GB2201392A

GB2201392A - Sterilisation of closed containers

Info

Publication number: GB2201392A
Application number: GB08802183A
Authority: GB
Inventors: Edward Mcmillan Cunningham; Graham Paul Conkie; Alexander Bulloch
Original assignee: Greater Glasgow Health Board
Current assignee: Greater Glasgow Health Board
Priority date: 1987-01-31
Filing date: 1988-02-01
Publication date: 1988-09-01
Also published as: GB8802183D0; GB8702194D0

Abstract

The sterilisation of aqueous liquids e.g. medicinal products, held in a closed container for clinical use, particularly aqueous solutions or suspensions, is carried out by subjecting said container of liquids to heat treatment by use of steam in a downward displacement steriliser without air ballast, and involves the use of a container having a structurally stable wall 1 and closure means 4, 5, 6 at least part of either of which is a flexible component 7 which accommodates any expansion of contents during the sterilisation process thereby avoiding rupture of the container which can be mainly of glass, ceramics or other fragile materials or of a flexible plastics material. The flexible component may comprise a membrane overlying an apertured cap with a frangible spout, or the flexible component may be a region of the closure means (27, Figure 3) or the bottom wall (37, Figure 4). The sterilising apparatus preferably includes a mechanical arrangement acting directly on the flexing region after container filling and prior to closure. <IMAGE>

Description

Sterilisation Method This invention relates to the sterilisation of liquids held in a closed container for clinical use, particularly aqueous solutions or suspensions, by heating the container with steam, and involves the use of an improved container for said liquids which is capable of surviving the sterilisation process to provide for transport, storage and subsequent use of the sterilised liquid.

The term "sterile" means "free from demonstrable forms of life". Sterilisation is the process of making something sterile; in practice though it has come to mean "the process of achieving a sterile state with the minimum acceptable calculated risk of viable survivors".

it is common practice to render medicinal products sterile by heat-treating the product in the container in which the product will be transported, sold, stored and ultimately dispensed or discharged from. Traditionally, medicinal products have been contained in glass bottles, and steam has provided the most preferred means of rendering the whole sterile. Steam sterilisation is conveniently effected using an autoclave i.e. a sealable enclosure in which the bottled product (the load) is placed and into which steam is passed to raise the temperature of the load sufficiently to render it sterile. One major problem met in this process is the presence of air within the autoclave and within the container to be sterilised itself. In the first instance air acts as an insulator, preventing uniform heat distribution throughout the steriliser load, and may result in a non-sterile product.Secondly, unless the container to be used has a certain structural resistance to deformation when subjected to changes in temperature and pressure, it will distort or rupture rendering both it and its contents useless for the intended purpose. The exclusion of air from the sterilisation apparatus and containers of liquids to be sterilised is thus a desirable objective.

In the conventional downward-displacement steriliser, steam is admitted at the top, and the cooler air within is displaced downwards and vented to atmosphere, so that at least initially the internal pressure remains at or near atmospheric pressure. Although glass bottles can be used in such a steriliser, the advent of plastic bottles, and other deformable containers (such as plasma or saline drip bags), has introduced a problem where the medicinal product which is to be sterilised is a liquid. The problem arises from the thermal expansion of the liquid which occurs due to the heating effect of the steam used in the sterilisation process. Glass bottles can easily withstand the temperatures and internal pressures which build up during steam sterilisation.However if a plastic container, either formed in the traditional bottle shape or as a non-rigid sachet or bag, is used to hold a liquid to be sterilised in this way, its expansion within the container is sufficient to increase the internal pressure to a point where the container becomes permanently deformed or even bursts during sterilisation. Hitherto, in order to counter this internal pressure increase, sterile air was pumped into the autoclave during sterilisation, thus increasing the internal chamber pressure and thereby reducing the pressure difference to minimise deformities. However due to circulating pockets of air within the sterilisation chamber during processing, control of the process remains difficult. Moreover, the equipment required, an air-ballast steriliser, is expensive, as is the conversion of existing sterilisers to this form.

