WO2017166458A1 - 一种动物血浆、血清或血液的生物安全性质量控制系统 - Google Patents

一种动物血浆、血清或血液的生物安全性质量控制系统 Download PDF

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WO2017166458A1
WO2017166458A1 PCT/CN2016/087194 CN2016087194W WO2017166458A1 WO 2017166458 A1 WO2017166458 A1 WO 2017166458A1 CN 2016087194 W CN2016087194 W CN 2016087194W WO 2017166458 A1 WO2017166458 A1 WO 2017166458A1
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plasma
blood
tube
animal
serum
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PCT/CN2016/087194
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English (en)
French (fr)
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万华印
张俊辉
付岩霖
李伟达
樊鸿浩
邓乐君
万文悦
朱晋辉
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广州市众为生物技术有限公司
广州市拜特淞医药科技有限公司
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Publication of WO2017166458A1 publication Critical patent/WO2017166458A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/15—Devices for taking samples of blood
    • A61B5/150007—Details
    • A61B5/150015—Source of blood
    • A61B5/15003—Source of blood for venous or arterial blood
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/15—Devices for taking samples of blood
    • A61B5/150007—Details
    • A61B5/150053—Details for enhanced collection of blood or interstitial fluid at the sample site, e.g. by applying compression, heat, vibration, ultrasound, suction or vacuum to tissue; for reduction of pain or discomfort; Skin piercing elements, e.g. blades, needles, lancets or canulas, with adjustable piercing speed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/15—Devices for taking samples of blood
    • A61B5/153—Devices specially adapted for taking samples of venous or arterial blood, e.g. with syringes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61D—VETERINARY INSTRUMENTS, IMPLEMENTS, TOOLS, OR METHODS
    • A61D3/00—Appliances for supporting or fettering animals for operative purposes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6844—Nucleic acid amplification reactions
    • C12Q1/686—Polymerase chain reaction [PCR]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/70—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving virus or bacteriophage
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61D—VETERINARY INSTRUMENTS, IMPLEMENTS, TOOLS, OR METHODS
    • A61D3/00—Appliances for supporting or fettering animals for operative purposes
    • A61D2003/003—Appliances for supporting or fettering animals for operative purposes with head or neck restraining means
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61D—VETERINARY INSTRUMENTS, IMPLEMENTS, TOOLS, OR METHODS
    • A61D3/00—Appliances for supporting or fettering animals for operative purposes
    • A61D2003/006—Appliances for supporting or fettering animals for operative purposes with leg or foot restraining means

Definitions

  • the invention relates to the fields of biotechnology, biomedicine, biological materials, medical instruments, etc., in particular to a biosafety quality control system for animal plasma, serum or blood.
  • composition of most mammalian plasma proteins is similar to that of humans and has low immunogenicity. Due to its wide range of sources and low cost, with the continuous development of biomedical technology, researchers have extracted a variety of biological products from animal plasma or serum for clinical drugs, such as porcine fibrinogen, porcine thrombin, Bovine thrombin, porcine albumin, porcine immunoglobulin, etc. In the future, with the advancement of biotechnology, the technology of genetic engineering can be used to express the protein molecules required by humans in the blood of animals. More and more biochemical drugs may be extracted from animal plasma or serum.
  • animal plasma or serum is increasingly used in biomedicine, its biosafety will receive sufficient attention.
  • the breeding, quarantine and slaughtering of animals belong to different departments. Their respective standards and norms are not uniform and uncoordinated, so they will cause serious quality hazards to the biosafety of animal plasma or serum.
  • the requirements for animal plasma or serum in biological product management were not as strict as those of human plasma, so there is no complete systematic method for quality control of animal plasma or serum biosafety.
  • the technical problem to be solved by the present invention is to provide a biosafety quality control system for animal plasma, serum or blood, which can effectively control harmful factors affecting biological safety such as viruses, pyrogens and pathogenic bacteria in animal plasma, serum or blood. .
  • the technical solution of the present invention is: a biosafety quality control system for animal plasma, serum or blood, including an inspection system for testing whether an animal is healthy and conforming to blood collection standards, an animal blood collection system, a blood storage system. And blood transport systems;
  • the blood collection system includes a venous blood collection catheter, a plasma pump, a centrifuge for separating blood into blood plasma and blood cells, and a plasma bag, the venous blood collection catheter is provided with a Y-shaped catheter interface; the venous blood collection catheter is connected to the plasma pump through a catheter
  • the plasma pump is connected to the centrifuge through a catheter, the centrifuge is connected to the plasma bag through a catheter, the venous blood collection tube, the plasma pump, the centrifuge, the plasma bag constitute a plasma collection line;
  • the centrifuge, the plasma pump, the venous blood collection tube are composed a blood cell return line;
  • the venous blood collection tube comprises a tube body, a connecting seat, an epitaxial tube, a sliding buckle and an epitaxial tube joint, the rear end of the tube body is connected to one end of the epitaxial tube through a connecting seat, and the other end of the epitaxial tube is connected with the epitaxial tube joint Connecting; the side of the front end of
  • the blood collection system includes a pig apheresis plasma fixation device, which includes a metal holder for supporting a pig, a strap for fixing the pig on the metal holder, and a pig nose metal holder;
  • the metal holder includes Two symmetrically disposed supporting legs, a middle portion of the metal fixing frame is provided with a pad, the pad is erected on the supporting leg, and two sides of the pad are provided with a middle tube, and the middle tube
  • the two ends are respectively connected to the two supporting legs, and the outer side of the middle tube is provided with an outer tube, and the two ends of the outer tube are respectively connected with the two supporting legs; the front end of the backing plate and the front end of the middle tube are respectively provided with protective cotton pad.
  • the invention performs strict quality control on the blood collection link, especially the blood collection system.
