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Lyophilizer Loading and Unloading Systems for Product In Vials

Tue, 11/08/2011 - 6:24am
Dr. Paul Stewart, President Telstar North America (Telstar Group)

When automatic loading/unloading systems were first introduced in the early 1990s they were based on the use of a vehicle, or transporter, which moved packs of vials between the process stations of filling, lyophilization and capping. Such systems (termed ‘flexible’ because they were able to support simultaneous loading and unloading operations across a number of process stations) were suited to large scale installations in traditional clean rooms, where several (usually three or more) large lyophilizers were installed. Indeed, in 2006, over 50% of automatic loading/unloading system installations were of the ‘flexible’ design.

In the past few years, however, a number of trends have resulted in the overwhelming use of loading/unloading systems based upon use of transport conveyors (rather than vehicles). Although such systems (termed ‘fixed’) are less flexible logistically they have a number of distinct advantages, in that they are:

• Economic to apply to a single lyophilizer;

• Convenient for small-scale and medium-scale environments;

• Readily integrated with RABs and isolation technologies.

In fact, these three points reflect major trends in the global pharmaceutical industry towards products with high toxicity or potency produced in smaller batch volumes and higher levels of productivity at increased standards of safety and with reduced levels of environmental pollution.

At the same time, today’s pharmaceutical companies do not carry the scale of corporate engineering staff they did in the past, so capital equipment projects typically involve outsourcing engineering, construction and validation activities. This in turn makes it attractive for companies to reduce the number of suppliers with which they have to deal during a particular project.

Telstar has recognized these developing requirements and is currently involved in several projects in which services such as engineering and validation provide support to the process equipment solutions.

 The ‘Fixed’ System – How it Works

At clinical and commercial scales, the automatic loading and unloading of a lyophilizer takes place at a constant level; the working level of the filling and capping lines. In order for this to happen, the lyophilizer must be equipped to position each of its shelves at this level in sequence, starting with the uppermost product shelf.

A ‘fixed’ lyophilizer loading/unloading system (see Figure 1) is typically comprised of a pushing mechanism that transfers a single row of vials from a conveyor onto a plate which bridges the gap between the conveyor and the shelf of the lyophilizer. The system must operate in such a manner that the flow of vials from the filling line is continuous. This is of paramount importance because the filling machine must have the freedom to run continuously for reasons of process consistency and accuracy and in some cases because the nature of the product demands it. However, the loading cycle is actually intermittent, since the conveyors must come to a halt so that vials can be transferred onto the bridge plate. To create a time slot during which the conveyor can stop, the conveyor linking the exit of the filling machine with the infeed of the loading system operates at a higher speed than the filling line itself and therefore each vial has a space between it and its neighbors. When the infeed stops, each of these spaces is removed as the line of vials compresses and the time slot thus created is utilized for the row loading cycle.

Each row of vials is displaced by one-half of one diameter from the preceding row, so that vials are close packed for maximum shelf space utilization.

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Figure 1: General arrangement of a ‘Fixed Row-by-Row’ loading system.

The ‘row-by-row’ loading process continues until the number of rows required to fill a shelf have been assembled, at which time the pusher transfers the entire pack clear of the bridge plate and onto the shelf, so that the next shelf can be indexed into position. Note that it is not necessary for the filling line to stop while the lyophilizer performs shelf indexing, since the bridge plate has sufficient storage capacity to act as a buffer during this operation.

The ‘row-by-row’ loading process continues until the number of rows required to fill a shelf have been assembled, at which time the pusher transfers the entire pack clear of the bridge plate and onto the shelf, so that the next shelf can be indexed into position. Note that it is not necessary for the filling line to stop while the lyophilizer performs shelf indexing, since the bridge plate has sufficient storage capacity to act as a buffer during this operation.

To remove the vials after the freeze drying process, the vials are pushed off each shelf in turn by a pushing mechanism mounted through the rear of the chamber (see Figure 2) across the bridge plate and onto the conveyor which directs them to the outfeed and then on to the capping machine. In applications where the vials cannot be pushed off the shelf (for example, when unloading from the opposite side of the chamber) a mechanism which pulls vials from the shelf is utilized.

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Figure 2: Compact rear pusher of a ‘Fixed Row-by-Row’ unloading system.

Lyophilizer Design – How it is affected

In order to successfully integrate a ‘fixed’ loading/unloading system to a Lyophilizer the following equipment features should be considered:

• Slot ‘Pizza’ Door: Since the loading system is permanently sited in front of the lyophilizer it is not practical to open a full size door for loading.

• Maintenance Door: A full-size door is required in the technical area, either on the side of the chamber (preferred for layout reasons) or on the rear of the chamber.

• Constant Level Loading: This is essential and involves being able to accurately position each shelf to be loaded. The hydraulic stoppering piston should be equipped with an encoder or sensor with a resolution of the order of 0.1mm (0.004”).