As a result, downward displacement sterilisers, although readily controllable, are limited to the use of medicinal products contained within a sturdy glass vessel.

Unfortunately, from an economic point of view, glass containers compare unfavourably with similar containers formed from plastics materials, especially bearing in mind the cost of collection for re-sterilisation and re-use.

The present invention seeks to obviate or mitigate this problem by providing an improved method utilising a container which may be used successfully in existing downward-displacement sterilisers without the need to carry out expensive modifications thereto. The present invention has the further objectives of providing improved methods of sterilisation and apparatus for facilitating sterilisation of the contents of a closed container using existing sterilisers.

Accordingly this invention provides a container comprising a structurally stable wall which is resistant to permanent chemical and physical change during heat treatment by use of steam which wall defines a chamber for receiving fluid and has at least one aperture therein for filling and emptying said chamber, and closure means for said aperture, characterised in that at least part of said wall or said closure means is of variable geometry to accommodate the expansion of contents in use during said heat treatment.

The structural stability required of the container is such that it survives the sterilisation process to emerge in an intact condition which is not obviously different from its condition prior to sterilisation treatment, i.e. it should neither melt nor decompose when in contact with steam. A certain degree of softening is acceptable provided that the form or shape of the container is not permanently lost.

The container may be shaped from rigid or semi-rigid materials to provide conventional structural forms such as a bottle, tub, pot, or jar, or alternatively may be made from flexible materials to provide containers of indefinite shape such as sachets, plastic tubing and bags.

A preferred embodiment of the container utilised in this invention provides the required variable geometry by including a flexible component which is responsive to pressure variations either as part of the closure means for the container or alternatively it is incorporated in a region of the wall of the container. The flexible component may be a membrane which at normal and sterilising ranges of temperature and pressure is fluid-impermeable.

Thus for use with this invention there is provided a closable container which is preferably a container formed from a shape-retaining plastics material to define a chamber for receiving a liquid through an opening preferably provided in a neck portion of the container which may be provided with a pouring nozzle or spout and which further comprises as part of the closure means a membrane which is fluid-impermeable at normal ambient room and sterilising temperatures and pressures.

Shape-retaining plastics are those such as thermoplastics ranging from quite flexible ones like polyethylene, high-density polyethylene, semi-rigid ones like polypropylene or polycarbonate through to quite rigid materials such as the polyacetals, and those such as thermosetting materials like the novolac resins, all of which can be formed into a recognisable shape which will be retained throughout the sterilisation process without substantial variation in form.

Use of rigid materials which themselves may not be sufficiently resistant to breakage when subjected to pressure differentials between contents and ambient is acceptable due to the provision of the said flexible component which is capable of accommodating an expansion of the contents of the container whenever the closed container is subjected to heat treatment. In fact, by virtue of this feature it'is also possible toVuse relatively brittle materials such as clay or fine glass. Therefore, in accordance with this invention the container may be formed from any material capable of withstanding heat treatment such as ceramics, metal, glass or plastics materials. The container may be formed from composites such as resin-coated or foil-covered cardboard.

-For the purposes of sterilising medical products such as aqueous liquids or suspensions, the main structural body of the container should be formed from any appropriate material which is thermally stable slightly above the selected sterilising temperature, up to 1360C which is a higher temperature than that used in current practice.

The flexible component may be located at any convenient position on the container provided that it can respond to pressure variations within the closed container caused by thermal expansion of the contents. For example, the container may be formed from a plastic material such as polypropylene to a closed substantially cylindrical shape so as to have a relatively thick cylindrical wall and at one end, thinner material forming a flexible region as a base therefor whilst the other end is formed to a bottle-neck.

In order to provide for satisfactory use of such a container a false base such as a cardboard tube or plastic cup (as is conventionally used for blow-moulded plastics bottles for soft drinks and the like) could be fitted.

