Pilot-laboratory batches development

A reaction was believed to be thermally neutral, as no rise in temperature was observed in the laboratory. No cooling was provided on the pilot plant, and the first batch developed a runaway. Fortunately the relief valve was able to handle it. Subsequent research showed that the reaction developed 2 watts/kg/°C. Laboratory glassware has a heat loss of 3-6 watts/kg/°C, so no rise in temperature occurred. On the 2.5-m3 pilot plant reactor, the heat loss w as only 0.5 watt/kg/°C [21]. Reference 22 lists heat losses and cooling rates for vessels of various sizes. 

During the development phase a series of laboratory or pilot-scale batches will be subjected to this stability program. As soon as the process is scaled up to production-size batches, the first few, and at least one per year thereafter will also go on stability. Submission is only possible if the product completes a minimal combination of tests, e.g., one full-size batch for 12 months and two reduced-size batches for 6 months... 

The RC1 is an automated laboratory batch/semi-batch reactor for calorimetric studies which has proven precision. The calorimetric principle used and the physical design of the system are sound. The application of the RC1 extends from process safety assessments including calorimetric measurements, to chemical research, to process development, and to optimization. The ability of the RC1 to generate accurate and reproducible data under simulated plant scale operating conditions may result in considerably reduced testing time and fewer small scale pilot plant runs. 

A typical example of the mathematical penetration of problems supported by computers was the development and design of a high-pressure polyethylene (PE) plant with a capacity of 24,000 tons/year in 1958 based on laboratory batch experiments only without a pilot plant by three doctoral candidates. (58, 59, 60). 

Specific reactor characteristics depend on the particular use of the reactor as a laboratory, pilot plant, or industrial unit. AH reactors have in common selected characteristics of four basic reactor types the weH-stirred batch reactor, the semibatch reactor, the continuous-flow stirred-tank reactor, and the tubular reactor (Fig. 1). A reactor may be represented by or modeled after one or a combination of these. SuitabHity of a model depends on the extent to which the impacts of the reactions, and thermal and transport processes, are predicted for conditions outside of the database used in developing the model (1-4). 

The main driver was to develop a laboratory-scale micro-channel process and transfer it to the pilot-scale, aiming at industrial fine-chemical production [48, 108]. This included fast mixing, efficient heat transfer in context with a fast exothermic reaction, prevention offouling and scale-/numbering-up considerations. By this means, an industrial semi-batch process was transferred to continuous processing. 

Documentation requirements are predicated on the types of batches to be manufactured at the pilot facility. For the development of novel formulations, laboratory notebooks are the primary source of documentation. Room and equipment logbooks should be maintained. Personnel training records and SOPs must also be maintained. Once the facility is used for the larger-scale batches described earlier, what was recommended now becomes required. Manufacturing runs need to be documented accurately, preferably in batch records. Logbooks should maintain an accurate record of the product history in rooms and equipment. At this level of manufacturing, it is also important that personnel training records be kept. These... 

It is usually prepared in small pilot equipment within a designated CGMP-approved area of the development laboratory. The number and actual size of the laboratory pilot batches may vary in response to one or more of the following factors ... 

In developing trans-free fat, various methods for laboratory-scale, pilot plant, and commercial batch reaction were described by Erickson (256). List et al. 

Because of the favorable results obtained in the laboratory scale study, an experiment was conducted to assess the ability to predict the potency of pilot scale rotogranulated beads using data from the experiments performed in the laboratory. The calibration developed for the 55% laboratory scale beads was used to predict the potency of a 30-kg pilot batch. Figure 3 shows a plot of predicted versus actual potency. Prediction error for this study, although acceptable, was slightly higher than in the laboratory study. This error may be attributed to differences in surface characteristics and density between laboratory and pilot scale beads. 

Often the analysis of a compound is best left to specialists. Analytical chemists may be very helpful in developing an in-process assay for the laboratory or pilot plant and in purifying an impurity. Quality control (QC) chemists may be key in recognizing a new impurity in a manufacturing batch. Spectroscopists know how to get the best performance from their instruments. Good teamwork among the analysts and other chemists is essential to the efficient development of a process. 

The first batch of reference standard usually evolves from an HPLC peak or a TLC band deemed to be present at a level important to the analyst. Assumptions must be made initially about response to a UV detector or to a TLC detection method. The best source of authentic material matching the peak or band of concern is from the process that led to the sample displaying the impurity. The development laboratory and/or the pilot plant is usually that source. LC-MS at this point can give a theoretical mass that may be informative. Enrichment of the impurity follows until the structure can be determined using other instrumentation. 

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