How can an efficient continuous flow manufacturing process be applied in biopharmaceuticals?

Drug Crystal Formation Research and Development

Currently, the biopharmaceutical industry is growing rapidly, especially with the increase in upstream expression and scale-up. Conventional batch production is of limited efficiency, while continuous flow production shows promising applications in terms of increased capacity, cost reduction and time reduction.

Background

China’s biopharmaceutical industry has just started, and Chinese drug companies have a big gap with foreign biopharmaceutical giants in terms of both technology level and production scale and efficiency. If they still follow the batch production mode of foreign originator drugs, they will not have any advantage in production cost, and will be in a disadvantageous position in the bidding of the band purchasing. Therefore, in order to win in the fierce competition, Chinese biopharmaceutical companies must have a better production process, higher production efficiency and lower production costs than the original drug manufacturers. The application of continuous production technology will be a breakthrough for Chinese biopharmaceuticals to gain a competitive advantage. Continuous production technology has just started, and domestic and foreign companies are basically at the same starting line. If Chinese biosimilar companies can seize the opportunity to prioritise the development and use of continuous production technology, they will be able to take advantage of the latecomer’s advantage of improving production efficiency and lowering production costs.

Traditional biologics production uses a batch production process, which requires a series of intervals of production steps. Each interval step in the whole process will bring about a reduction and delay in production efficiency and increase the probability of product defects and operational errors. Continuous production pharmaceutical technology is an emerging technology that still faces many regulatory issues and technological challenges, but the superiority of continuous production is obvious and a general trend in the development of biopharmaceutical processes, which can improve the robustness and reliability of the production process, reduce production and fixed asset expenditures, reduce plant construction time, and reduce the time required for product changeover in production.

In the downstream production process, the implementation of continuous flow is mainly through the use of continuous flow chromatography, on-line testing and other technologies to integrate multiple process units (Figure 1), which can improve the production efficiency and plant utilisation while reducing intermediate storage, waiting time between steps, and the scale of instrumentation and corresponding inputs, so as to achieve the goal of shortening the cycle time and lowering the production cost. The goal is to shorten the production cycle and reduce production costs.

Case Study

As far as the downstream purification process is concerned, it mainly consists of the following: the first step involves capturing the antibody with Protein A affinity media; the second step uses cation chromatography as an intermediate purification to remove the antibody polymers, HCP, DNA, etc.; and the third step uses anion chromatography media to finely separate residual DNA, HCP, Protein A, endotoxin, etc. to achieve the purpose of purification (Figure 2). The third step is the fine separation of residual DNA, HCP, Protein A, endotoxin and other impurities by anion chromatography medium to achieve purification (Figure 2).

The main purpose of the downstream purification process is to increase the purity and yield of the product through separation and purification, and to guarantee product quality and stability. Continuous production requires linking all the steps so that the production process can be highly integrated and highly automated, and to ensure product stability and consistency, etc. (Figure 3).

The continuous flow process can improve filler utilisation, reduce process time and increase capacity (Figure 4). The application of the continuous flow process will be described in several case studies below.