remains how to assay this ideal source of new, biologically active compounds within the current timeframe necessary for modern drug discovery research. At the heart of this issue is the fact that traditional isolation and scale-up procedures are inefficient and often become the bottleneck in natural products dereplication. 

Apart from development of new catalysts with enhanced activity, few processes with innovative chemistry are currently developed for C-H transformation in aromatics. Though new processes using cheaper raw materials or reducing the number of reaction steps may seem attractive at first glance, efforts for process development including research, scale-up, pilot plant, and timeline must be considered. Especially for large scale-synthesis of bulk chemicals process economics... 

Furthermore, samples generated from large-scale clinical trials along with the ambitious development timelines to get safe and efficacious drugs to market warrant the use of HT bioanalysis. Numerous improvements in speed, sensitivity, and accuracy, augmented with innovations in automation in conjunction with mass spectrometry (MS) detection, have allowed for versatile and multifaceted platforms [6-8]. 

There are many advantages for choosing to develop and scale-up a capsule formulation over a tablet. As there is no need to form a compact that must withstand rigorous handling, development timelines can be reduced. Encapsulated products allow for easier blinding of clinical supplies and the ability to manufacture unique fills such as tablets in capsules, sustained release pellets, liquids, or semisolids. However, the costs of the capsule shells add an additional expense above the costs of tablet manufacture. 

A very potent means of computation on computer chips of this scale would be to use them for quantum computing. Already in the microscopic world, and for a short time, multiple universes can occur for an event, and this promises an extraordinarily high degree of parallelism for extremely efficient computing. It unlikely to develop soon until a bottleneck problem called decoherence is overcome, in which these multiple universes collapse to one and give us the common sense world we see. With advances in quantum computing there will come smaller, more powerful computers and electronics that will allow appliances and other products to make intelligent decisions for us. But it is very difficult to establish a timeline 2010 2030 2050 ... 

During our exploratory studies on this route, the amidation reaction (Step IB) reached 90% conversion in approximately 4 h, and was typically complete in less than 12 h. However, when attempts were made to run this chemistry in the pilot plant on a multi-kilogram scale, the amidation reaction was substantially slower, reaching only 37% completion in 4 h, and about 50% in 12 h. There was no option but to extend the reaction stir time and wait. While the reaction was slowly progressing in the pilot plant, we started thinking about what could have gone wrong. The reaction eventually reached completion in 50 h however, the problem had to be resolved almost inunediately because the next batch was slated to start in 3 days, and any delay had the potential to adversely affect project timelines. 

The terminology graphical rate equation derives from our attempt to relate rate behavior to the reaction s concentration dependences in plots constructed from in situ data. Reaction rate laws may be developed for complex organic reactions via detailed mechanistic studies, and indeed much of the research in our group has this aim in mind. In pharmaceutical process research and development, however, it is rare that detailed mechanistic understanding accompanies a new transformation early in the research timeline. Knowledge of the concentration dependences, or reaction driving forces, is required for efficient scale-up even in the absence of mechanistic information. We typically describe the reaction rate in terms of a simplified power law form, as shown in Equation 27.4 for the reaction of Scheme 27.1, even in cases where we do not have sufficient information to relate the kinetic orders to a mechanistic scheme. 

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