USOO7404278B2
`
`(12) United States Patent
`US 7,404,278 B2
`(10) Patent No.:
`
`Wittland et al.
`(45) Date of Patent:
`Jul. 29, 2008
`
`(54) METHOD FOR PRODUCING PREFILLABLE
`SYRINGES
`
`(75)
`
`Inventors: Frank Wittland, Enger (DE); Erik
`Brandhorst, Hiddenhausen (DE)
`
`(73) Assignee: Gerresheimer Buende GmbH, Buende
`(DE)
`
`................ 141/11
`1/1988 Jurgens et 31,
`4,718,463 A *
`5,372,252 A * 12/1994 Alexander
`................... 422/25
`5,597,530 A *
`l/l997 Smith etal. ................... 422/28
`
`4/1997 Heffeman 6t 31.
`5,620,425 A
`5,687,542 A * 11/1997 Laweckiet a1,
`............... 53/167
`6,164,044 A * 12/2000 Porfano et 31, .......... 53/471
`
`2/2001 Odell et a1. ............. 53/425
`
`................ 53/471
`6/2001 Porfano et 31,
`7/2001 Odell et al.
`
`6,189,292 B1 *
`6,250,052 B1 *
`6,263,641 B1
`
`(1:) Notice:
`
`Subject to any disclaimer, the term Ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`6,447,610 B1:
`6,792,743 B2
`2006/0144705 A1 *
`
`9/2002 Vetter ......................... 118/215
`
`9/2004 Odell et a1.
`.
`..... 53/426
`7/2006 Hansteln ..................... 204/415
`
`(21) Appl.No.: 11/706,787
`
`(22)
`
`Filed:
`
`Feb. 14, 2007
`
`(65)
`
`(30)
`
`Prior Publication Data
`
`Aug. 16, 2007
`US 2007/0186510A1
`Foreign Application Priority Data
`
`(EP)
`
`.................................. 06002901
`
`Feb. 14, 2006
`(51)
`Int Cl
`(2006 01)
`B651} £504
`' 53/167' 53/127' 53/471
`U S Cl
`F'- Id fCl""":limt:"""S'""" h
`’
`353/167
`j
`1e
`0
`ass1 ca lon earc
`""""""""""'
`53/42554265467547154714755478! 422/283
`1,
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`e or comp e e searc
`1s ory.
`References Cited
`U.S. PATENT DOCUMENTS
`
`52
`(58)
`(
`)
`
`(56)
`
`8
`
`* cited by examiner
`
`Primary ExamineriLouis K Huynh
`(74) Attorney, Agent, or FirmiLaurence A. Greenberg;
`Werner H. Stemer; Ralph E. Locher
`
`(57)
`
`ABSTRACT
`
`A method for producing prefillable syringes includes the
`steps of producing syringe bodies with a cylindrical drum
`portion which has a first open end for receiving a syringe
`plunger and has a second open end for discharging of con-
`tents. An inner surface of each syringe body is then cleaned.
`Siliconization is then performed by applying a quantity of
`silicone oil or silicone emulsion to at least a partial area ofthe
`inner surface of each syringe body. Some of the applied
`quantity of silicone is then removed. Finally, the syringe
`bodies are packaged. The siliconization, removing and pack-
`aging steps are all carried out under controlled clean-room
`condrtlons.
`
`4,628,969 A
`
`12/1986 Juergens, Jr. et 21,
`
`19 Claims, 1 Drawing Sheet
`
`.
`
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`
`Regeneron Exhibit 1026.001
`
`

`

`US. Patent
`
`Jul. 29, 2008
`
`US 7,404,278 B2
`
`3
`
`Syringe lorrmng
`
`Uncontrolled area
`
`
`a1
`
`b1
`
`b
`
`Packaging
`
`Clean-roan class BO 3 under operating conditions according to
`EN ISO 14644-1 alternatively also an uncontrolled area
`
`Unpacking
`
`C——leaningthe 'nner
`
`surface with lil ered air
`
`CIean-room class lSO 8 under taminar flow operating conditions
`according to EN ISO 14644-1 (class C)
`
`
`
`
`
`
`
`
`
`C “4 Siliconization
`
`1‘—
`
`
`
`C1
`
`ii
`
`02 ~|
`
`Visual inspection
`
`as
`
`Encapsulated oven linked to clean-room of lSO class a
`
`’—,
`
`
`
`
`
`Clean-room class lSO 8 under laminar flow operating conditions
`according to EN lSO 14644-1 (class C)
`
`i
`
`
`c4-
`
`Washing the syringe
`- WFI 85°C
`- Sterile air
`
`L-..
