Pilot-laboratory batches

If the formulation is deemed stable, preparation of additional pilot-laboratory batches of the drug product for expanded nonclinical and/ or clinical use. 

The qualification trials using (10 x size) pilot-laboratory batches have been completed, in which the critical processing steps and process variables have been identified, and the provisional operational control limits for each critical test parameter have been provided... 

Pilot-laboratory batches are usually prepared in small pilot equipment within a designated current GMP approved facility. The number and size of these pilot-laboratory batches may vary, depending on one or more of the following factors ... 

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. 

The construction required the production of 7.5 tons (6.8 tonnes) of each of the three Sulphlex binders. Scale-up to these quantities was required from laboratory batch size without benefit of investigating intermediate batch production. (Refer to (9) and (10) for discussion of Sulphlex manufacture in laboratory and pilot-scale batches.)... 

After the (1 x) laboratory batch is determined to be both physically and chemically stable based on accelerated, elevated temperature testing (e.g., 1 month at 45°C or 3 months at 40°C or 40°C/80% RH), the next step in the scale-up process is the preparation of the (10 x) laboratory pilot batch. The (10 x) laboratory pilot batch represents the first replicated scale-up of the designated formula. The size of the laboratory pilot batch is usually 30-100 kg, 30-100 liters, or 30,000 to 100,000 units. 

Minimum three, using, where possible, identifiably different batches of API Minimum two pilot scale batches plus one additional batch, which may be smaller (e.g., 25,000 to 50,000 solid oral dosage units), but not laboratory scale Same as the marketed product Meaningful simulation of process for the marketed product Same as the marketed product... 

Most laboratory processes are rarely scalable, since piloting is a scaled-down version of manufacturing not a scaled-up version of the laboratory batch. 

Rushing through the first (lOOx) pilot-production batch in order to proceed with formal validation should be discouraged. Small problems that often arise during (lOOx) scale-up should be addressed immediately and not ignored. Such problems are often best addressed by returning to the laboratories (10x) for supplemental process characterization and qualification studies. 

Using these large seed crystals, tuns of increasing size were made in the laboratory to make enough seed for a pilot plant batch. The amount required, as indicated above, is 10-20% to ensure sufficient surface area for growth. 

A useful approach to process optimisation is to identify all the critical process parameters that could potentially affect product quality or performance and prepare a Process Optimisation Protocol. Typically, data used to identify critical process parameters will be derived from laboratory or pilot-scale batches, and do not need to be confirmed on full-scale batches unless the control of the particular parameter can only be evaluated on a production scale. There is good incentive to use the production facilities at the earliest opportunity, drug availability permitting, to iron out any transfer difficulties. Manufacture of the stability batches to support Phase III studies, and also the Phase III clinical batches, at the final commercial site should minimise any questions from the FDA during PAI about possible differences between R D and Production process used. 

Excipient manufacturing plants often produce laboratory or pilot lots/batches. Scale-up to commercial production may involve several stages and data should be reviewed to demonstrate the adequacy of the scale-up process. Scale-up may introduce significant problems in consistency among lots/batches. Pilot lots/batches should serve as the basis for establishing in-process and finished product purity specifications. 

Written procedures should be established to monitor the progress and control the performance of those manufacturing processes that may cause variability in the quality characteristics of APIs and intermediates. In-process controls and specifications should be derived from laboratory-, or pilot-scale batches and may be adjusted later based on data obtained from full-scale production batches. 

Determination of the range for each critical process parameter expected to be used during routine manufacturing and process control. Data to substantiate the ranges for critical process parameters generally should be obtained from laboratory- or pilot-scale batches, unless a specific parameter can only be determined from a production-scale batch. 

When prospectively validating a process, data from laboratory-and/or pilot-scale batches should identify critical quality attributes and specifications, critical steps, control ranges, and in-process tests. Scale-up batches could be used to generate data to confirm or refine earlier work, and production-scale batches should provide data showing consistency of the process. 

Obtain the experimental product distribution in a laboratory or pre-pilot-plant batch reactor. 

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). 

The most potent means of diagnosis are visualization and depthwise probing. These can be of coating as it is transported past successive fixed stations on a production or pilot line or of samples selected after the line has been abruptly halted or of samples arrested at successive times of a laboratory batch approximation to the solidification process. Once arrested, the samples can be spatially sectioned by fracturing, microtoming, confocal microscopy, etc., to examine depthwise and transverse variations. 

The simplicity of the batch and semi-batch reactors allows us to respond quickly to evolving market opportunities. As soon as we have successfully determined the reaction or process conditions in a laboratory batch or semi-batch reactor and established the heat transfer requirements of the reaction or process, we can move to pilot plant-sized or commercial-sized equipment. If the heat transfer requirements are met by currently available equipment, then we can quickly produce product for market sampling. Such rapid response is important in today s global... 

Figure 18. Correlation between process aid additions for maximum primary bitumen recovery and process aid additions required to attain maximum bitumen/aqueous surface charge (Zeta potential). The data are for continuous pilot plant operation (Hj and laboratory batch extractions (%). (From Schramm and Smith [111].)...

Evaluation methods Except for the pilot plant batch or counter-current extraction described by various laboratories, most of the solvent extraction evaluation work found in the literature was done in one or several of the laboratory scale devices. The percolation batch-extraction apparatus of the Soxhlet type has often been used to evaluate the... 

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). 

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