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The new OPTIMA LYO-SCALE laboratory freeze-dryer is madefor perfect scale-up of recipe parameters that can be applied to larger systems. This article shows the special functions of the new system and the reasoning behind it.
Freezing and drying – by definition, these are the two physical processes that work together to achieve freeze-drying. The development of recipe parameters for a stable process include extensive laboratory work, especially because every drug formulation is unique in its freeze-drying behavior.
Such behavior can be seen, for example, in the specific ice crystal formation of a drug during freezing. This also applies to sublimation (skipping the liquid state of aggregation) and applying a vacuum (evacuation): What are the optimal temperature and pressure conditions so that vapor can escape easily through the ice crystal structure in the vial?
From the laboratory to production: The new OPTIMA LYO-SCALE has all the prerequisites for developing precise parameters for freeze-drying processes in production plants.
To freeze-dry a drug and create a high-quality lyophilisate the formulation must be developed in the laboratory. Therefore, the active ingredient (API – Active Pharmaceutical Ingredient) is refined into a product that can be transported and stored. In this process, pharmaceutical water and additional substances like skeleton-forming agents are added, which influence the crystallization during freeze-drying. If a formulation, which meets the quality requirements for a lyophilisate and thus the requirements for a successful freeze-drying process, has been found and defined, the “scale-up” follows. During scale-up, the process parameters of laboratory freeze-dryers are transferred on a commercial scale freeze-dryer.
Now, the system specifications come into play. These have a major impact on the final freeze-drying recipe for a medical product. Ideally, the process parameters from the lab-scale freeze-dryer can be transmitted and applied in full to the production freezedryer or only a few parameters should require minor adjustments. Indeed, the scale-up of parameters from the laboratory to production also depends on various system properties, which are discussed below.
It is easily explained why recipe development is carried-out with laboratory freeze-dryers. Initially, recipe development is an equation with several unknowns. Production systems would have a long period of downtime if this development work had to be completed with a production system. The energy consumption would also be disproportionate, even if only one shelf of a production system was loaded, since the entire system is cooled, heated and evacuated during each freeze-drying process.
The systems themselves must also be considered. If freezedrying processes were to be developed on a production system with only a small amount of product, the values would in all likelihood have to be adapted to the production scale again, which would be a time-consuming process. Because the existing amount of liquid in relation to the mass of stainless steel that has to be cooled and heated, and other properties would have an influence on the results that would be difficult to calculate, i.e. the generated recipe. So, what are the requirements for a laboratory freeze-dryer to scale a recipe into production effectively and efficiently? Optima accepted the challenge: The freeze-drying experts provide exciting answers with the new LYO-SCALE laboratory freeze-dryer.
To fulfill the parameter development mission, geometric equality ratios are a central prerequisite. Laboratory freeze-dryers should ideally depict the production processes on a smaller scale. All Optima freeze-dryers already show this “proportionality” in the production area. With the new OPTIMA LYO-SCALE, this principle is now extended to laboratory systems.
This initially concerns the surface dimensions of the shelves and the surrounding chamber. The size ratios should be identical in the laboratory and production freeze-dryer. This includes shelf thickness measurements in order to achieve the same ratio of heat transfer coefficients from steel to glass.
In addition, the size of the valve between the drying chamber and the condenser, as well as the size of the cold surface of the condenser must be considered. For example, a shelf surface of 40 m² that is loaded with 10 ml vials corresponds to a quantity of about 75,000 vials per load. This creates a steam volume flow of 128,500 m³/h, which flows through the steam passage - the valve between the drying chamber and the condenser. This volume flow must pass through a correctly sized valve (whereby further physical restrictions must be observed when calculating this flow channel). Additionally, the vapor passing through must meet a specifically designed condenser cold surface size. The design of the surface size is in turn strongly dependent on the capacity of the cooling system.
If all of the above-mentioned criteria are identical in the laboratory and production systems, the optimal conditions for a precise process parameter scaling from the laboratory to production system are given.
Both freezing and drying are equally critical to achieving high quality freeze-drying results. The goal is a homogeneous freeze- drying cake in the container with minimized, defined residual moisture. This is achieved by controlling the temperature curves and pressure (negative pressure or positive pressure). In the course of recipe development, it is also determined whether it is better to thaw in stages or continuously, with rapidly or slowly increasing temperature, when and how much pressure is applied, and how to evacuate. Various sensors measure all of these parameters in both laboratory and production freeze-drying systems. The similarity principle between laboratory and production systems should also apply to components like sensors. Temperature and pressure sensors, but also control devices from identical manufacturers, will lead to a more precise scaling of parameters from the laboratory to the production system. Wherever possible, Optima uses identical parts and components in laboratory and product on systems. If it is not feasible, the identical functional principle is achieved through similar components.
The Optima operating software of the HMIs is the same for the laboratory and production freeze-dryers. With known recipe structures and operating concepts that are already understood by the employees, the probability of errors decreases significantly. In addition, the identical software ensures optimal transferability between the system types.
Directly to the production systemOptima is known in the industry as an expert for production system manufacturing – particularly for pharmaceutical freezedrying systems. It is an advantage to know and understand the special requirements of large production systems in order to be able to transfer them to and in laboratory systems.
The OPTIMA LYO-SCALE is now being launched with identical software and practically identical mechanical and process engineering conditions to achieve the best results in parameter development. For the LYO-SCALE user, this means that the parameter transfer from the laboratory to the production line will result in a freeze-drying process that produces a lyophilisate of the same high quality as in the laboratory. This reduces the readjustments required during the product transfer and reduces downtime of the production machine.
For recipe parameters and diagnostic productsThe first LYO-SCALE is currently being set up in Gladenbach/Mornshausen, Optima’s lyophilization technology center in Germany. This laboratory freeze-drying system will be connected to an OPTIMA MultiUse LAB filling and closing system and is a turnkey project (see also p. 20). The possible batch sizes of the freezedryer range from 200 to 4,000 objects, depending on the container sizes and the number of loaded shelves. This LYO-SCALE system is intended for a CDMO for recipe development of freeze-drying processes, as well as for the development of drug formulations as an additional service offering to customers. The second LYOSCALE commissioned to date will also be used by a research-based pharmaceutical company for the production of individual, very small product batches and for internal scale-ups. Drug studies could also be carried out with the LYO-SCALE at any time prior to the clinical phases. This type also has applications for the freeze-drying of diagnostic products. A sterilizable version of the OPTIMA LYO-SCALE laboratory freeze-dryer is also in development. In the future, this will make it possible to freeze-dry pharmaceuticals in approval procedures for clinical phases 1 to 3, as well as small commercial batches of very high-quality pharmaceuticals, for example cell and gene therapies, in a very efficient manner.
Optima’s laboratory freeze-dryer portfolio includes additional LYO-SCALE versions. These will initially differ in terms of the installation area and the redundancy of process-critical components. For example, the production of very expensive pharmaceuticals requires – even with small batches – maximum process security with partially redundant components. In turn, this would cause unnecessary costs for systems that are used purely for parameter development. Therefore, the perfectly suitable OPTIMA LYO-SCALE laboratory and production system can be configured for every requirement.
