The annual project throughput is a key metric in early clinical trials as companies wish to push as many projects through the facility as possible, since proof of concept in the clinic and rapid identification of promising candidates are viewed as key drivers. The tool predicted that the disposable and hybrid pilot plants would be able to achieve higher throughputs of 8 and 7 projects respectively, as opposed to 6 projects in the conventional stainless steel case. This can be attributed to the lack or reduction in cleaning and sterilising operations and the faster turnaround times between campaigns.
From the tool, it is possible to view the operating costs on a category basis such as materials, utilities, staff, fixed overheads and depreciation charges. The cost outputs generated by the tool on a cost category basis are shown in Figure 5.4 for a stainless steel, a disposables-based and a hybrid pilot plant. The graph shows the cost of goods per gram in the first year of operation relative to the stainless steel case. Comparing the total annual cost of goods per gram for the three cases, the disposables and hybrid plants are seen to offer significant reductions (30% and 19% respectively) in operating costs relative to the conventional stainless steel case. This is due to the higher number of projects completed relative to the conventional case, hence increasing the annual gram output, as well as associated drops in certain cost categories. Examining the stainless steel case indicates that the COG/g is dominated by the fixed overhead costs (maintenance, local tax, insurance and general utilities) and depreciation charges, which represent 67% of the cost. These costs are proportional to the capital investment required which is highest in the stainless steel case. In contrast, in the disposables and hybrid cases these fixed costs fall by at least a third of the conventional value.
The staff and utilities costs are lower in the disposables and hybrid cases owing to the fewer number of ancillary operations such as cleaning and sterilising equipment. For the first year’s operation, the annual material costs double when a switch from a conventional plant to a disposables or hybrid plant is made. Here the stainless steel case benefits from lower annual material costs as it was assumed that each manufacturing campaign for a new drug candidate would not require the purchase of new consumables, such as chromatography matrices. In this hypothetical case, the
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increase in materials costs is not larger when disposables are used since the chemicals cost per batch is significantly lower owing to fewer ancillary operations. In addition cheap disposable hollow fibre membranes were utilised for diafiltration operations, rather than conventional membranes which can be an order of magnitude more expensive.
Figure 5.5 shows the direct cost of goods per gram for each of the manufacturing tasks for a pipeline of projects that were completed within the first year of plant operation. This reflects the cost of the direct materials, utilities and staff allocated to each task, thereby providing the capability to view where these resource costs are concentrated. The figure does not include the indirect expenses for resources, overheads and depreciation. In this hypothetical case, the cleaning-in-place (CIP) procedures in the stainless steel case and the capture chromatography steps in the disposable and hybrid cases consume the most resources, and are hence the most expensive. The fact that cleaning operations present such a cost burden in conventional plants may not have been transparent before such an analysis and indicates a particular virtue of this form of modelling.
100% 80% R elative 60% cost per gram 40% 20% ü D e p r e c ia tio n □ Facility o v e r h e a d s □ Staff
■ M a teria ls & D irect u tilities
SS DISP HYB
Figure 5.4 Annual cost of goods per gram (COG/g) on a cost category basis for the stainless steel (SS) pilot plant, the disposables-based (DISP) pilot plant, and hybrid (HYB) pilot plant, each assumed to produce the same yield per batch. The costs are relative to the baseline stainless steel case.
Annual direct c o s t p e r gram ($/g)
D S P
Figure 5.5 Annual direct cost of goods per gram (COG/g) on a task basis for the stainless steel (SS) pilot plant, the disposables-based (DISP) pilot plant, and hybrid (HYB) pilot plant, each assumed to produce the same yield per batch. The most expensive tasks are the GIF’s in the stainless steel case and the capture chromatography steps in the disposable and hybrid plants.
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The use of disposable equipment eliminates the need for cleaning and sterilising operations and hence these costs are reduced in the disposable and hybrid cases. However, the cost balance tips towards the costs for chromatography steps. Here the major contributor to the cost is the Protein A matrix which tends to distort the cost distribution. This implies that the process development team must have good processing reasons to defend the use of such an expensive step in a disposable manner.
The above analysis highlights the benefits of presenting costs on a task basis to help focus cost reduction efforts on specific tasks to obtain a more balanced distribution of costs.
From Figure 5.5, it is apparent that the disposable and hybrid options have significantly higher direct costs than the stainless steel case, owing to the higher material demands. However, examination of the balance between direct and indirect costs reveals that the indirect costs represent 52-67% of the total annual operating costs. Since the indirect costs are proportional to the capital investment, the stainless steel case has significantly higher indirect costs and hence higher overall operating costs as illustrated earlier in Figure 5.4.
The tool also generates utilisation curves for the resources. Figures 5.6 a, b and c show the combined media and buffer utilisation over time for each pilot plant for both the product manufacture recipe and the equipment preparation recipes (CIP, SIP). Here media refers to fermentation media and buffer refers to the solutions used during the equilibration, wash and elution stages of chromatography and to the CIP solutions. The figures highlight the greater demand on buffer in a stainless steel pilot plant that can be attributed to the need for CIP procedures in addition to the tasks involved in the product manufacture recipe. A simplification for the case study was that media and buffer arrived ready-made to each plant. This is certainly appropriate for the disposables-based plant since they could arrive pre-sterilised in bags ready for use. However, in a stainless steel plant, it is more likely that these materials would be prepared in-house. Consequently, the utilisation curves indicate that more media and buffer preparation steps are required in a stainless steel plant. This would further accentuate the differences in cost of goods between the cases.
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a)
b)
Stainless steel media & buffer utilisation (L) 1000 750 500 250 0 0.0 4.0 8.0 12.0 16.0 20.0 Time (weeks) Disposable media & buffer utilisation (L) 750 r 500 250 0. 0.0 4.0 8.0 12.0 16.0 Time (weeks) c) Hybrid
media & buffer utilisation (L) 750 500 250 0 0.0 4.0 8.0 12.0 16.0 20.0 Time (weeks)
Figures 5.6 a, b and c Combined utilization of media and buffer over time for (a) the stainless steel pilot plant, (b) the disposables-based pilot plant and (c) the hybrid pilot plant. The peaks in the stainless steel plant correspond to the high buffer demands in cleaning-in-place (CIP) steps, which are absent in the disposables-based plant and reduced in the hybrid plant.
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A final feature that was considered was the utilisation of operator resources. An example of the demand on all the operators in the stainless steel plant is illustrated in Figure 5.7. The customised “current-utilisation” curve for the operator resources highlights the level of peak demands and when they occur. Examination of this curve indicates that, typically, a maximum of 6 operators is used at any time in the process but that the demand for operators is intermittent. The “average utilisation” of all the operators was also probed. This measures the total amount of time that a resource is allocated to a task, compared to the duration of the manufacturing campaign. The average utilisation for this scenario was 1.2 operators. This low value can be attributed to the significant duration of the inoculum-grow-up stage, which is not labour-intensive and hence has a low operator utilisation to reflect this.
O p e r a t o r utilisation
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