`
`.
`,
`Fm'ggglz. nszdle
`9
`p
`p
`
`Placing syringe body
`in tra and tub
`
`Sealing tray
`and tub
`
`d
`
`{31
`
`
`
`,
`
`Controlied area
`Clean-room class ISO 8 under
`laminar flow operating conditions
`according to EN ISO 14644-1 (class B)
`
`
`
`i
`
`
`
`
`
`
`
`Regeneron Exhibit 1026.002
`
`

`

`US 7,404,278 B2
`
`1
`METHOD FOR PRODUCING PREFILLABLE
`SYRINGES
`
`CROSS-REFERENCE TO RELATED
`APPLICATION
`
`This application claims the priority, under 35 U.S .C. § 1 19,
`ofEuropean application EP 06 002 901.4,filedFeb. 14, 2006;
`the prior application is herewith incorporated by reference in
`its entirety.
`
`BACKGROUND OF THE INVENTION
`
`Field of the Invention
`
`The invention relates to a method for producing prefillable
`syringes. Syringe bodies are produced with a cylindrical
`drum portion which has a first open end for receiving a
`syringe plunger and has a second open end for discharging of
`contents. The inner surface of each syringe body is then
`cleaned and siliconization is achieved by applying a quantity
`of silicone oil or silicone emulsion to at least a partial area of
`the inner surface of each syringe body.
`A method ofthis kind is known from U.S. Pat. No. 6,263,
`641 B1, for example, in which provision is also made that the
`syringe bodies are disposed in an array after siliconization
`and are packaged in a container. These can be syringe bodies
`made of plastic or glass.
`When syringe bodies produced in this way are filled with a
`desired injectable medicament, some of the silicone oil,
`which in itself is medically safe and neutral, may interact
`adversely with the medicament and cause a deterioration in
`the effect ofthe latter. Ifthe applied silicone oil or the silicone
`emulsion has been fired in during the production of the
`syringes, i.e. has been subjected to a temperature treatment of
`approximately 120° C. to 300° C. and more, some of the
`silicone is bonded covalently or by secondary valency to the
`glass surface ofthe syringe. However, an undesired crossover
`of the silicone into the medicament may occur as a result, for
`example, ofthe silicone oil being applied in excess quantities
`in some areas.
`
`SUMMARY OF THE INVENTION
`
`It is accordingly an object of the invention to provide a
`method for producing prefillable syringe that overcomes the
`above-mentioned disadvantages of the prior art methods of
`this general type, which, as far as possible the situation is
`avoided where the effect of a medicament introduced into the
`
`prefillable syringe is impaired due to interaction with insuf-
`ficiently bonded silicone oil.
`With the foregoing and other objects in view there is pro-
`vided, in accordance with the invention, a method for produc-
`ing prefillable syringes. The method includes the steps of:
`a) producing syringe bodies having a cylindrical drum portion
`with a first open end formed therein for receiving a syringe
`plunger and a second open end formed therein for discharg-
`ing of contents;
`b) cleaning an inner surface of each of the syringe bodies;
`c) performing a siliconization step by applying a quantity of
`silicone, selected from the group consisting of silicone oil
`and silicone emulsion, to at least a partial area of the inner
`surface of each of the syringe bodies;
`cl) fixing the silicone applied on the syringe bodies by heat
`treatment at temperatures between 120° and 350° C.;
`d) removing at least part ofthe silicone not covalently bonded
`or bonded by secondary valency; and
`
`2
`
`e) packaging the syringe bodies, and carrying out the steps c)
`through e) under controlled clean-room conditions.
