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WO2006013360A1 - Appareil de séchage par lyiophilisation - Google Patents

Appareil de séchage par lyiophilisation Download PDF

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Publication number
WO2006013360A1
WO2006013360A1 PCT/GB2005/003041 GB2005003041W WO2006013360A1 WO 2006013360 A1 WO2006013360 A1 WO 2006013360A1 GB 2005003041 W GB2005003041 W GB 2005003041W WO 2006013360 A1 WO2006013360 A1 WO 2006013360A1
Authority
WO
WIPO (PCT)
Prior art keywords
tray
lid
freeze
container
membrane
Prior art date
Application number
PCT/GB2005/003041
Other languages
English (en)
Inventor
John Landon
Original Assignee
Micropharm Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Micropharm Limited filed Critical Micropharm Limited
Publication of WO2006013360A1 publication Critical patent/WO2006013360A1/fr

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Classifications

    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F26—DRYING
    • F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
    • F26B5/00—Drying solid materials or objects by processes not involving the application of heat
    • F26B5/04—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum
    • F26B5/06—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum the process involving freezing

Definitions

  • Ther present application relates to a method and apparatus for freeze-drying a product under sterile conditions.
  • Freeze-drying also known as "lyophilisation" of an aqueous solution of product involves freezing followed by removal of most of the water by direct sublimation from the solid (ice) to the gaseous (water vapour) phase (Murgatroyd 1997a).
  • Freeze-drying of pharmaceutical products is usually undertaken in vials but may be carried out in ampoules or in bulk. Sterility is essential when freeze-drying medicinal products intended for systemic use in order to avoid bacterial or other contaminants. Similar conditions apply if the product to be freeze-dried must be contained because it is, for example, potentially hazardous. For example, it is known that large numbers of influenza viruses or Escherichia coli can be lost from a vial during freeze-drying as a result of ablation due to particle entrapment in the sublimating water vapour, with severe contamination of the inside of the freeze-dryer and immediate environment (Adams, 1991a).
  • freeze-drying is undertaken in a pharmaceutical cleanroom with an HVAC air supply.
  • the room must be kept scrupulously clean and must be assessed regularly as to the particulate and bacterial counts.
  • the chamber of conventional freeze-dryers opens directly into the cleanroom while the bulk of the instrument extends outside to facilitate maintenance and avoid adding to the particle count.
  • the freeze-dryer must be cleaned thoroughly and sterilised prior to use. This is usually undertaken in place with sterilisation being best achieved by the use of steam for several hours. This, in turn, requires a suitable steam generator and a source of sterile water. Filling must be carried out in a grade A environment (as defined in Annex I of E. C. Guide to Good Manufacturing Practice).
  • the product is subjected to a freeze-drying cycle lasting at least 24 hours. This comprises its cooling then freezing (4 to 8 hours) followed by primary ( ⁇ 14 hours) and then secondary (-10 hours) drying under a vacuum of -0.4 torr (Adams, 1991b).
  • Primary drying involves the removal of free moisture from the frozen product by sublimation. In freeze-drying of an aqueous solution, this involves the removal of around 90% of the water molecules present.
  • Secondary drying involves the removal of most of the bound moisture from the frozen product by a combination of desorption and evaporation. In freeze-drying of an aqueous solution, this involves the removal of a further 5 to 8% of the water molecules which are adsorbed to or structurally integrated with non-crystallisable solute.
  • primary and secondary drying involves the rapid migration of around 97% of all the water molecules present in the frozen product.
  • freeze-dryer following completion of the freeze-drying cycle and removal of the product, parts of the instrument and especially its condenser coils are covered by thick layers of ice.
  • the freeze-dryer must be defrosted, usually by passing large volumes of water through the condenser to waste, then cleaned thoroughly, and finally steam sterilised and cooled prior to reuse. Cleaning and sterilisation must be especially rigorous following the freeze-drying of a potentially hazardous product since contamination of the freeze-dryer is virtually certain. If it is intended to freeze-dry potentially hazardous products as well as conventional products, a second, separate cleanroom and a second freeze-dryer are required.
  • One such container, which enables sterile freeze-drying in an unclean environment, is described by Taylor et ah, 1978.
  • the base of the container described in Taylor et al is fitted with two biological filters made from pleated glass fibre which ensure containment and prevent contamination while only slightly impeding vapour flow.
  • Vial closure under vacuum in the freeze-dryer is effected by the use of a vial stopper closure plate, which moves independently of the lid and which is depressed by five plungers.
  • Four spring loaded fasteners secure the lid to the box.
  • US patent number 5,309,649 (Boehringer Mannheim) describes a process and container for freeze-drying under sterile conditions. Freeze-drying of a product in bulk was undertaken in a bag, tube or trough comprising part synthetic resin and part a hydrophobic, porous, micro-organism-impermeable, water vapour-permeable membrane.
  • the container described in US 5,309,649 is suitable only for bulk product and not for vials or ampoules, which is a severe disadvantage.
  • a further example of a container for use in sterile freeze-drying is the LYOGU ARD ® tray (W. L. Gore and Associates, Livingston, UK).
  • the top of the tray is made from GORE- TEX ® expanded PTFE (polytetrafluoroethylene) membrane, which was developed specifically for lyophilisation.
  • the membrane and tray are welded together thermally with the tray having a thin, flexible base which conforms closely to the drying shelf to ensure efficient temperature transfer.
  • a fill port in one corner of the tray enables the introduction of from 500ml to 1800ml of product for freeze-drying in bulk.
  • the LYOGU ARD ® tray can only be used once and is expensive. Moreover, it is not suitable for either vials or ampoules.
  • each tray must be placed inside a foil barrier pouch to prevent degradation of the dried product by ambient moisture or by oxygen or carbon dioxide.
  • a vacuum box system is also produced by Usifroid, the French Freeze-dryer Company.
  • the Usifroid vacuum box comprises a metal external tray with a gasket around its rim, which can be sealed hermetically by a closely fitting metal lid.
  • Product is placed in an internal tray either in bulk or in ampoules and this is placed in the external tray and the lid put in place with four stoppers in the "open” position.
  • the whole box is then placed in the freeze-drier.