  • the blood collection system of the invention is a system for aseptically collecting animal plasma for collecting a large amount of whole blood or plasma of an animal.
  • the whole blood or plasma of the animal collected in the aseptic system avoids contamination as much as possible, improves the safety and effectiveness of the product, and at the same time reduces the damage to the animal, in line with animal ethics standards. Animals after blood collection can continue to be maintained, and blood collection can be carried out several times during the feeding process, reducing the waste of slaughter.
  • the indwellable catheter is located on the surface of the animal, which can avoid multiple punctures. After connecting with the disposable single plasma separator catheter, blood can be collected.
  • the indwelling catheter can be used for daily disinfection to ensure plasma quality and animal health.
  • the sterile blood collection system forms a complete system for the quality control of animal plasma or serum biosafety in conjunction with the testing system, blood storage system and blood transport system, eliminating the quality hazards associated with the biosafety of animal plasma or serum.
  • the two side holes are respectively located on opposite side walls of the pipe body.
  • the aperture of the side hole is 1/3-2/3 of the diameter of the tube body, the holes on both sides are 3-8 mm apart, and the side hole near the nozzle is 5-10 mm from the rear of the nozzle.
  • the tube body is a straight single-lumen catheter, and the tube body has a diameter ranging from 1.40 to 2.70 mm.
  • the front end of the tubular body 4 mm is a thickened wear-resistant tapered nozzle.
  • the nozzle material is silica gel, polyvinyl chloride or polyurethane.
  • the epitaxial tube is a thickened transparent tube whose inner wall smoothness is similar to the smoothness of the tube body.
  • the end of the pad is provided with a plastic film for discharging the excrement;
  • the strap includes a limb strap provided at both ends of the outer tube and a body strap disposed at the middle of the middle tube and spanning the pad.
  • the inspection system inspects the animal, and the inspection method includes:
  • each plasma or blood of swine fever virus, pseudorabies virus, foot-and-mouth disease virus, Japanese encephalitis virus and Streptococcus suis should be negative, and the titer of porcine parvovirus should be no more than 10.0 IU/ ⁇ l.
  • Each plasma or blood porcine scorpion virus antibody, foot-and-mouth disease virus antibody should be positive;
  • the animal plasma endotoxin should not be higher than 0.1 IU/ml.
  • the blood storage system should be frozen to below -20 °C within 6 hours after animal plasma collection; the blood transport system is below -15 °C in the transport environment.
  • the blood collection system of the present invention is used for collecting a large amount of whole blood or plasma of an animal, and then using blood or plasma to produce related biological products.
  • the whole blood or plasma of the animal collected in the aseptic system avoids pollution as much as possible, improves the safety and effectiveness of the product, and at the same time reduces the damage to the animal, in line with animal ethics standards; the animals after blood collection can continue to support and raise
  • the process can be used for blood collection multiple times, reducing the waste of slaughter.
  • the indwellable catheter is located on the surface of the animal, which can avoid multiple punctures. After the single-shot plasma separator catheter is connected, the blood can be collected.
  • the indwelling catheter can be used for daily disinfection to ensure plasma quality and animal health.
  • the venous blood collection catheter of the blood collection system is provided with a side hole at the front end of the tube body, and the side hole relatively increases the diameter of the blood drawing, thereby accelerating the blood collection speed and making the fibrin sheath difficult to form, thereby solving the difficulty in increasing the blood collection speed or the difficulty of catheterization.
  • the holes on both sides are not on the same side of the tube body, which can reduce the possibility of the catheter deflecting to one side. Controlling the distance between the holes on both sides and the size of the hole can avoid the weakness of the side hole when the tube is inserted, and the side hole is too much. It will also increase the difficulty of catheterization.
  • the invention has the advantages of simple structure and simple operation, and no anesthesia is required when placing the vein of the neck of the pig.
  • the speed of plasma collection can be greatly increased, and the possibility of catheter clogging can be reduced. Meanwhile, increasing the dispersion velocity of the side hole can reduce the pain or injury of the animal. It conforms to animal ethics standards; partial modification of materials for epitaxial tubes and nozzles can ensure the smoothness of secondary blood collection after indwelling catheters, achieve multiple blood collection, and reduce the cost of animal blood collection;
  • the blood collection system of the pig single-collection plasma fixation device can make the pig's supine fixation relatively reduce the pain and damage of the pig, greatly increasing the time of fixing the pig, generally can be fixed for up to 3-4 hours, reducing the pig's bark Frequency, only two people are required to care for the pig after lifting the holder;
  • the metal holder is a tube frame structure, which can obviously expose the dimples on both sides of the pig neck, which is beneficial to the use of a single plasma machine in the anterior vena cava of the pig.
  • the use of the holder facilitates observation of the condition of the ventral surface of the pig, and provides sufficient operation time and appropriate posture for the treatment operation or anatomical examination of the sick pig, and is expected to reduce the pigs of the pig farm. mortality rate.
  • the present invention performs quality control on animal test, collection of animal plasma or blood, pathogen detection of animal plasma or blood, storage and transportation of animal plasma or blood, thereby effectively controlling viruses, pyrogens, pathogenic bacteria, etc. Harmful factors affecting biosafety.
  • Figure 1 is a schematic view of a puncture needle prior to blood collection in an animal.
  • Figure 2 is a schematic view of the installation of a venous blood collection catheter.
  • Figure 3 is a schematic diagram of blood collection and separation of a blood collection system.
  • Figure 4 is a schematic view showing the structure of a venous blood collection catheter.
  • Figure 5 is a schematic illustration of the connection of a venous blood collection catheter to a three-way valve.
  • Figure 6 is a schematic view showing the structure of a pig plasma collection device.
  • a biosafety quality control system for animal plasma, serum or blood including an inspection system for testing whether an animal is healthy in accordance with blood sampling standards, an animal blood collection system, a blood storage system, and a blood transportation system.
