WO2008039494A1 - Dispositif et procédés d'inactivation du virus de la grippe et agents adventifs avec lumière ultraviolette - Google Patents

Dispositif et procédés d'inactivation du virus de la grippe et agents adventifs avec lumière ultraviolette Download PDF

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Publication number
WO2008039494A1
WO2008039494A1 PCT/US2007/020776 US2007020776W WO2008039494A1 WO 2008039494 A1 WO2008039494 A1 WO 2008039494A1 US 2007020776 W US2007020776 W US 2007020776W WO 2008039494 A1 WO2008039494 A1 WO 2008039494A1
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WO
WIPO (PCT)
Prior art keywords
fluid
source
elongated tube
tube
radiation
Prior art date
Application number
PCT/US2007/020776
Other languages
English (en)
Inventor
Frederic Dutil
George Oliveira
Nadine Pelletier
Micheline Poulin
Alexander George Tschumakow
Original Assignee
Id Biomedical Corporation Of Quebec
Le Group Enico, Inc.
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 Id Biomedical Corporation Of Quebec, Le Group Enico, Inc. filed Critical Id Biomedical Corporation Of Quebec
Priority to CA002666980A priority Critical patent/CA2666980A1/fr
Priority to EP07838884A priority patent/EP2066358A1/fr
Publication of WO2008039494A1 publication Critical patent/WO2008039494A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
    • A61L2/0011—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using physical methods

Definitions

  • the present invention relates generally to a device and methods of inactivating infectious virus, for reducing microbial bioburden, and inactivating potential adventitious agents with ultraviolet (UV) light.
  • UV ultraviolet
  • Vaccines are designed to stimulate the immune system through the use of inactivated or weakened viruses and bacteria, so that live viruses and other foreign microbial organisms can be recognized quickly allowing the body to mount an immune response before infection can set in.
  • Certain vaccines are produced from naturally or engineered live-attenuated, or non-pathogenic, strains of pathogen. In other cases, a virulent, infectious strain of pathogen is killed or inactivated to produce a vaccine.
  • Viruses and other pathogenic microorganisms have been inactivated using a variety of methods, including heat, treatment with chemicals, such as formalin or propiolactone, gamma irradiation and ultraviolet irradiation, or combinations of such methods.
  • UV irradiation has become accepted, typically in combination with chemical (e.g., formalin) treatment, in the production of viral vaccines because it is effective for inactivating a wide variety of viral, as well as bacterial, pathogens.
  • chemical e.g., formalin
  • UV light primarily targets nucleic acids, leaving the antigenic proteins relatively untouched.
  • the excitation energy of the UV wavelength radiation disrupts the covalent bonds of the purine and pyrimidin bases, resulting in damage to target virus as well as adventitious agents and bacterial bioburden.
  • UV inactivation Although the process of UV inactivation has proven safe and effective in the manufacture of vaccines, such as influenza vaccine, the devices currently available for inactivation are subject to numerous operating limitations that have limited their application in the industrial scale manufacture of vaccines.
  • the present disclosure provides an improved UV irradiation device suitable for the manufacture of vaccines in a high-throughput industrial setting. These improvements render UV inactivation feasible in the context of an integrated industrial manufacturing process, suitable for the production of vaccines from highly infectious viruses, including pandemic and avian strains of influenza.
  • This disclosure concerns the industrial production of safe and effective viral vaccines, and provides a device for ultraviolet inactivation of live infectious viruses in biological fluids. This disclosure also provides operating parameters and methods for safely and effectively inactivating virus in a fluid, e.g., for the manufacture of vaccines.
  • FIG. 1 is a perspective view of an irradiator assembly according to an exemplary embodiment
  • FIG. 2 is a side elevational view of the irradiator assembly shown in FIG. 1;
  • FIG. 3 is a side view, partially in section, of an irradiator unit mounted on the irradiator assembly of FIGS. 1 and 2;
  • FIG. 4 is a perspective view of an embodiment of an injector box mounted on an injection end of the irradiator unit shown in FIG. 3;
  • FIG. 5 is a side elevational view of the injector box shown in FIG. 4;
  • FIG. 6 is a sectional view of the injector box taken along lines 6—6 of FIG. 5;
  • FIG. 7 is a sectional view of the injector box taken along lines 7—7 of FIG. 5;
  • FIG. 8 is a perspective view of an exemplary embodiment of an injection needle that is inserted into the injection box of FIG. 4-7;
  • FIG. 9 is a bottom view of the injection needle shown in FIG. 8;
  • FIG. 10 is a side elevational view of the injection needle of FIG. 8;
  • FIG. 11 is a photograph of the injection box of FIGS. 4-7, with the injection needle of FIGS. 8-10 and sensors inserted therein;
  • FIG. 12 is a photograph of the injection box of FIGS. 4-7, showing fluid being injected from the injection needle of FIGS. 8-10 into the injection box and irradiator unit;
  • FIG. 13 is an exploded perspective view of an exemplary embodiment of an ultraviolet radiation source of the irradiator assembly of FIG. 1;
  • FIG. 14 is a side elevational view of the ultraviolet radiation source shown in FIG. 13;
  • FIG. 15 is an enlarged view of the discharge and of the irradiator unit;
  • FIG. 16 is a perspective view of an end cap of a collector hub assembly shown in FIG. 15;
  • FIG. 17 is a side elevational view of the end cap shown in FIG. 16;
  • FIG. 18 is a front elevational view of the end cap shown in FIG. 16;
  • FIG. 19 is an exploded perspective view of an exemplary embodiment of a bearing assembly used in the irradiator assembly of FIGS. 1 and 2;
  • FIG.. 20 shows the UV inactivation results from at varying UV intensities for each of three flu strains; and FIG. 21 shows the UV inactivation via a dose response curve for the 6 adventitious agents.
  • UV light acts on the DNA of viruses, such as influenza virus, and other microorganisms, rendering them incapable of replication, thereby making the viruses non-infectious.
  • a biological fluid containing live virus is subjected to UV irradiation to inactivate the virus and make it safe for administration as a vaccine.
  • the present invention provides a device for irradiating a fluid.
  • the device comprises an elongated tube having a fluid injection port and a fluid discharge port, wherein the elongated tube is rotatable about a longitudinal axis.
  • the longitudinal axis extends at an angle oblique to the horizontal.