  • the stoppers are depressed to their "closed” position by lowering the shelves of the freeze- dryer such that the box is now completely sealed.
  • the box is removed and transferred to a sterile area while its contents are still under vacuum. Only then are the stoppers lifted to break the vacuum, the lid removed and access gained to the product. If ampoules have been used, these are then sealed.
  • the Usifroid vacuum box is unduly complex. Since initial transfer to the freeze-dryer and the freeze-drying cycles are conducted with the stoppers in the "open" position, neither containment of the product nor prevention from contamination can be ensured - at least from a regulatory standpoint. There is a paucity of groups in Europe able to undertake sterile lyophilisation of small numbers (a few thousand or less) of vials for research purposes or clinical trials. Consequently costs are high, delays common and small groups must often send products abroad for freeze-drying. There are several reasons for this, including technical complexity, with the consequent need for highly experienced staff and rigorous quality control. Among the most important is cost: it takes more than a year and a substantial amount of money to establish, validate and obtain regulatory approval for even a small facility.
  • the present invention provides a method for freeze-drying a product which, i) enables products to be freeze-dried whilst preventing the risk of their contamination by, for example, microorganisms in the external environment; ii) prevents the product from contaminating the freeze-dryer and external environment, which is particularly important where the product contains potentially hazardous products, such as infectious agents; and iii) enables the closure of vials containing lyophilised product whilst still under vacuum and prior to their removal from the freeze-dryer.
  • the invention also provides containers for use in a method according to the invention and components of the container for use in a method according to the invention.
  • Use of a method according to the present application improves the steps of sterile transfer of the filled vials and loading into a clean, sterile freeze-dryer; sealing under vacuum; sterile unloading of vials from the freeze-dryer and sterilisation of the freeze-dryer.
  • the steps of cooling, freezing and primary drying in the freeze-drying cycle are also preferably improved.
  • the use of a method according to the present application overcomes the problems associated with the high costs of prior art methods.
  • the invention provides a method of freeze-drying a product comprising the steps of:
  • a) placing a closeable vial containing the product in a container comprising:
  • lid and tray co-operate to form a hermetic seal therebetween and the lid can move relative to the tray to effect closure of the closeable vials;
  • the invention further relates to containers for use in the method recited above.
  • the invention provides a container for freeze-drying a product comprising:
  • a membrane wherein in use the lid and tray cooperate to form a hermetic seal therebetween and the entire lid can move relative to the tray to effect closure under vacuum of the closeable vials within the container.
  • the invention provides a container for freeze-drying a product comprising:
  • the membrane forms a lid and in use the lid and the tray cooperate to form a hermetic seal therebetween and at least a part of the lid can move relative to the tray to effect closure under vacuum of closeable vials within the container.
  • Figures Ia and Ib show a partial cross-sectional view of a container containing a vial wherein the container is located in a freeze-drying chamber;
  • Figures 2a, 2b and 2c show partial cross-sectional views of configurations of seal
  • Figure 3a shows a plan view from above of a lid having holes
  • Figure 3b shows a plan view from below of a lid wherein a membrane covers the holes
  • Figure 4a shows a partial cross-sectional view of a container having a membrane for a lid
  • Figure 4b shows a plan view of a clamp for forming a seal with the container of Figure 4a
  • Figure 4c shows a partial cross-sectional view of the depression in the tray into which the clamp of Figure 4b may fit.
  • the invention provides a method of freeze-drying a product comprising the steps of: a) placing a closeable vial containing the product in a container comprising:
  • lid and tray co-operate to form a hermetic seal therebetween and the lid can move relative to the tray to effect closure of the closeable vial;
  • a method according to the present invention preferably provides a dry (1-3% water), shelf- stable, active, readily soluble product of acceptable appearance.
  • One or usually more vials may be contained in the container used in the method of the present invention.
  • the closeable vials are closed whilst under vacuum by movement of the lid relative to the tray.
  • the lid moves relative to the tray in a direction perpendicular to the openings, i.e., parallel to the axis of the openings of the one or more vials, which leads to the closure of the vials.
  • the entire lid moves relative to the tray to effect closure of the vials.
  • the method does not encompass the use of a container wherein closure of the vial is effected by a plunger mechanism which moves independently of the lid.
  • the lid should be able to move relative to the tray by a sufficient distance to permit closure of the or each closeable vial located in the tray.
  • the lid is able to move by at least 10 mm relative to the tray. More preferably, the lid is able to move by between 10 and 15 mm relative to the tray.
  • the lid is moved relative to the tray by compression between two shelves in the freeze-drying chamber thereby closing the one or more vials whilst under vacuum.
  • Figures Ia and Ib show a vial (1) in a tray (2) located in a freeze-drying chamber having an upper shelf (4) and a lower shelf (11).
  • closure of the vial is achieved by depressing a stopper (8) in the vial.
  • the stopper (8) is a ventilated stopper having an "open" position (illustrated in Figure Ia) and a “closed” position (illustrated in Figure Ib) and movement of the lid (7) relative to the tray (2) depresses the stopper (8) into the vial (1) from the "open” position to the "closed” position.
  • the stopper In the "open” position, the stopper is partly inserted in the opening (6) of the vial (1) but allows the passage of water vapour out through the stopper (8).
  • the stopper hermetically seals the vial.
  • the stoppers are preferably made from rubber but may alternatively be made from any other material which is suitable for hermetically sealing the individual vials and which can endure the conditions required for sterilisation and freeze-drying.
  • the stoppers are preferably brought into contact with the lid as the lid is depressed towards the opening of each vial.
  • the lid may contact the stopper via an adapter member which may be associated with the stopper or the lid and which may be integral thereto.
  • the adapter may alternatively be located in the container between the stopper and lid but not in contact with either until the shelves of the freeze-drying apparatus are compressed.
