IES62195B2 - Isolation unit - Google Patents

Description

This invention relates to isolation units for providing a sterile, dust-controlled manufacturing environment and, in particular, to isolation units in which ampoules are filled with solutions and are 5 subsequently sealed.

Isolation units are used to achieve sterile, dust-controlled environments in many types of industry by providing an isolated space which is sterilised and supplied with filtered air, the air pressure inside the isolation unit being greater than the air pressure outside the 10 isolation unit to ensure that air cannot enter the isolated space except via the air supply system.

Dust-controlled environments are classified according to certain standards which are based on the maximum allowable size of dust particle and the maximum number of particles per unit volume. A 15 Class A environment is one in which there are a maximum of 3,500 particles per cubic metre equal to or above 0.5 um in size and no particles equal to or above 5μπι. In addition the maximum permitted number of viable micro-organisms per cubic metre is, on average, less than 1. In a Class B environment, the same particle limits apply but the 20 maximum permitted number of viable micro-organisms is 5. Full details of the required standards are set out in the Rules and Guidelines for Pharmaceutical Manufacturers 1993, published in London by HMSO.

It is necessary to ensure that the interior of the isolation unit is 25 sterile at all times. Accordingly, one must undertake a regular cleaning routine and invariably sterilise all objects entering the isolation unit, as well as ensuring that when an item enters the isolation unit, no unsterile air is allowed to enter therewith.

In general, the filling of glass ampoules is carried out as follows: before filling, glass ampoules are in the form of hollow cylinders sealed at one end and open at the other end. A metered volume of solution or diluent for injection is deposited in the ampoule, and the open end of the ampoule is heated with a flame to allow partial melting and is then sealed and allowed to cool. For the purposes of large scale production, the ampoules are filled and sealed in batches to increase efficiency.

A conventional isolation unit which is adapted for use in the filling and sealing of ampoules will now be described.

The isolation unit is situated in a clean room having a Class C environment. Air from the clean room is fed into the isolation unit via a HEPA (high efficiency purified air) filter unit typically situated in the roof of the isolation unit, and air is extracted from the isolation unit via an extractor duct. The area in which the ampoules are filled is situated directly below the HEPA filter inlet. Thus, a laminar air flow (LA) is set up over the filling area, thereby ensuring that, during filling, the ampoule and the metered dose are in a stream of filtered air free from dust and microorganisms.

The clean room (Class C) is typically kept at an over-pressure of +•15 Pa to the external environment and the isolation unit is typically kept at an over-pressure of -+15 Pa to the clean room. Thus, it is impossible for air to enter the clean room from the external environment except via the clean room filtering system, and it is impossible for air from the clean room to enter the isolation unit except via the HEPA filter.

Empty ampoules are fed continuously into the isolation unit through an open access port. Outside the unit, empty ampoules are fed onto the production line. They first pass through a washing machine which washes, dries, and again washes and dries the ampoules before rinsing them with sterile water. The ampoules are then heated to ensure complete sterilisation (for example to 300°C or hotter) before being cooled immediately prior to passing into the isolation unit.

The access port is open permanently throughout the production of a batch of filled ampoules. Therefore, since the beginning of the production line is at atmospheric pressure, the isolation unit is consequently at an over-pressure of -4-30 Pa. Sensitive pressure 5 controls ensure that the over-pressure is maintained (to within ± 1 Pa) by providing a sufficient intake of air through the HEP A filter unit to account for losses via the extractor duct and the open access port through which the ampoules arrive. As the ampoules pass through the sterilising tunnel, they pass through the heating and cooling stages 10 which are fed with HEPA filtered air. The heating mechanism is calibrated to account for the fact that a steady stream of air is being fed therethrough, which tends to have a cooling effect. When the ampoules enter the isolation unit, an automated filling mechanism fills the ampoules with a metered dose of a sterile product, after which the open 15 necks of the ampoules are heated and sealed in conventional manner before leaving via an open exit port.

