WO2010081838A2

WO2010081838A2 - Sterile prefilled container

Info

Publication number: WO2010081838A2
Application number: PCT/EP2010/050365
Authority: WO
Inventors: Didier Bazile; Olivier Timbal; Juergen Sigg; Christian Schoch
Original assignee: Novartis Ag
Priority date: 2009-01-14
Filing date: 2010-01-13
Publication date: 2010-07-22
Also published as: WO2010081838A3

Abstract

Described herein is an assembly (100) for encasing a sterile prefilled container (102) and methods of preparing same. The assembly (100) is ideally suited for end use involving intravitreal injection. The methods described herein provide a prefilled container (102) with sterile exterior surfaces to an end user, even in the absence of terminal sterilization. This is particularly beneficial when the drug product contained in the prefilled container is otherwise sensitive to classical means of terminal sterilization.

Description

Sterile Prefilled Container

FIELD OF THE INVENTION

The present invention generally relates to an assembly for encasing a sterile prefilled container and methods for encasing a sterile-prefilled container.

BACKGROUND

Prefilled containers, such as syringes, although filled under aseptic conditions, are not packed into their secondary packaging containers — such as pouches, boxes or blister packs — in an aseptic environment, and are therefore likely to be microbiologically contaminated on their external surfaces. Terminal sterilization of prefilled containers in secondary packaging is one way to provide these containers to an end user with a low exterior bio-burden and low risk of contaminants, for safe application of the product by the end user. If, however, the drug product in the container is sensitive to the action of classical sterilization methods, like heat, gases or radiation, a terminal sterilization cannot be performed. Such is the case with prefilled containers housing sensitive biomolecules; the container, to remain sterile, must be protected from direct contact with the environment in the absence of application of terminal sterilization. Blister packs and pouches are currently used to this end, but cannot be adapted to an aseptic environment without great difficulty. For instance, the blister packaging process can create a significant amount of particles which would contaminate a pharmaceutical filling line. Those particles present problems for downstream applications with the drug product and problems to the end user. Moreover, the necessity to inject drugs intravitreally has significantly increased.

Sterility is absolutely critical for this type of injection. An introduction of germs inside the eye as a consequence of an injection can result in a severe infection leading to blindness. Whereas it is possible to withdraw a drug solution for injection from a vial that is not sterile on the vial exterior surface for placement into a completely sterile syringe, the case is quite different with a prefilled syringe. The contents of a prefilled syringe are not transferred to a separate device, therefore the prefilled syringe must be sterile on the outside surface if it is to be used in applications such as intravitreal injection, or in any environments where sterility is of great concern, such as in a surgical suite.

SUMMARY Described herein is an assembly for encasing a sterile-prefilled container and methods for encasing a sterile-prefilled container. The assembly ensures surface sterility of the sterile-prefilled container by encasing the prefilled container in a hermetically-sealed tube.

Although a method of this invention is described with respect to an exemplary assembly — a tube encasing a sterile-prefilled container — this method and others described herein may not be restricted to use with this particular assembly, and can be used with other suitable types of assemblies as would be readily apparent to those skilled in the art after having the benefit of this disclosure.

The exemplary assembly and methods described herein provide a prefilled container, with sterile exterior surfaces, to an end user, even in the absence of terminal sterilization. This is particularly beneficial when the drug product contained in the prefilled container is otherwise sensitive to classical means of terminal sterilization, such as by exposure to moist or dry heat, gas or radiation. The adaptation of traditional pharmaceutical packaging to an aseptic environment has not previously been feasible due to persistent problems, such as requirements for sterility, excessive particle generation and subsequent contamination, and the prohibitive size of equipment needed to be placed in isolation, for example, Grade A according to EC Guide to Good Manufacturing Practices. It has been discovered that a tube or other housing/material encasing and sealing a sterile-prefilled container with sterile surfaces, can be prepared via the process described herein, employing aseptic methods in isolation, or with a combination of aseptic and classical sterilization methods, and most significantly, at a point in the pharmaceutical packaging stream at the core of the pharmaceutical filling line.

In one embodiment, the entire method can be performed manually, if necessary. In another embodiment, a portion of, or the entire method, is automated or under the control of an automated system. In one embodiment, the container is pre-sterilized, and is aseptically filled with a therapeutic agent, such as a drug solution, in isolation.