  • the vacuum can be released, the container unloaded and the vials oversealed in a non-sterile area.
  • the closure of the closeable vial containing the lyophilised product whilst still under vacuum and prior to removal of the vial from the freeze-dryer prevents the risk of contamination of the product by, for example, microorganisms in the external environment and prevents the product from contaminating the freeze-dryer and external environment.
  • the ability to contain the product is particularly important where the product contains potentially hazardous products, such as infectious agents. Therefore, the use of a method of the present invention means that it is not necessary to release the vacuum in a sterile area. However, as the outside of the vials may be contaminated, the vacuum should preferably be released in a containment area.
  • a method according to the present invention enables these aims to be achieved by the use of a membrane in combination with the presence of a hermetic seal between the lid and the tray.
  • a membrane for use in a container according to the present application is permeable to water vapour and atmospheric gases in order to allow vapour molecules to exit the container through the membrane.
  • the membrane should also be impermeable to bacteria, viruses and other microorganisms that may be present in the external environment. This ensures that contaminants from the external environment do not enter the container and contaminate the product. However, as the membrane is permeable to water vapour and atmospheric gases, the vapour molecules are still able to exit the container through the membrane. More preferably, the membrane should also be impermeable to other agents that may be present in the external environment, but for practical purposes, the most important environmental contaminants of relevance are bacteria.
  • non-hazardous products examples include killed microorganisms as vaccines; human blood products such as clotting factors (e.g., factor VIII, etc); animal blood products such as polyclonal antibodies and their fragments (e.g., antivenoms, anti drugs such as DigibindTM, etc.); monoclonal antibodies; enzymes such as L-asparaginase and catalase; and labile molecules such as vitamins and hormones.
  • clotting factors e.g., factor VIII, etc
  • animal blood products such as polyclonal antibodies and their fragments (e.g., antivenoms, anti drugs such as DigibindTM, etc.); monoclonal antibodies; enzymes such as L-asparaginase and catalase; and labile molecules such as vitamins and hormones.
  • a membrane for use in a method according to the present invention is impermeable to potentially hazardous molecules, particularly those that may be present in the product and which it is desirable to contain within the container.
  • potentially hazardous products is numerous and diverse. They include infectious agents (bacteria, viruses and fungi), for example, which may be present in attenuated vaccines, in blood, plasma or serum or in other biological samples such as bone or cornea. They may also include potentially sensitising molecules such as penicillin and other antibiotics, and highly toxic compounds such as the tetrameric enzyme L- asparaginase, cytotoxic drags such as cysplatin and botulinum and other toxins.
  • infectious agents bacteria, viruses and fungi
  • infectious agents infectious agents
  • viruses and fungi infectious agents
  • they may also include potentially sensitising molecules such as penicillin and other antibiotics, and highly toxic compounds such as the tetrameric enzyme L- asparaginase, cytotoxic drags such as cysplatin and botulinum and other toxins.
  • a membrane for use in a method according to the present invention is impermeable to bacteria, viruses and other microorganisms that may be present in the external environment and is impermeable to potentially hazardous molecules whilst being permeable to water vapour and atmospheric gases.
  • the membrane preferably has a
  • the pore size of the membrane is adapted to take this into account. Further, in embodiments in which the product being freeze-dried contains potentially hazardous molecules that are smaller than bacteria, it will be necessary to use a membrane with a pore size that, will prevent these smaller products from exiting the container.
  • a membrane for use in a method according to the present invention will also preferably be sterilisable and/or have low extractables and particulates and/or be compatible with the product.
  • the membrane will be reusable such that it is not damaged by repeated freeze-drying cycles/sterilisation but this is not essential provided that the membrane is inexpensive to manufacture and easy to obtain.
  • a membrane for use in a container according to the present application has all of these characteristics.
  • a method according to the present application may make use of different membranes according to the nature of the product being freeze-dried and/or according to the environment in which the freeze-drying is taking place.
  • Materials which are suitable for use as a membrane include semi-permeable paper such as pleated glass fibre paper (e.g., No. 6, Mk 2 dust filter available from Leyland and
  • cellulose and usual cellulose derivatives such as cellulose acetate; films of polymer compounds such as polypropylene or PTFE (polytetrafluoroethylene); films of sterilisation paper according to German
  • a membrane for use in a method according to the invention may be made of other materials provided that it has the characteristics listed above that are necessary for its use.
  • a method of the invention involves using a container comprising a membrane which is exposed to both the inside and the outside of the container so that water vapour and atmospheric gases can escape from the container.
  • the membrane may be situated in one or more of the sides of the container, in the base of the container and/or in the lid of the container. Preferably, the membrane is situated in the lid.
  • the amount of membrane that is exposed to both the inside and the outside of the container is a sufficient amount so as not to significantly impede the flow of water vapour.
  • the amount of membrane that is exposed may make up at least 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15% or 20% of the surface area of the container.
  • a container according to the present invention to prevent contamination and ensure containment when freeze-drying a product, depends upon maintaining an hermetic seal between the tray and its lid during the transfer of the container from the sterile filling unit to the freeze-dryer and during the freeze-drying cycle until closure of the vials whilst still under vacuum.
  • the presence of the hermetic seal between the lid and the tray ensures that no air can penetrate the seal.
  • the term "hermetic" as used herein means "airtight".
  • the hermetic seal between the lid and the tray also ensures containment of the product and prevents contamination of the product.
