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API Scale-Up During Research and Development (continued)

Safety precautions. Material safety. At the time of route finalization, R&D chemists should collect all raw material safety information—typically,material safety data sheets (MSDS). The storing and handling risks of these materials should be assessed, and appropriate measures should be taken to minimize them. Process safety. During process development, significant consideration should be given to the safety of the chemistry being developed. The majority of industrially useful reactions are exothermic, thereby suggesting the need for risk assessment. Figure 1 shows the reaction enthalpies of two common reactions, indicating the high degree of process hazard associated with them (2). The magnitude of overall heat release can be influenced by the kind of solvents used, concentration, other simultaneous processes taking place, and so on. Together, these factors may have enormous destructive power if they are not controlled properly. Therefore, all chemical processes that may be performed in a pilot plant should be subjected to a safety evaluation. Initially, the thermal stability of the compounds (e.g., raw materials and intermediates) should be screened using differential scanning calorimetry to detect endothermic or exothermic behavior. Then, these results can be used to determine whether more careful and tedious measurements are required. In some scale-up cases, an exothermic reaction can lead to thermal runaway, which begins when the heat produced by the reaction exceeds the heat removed. The rate of heat production may increase exponentially. Once control of a reaction is lost, the reaction vessel may be at risk of overpressurization caused by violent boiling or rapid gas generation. Elevated temperatures may initiate secondary, more hazardous runaway or decomposition. Such a reaction hazard should be assessed in a laboratory using methods such as thermal gravimetric analysis (measuring the thermal stability of the reactants or products) and adiabatic calorimetry (measuring the decomposition and release of gases). A process should not be performed in the pilot plant before such safety assessment. Other process hazards such as dust explosion during milling or storage may also be assessed at an early stage, depending upon the potential of such risks. Materials and vendors. It is important to conduct vendor audits and approval to ensure consistent quality and supply of raw materials, packaging materials, and other process components such as filtration media, gaskets, and O rings that might contact raw materials, process fluids, intermediates, or the API. Vendors should be selected according to criteria such as their market recognition, record, ability to supply consistent quality materials in time, and customer orientation. Certificates of analysis (CoA) and MSDS of the materials should be obtained from vendors. Such information is useful while designing the specifications of raw materials and packaging materials and for obtaining recommended storage conditions. Developing the specifications In-house specifications can be developed on the basis of the results of user trials and the CoA of a vendor’s samples. Process scale-up issues. It is important for R&D chemists to identify potential plant issues and to attempt to address these concerns suitably at the R&D stage. Laboratory studies such as those described below can help address many issues a priori to avoid surprises that might occur in the plant scale-up batches. Simulating the R&D plant environment. Once the route is finalized, the plant environment in R&D should be simulated as far as possible by: using reaction vessels of similar type and shape (e.g., material of construction, vessel shape, stirrer type, number of baffles, and diameter:length ratio of the vessel); using the same charging sequence of the raw materials; using similar mixing pattern and stirring parameters that are achievable in plant vessels (e.g., similar tip speed or power requirement per unit volume of the reaction mass that can be maintained in R&D); developing suitable in-process sampling procedures that are feasible in the “controlled” environment of a good manufacturing practice plant; using similar filtration cloth or medium; using a similar type of dryer and drying parameters. Such simulation experiments can help achieve better reproducibility at that plant scale because the possible deviations can be minimized. Determining the scale-up factor. Many scale-up operations require more time than laboratory-scale experiments because the volume of materials is larger. R&D chemists should take into account the scale to which the process can be operated in the plant and the required time cycles for such process steps. They should deliberately increase the process time cycles in a laboratory experiment to match the plant time cycles for similar operations. Process steps that may be considered for such studies include: adding reactants; mixing; filtration; centrifugation; drying; maintaining temperature. The effect of such an increased cycle time on product quality and yield should be assessed. Thus, a scale-up factor at which the process can be operated without affecting the quality and yield can be determined prospectively. (continued)