Scale batch size

Figure 5.19 displays a typical course of discontinuous SSP on the commercial scale (batch size, 221) with respect to the variables of temperature, time, vacuum and intrinsic viscosity. This figure shows the IV plotted as a function... 

Similar to the requirements for small molecules, at least three batches of drug substance of pilot or full scale batch size and representative of the process used in pre-clinical, clinical, and proposed manufacturing scale should be studied. If pilot scale lots are used in the stability study for the Biologies License Application (BLA), a commitment must be made to place the first three commercial batches on stability. 

Generally, pilot- or production-scale batches are tested. It is recommended that each batch used is no smaller than 10% of the proposed production-scale batch size. 

That work led to a routine 700 gram scale oxide reduction process that has been in use since that time. Recent development work at LANL has increased the batch size to one kilogram of oxide feed. It appears that the ultimate limitation on DOR batch size will be from criticality safety constraints. 

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... 

Figure 4.42. Trend analysis over 46 batches of a bulk chemical produced according to the same manufacturing procedure Small and scaled-up batch size [kg], HPLC and Titration assays [%], resp. individual HPLC impurity levels [%], versus batch number. The lack of full correlation between assays indicates that the titration is insensitive to some impurities detected by HPLC. The mass balance, where available, suggests that all relevant impurities are quantified. Impurities B and C, for instance, are highly correlated (r = 0.884, p = 0.0002).

While implementing production processes into multi kilogram batch sizes for NHC complexes (Fig. 14.1), a complete quality control of the imidazolium or imi-dazolidinium starting material was required. Therefore, Umicore has implemented large-scale manufacturing of the salts in-house, resulting in stable and reproducible synthetic protocols for the transition metal complexes. 

Batch-type production processes, particularly those with small batch sizes, have less energy efficiency as compared to continuous processes. A typical example of a batch operation on a relatively small scale is the production of titanium in 1-ton batches of the metal. The energy efficiency of the process is much less than that of continuous methods such as iron being produced in a blast furnace, or even of large-scale batch methods such as basic oxygen steel-making. The heat losses per unit of production are much less in continuous and large-batch processes, and this also enables the waste heat from process streams to be used. 

Scale Up of Process. The scale up of fluidized bed coating processes has received little attention in the literature. Current practices in the pharmaceutical industry are reviewed by Mehta (1988). The basic approach described by Mehta (1988) is to scale the airflow and liquid spray rates based on the cross-sectional area for gas flow. This seems reasonable except for the fact that in the scaling of the equipment, the height of the bed increases with increasing batch size. For this reason, a time scale factor is also required. 

Test runs using a 150 mm diameter fluid bed coater indicated that a batch of 2 kg of material could be coated using a liquid spray rate of 10 ml/min for 50 minutes and a fluidizing gas rate of 40 scfm. It is desired to scale-up this process to a batch size of 200 kg of bed material. For the scaled up process, determine the bed size the liquid and airflow rates and the new run time. 

Minimal bounds on the production quantity are most often process dependent. Typically, a minimal campaign length is required if for example a critical mass is necessary to initiate a chemical reaction. The same is valid for maximal bounds on the production quantity. The rationale here is that a cleaning operation may be required every time a certain amount has been produced. Finally, batch size restrictions often arise in the chemical industry, if for example the batch size is determined by a reactor load or, as discussed above, the processing time for a certain production step is independent of the amount of material processed. In these scenarios, when working with model formulations using a discrete time scale, it is important that the model formulation takes into account that lot sizes may comprise of production in several adjacent periods. 

In Scheme 4 it can be seen that cyclisation of the ketoester with hydrazine-hydrate was part of a reaction sequence given to the kilo lab and is described in literature with a yield of approximately 60% (Schenker and Salzmann 1979). Under conventional conditions (refluxing in ethanol for 4 h), we obtained the product in 53% yield. Performing the same reaction in the Synthos 3000 microwave reactor at 140°C for 20 min, we improved the yield to 64% on a 20-g scale. Further scale-up to a batch size of 130 g of product was performed under the same conditions (140°C/20 min) with no significant problems. 

Full scale mixing studies were conducted without incident using 100, 250, 500, and 1,000 pound batch sizes. Electrostatic charge generation during the blending cycle was several orders of magnitude below that required for initiation. 

Therefore, even a moderate error in the mixer scale-up will have only a small effect on the agitator-side heat transfer coefficient. Other factors that include heat transfer area per unit volume are considerably more significant. For instance, in the jacketed tank, the heat transfer area per unit volume decreases upon scale-up. In order to assure the same proportionate heat removal or addition per unit batch size, additional heat transfer area (e.g., coils) may be required. Additionally, other variables such as temperature driving force may have to be adjusted to compensate for decreased heat... 

The batch size ranged from 3.75 up to 60 kg. To obtain precise scale-up measurements, the excipients which were used belonged to identical lots of primary material [10% (W/W) corn starch, 4% (W/W) polyvinylpyrrolidone as binder, and 86% (W/W) lactose]. As can be seen from Figure 4, the amount of granulating liquid is linearly dependent on the batch size. During the scale-up exercise, the rate of addition of the granulation liquid was enhanced in proportion to the larger batch size. Thus the power profile, which was plotted... 

No necessity for scale-up experiments The granulation and drying of subunits of 7-9 kg, instead of a whole batch, gives the possibility to use the plant for laboratory and production scale, because the batch size is no longer characterized by the machine size, but by the number of produced subunits. Using the same plant in Galenical research, development and production may shorten the time to market for new solids specialties. 

Irrespective of the method used to produce the granules and the consequent batch size, a signiflcant factor in scale-up is the increase in drying capacity in larger equipment. The heat delivered to the bed of fluidizing granules comes from a combination of inlet air temperature and volume, and, to a lesser extent, inlet air dew point. As previously mentioned, the process air volume is also responsible for fluidization behavior, and this will be the first variable to be considered. 

Figure 16 Influence of increasing batch size on product differential pressure and process air volume for a pilot scale top spray layering and coating process.

In summary, it appears that roller compaction pre- and postblends can be NIR monitored during scale-up, independent of batch size and blender type. Using real time NIR monitoring would advance blender unit operations knowledge and provide continuous information and assurance about specific unit operations such as roller compaction, a key FDA Process Analytical Technology goal. 

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