  • Freeze-drying will always be a relatively complex procedure and will require highly experienced staff. However, use of a method according to the present application will simplify matters significantly. It is difficult to incorporate a large item of equipment, such as a freeze-dryer, into a cleanroom. Working within pharmaceutical cleanrooms also involves gowning up and constant checks as to the integrity of the air supply and freedom from particulates and environment contaminants. Working within the confined space of an isolator sited in a cleanroom adds to the problems. Thus working in an isolator in a cleanroom is uncomfortable and the need to wear gloves impairs performance. It follows that, ideally, as few steps as possible in freeze-drying should need a sterile environment.
  • any group freeze-drying conventional and hazardous products requires a separate cleanroom and freeze-dryer dedicated to each. It is mandatory to prevent a hazardous material from contaminating the freeze-dryer and immediate environment in which a medicinal product for systemic use will be freeze-dried subsequently.
  • pathogens or hazardous products have to be freeze-dried it is unwise to rely on the primary container (that is the vial and stopper) or the medium formulation as the sole mechanism for preventing contamination of the inside of the freeze-dryer.
  • the use of a method according to the present invention allows the transfer of the container to or from the freeze-dryer to be undertaken through the normal environment without the need for a transfer isolator or laminar flow cabinet.
  • the vials can be sealed while still under vacuum and thus the container need not be opened in a sterile facility when vials are used.
  • the container should be opened in a containment area since the outside of the vials will be contaminated.
  • the container is then preferably decontaminated with, for example, a weak solution of formaldehyde immediately upon opening.
  • freeze-drying cycle time in conventional freeze-drying is concerned with cleaning and sterilising the plant and freezing the product.
  • the use of a method according to the invention minimises operating time for freeze-drying leading to enhanced utilisation and decreased costs. For example, not only does it save several hours of steam sterilisation time but also the prolonged period ( ⁇ 6 hours) required for the instrument to cool down.
  • freeze-drying chamber does not have to withstand temperatures of -127 0 C and overcomes certain health and safety issues such as the need for a door locking device to prevent the chamber being opened while still under positive pressure. Thus a less expensive instrument may suffice.
  • Freezing in a conventional freeze-dryer is inefficient and slow as it is dependent largely on conduction via several layers that seldom make perfect contact. Conduction proceeds through the metal of the cooling shelves, the base of the tray, the glass bottom of the vial and then up through the product starting at its base. Further, for a significant period of time, the pharmaceutical freeze-dryer is utilised only as a freezing cabinet, thereby reducing the economic effectiveness of the plant.
  • Pharmaceutical products dispensed into vials as may be used in a method according to the present invention, can be prefrozen in a cold chamber, which has the advantage of maximising throughput. However, problems associated with maintaining product cleanliness have previously limited the appeal of external prefreezing procedures.
  • the use of a method according to the present invention overcomes such problems by allowing freezing to be undertaken in a separate refrigeration unit if desired.
  • the freezing time is greatly reduced.
  • the rate of nucleation (on which ice formation depends) in pure water at -3O 0 C is only 15 X lO 1 nuclei-second.m 3 compared with 4.3 x 10 15 nuclei-second.m 3 at -4O 0 C.
  • a separate unit allows freezing to occur in a way which also shortens the time required to complete primary drying (sublimation).
  • the heat transfer is through the bottom of the product with the ice front rising and sweeping the water-soluble components towards the top of the containing vial in the form of a plug of gradually increasing concentration. This can form a 'skin' near the surface which is poorly permeable to water vapour and, therefore, markedly impairs primary drying.
  • more than 60% of the impedance to vapour flow during drying is due to the product itself and, especially, the dry layer on its surface.
  • the method according to the present invention may additionally employ the step of pre-freezing the product. Pre-freezing may be accomplished using a separate refrigeration unit, which is designed to ensure controlled, rapid freezing.
  • a simpler freeze-dryer having shelves which do not need to reach such low temperatures as those of conventional freeze-dryers, where there will be no requirement for steam sterilisation and/or where the product will not be subjected to positive pressures, may also be used in a method according to the present invention.
  • the use of a method according to the present invention offers a number of significant advantages over the use of methods available in the prior art. It reduces the time taken to complete the freeze-drying of a product and, thereby, increases throughput and further reduces costs. It also enables a reduction in the cost of the facilities and equipment needed to undertake conventional, small scale sterile freeze-drying in vials. Moreover, it simplifies the process.
  • the invention also encompasses containers for use in a method according to the invention and components of the containers.
  • a container according to the present application is suitable for holding one or more vials containing the product.
  • the container may alternatively or additionally be used to hold product in bulk or in ampoules.
  • a container for freeze-drying a product comprises:
  • a membrane wherein in use the lid and tray cooperate to form a hermetic seal therebetween and the entire lid can move relative to the tray to effect closure under vacuum of the closeable vials within the container.
  • Figure 2a shows a seal (gasket) (20) clamped over the entire upper ridge (21) of the tray (2).
  • a seal gasket
  • Figure 2b shows a seal (22) placed around the upper and outer side (23) of the tray (2).
  • this may be somewhat similar to a thick rubber band.
  • a groove (26) or ridge on the tray's outer surface is present to keep the seal secure when the lid (7) is depressed; or
  • Figure 2c shows a seal (24) placed around the outer side of the lid (7).
  • a groove (27) or ridge on the lid's outer surface is present to keep the seal secure when the lid is depressed.
  • This type of configuration has the advantage that the tray need not be modified.
  • the lid (7) moves down inside the tray (2) and thus a rim (25) is preferably also present around the periphery of the inside of the tray (2) to prevent the lid 'snagging' the most peripheral vials (or ampoules).
  • the rim may be a separate component or may form an integral part of the tray.
  • the seal will be made of rubber or other suitable elastic material.
  • the exact type of seal used will depend upon the conditions used in the freeze-drying cycle and the sterilisation procedure. For example, if the seal needs to cope with temperatures as low as -5O 0 C and steam or some other form of sterilisation, suitable material that can withstand these temperatures should be chosen for the seal.