  • a source of radiation extends within the elongated tube along the longitudinal axis.
  • the source of radiation can be one, or more than one, ultraviolet light sources (e.g., lamps).
  • a sleeve extends within the elongated tube and surrounds a length of the source of radiation, thereby defining an airflow path between the source of radiation and the sleeve.
  • An air flow source is in fluid communication with the airflow path proximate to the fluid injection port.
  • An air flow discharge is in fluid communication with the airflow path proximate to the fluid discharge port.
  • the fluid injection port and the fluid discharge port are in communication with the space between the tube and the sleeve.
  • the present invention provides an injection box mounted at the fluid injection end of the elongated tube. At least one sensor is disposed within the injection box upstream of the fluid injection end of the elongated tube and is targeted to obtain data from the elongated source of radiation.
  • a fluid injection needle is coupled to the injection box and positioned to inject fluid downstream of the sensor and the elongated tube so as to avoid sensing fluid flowing through the elongated tube. The discharge end of the fluid injection needle extends into the space between the sleeve and the elongated tube.
  • the present disclosure provides a single bearing assembly, comprised of at least two axially spaced apart bearing members surrounding and supporting the elongated tube between the fluid injection port and the fluid discharge port and permitting the rotational movement thereof.
  • the present invention also provides a method for inactivating a virus comprising the steps of introducing a fluid comprising introducing a live virus into an apparatus as previously described, dispersing the fluid along an interior length of the elongated tube; irradiating the fluid with a radiation source disposed within the tube, thereby transforming the live virus to an inactivated virus while protecting the radiation source from direct contact with the live virus by providing a sleeve between the radiation source and the live virus along the length of the elongated tube.
  • a desired temperature range of the radiation source is maintained by providing a flow of air along a length of the radiation source between the radiation source and the sleeve.
  • the disclosed method is suitable for inactivating influenza viruses and potential adventitious agents present in allantoic fluid or other culture media used to grow and culture the influenza virus.
  • the processes described herein yield inactivated influenza virus particles that can then be further treated (e.g., with a chemical agent such as formalin), purified and/or split for ultimate formulation into a vaccine that can be administered to patients.
  • the method for inactivating a virus involves introducing a fluid comprising introducing a live virus to an elongated tube that is inclined relative to the horizontal; rotating the elongated tube along its longitudinal axis to disperse the fluid and cause it to flow along the interior length of the elongated tube; and irradiating the fluid with a radiation source disposed within the tube (and extending along its longitudinal axis) to inactivate the virus.
  • the radiation source typically emits ultraviolet (UV) light at a wavelength of about 254 nanometers.
  • Exposure of the fluid to the radiation source as it flows through the elongated tube transforms the live virus to an inactivated virus, which can be recovered by causing the fluid containing the inactivated virus to exit the elongated tube.
  • the radiation source is protected from direct contact with the live virus by providing a protective sleeve (such as a quartz sleeve) between the radiation source and the live virus along the length of the elongated tube.
  • a protective sleeve such as a quartz sleeve
  • a desired temperature range of the radiation source is maintained within the protective sleeve by providing a flow of air along a length of the radiation source between the radiation source and the sleeve.
  • the fluid is introduced and flowed through the device where it is exposed to UV light emitted by the radiation source.
  • the rate of introduction and flow is set to insure that the fluid remains exposed to the UV light for a period sufficient to fully eliminate bioburden and inactivate virus.
  • the fluid is typically introduced at a rate of at least 600 ml/min (0.6 L/min).
  • the fluid can be introduced at rates up to approximately 3500 ml/min without compromising inactivation.
  • the fluid can be introduced and flowed through the device at rates of up to approximately 1700, or 1900 or 2200 or 2800 or 3500 ml/min, or at any convenient rate within this range.
  • the fluid is introduced along an interior wall of the elongated tube at a flow rate of at least about 600 ml/min and no greater than about 900 ml/min. More typically, the fluid is introduced at a flow rate of at least about 650ml/min, such as at least about 675ml/min. Usually the fluid is flowed into the elongated tube at a flow rate of at least about 680ml/min. Typically, the flow rate does not exceed about 850ml/min, more commonly, the flow rate is set below about 840ml/min, such as less than about 830ml/min.
  • the method involves introducing the fluid containing live virus at a flow rate of about 755ml/min.
  • the fluid is flowed through the elongated tube (e.g., at the rates indicated above).
  • the elongated tube is typically in the shape of a cylinder.
  • the fluid can be caused to flow through the elongated tube by way of gravity by inclining the elongated tube relative to the horizontal with the inflow placed at a higher elevation than the outflow.
  • the elongated tube is inclined at an angle of at least 20 degrees relative to the horizontal.
  • the elongated tube can be inclined at an angle of between about 20 degrees and about 40 degrees relative to the horizontal.
  • the elongated tube is inclined about 30 degrees relative to the horizontal.
  • the radiation source includes one or more (e.g., a plurality of) UV lamps.
  • the radiation source irradiates the fluid with UV light the fluid at an intensity of at least about 10 mWatts/cm 2 .
  • the intensity of UV light is maintained between 10 and 14 mWatts/cm 2 , such as at a UV light intensity of about 12 mWatts/cm 2 .
  • the disclosed method is suitable for inactivating a wide range of viruses, including both non-enveloped and enveloped viruses (such as orthomyxoviridae, e.g., influenza virus), including highly pathogenic viruses.
  • the method involves inactivating a live influenza virus, such as a pandemic or avian strain of influenza.
  • the method is capable of inactivating virus in the various fluids in which virus is grown, such as allantoic fluid (for example, from embryonic chicken or other poultry eggs), and from tissue or cell culture media.
  • allantoic fluid for example, from embryonic chicken or other poultry eggs
  • the methods disclosed herein inactivate adventitious viruses and bacteria ("bioburden") present in the fluid.
  • bioburden adventitious viruses and bacteria
  • assembly 100 may be used to inactivate virus in allantoic fluid, in accordance with another embodiment of this invention. More specifically, assembly 100 may be used to irradiate a virus contained in a fluid flowing through assembly 100 such that the virus is inactivated by the UV light as the virus flows through assembly 100.
  • the fluid is injected into assembly 100 from a virus supply (not shown), processed through assembly 100, and then discharged from assembly 100 for additional processing, such as for formalin processing.
