* * * INSIGHT * * *
The Freeze Dryer Stoppering System
by
Dr Kevin Murgatroyd
A message from the author
My friend, Tom Jennings, asked me to write an article for Insight. Despite living on opposite sides of the Atlantic Tom and I have had many interesting and stimulating debates about some of the finer points of freeze drying over the years, often to the amusement of the onlookers. However one of the things that we share is a deep interest in the freeze dryer and the freeze drying process, it is therefore my pleasure to comply with Tom’s request and it is my hope that you, the reader, find this article of use and of interest
Dr Kevin Murgatroyd
STERIS Corporation
Introduction
A freeze dryer is likely to have a stoppering system unless it is intended to be dedicated to bulk applications only. Whilst the stoppering system tends to be ignored as a minor subsystem that is only used once a cycle it has many effects on the freeze dryer and the freeze drying process.
The stoppering system is the means by which the shelves are closed together, effecting a final product container closure by means of pushing a partially inserted stopper into the vial as part of the freeze drying cycle. This has the advantage of not only sealing the vials, as a preliminary to capping, under aseptic conditions, but also under a controlled atmosphere. This atmosphere can vary from the freeze dryer vacuum to over 900 mbar of an inert gas. In general a pressure below atmospheric pressure is preferred as this prevents the stopper “popping out” when the shelf stack relaxes under atmospheric pressure, and also aids the introduction of diluent during the reconstitution process prior to use.
Principles - Top down and Bottom-up Stoppering
The stoppering system will close the shelves between the top and the bottom pressure plates. These pressure plates are very rigid and usually of a webbed, or braced, construction with a flat plate as the shelf contact surface. One of these pressure plates is fixed; the other is the surface that moves the shelf stack. Therefore, it can be seen that there are only two types of stoppering systems: a top-down stoppering system, where the top pressure plate moves down, and a bottom-up stoppering system, where the bottom pressure plate moves, predictably, up. There are, of course, many different methods of moving the pressure plates. The position of the prime mover, which is usually the hydraulic piston, is immaterial; it is the moving pressure plate that defines the type of system. For simplicity, the prime mover, for the rest of this article will be assumed to be a hydraulic piston unless defined otherwise.
Top-down Stoppering.
Top-down stoppering systems involve the top pressure plate being supported by the actuating device. The top radiation shelf is suspended from the top pressure plate by stainless steel dumbbell-shaped rods. Each lower shelf is suspended from the shelf above. The bottom pressure plate is fixed to the chamber floor, it is not attached to the shelf stack, unless it acts as a base for the shelf guides. When stoppering is actuated, the top pressure plate moves down and the bottom shelf settles onto the bottom pressure plate. As the top pressure plate descends further, the second shelf from the bottom sinks until its lower surface rests on the tops of the stoppers of the vials on the bottom shelf. The supporting rods between the bottom and second to bottom shelves are now no longer under tension and slide through their attachment points; the shelf stack is kept in line by shelf guides. At this point, it is not important as to whether or not the stoppers have been inserted. Eventually, all the shelves are resting on the stoppers on the shelf below and all the support rods are loose. The shelf rods on different shelves must be staggered to avoid contact with each other. As the top pressure plate descends further, it pushes the stoppers fully home; some of the lower shelves may have already experienced stoppering because of the weight from the shelves above. When the stoppering mechanism is relaxed by raising the top pressure plate, the reverse occurs. The top two shelves open first, followed in sequence by the others.
Bottom-up Stoppering
A bottom-up stoppering system is the exact opposite of a top-down stoppering system. Bottom-up stoppering systems involve the bottom pressure plate being raised up by the actuating device. The bottom shelf is suspended just above the bottom pressure plate by pegs protruding from the side of the shelf that rest on the shelf support system. Each shelf is suspended in the same way. The shelves are not fastened to each other, but are constrained within the shelf guides. The top pressure plate is fixed to the chamber roof and is not attached to the shelf stack, unless it acts as a support for the shelf guides. When stoppering is actuated, the bottom pressure plate rises to meet the bottom shelf. As the bottom pressure plate ascends further, the bottom shelf rises until the tops of the stoppers of the vials push onto the bottom of the second shelf from the bottom. This lifts the second shelf’s pegs from their resting places; the shelf stack is kept in line by shelf guides. At this point, it is not important as to whether or not the stoppers have been inserted. Eventually, all the stoppers are pushing on the shelf above and the radiation shelf is pushing onto the top pressure plate. As the bottom pressure plate ascends further, it pushes the stoppers fully home; some of the lower shelves may have already experienced stoppering because of the weight from the shelves above. When the stoppering mechanism is relaxed by lowering the bottom pressure plate, the reverse occurs. The top two shelves open first, followed in sequence by the others.
Implications and choice of Stoppering Principle
The main difference between the two types of stoppering, i.e. the direction in which the shelves move and the attendant characteristics of this movement, will usually make the choice between which stoppering principle is employed.
