Flash! CDE issued the Technical Guiding Principles for Pharmaceutical Research and Evaluation of Specific Human Immunoglobulin.

      In order to standardize and guide the R&D, production and registration of specific human immunoglobulin, and further clarify the technical evaluation standards, under the deployment of National Medical Products Administration, the Drug Testing Center organized and formulated the Technical Guiding Principles for Pharmaceutical Research and Evaluation of Specific Human Immunoglobulin (see Annex).
       According to the requirements of the Notice of the General Department of National Medical Products Administration on Printing and Distributing the Release Procedures of Drug Technical Guidelines (No.9 [2020] of the General Administration of Drug Administration), with the approval of National Medical Products Administration, it is hereby promulgated and shall come into force as of the date of promulgation.
       This is for your information.

       Appendix: Technical Guiding Principles for Pharmaceutical Research and Evaluation of Specific Human Immunoglobulin
National Medical Products Administration yaoshen center
May 20, 2022   
I. Overview

Specific human immunoglobulin (HIG) is a highly effective immunoglobulin preparation prepared from plasma containing specific antibodies.

The sources of plasma include plasma with high titer antibody after the patient recovered from infection with a pathogen, and plasma containing specific antibodies by hyperimmune injection of healthy blood donors, that is, injection of vaccines or other antigens to make the injected people produce antibodies. Specific human immunoglobulin (hereinafter referred to as "special immune product") is an indispensable blood product because it contains specific antibodies with high titer, and its effectiveness in preventing and treating specific diseases is better than that of ordinary human immunoglobulin.

In order to encourage, standardize and guide the research and development of special exemption products, this guiding principle is formulated with reference to the relevant technical requirements at home and abroad and combined with the actual situation in China. This guiding principle is only based on the current technical development and scientific cognition, aiming at the general pharmaceutical research technical requirements of special exemption products. The applicant/holder can also adopt other more effective methods and means according to the actual situation of the research and development of the exempted products, but it should conform to the law of drug research and development and provide scientific and reasonable basis to ensure the safety, effectiveness and controllable quality of the products. 

Second, the scope of application 

These guiding principles are applicable to the special immunity products made of specific antibody plasma obtained by direct screening of specific antibody of plasma donors and active immunization. They have similar product characteristics and pharmacological characteristics, and their pharmaceutical requirements are both common and different. At present, the varieties included in People’s Republic of China (PRC) Pharmacopoeia (hereinafter referred to as China Pharmacopoeia) include hepatitis B human immunoglobulin, rabies human immunoglobulin, tetanus human immunoglobulin, etc. The research and development and registration of special exemption products at home and abroad are shown in Schedule 1, and the modes of administration are divided into intravenous injection, intramuscular injection and subcutaneous injection.

III. General principles 

1. Security. 

Because of the particularity of blood products, there is a potential risk of virus pollution, and virus safety control is the core content of blood products quality control. The collection, inspection, storage, transportation, traceability and the immune requirements of plasma donors of the plasma exempted products shall conform to the provisions of "Plasma for Blood Products Production" in China Pharmacopoeia and "Quality Management Standard for Plasma Collection Stations". It is suggested that screening research on B19 and other pathogens should be carried out according to product characteristics and clinical users, especially some special varieties (such as anti-D immunoglobulin). It is suggested that the applicant/holder cooperate with relevant departments to carry out epidemiological monitoring in the area where the plasma station is located. Actively promote the detection technology of nucleic acid in raw plasma and mixed plasma, and formulate standards and requirements. Special attention should be paid to the epidemic situation and detection methods of new and sudden infectious diseases.

2. Specific antibody screening. 

The accuracy and reliability of specific antibody screening results is the key to ensure the quality of raw plasma. In the case of large-scale production, the amount of single plasma detection involved is large, so it is necessary to establish a suitable antibody titer detection method and fully verify it by the method in the early stage of research and development. Single plasma can be screened for specific antibodies by immunolabeling method, and the correlation between binding titer and neutralization titer can be established. The combined plasma, stock solution and preparation shall be tested for specific antibodies by the method specified in China Pharmacopoeia or the verified method. Usually, based on virus neutralization test (mouse neutralization test, micro-cell lesion count and plaque reduction test), immunolabeling test (enzyme labeling, fluorescence labeling, isotope labeling, etc.), hemagglutination inhibition test, immunodiffusion test, immunoturbidimetry test or other immune/biochemical tests, the research is carried out by quantitative and semi-quantitative methods based on reference materials.