In another embodiment, prior to transfer from the sterile environment of isolation, the prefilled container is packed into a previously sterilized pre-formed housing material, such as a tube, and hermetically sealed. Encasing the pre-sterilized container filled with sterile contents — while the prefilled container and tube remain in the aseptic manufacturing environment, such as isolation — ensures that the entire contents of the tube remains sterile.

In one embodiment, the tube may include a transparent portion, which allows visual inspection of the prefilled container upon departure of the assembly from the filling line, a feature that is not possible if the prefilled container is packaged in traditional packaging, such as an opaque pouch or a blister pack.

In another embodiment, the process described herein provides means of manipulating the prefilled container without compromising its sterility, i.e. during visual control, labeling, packaging, etc. In yet another embodiment, the process described herein also guarantees that an end user, such as a surgeon, is provided a container with sterile surfaces that can be introduced into an environment, such as a surgical suite, without further precautions or risk of contamination.

In another embodiment, labeling of the assembly can include information required by health authorities to be placed on the prefilled container packaging. Such labeling can be accomplished by the use of pre-printed containers or imprinting of data to containers, followed by cleaning of container, siliconization if necessary and sterilization of the labeled container prior to filling.

Generally, the assembly presented herein is adaptable to all drug products and containers or devices having requirements or desirability for sterility at their end use.

The foregoing summary provides an exemplary overview of some aspects of the invention, it is not intended to be extensive, or absolutely require any key/critical elements of the invention. BRIEF DESCRIPTION OF THE DRAWINGS

The detailed description is explained with reference to the accompanying figures. In the figures, the left-most digit(s) of a reference number identifies the figure in which the reference number first appears.

Fig. 1 shows a front view of an exemplary assembly for encasing a sterile prefilled container.

Fig. 2 shows a side view of the exemplary assembly encasing a sterile prefiiled container shown in Fig. 1. Figs. 3-11 show several exemplary devices used in concert with each other as part of a process to hold, transfer, and secure prefilled containers and portions of the exemplary assembly during the process.

DETAILED DESCRIPTION The assembly described herein provides a rigid pre-formed material, such as a tube, encasing a sterile prefilled container, ideally suited for use in intravitreal injections.

The assembly, thereby, eliminates the need for withdrawals from separate vials of drug solution, thus simplifying intravitreal administration and reduces the risks of contamination or eye infection. Furthermore, the process described herein preserves sterility of prefilled containers, assembled in isolation, especially those that cannot be subjected to additional terminal sterilization steps.

The assembly and method described herein permits a sterile-prefilled container to be manipulated, labeled, and/or packaged, without compromising sterility of the container, its surfaces, and/or its contents.

Definitions

In describing and claiming the assembly and method for providing encasement of a sterile-prefilled container, the following terminology will be used in accordance with the definitions set forth below. "Aseptic" conditions refer to conditions free of bacterial or microbial contamination as they are defined, for example, in the PIC Guide to Good Manufacturing Practice of Medicinal Products, Sterile Annex (Aug. 2006).

"Administration" refers to the method of administering treatment to a subject or patient in need thereof, such as parenteral administration, intravenous administration and intravitreal administration.

"Container", as used herein, is meant to include syringes, tubes, vials, bags, bottles, or other pre-formed containers or other means useful for housing a therapeutic agent, such as a drug product. Containers may be fabricated using standard methods or may be containers as available and provided from known manufactures or suppliers. They may be manufactured from transparent, semi-transparent or opaque plastic materials, glass, metal or other suitable materials. "Prefilled container", refers to a container as described above that is filled with a drug product, whether in solid or liquid form, or other biological agents, such as peptides, proteins or recombinant biologicals, whether in solid or liquid form, under aseptic conditions.

"Device", as used herein, refers to a device used, in part, for administering medical treatment and whose production or sale may, in part, be required to comply with requirements, such as safety requirements, set forth by a government agency, such as the Food and Drug Administration. "Encased" as used herein refers to material, such as a tube, encasing or housing a prefilled container, and is meant to include tubes, cylinders, bags, bottles, vials, or other suitable materials capable of housing a prefilled container.

"Filling line", as used herein, refers to the filling line in pharmaceutical production and packaging, such as by an automated process designed to fill and seal a container, such as by placing stopper in the container or aluminum crimp cap or by closing the container by other mean, such as with heat, under aseptic conditions.