  • irradiator assembly 100 includes a pair of irradiator units 102 mounted on a support frame 104.
  • Each of irradiator units 102 may be a mirror image of the other irradiator unit 102. All of the elements in one irradiator unit 102 are also present in the other irradiator unit 102 and consequently, only one irradiator unit 102 will be discussed herein.
  • Irradiator unit 102 is mounted on a support frame 104.
  • Irradiator unit 102 includes a cylindrically shaped elongated vessel or tube 106 having a fluid injection end or port 106a, a fluid discharge end or port 106b, and a longitudinal axis 107 extending therethrough from the fluid injection end 106a to the fluid discharge end 106b.
  • tube 106 is constructed from stainless steel in order to minimize and chemical reaction between tube 106 and the fluid being transmitted through tube 106.
  • tube 106 has an inner diameter of about 2-3/4 inches (7 cm) and a length of about 28 inches (about 71 cm).
  • An injection box assembly 108 is mounted at fluid injection end 106a of tube 106 and a collector hub assembly 110 is located at fluid discharge end 106b.
  • Support frame 104 is mounted on a plurality of castor wheels 112, which allow irradiator assembly 100 to be maneuvered from one location to another, such as by pulling or pushing on a handle 114 extending from support frame 104.
  • irradiator units 102 are each mounted on support frame 104 at an oblique angle relative to the horizontal.
  • irradiator units 102 are angled relative to the horizontal at an angle sufficient to impart gravity flow of a fluid along the length of tube 106 from fluid injection end 106a to fluid discharge end 106b.
  • the oblique angle is between about 25 degrees and about 35 degrees. In another exemplary embodiment, the oblique angle is about 30 degrees. Referring now to FIG. 3, a partial sectional view of irradiator unit 102 is shown. A
  • UV light source 116 is disposed within tube 106 and extends along a length of tube 106 between fluid injection end 106a and fluid discharge end 106b, along longitudinal axis
  • Tube 106 rotates about its longitudinal axis 107 to spread the fluid containing the virus into a thin film along the rotationally moving surface thereof as the fluid flows down from injection box assembly 108 to collection hub assembly 110. In an exemplary embodiment, tube 106 rotates at a speed of about 300 revolutions per minute.
  • the thin film provides a sufficiently thin profile to allow UV light source 116 to penetrate the fluid, and thus to expose as much of the virus as possible for inactivation by UV light source 116. UV light source 116 also extends at least partially into injection box assembly
  • UV light source 116 is used to inactivate the virus as the virus flows through tube 106. UV light source 116 emits a light having a wavelength of about 254 nanometers, which is the wavelength absorbed by nucleic acids. A photochemical process within the virus is generated, causing a rearrangement of the genetic information of the virus, thereby interfering with the cell's ability to reproduce. A virus that cannot reproduce is considered inactive because it is not able to multiply to infectious numbers within a host.
  • an injection box 118 which is part of injection box assembly 108, is shown, with the downstream end thereof to the left in FIG. 4 and to the right in FIGS. 5 and 6.
  • a reducer 118a extends from the downstream end of injection box 118 and is coupled over fluid injection end 106a of tube 106.
  • Injection box 118 is generally tubular in shape, with a generally circular cross section, and has a plurality of openings in the side wall to accommodate various features.
  • a pair of sensor openings are diametrically opposed from each other and accommodate UV sensors (not shown in FIGS. 4-7) that measure the intensity of UV light source 116.
  • Sensor openings are defined by bosses 120 that extend from an exterior of injection box 118 with a slight penetration into the interior of injection box 118. The UV sensors are inserted into each respective boss 120.
  • a cap (not shown) is threaded over each sensor and onto boss 120 to secure the sensor within boss 120.
  • Injection box 118 further includes a needle opening that is sized to allow insertion of an injection needle 126 (partially shown in phantom in FIGS. 5-6) into injection box 118.
  • the needle opening is defined by a needle boss 122 that extends outwardly from the cylindrical outer surface of injection box 118. Needle boss 122 is spaced from bosses 120 downstream from bosses 120 such that fluid flow that is discharged from injection needle 126 does not contact the sensors, which would reduce reading obtained from the sensors. As shown in FIG.
  • needle boss 122 is located below the centerline of injection box 118 and is pointed slightly downwardly so as to introduce fluid more or less tangentially to the lower surface of injection box 118. More specifically, needle boss 122 is disposed at a declination angle between about 3 degrees and about 7 degrees with respect to the horizontal of a central plane of tube 106 and injection box 118. In an exemplary embodiment, the declination angle is about 5 degrees. Such declination angle allows the fluid to be injected along an inside surface of tube 106 and minimizes splashing of the fluid. Injection box 118 also includes a view port 124 that enables a person, such as an a operator, to peer into view port 124 to observe fluid flow from injection needle 126.
  • a spill port boss 125 extends outwardly from the bottom of injector box 118 proximate to reducer 118a.
  • Spill pott boss 125 may be used to evacuate liquid from injection port 118 in the event of a spill.
  • spill port boss 125 may be used to insert a monitoring device, such as a temperature probe or spectrometer (not shown) into injection box 118.
  • Needle 126 is constructed from a stainless steel tube having a supply end 128 and a discharge end 130. Needle 126 extends into and through injection box 118 such that discharge end 130 of needle 126 extends into tube 106 (shown in phantom in FIGS. 5 and 6 for injection of fluid into elongated tube 106.
  • the supply end 128 is generally circular in cross section and includes a clamp 132 that is used to secure a fluid supply (not shown) containing active virus to needle 126.
  • the body of needle 126 is curved proximate to clamp 132 in order to facilitate the coupling of the fluid supply to supply end 128 of needle 126.
  • Body 126 is curved proximate to discharge end 130 in order to angle discharge end 130 against the inner wall of tube 106.
  • Such angling of discharge end 130 of needle 126 at about a 60 degree angle relative to longitudinal axis 107 in an exemplary embodiment, assists in maintaining the flow of fluid against the inner surface of tube 106, reducing the likelihood of splashing the fluid.
  • discharge end 130 includes a generally oblong opening 134 to spread out the fluid and to facilitate discharge of the fluid along the inner surface of tube 106.
  • Discharge end 130 of fluid injection needle 126 extends along a discharge axis 131, and generally oblong discharge opening 134 extends at an angle " ⁇ " oblique to the discharge axis (131). Such angle also assists in reducing the likelihood of splashing the fluid as the fluid is discharged from needle 126. In an exemplary embodiment, angle " ⁇ " may be between about 20 degrees and about 60 degrees.
