Super dry: The use of monoclonal antibodies

Robert Turok, SPX Flow, discusses high yield spray drying of monoclonal antibodies and its use in the production of fine biopharmaceutical powders.

Tests on spray dryers have revealed they can offer high yields in the manufacturing of monoclonal antibodies (mAb); producing powders that offer advantages in storage and transportation compared with liquid or frozen alternatives. The process has been shown to produce good stability and potency; offer practical reconstitution times, and proven scalability – giving manufacturers a viable and beneficial alternative to conventional ultrafiltration (UF) and freeze drying (lyophilisation) processes. The resulting spray-dried powders give no process limitation to solution viscosity in the preparation of high concentration mAb formulations.

What are monoclonal antibodies?

Antibodies are proteins produced by the body's immune system when it detects harmful substances such as bacteria and viruses that might cause an infection. Monoclonal antibodies are clones of a single type of antibody that recognise and attach to specific proteins produced by cells in the body. They work in different ways to help with the treatment of cancer. These include triggering the immune system to attack cancer cells; stopping checkpoint inhibitors in the body so the immune system can work effectively; blocking signals that tell cancer cells to divide, and acting as carriers to transport cancer drugs or radiation to cancer cells.  They are also used in diagnostic tests, including pregnancy tests; to help stop organ rejection after a transplant, treatment of other diseases such as multiple sclerosis, and by researchers to identify and trace specific cells or organisms.

Conventional mAb production process

As with many other biological drug substances, mAb tend to be produced over periods and may be stored for long intervals until needed to produce the final drug product in line with market demands. Traditionally they are produced using a single UF/diafiltration (DF) process which produces a drug substance that is in liquid form. This is then shipped and stored in a frozen state to reduce instability and prolong its shelf life. When needed at the drug production plant, it is thawed and filtered ready for use.

The problem with handling frozen drug substances is the equipment needed to store them. They can be kept in large volume cryogenic tanks, small volume plastic bottles or small volume disposable bags. Maintaining this cold storage, however, is costly and troublesome. Large stainless steel or Hastelloy storage tanks are expensive; regular maintenance and cleaning are required, and systems require validation. Furthermore, bulk storage creates long freeze-thaw cycles, requires a lot of space and careful control of temperature and temperature change rates. Small volume storage options use a lot of bags or bottles per production batch and produce more challenging conditions for sampling and maintaining quality.

If higher concentration levels of mAb are required, the drug substance production plant may introduce a second UF stage. This can, however, present additional challenges as gelation can occur at the filter membrane as viscosity increases and permeate flux (flow rate through the membrane) reduces. An increase in process temperature will lessen the solution viscosity and alleviate this problem, but the higher temperature may cause problems in sensitive proteins and degrade product stability.

Use in the production of fine biopharmaceutical powders

Spray drying using a cyclone to collect powder is a well-established process and is widely used in pharmaceutical applications including areas such as encapsulation, microencapsulation and agglomeration. It is also gaining in popularity in biopharmaceutical applications and offers producers the capability to control particle characteristics with consistent precision and performance. The dryers use heated gas that mixes with an atomised feed in a chamber to create a dry powder. The thermal energy of the hot gas is consumed in evaporation so there is reduced heat exposure to the product being treated, making spray drying ideal for the processing of heat sensitive compounds.

Historically spray dryers have not been used for larger production capacities with particles less than 10 microns. This is because cyclones were designed for lower pressure drops therefore imparting reduced forces to the particles collected. Higher efficiency cyclones with increased pressure drops have been successfully applied to large molecule bio-pharm applications. Pharmaceutical particles have been found to be physically robust and have not experienced attrition or smearing within the cyclone. Multiple high efficiency cyclones may also be used, smaller cyclones will generally have greater small particle collection efficiency. This means that high yield, predictable and consistent performance can now be achieved using spray drying in such applications.

The clear benefit of using spray dryers is that the drug substance is in powder form. This alleviates the difficulties and cost of cryogenic storage of the liquid product, enables easy handling and transport as required and, although reconstitution is required, removes the need for long freeze / thaw cycles. Tests on spray drying mAb formulations have given very positive results that make this an interesting alternative to traditional methods of producing this important drug substance.

Tests using multiple mAb formulations

Carbohydrate sugars can be used to stabilise mAb in a dehydrated state. Too much sugar in the formulation, however, can reduce yields as the resulting powder can have a reduced glass transition temperature and stickier properties resulting in particles sticking to the sides of the drying chamber. Organic or inorganic salts can be used to reduce viscosity to aid processing. Tests on the effectiveness of spray drying were carried out using multiple mAb formulations with sugar (trehalose) and/or salt (arginine succinate). With a limit of 220:1 molar ratio of sugar to mAb, spray drying produced powders with approximately 5% moisture and yields typically greater than 95%.

Formulations were tested on a lab-scale Anhydro MicraSpray35 (38 kg/h drying gas rate) and pilot scale Anhydro MicraSpray150 (154 kg/h drying gas rate). Under similar drying conditions both dryers produced powders of similar moisture content, particle size and powder yield; showing the scalability of the process.

As a result of the spray drying process, mAb powder samples were stored at 40 °C for up to three months and at 25 °C for up to six months. When liquid formulations from the reconstituted powder were compared with liquid formulations prior to spray drying, the results were similar. Both aggregation and fragmentation were comparable, suggesting that the high temperature spray drying had a negligible effect on the stability or quality of the spray-dried mAb stored over long periods.

The reconstitution properties of the mAb formulation powders are obviously a critical factor in using spray dryers. The reconstitution time may depend upon factors such as protein concentration, particle size, solubility and agitation intensity. The spray dried powder showed reasonable reconstitution time; generally less than three minutes to typical bulk drug substance concentration levels. It also showed good reconstituted solution turbidity, with similar characteristics to the original liquid after the subsequent filtration stage that both liquid and reconstituted powder formulations would require.

Summary

Spray dryers offer highly efficient drying capability with the potential to significantly reduce production time and cost. Their high inlet temperature has been shown to have negligible detrimental effects on the quality of mAb, which showed good stability and potency after processing.

The use of high efficiency cyclone technology has enabled very high yields for fine powders in larger scale spray dryers; offering pharmaceutical and biotechnology producers a viable and more compact alternative to expensive freeze-drying processes. Spray drying is a continuous process facilitating validation in FDA regulated applications. The ability to achieve powder moisture levels of around 5% further offers manufacturers significantly simplified storage and transportation of drug substances. Tests on mAB showed that powders can reconstitute in a reasonable time and the reconstituted liquids give comparable viscosity and osmolality (concentration) to the liquid formulation prior to spray drying.

Alongside high yield, high efficiency and scalability; spray drying offers the significant advantage in the production of mAb of enabling the creation of high concentration, high viscosity formulations without the concentration limitations of conventional UF processes.