Generally it is preferred that said flexible component forms part of the closure means for the aperture for filling or emptying the chamber. Thus, if the container is in the form of a tub, pot or jar the flexible component may comprise a substantial proportion of the lid therefor.

Further, it is preferred for certain applications that said closure means comprises a nozzle or spout for ease of dispensing the contents of the container in which case it is preferred that the flexible component is formed from a resilient material which is fluid-impermeable. The closure means includes a ventilated cap to provide for displacement of excess volume during heat treatment. Such a membrane is overlaid on the nozzle, spout or cap to cover same after filling of the container. It is preferred that as the membrane is overlaid, the outside of the container is pressurized, slightly displacing fluid, resulting in a slight vacuum on closure. The loss of contents in this way has an insignificant effects on its intended use, but significantly improves the seal around the aperture to ensure long term storage capability without the contents becoming non-sterile.In the case of an impermeable membrane plus vented cap arrangement, the contents displaced through the cap during sterilisation are simply held within the swollen membrane during sterilisation and return through the vented cap upon cooling.

In a particular preferred embodiment the closure means for the container is an apertured cap provided with a spout, advantageously a sealed tubular spout having a frangible tip, through which the contents of the container may be removed for use, and the membrane is fixed over the spout to exclude ambient contaminants from the closure. The aperture(s) in the cap are also covered by the membrane so that in use the contents are protected by the impermeable membrane but expansion of the contents is possible through the cap during heat treatment of the container. This expansion prevents a build up of pressure within the container and avoids any deformation of the container or rupture thereof.

This invention thus provides a method of sterilising an aqueous liquid contained within sealed container for clinical use by heat treatment using steam comprising: (a) providing a container comprising a structurally stable wall of a material which is resistant to permanent chemical and physical change during heat treatment by use of steam which wall defines a chamber for receiving said liquid and has at least one aperture therein for filling and emptying said chamber, and closure means for said aperture, at least part of said wall or closure means comprising a flexible region or component which is capable of changing its configuration in response to an internal/external pressure differential brought about by conditions of steam sterilisation, the said change in configuration being suff-icient to mitigate the effects of the pressure differential upon the container thereby avoiding rupture of the container; (b) dosing a quantity of liquid to be sterilised into said container; (c) closing said container by means of the said closure means; and (d) subjecting the closed container to heat treatment by the application of steam to the closed container in a non-air-ballasted downward-displacement steriliser.

This method has the advantage that the liquid may be sterilised by the existing steam sterilisation apparatus which has been tried and tested for many years which means that from the point of view of economy and safety the method is satisfactory. Further by virtue of this invention the liquid can be contained, sterilised and stored by a method which preserves the container in an intact usable condition without resorting to expensive pressure compensating devices.

The method of this invention is realised by an apparatus for sterilising quantities of liquids held in closed containers of the aforementioned type having a flexible region or component responsive to ambient pressure changes which comprises: (a) a container dosing station provided with means for dosing the liquid to be sterilised into containers; (b) means for presenting a container to said dosing means to receive a dose of liquid which means is characterised by the provision of means for reducing the internal volume of the container prior to closure to provide a reduction in internal pressure when the container -is closed; (c) a container closing station provided with means for applying fluid-impermeable closure means to said container whilst maintaining the said reduction in internal volume so as to maintain an underpressure in the closed container; and (d) means for subjecting the closed container to heat treatment by use of steam in order to sterilise the contents of the said container.

Preferably the means for reducing the internal volume of the container comprises a container handling device including means for compressing a flexible region or component of the said container. This may be most easily accomplished by a mechanical arrangement acting directly upon the flexible region or component of the container. If the compression step is carried out after filling of the container account should be taken of the amount of liquid which may be displaced to avoid wastage. This may be avoided in most cases since the volume reduction necessary to provide a sealed-in underpressure to counter a subsequent expansion of contents during heat treatment is not substantial. The volume reduction required depends on the expansion characteristics of the container and the liquid contents but this may easily be determined by preliminary tests.