  • a tightening cylinder 136 is slidably disposed about the body of needle 126 between supply end 128 and discharge end 130.
  • needle 126 is inserted into needle boss 122 a desired distance and tightening cylinder 136 is slid along body of needle 126 until tightening cylinder 136 engages needle boss 122. Screws (not shown) in tightening cylinder 136 engage threaded openings 122a in needle boss 122 (shown in FIG. 7). As screws are tightened down, tightening cylinder 136 tightens around needle 126, locking needle 126 into place relative to injection box 118.
  • FIG. 11 is a photograph of an internal view of injection box 118, showing a pair of sensors 138 diametrically opposed from each other within injection box 118.
  • Sensors 138 are each removeably installed within injection box 118 upstream from fluid injection port 106a a predetermined distance from UV light source 116 (not shown in FIG. 11) and targeted to obtain data from UV light source 116.
  • Sensors 138 are electronically coupled to UV light source 116 to regulate the amount of power emitted from UV light source 116.
  • UV light source 116 emits light having an intensity of 12 mW/cm 2 ⁇ 2 mW/cm 2 as measured at sensors 138.
  • the intensity may be between about 10 mW/cm 2 and 14 mW/cm 2 . In another exemplary embodiment, the intensity may be about 12 mW/cm 2 .
  • Each sensor 138 includes a filter (not shown) that ensures sensitivity of sensors 138 at 254 nanometers.
  • needle 126 is shown extending into injection box 118.
  • Discharge end 130 of needle 126 is aimed into tube 106 such that fluid discharged from needle 126 is expressed along the inside wall of tube 106.
  • Discharge end 130 of needle 126 is coupled to injection box 118 between sensors 138 and tube 106 such that sensors 138 are not exposed to fluid and do not sense fluid flowing through tube 106. With sensors 138 not being exposed to the fluid, sensors 138 are able to provide more accurate readings of the intensity of UV light source 116.
  • FIG 12 shows fluid "F" being discharged along the inner wall of tube 106 as tube 106 rotates about its longitudinal axis.
  • FIGS. 13 and 14 show an exemplary embodiment of UV light source 116 used in assembly 100.
  • UV light source 116 includes a plurality of UV light tubes 140 bundled in a group and extending parallel to longitudinal axis 107. While FIG. 13 shows four (4) UV light tubes 140, those skilled in the art will recognize that other numbers of UV light tubes 140 may be used.
  • UV light tubes 140 may be operated by either an electromagnetic ballast or an electronic ballast (not shown).
  • a support rod 142 extends within a perimeter of UV light tube 140 and extends along a length of UV light source 116 to provide support to UV light source 116 within tube 106.
  • Each UV light tube 140 includes its own grounding wire 144, which extends along its respective UV light tube 140 parallel to support rod 142. Only one grounding wire 144 is shown in FIG. 13 for clarity. Grounding wires 144 are separate from support rod 142.
  • a quartz sleeve 146 extends within tube 106 and is disposed around and surrounds UV light tubes 140. Quartz sleeve 146 protects UV light tubes 140 by preventing any fluid travelling along the length of tube 106 from inadvertently splashing onto UV light tubes 140, which would potentially damage and/or contaminate UV light tubes 140. Sleeve 146 also defines a fluid flow path between sleeve 146 and tube 106. Fluid injection port 106a and fluid discharge port 106b are in communication with the space between tube 106 and sleeve 146. Discharge end 130 of needle 126 extends into the space between sleeve 146 and tube 106.
  • Sleeve 146 is constructed of quartz because quartz is a UV permeable barrier and allows the penetration of UV light with minimal losses.
  • Sleeve 146 is coupled to a socket holder assembly 148 to support sleeve 146 at the fluid injection end of sleeve 146.
  • a socket plug 150 extends from a rear end of socket holder assembly 148 and provides for an electrical and structural connection (not shown) to UV light bulbs 140.
  • a mounting sleeve 152 supports a wire cover 154 and a socket holder 156. Mounting sleeve 152 is mounted at a rear of a top lamp holder assembly 158, which supports quartz sleeve 146 and socket holder assembly 148.
  • Gasket 160 seals the fluid injection end of sleeve 146 with respect to top lamp holder assembly 158.
  • a flange 162 couples top lamp holder assembly 158 to the upstream end of injection box 118.
  • Top lamp holder assembly 158 also includes an air flow supply 164, which provides a cooling air flow to UV light tubes 140.
  • a downstream end of UV light source 116 includes a bottom lamp holder 166 that supports the downstream end of UV light tubes 140.
  • a helical spring 168 biases the downstream end of light tubes 140 away from bottom lamp holder 166.
  • a downstream end of support rod 142 is inserted into and supported by bottom lamp holder 166.
  • a downstream end of quartz sleeve 146 is also inserted into bottom lamp holder 166, with a gasket 170 sealing quartz sleeve 146 to bottom lamp holder 166.
  • Gaskets 160, 170 seal each end of quartz sleeve 146, preventing any fluid flowing through tube 106 from entering sleeve 146 and potentially contaminating UV light tubes 140.
  • Bottom lamp holder 166 also includes at least one opening 172 that allows for air flowing through sleeve 146 from air flow supply 164 to be discharged from sleeve 146.
  • Air flow through sleeve 146 and around UV light tubes 140 draws away heat that is generated by UV light tubes 140, maintaining UV light tubes 140 within a predetermined temperature range in order to reduce wear and extend the life of UV light tubes 140.
  • Such temperature control also serves to regulate the intensity of UV light discharged from UV light tubes 140, thus maintaining a desired UV intensity to inactivate viruses in the fluid.
  • a shield 172 encircles tube 106 at the fluid discharge end 106b of tube 106 in order to prevent an operator from inadvertently engaging tube 106 as tube 106 rotates.
  • Shield 172 may be constructed from Lexan ® or another transparent material, so that operator may be able to view discharge end of tube 106.
  • Collection hub assembly 110 includes a collection cup 174 that is releasably coupled to bottom lamp holder 166 to collect treated fluid as it is discharged from tube 106.
  • Fluid “F” is shown in FIG. 15 extending between tube 106 and quartz sleeve 146, then discharging into collection cup 174.