  • the inspection system includes testing animals and testing plasma.
  • the inspection of animals should meet the following criteria:
  • Live pigs to be collected should meet health standards through inspections such as visual inspection, palpation and auscultation. By examining the individual's mental state, body temperature, breathing, skin, coat, visible mucous membranes, thorax, abdomen and body surface Bark, excretion action and excrement traits, etc., to determine whether the animal individual is healthy.
  • the weight of pigs should be no less than 50kg.
  • Plasma tests include:
  • the blood collection system includes a venous blood collection tube b inserted into a body vein of an animal, a plasma pump 13, a centrifuge 11, a plasma bag 16, an anticoagulant pump 14, and an anticoagulant bag 15.
  • the venous blood collection tube b is provided with a Y-shaped catheter interface 9, and the venous blood collection tube b is provided with a soft plastic anchor with a hole, and the venous blood collection tube b is provided with a control catheter interface 9 near the catheter interface 9 Closed snap valve 10.
  • the venous blood collection tube b is connected to the plasma pump 13 through a catheter, and the plasma pump 13 is connected to the centrifuge 11 through a catheter.
  • the centrifuge 11 is connected to the plasma bag 16 through a catheter, and the blood is sequentially passed through the venous blood collection tube b from the animal body.
  • the plasma pump 13, the centrifuge 11 and the plasma bag 16 constitute a plasma collection circuit, and the blood cells are sequentially returned from the centrifuge 11 through the plasma pump 13 and the venous blood collection tube b to the animal body to form a blood cell return line; the venous blood collection tube b and the plasma pump
  • a pressure sensor 19 is disposed on the conduit between the 13; the pressure sensor 19 is provided with a valve 20 for controlling the opening of the conduit; and a conduit between the plasma pump 13 and the centrifuge 11 is provided with a flow velocity sensor 18;
  • the blood bag 16 is hung in On the gravity sensing rod 17, the gravity sensing rod 17 controls the plasma pump 13 to rotate forward or reverse through the controller.
  • the anticoagulant bag 15 is connected to the anticoagulant pump 14 through a catheter, and the anticoagulant pump 14 is connected to the venous blood sampling tube b through a catheter.
  • the blood collection system of the present invention is a device for aseptically collecting animal plasma for collecting a large amount of whole blood or plasma of an animal, and then using blood or plasma to produce related biological products.
  • the whole blood or plasma of the animal collected in the aseptic system avoids contamination as much as possible, improves the safety and effectiveness of the product, and at the same time reduces the damage to the animal, in line with animal ethics standards. Animals after blood collection can continue to be maintained, and blood collection can be carried out several times during the feeding process, reducing the waste of slaughter.
  • the indwellable catheter is located on the surface of the animal, which can avoid multiple punctures. After connecting with the disposable single plasma separator catheter, blood can be collected.
  • the indwelling catheter can be used for daily disinfection to ensure plasma quality and animal health.
  • the venous blood sampling catheter includes a tube body 21, a connecting seat 25, an epitaxial tube 27, a slider 26 and an epitaxial tube joint 28.
  • the rear end of the tube body 21 passes through the connecting seat 25 and one end of the epitaxial tube 27. Connected, the other end of the epitaxial tube 27 is connected to the epitaxial tube joint 28.
  • the tube body 21 is a straight single-cavity catheter, and the tube body has a diameter ranging from 1.40 to 2.70 mm (including the existing catheter specification range of 18-12Ga or 4-8Fr), and the caliber is too thin to be conducive to blood collection, and the caliber is too thick. It is not suitable for venous catheterization.
  • 4mm of the front end of the tubular body 21 is a flexible wear-resistant silicone, polyvinyl chloride or polyurethane (PU) material conical nozzle 22, the inner wall of the nozzle 22 is thickened, to avoid blood flow and wear the nozzle and leave the second Secondary blood collection is unfavorable.
  • the two side holes 23, 24 are located at the symmetric ends of the side wall of the tube body 21.
  • the apertures of the side holes 23, 24 are 1/3-2/3 of the tube body 21, and the holes 23, 24 on both sides are 5-8 mm apart.
  • the side hole 23 of the front end is 5-10 mm from the rear of the nozzle 22.
  • the epitaxial tube 27 is a transparent soft material, the inner wall smoothness is similar to the tube body, and the epitaxial tube 27 is provided with a slider 26 for controlling the passage of the tube.
  • the epitaxial pipe joint 28 is provided with a sliding wire capable of connecting the medical three-way valve, and can be connected to the consumable of the single plasma collecting machine through the medical three-way valve.
  • Pig blood collection The pigs that were tested were born for 3-4 months and weighed about 70 kg. The epidemic was qualified. The pigs were individually subjected to blood collection by slaughter and blood collection and ordinary 14Ga double lumen catheter (total diameter 2.00 mm), 14Ga catheter of the present invention, and 12Ga catheter (2.70 mm) tube-type blood collection method of the present invention. Plasma collection, blood collection rate, protein content, and whether or not the bacteria were detected.
  • Slaughter and blood collection In the pig slaughterhouse, the pigs are inverted and bound and slaughtered on the production line. The body surface is not sterilized, and the knife directly penetrates into the heart of the pig. The blood flows directly from the wound, and is collected by the basin. After the whole blood is collected, the blood is obtained by anticoagulation and centrifugation.
  • Tube-type blood collection the pigs are fixed on the lifting bar on the back, and the relevant experimental personnel personally do the disinfection work, prepare the skin for the right front limbs of the pig, and disinfect with the iodine and alcohol, and touch the internal jugular vein on the right side of the pig.
  • the external jugular vein pulse the pig is puncture, skin expansion, and placed into the venous blood collection catheter, wherein the puncture and catheterization method The same method as the existing central venous catheter.