  • the membrane is preferably located in the lid.
  • the membrane may be located elsewhere in the container, such as in the base of the container and/or in one or more of the walls of the container.
  • the container may comprise a membrane in one, two or more different locations, for example, in the lid, in the lid and base or in the lid, walls and base.
  • the membrane may form part or all of one or more of the lid, base and/or walls. Where the membrane forms all of the lid, the membrane is preferably sufficiently rigid to enable vial closure to be effected upon compression between the shelves of the freeze-dryer.
  • the membrane preferably covers one or more holes in the container which allow the free passage of water vapour and atmospheric gases out of the container.
  • the hole(s) may be located in the lid or the tray (e.g., in the top, side walls or base of the container).
  • the number, size and spatial arrangement of the one or more holes should allow a sufficient area for water vapour to escape from the container.
  • the arrangement of the one or more holes also enables an equal exposure of each vial to the one or more exit holes.
  • the lid comprises one or more holes covered by the membrane.
  • Figure 3 a shows a lid (7) as viewed from the outside of the container, which comprises holes (30).
  • Figure 3b represents a view of the lid (7) from the inside of the container and shows that the holes (30) are covered by a membrane (31), which is attached to the inner surface of the lid (7).
  • the number, size and spatial arrangement of the one or more holes should also ensure the strength and rigidity of the lid essential for the closure mechanism.
  • these one or more holes are preferably significantly smaller than the size of stoppers used to close the vials to ensure that the stoppers themselves do not pass through the one or more holes.
  • a lid of typical size 255 x 355 mm may comprise around 120 holes each having a diameter of about 10mm.
  • the lid may comprise one 10mm diameter hole per 750 mm .
  • the membrane is present on the internal surface of the container, for example the internal surface of the lid.
  • the membrane is preferably attached to the container by heat welding. It is preferable to avoid the use of adhesive for regulatory reasons. Welding the membrane to the internal surface of the container improves the appearance of the container and ensures close contact of the two during the freeze-drying cycle and especially during primary and secondary drying when the chamber is under vacuum.
  • the invention provides a container for freeze-drying a product comprising:
  • the membrane forms a lid and in use the lid and the tray cooperate to form a hermetic seal therebetween and at least a part of the lid can move relative to the tray to effect closure under vacuum of the closeable vials within the container.
  • the membrane itself forms the lid.
  • the membrane is preferably flexible and thus movement of the lid relative to the tray is possible by depressing part of the membrane, thereby effecting closure of the vials.
  • the entire membrane lid can move relative to the tray.
  • this alternative embodiment preferably encompasses the use of membrane lids that are sufficiently flexible to enable the vials to be closed fully whilst still in the freeze-dryer under vacuum by depressing part of the membrane but also encompasses the use of rigid membrane lids that can move in their entirety relative to the tray, thereby effecting closure of the vials whilst under vacuum.
  • the membrane for use in this alternative embodiment forms an airtight seal with the tray.
  • the membrane is also preferably sufficiently strong to prevent breakage of the membrane during transport of the container to and from the freeze-drying apparatus and during the effecting of closure of the vials.
  • the membrane should also preferably be available in sheets.
  • the vials are filled, partially stoppered in the open position and loaded into the tray and then the sheet of membrane is placed lightly over the top of the vials.
  • a hermetic seal is preferably formed between the lid and the tray by folding the membrane down over the sides of the tray and fixing it there in such a way as to ensure an airtight seal between the tray and the membrane.
  • the membrane can be sealed hermetically to the sides of the tray by means of an elastic ring.
  • a clamp e.g., made from metal
  • Such a clamp will preferably be resistant to repeated freeze-drying cycles, easy to sterilise and suitable for repeated use.
  • Figure 4a shows an example of a container (40) according to this embodiment comprising a tray (2) containing vials (1) having stoppers (8) in their "open” position.
  • the clamp (42) is used to effect an airtight seal between the membrane (41) and the sides of the tray (2).
  • the clamp of Figure 4a is shown in more detail in Figure 4b and a method of fixing the clamp to the tray is illustrated further in Figure 4c.
  • the inside dimensions of the clamp (42) are slightly smaller than the outer dimensions of the tray (2) such that the clamp (42) fits within a depression (43) in the tray (2).
  • the clamp (42) is hinged at hinges (44) such that it can be opened to allow the clamp (42) to be placed around the tray (2) in the depression (43). Once the clamp (42) is in position, a clip (45) fastens the opened ends of the clamp (46) together to hold the clamp (42) in place.
  • the tray can then be transferred safely via a non-sterile environment into a non-sterilised freeze-dryer.
  • the stoppers and tops of the vials preferably extend above the sides of the tray so that the stoppers can be inserted fully into the vials by compression between shelves of the freeze-drying chamber following freeze-drying while still under vacuum.
  • a container for use in a method according to the present application may additionally comprise terminals to allow thermocouples to record temperature changes of the product in one of the vials.
  • these thermocouples are present in the lid of the container.
  • the lid may also be transparent to permit viewing of the product, preferably of the product in the vials, through the chamber door during the freeze-drying cycle and their closure. This requires that the membrane, when it forms part of the lid, is transparent, or very small in area as compared with the lid.
  • a tray for use with a container according to the present invention is preferably constructed from a strong, light material that conducts temperature changes rapidly from the freeze- dryer shelves to the product being freeze-dried.
  • the tray also preferably has a flat smooth base to ensure maximum contact with the cooling shelves.
  • the tray may be made from any material with suitable mechanical and thermal conductivity properties, e.g., steel.
  • the tray may be constructed of aluminium or of various plastics. Aluminium has ideal thermal properties. However, it is not as strong mechanically as stainless steel and warps and distorts when heat sterilised. It also corrodes when in contact with saline and products may stick unless the aluminium has been Teflon coated. Thus steel is preferred despite its poorer thermal qualities.