Constant Height Loading. (Top-down Stoppering)
Top-down stoppering will allow the indexing of the shelves past a low level datum point which, if the facility designer is really clever, is also the height of the filling line thereby allowing automatic loading and unloading. This is achieved by extending the hydraulic piston so that all of the shelves move to the bottom of the chamber. As the shelves are raised the hydraulic cylinder can stop the mechanism as each shelf sequentially reached the datum point. Although bulk applications do not need a stoppering system a top-down stoppering system is often employed to ease the ergonomics of placing large, liquid filled trays on the higher shelves. Bottom-up systems cannot perform this function.
Variable Shelf Interdistance. (Bottom-up Stoppering)
Many freeze dryers are not dedicated to the processing of a single product and multiple products would imply the use of different product containers between batches. It is an efficient use of the freeze dryer if, for a given chamber size, the maximum amount of product is processed in a single batch. If, for instance, two container types were needed, a vial at 50mm height and an ampoule at 120mm height then it would obviously be inefficient if the shelf interdistance was always 150mm to allow the ampoules to be processed. If the dryer were to contain 8 shelves with a shelf interdistance of 70mm then the vials could be processed but not the ampoules. However if the shelf stack could be manipulated so that a smaller number of shelves, with a greater shelf interdistance, could be utilised then efficient use of the freeze dryer is achieved. In this case 4 shelves with a shelf interdistance of 150mm could be used as a second configuration. Bottom-up stoppering can perform this function by raising all the 8 shelves to the top of the chamber and then altering the shelf supports so that the shelves reconfigure to allow 4 usable shelves and 4 stacked at the bottom of the chamber when the shelf stack is relaxed. The altering of the supports can be achieved in many ways and usually takes seconds. Top-down stoppering can achieve this flexibility but involves the use of collars on the shelf support rods, different shelf support rods or latches and is more cumbersome.
The stoppering system has many other implications on other factors which may influence the choice: the room layout, batch size, automation, GMP and cleaning being the main ones.
Stoppering Mechanisms
The sophistication and complexity of stoppering systems has increased over the last 20 years with many mechanisms available as the prime mover.
Bladder Stoppering
The earliest stoppering systems were of the bladder type with a fixed shelf stack. Under each shelf, there was an aluminium platen that was supported on springs. Between the platen and the shelf, there was a bladder. The bladder was evacuated and, on completion of drying, was exposed to atmosphere with the chamber still under vacuum. The bladder would inflate, push the platen down, and stopper the vials. Unfortunately, many things could, and did, go wrong. The platens were thin to save weight, and would often bend and stick. If the bladder was not evacuated prior to chamber evacuation, then it would inflate, stopper the vials prior to drying, and leave a liquid fill, not a lyophilised product. Worst of all, the bladder could rupture. These bladders were filled with chalk to prevent the inside surfaces from sticking together. The effect on particle count can only be imagined! Fortunately, there are very few of these systems in operation today.
Hydraulic Stoppering.
With the advent of flexible shelf hoses, it became possible to have a mobile shelf stack, and hydraulic systems were developed. These hydraulic systems, heavily modified from the original, are still the most prevalent form of stoppering actuation today. A simple top-down stoppering systems consisted of a hydraulic cylinder mounted on top of the chamber, with the hydraulic piston protruding through a vacuum seal and then attached to the top pressure plate. Bottom-up stoppering systems were similar, but underneath and attached to the bottom pressure plate. They have the added complication that it may have been necessary to have a pit, beneath the freeze dryer, to accommodate the hydraulic cylinder.
Saddle Stoppering.
An interesting variant of hydraulic stoppering is known as saddle stoppering. Saddle stoppering consists of a yoke, or beam, that is supported over the chamber by either a single hydraulic cylinder mounted on the top of the chamber or two hydraulic cylinders mounted on the outside sides of the chamber. In the latter case, the hydraulic pistons are kept in synchronisation by microswitches. Lifting rods are attached to the yoke and these pass through the chamber roof to connect to the bottom pressure plate. This type of stoppering is, therefore, bottom-up stoppering, even though the hydraulic cylinder is situated on top of the chamber (or two on the sides). When the hydraulic cylinder(s) were actuated, they would lift the yoke, which would then withdraw the lifting rods from the chamber, thereby lifting the bottom pressure plate. The advent of saddle stoppering, as a means of bottom-up stoppering, effectively meant the end of systems that used a bottom entry hydraulic piston to achieve bottom-up stoppering.
An added advantage is that if the hydraulic cylinders are placed on either side of the chamber then the space requirement above the chamber is drastically reduced.
Screw Stoppering
There are two types of screw stoppering. The simplest is an electrical drive that turns a screw thread, which in turn inserts a smooth rod into the chamber which moves the pressure plate. In all other aspects the method of operation is the same as for a hydraulic system. The drive can be above or below the chamber.