Alternatively, the container may be subjected to a reduced pressure during filling to remove a quantity of air from the container. This may be accomplished by contacting the filling aperture of the container with a combined dosing nozzle / vac-line, the reduced pressure in the vac-line being just sufficient to withdraw air without entraining any of the liquid being dosed to the container.

The invention will now be further described by way of example with reference to the accompanying drawings in which: Figs. 1 (a) to (d) illustrate the neck portion of a bottle-shaped container used in this invention which is fitted with a pouring spout, and the method of use thereof; Fig. 2 is a perspective view of a pot-shaped container used in this invention; Fig. 3 is a section through the pot-shaped container illustrated in Fig. 2; and Fig. 4 is a section through a bottle-shaped container used in this invention (minus false base).

Example 1 A sterilisable container which enables the sterilisation of a liquid contained therein by steam sterilisation comprises a high-density polypropylene or similar structural wall (1) defining a liquid-receiving chamber (2) and a neck portion (3) for the purposes of filling and emptying the container which is adapted to receive closure means (4) in the form of a ventilated cap (5) provided with a spout (6) and a flexible component formed from a resilient membrane (7) of silicone rubber which under normal temperatures and pressures is fluidimpermeable and remains under sterilisation conditions impermeable to the liquid contained in the chamber (2).

In use the container is dosed with a quantity of the liquid which is to be sterilised and stored for use in the container. The cap (5) and the spout (6) are secured to the neck portion (3) and the membrane (7) is close fitted over the spout (6) and secured in place with an Oring (8) or the like. The O-ring can be an integral part of the membrane. The product integrity may be secured by the fixing of a crimped cap (9) which permanently seals the membrane (7) over the cap (5) and spout (6). In this embodiment the spout (6) has a line of weakening (10) enabling the tip (11) to be snapped off or severed easily to discharge the contents of the container.

During filling and the placement of the membrane (7) a slight vacuum is generated within the plastic container such as to cause the membrane to close-fit around cap (5) sealing off the holes therein.

The sterilisation process involves placing the closed container in a steam steriliser and carrying out the usual procedure to avoid air pockets between the containers to ensure that air can be displaced by steam in a downward direction.

The behaviour of the container during heat treatment in the steriliser is as follows. The temperature of steam sterilisation causes the contents of the container to expand, but the internal pressure which would otherwise tend to swell the plastic container is relieved sterilisation causes the contents of the container to expand, but the internal pressure which would otherwise tend to swell the plastic container is relieved by lifting of the membrane, allowing excess volume of contents to pass through the ventilated cap (5) to a newly formed chamber (7') beneath the lifted and swelling membrane (7). This transfer of excess volume to a contained space outside the chamber (2) provides a balance of pressure between the ambient steriliser load-chamber pressure and the internal container pressure and consequently there is negligible stress to the container structural material.After the sterilisation cycle has been completed and upon cooling, the excess liquid displaced returns to the chamber (7) through the holes in the ventilated cap (5) and the membrane shrink-fits over the cap (5) to seal same. When required for use the membrane is torn or cut from the spout (6), the tip (11) is severed to allow dispensing of the contents. Alternatively the cap (5) may be removed. In certain variations of this embodiment the cap may be threaded (instead of being crimped) to facilitate release if necessary.

Example 2 A sterilisable container which enables the sterilisation of a liquid contained therein by steam sterilisation comprises a vacuum-formed or injection moulded polypropylene or similar structural wall (21) defining a liquid-receiving chamber (22) to form an open pot having an upper -rim (23) defining an aperture for the purposes of filling and emptying the container which is adapted to receive closure means (24) in the form of a substantially flat or concave lid (25), at least a portion of which comprises a flexible component formed from a resilient membrane or diaphragm (27) which under normal temperatures and pressures is fluid-impermeable and is under sterilisation conditions impermeable to the liquid contained in the chamber (23).

