Process for preparing a lyophilised material

This invention relates to a process for providing lyophilised materials and to apparatus for use in such a process.

Lyophilisation is a well known process in the pharmaceutical and vaccines industries in which a dispersion, e.g. a solution or suspension, of a material in a carrier liquid, normally aqueous, is frozen then exposed to reduced pressure to cause the liquid to evaporate, e.g. to perform a sublimation transition from the frozen to the vapour state. This process makes it possible to withdraw water contained in a material to make the material more stable at ambient temperature and thus to facilitate its conservation. A typical lyophilisation process is disclosed in EP-A-0 048 194.

Normally the dispersion is contained in a container typically a vial, which is exposed to the reduced pressure so that the liquid can evaporate out through an opening of the container e.g. the open mouth of a vial. Vial closures are known which can be mated with a vial mouth in a first, upper, position leaving a vent for the escape of evaporating liquid, and which can be moved downward into a second position when the lyophilisation process is complete to seal the vial. Typically vials which such closures in their upper, vented, position are arranged in a two dimensional array on a shelf for freezing and then exposure to a reduced pressure. Plural shelves are stacked vertically above each other with the underside of an upper shelf above the closures of vials on the shelf below, and when the lyophilisation process is complete upper shelves are lowered onto the closures of vials on the shelf immediately below to push the closures into the lower closed position.

Numerous types of apparatus are known for performing the lyophilisation process on such containers, generally comprising a chamber which can be hermetically closed with the containers inside and inside which suitable conditions of temperature and reduced pressure can be maintained.

A specific type of vial with a closure is disclosed in WO-A-04/018317 but is not disclosed therein for use in a lyophilisation process.

Some problems of known lyophilisation processes using the above described vials are that the mouth openings and vents of these known vials allow opportunity for ingress of contamination after a dispersion of the material has been introduced into the vial, e.g. during the subsequent stages of loading the vial containing the dispersion onto shelves suitable for the lyophilisation apparatus and of transporting such vials to the lyophilisation apparatus.

It is an object of the present invention to address these problems, and to offer further advantages, as will be disclosed below.

In a first aspect this invention provides a process for preparing a lyophilised material comprising:

providing a container bounded by an envelope having a penetrable region and containing a dispersion of the material in a carrier liquid,

with the penetrable region penetrated with a penetrator such that the penetrator provides a conduit through the envelope to provide communication between the inside and outside of the container when the penetrator has penetrated the penetrable region,

evaporating the carrier liquid out of the container via the conduit,

withdrawing the penetrator from the penetrable region.

Such a process may be performed by providing a container bounded by an envelope having a penetrable region and containing a dispersion of the material in a carrier liquid, penetrating the penetrable region with the penetrator such that the penetrator provides a conduit through the envelope to provide communication between the inside and outside of the container when the penetrator has penetrated the penetrable region, evaporating the carrier liquid out of the container via the conduit, then withdrawing the penetrator from the penetrable region.

The container may be a vial, e.g. a typical pharmaceutical vial, made of glass or plastics material, having a mouth opening closed by an elastomeric closure e.g. which plugs into the mouth opening, and the penetrable region may comprise a region of this elastomeric closure. In such a construction the combination of vial and closure comprise the said envelope.

Evaporation of the carrier liquid out of the container via the conduit may be by generally conventional lyophilisation conditions, e.g. maintaining the dispersion at a temperature such that the carrier liquid is frozen, and application of reduced pressure so that the frozen liquid sublimates directly from the solid to the vapour state. Suitable conditions of temperature and reduced pressure are for example disclosed in the Example of EP-A-0 048 194.

By “penetrates” and derived terms as used herein is included at least partially penetrates, and the term includes opening a communication passage through the penetrable region, for example actual passage of the penetrator from one surface of the envelope to another, e.g. puncturing and physically disrupting of the envelope, expansion of an already existing hole by means of the penetrator, disruption of a weakened area of the envelope by the penetrator to create an opening through the envelope.

The penetrable region may comprise a previously-formed puncture hole. For example such a previously-formed formed puncture hole may have been formed by driving a puncturing means such as a needle through the penetrable region. Such a needle may be a hollow filling needle which has been passed through the envelope and via which the dispersion has been introduced into the vial, the needle then subsequently withdrawn, and the liquid so introduced may subsequently be cooled and frozen for lyophilisation. For example such a needle may be passed through the elastomer closure of a vial. Typically with a suitable thickness of the elastomer material of the closure the elastic nature of the closure causes the elastomer material to close when the needle has been withdrawn, to thereby close the residual needle hole sufficiently to reduce the possibility of contaminants entering the vial via the puncture hole before the hole can be sealed. This offers the advantage that after introducing the liquid into a vial using a filling needle there is much less opportunity for contamination to enter the vial than would be the case with the above-mentioned known vial in which, after a liquid has been introduced into the vial, the closure is inserted into the vial mouth but in a partly open vented state. Also, advantageously after filling using such a filling needle and leaving a closed puncture hole the vial may be inspected through its transparent wall for particles, with less threat of contamination than would be with the known vials.

The process of the invention may therefore include the preceding step of providing the container bounded by an envelope having a penetrable region therein by passing a hollow filling needle through the envelope, introducing the dispersion into the container via this needle, then subsequently withdrawing the needle to leave a residual puncture hole in the closure. Preferably such a filling needle has a pyramidal point, as it is found that such a needle cuts a hole in controlled directions. Preferably such a pyramidal point has three faces to cut the hole in three controlled directions. A preferred construction of such a filling needle is for example disclosed in WO2004/096114.

A suitable construction of such a vial and closure is that disclosed in WO-A-04/018317, specifically as disclosed in and with reference to FIG. 6 thereof. Such a vial has an upwardly-facing mouth opening bounded by a rim, and a closure system comprising an elastomer closure part shaped to sealingly engage with the mouth opening, having a lower surface facing the interior of the vial and an opposite upper surface facing away from the vial, and capable of being punctured by a needle, and a clamp part able to engage with the vial, particularly with the rim of the mouth opening, and able to bear upon the upper surface of the closure part to hold the closure part in a closing relationship with the mouth opening, the clamp part having an aperture therein through which a region of the upper surface of the closure part is exposed when the clamp part is engaged with the vial.

In this embodiment the said exposed region of such an elastomeric closure, suitably when previously punctured by a needle as described above, may comprise the penetrable region. An advantage of such a vial is that it may be provided sealed by the closure and with a sterile interior, e.g. sterilised by radiation, or for example when made in a sterile state by the manufacturing process disclosed in WO2005/005128.

The process preferably comprises the further step of sealing or otherwise covering the penetrable region after the penetrator has been withdrawn from the penetrable region.

In another aspect the invention provides apparatus suitable for use in the process described herein comprising:

a penetrator capable of penetrating a penetrable region of a container bounded by an envelope having a penetrable region therein and containing a dispersion of the material in a carrier liquid such that the penetrator when penetrating the penetrable region provides a conduit through the envelope to provide communication between the inside and outside of the container when the penetrator has penetrated the penetrable region,