A method of screw stoppering has been developed that does not involve the insertion of any part into the freeze dryer. Two stainless steel, helical screws are rotated, in synchronisation, by an electrical motor. The motor is mounted on top of the chamber, and the screws are mounted on either side of the shelf stack within the chamber. Where the screws pass through the chamber wall, they are smooth and the action is a rotary action only. Each screw passes through a carrier that may, in theory, be mounted on either the top or the bottom pressure plate. As the screws rotate, and as the carrier is fixed to the pressure plate, the carriers will move up or down the screw, depending on the direction of rotation. The movement of the carrier moves either the top or bottom pressure plate, so either top-down or bottom-up stoppering can be achieved. In practice, only top-down stoppering systems are built in this way; there is no technical reason why bottom-up stoppering systems cannot be built.
Others
There are also scissor mechanisms on the market today; most of which move the shelf stack efficiently but are restricted in their flexibility and by the fact that they include hinges within the chamber which are dirt traps, generate particles and have hidden areas. Systems that rely on cables or need lubrication should, in general, be avoided for obvious reasons.
GMP Considerations
Stoppering used to be a simple system.. The advisability of introducing a nonsterile hydraulic piston, or actuating device into a sterile chamber when the product containers were still open was then raised. The ramifications of this observation have guided stoppering system design for more than the last two decades. Engineering efforts have centred around the protection of the intruding actuation device and fall into the two categories of bellows and steam chests. Saddle stoppering withdraws the prime movers from the sterile chamber, thereby avoiding the issue, but is a “one shot process”. Internal screw stoppering engineers around the issue by removing the requirement to insert the prime mover by using rotation.
Bellows
The rationale of this method is to place stainless steel, or a suitable plastic, bellows around the prime mover. The bellows are attached to the chamber and the relevant pressure plate, so that sterilisation is not necessary for every batch (although it should be for other reasons)
There is a wariness, within the industry, of the effect of the bellows splitting. This is a remote possibility, since the bellow’s manufacturers guarantee the bellows for an extraordinary number of operations. A bellows failure during a cycle would manifest itself as a vacuum alarm. A failure during sterilisation would result in condensate being trapped within the bellows, and an inability for the plant to reach vacuum, during leak test, as the condensate boiled off.
The point that is rarely noted is that if a bellows is used, then the sterilisation exposure time must be doubled. If the bellows are open, then the shelf stack is closed, with the result that steam will not penetrate to the surfaces of the shelves. If the shelf stack is open, then the bellows are closed and steam will not penetrate the convolutions in the bellows. There is no halfway point, as this would involve some of the shelves still being closed. Therefore, it is necessary to steam the plant, operate the stoppering system whilst still at sterilising temperature, and then repeat the exposure time. The stoppering must also be operated during the drying segment of the sterilisation cycle. In this case it is better to start the liquid ring pump with the shelf stack collapsed to dry the bellows which have a small heat capacity. The shelves, with a large heat capacity, can be dried afterwards.
The other item of concern is the cleaning of the bellows. However, this is of no greater magnitude than the problems experienced in the cleaning of flexible hoses.
Steam Chests
An alternative was to pass the actuating device through a steam chest so that they were sterilised with the plant and could also, possibly, be steamed during reinsertion. If the steaming is performed during stoppering then the residence time of the lifting rod within the steam chests means that the lifting rods are only sanitised, not sterilised, during stoppering. Sterilisation is achieved when the actuator is steamed in conjunction with the rest of the plant but it can be argued that as soon as the actuator moves then a non-sterile element is introduced into the steam chest, the steam chest is then contaminated and so the actuating device also becomes contaminated. It is therefore obvious that a steam chest is not the complete answer but is an improvement on a system which has no protection.
Saddle Stoppering
The system relies on the freeze dryer being sterilised prior to every batch. If sterile lifting rods are within the chamber and withdrawn from the chamber during stoppering, then there is no challenge to the sterility of the product. They are only reinserted, nonsterile, into the chamber once vial closure has taken place. An added refinement is to place stainless steel bellows around the lifting rods, attached to the chamber roof and the bottom pressure plate, so that sterilisation is not necessary for every batch. This bellows system is effective and sterile, as both the bellows and the shelf stack are in the relaxed (i.e., open), position during sterilisation.
Screw Stoppering
With an internal screw stoppering mechanism, no part will enter the chamber, unlike a hydraulic system, as the actuation is by rotation and a rotating seal is acceptable. However the carrier mechanism will need careful validation with regard to sterilisation and particle generation (even sterile particles!) could be an issue.
Others
Scissor mechanisms also suffer from the nonsterile insertion problem, as they must be externally actuated, and require a bellows. However, it should be possible to rotate the actuator to use a sanitary screw to open the scissors.
Cable and pulley systems are unsanitary and should be avoided
Operation
The operation of the shelf stoppering system should be smooth. This is of special importance for a constant height loading system, where unfrozen vials must be transported. An uneven stoppering action will cause the liquid to swill up the sides of the vial. This will look unsightly after drying; worst case would cause spillage or contamination of the stopper. A good test for the smoothness of stoppering is to balance a coin, on its edge, in a place on the shelf stack that will move but where it will not become sandwiched between two shelves. This is usually on the relevant pressure plate. If the coin does not fall over when the stoppering mechanism starts to move, then the action is acceptable.
Dr Kevin Murgatroyd
STERIS Corporation
Vol 2. No. 10 October 1999
