Producing a freezedried cake with the desired characteristics — moisture content, stability and reconstitution — often requires a number of trials, each one requiring the necessary facilities, time, personnel and media (power, WFI, etc.). The media is frequently very expensive and for this reason it is vitally important to ensure that scaleup can be achieved smoothly and effectively to avoid unnecessary expense and delays in time to market.
In some cases, it is possible to scaleup from a laboratory-sized lyophiliser to small production equipment in a single stage. However, scaleup processes are often required in two stages: laboratory to pilot production, and pilot production to full commercial volumes. The pilot stage is required to produce sufficient product under relevant GMP conditions for clinical validation. A rule of thumb for size categorisation is:
- laboratory lyophiliser (<0.3 m2)
- pilot (development) lyophiliser (from 0.1 m2 to 8 m2)
- production lyophiliser (from 8 m2 to 55 m2).
The process design depends on the requirements of each application. Therefore, a flexible approach is required to ensure the best security of outcome.
Definition of the scale-up process
In theory, the scale-up process is very simple: the outcome from the pilot (or laboratory) production must be recreated in the production lyophiliser. For this to be achieved, however, the conditions within the product and on the product's surface must be identical. There are several influencing factors that have an enormous impact on the process:
- Finding a formulation (soup or cocktail) with sufficient interaction between different excipients — buffers, bulking agents, preservatives, tonicity agents, stabilisers, surfactants, solubilising agents and antioxidants — is the most difficult step in lyophilisation. The intention is to avoid changing the formulation during scaleup as much as possible, but this is often difficult to achieve.
- The vacuum profile during primary and secondary drying influences the sublimation and desorption processes. Some influencing factors are:
– the vapour pressure difference between the ice drying front
– the vapour pressure at ice surface in the condenser
– the methods of vacuum control used
– the instrumentation used in achieving comparable conditions for pressure regulation.
- During drying, the product temperature can be controlled by pressure; however even then the heat transfer fluid in the shelves and cooling of the condenser has a huge impact on the performance of the process.
Other influencing factors are heat input and vapour transport out of the product; the different contact conditions from containers to the shelves owing to tolerances and surface variations; radiation and heat convection of surrounding areas; temperature gradient from product to the ice condenser; and the temperature difference within the shelves. Any one or combination of these conditions can lead to differences in the final outcome.1
As a temperaturerelated parameter, the freezing rate is also a major influencing factor on pore diameter, product quality and drying time. 2
Figure 1 shows the influence of freezing rate on the pore diameter of a dextrin solution.
Figure 1: The influence of freezing rate on the pore diameter of dextrin solution.
The influence of design parameters and dimensions
The design of the separation valve between chamber and condenser has a significant influence on the flow characteristics of the vapour. The kind of valve (mushroom, plate or butterfly), size of opening and position of this valve are all important (Figure 2).1 In addition to the separation valve, other vapour flow influencing factors have to be considered, including the position of the condenser, the design of the evaporator (pipes or plates),1 the size and the inter-distance of the shelves.
Figure 2: Design of a mushroom valve.
A number of other design parameters and factors must also be considered during the scaleup process:
- Smaller lyophilisers use doors made partly from acryl. This material has a strong influence on the temperature at the front of the shelves caused by different heat radiation characteristics compared with stainless steel doors. To reduce this influence, aluminium foil is often placed on the inside of the door, but this has only a limited corrective effect.3
- Pilot and development equipment is not usually subject to the same clean room conditions as production lyophilisers. This leads to a potential problem as particles contaminating the containers can affect crystallisation points and lead to different freezing behaviour.
- The ratio of heat transfer media flow to the amount of product has an influence on the outcome; the amount of thermal energy required is dependent on the area and the amount of product to be brought to the required temperature (heating or cooling). A different ratio in mass flow will lead to a different freezing period and different temperature set points.4 Different flow conditions also have an impact on the implementation of thermal energy into the system especially within ramps (during static conditions this influence is negligible).
- The ratio of stainless steel mass and surface area within the lyophiliser leads to different process conditions as the walls and shelves affect the conductive, radiation and convective heat transfer. Varying distances from the shelves to the chamber walls also has an effect.5
- Behaviour during temperature and pressure ramping, the overshoots and control accuracy of set values all have an impact on product characteristics. It is necessary, for example, to establish whether the heat transfer system for the shelves is controlled by shelf inlet or outlet temperature. Similarly, the condenser can be controlled by direct expansion (which both may be cooled by LN2 or compressors) or by circulation heat transfer fluid.
- The type, amount and sequence of collected variables mean that the data and reports generated from the control systems may not be directly comparable.
- The instrumentation used for process control, such as product temperature probes, may be different for pilot equipment and production size lyophilisers. Product probes are used easily in laboratories for small projects with a small amount of containers and good access. Under production conditions, however, it is difficult to handle probes especially when using isolators, or if the ratio of values is not comparable (e.g., 1 probe/50000 vials instead of 1 probe/50 vials).6 The type of vacuum control, whether capacitance or pirani, has a huge influence as well.1 The use of mass flow controllers (calibrated leaks) compared with the option of opening and closing the vacuum valve must also be considered.
These factors make the transfer of lyophilisation processes difficult from one type of equipment to another. Experience allows some factors to be estimated with sufficient accuracy; however, all too often it is only through trial and error that production is successfully transferred from development to production.