Even with an isolation unit adapted for use in the filling and sealing of ampoules, as described above, a number of drawbacks exist. Firstly, the isolation unit must be sterilised regularly, such as once per 20 week. This is done by shutting down production, sealing all of the inlets and outlets in a specified order to ensure that the isolation unit is sealed from the clean room and from the external environment without any unfiltered air entering, pumping an atomised spray of a sterilising agent (such as chlorine dioxide, a powerful oxidising agent) into the 25 unit, opening certain inlets and outlets to ensure that the sterilising agent makes contact with all surfaces which should be sterile (including, for example, the interior surface of outlet ducts and vents), resealing the system to allow the sterilising agent to take effect (this may typically take between 5 and 10 hours), repressurising the isolation 30 unit and extracting the sterilising agent with the outflow of air from the isolation unit.

It is necessary to carry out a large number of steps between the time when production is shut down before sterilisation and the time when production is restarted after sterilisation. Great care must be taken when opening and sealing each vent and valve, since an improperly sealed vent or valve or the opening or sealing of vents in the wrong order may result in unsterilised air entering the isolation unit and contaminating the isolated environment, in which case it is necessary to resterilise the interior, provided the mistake is noticed. A real danger of product contamination exists where the mistake goes unnoticed and production is restarted in an unsterile environment.

The access port has an adjustable shutter which can be raised or lowered when necessary. When completely lowered, an airtight seal is formed (sealing the access port), such as may be required, for example, during sterilisation. Before production, the shutter may be raised by a sufficient amount to provide a gap which will just allow the ampoules to enter.

Ampoules are typically filled in batches numbered in tens or hundreds of thousands. Prior to the production cycle, the shutter will be adjusted to the correct height for the ampoules in question. This provides a large gap which tends to reduce the over-pressure because it allows an increased outflow of air from the isolation unit. The pressure controls must be adjusted to prevent the pressure in the isolation unit from equalising with the surrounding environment.

As the ampoules arrive through the open access port, the port is effectively blocked by the steady stream of ampoules, causing the overpressure to increase (due to the reduced outflow of air from the unit). Again, this must be adjusted for by the pressure controls.

At the end of the batch, as the last ampoules move through the access port, it again becomes unblocked allowing for the escape of air through the large access port. Again, the pressure controls must compensate for this effect.

This causes a serious problem if, as is often the case, the pressure controls do not adjust sufficiently quickly to account for the blocking and unblocking of the port.

A further consequence of blocking the open port is that the sterilising tunnel must be adjusted to compensate for the change in the rate of a cooling air flow therethrough, in order to maintain a constant selected temperature, typically between 270°C and 360°C.

A problem which is particular to the filling and sealing of glass ampoules is that of breakages. Breakages, in the course of normal production, cause problems as production must stop to ensure that all fragments of glass are removed from the filling area and, thereby, that contamination is avoided. This is not easily achieved, however, in an 10 isolated system since there is no easy way of removing glass from the isolation unit. Accordingly, if there is a danger of contamination of the injectible doses, production must stop while the unit is cleaned of glass; after cleaning, the unit will require sterilisation.

For the above reasons, it is an object of the present invention to provide an improved isolation unit which allows increased efficiency and productivity and overcomes the problems associated with the prior art.

Specifically, the invention seeks to provide a fast, efficient and reliable means for sterilising the isolation unit, while providing a 20 means for verifying that no contamination of the isolation unit has occurred during the sterilisation process; the invention also seeks to provide an isolation unit which can compensate for the increases and decreases in over-pressure associated with the periodic entry of objects into the isolation unit via an open port; and the invention seeks to 25 provide a means for removing glass from an isolation unit without necessarily stopping production and resterilising the unit.

Thus, there is provided, according to the invention, an isolation unit for providing a sterile, dust-controlled environment by maintaining an atmosphere of filtered air at a controlled over-pressure 30 with respect to the external environment, comprising an aperture sealable from an external environment, the aperture being provided with a sensor, a pre-programmable controller in communication with the sensor and means for automatically opening or sealing the aperture, said controller being adapted to provide a signal to activate the means for opening or sealing the aperture, while continuously monitoring the sensor associated with the aperture, such that said controller can carry out a pre-programmed cycle of opening and sealing the aperture while verifying that the aperture is correctly opened or sealed, as the case may be, at all times during the cycle.