  • Collection cup 174 includes a generally angular chamber which collects the fluid "F.” The fluid "F” is then gravity drained from collection cup 174 away from irradiator unit 102 by a drain tube 176. Drain tube 176 may be coupled to a receiver (not shown), which collects the treated fluid discharged from drain tube 176 for further processing.
  • Collection hub assembly 110 also includes a center tube 178 that is inserted into and releasably coupled to bottom lamp holder 166 so that entire collection hub assembly 110 may be removed from irradiator unit 102, such as for cleaning.
  • Center tube 178 provides a passage for the air flowing through the space defined by quartz sleeve 146 and UV light tubes 140 to exit irradiator unit 102.
  • An air exhaust tube 180 fluidly communicates with center tube 178 to allow the air flow to exhaust from irradiator unit 102.
  • exhaust tube 180 may be coupled to an air hose to direct the exhaust air away from the operator.
  • a tang 182 extends from a flange 184 which defines the discharge end of center tube 178.
  • Tang 182 mates with a corresponding opening (not shown) in collection cup 174 in order to properly locate the relative location of drain tube 176 with respect to irradiator unit 102.
  • An airflow path is formed between UV light source 116 and sleeve 146 such that air flow source 164 is in fluid communication with the airflow path proximate to fluid injection port 106a and air flow discharge, or exhaust tube 180, is in fluid communication with the airflow path proximate to fluid discharge port 106b.
  • irradiator unit 102 and in particular, tube 106 is rotated by a motor assembly 186, which is shown in more detail in FIG. 19.
  • motor assembly 186 is powered by a motor 188, which may be a brushless DC motor.
  • Timing belt is drivingly coupled to a driven timing pulley 194, which is fixedly coupled to tube 106 via bolts 196 fixed to driven timing pulley and extending through a flange 198, which is circumferentially disposed around tube 106.
  • Nuts 200 secure bolts 196 to flange 198. As shown in FIG.
  • tube 106 is rotatably mounted in a bearing assembly 202, which concentrically surrounds and supports tube 106 approximately halfway between fluid injection port 106a of tube 106 and fluid discharge port 106b of tube 106 and permits rotational movement of tube 106 about axis 107.
  • Bearing assembly 202 includes a pair of ball bearing sleeves 204 that are fixedly mounted within a housing 206 and axially separated from each other by an annular spacer 208. By mounting bearing sleeves 204 within housing 206, bearings 204 may be aligned with each other.
  • Alignment of bearing sleeves 204 with each other may offer multiple advantages, such as, for example, reduced noise and vibration, extended operating life of bearing sleeves 204, and reduced maintenance cost. Furthermore, by containing bearing sleeves 204 in housing 206 distanced from the inflow and outflow of the fluid, bearing lubricant is prevented from entering any portion of irradiator unit 102 that enters into contact with the fluid to be irradiated.
  • Support brackets 210, 212 support bearing housing 206 and are each mounted to a mounting bracket 214.
  • Gaskets 216, 218 seal bearing assembly 202 in order to prevent the fluid flowing from tube 106 from coming into contact with bearing sleeves 204 or any bearing grease that may be used to lubricate bearing sleeves 204.
  • Mounting bracket 214 is fixably coupled to support frame 104 to support bearing assembly 202 and tube 106 on support frame 104 (shown in FIG. 1).
  • An inductive sensor 220 is mounted to support bracket 210 to sense and regulate the rotational speed of tube 106 during operation.
  • device 100 is used to irradiate a fluid, such as allantoic fluid obtained from, for example, embryonic chicken eggs or a cell culture medium, to inactivate a live virus contained within the fluid.
  • Fluid comprising the live virus is placed in fluid communication with device 100 from a fluid supply (not shown) by coupling the fluid supply to supply end 128 of injection needle 126.
  • an air supply (not shown) is coupled to air flow supply 164.
  • UV light source 116 is activated by energizing UV light tubes 140.
  • Sensors 138 regulate output power of UV light source 116 by sensing output from UV light supply 116 and transmitting a signal to a controller (not shown), which in turn regulates power to UV light source 116.
  • output power of an exemplary embodiment of UV light source 116 is regulated to 12 mW/cm 2 ⁇ 2 mW/cm 2 .
  • sensors 138 may be inserted into bosses 120 using a cap (not shown) to secure sensor 138 within boss 120.
  • air flow is generated from an air supply, through air flow supply 164 and into the space defined between sleeve 146 and UV light tubes 140 to cool UV light tubes 140 to within a predetermined temperature range such as, for example, between about 35 degrees Celsius and about 55 degrees Celsius.
  • the temperature range may be between about 39 degrees Celsius and about 49 degrees Celsius.
  • the temperature is maintained between about 42 degrees Celsius and about 44 degrees Celsius.
  • the air flows out of air exhaust tube 180, where the air is discharged from irradiator unit 102. Air flow between sleeve 146 and tube 106 and then exiting exhaust tube 180 is indicated by arrows in FIG. 15.
  • Elongated tube (106) is rotated along its longitudinal axis (107) by motor 188.
  • Motor 188 in turn drives timing belt 192, which in turn rotates tube 106
  • tube 106 is rotated at a rotational speed of 300 rpm.
  • Inductive sensor 220 measures rotational speed of tube 106, and transmits a signal to a controller (not shown) to regulate rotational speed of tube 106.
  • the fluid to be treated is introduced to device 100 via needle 126.
  • Fluid may be introduced into device 100 at a rate of between 600 and 900 liters per minute. In an exemplary embodiment of the present invention, the fluid may be introduced at a rate between about 600 and about 900 liters per minute. In another exemplary embodiment, the fluid may be introduced at a rate between about 700 and about 800 liters per minute. In yet another exemplary embodiment, the fluid may be introduced at a rate of about 755 liters per minute.
  • the oblong shape of needle 126 and its declination angle relative to the centerline of injection box 118 allow the fluid being discharged from needle 126 to be dispersed in a relatively thin film along fluid injection end 106a of tube 106 without splashing fluid onto sleeve 146, protecting UV light source 116 from direct contact with the live virus Such dispersion is shown in the photograph of FIG. 12.
  • the rotation of tube 106 about its longitudinal axis 107 serves to further disperse the fluid along the interior length of elongated tube 106.