  • the 14Ga catheter of the present invention is inserted into the scale of the tube body 21 between 11-13 cm, and the nozzle 22 reaches the anterior vena cava of the pig; as shown in Fig.
  • the epitaxial tube joint 28 of the catheter is connected to the port of the medical three-way valve
  • the three-way valve b port is connected with the disposable apheresis plasma separator tube which has been installed in the single plasma collection machine, and is connected with the anticoagulant bag, and the blood collection and plasma separation are performed by the single plasma collection machine;
  • the three-way valve c port It is connected to a syringe filled with physiological saline to supplement the physiological saline when the blood cells are returned to the pig body.
  • the tube placement and blood collection methods of the conventional 14Ga double lumen catheter (total diameter 2.00 mm) and the 12 Ga catheter (2.70 mm) of the present invention are the same as those described above.
  • the table below compares the test results for blood collection in different ways (or catheters).
  • the total protein content in plasma should be ⁇ 45g / L;
  • **Separate transfer within the same system means that the catheter is connected to the plasmapheresis and the plasma is directly separated into the plasma bag.
  • the pig was lifted again to the lifting bar.
  • the relevant staff did the disinfection work, disassembled the plastic protective film and suture, and disinfected the epitaxial pipe joint 28.
  • 3-10 ml of heparin physiological saline (100 u/ml) was injected into the epitaxial tube joint 28, and the catheter was again connected to a plasma collection machine, and the collected amount was 400 ml.
  • the rate of secondary blood collection is the same as that of the first time.
  • the plasma is tested for protein content and bacteria count.
  • the blood collection system further includes a pig apheresis plasma fixation device, which comprises a metal holder for supporting pigs, a strap for fixing pigs on a metal holder, and a pig nose metal holder.
  • the metal fixing frame 31 is welded by 14 iron hollow cylindrical tubes, and includes two symmetrically arranged supporting legs, the supporting legs are composed of two intersecting iron pipes; the metal fixing frame 31 is in the middle of the top a support plate 32 is disposed on the supporting leg, and two sides of the backing plate 32 are provided with a middle tube, and two ends of the middle tube are respectively connected with two supporting legs, An outer tube is disposed on an outer side of the tube, and two ends of the outer tube are respectively connected to the two supporting legs.
  • the metal holder 31 has a length of 130 cm, a height of 60 cm, a low height of 60 cm, an inner diameter of 2.0 cm, and an outer diameter of 2.5 cm.
  • the hollow tube frame structure is convenient for observing the pig condition in all directions and is easy to operate;
  • the metal holder 31 has a length of 130 cm and a height of 60 cm. It is designed according to the size of the pig.
  • the height of the lower part is 60 cm, which is suitable for the operator to operate the height.
  • the size of the holder and the thickness of the tube determine the ability to bear the weight of the pig.
  • the front end of the backing plate 32 and the front end of the middle tube are provided with a protective cotton pad 33.
  • the material of the protective cotton pad 33 is a black cable tie for the air conditioning tube, which can protect the collision of the pig head; the protective cotton pad 33 on the front end of the plate pad Embedded in the wood skeleton, the wood skeleton is nailed to the board pad 32 to stabilize the protective cotton pad 33.
  • the strap includes a limb strap 34 disposed at both ends of the outer tube and a body strap 37 disposed in the middle of the middle tube and spanning the pad 32. In operation, after the pig is lifted on the metal holder 31 in a supine manner, the limbs 34 are tied by the limb straps 34 (ie, between the elbow joint and the pig's trotter) and fixed to the welding points of the metal holder 31.
  • the body straps 37 are placed transversely on the middle of the pad 32, and the pig's underarms and waist are tied before the pigs are lowered, so that the pigs can be lifted down the metal holder 31.
  • the lasso of the pig's nose metal retainer 35 is used to cover the upper jaw of the pig, the lasso is tightened, and the part of the pig's maxilla is covered with a soft rubber.
  • the hook of the metal ballast 35 bypasses the crossbar 1-2 turns at the bottom of the metal holder 31 and hooks on the iron pipe at the bottom of the metal holder 31.
  • the pig's howling frequency can be relatively reduced.
  • a plastic film 36 is provided on the rear end of the backing plate 32 for picking up and dropping pig excrement. If it is a male pig, a towel can be placed on the belly of the pig to prevent urine contamination.
  • the blood storage system should be frozen to below -20 °C within 6 hours after animal plasma collection.
  • the blood transport system is at a temperature below -15 ° C in the transport environment.
  • porcine plasma the pig plasma/serum obtained according to the above procedure is used to extract porcine fibrin Protozoa, porcine prothrombin, porcine albumin, porcine immunoglobulin.
  • the invention can be applied to cattle, horses, sheep, dogs, deer, monkeys and the like in addition to pigs.