An "instruction" or "instructional material" includes a publication, a recording, a diagram or any other medium of expression which can be used to communicate the usefulness of the assembly and/or method of the invention for its designated use. The instruction or instruction material may be presented together as part of the assembly and/or process or provided independently/separately of the assembly and/or process to an end user.

"Isolation" and/or "Isolator", as used herein, refer to practices in pharmaceutical production, filling and packaging, wherein a clean, or sterile environment, is separated from a non-sterile environment to limit or prevent the introduction or spread or contamination of infectious agents, such as microorganisms.

"Solution" as used herein refers to the contents of a prefilied container and includes solutions of biological therapeutics and drug products, protein products, peptide products, biological products, imaging solutions and aqueous solutions. Solutions include those that are temperature, oxidation or radiation sensitive due to the molecular make-up of the solution.

"Sterility" as used herein is meant to refer to complete absence of microbial life as defined by a probability of non-sterility or a sterility assurance level (SAL). The SAL for a given product is based on regulatory requirements. For example, SALs for health care products are defined to be at least 10^~6, i.e. a chance of less than 1 :1 million of a non-sterile product for aseptically and terminally processed products, respectively.

Reference herein to "one embodiment" or "an embodiment" means that a particular feature, structure, operation or characteristic described in connection with the embodiment is included in at least one embodiment of the invention. Thus, the appearances of such phrases or formulations herein are not necessarily referring to the same embodiment. Furthermore, various particular features, structures, operations or characteristics may be combined in any suitable manner in one or more embodiments. Assembly encasing a sterile prefilied container

Fig. 1 shows a front view of an exemplary assembly 100 comprising a tube 104 for encasing a sterile-prefilled container 102.

In one embodiment, tube 104 acts as housing for encasing the container 102. Tube 104 can be configured to include sections, such as a top portion and a bottom portion of the tube such that the sections, or portions, are separable and joinable from each other. In one embodiment, the tube 104 has a length and width generally larger than the height and width of container 102. Thus, tube 104 can be over varying sizes which depend, in part, on the size, shape or volume of the prefilied container encased therein. In one embodiment, container 102 is held securely in place within tube 104 by a securing mechanism 108, such as a flange, that engages when tube 104 is closed or sealed.

In one embodiment, tube 104 is capable of being sealed and/or unsealed via a sealing mechanism 106, such as a cap, snap, lid or screw.

In one embodiment, a portion of tube 104 is transparent. In one embodiment, tube 104 is configured with a transparent portion, such as a window 110. In another embodiment, window 110 is configured where a portion of the tube 104 varies in thickness, providing greater transparency. In another embodiment, window 110 is configured as a magnifying portion to permit visual examination of the tube 104 interior, including the prefilled container 102 and its contents. in one embodiment, an optional identification label 112, such as an adhesive, can be adhered or otherwise fixed to tube 104. In another embodiment, identification label 112 contains information regarding the assembly 100, such as information allowing the device 100 to be tracked along a manufacturing and distribution chain. In another embodiment, the label 112 is in the form of a scannable bar-code that holds identifying information. In yet another embodiment, identifying information could be information regarding the assembly and/or the drug product contained therein, such as administration guidelines, safety information, storage information and the like. In one embodiment, the prefilled container 102 comprises a syringe of appropriate volume suitable for the drug product contained therein. In another embodiment, the syringe is sterilized prior to filling with drug product under aseptic conditions. In one embodiment, a suitable syringe can include multiple parts, such as a syringe body, a piston, a plunger, a seal, a shaft, a luer or needle shield. In another embodiment, the syringe can include a needle and /or needle cap. The syringe and syringe components may be fabricated via any known process in the art, such as injection molding or conventional glass processing and with any material suitable for use as syringe components, or any syringe available from medical supply manufacturers or suppliers as known by those skilled in the art. In one embodiment, syringe components are sterilized in a clean room environment. P re-sterilized syringes are then suitable for filing with desired solution or drug product. In one embodiment, the syringe is filled with solution under aseptic conditions, whether by an automated or manual process. Thus, the contents of the syringe are sterile. The term "filled" is meant to refer to the placement of contents, such as solution, into the syringe in an appropriate amount, such as an appropriate volume or appropriate concentration. As apparent to one skilled in the art, the appropriate amount, volume or concentration will vary depending on the nature of the contents and their intended use.

