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28 Pharmaceutical Technology TRENDS IN MANUFACTURING 2022 eBOOK P h a r mTe c h . c o m Biologics but neither is completely environmentally friendly. Thus, refrigerants with a low global warming poten- tial (compared to R404A/R507) can still be used in leak-tight, two-stage refrigeration systems. "There are two variations that can be considered: direct and indirect cooling of the ice condenser. From a tech- nical point of view, the indirect cooling of the ice condenser makes the system future-proof. Here the refrigeration system is designed to provide indirect cooling of the ice condenser," says Rosenbaum. Flammable refrigerants can also be used at a later date by replacing the refrigeration system, Rosen- baum continues. It is not yet possible to say, however, whether the classic design—where the ice condenser is cooled directly—will require future design changes to the ice condenser to comply in the long term with the F-gas Regulation. "First and foremost, with this solution the investment costs are lower than with the solution referred to above. However, retrofitting could be technically complex or even technically impossible. Should a retrofit of the ice condenser be deemed nec- essary and technically possible, the total investment will be greater than for indirect cooling of the ice con- denser, which will be implemented immediately. The operating costs for both variants are higher (approx. +10% to +30% compared to conventional freeze-dry- ing systems)," says Rosenbaum. Meanwhile, solutions for flammable, environmen- tally friendly refrigerants include developing another future-proof, environmentally friendly variant. In this case, the refrigeration system should be designed as a cascade system, for example. In addition, the indirect cooling of the ice condenser must also be performed via a second circuit. "Investment costs are higher than those for classic freeze-drying plants (up to +40% higher). Operating costs are also higher by [approxi- mately] 30%," Rosenbaum notes. Where biomolecules are most at risk From a pharmaceutical point of view, the thawing of the raw material (as in the case of proteins, for exam- ple) prior to formulation and filling plays a decisive role in determining where the biomolecule is most at risk. Concentration differences during the thaw- ing process can negatively affect the stability of the drug substance, specifies Rosenbaum. During filling of the finished formulation into vials, factors such as pressure and shear stress due to pumping processes, among other things, can lead to aggregation of sensi- tive biotherapeutics. The choice of the right pumps as well as suitable tubing materials is therefore essential. "During the freeze-drying process, special at- tention is paid to the freezing step. The cryocon- centration that takes place causes stress to the protein drug and can degrade its physical and conformational stability. Another essential step for maintaining the quality of the product is to find a right balance during primary drying between too conservative drying processes that increase production costs and too aggressive drying above the characteristic parameters Tg (glass transition temperature) or Tc (collapse temperature) leading to product loss," Rosenbaum explains. From a technological point of view, being able to determine a biomolecule's vulnerability involves the design of the drying processes within the de- sign space, Rosenbaum adds. With what he calls the 'design space approach', a biomanufacturer can develop an understanding of the boundaries within which freeze-drying for a certain product can be safely done. "The critical process and mate- rial attributes for the quality are unique to every product," Rosenbaum says. "By specifying a design space, the conditions for a sustainable quality of the product are defined in advance."