  • the fluid As the fluid travels the length of tube 106, the fluid is irradiated with light from UV light source 116, thereby transforming the live virus to an inactivated virus.
  • the fluid containing the virus flows into collection cup 174, where the fluid then drains from collection cup 174 through drain tube 176.
  • the fluid may be collected from drain tube 176 into a receiver (not shown) for further processing.
  • the methods disclosed herein are useful for inactivating viruses in the production of immunogenic pharmaceutical compositions, including vaccines.
  • the methods are suitable for producing vaccines from highly pathogenic and infectious viruses, including highly pathogenic (pandemic and/or avian) influenza strains.
  • the device and methods disclosed herein are used in manufacturing influenza vaccine to inactive live virus.
  • influenza vaccine the virus stock is typically grown and harvested from embryonic chicken eggs.
  • virus stock can be grown in cultured cells, where it is harvested from the culture media (for example, as described in US Patent Publication 2004/0029251, 6,656,720, 6,344,3546,825,036, 6,951,752, which are incorporated herein by reference).
  • biological contaminants include "adventitious agents.”
  • the term "adventitious agent” refers to a mammalian or avian virus, Mycoplasma, or bacteria. These are biological contaminants that may be present in process intermediates during the production of a finished vaccine suitable for administration to humans. Integrationitious agents could be present in the starting materials due to undetected disease in the hens or introduced as a foreign contaminant during processing.
  • bioburden refers to the population of bacteria present in a fluid. Bioburden is typically expressed as Colony Forming Units (CFU) per milliliter (ml) of fluid tested. It is an important feature of the method disclosed herein that adventitious agents and bioburden are inactivated during the UV processing. For example, although formalin inactivation procedures are capable of inactivating adventitious viral agents, bacteria are relatively resistant to treatment with formalin. The procedures disclosed herein for inactivating virus, advantageously also inactive bacterial contaminants reducing bioburden early in the processing and facilitating recovery of the virus for vaccine production.
  • the allantoic fluid is usually clarified by centrifugation to remove particulate matter prior to subsequent processing.
  • the virus-containing fluid is subjected to a UV irradiation step.
  • the UV irradiation unit consists of an elongated tube, such as a stainless steel cylinder, rotating at high speed, in the center of which are situated the UV light source. Allantoic fluid is introduced into the elongated tube (e.g., along an interior wall) from the collection tank, and flows by gravity through the rotating tube, which is set at an angle of 30° (e.g., 20°-40°) relative to the horizontal. The rotation speed allows the flowing liquid to form a very thin layer along the length of the cylinder wall.
  • the radiation source consists of one or more UV lamps.
  • the UV radiation source is protected from direct contact with the live virus by encasing the lamps within a sleeve made from a UV permeable material, such as quartz.
  • the lamps are maintained within a desired temperature range by passing a current of air within the sleeve so that it passes over the lamps in the opposite direction from the fluid flow). Exposure to UV light as the fluid passes through the elongated tube inactivates the virus, as well as any adventitious agents, and reduces bioburden.
  • the UV-inactivated allantoic fluid is collected into sterile (e.g. , autoclaved stainless steel) tanks.
  • the allantoic fluid is fed into and collected from the UV inactivator device via silicon tubing connected under laminar flow.
  • IOOOL mean of 10ml_/egg
  • Each tank has a unique identifying number in order to monitor the order in which they are filled.
  • Material is sampled in-line while filling each tank for measurement of HA titer. After each use, the UV units are disassembled and the removable parts (UV cylinder and other machine parts) are machine washed and autoclaved.
  • UV unit and its pumping system is cleaned-in-place. Prior to processing each lot, the UV units are reassembled, and connections are made under laminar flow. Non-autoclaved product- contact surfaces are sanitized with a formaldehyde solution, followed by a PBS rinse prior to use.
  • the flow rate is at least about 600 ml/min (such as at least about 650 ml/min, or at least about 675 ml/min, or at least about 680 ml/min).
  • the flow rate does not exceed about 900 ml/min (such as a rate of no more than about 850 ml/min, or 840 ml/min, or about 830 ml/min). Nonetheless, if desired to increase processing capacity, the flow rate can be modified to up to at least about 3500 ml/min.
  • UV light intensity can be increased, e.g., up to at least about 18 mW/cm 2 .
  • the collected allantoic fluid is typically treated with formalin (formaldehyde), concentrated and further processed to produce detergent split antigen suitable for administration as a vaccine.
  • formalin formalin
  • antigens such as influenza HA and NA antigens for vaccines
  • methods for preparing and formulating antigen are well known, and exemplary procedures are described in, e.g., U. S. Patent Nos. 3,962,421, 4,064,232, 4,140,762, 4,158,054, and 6,743,900. These exemplary procedures for preparing antigens and formulating vaccines are incorporated herein by reference.
  • antigens are suitable for administration to subjects, including human subjects for inducing an immune response against the virus.
  • the antigens are formulated into pharmaceutical compositions with a pharmaceutically acceptable excipient or carrier.
  • Such carriers are well know in the art, and numerous examples are described, for example in Gennaro: Remington's Pharmaceutical Sciences, 18 th Ed., Mack Pub. Co., Easton, PA (1995).
  • the pharmaceutical composition includes an adjuvant that further enhances the immune response to the viral antigen.
  • compositions e.g., vaccines
  • inactivated viruses e.g., inactivated viruses
  • viral antigens produced from inactivated viruses are encompassed by this disclosure, as are methods of protecting subjects from viral diseases by administering such pharmaceutical compositions.
  • Samples are typically analyzed for viral/ 'Mycoplasma titer by preparing serial dilutions of the test samples (referred to here as titration) and inoculation onto cell cultures (for analysis by TCID 50 ) or agar plates (to determine Mycoplasma colony counts).
  • titration serial dilutions of the test samples
  • TCID 50 cell cultures
  • agar plates to determine Mycoplasma colony counts.
  • LOD assay limit of detection
  • the assay LOD is an estimate of the theoretical titer based on the sample size using the Poisson distribution (the probability of detecting a low titer in a small representative sample). The LOD is decreased by increasing the sample size that is analyzed.
  • the log reduction factor was calculated using the large volume titer determination.
  • TCID 50 endpoints were calculated according to the Spearman Ka ' rber formula, as described in the Federal Gazette No. 84(4), May 1994, and by Schmidt, N.J. and Emmons, R.W. in DIAGNOSTIC PROCEDURES FOR VIRAL, RICKETTSIAL AND CHLAMYDIAL INFECTION, 6 th Ed. (1989).