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Abstract

一种动物血浆、血清或血液的生物安全性质量控制系统，包括检验系统、动物采血系统、血液储存系统和血液运输系统；采血系统包括静脉采血导管（b）、血浆泵（13）、将血液分离成血浆和血细胞的离心机（11）和血浆袋（16），静脉采血导管（b）、血浆泵（13）、离心机（11）、血浆袋（16）组成血浆采集线路；离心机（11）、血浆泵（13）、静脉采血导管（b）组成血细胞回流线路。无菌的采血系统再配合检验系统、血液储存系统和血液运输系统形成一套对动物血浆或血清生物安全性的质量控制的完整系统，消除对动物血浆或血清的生物安全性产生的质量隐患。

Description

一种动物血浆、血清或血液的生物安全性质量控制系统 技术领域
本发明涉及生物技术、生物医药、生物材料、医疗器械等领域，具体是一种动物血浆、血清或血液的生物安全性质量控制系统。
背景技术
大多数哺乳动物血浆蛋白的组成结构及人类相似，免疫原性较低。由于其来源广泛、成本较低的优点，因此随着生物医药技术的不断发展，研究人员从动物血浆或血清中提取出多种生物制品用于临床药品，例如猪纤维蛋白原、猪凝血酶、牛凝血酶、猪白蛋白、猪免疫球蛋白等。未来随着生物技术的进步，可通过基因工程重组的技术使动物血液中表达产生出人类所需的蛋白质分子，可能有越来越多的生化药物从动物血浆或血清中提取获得。
尽管动物血浆或血清在生物医药中的应用越来越广泛，但其生物安全性却会得到足够的重视。动物的养殖、检疫、屠宰分属不同的部门管理，它们各自的标准、规范之间存在着不统一、不协调，因此会对动物血浆或血清的生物安全性产生严重质量隐患。此外以往生物制品管理中对动物血浆或血清的要求不如人血浆要求严格，所以对动物血浆或血清生物安全性的质量控制没有一套完整系统的方法。
目前公开的专利文献中，只涉及到动物血液的采集。如刘金明发明的一种真空采血刀(CN203619567U)、李吉来等发明的一种真空采血装置(CN201278777Y)、邓仕泽等发明的一种鹿血真空采集机构(CN203447297U)、何红兵申请的一种生猪无菌采血工艺及装置(CN101755884A)。上述血液采血装置并不能保证采血整个过程的安全性。
发明内容
本发明所要解决的技术问题是提供一种动物血浆、血清或血液的生物安全性质量控制系统，可有效控制动物血浆、血清或血液中的病毒、热原、病原菌等影响生物安全性的有害因素。
为解决上述技术问题，本发明的技术方案是：一种动物血浆、血清或血液的生物安全性质量控制系统，包括用于检验动物是否健康符合采血标准的检验系统、动物采血系统、血液储存系统和血液运输系统；
所述采血系统包括静脉采血导管、血浆泵、将血液分离成血浆和血细胞的离心机和血浆袋，所述静脉采血导管设有Y型的导管接口；所述静脉采血导管通过导管与血浆泵连接，所述血浆泵通过导管与离心机连接，所述离心机通过导管与血浆袋连接，静脉采血导管、血浆泵、离心机、血浆袋组成血浆采集线路；离心机、血浆泵、静脉采血导管组成血细胞回流线路；所述静脉采血导管包括管体、连接座、外延管、滑扣和外延管接头，所述管体的后端通过连接座与外延管一端连接，外延管另一端与外延管接头连接；所述管体的前端管口侧面设有与管体相通的两个侧孔；
所述采血系统包括生猪单采血浆固定装置，其包括用于承托生猪的金属固定架、用于生猪绑扎固定在金属固定架上的绑带和猪鼻捻金属保定器；所述金属固定架包括两个对称设置的支撑脚，所述金属固定架顶部中间位置设有垫板，所述垫板架设在所述支撑脚上，所述垫板的两侧设有中管，所述中管的两端分别于两支撑脚连接，所述中管的外侧设有外管，所述外管的两端分别与两支撑脚连接；所述垫板的前端和中管的前端分别设有防护棉垫。
本发明在采血环节上进行严格的质量控制，尤其是采血系统，本发明的采血系统一种无菌采集动物血浆的系统，用于大量采集动物全血或血浆。无菌系统中采集的动物全血或血浆尽可能地避免污染，提高产品的安全性和有效性，同时又减少了对动物的伤害，符合动物伦理学标准。采血后的动物可继续豢养，饲养过程可多次进行采血，减少了屠宰的浪费。可留置的导管位于动物体表，可避免多次穿刺，与一次性单采血浆分离器导管连通后即可采血，留置的导管日常做好消毒工作即可保障血浆质量和动物健康。无菌的采血系统在配合检验系统、血液储存系统和血液运输系统形成一套对动物血浆或血清生物安全性的质量控制的完整系统，消除对动物血浆或血清的生物安全性产生的质量隐患。
作为改进，两所述侧孔分别位于管体相对的两侧壁上。
作为改进，所述侧孔的孔径为管体口径的1/3-2/3大小，两侧孔相距3-8mm，靠近管口的侧孔距离所述的管口后方5-10mm。
作为改进，所述的管体为直型单腔导管，所述的管体口径范围为1.40-2.70mm。
作为改进，所述管体前端4mm为增厚的耐磨性锥形管口。
作为改进，所述管口材料为硅胶、聚氯乙烯或聚氨基甲酸酯。
作为改进，所述外延管为增厚的透明管，其内壁光滑度与所述管体光滑度相近。
作为改进，所述垫板的末端设有接卸排泄物的塑料薄膜；所述绑带包括设于外管两端的肢体绑带和设于中管中部且横跨垫板的体部绑带。
作为改进，所述检验系统对动物进行检验，检验的方法包括：
a.检查动物接种记录，应已注射口蹄疫疫苗、猪瘟疫苗、蓝耳病疫苗和禽流感疫苗；