`According to the invention, the object is achieved, in a
`method of the type in question, by the steps of d) removing
`some ofthe applied quantity of silicone, and e) packaging the
`syringe bodies, with steps c) through e) being carried out
`under controlled clean-room conditions, in particular of ISO
`class 8, and under laminar flow operating conditions accord-
`ing to EN ISO 14644-1 (e.g. class B) or better. In the context
`of the invention, “controlled clean-room conditions” are
`understood as the continuous monitoring of air quality for
`maintaining fixed minimum standards, such as particle count
`or colony-forming units per cubic meter.
`The invention preferably entails that, between steps c) and
`d), the applied silicone oil is fixed (“fired in”) by heat treat-
`ment at temperatures of between 120° C. and 350° C. Provi-
`sion can further be made that silicone that is not bonded or is
`
`not covalently bonded or bonded by secondary valency is
`completely or partially removed, for example 10% through
`90% of the originally applied quantity, or 10% through 100%
`ofthe proportion ofthe original quantity that is not covalently
`bonded or bonded by secondary valency.
`in step d), a
`In particular, provision can be made that,
`flushing operation is carried out with water or a solvent, for
`example alcohol. This can be done at a temperature in the
`range of20° C. through 100° C., in particular 75 ° C. through
`95° C., and preferably at 85° C. It is advantageous if the
`flushing operation is followed by drying with sterilized air.
`Provision can further be made that, before step e), a needle
`guard or closure piece (a tip cap) is fitted.
`In step e), a number of syringe bodies can be placed in a
`tray, the tray is inserted into a container, the latter closed with
`a cover and sealed, and the container packaged. Provision can
`be made for the packaged receptacle to be sterilized.
`In one variant, provision can be made that the syringe
`bodies produced in step a) are packaged and, before step b),
`are unpacked under controlled clean-room conditions. In this
`connection, it is expedient that the syringe bodies are pack-
`aged and unpacked under clean-room conditions ofISO class
`8 and under laminar flow operating conditions according to
`EN ISO 14644-1 or better.
`
`10
`
`15
`
`20
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`25
`
`30
`
`35
`
`4o
`
`The invention further provides that step e) is carried out
`under controlled clean-room conditions of ISO class 8 and
`
`45
`
`under laminar flow operating conditions according to EN ISO
`14644-1 or better.
`
`50
`
`55
`
`60
`
`65
`
`Ifthe siliconization is fired in, provision can be made for an
`encapsulated oven to be used which is linked to a clean-room
`area, e.g. of ISO class 8 or better.
`In a further variant of the invention, provision can be made
`that syringe bodies produced in step c) are packaged and,
`before step d), are unpacked. Here too, it is possible for the
`syringe bodies to be packaged and unpacked under controlled
`clean-room conditions, in particular ofISO class 8 and under
`laminar flow operating conditions according to EN ISO
`14644-1 or better.
`
`In a preferred embodiment of the invention, provision is
`made that steps b) through e) are carried out under controlled
`clean-room conditions, in particular ofISO class 8, and under
`laminar flow operating conditions according to EN ISO
`14644-1 or better.
`Other features which are considered as characteristic for
`
`the invention are set forth in the appended claims.
`Although the invention is illustrated and described herein
`as embodied in a method for producing prefillable syringes, it
`is nevertheless not intended to be limited to the details shown,
`since various modifications and structural changes may be
`
`Regeneron Exhibit 1026.003
`
`

`

`US 7,404,278 B2
`
`3
`made therein without departing from the spirit of the inven-
`tion and within the scope and range of equivalents of the
`claims.
`
`The construction and method of operation ofthe invention,
`however, together with additional objects and advantages
`thereof will be best understood from the following descrip-
`tion of specific embodiments when read in connection with
`the accompanying drawings.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`The single FIGURE of the drawing is a flow chart showing
`an example of a sequence of a method for producing prefill-
`able syringes according to the invention.
`
`DESCRIPTION OF THE PREFERRED
`EMBODIMENTS
`
`Referring now to the single FIGURE of the drawing in
`detail, a method sequence is shown which illustrates the pro-
`duction of prefillable syringes right through to their being
`packaged in a form of an array of syringes in a closed and
`sterilized container (tub).