  • Log reduction factors (LRF) are calculated using the following formula:
  • the 95% confidence limits are calculated by the square-root of the sum of the squares divided by the number of samples as follows: (SQRT (((CL 1 2 ) + (CL 2 2 ) + ... (CL ⁇ 2 ))//7)) All of these studies were conducted by BioReliance Corp. at facilities in Rockville, MD, USA. UV inactivation studies were performed utilizing commercial scale equipment (a Dill UV unit was transferred to BioReliance). All study designs and LRF calculations were based upon guidance and examples provided in ICH document Q5A, "Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin", March, 1997, found on the World Wide Web at: www.ich.org/LOB/media/MEDIA425.pdf.
  • Example 2 UV inactivation of three strains of Influenza
  • UV inactivation studies were conducted with multiple strains of influenza, using manufacturing scale equipment, to demonstrate safety and efficacy. Three strains of influenza were selected, corresponding to those manufactured for the 2004-2005 season. Each lot was evaluated in two independent runs. Inactivation was evaluated at five UV intensity set-points (2, 6, 10, 12 and 14mW/cm 2 ) a predetermined production target (12mW/cm 2 ). All other conditions were representative of the exemplary manufacturing process described above (e.g., flow rate 755ml/min, rotational speed 320rpm, and cylinder angle 30°).
  • influenza virus containing allantoic fluid was harvested, and samples were taken prior to irradiation.
  • the material was processed through the irradiator at the various UV intensity set-points listed above, and a second set of samples was taken. All samples were evaluated for the presence of infectious influenza virus by EID 50 and for bioburden, samples were also analyzed for potential damage to the HA antigen.
  • Table 4 Logio Reduction Factors for UV Inactivation of Influenza Virus
  • the results illustrated in FIG. 20 demonstrate that inactivation for all three strains (New Caledonia, Wyoming, and Jiangsu) occurs at a minimum average set-point of lOmW/cm 2 .
  • the B/Jiangsu strain is inactivated at a set-point of 6mW/cm 2 .
  • a mean of 9.1 logs (7.6 to 9.7 dependent on the strain) reduction of influenza virus was observed. Residual infectivity remaining after UV inactivation was eliminated by formalin treatment.
  • UV irradiation of allantoic fluid containing A/New Caledonia influenza resulted in a decrease in viral infectivity. No bacterial growth was observed before or after UV irradiation, and UV irradiation had no effect on the hemagglutination properties (HA titer) of the virus.
  • Example 3 Comparison of UV Inactivation for the A/New York/55/2004 and A/New Caledonia strains
  • influenza virus manufacturing processes of the instant invention have been sufficient for all strains used to date. Nevertheless, the inactivation steps are typically re-validated for all new strains of influenza virus on a yearly basis to confirm suitability of the process. For example, in the 2005-2006 season, one new strain (A/New York/55/2004) was used. The ability of the manufacturing process to provide complete influenza virus inactivation was assessed by the following experiments:
  • Allantoic fluid containing virus of the A/New York/55/2004 strain was clarified by low speed centrifugation (3000 rpm, 10 min., room temperature); this clarification procedure was previously shown not to alter viral concentration.
  • Allantoic fluid containing the A/New Caledonia strain was clarified and used as a control for this experiment. Both samples were UV-irradiated using the same conditions described above, and aliquots were taken for analysis. Under manufacturing conditions, the UV irradiated fluid is subsequently treated with formaldehyde. The results for the A/New Caledonia and A/New York strains are shown in Table 6.
  • UV irradiation of allantoic fluid containing A/New Caledonia influenza resulted in a decrease in viral infectivity of at least 8.6 logi 0 as measured by EID 50 (Table 6). This level of viral inactivation is similar to that previously observed with this strain and serves as a control for the experiment with the New York strain. No bacterial growth was observed before or after UV irradiation, and UV irradiation had no effect on the hemagglutination properties (HA titer) of the virus.
  • UV irradiation of the clarified allantoic fluid containing the A/New York strain produced an 8.8 log reduction in viral infectivity as measured by EID 50 (Table 6). This level of inactivation is comparable to that of A/New Caledonia. Again, the 8.8-log reduction of viral infectivity of A/New York by UV irradiation alone did not result in full inactivation, as live virus was detected by the viral inactivation assay in the UV irradiated sample. No bacterial growth was observed in the A/New York test samples, either before or after irradiation, and UV irradiation had no effect on the hemagglutination properties (HA titer) of the virus.
  • HA titer hemagglutination properties
  • test article to which the spiking microorganism was added consisted of allantoic fluid harvest containing influenza virus (A/Wyoming strain). This strain of virus was chosen because it contained the highest virus titer among strains being produced at the time the studies were performed (2004- 2005 strains), and thus offered the most potential to interfere with the UV inactivation of any adventitious agents present.
  • influenza virus itself was first inactivated, so that it would not interfere with detection of the spiking agents.
  • test material UV-treated allantoic fluid
  • model virus or Mycoplasma of interest An aliquot of the test material (UV-treated allantoic fluid) was spiked with a known quantity of the model virus or Mycoplasma of interest. Aliquots were taken to serve as pretreatment samples which were analyzed immediately, and hold samples, which were not further processed, but were analyzed with the UV-irradiated samples, to serve as a control for any potential holding time effects. The remaining volume of test material was divided into two aliquots, and each aliquot was independently processed at the selected UV irradiation level. This procedure was repeated for each of the five UV doses tested.
  • the UV irradiation doses used were 2, 6, 10, 12 (manufacturing set-point), and 14mW/cm 2 .
  • each aliquot was analyzed to determine the titer of the model agent by the appropriate methods as described above, both titration and large volume plating were used. See the above discussion on titer determination by titration and large volume plating. When no challenge organism is detected in the titration sample, the large volume plating value is reported because of the improved limit of detection.
  • the log-reduction factor (LRF) is calculated as the logio of the ratio of the virus load in the starting material to that in the irradiated sample.
  • XMuLV Xenotropic Murine Leukemia Virus
  • ALV avian leukosis virus
  • ALV genomic RNA and reverse transcriptase have been detected in chick cell- grown vaccines, and endogenous ALV antigens and reverse transcriptase activity can be found in eggs, but evidence of human infection due to these vaccines is lacking.