Such a unit allows for an automatic cycle of opening and sealing the aperture. This allows the aperture to be controlled and automatically monitored at all times such as, for example, during manufacture, testing, maintenance and sterilisation. Preferably, there is more than one aperture such as, for example, if there are a number of filtered air inlet and extractor vents and one or more product access ports through which sterile items can be admitted to the unit. The term aperture, as used herein, can encompass all connections between the interior and exterior of the isolator unit, including vents, access ports, exit ports, outlets and inlets. Certain connections may be manually controlled while others may be automatically controlled, depending on which option is more suitable for that type of connection.

Suitably, said programmed cycle is adapted for use in sterilising the isolation unit. In practice, a cycle of opening and sealing the aperture or apertures is chosen so as to ensure that the unit is completely sterilised. This cycle is then programmed into the controller, thereby providing a fully automated process which has a number of advantages over manually controlled sterilisation. These advantages include more precision in the timing of the opening and sealing of apertures, the possibility of providing an alarm feature if an aperture is not correctly opened or sealed at a particular time, consistency in the standard of sterilisation, a reduction in the number of man-hours required to carry out and supervise sterilisation, the possibility of providing a permanent record of the cycle of opening and sealing apertures which can later be looked at and verified, and the safety feature inherent in a sterilisation process which is dependent on a single set of well-checked instructions and which is not susceptible to negligence, lapses of memory or misinterpretation of instructions as a manually-controlled process necessarily is.

Suitably, said pre-programmed cycle is additionally or alternatively adapted for use during a manufacturing process.

Furthermore, a pre-programmed cycle can be adapted for use in testing the opening and sealing of apertures.

Preferably, the isolation unit comprises an access port through which objects enter the unit, and a self-actuating over-pressure valve which automatically opens or closes to maintain a fixed over-pressure 10 in the unit with respect to the external environment, thereby compensating for any change in the rate at which air leaves the unit occurring as a result of an object entering through the access port.

Preferably, the access port remains open at all times during production and is sealed only when production ceases and during the 15 sterilisation process. Such an access port is suitable for admitting a constant stream of items, such as ampoules. Suitably, the access port is manually adjustable to be opened by varying amounts or to be completely sealed.

Alternatively, said access port can be an aperture provided with a 20 sensor and means for automatically opening and sealing the aperture.

When the access port is open during production, it is desirable to minimise the amount of air escaping from the unit through the access port by having the size of the access port only slightly larger than the objects which are admitted therethrough. This has the effect, however, 25 of causing the access port to be at least partially blocked when an object enters or exits therethrough. As previously explained, this reduces the amount of air escaping from the access port leading to excessive overpressure within the unit. A self-actuating over-pressure valve can be used, suitably in the form of a finely balanced blade pivoting on sealed 30 ball bearings with a centrally located balance weight assembly. Such a valve is also known as a pressure stabiliser. Suitable valves for use according to the invention are AERCON type W air-pressure control valves, available from Power Utilities Limited, U.K. (AERCON is a Trade Mark). Such valves allow the over-pressure to be maintained while the access port is blocked and unblocked without necessitating an adjustment of the air intake or air extraction rate.

Preferably, the unit also comprises a flexible hose within the unit connectible to an outlet, said outlet being adapted to receive means for creating a vacuum.

A vacuum cleaner can be connected to said outlet as required, thereby allowing debris to be removed from the unit while maintaining the sterile conditions within the unit.

Suitably, said flexible hose can be removably connected to a pipe which leads to the outlet, the pipe being sealed, when the hose is removed, by a spring-loaded flap. Preferably, the unit is provided with a plurality of pipes leading to one or more outlets, such that the hose can be mounted on a pipe close to the debris which is to be removed. The unit is suitably provided with a glove assembly to allow manipulation of the hose within the unit. Such glove assemblies are well known from applications in many fields where objects within a sterile environment require manipulation from an external environment.

The vacuum cleaner assembly is particularly suitable for an isolation unit which is used in the filling and sealing of glass ampoules because of the problems associated with ampoules breaking during production.

Suitably, the outlet which is adapted to be connected to a vacuum cleaner is a sealable aperture provided with a sensor and means for automatically opening or sealing the aperture.

