Traditionally small molecule drugs used to be produced in batches. Batch manufacturing of drugs was a time-consuming and costly process with low efficiency and yield. A technology called Continuous Flow Manufacturing is now being developed by a joint initiative between Novartis and MIT in 2007, which is capable of converting drug components into tablets in one continuous process.

CFM in Small Molecules
The process is unique from traditional batch processing methods in that the reactions mostly occur in tubes through which the reactants flow. This is in contrast to large vats in which the reactions traditionally took place.

Some advantages of continuous flow manufacturing with respect to batch manufacturing:

• Less space requirements: The equipment used in continuous flow manufacturing is much smaller in size as compared to batch processing.
• Faster output: Previously, the API had to be synthesized and transported to another site where it would be converted to pills. The entire process used to take weeks or months for a single batch.
• Flexibility in manufacturing: New ingredients can be added to the flow at specific points, and components can be swapped in and out to create different drugs.
• Higher cost savings: Total cost savings by adopting continuous flow manufacturing over batch manufacturing is expected to be close to 15% to 50%.
• Continuous monitoring: Quality assurance testing can be improved as it is easier to monitor the process in continuous flow manufacturing as opposed to batch processing. The process is more efficient in that monitoring of the product and intermediates can be done in the middle of the process itself, and not as a huge batch at the end. Chances of errors are less in continuous flow manufacturing.
• Environmental benefits: Continuous flow systems are more efficient in heat management and waste management as compared to batch processing.

The technology is being regarded as an integral step in lean operations for pharmaceutical manufacturing, due to efficient waste management, lesser space utilization, higher efficiency of process and better quality of products.

CFM in Downstream Biologics Processing
Continuous flow manufacturing technology is still in its infancy. Its small molecule applications are being investigated mostly by the Novartis-MIT collaboration, but there are limitations when it comes to adopting continuous flow manufacturing in biologics. For one, economies of scale cannot be achieved in biologics manufacturing, due to the complexities of the processes involved.

Biologics manufacturing consists of two stages: upstream biomanufacturing (including cell line development and expression systems) and downstream processing (purification of bio-molecules and filtration). The downstream processing stages used to be a bottleneck for most biologics manufacturers, as the components and processes involved in downstream processing are very expensive and have low yield.

Traditionally, the downstream processing was done in batches in large chromatography columns, and was heavily dependent on stationary phase purification methods such as Protein A.

ChromaCon AG, in collaboration with MIT, has recently devised a new Continuous Chromatography system called the Multicolumn Countercurrent Solvent Gradient Purification (MCSGP) system, which has opened new avenues for implementing continuous manufacturing for biologics.

Multicolumn Countercurrent Solvent Gradient Purification
The MCSGP system works on the basis of two chromatography columns kept in a unique arrangement through which the solutions pass and the impurities are separated from the target proteins continuously. Impurities in feedstock could be of various types: host cell protein, DNA, adventitious and endogenous viruses, endotoxins, aggregates and other species.

The MCSGP technology is based on a simple principle that the gradient eluent adsorbs the target products and impurities separately, thus performing selective filtering. This process is further aided by a countercurrent that flows in the opposite direction of the gradient flow. The feedstock is separated into three fractions:

• the early eluting, weakly adsorbing impurities,
• the desired product, and
• the late eluting, strongly adsorbing impurities.

This process leads to a higher yield and lower solvent consumption. Compared to the traditional batch chromatography systems, the continuous chromatography system has a higher load of the column and better retention of target products. The system is very flexible and can be used to manufacture a variety of biologic drugs on a continuous basis. The MCSGP system is being implemented to eliminate the limitations and shortcomings in bio-manufacturing.

Here’s a short list of advantages to implementing continuous chromatography system in a biomanufacturing process:

• Reduction of footprints of units and utilities in the manufacturing process by 70%. Solvent requirement is expected to reduce by 90% as compared to Batch chromatography processes.
• Increase in yield close to 50% as compared to batch chromatography processing. Productivity of the downstream process is expected to increase by 10 times as compared to batch chromatography process.
• Reduction of cost of goods or operating costs by about 50%. In an independent project done by a collaborative team of MIT and Sandoz, it was established that the implementation of continuous chromatography system led to a reduction in costs close to $8.5 million per year for a single biologic drug. This also implies that the payback time for the manufacturer for a single biologic drug would be shortened significantly.
• Time of operation, or the time required to complete a full cycle of biologic production right from the upstream biologics through to downstream processing stages, will be shorter than batch chromatography. The time of operation is expected to be one-tenth to one-fifth of the time of operation in batch chromatography.
• Flexibility in manufacturing cycles. The MCSGP process can be run continuously for 24 hours or 48 hours or even for one year, as per the properties of the biologic drug. The MCSGP process doesn’t affect the capacity utilization directly, but improves the flexibility in the machine operation. A single process could be used to manufacture a variety of biologics and the process needn’t be changed even if the time of operations varies.
• Higher purity levels would be achieved, as the efficiency of continuous chromatography is expected to be more than batch chromatography process. Purity levels of 90% are expected to be achieved in the MCSGP process. The purity levels of MCSGP process are expected to be close to the purity levels of Protein A purification methods.
• Low switching costs. Only one extra column will be added into the arrangement, and overall size of the equipment will come down. The switching costs involved in the modification of a complete batch process are significantly high. In case of MCSGP system, there would be significantly lower switching costs mainly because only a single column is being modified, keeping the rest of the system constant. The cost of maintenance for this system would also be low as compared to a traditional batch system.
• Regulatory costs will be low, as the physical and chemical properties of the drug are unlikely to change. Hence, this process could be implemented for new biologics drugs such as biosimilars and biobetters, as well as for existing biologics drugs.

Novartis has put forward new initiatives on developing continuous flow manufacturing in biologics along with small molecules. With the kind of benefits that continuous manufacturing is expected to bring in the manufacturing process of biologics, it is clear that drug companies will be looking to adopt the technology sooner or later into their manufacturing facilities.

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Aloke Das is a senior research analyst (Biologics) at Beroe Inc. He can be reached at aloke.das@beroe-inc.com.