b.通过视诊、触诊和听诊确定动物应符合健康标准；
c.动物应具有完整的编号和生长记录；
d.采用PCR方法或RT-PCR方法检测，每份血浆或血液的猪瘟病毒、伪狂犬病毒、口蹄疫病毒、乙型脑炎病毒和猪链球菌应为阴性，猪细小病毒滴度应不大于10.0IU/μl。每份血浆或血液的猪瘟病毒抗体、口蹄疫病毒抗体应为阳性；
e.采用中国药典细菌内毒素检查法检测，动物血浆细菌内毒素应不高于0.1IU/ml。
作为改进，所述血液储存系统在动物血浆采集后应在6小时内冷冻至-20℃以下；所述血液运输系统在运输环境温度在-15℃以下。
本发明与现有技术相比所带来的有益效果是：
1、本发明采血系统的用于大量采集动物全血或血浆，再利用血液或血浆生产相关生物制品。无菌系统中采集的动物全血或血浆尽可能地避免污染，提高产品的安全性和有效性，同时又减少了对动物的伤害，符合动物伦理学标准；采血后的动物可继续豢养，饲养过程可多次进行采血，减少了屠宰的浪费。可留置的导管位于动物体表，可避免多次穿刺，与一次性单采血浆分离器导管连通后即可采血，留置的导管日常做好消毒工作即可保障血浆质量和动物健康；
2、采血系统的静脉采血导管在管体的前端设置侧孔，侧孔相对增加了抽血的口径，从而加快采血速度并使纤维蛋白鞘不易形成，解决了难以提高采血速度或置管困难的问题；两侧孔不在管体的同一侧能减少导管偏向单侧弯曲的可能，控制两侧孔距离以及孔径大小能避免插管时因有侧孔部位变软而不受力，侧孔过多也会增加置管的难度。本发明结构简单、操作简便，置入猪颈部静脉时无须麻醉，置管后能大大增加血浆采集的速度，减少导管堵塞的可能；同时，增加侧孔分散流速能减轻动物的疼痛或伤害，符合动物伦理学标准；对外延管和管口等进行材质的部分改造能保证留置导管后二次采血的顺畅度，实现多次采血，降低动物采血的成本；
3、采血系统的生猪单采血浆固定装置可让猪仰卧固定相对减少了猪的痛苦和受损程度，大大增加了固定生猪的时间，一般最长可固定3-4小时，减少猪的嚎叫频率，抬上本固定架后只需两人看护生猪；金属固定架为管架结构，能够明显地暴露猪颈部两侧的凹陷窝，有利于在猪的前腔静脉使用单采血浆机进行大量采血并离心出血浆；此外，使用本固定架便于观察猪腹腔面的状况，为对病猪的治疗操作或解剖检验提供了足够的操作时间和合适的体位，有望减少生猪养殖场病猪的死亡率。
4、本发明对动物检验、动物血浆或血液的采集、动物血浆或血液的病原检测、动物血浆或血液的储存和运输等多个过程步骤进行质量控制，从而有效控制病毒、热原、病原菌等影响生物安全性的有害因素。
附图说明
图1为穿刺针穿刺动物采血前的示意图。
图2安装静脉采血导管的示意图。
图3为采血系统的采血与分离示意图。
图4为静脉采血导管结构示意图。
图5为静脉采血导管与三通阀连接的示意图。
图6为生猪单采血浆固定装置结构示意图。
具体实施方式
下面结合说明书附图对本发明作进一步说明。
一种动物血浆、血清或血液的生物安全性质量控制系统，包括用于检验动物是否健康符合采血标准的检验系统、动物采血系统、血液储存系统和血液运输系统。
所述检验系统包括对动物进行检验和对血浆进行检验。对动物的检验应该符合以下标准：
(1)检查生猪接种记录，应已注射猪口蹄疫疫苗、猪瘟疫苗、蓝耳病疫苗、猪伪狂犬疫苗及其他强制免疫疫苗。应详细记录接种日期、接种人、动物编号、疫苗规格、厂家、接种量等信息。
(2)通过视诊、触诊和听诊等方面检查，待采血的生猪应符合健康标准。通过检查动物个体精神状况、体温、呼吸、皮肤、被毛、可视粘膜、胸廓、腹部及体表淋 巴结，排泄动作及排泄物性状等，判断动物个体是否健康。
(3)检查生猪的编号和生长记录，应真实完整。
(4)猪体重应不低于50kg。
血浆检验包括：
(1)采用胶体金法检测血浆中的猪细小病毒抗体、猪乙型脑炎病毒抗体、猪伪狂犬病毒抗体、口蹄疫病毒抗体、猪瘟病毒抗体。
(2)采用PCR法检测猪伪狂犬病毒、猪细小病毒和猪链球菌，采用RT-PCR法检测猪口蹄疫病毒、猪乙脑病毒和猪瘟病毒。
(3)按照中国药典2015年版四部1101无菌检查法进行无菌检测。
(4)依照中国药典2015年四部1143细菌内毒素检查法对单采猪血浆进行细菌内毒素检查。
检测250袋单采猪血浆，结果如表1。再将不合格的单份血浆剔除，合格血浆外袋消毒后破袋混合成合并血浆，各项目检测均符合规定。
表1血浆生物安全性相关项目检测结果
Figure PCTCN2016087194-appb-000001
表2血浆其他理化性质检测
Figure PCTCN2016087194-appb-000002