As previously indicated, it may be preferable to have a number of inlets, outlets and access ports leading from the external environment to the isolation unit and vice versa. Preferably, therefore, the isolation unit has a plurality of apertures each of which is provided with a sensor which provides a signal to indicate whether the aperture is in an open state or a sealed state and with means for automatically 5 opening or sealing the aperture in response to an electrical signal, the pre-programmable controller being in communication with each sensor and the means for opening or sealing each aperture, such that said cycle can involve opening and sealing each of said apertures simultaneously, successively or independently of one another.

According to a preferred embodiment of the invention, therefore, some or all of the inlets, outlets and access ports are sealable apertures provided with a sensor and means for automatically opening or sealing the aperture. It may be desirable, in some cases, for every inlet, outlet and access port to be a sealable aperture as hereinbefore defined, or it may be preferable to have certain inlets, outlets or access ports permanently open to the external environment or only manually sealable from the external environment.

The invention will be further illustrated by the following description of an embodiment thereof given by way of example only 20 with reference to the accompanying Drawings in which: Fig. 1 is a top plan section of an isolation unit according to the invention; and Fig. 2 is a perspective cutaway view of a production line for sterilising, filling and sealing ampoules, incorporating an 25 isolation unit according to the invention.

Fig. 1 shows an isolation unit, indicated generally at 10, in a top plan sectional view. The unit 10 is adapted for use in the filling and sealing of glass ampoules. Unit 10 is situated in a clean room 11 and has an atmosphere which is isolated from that of the clean room 11.

The atmosphere within unit 10 is controlled predominantly by the air intake rate through a HEP A filter unit (not shown) located in the roof and by the extraction rate of an extractor (not shown) located below unit 10. An over-pressure of -r 15 Pa is maintained between unit 10 and clean room 11. Ampoules enter unit 10 through an access port 12 and exit the unit through an exit port 13. However, the over-pressure within unit 10 ensures that no air enters through either the access port 12 or the exit port 13.

Ampoules enter unit 10 via access port 12 on a conveyor belt 14. The ampoules entering unit 10 along conveyor belt 14 have been cleaned by ultrasonic treatment, rinsing and drying and have been sterilised at 320°C. Open access port 12 is effectively a gap leading into a tunnel through which conveyor belt 14 moves. It is provided with a shutter which can be raised to allow various sizes of ampoules to pass therethrough and lowered to form an airtight seal when production has finished.

The ampoules move in a constant stream (at a rate of 24,000 per hour, for example) from conveyor belt 14 onto area 15, where they are pushed by the ampoules directly behind onto a carrier 16 in the form of a rotating helix which carries the ampoules along the length thereof as it rotates about its longitudinal axis. A wheel 17 guides the ampoules from carrier 16 onto production line 18 where they are filled and then sealed. Two other wheels 19,20 and a second helical carrier 21 guide the filled, sealed ampoules out of exit port 13 into a collection tray 22.

The rate at which air flows out of access port 12 is dependent on whether or not ampoules are moving through and partially blocking access port 12. When the stream of ampoules stops, the rate of air flow through access port 12 increases and the over-pressure tends to drop. An AERCON type W over-pressure valve (not shown) stabilises the over-pressure, however. This over-pressure valve works by allowing air to escape continuously therethrough at a variable rate determined by the pressure differential across the valve. The valve is balanced to maintain a constant pressure differential by opening further if the overpressure increases and closing further if the over-pressure decreases.

Also indicated in Fig. 1 are five pairs of glove assemblies 23,24, 25,26,27. The left handed glove of assembly 25 is illustrated. None of the other gloves are shown but their positions are indicated by the assembly mounting points. The glove assemblies allow an operator to manipulate objects within the unit 10 while maintaining a physical barrier, namely the glove, between the operator in clean room 11 and the interior of unit 10.

A half-suit assembly 28 is also provided. This assembly is in the form of a cabinet integral with unit 10 and having an interior open to the interior of unit 10 and consequently isolated from clean room 11. The cabinet extends upwards from approximately waist height and has a half-suit integral with the underside thereof. An operator can therefore crouch under the cabinet and stand upwards into the half-suit which encloses his/her torso, arms and head in much the same way as the glove assembly encloses the arm and hand of the operator.