In one embodiment, the prefilled container is filled with a drug product, such as in the form of liquid, solution, powder or solid. In another embodiment the drug product is a solution, such as a drug solution or protein solution, which is otherwise sensitive to standard sterilization methods, such as exposure to high temperatures or exposure to radiation, in another embodiment, the drug product is one that has been lyophilized, in other words a solid, and requires constitution in liquid or solution prior to use. In one embodiment, a drug product is any drug product having requirements or desirability for sterility of the drug product container surface. In one particular embodiment, the drug product is a protein solution, such as ranibizumab (e.g. 6mg/ml or 10 mg/ml) solution for intravitreal injection.

In one embodiment, the tube 104 is of suitable size and of any suitable material for encasing or housing a prefilled container, such as a prefilled syringe. In one embodiment, a portion of the tube is transparent. In another embodiment, the transparent portion of the tube is configured as a window into the tube interior, such as shown and described above in Fig. 1. In another embodiment, a portion of the tube window is configured in such a way as to act as a magnifying glass, thereby allowing closer visual inspection of the tube contents. In yet another embodiment, the tube is configured to hold a single prefilled container securely in a pre-defined position.

In one embodiment, the tube is configured with a sealing mechanism. Suitable sealing mechanisms include lids, caps, screws, stoppers, snaps or seals, or other mechanisms capable of hermetically sealing the tube and allowing the tube to be unsealed when desired for withdrawal of the prefilled container. In one embodiment, the sealing mechanism is reversible, such that at appropriate time of end use the encapsulated material, such as the prefilled container, may be released and presented to an end user. Sealing mechanisms can be comprised of like material as the tube or of another material, such as a rubber materials or plastics of differing flexibility. In another embodiment, suitable sealing mechanisms include those capable of sealing the contents of the tube tightly, such as sealing performed under vacuum. Suitable sealing mechanisms must prevent contamination ingressing through the tube during transport or storage once the encased prefilled syringe has left the sterile environment of isolation.

In one embodiment, the tube is comprised of a transparent, optically neutral polymer, such as polycarbonate, polystyrene, PET, cyclo-olefin polymer or cyclo-olefin copolymer. Suitable tubes can be fabricated under suitable conditions known in the art, such as by injection molding, injection blow molding, or other technologies. In another embodiment, the tube is manufactured from non-plastic material, like glass or metal.

Tubes or other suitable rigid pre-formed housing may also be provided by recognized manufacturers and suppliers as known in the art. In one embodiment, the tube is sterilized by any suitable sterilization method, such as exposure to moist or dry heat or radiation sterilization, prior to receiving the prefilled container for housing within the tube once the encapsulant and prefilled container are in isolation.

In one embodiment, previously sterilized syringes are filled with a formulation as described in U.S. Patent No. 7,060,269 under aseptic conditions in isolation following filtration through a sterilization-grade syringe filter (e.g. with a pore size of 0.2μm), and prefilled syringes are then encased within tube and hermetically sealed, whether by an automated or manual process.

Exemplary method encasing a sterile prefilled container Figs. 3-11 show several exemplary devices used in concert with each other as part of a process to hold, transfer, and secure prefilled containers and portions of assembly 100 throughout the process. This exemplary process may be performed in an isolator (not shown), or in a clean room in aseptic conditions.

Fig. 3 shows an exemplary tray 302 with exemplary plastic caps 304. Tray 302 rotates about a horizontal axis point 306 (i.e., 180 degrees or 360 degrees, etc.). Fig. 4 shows an exemplary tray 402 holding prefilled containers 102. Specifically, containers 102 are resting within portions 404 of tray 402.

Fig. 5 shows tray 302 rotated about axis point 306 with caps 304 aligned for engagement with prefilled containers 102, which are held by tray 402. Fig. 6 shows tray 302 rotated back to its original position, with tray 402 flipped about horizontal axis 306; so, contents of tray 402 are now transferred into caps 304. Fig. 7 shows tray 402 removed from engagement with tray 302. Fig. 8 shows tray 802 holding a portion of tube 104.

Fig. 9 shows tray 802 flipped over tray 302 in a position so that portions of tubes 104 can engage caps 304 held in position by tray 302.

