Pilot-laboratory batches preparation

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

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 ... 

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. 

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. 

In the first case, as discussed in Sec. VII below, a retrospective review of multiple batch records can provide considerable insight to support a defined PAR. A similar approach might involve a spreadsheet that summarizes critical parameter values for a series of R D lots when preparing to transfer the technology to R D s production colleagues. Often such retrospective data can be reinforced where gaps occur by some prospective laboratory or pilot plant experiments. 

A pilot plant scale starch solution, approximately 300 l, was prepared in a stainless steel container equipped with a paddle wheel electric stirrer, steam-heated coils, steam injection, an external gear pump with recirculation capability, insulation surrounding the container, a container lid, and a vent. The starch solution was prepared with the same percentage composition and duration of heating as described for the laboratory scale process. The first batch was pimped into the "sizing box" of the slasher and utilized immediately hot as a conventional yarn treatment. 

A batch size up to 100 gm was prepared in the laboratory. Large-scale production, including piloting, was not initiated due to a change in the clinical program. 

Recipes which resulted in better quality precipitates were tried for further investigation and the samples were subjeeted to various physico chemical tests viz surface area determination, porosity, pore size distribution and CO-Conversion activity following techniques described in earlier communications [12] from this Laboratory. Details of such studies are given in Table-II. In a particular series, obtained by direct precipitation techniques, pore size distribution in the 4-60 A was found to increase with R values. Basing on these studies some 50 kg batches were prepared in Pilot Plant following reverse technique. Quality eis obtained in Laboratory... 

Following the laboratory- or beaker-scale experimentation when the students are satisfied as to feasibility of the preparation and have enabled themselves to acquire sufficient information to undertake a large-batch operation (5 to 10 lb), a small-scale-process laboratory study should then be undertaken. Attention should be paid to the engineering considerations involved in the production of the commodity. In order to obtain engineering data essential for the pilot plant investigation of the commodity selected, the following considerations may be important ... 

Aside from the preparation and handling of overly large production batches under conditions of inadequate shielding or absence of remote control, the potentially must hazardous pyrotechnic operation seems to be the pilot production that is too small or too intimately connected with the laboratory group to be put in the production area and is performed in the crowded and insufficiently policed area of the laboratory rather than in a specially designed and suited experimental pilot-production station. 

Scale-up from laboratory to a modest pilot plant scale was no minor task for preparations of calcium polyphosphate samples of 50 to 100 lb per batch. Containment problems suddenly take on a new complexion. To lose control of 100 lb of molten phosphate at temperatures approaching 1000 °C could cause major prob-... 

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