  • XMuLV is an enveloped RNA virus of 80-110 nm.
  • XMuLV was chosen as a model for ALV because of the inability to grow ALV to sufficiently high enough titers to facilitate spiking studies. Inactivation of XMuLV is measured by the change in the 50% tissue culture infectious dose (TCID 50 ) endpoint assay in PG-4 cells.
  • Adenovirus 2 (Ad2) is a model for avian adenoviruses and other non-enveloped DNA viruses. Adenoviruses are ubiquitous in nature and have been shown to infect many vertebrate species, including birds.
  • the avian adenoviruses have a wide range of virulence in chickens, with infections ranging from sub-clinical to symptomatic outbreaks. Adenoviruses can be transmitted horizontally or vertically via the egg. Virus shedding may produce a potentially high titer in allantoic fluid, although no shedding is usually detectable following seroconversion. Avian adenoviruses are not generally believed to be of public health significance, as they are unable to undergo productive replication in human cells, and are more of an environmental concern.
  • Ad2 is a non- enveloped DNA virus of 90nm in diameter that can be readily grown in culture to high titers and reliably assayed, making it suitable for use in such spiking studies. Inactivation of Ad2 is measured by the change in the 50% tissue culture infectious dose (TCID 50 ) endpoint assay in A549 cells.
  • Mycoplasma Species Various species of Mycoplasma are known to infect and cause disease in avian and mammalian hosts. Some species of Mycoplasma, such as M. gallisepticum and M. synoviae, are likely to occur in chickens, but are not known to be mammalian pathogens. Other species, such as M. orale and M. pneumoniae, are of human origin and may enter the process stream via infected operators. These species can be grown to high titers (with the exception of M. synoviae) and reliably assayed, making them suitable for spiking studies. Inactivation of Mycoplasma is measured by the change in titer determined from CFU counts on agar plates.
  • the log reduction factors range from at least 2.28 to 3.86 at a UV irradiation level of 12mW/cm 2 , however the calculated values were limited by the starting titers and assay limits of detection due to sample dilutions and statistical considerations.
  • aAII values are shown as the average log reduction factor and 95% confidence interval of duplicate runs.
  • AII publications and references, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference in their entirety, as if each individual publication or reference were specifically and individually indicated to be incorporated by reference herein as being fully set forth.

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Abstract

La présente invention concerne un dispositif (100) destiné à irradier un fluide. Le dispositif (100) comprend un tube allongé (106) présentant un orifice d'injection de fluide (106a) et un orifice d'évacuation de fluide (106b), le tube allongé (106) pouvant tourner autour d'un axe longitudinal (107). L'axe longitudinal (107) s'étend en formant un angle oblique par rapport à l'horizontale. Une source de rayonnement (116) s'étend dans le tube allongé (106) sur l'axe longitudinal (107). Une gaine (146) s'étend dans le tube allongé (106) et entoure un segment de la source de rayonnement (116), définissant ainsi un trajet de flux d'air entre la source de rayonnement (116) et la gaine (146). Une source de flux d'air (164) est en communication fluidique avec le trajet de flux d'air à proximité de l'orifice d'injection de fluide (106a). Un système d'évacuation du flux d'air (180) est en communication fluidique avec le trajet de flux d'air à proximité de l'orifice d'évacuation de fluide (106b). L'orifice d'injection de fluide (106a) et l'orifice d'évacuation de fluide (106b) sont en communication avec l'espace compris entre le tube (106) et la gaine (146). L'invention concerne également un procédé d'inactivation d'un virus et un virus inactivé fabriqué selon le procédé.
PCT/US2007/020776 2006-09-26 2007-09-26 Dispositif et procédés d'inactivation du virus de la grippe et agents adventifs avec lumière ultraviolette WO2008039494A1 (fr)

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WO2010077986A2 (fr) 2008-12-16 2010-07-08 Baxter International Inc. Production de vaccins viraux
EP2566958B1 (fr) 2010-05-03 2015-12-30 GlaxoSmithKline Biologicals S.A. Procédé pour l'inactivation du virus de la grippe

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Publication number Priority date Publication date Assignee Title
KR20200138708A (ko) * 2017-12-18 2020-12-10 에스.아이.피.에이. 소시에타’ 인더스트리아리자지오네 프로게타지오네 이 오토마지오네 에스.피.에이. 열가소성 재질 용기의 제조 장치 및 방법
US10730764B2 (en) * 2018-04-20 2020-08-04 Asahi Kasei Kabushiki Kaisha Ultraviolet light irradiation device

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WO1999006529A1 (fr) * 1994-03-07 1999-02-11 Dill Instruments, Inc. Dispositif de support et d'entrainement d'un cylindre rotatif
WO2000003750A1 (fr) * 1998-07-15 2000-01-27 Pathogenex Gmbh Irradiation d'un liquide dans un cylindre en rotation

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GB655198A (en) * 1947-09-30 1951-07-11 Allied Lab Inc Process and apparatus for the irradiation of liquids
US2569153A (en) * 1949-10-19 1951-09-25 John J Dill Apparatus for sterilizing plasma, vaccine, and other fluids
US4179616A (en) * 1978-02-21 1979-12-18 Thetford Corporation Apparatus for sanitizing liquids with ultra-violet radiation and ozone
US5133932A (en) * 1988-03-29 1992-07-28 Iatros Limited Blood processing apparatus
US4904874A (en) * 1988-08-02 1990-02-27 Ultraviolet Purification Systems Apparatus for irradiating fluids
WO1999006529A1 (fr) * 1994-03-07 1999-02-11 Dill Instruments, Inc. Dispositif de support et d'entrainement d'un cylindre rotatif
WO2000003750A1 (fr) * 1998-07-15 2000-01-27 Pathogenex Gmbh Irradiation d'un liquide dans un cylindre en rotation

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Publication number Priority date Publication date Assignee Title
WO2010077986A2 (fr) 2008-12-16 2010-07-08 Baxter International Inc. Production de vaccins viraux
US9884105B2 (en) 2008-12-16 2018-02-06 Ology Bioservices, Inc. Production of viral vaccine
EP2566958B1 (fr) 2010-05-03 2015-12-30 GlaxoSmithKline Biologicals S.A. Procédé pour l'inactivation du virus de la grippe

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