如图1至3所示，所述采血系统包括插入动物体静脉血管内的静脉采血导管b、血浆泵13、离心机11、血浆袋16、抗凝剂泵14和抗凝剂袋15。所述静脉采血导管b设有Y型的导管接口9，所述静脉采血导管b上设有带孔软胶锚，静脉采血导管b上靠近所述导管接口9处设有控制导管接口9通/闭的卡管阀10。所述静脉采血导管b通过导管与血浆泵13连接，所述血浆泵13通过导管与离心机11连接，所述离心机11通过导管与血浆袋16连接，血液从动物体依次通过静脉采血导管b、血浆泵13、离心机11、血浆袋16组成血浆采集线路，血细胞从离心机11依次通过血浆泵13、静脉采血导管b回到动物体内组成血细胞回流线路；所述静脉采血导管b与血浆泵13之间的导管上设有压力感应器19，所述压力感应器19上设有控制导管开通的阀门20；述血浆泵13与离心机11之间的导管上设有流速感应器18；所述血浆袋16挂在 重力感应杆上17，重力感应杆17通过控制器控制血浆泵13正转或反转。所述抗凝剂袋15通过导管与抗凝剂泵14连接，抗凝剂泵14通过导管与静脉采血导管b连接。本发明采血系统是一种无菌采集动物血浆的装置，用于大量采集动物全血或血浆，再利用血液或血浆生产相关生物制品。无菌系统中采集的动物全血或血浆尽可能地避免污染，提高产品的安全性和有效性，同时又减少了对动物的伤害，符合动物伦理学标准。采血后的动物可继续豢养，饲养过程可多次进行采血，减少了屠宰的浪费。可留置的导管位于动物体表，可避免多次穿刺，与一次性单采血浆分离器导管连通后即可采血，留置的导管日常做好消毒工作即可保障血浆质量和动物健康。
如图4所示，所述静脉采血导管包括管体21、连接座25、外延管27、滑扣26和外延管接头28，所述管体21的后端通过连接座25与外延管27一端连接，外延管27另一端与外延管接头28连接。所述管体21为直型单腔导管，所述管体口径范围为1.40-2.70mm(包括了现有导管规格范围18-12Ga或4-8Fr)，口径过细不利于采血，而口径过粗则不适合静脉置管。管体21前端4mm为软质耐磨性硅胶、聚氯乙烯或聚氨基甲酸酯(PU)材料的锥形管口22，管口22内壁增厚，避免血流磨损管口而留置后二次采血不利。两侧孔23、24位于管体21侧壁对称的两端，侧孔23、24的孔径大小为管体21的1/3-2/3，两侧孔23、24相距5-8mm，近前端的侧孔23距离管口22后方5-10mm。所述外延管27为透明软质材料，内壁光滑度与所述的管体相近，外延管27上设有控制导管通闭的滑扣26。外延管接头28上设有能连接医用三通阀的滑丝，通过医用三通阀导管能与单采血浆机的耗材连接。
猪采血：进行试验的生猪生长期为3-4个月，体重约为70kg，防疫合格。分别用屠宰采血和普通14Ga双腔导管(总管径2.00mm)、本发明14Ga导管以及本发明12Ga导管(2.70mm)置管式采血方法对分别生猪进行采血。对血浆采集量、采血速度、蛋白含量和是否染菌进行检测。
屠宰采血：在生猪屠宰场中，生猪倒立绑定后在生产流水线上进行屠杀。体表不经消毒，用刀直接刺入猪心脏部位，血液直接从伤口流出，用盆收集，全血收集后经过抗凝和离心处理得到血浆。
置管式采血：将生猪仰卧固定在抬杠上，相关实验人员个人做好消毒工作，对猪右前肢凹陷窝区域进行备皮，并先后用碘酊、酒精消毒，摸出生猪右侧的颈内静脉或颈外静脉脉搏后，对猪进行穿刺，扩皮，置入静脉采血导管，其中的穿刺、置管方法 同现有的中心静脉导管置管方法。本发明14Ga导管插入至管体21上刻度11-13cm之间，管口22便到达猪的前腔静脉内；如图5所示，接着导管的外延管接头28与医用三通阀a口连接；三通阀b口与已安装在单采血浆机的一次性单采血浆分离器管路连接，并接上抗凝剂袋，借助单采血浆机进行采血及血浆分离；三通阀c口与装有生理盐水的注射器连接，用作回输血细胞到猪体时补充生理盐水。普通14Ga双腔导管(总管径2.00mm)和本发明12Ga导管(2.70mm)的置管、采血方法与上述过程相同。下表为不同方式(或导管)采血的检验结果比较。
Figure PCTCN2016087194-appb-000003
备注：*根据欧洲药典要求是：血浆中的总蛋白含量应≥45g/L；
**同一系统内分离转移表示：导管连接单采血浆机后直接分离出血浆至血浆袋中。
留管后对猪的二次采血：首次血浆采集完成后，在三通阀c口脉冲式注射3-5ml低浓度肝素生理盐水(100u/ml)，关闭外延管25上的滑扣26，拆卸外延管接头28上的医用三通阀a口，用酒精棉球消毒外延管接头28，并盖上肝素帽。接着用塑料保护膜包住外延管接头28，再用缝合线在连接座25上将采血静脉导管呈“U”型缝合固定于猪表皮上，留置静脉采血导管，放养。五天后，把该生猪再次抬上抬杠，实验前相关工作人员做好消毒工作，拆卸塑料保护膜和缝合线，消毒外延管接头28， 外延管接头28处注射3-10ml肝素生理盐水(100u/ml)，将导管再次与血浆采集机连接，采集量为400ml。二次采血的速度与首次采速度一样，血浆进行蛋白质含量检测和细菌数检查，均检验合格。
如图6所示，所述采血系统还包括生猪单采血浆固定装置，其包括用于承托生猪的金属固定架、用于生猪绑扎固定在金属固定架上的绑带和猪鼻捻金属保定器。所述金属固定架31采用14根铁质空心圆柱管焊接而成，其中包括两个对称设置的支撑脚，所述支撑脚由两根交叉设置的铁管组成；所述金属固定架31顶部中间位置设有垫板32，所述垫板32架设在所述支撑脚上，所述垫板32的两侧设有中管，所述中管的两端分别与两支撑脚连接，所述中管的外侧设有外管，所述外管的两端分别与两支撑脚连接。金属固定架31长度为130cm，高处宽度为60cm，低处高度为60cm，其管内径为2.0cm，外径为2.5cm；空洞的管架结构有利于全方位地观察猪状况和便于操作；金属固定架31长度为130cm、高处宽度为60cm是根据猪的体型设计的，低处高度为60cm适合操作者操作高度，固定架的大小和管的粗细决定了承受猪重量的能力。垫板32的前端以及中管的前端上置有防护棉垫33，防护棉垫33的材质为包空调管的黑色扎带，可防护猪头部的碰撞；板垫前端上的防护棉垫33内嵌有木头骨架，木头骨架被钉在板垫32上，使防护棉垫33稳固。