  • stainless steel such as pharmaceutical grade, polished stainless steel is used, as specified by GMP.
  • plastic trays may also be used despite having inferior thermal conduction properties to metal trays as they may be much less expensive to produce.
  • a tray of a container according to the present application may vary, since vials and ampoules come in many different sizes and since the surface area of the freeze-dryer shelves and the distance between them may vary markedly, sometimes even within a single company.
  • the dimensions of a container according to the present application may vary depending on the freeze-dryer that it is for use with.
  • the size of the trays will be dictated by their ease of handling and weight when fully loaded.
  • the tray is available in a wide range of sizes, both with respect to height and surface area, to fit all existing freeze-dryers and to be suitable for all sizes of vials and ampoules.
  • the vials are usually carefully loaded into trays for transfer to the freeze-dryer. When a tray has been filled completely with vials or ampoules there is no danger that any will fall during transfer.
  • the tray may additionally comprise a barrier placed around the vials or ampoules.
  • the barrier may form a wall around the periphery of the one or more vials or ampoules contained in the tray.
  • Individual barriers may be used for individual vials or ampoules or groups of vials or ampoules.
  • the barrier may comprise a rack comprising compartments each capable of holding one or more, preferably one, vial.
  • the barrier can be of varying size and/or shape to cope with different numbers of vials or ampoules and, thereby, stabilise and locate them as desired.
  • the barrier is preferably made from metal or plastic.
  • the barrier may be a separate component or may form an integral part of the tray.
  • the use of a barrier as described above will prevent the vials or ampoules from falling during transfer.
  • the barrier may also be used to alter the position of the vials or ampoules in relation to the membrane.
  • the barrier allows each vial to be positioned in equal juxtaposition to the membrane.
  • the components of a container according to the present application comprise at least a lid and a tray, as the membrane may form the lid.
  • the lid and the tray for use with a container according to the present invention each individually form a separate aspect of the invention.
  • the application also relates to lids as described herein for use with a container according to the present application and trays as described herein for use with a container according to the present application.
  • the components of a container according to the present application should be sufficiently strong for their purpose. They are preferably also simple and relatively inexpensive to manufacture. Preferably, the components of a container according to the present application have a smooth surface to facilitate cleaning. Preferably, the components of a container of the present application are reusable. In order to be reusable, the components must be resistant to repeated freeze-drying and to autoclaving and/or sterilisation with steam (or, possibly, hydrogen peroxide) without bending, bubbling or other damage. Since some products may be freeze-dried in bulk within the container, its constituents also preferably have low extractables and particulates, are compatible with the products and are available in a wide range of sizes.
  • a pharmaceutical cleanroom with HVAC air supply is used to house the grade A isolator used for sterile filling.
  • the cleanroom is scrupulously cleaned and assessed and the isolator is sterilised with hydrogen peroxide prior to use.
  • the freeze-dryer need not open into the cleanroom and can be sited in any clean non-sterile area, such as a general purpose laboratory. Although it must be cleaned thoroughly before use, it never needs to be sterilised, thereby avoiding the need for a steam generator and a source of copious volumes of sterile water.
  • the vials are generally filled within a purpose designed grade A isolator sited in a grade C/D cleanroom.
  • the isolator and its contents are sterilised using a hydrogen peroxide
  • the product for lyophilisation is pumped into the isolator via a 0.2 ⁇ m filter to
  • vials (after being washed and depyrogenated in an oven); sterilised trays into which the vials will be placed; and the closure system, including ventilated rubber stoppers (after being washed to remove particulates and then sterilised in an autoclave or by gamma irradiation).
  • the vials After delivering accurately into each vial the required volume of product, the vials are placed in the trays and the rubber stoppers introduced by hand in their "open” position ( Figure Ia). The lids are placed carefully over the trays and lowered gently until just in contact with the ventilated stoppers. At this time, the hermetic seal between the lid and the tray is now present and thus the contents of the vials are fully protected against environmental contamination and any potentially hazardous products are contained within the container.
  • the container can be removed from the isolator and cleanroom into a non-sterile environment. Normally, they will be transferred directly to the freeze-dryer which, itself, is in a non-sterile site. Alternatively, the container can be stored for prolonged periods prior to freeze-drying, especially if kept at -2O 0 C. This also makes possible the initial freezing stage of the freeze- drying cycle in a separate refrigeration unit.
  • the cycle is similar to that of conventional freeze-drying since the membrane does not impede vapour flow.
  • the vials are closed by lowering the upper shelves which, in turn, press down the lid to depress fully the rubber ventilated stoppers into the vials (see Figure Ib). Closure while still under vacuum avoids the freeze-dried product being exposed to the moisture, oxygen and carbon dioxide in the atmosphere, all of which may impair its activity. It also ensures the protection of the product within the vial from contaminants in the environment and of the environment against potentially hazardous products in the vial.
  • the container with freeze- dried product in vials is removed to a non-sterile setting for their initial assessment and final oversealing of the vials with a crimped metal ring.
  • the vials/ampoules After final stoppering/sealing the vials/ampoules are subject to 100% integrity testing, various microbiological procedures (pyrogenicity, sterility and bioburden), measurement of their moisture content and activity and determination of their reconstitution time and the clarity of the reconstituted product. They are then labelled and stored prior to distribution and use.
  • the freeze-dryer is defrosted and cleaned thoroughly. It does not need to be sterilised even when used to freeze-dry potentially hazardous products. However, in the latter instance, the inside of the container and the outside of the vials will generally have been contaminated. Thus the container should be opened only in a suitable containment area and subjected immediately to sterilisation with, for example, alcohol or formalin.