Fig. 10 shows portions of tubes 104 fully engaged with caps 304 forming a fully encased-prefilled container 102.

Fig. 11 shows assemblies 100 (fully encased-prefilled containers 102) in their upright position upon completion of the process shown in Figures 3-11. In one embodiment, one tray (e.g. 302 in Fig. 3) holds a portion of the previously sterilized tubes, for example securing mechanism portions such as caps for securing the tubes sealed once the caps are in engagement with the other portion of the tube.

In another embodiment, a second tray (e.g., 402 in Fig. 4) holds containers prefilled with drug solution under aseptic conditions. The second tray is a tray similar to those used for filling of ready-to-fill syringes, such as sold by Beckton-Dickinson under the name SCF, by Gerresheimer under the name RTF or by Nuova Ompi under the name EZ-FiII, and the like. The first tray and second tray are positioned vertically on top of each other, such that the prefilled containers become mounted within the caps held by the opposite tray. As the prefilled containers become positioned inside the portion of the tube making up the caps, they are released from the tray formerly holding the prefilled containers, by placing the so assembled trays upside down and pulling off the syringe tray (referred to as a "nest").

In another embodiment, a third tray (e.g. 802 of Fig. 8) holding the other portion of the tube is then engaged vertically over the prefilled containers mounted within the tube caps. The two portions of the tube, essentially the bottom half of the tube and the top half (cap) of the tube, are engaged together and are sealed, such as by snapping the portions of the tube together, so that the tube is securely sealed off to the outside environment.

In another embodiment, the outside of the tube housing the sterile prefilled container can be labeled, such as with a tracking label, identification label or any other identifying information that may be necessary or useful to convey on the exterior surface of the tube.

In another embodiment, the assembled tube encasing the sterile prefilled container is then transported for further packaging or processing outside of the isolator. As the top and bottom part of the tubes are snapped into the trays they now can easily be removed from the trays and can be processed individually.

In another embodiment, the trays are designed such that their outside dimensions are compatible with commercially available syringe trays and they are hermetically closed by using a sealed-on foil, such as Tyvek. They can then be passed through a commercial syringe filling line (similarly to those trays containing empty syringes), including equipment for outside sterilization of the syringe trays when entering the aseptic filing environment or isolator. While the syringe filling line is adjusted to fill only the syringe trays, the trays with the tubes and caps are just passed through the filling station without processing. In the space after the filling station, the trays can be assembled, either manually or automatically, to enclose the syringes into the trays in a very economical fashion.

The described embodiments are to be considered in all respects only as exemplary and not restrictive. The scope of the invention is, therefore, indicated by the subjoined claims rather than by the foregoing description. All changes which come within the meaning and range of equivalency of the claims are to be embraced within their scope.

Claims

We claim:

1 An assembly encasing a sterile prefilled container, comprising: a pre-sterilized tube, wherein a portion of the tube is transparent, and a prefilled container housing a sterile drug solution, the prefilled container encased in the tube and hermetically sealed while the prefilled container and tube are in isolation, thereby providing a prefilled container with sterile surfaces.

2 The assembly of Claim 1 , wherein the prefilled container is a syringe.

3. The assembly of Claim 1 , wherein the drug solution is a solution sensitive to terminal sterilization techniques.

4. The assembly of Claim 1 , wherein the drug solution is a therapeutically effective amount of ranibizumab for intravitreal injection.

5. The assembly of Claim 1 , wherein the tube is configured with a sealing mechanism.

6. The assembly of Claim 1 , wherein the transparent portion of the tube further comprises a magnifying portion

7. A kit for providing an assembly comprising a tube encasing a sterile prefilled container, the kit comprising: an instruction for (i) filling a pre-sterilized container with a drug solution under aseptic conditions; (ii) encasing the sterile prefilled container within a pre-sterilized tube while the prefilled container and pre-sterilized tube are in isolation; and (iii) hermetically sealing the pre-sterilized tube encasing the sterile prefilled container, such the contents of and surfaces of the prefilled container are impermeable to contamination while encased in the tube upon removal from isolation.

8. A method for encasing a prefilled container with a solution under aseptic conditions, comprising: positioning the prefilled container within a first portion of an assembly; positioning the prefilled container within a second portion of the assembly; and engaging the first portion and second portion of the assembly thereby hermetically sealing the prefilled container inside the assembly.