所述绑带包括设于外管两端的肢体绑带34和设于中管中部且横跨垫板32的体部绑带37。操作时，把生猪呈仰卧式抬上金属固定架31后，用肢体绑带34将猪的四肢(即肘关节到猪蹄之间)套索式绑住并固定在金属固定架31的焊接点上，防止绑带滑动。体部绑带37横放于垫板32的中部上，在生猪下架前捆住猪的腋下和腰部，便于把猪抬下金属固定架31。生猪被抬上金属固定架31并绑住后，用猪鼻捻金属保定器35的套索套住猪的上颌骨，收紧套索，套住猪上颌骨的部分有软套胶，能减轻对猪上颌骨的伤害，金属保定器35的牵勾则绕过金属固定架31底部的横杆1-2圈，勾在金属固定架31底部铁管上。由于金属保定器35实际上不像站立式保定法一直处于用力牵拉状态，所以猪的嚎叫频率能相对减少。在垫板32的尾端上设有塑料薄膜36，用于接卸猪的排泄物，若为雄性生猪，还可在猪的腹部铺上毛巾以防尿液污染。
所述血液储存系统在动物血浆采集后应在6小时内冷冻至-20℃以下。
所述血液运输系统在运输环境温度在-15℃以下。
猪血浆的应用，将按照上述步骤得到的猪血浆/血清分别用于提取猪纤维蛋白 原、猪凝血酶原、猪白蛋白、猪免疫球蛋白。
本发明除了用于猪以外，也可改进后应用于牛、马、羊、犬、鹿、猴等动物。

Claims (10)

  1. 一种动物血浆、血清或血液的生物安全性质量控制系统，其特征在于：包括用于检验动物是否健康符合采血标准的检验系统、动物采血系统、血液储存系统和血液运输系统；
    所述采血系统包括静脉采血导管、血浆泵、将血液分离成血浆和血细胞的离心机和血浆袋，所述静脉采血导管设有Y型的导管接口；所述静脉采血导管通过导管与血浆泵连接，所述血浆泵通过导管与离心机连接，所述离心机通过导管与血浆袋连接，静脉采血导管、血浆泵、离心机、血浆袋组成血浆采集线路；离心机、血浆泵、静脉采血导管组成血细胞回流线路；所述静脉采血导管包括管体、连接座、外延管、滑扣和外延管接头，所述管体的后端通过连接座与外延管一端连接，外延管另一端与外延管接头连接；所述管体的前端管口侧面设有与管体相通的两个侧孔；
    所述采血系统包括生猪单采血浆固定装置，其包括用于承托生猪的金属固定架、用于生猪绑扎固定在金属固定架上的绑带和猪鼻捻金属保定器；所述金属固定架包括两个对称设置的支撑脚，所述金属固定架顶部中间位置设有垫板，所述垫板架设在所述支撑脚上，所述垫板的两侧设有中管，所述中管的两端分别于两支撑脚连接，所述中管的外侧设有外管，所述外管的两端分别与两支撑脚连接；所述垫板的前端和中管的前端分别设有防护棉垫。
  2. 根据权利要求1所述的一种动物血浆、血清或血液的生物安全性质量控制系统，其特征在于：两所述侧孔分别位于管体相对的两侧壁上。
  3. 根据权利要求1所述的一种动物血浆、血清或血液的生物安全性质量控制系统，其特征在于：所述侧孔的孔径为管体口径的1/3-2/3大小，两侧孔相距3-8mm，靠近管口的侧孔距离所述的管口后方5-10mm。
  4. 根据权利要求1所述的一种动物血浆、血清或血液的生物安全性质量控制系统，其特征在于：所述的管体为直型单腔导管，所述的管体口径范围为1.40-2.70mm。
  5. 根据权利要求1所述的一种动物血浆、血清或血液的生物安全性质量控制系统，其特征在于：所述管体前端4mm为增厚的耐磨性锥形管口。
  6. 根据权利要求4所述的一种动物血浆、血清或血液的生物安全性质量控制系统，其特征在于：所述管口材料为硅胶、聚氯乙烯或聚氨基甲酸酯。
  7. 根据权利要求1所述的一种动物血浆、血清或血液的生物安全性质量控制系统，其 特征在于：所述外延管为增厚的透明管，其内壁光滑度与所述管体光滑度相近。
  8. 根据权利要求1所述的一种动物血浆、血清或血液的生物安全性质量控制系统，其特征在于：所述垫板的末端设有接卸排泄物的塑料薄膜；所述绑带包括设于外管两端的肢体绑带和设于中管中部且横跨垫板的体部绑带。
  9. 根据权利要求1所述的一种动物血浆、血清或血液的生物安全性质量控制系统，其特征在于：所述检验系统对动物进行检验，检验的方法包括：
    a.检查动物接种记录，应已注射口蹄疫疫苗、猪瘟疫苗、蓝耳病疫苗和禽流感疫苗；
    b.通过视诊、触诊和听诊确定动物应符合健康标准；
    c.动物应具有完整的编号和生长记录；
    d.采用PCR方法或RT-PCR方法检测，每份血浆或血液的猪瘟病毒、伪狂犬病毒、口蹄疫病毒、乙型脑炎病毒和猪链球菌应为阴性，猪细小病毒滴度应不大于10.0IU/μl。每份血浆或血液的猪瘟病毒抗体、口蹄疫病毒抗体应为阳性；
    e.采用中国药典细菌内毒素检查法检测，动物血浆细菌内毒素应不高于0.1IU/ml。
  10. 根据权利要求1所述的一种动物血浆、血清或血液的生物安全性质量控制系统，其特征在于：所述血液储存系统在动物血浆采集后应在6小时内冷冻至-20℃以下；所述血液运输系统在运输环境温度在-15℃以下。
PCT/CN2016/087194 2016-03-30 2016-06-25 一种动物血浆、血清或血液的生物安全性质量控制系统 WO2017166458A1 (zh)

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