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  • Engineering & Computer Science (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Mechanical Engineering (AREA)
  • General Engineering & Computer Science (AREA)
  • Drying Of Solid Materials (AREA)
  • Medical Preparation Storing Or Oral Administration Devices (AREA)

Abstract

L’invention est un procédé de séchage par lyophilisation d’un produit consistant à : a) placer un flacon à bouchon (1) renfermant le produit dans un contenant comprenant : i) un plateau (2) ; ii) un couvercle (7) et iii) une membrane (31) ; ledit couvercle (7) et le plateau (2) s'associent pour former une capsule hermétique intermédiaire et le couvercle (7) peut se déplacer par rapport au plateau (2) pour effectuer la fermeture des flacons (1); b) lyophiliser le produit et c) déplacer le couvercle (7) et le plateau (2) liés l’un à l’autre pour effectuer la fermeture des flacons (1). L’invention concerne également des contenants dans l’utilisation de ce procédé.
PCT/GB2005/003041 2004-08-03 2005-08-03 Appareil de séchage par lyiophilisation WO2006013360A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0417309.2 2004-08-03
GB0417309A GB0417309D0 (en) 2004-08-03 2004-08-03 Freeze-drying apparatus

Publications (1)

Publication Number Publication Date
WO2006013360A1 true WO2006013360A1 (fr) 2006-02-09

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GB (1) GB0417309D0 (fr)
WO (1) WO2006013360A1 (fr)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007128385A1 (fr) * 2006-05-09 2007-11-15 Ima Life S.R.L. Étagère de lyophilisateur
US7633629B2 (en) 2007-02-05 2009-12-15 Palo Alto Research Center Incorporated Tuning optical cavities
EP2157387A1 (fr) * 2008-08-19 2010-02-24 DRK-Blutspendedienst West gemeinnützige Gesellschaft mit beschränkter Haftung Récipient non démontable et non pliable pour la lyophilisation d'un produit
DE102007049278B4 (de) * 2007-10-12 2010-08-05 Gea Lyophil Gmbh Vorrichtungen zum Gefriertrocknen
EP2138787A3 (fr) * 2008-06-27 2012-02-29 Optima Group pharma GmbH Fixation
WO2016022385A1 (fr) * 2014-08-04 2016-02-11 Genentech, Inc. Appareil et procédés pour enfermer hermétiquement un médicament à l'intérieur d'un dispositif d'administration médical
LU92648B1 (en) * 2015-02-04 2016-08-05 Project Pharmaceutics Gmbh Method and device for optimized freeze-drying of a pharmaceutical product
JP2017035499A (ja) * 2011-04-04 2017-02-16 ジェネシス パッケージング テクノロジーズＧｅｎｅｓｉｓ Ｐａｃｋａｇｉｎｇ Ｔｅｃｈｎｏｌｏｇｉｅｓ 複数の薬剤バイアルにキャップする方法
CN106643116A (zh) * 2016-12-23 2017-05-10 吴小峰 真空冷冻干燥用透气膜材、真空干燥用容器及其制作方法
ES2677446A1 (es) * 2017-02-01 2018-08-01 Jose Manuel GARCIA ARIAS Aparato y metodo de deshidratacion y destilacion domestica en vacio, sin uso de bombas externas, ni productos secantes
TWI683095B (zh) * 2019-01-24 2020-01-21 美商慧盛材料美國責任有限公司 用於容器的乾燥及分析測試之系統及方法
EP3949732A1 (fr) * 2015-08-03 2022-02-09 Gen-Probe Incorporated Réceptacle pour recevoir une ou plusieurs substances devant être lyophilisées
US11781811B2 (en) 2015-08-03 2023-10-10 Gen-Probe Incorporated Apparatus for maintaining a controlled environment
WO2024003424A1 (fr) * 2022-06-28 2024-01-04 Compliance Consulting And Engineering Services, S.L. Système de commande du procédé de lyophilisation dans un lyophiliseur avec système de château de plaques et procédé pour la génération d'un espace de conception
WO2024137748A1 (fr) * 2022-12-20 2024-06-27 Teleflex Life Sciences Llc Ensemble plateau de lyophilisation
DE102023118662B3 (de) 2023-07-13 2024-07-11 Jürgen Kögel Gefriertrocknungsbehälter

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EP0413620A1 (fr) * 1989-08-16 1991-02-20 Societe D'utilisation Scientifique Et Industrielle Du Froid Usifroid Boîte d'isolation de l'atmosphère ambiante pour traitement de produits
FR2740108A1 (fr) * 1995-08-22 1997-04-25 Lab Francais Du Fractionnement Emballage etanche pour sechage, notamment lyophilisation, et procede de sechage, notamment de lyophilisation, a l'aide d'un tel emballage
US6199297B1 (en) * 1999-02-01 2001-03-13 Integrated Biosystems, Inc. Lyophilization apparatus and methods
US6517526B1 (en) * 2000-12-29 2003-02-11 Yehuda Tamari Container for lyophilizing biological products
US20050086830A1 (en) * 2003-10-24 2005-04-28 Zukor Kenneth S. Processing cap assembly for isolating contents of a container