Use of the container is similar to that of Example 1.

During sterilisation the membrane or diaphragm (27) swells to accommodate an expansion of the contents of the pot.

After sterilisatiion and upon cooling, the membrane returns approximately to its original unswollen condition.

In a variation of this embodiment, the closure means (24) comprises an aluminium foil which is hot pressed using a hot melt adhesive (or any thermoplastics which becomes tacky with heating for the pot) onto the rim (23) to seal the pot. The aluminium foil has sufficient flexibility to allow for expansion of contents during sterilisation without rupture of the pot.

Other possible variations include the use of ceramics, glass, metals or other rigid materials for the structural wall with a tightly fitting rubber-sealed lid incorporating a flexible membrane or impermeable diaphragm to accommodate expansion as described above. It is also possible to use injection/blow moulding techniques to form the structural wall of the container.

Example 3 A sterilisable container which enables the sterilisation of a liquid contained therein by steam sterilisation comprises a structural wall (31) formed from a flexible plastics material using an injection/blow moulding technique and defining a chamber (32) and a neck portion (33) for the purposes of filling and emptying the container which is adapted to receive closure means (34) in the form of a cap (35), optionally provided with a spout (36).

During the forming operation a region of the wall is formed of thinner material in relation to the remainder to allow for considerably greater flexibility in that region. This region is so formed as to provide a diaphragm (37) which is flexible from a concave configuration to a convex configuration with respect to the chamber (32). The material chosen for the container is substantially impermeable and changes in internal pressure due to sterilisation are absorbed by the structural reversal of configuration of the thin diaphragm (37). In this embodiment the diaphragm (37) is defined within the base area of the container. This requires use of a false base support for the container such as a cardboard cylinder, plastics cup or similar support allowing flexing of the diaphragm (37) in the base of the container.

Claims

1. A method of sterilising an aqueous liquid contained within a sealed container for clinical use by heat treatment using steam comprising: (a) providing a container comprising a structurally stable wall of a material which is resistant to permanent chemical and physical change during heat treatment by use of steam which wall defines a chamber for receiving said liquid and has at least one aperture therein for filling and emptying said chamber, and closure means for said aperture, at least part of said wall or closure means comprising a flexible region or component which is capable of changing its configuration in response to an internal/external pressure differential brought about by conditions of steam sterilisation, the said change in configuration being sufficient to mitigate the effects of the pressure differential upon the container thereby avoiding rupture of the container;; (b) dosing a quantity of liquid to be sterilised into said container; (c) closing said container by means of the said closure means; and (d) subjecting the closed container to heat treatment by the application of steam to the closed container in a non-air-ballasted downward-displacement steriliser.

2. A method according to claim 1 wherein the closure means comprises a ventilated cap to provide for displacement of excess volume during heat treatment and a flexible membrane, which at normal and sterilising ranges of temperature and pressure is substantially fluid impermeable, said membrane being overlaid upon said cap to accomodate the displaced excess volume arising from expansion of contents in use and provide a seal around the cap after sterilisation to improve long term storage capability and mitigate the risks of the contents becoming non-sterile.

3. A method according to claim 2 wherein the closure means for the container is further provided with a sealed tubular spout having a frangible tip, through which the contents of the container may be removed for use and said membrane is fixed over the spout to exclude ambient contaminants.

4. A method according to any one of the preceding claims wherein the aqueous liquid is an aqueous solution or suspension.

5. A method according to any one of the preceding claims wherein the container is a unit-dose container.

6. A method according to claim 5 wherein the container is a container substantially as hereinbefore described with reference to and as shown in Figs. la, lb, lc and ld; or Figs. 2 and 3; or Fig. 4 of the accompanying drawings