`Step a concems the production of a syringe body as such
`directly from forming of plastic or glass by a suitable device
`which is known per se and is not described in detail. In step a,
`syringe bodies are produced with a cylindrical drum portion
`which has a first open end for receiving a syringe plunger and
`has an opposite, second open end of smaller cross section for
`a discharging of contents. An injection needle is secured on
`the second open end at a suitable stage of the method
`described here, or not until immediately before the use of the
`fillable or already filled syringe. For this purpose, various
`techniques are employed which are known per se and are not
`described in detail here, for example gluing, mounting or
`locking.
`In step al, the syringe bodies that have been produced in
`this way are packaged. The packaging operation can be car-
`ried out under controlled clean-room conditions, in this case
`of ISO class 8, and under operating conditions according to
`EN ISO 14644-1. Alternatively, the syringe bodies are pro-
`duced and also packaged in a production area in which the
`degree of cleanliness is not controlled.
`In step bl, the syringe bodies that have been packaged as
`described above are unpacked under controlled clean-room
`conditions, in this case ofISO class 8, and under laminar flow
`operating conditions according to EN ISO 14644-1 (e.g. class
`C).
`In a fiirther step b, the inner surface of the syringe body is
`cleaned, for example with cleaned or sterile air, or with ion-
`ized air, likewise under controlled conditions as in step bl.
`In step c, the inner surfaceofthe syringe body is siliconized
`under controlled conditions as in steps bl and b, with silicone
`oil or a silicone emulsion being suitably applied to the inner
`surface, for example sprayed onto it. In this connection, a
`predetermined quantity of silicone can be applied. Provision
`can additionally be made for excess silicone to be immedi-
`ately removed, for example by wiping or flushing it off.
`In step cl, provision is preferably made for the applied
`silicone oil to be fixed in a suitable manner, in this example by
`a temperature treatment at least approximately 120° C. (auto-
`claving) up to 350° C. (firing in) for a prescribed duration of
`treatment. For the temperature treatment, an encapsulated
`oven is used which is linked to a clean-room area, in particular
`to an area with ISO cleanliness class 8.
`
`Step c2 involves a visual inspection of the syringe bodies
`under clean-room operating conditions, in particular as in
`
`10
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`15
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`20
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`25
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`30
`
`35
`
`40
`
`45
`
`50
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`55
`
`60
`
`65
`
`4
`
`steps bl through c, and step c3 involves packaging the syringe
`bodies under corresponding conditions.
`Step c4 involves unpacking the syringe bodies packaged in
`step c3, and these syringe bodies, in step d, are then, flushed
`through in the prescribed manner with WFI (water for injec-
`tion, flushing water with a prescribed purity specification),
`for example at a temperature of 85° C. They are then dried
`with sterile air.
`
`In step e1, the syringe bodies are provided with further
`parts, depending on the type of syringes to be manufactured,
`for example with a needle guard, a closure piece (tip cap)
`and/or other parts.
`Step e2 involves arranging a group of syringe bodies in a
`tray which is placed in a container (tub) which is in turn then
`closed once a cover has been applied (step e3).
`In step f, the syringe bodies located in the packaging, and
`the packaging itself, are sterilized, in particular with gas, for
`example ethylene oxide (ETO). This step can be carried out
`remote from and independently of the preceding steps.
`In the example shown, all of method steps c4 through e3
`take place under controlled clean-room conditions, in this
`case under conditions of ISO class 8 and under laminar flow
`
`operating conditions according to EN ISO 14644-1 (e.g. class
`B), or better.
`As is indicated in the figure by the bolded horizontal divid-
`ing lines, the otherwise continuous method sequence can be
`interrupted between steps a1 and bl and/or between steps c3
`and c4 and/or between steps e3 and f, by the packaged syringe
`bodies being intermediately stored, for example, and then
`being delivered as and when required to the respective
`unpacking step bl or c4 or sterilization step f. Alternatively,
`the packing and unpacking steps can be omitted and the
`production method can be carried out completely continu-
`ously, and at all times under clean-room conditions.