A flexible hose 29 is provided inside unit 10. Two pipes 30 adapted to receive hose 29 are situated close to half-suit assembly 28, allowing hose 29 to be connected to one of pipes 30, each of which leads to an outlet connected to vacuum means. This enables hose 29 to be used as a vacuum cleaner attachment. Pipes 30 are covered with spring-loaded flaps to allow hose 29 to be removably connected and to ensure pipes 30 are sealed when hose 29 is removed.

A small lockable door 31 and a large lockable door 32 are provided to allow sterilised objects to be introduced into the unit 10. Doors 31,32 are part of a system which comprises a sealable pod having a door which is adapted to fit the lockable door of an isolation unit in such a way that the pod forms a tight seal around the door. Both doors can be locked together and then opened into the isolation unit. In order to introduce an object into the unit, the object is put into the pod, the pod is sealed and the interior of the pod and the object are then sterilised (using an autoclave for example). Then, by locking together the door of the isolation unit and the door of the pod and opening the locked doors into the isolation unit, the object can be moved from the pod into the unit without contaminating the interior of the unit. Such a system is available, for example, from La Calhene of France, under the trade name DPTE-S.

Lockable door 31 is used, in conjunction with a pod, to introduce a sterile tube (not shown) which leads from a container containing the product with which the ampoules are to be filled. This tube is then connected to a conventional filling assembly 33. Door 32 is used to introduce suitable machine parts (such as needles, pumps and filling heads) for filling a particular ampoule type with the required product.

A sealing assembly 34 beside filling assembly 33 is situated under an extractor outlet 35. This outlet 35 is required to extract the combustion gases produced during the sealing of the ampoules, since this operation is carried out using flames.

A spray head 36 is situated on an interior wall of the unit. This communicates with a push on connection attachment 37 on the exterior of the unit. A sterilisation unit (not shown) has a complementary connector such that a supply of sterilising agent such as chlorine dioxide (C1O2) can be sprayed into unit 10 at a selected rate and for a sufficient length of time to allow the complete sterilisation of the interior of the unit 10, as will be described below.

Referring to the embodiment illustrated in Fig. 2, an isolation unit 10 can be seen in a cut-away perspective view. This unit is almost identical to that illustrated in Fig. 1, and accordingly, the same reference numerals will be used to refer to features identical to those previously described. The cut-away view does not show the half-suit assembly or the enclosing panels which isolate unit 10 from the external environment and which have the glove assemblies mounted thereon. This drawing also shows a washing and sterilising tunnel indicated generally at 38, through which the ampoules move before entering unit 10.

Ampoules are fed into sterilising tunnel 38 at end 39 farthest from unit 10. The empty ampoules are picked up by a washing machine 40 and deposited on conveyor belt 14 which leads to area 15 as previously described. During the passage between end 39 of sterilising tunnel 38 and area 15, the ampoules are subjected to ultrasonic vibrations which loosen any particles adhered to or embedded in the surface of the glass, then they are rinsed, dried, rinsed again and dried again, before being heated to 320°C to ensure complete sterilisation. The sterilised ampoules are then cooled before they reach area 15.

The embodiment illustrated in Fig. 2 differs from that of Fig. 1 in that the embodiment of Fig. 2 has two collection trays 41,42 instead of one, and in that collection trays 41,42 are oriented at 90° to the position of tray 22 in Fig. 1, due to a different location of the outlet exit port through which the filled ampoules emerge.

Also illustrated in Fig. 2 is a pre-programmable controller 43, known as a programmable logic controller (PLC). PLC 43 is in electronic communication with a LAF (laminar airflow) HEP A filter intake unit 44 situated above the filling and sealing area of unit 10 and the LAF extract outlet (not shown) situated below the filling and sealing area. HEPA filter unit 44 operates at a constant rate calculated to maintain the required over-pressure, although PLC 43 can switch HEPA filter unit 44 on and off as required. PLC 43 is also in electronic communication with flame extractor outlet 35 and vacuum hose receiving pipes 30 illustrated in Fig. 1. PLC 43 can open or seal each aperture to which it is connected and can continuously verify that each aperture is in the correct state (open or sealed). Pre-progiammed instructions can be entered into PLC 43 to enable it to carry out controlled sequences of opening or sealing the apertures. PLC 43 also controls the LAF intake and extraction rates, as well as the rate of delivery (during sterilisation of the interior of unit 10) of an oxidising agent from a sterile pod through lockable door 32 (Fig. 1) An example of the steps which might be carried out by PLC 43 during a sterilisation cycle is as follows.