• Shelf Docking: A means of mechanically latching the bridge plate to the shelf, so that small misalignments (which can result in fallen vials) do not occur.

• Small Shelf Dimensions: Automatically loaded lyophilizers tend to have a relatively large number of relatively small shelves so that the tolerances of individual vials do not build up to cause geometrical distortion to the pack of vials during its transfer onto the shelf.

• Guide Rails: During loading and unloading, each shelf requires a vial guidance system down the full length of each side so that vials move in an orderly fashion. The guide rails need to be relatively high (approximately 15mm or 0.6”) since sterile vials have a tendency to ‘climb’ rails which are too low. Rather than having rails fixed to each individual shelf the preferred approach is to have a single set of guides mounted in the chamber at the constant loading height which can be brought into position after each shelf is positioned. This enables any combination of shelves to be loaded without the need of removing rails from any shelves which will remain empty.

Some Process Considerations

There are two process-based events that when loading lyophilizers manually are accommodated by operators but which need consideration when operating in an automated environment. These are represented in Figure 3 and relate to product temperature monitoring and loading at low temperatures.

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Figure 3: Product temperature monitoring and low temperature loading.

• Low Temperature Loading: Some product formulations require that vials be placed on lyophilizer shelves pre-cooled to low temperatures (say, -40°C) a short time after filling, so it is not permissible under these conditions to load (over several hours) at room temperature and then freeze after the batch is completely loaded. If the environment outside of the lyophilizer is at a temperature of (say) 20°C at 30%RH a considerable amount of frost will build up on the shelves during the loading period and this frost can be disruptive to automatic loading systems. (Note that the frost can also cause process issues by disrupting vacuum control at commencement of primary drying.)

• Low Temperature Loading: Some product formulations require that vials be placed on lyophilizer shelves pre-cooled to low temperatures (say, -40°C) a short time after filling, so it is not permissible under these conditions to load (over several hours) at room temperature and then freeze after the batch is completely loaded. If the environment outside of the lyophilizer is at a temperature of (say) 20°C at 30%RH a considerable amount of frost will build up on the shelves during the loading period and this frost can be disruptive to automatic loading systems. (Note that the frost can also cause process issues by disrupting vacuum control at commencement of primary drying.)

• Low Temperature Loading: Some product formulations require that vials be placed on lyophilizer shelves pre-cooled to low temperatures (say, -40°C) a short time after filling, so it is not permissible under these conditions to load (over several hours) at room temperature and then freeze after the batch is completely loaded. If the environment outside of the lyophilizer is at a temperature of (say) 20°C at 30%RH a considerable amount of frost will build up on the shelves during the loading period and this frost can be disruptive to automatic loading systems. (Note that the frost can also cause process issues by disrupting vacuum control at commencement of primary drying.)

The simplest way to eliminate this potential issue is to reduce the frost build-up to a level where it is not significant. This is done by reducing the temperature and humidity within the loading enclosure to levels around 5°C at 5%RH. It is not generally practical to prevent moist air entering the chamber by providing a flow of dry air into the chamber since the flow required is too large (of the order of 100 m3/hr or 60 cfm). It is, however, possible to reduce moist air flow into the chamber by closing the slot door so that it is only slightly about the height of the partially stoppered vials.

Note also that warm, moist air enters the upper regions of the slot door opening while at the same time a stream of cold, dry air exits from the lower regions.

• Temperature Probes: It is not practical to insert temperature probes into vials for monitoring of product temperature beyond that required for validation exercises. The approach required when automated loading is employed is either to validate the cycle so that only shelf temperature requires recording during production runs or to replace hard sensors with a ‘soft’ sensor system, such as Telstar’s DPE (Dynamic Parameters Estimator) which can calculate parameters such as sublimation interface temperature and vapor mass flow without the need to insert probes into vials.

Considerations when Mounting Equipment to Lyophilizers

Lyophilizers change shape by a significant amount when they are sterilized with steam. This is manifest not only as changes in length (linear expansion) but also due to the geometrical distortions caused by the combined effects of temperature, vacuum and pressure over the course of the cycle. Whenever possible, therefore, peripheral equipment should not be directly attached to Lyophilizers.

Loading systems should be attached to the main frame of the Lyophilizer (or the floor, if it is guaranteed to remain stable relative to the lyophilizer).

Isolators, which must be attached to the Lyophilizer in order to function, should be attached via flexible membranes which isolate the equipment from relative movements in temperature and position.

Concluding Remarks

Telstar is able to provide services and integrated process solutions for a range of pharmaceutical applications including lyophilizer systems with automated loading and unloading operating under isolation technology. Telstar maintains a technology center at its headquarters in Barcelona, Spain at which loading system technology is permanently available for customer testing and a process laboratory is able to carry out lyophilization cycle development.

 

Telstar North America, Inc.,

Telstar Group

1504 Grundy’s Lane

Bristol PA 19007

215-826 0770

www.telstar.eu

 

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