`
`We claim:
`
`1 . A method for producing prefillable syringes, which com-
`prises the steps of:
`a) producing syringe bodies having a cylindrical drum
`portion with a first open end formed therein for receiving
`a syringe plunger and a second open end formed therein
`for discharging of contents;
`b) cleaning an inner surface of each of the syringe bodies;
`c) performing a siliconization step by applying a quantity
`of silicone, selected from the group consisting of sili-
`cone oil and silicone emulsion, to at least a partial area of
`the inner surface of each of the syringe bodies;
`c 1) fixing the silicone applied on the syringe bodies by heat
`treatment at temperatures between 120° and 350° C.;
`d) removing at least part of the silicone not covalently
`bonded or bonded by secondary valency; and
`e) packaging the syringe bodies, and carrying out the steps
`c) through e) under controlled clean-room conditions.
`2. The method according to claim 1, which fiirther com-
`prises carrying out the steps c) through e) continuously under
`clean-room conditions ofISO class 8 and under laminar flow
`
`operating conditions according to EN ISO 14644-1 or better.
`3. The method according to claim 1, which fiirther com-
`prises during the step d), carrying out a flushing operation
`with one of water and a solvent.
`
`4. The method according to claim 3, which fiirther com-
`prises carrying out the flushing operation at a temperature in
`a range of20° C. to 120° C.
`5. The method according to claim 3, which fiirther com-
`prises following the flushing operation, performing a drying
`step with sterile air.
`
`Regeneron Exhibit 1026.004
`
`

`

`US 7,404,278 B2
`
`5
`6. The method according to claim 3, which further com-
`prises carrying out the flushing operation at a temperature in
`arange of75O C. to 95° C.
`7. The method according to claim 1, which further com-
`prises before perfonning the step e), fitting one of a needle
`guard and a closure piece to each of the syringe bodies.
`8. The method according to claim 1, which further com-
`prises during the step e):
`placing a number of the syringe bodies in a tray;
`inserting the tray into a container;
`closing the container with a cover for sealing the container;
`and
`
`packaging the container.
`9. The method according to claim 1, which further com-
`prises packaging the syringe bodies produced in the step a)
`and, before performing the step b), unpacking the syringe
`bodies under the controlled clean-room conditions.
`
`6
`13. The method according to claim 1, which further com-
`prises:
`packaging the syringe bodies produced in the step c); and
`unpacking the syringe bodies before performing the step
`d).
`14 . The method according to claim 13, which further com-
`prises perfonning the packaging step and the unpacking step
`under the controlled clean-room conditions.
`
`10
`
`15. The method according to claim 14, which further com-
`prises perfonning the packaging step and the unpacking step
`under the controlled clean-room conditions of180 class 8 and
`
`under laminar flow operating conditions according to EN ISO
`14644-1 or better.
`
`15
`
`16. The method according to claim 1, which further com-
`prises carrying out the steps b) through e) under the controlled
`clean-room conditions.
`
`10. The method according to claim 9, which further com-
`prises perfonning the packaging and the unpacking steps of
`the syringe bodies under clean-room conditions of 180 class 20
`8 and under laminar flow operating conditions according to
`EN ISO 14644-1 or better.
`
`11. The method according to claim 1, which further com-
`prises carrying out the step e) under clean-room conditions of
`180 class 8 and under laminar flow operating conditions 25
`according to EN ISO 14644-1 or better.
`12. The method according to claim 1, which further com-
`prises using an encapsulated oven linked to a clean-room area
`of180 class 8 or better for performing the heat treatment step.
`
`17. The method according to claim 16, which further com-
`prises carrying out the steps b) through e) under the clean-
`room conditions of 180 class 8 and under laminar flow oper-
`ating conditions according to EN ISO 14644-1 or better.
`18. The method according to claim 1, which further com-
`prises during the step d), carrying out a flushing operation
`with one of water and alcohol.
`
`19. The method according to claim 1, which further com-
`prises before perfonning the step e), fitting one of a needle
`guard and a tip cap to each of the syringe bodies.
`
`*
`
`*
`
`*
`
`*
`
`*
`
`Regeneron Exhibit 1026.005
`
`