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US3246674A (en) * 1963-06-12 1966-04-19 Thermovac Ind Corp Vacuum flask and coupling
US3488860A (en) * 1967-10-09 1970-01-13 Virtis Co Inc Filter tray for freeze drying
US4024648A (en) * 1975-10-22 1977-05-24 Bender Charles E Safety flask for freeze drying
EP0413620A1 (fr) * 1989-08-16 1991-02-20 Societe D'utilisation Scientifique Et Industrielle Du Froid Usifroid Boîte d'isolation de l'atmosphère ambiante pour traitement de produits
FR2740108A1 (fr) * 1995-08-22 1997-04-25 Lab Francais Du Fractionnement Emballage etanche pour sechage, notamment lyophilisation, et procede de sechage, notamment de lyophilisation, a l'aide d'un tel emballage
US6199297B1 (en) * 1999-02-01 2001-03-13 Integrated Biosystems, Inc. Lyophilization apparatus and methods
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Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101449125A (zh) * 2006-05-09 2009-06-03 Ima莱弗有限责任公司 冷冻干燥器架
JP2009536310A (ja) * 2006-05-09 2009-10-08 アイエムエイ ライフ ソシエタ ア レスポンサビリタ リミタータ 凍結乾燥機の棚
US8722169B2 (en) 2006-05-09 2014-05-13 Ima Life S.R.L. Freeze dryer shelf
WO2007128385A1 (fr) * 2006-05-09 2007-11-15 Ima Life S.R.L. Étagère de lyophilisateur
US7633629B2 (en) 2007-02-05 2009-12-15 Palo Alto Research Center Incorporated Tuning optical cavities
DE102007049278B4 (de) * 2007-10-12 2010-08-05 Gea Lyophil Gmbh Vorrichtungen zum Gefriertrocknen
EP2138787A3 (fr) * 2008-06-27 2012-02-29 Optima Group pharma GmbH Fixation
EP2157387A1 (fr) * 2008-08-19 2010-02-24 DRK-Blutspendedienst West gemeinnützige Gesellschaft mit beschränkter Haftung Récipient non démontable et non pliable pour la lyophilisation d'un produit
JP2017035499A (ja) * 2011-04-04 2017-02-16 ジェネシス パッケージング テクノロジーズＧｅｎｅｓｉｓ Ｐａｃｋａｇｉｎｇ Ｔｅｃｈｎｏｌｏｇｉｅｓ 複数の薬剤バイアルにキャップする方法
RU2693675C2 (ru) * 2014-08-04 2019-07-03 Дженентек, Инк. Устройство и способ герметизации лекарственного вещества внутри лечебного устройства для доставки
US10729616B2 (en) 2014-08-04 2020-08-04 Genentech, Inc. Apparatus and methods for sealing a medicament within a medical delivery device
US11523969B2 (en) 2014-08-04 2022-12-13 Genentech, Inc. Apparatus and methods for sealing a medicament within a medical delivery device
WO2016022385A1 (fr) * 2014-08-04 2016-02-11 Genentech, Inc. Appareil et procédés pour enfermer hermétiquement un médicament à l'intérieur d'un dispositif d'administration médical
LU92648B1 (en) * 2015-02-04 2016-08-05 Project Pharmaceutics Gmbh Method and device for optimized freeze-drying of a pharmaceutical product
WO2016125095A1 (fr) * 2015-02-04 2016-08-11 Project Pharmaceutics Gmbh Procédé et dispositif pour optimiser la lyophilisation d'un produit pharmaceutique
US10809002B2 (en) 2015-02-04 2020-10-20 Project Pharmaceutics Gmbh Method and device for optimized freeze-drying of a pharmaceutical product
EP3949732A1 (fr) * 2015-08-03 2022-02-09 Gen-Probe Incorporated Réceptacle pour recevoir une ou plusieurs substances devant être lyophilisées
US11668525B2 (en) 2015-08-03 2023-06-06 Gen-Probe Incorporated Apparatus for maintaining a controlled environment
US11781811B2 (en) 2015-08-03 2023-10-10 Gen-Probe Incorporated Apparatus for maintaining a controlled environment
CN106643116A (zh) * 2016-12-23 2017-05-10 吴小峰 真空冷冻干燥用透气膜材、真空干燥用容器及其制作方法
ES2677446A1 (es) * 2017-02-01 2018-08-01 Jose Manuel GARCIA ARIAS Aparato y metodo de deshidratacion y destilacion domestica en vacio, sin uso de bombas externas, ni productos secantes
TWI683095B (zh) * 2019-01-24 2020-01-21 美商慧盛材料美國責任有限公司 用於容器的乾燥及分析測試之系統及方法
WO2024003424A1 (fr) * 2022-06-28 2024-01-04 Compliance Consulting And Engineering Services, S.L. Système de commande du procédé de lyophilisation dans un lyophiliseur avec système de château de plaques et procédé pour la génération d'un espace de conception
CN119698536A (zh) * 2022-06-28 2025-03-25 合规咨询与策划服务有限公司 用于控制具有板堆系统的冻干机的冻干过程的系统和生成设计空间的方法
US12379157B2 (en) 2022-06-28 2025-08-05 Compliance Consulting And Engineering Services, S.L. System for controlling the freeze-drying process in a freeze dryer with a plate stack system and a method for generating a design space
WO2024137748A1 (fr) * 2022-12-20 2024-06-27 Teleflex Life Sciences Llc Ensemble plateau de lyophilisation
DE102023118662B3 (de) 2023-07-13 2024-07-11 Jürgen Kögel Gefriertrocknungsbehälter
EP4491989A1 (fr) 2023-07-13 2025-01-15 Jürgen Kögel Récipient de lyophilisation

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