Introduction

Continuous processing technologies are increasingly being employed in the biopharmaceutical sector as an alternative to traditional stainless steel-type technologies. While there are numerous advantages to continuous buffer manufacturing setups, they have yet to be quantified. The purpose of this analysis was to investigate the economic, operational and environmental consequences of full deployment of continuous buffer manufacturing in a biopharmaceutical process using an existing process as a case study.

Conventional buffer manufacturing process

The buffer manufacturing process on almost all biotech sites is a highly manual one, with very little flexibility. Shown in Figure 1 (main image) is a high-level process flow diagram schematic which shows the main steps in this process: For the production of a single biopharmaceutical protein, multiple different buffer formulations are required. Due to the large quantities used, buffer management tends to become a bottleneck in the production process and therefore requires careful planning into the production schedule. In addition to high labour cost, there is a risk of human error associated with such a time and labour intensive manual activity.

Inline conditioning of buffers

Inline Conditioning (ILC) is a new technology, which is used to manufacture buffers on demand. A high-level process flowdiagram of howan inline conditioning processworks is shown in Figure 2. With ILC, buffers are prepared in-line from concentrated, single-component stock solutions of acid, base, salt and WFI. In comparison to all current methods, continuous buffer manufacturing offers a number of advantages: 1.) Solutions contain only one buffer component and can thus be much more concentrated than a prepared concentrated buffer. 2.) The possibility to prepare buffers of different strength, pH and salt concentration from these component stock solutions. 3.) Less consumables are required for transfer and storage of buffers 4.) Decreased use of buffer vessels and ideally no use of buffer vessels 5.) More availability of buffer vessels and CIP skids to allow for manufacturing expansion

Results

The data collected for this analysis is site data for batches over the timeframe of a year. Total costs on a per batch basis for both the batch and continuous buffer manufacturing configurations is shown in Figure 3. The relationship between the CAPEX cost of the ILC skid, the total number of yearly batches manufactured on the site, and total operating costs per batch is shown in Figure 4. 1. The ILC total costs per batch is approximately 40 per cent lower than the batch manufacturing setup. 2. The consumable cost in the continuous setup is effectively zero. 3. The CIP Cost in the continuous ILC setup is reduced by approximately reduced by 90 per cent. It was also noted that the economic benefits of moving to a continuous system are proportional to total buffer volume required and also inversely proportional to buffer component variability, that is, having multiple buffers with similiar components will allow for a greater reduction in storage volume required.

Operational analysis

In addition to the economic analysis, the operational differences between the conventional and continuous setup were analysed in terms of space usage, waste processing, inventory required, process defects and time spent manufacturing. Space Shown in Figure 5 and Figure 6 are high level schematics of typical batch and continuous buffer manufacturing processes respectively. The flow of materials for the batch process is as follows: 1. Buffer Manufacturing Room 2. Storage Room 3. Chromatography Area [caption id="attachment_48913" align="alignright" width="203"] Fig 5 and 6: The effect of this is significant as it allows the buffer manufacturing space to be used for value added activities.[/caption] The main difference in space here is the lack of a buffer preparation area in the continuous setup, which effectively is replaced by the ILC skid in the chromatography area. Buffer waste By replacing the buffer storage stage, the continuous setup has the potential to reduce waste processing costs by removing the inherent waste associated with this step. Batch processes do not have the flexibility to produce only as much as is needed and must produce some excess, therefore there will be varying amounts of buffer not used in purification, which does not have any value. ILC has the potential to remove this source of waste as it manufactures buffer ’just-in-time’ for purification. There will never be any overproduction associated with this buffer manufacturing setup. Inventory The inventory setup, which in this case will be taken to be the buffer/single component storage area, will be different depending on the manufacturing setup in a number of key ways. Shown below is a schematic of the ILC continuous storage setup compared to conventional buffer manufacturing. Shown in this case, the three buffer totes of single components acid, base and salt have the capacity to make the equivalent volume of buffer to specification shown underneath. When applied to the whole buffer manufacturing process of all 31 buffers, this equates to a 90 per cent reduction in storage volume. Defects An ideal batch of buffers would have no records of failed buffer batches, or consumables not meeting specifications. In reality, there will be a defect rate of consumables per batch and a number of failed batches of buffer. The effect of this analysis was conducted, taking defect rates from site data of 10 per cent for consumable defect rates and two per cent for buffer batch fail rates. In this case, this averages an additional three per cent operating costs per batch (e12,747 per batch in this case). Time Conducting analysis to find inefficiencies in setup time is worthwhile as it has the potential to free up additional time for value added activities that would otherwise be used in buffer preparation. Conventional buffer manufacturing occupies a significant block of time in the manufacturing campaign. A single buffer takes approximately two to four hours to manufacture. The table below shows the approximate time spent on buffer manufacturing alone per batch. Table: Parameter and Value Preparation time per buffer: two to four hours Number of buffers per batch: 31 Total preparation time: 62 to 124 hours As this analysis is focused on the buffer preparation stage only, there is no equivalent time in the ILC continuous setup. Therefore for the purpose of this analysis, it can be said that all of this time can be used for other value added activities if the ILC manufacturing setup is in full use.

Environmental analysis

To conduct an environmental analysis, the environmental effects of both buffer manufacturing processes were analysed and compared. The metric used to compare both processes was effective mass of CO2 released during manufacturing of the process components. For both systems the components analysed for environmental impact were: 1. Steel 2. Plastic 3. CIP The total CO2 emissions from each segment of the manufacturing process on a per batch basis is shown below. Again, similar to the economic analysis, the environmental effects of the continuous process are significantly improved when compared to the conventional process.

Conclusions

As shown in this analysis, buffer manufacturing is an area for significant improvement in the move towards continuous bioprocesing. Continuous buffer manufacturing has the capability to offer companies flexible, multi-product factories with reduced turnaround time and significantly reduced CIP operations. Economic evaluation of continuous buffer manufacturing shows the saving opportunities available (reduction of approximately 40 per cent in this case). The higher capital cost is significantly outweighed by the lower operating costs. Environmental impact of the continuous system is reduced due to the change in manufacturing system to a ’just-in-time’ philosophy, significantly reducing multiple waste sources. Finally, the operational benefits of continuous buffer manufacturing in the areas of reducing waste, space, inventory on hand, defects and time are all significant in that they allow biotech sites to focus more time and resources on value added activities. The clear gap between upstream and downstream productivities can be bridged by developments towards continuous chromatography systems. Continuous buffer manufacturing can only aid the move towards continuous chromatography, and as a result, increasing the productivity of downstream operations to match the upstream counterpart. Author: Odhran O’Callaghan, UCC, Process and Chemical Engineering; Dr Maria de Sousa Gallagher, academic supervisor; Fergal Lalor, industrial supervisor