Pilot-scale batch

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... 

Some very nice engineering and experimental work was performed by Pollard et al. in measuring a fungal fermentation in real time.21 The work was performed on a 75-1 fermentor and showed detection limits for fructose, glutamate, and proline in production matrices of 0.1,0.5, and 0.5 g/1, respectively. Glucose and phosphate were measured in a 280-1 pilot scale batch with detection limits for both of 0.1 g/1. 

Pilot Scale Batch — A batch of a drug substance or drug product manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch. For solid oral dosage forms, a pilot scale is generally, at a minimum, one-tenth that of a full production scale or 100,000 tablets or capsules, whichever is larger. 

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.)... 

In most cases (except those involving scale up), stability data from pilot scale batches will be acceptable to support the proposed change. 

Pilot Scale Batch The manufacture of drug product by a procedure fully representative of and simulating that intended to be used for full manufacturing scale. Preservative An agent that prevents or inhibits microbial growth in a formulation to which it has been added. 

An extension of an expiration dating period based on (1) data obtained under a new or revised stability testing protocol that has not been approved in the application or (2) full shelf life data on pilot scale batches using an approved protocol. 

The stability data for the pilot scale batch of Penclomedine is presented in Figure 21.5. The data indicate that this drug is fairly stable in various vehicles under consideration. Ahuman Phase I clinical batch in Neobee Oil was produced and its shelf-life surveillance at controlled room temperature has shown 3 years of stability. 

For API processes, the FDA does not expect validation of all manufacturing steps, but accepts validation of critical process steps. Section XI.A of the March 1998 draft API guidance document states, Validation should embrace steps in the processing of APIs that are critical to the quality and purity of the final API. The FDA, however, does not specify what it considers critical, but wants the manufacturer to determine the critical process steps and critical process parameters. For new chemical entities, data used to identify critical processing steps and critical parameters would be derived from research or pilot scale batches. For established API processes this information could be obtained from previously manufactured production scale batches. 

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... 

For APIs, stability data should be generated on a minimum of one pilot-scale batch made using equipment of the same design and operating principle as the manufacturing-scale equipment (with the exception of scale). 

A minimum of three pilot-scale batches (two at least pilot scale and one smaller batch, e.g., 25,000 to 50,000 units for solid oral dosage forms) are required for the following dosage forms, and other exceptions, which should be discussed with FDA ... 

In order to assess the state of SPC, a sufficient number of pilot- or commercial-scale batches should be manufactured (at least 10% of anticipated commercial scale) using the same process anticipated for the scaled-up product. When the formulation is finalized, the critical in-process and final product control specifications will be challenged through process validation studies on at least three full- or pilot-scale batches. 

A prior approval supplement is necessary to extend a tentative expiration date based on three pilot-scale batches. The expiration dating remains tentative until confirmed with full long-term data from at least three production batches. 

Table 14 Conditions in film coating pan for pilot scale batch...

Two of the three batches should be at least pilot scale batches, and the third one can be smaller if justified. Where possible, batches of the dosage form should be manufactured by using different batches of the active ingredient. 

Studies were also conducted to assess the ability to monitor clinical batch pellet production and predict endpoint pellet potency. Two 30-kg pilot scale batches were processed in order to optimize scale-up process parameters. From each batch, 18 samples ranging from 90 to 100% theoretical potency were analyzed and used to develop potency calibrations. The regression results for PCR, PLS, and single-wavelength calibration... 

For APIs, limits are set on chemical purity, mean particle size, PSD, and other appropriate physical attributes by the biobatch model for clinical evaluation. The term biobatch refers to the regulatory requirement of identifying a particular batch, normally a pilot scale batch used in clinical trials, as the defining standard for physical and chemical attributes that must be reproduced at the manufacturing scale to be acceptable for sale. The critical process attributes (CPAs), once established, must be met on scale-up to the manufacturing facility. In addition, the process must be operated within the ranges established as critical process parameters (CPPs). Development of a crystallization process must include determination of realistic and reproducible ranges for both the CPPs and the CPAs. 

Preliminary API expiry or retest dates can be based on pilot-scale batches if (z) the pilot batches employ a method of manufacture and procedure that simulates the final process to be used on a commercial manufacturing scale and (zz) the quality of the API represents the material to be made on a commercial scale. 

Table 10.1 Synthesis of a spiro lactone in a pilot-scale batch plant...

In a pilot-scale batch process using an 800 L tank, the first lithiation is conducted by adding BuLi to a phenyl isonicotinamide solution while keeping the inner temperature below —60°C. In the second step, the dilithiated intermediate is added to 4-oxocyclohexanecarboxylate. Because no major problems are encountered in the first step, the second reaction is carried out while varying the temperatures and the addition rate (Table 10.1). Under these conditions, the maximum yield of the desired compound is 82.9%. When the scale of the second reaction is increased to 2000 L at the same jacket temperature (addition time 36 min), the yield decreases to 77.3%, indicating difficulty in scaling-up this type of reaction. 

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. 

For the purpose of approval of drug applications, stability data on pilot-scale batches should include results from microbial challenge studies performed on the drug product at appropriate intervals. In general, microbial challenge studies conducted initially, annually, and at the end of the expiration dating period are adequate. Chemical assays of preservative contents should be performed at all test points. 

Alternatively, if the stability study on at least three pilot-scale batches is continued after the NDA/BLA approval, it is feasible to extend the tentative expiration dating period based on full long-term data obtained from these batches in accordance with the approved protocol, including statistical analysis if appropriate, through a Prior Approval Supplement. However, the expiration dating period thus derived remains tentative until confirmed with full long-term data from at least three production batches. 

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