When the operator initiates the sterilisation cycle, the PLC enters fumigation mode and carries out the following steps: (a) turns off LAP intake unit 44; (b) turns off the flame extractor fan and closes the damper of flame extractor outlet 35; (c) turns off LAP extractor fan and closes associated dampers; (d) turns off air supply and extractor fan and closes dampers to clean room 11 (Fig. 1); (e) closes inlet LAP damper; (f) closes the Aercon exhaust duct door; (g) checks that external door leading into clean room 11 (Fig. 1) is closed; (h) checks that fumigation unit is connected; (i) checks that access port 12 and exit port 13 (Fig.l) are closed; Each of these steps is verified to ensure that they have been completed and if any step has not been carried out correctly, an alarm light flashes. When all of the steps have been carried out, the PLC activates the fumigation unit which sprays chlorine dioxide (CIO2) into unit 10 continuously throughout a period of 30 minutes. Five minutes after the spraying has begun, the vacuum cleaner is activated for 8 seconds (a hose 29 having been attached to each pipe 30 to ensure the pipe 30 is open); the flame extract damper opens for 10 seconds; the flame extractor fan comes on for 10 seconds; the isolation unit extractor damper opens for 10 seconds; and the isolation unit extractor fan comes on for 10 seconds. When spraying is complete, the PLC I enters holding mode for 6 hours before switching over to purge mode; during which the PLC carries out the following steps: (a) turns on room AHU (air handling unit); (b) opens LAP inlet damper; (c) turns on LAP unit; (d) opens flame extractor damper and turns on flame extractor fan; (e) opens isolation unit extractor damper and turns on isolation unit extractor fans; (f) opens clean room air supply and exhaust dampers and turns on extractor fan; and (g) opens the Aercon valve exhaust duct door.

Using this cycle, it can be ensured that the CIO2 is completely removed with the air flow from the isolation unit. Finally, the flame extractor fan is switched off and the clean room air supply is changed to automatic over-pressure control. At this stage, the cycle is complete and a light comes on to indicate this fact and an alarm sounds. The supervisor can then re-enter the clean room and restart production.

It can be seen that this complicated cycle of opening and sealing dampers and turning on and off air supplies and exhaust fans could be very susceptible to human error if carried out manually. The use of the PLC in electronic communication with each of the automatically sealable apertures, in accordance with the invention, reduces the risks associated with human error and ensures complete sterilisation under optimum conditions.

Claims (5)

1. Claims.-

1. An isolation unit for providing a sterile, dust-controlled environment by maintaining an atmosphere of filtered air at a controlled over-pressure with respect to the external environment, comprising an aperture sealable from an external environment, the aperture being provided with a sensor, a pre-programmable controller in communication with the sensor and means for automatically opening or sealing the aperture, said controller being adapted to provide a signal to activate the means for opening or sealing the aperture, while continuously monitoring the sensor associated with the aperture, such that said controller can carry out a pre-programmed cycle of opening and sealing the aperture while verifying that the aperture is correctly opened or sealed, as the case may be, at all times during the cycle.

2. An isolation unit according to Claim 1, comprising an access port through which objects enter the unit, and a self-actuating over-pressure valve which automatically opens or closes to maintain a fixed over-pressure in the unit with respect to the external environment, thereby compensating for any change in the rate at which air leaves the unit occurring as a result of an object entering through the access port.

3. An isolation unit according to Claim 1 or 2, comprising a flexible hose within the unit connectible to an outlet, said outlet being adapted to receive means for creating a vacuum.

4. An isolation unit according to any preceding claim, having a plurality of apertures each of which apertures is provided with a sensor which provides a signal to indicate whether the aperture is in an open state or a sealed state and with means for automatically opening or sealing the aperture in response to an electrical signal, the preprogrammable controller being in communication with each sensor and the means for opening or sealing each aperture, such that said cycle can involve opening and sealing each of said apertures simultaneously, successively or independently of one another.

5. An isolation unit according to Claim 1, substantially as hereinbefore described with particular reference to and as illustrated in Figs. 1 and 2 of the accompanying drawings.