3. Production technology 

The process development of this kind of products can refer to the process of similar products that have been listed, and platform technology can be used. The use of chromatography is encouraged to improve the purity of products, but the selection of chromatographic parameters and the influence of the quality of chromatographic resin on the quality of products should be fully considered, and the inactivation and removal ability of viruses by the process should be paid special attention to. The verification of virus inactivation/removal should meet the requirements of General Principles of China Pharmacopoeia "Virus Safety Control of Biological Products", "Technical Methods and Verification Guidelines for Virus Removal/Inactivation of Blood Products" and technical documents such as ICH and WHO.

Management rules and operating procedures should be established for personnel safety protection and wastes in the production process, bioactive substances and viruses should be inactivated according to proven inactivation treatment methods, and effective protective measures should be taken to protect operators to avoid risks such as virus transmission.

Four, pharmaceutical research and evaluation points 

(1) Raw plasma and materials for production 

1, plasma source and quality control 

Quality control of single plasma: single plasma must meet the relevant quality control requirements issued by the national health administrative department. Raw plasma used for production must have legal sources (plasma station certification documents, etc.) and pass inspection and quarantine, and should have complete reagent data (marketing certification documents, etc.) and screening records (antigens/antibodies/nucleic acids) for screening blood-borne infection markers.

Immune procedure: immune procedure and dosage of antigen used are the key factors to determine the concentration and titer of antibody in plasma. It is necessary to define the immunization methods. For example, when active immunization is carried out with approved vaccines or other antigens, these immunogens should have complete source certification information and batch information. The immunization program should refer to the requirements of vaccine instructions, or be formulated according to the immunogenicity of antigen and the reactivity of plasma donors, but the specific immunization program adopted should prove its safety. Subjects should have full right to know, and at the same time make corresponding countermeasures for possible problems. 

Quality control of mixed plasma: A certain amount of plasma should be mixed, which should meet the requirements of China Pharmacopoeia in combination with product characteristics. At present, ordinary people are required to mix the plasma of at least 1000 plasma donors. Specially exempted products generally require plasma mixing from at least 100 plasma donors, except for some special varieties (such as anti-D immunoglobulin products).

No matter the plasma obtained by active immunization with approved vaccine or immunogen or the plasma immunized after natural infection, the specific antibody content standard of each plasma and combined plasma should be formulated at the time of IND declaration. The plasma whose antibody level is up to the standard is used for plasma production. For varieties that have not been recorded in China Pharmacopoeia, there should be a clear basis and a proven detection method for determining the titer of specific antibodies in raw plasma and preparations. When NDA is declared for the varieties included in China Pharmacopoeia, the antibody titer standard should not be lower than the requirements of China Pharmacopoeia.

2. Raw materials for production 

Strict quality control of raw materials used in the production of special exemption products is a necessary measure to reduce the risk of contamination by exogenous factors or toxic impurities in products and avoid the activation of other factors in plasma. In addition to clear sources, quality standards and inspection reports, raw materials for production should also focus on the use of animal-derived raw materials (such as heparin) and avoid using animal-derived raw materials as much as possible. TSE/BSE risk assessment should be conducted for raw materials used in production. 

When using filter AIDS (perlite, diatomaceous earth, etc.), filter membranes and filter element materials in the separation process, it is necessary to establish appropriate quality control standards according to the requirements of different process stages, control the introduction risk of exogenous factors, control bacterial endotoxin and heavy metals, and formulate reasonable limit requirements. In addition, it is necessary to pay attention to the risk of residues that may be mixed into the final product and potentially harmful to human body, and control them if necessary.

(2) Production technology 

1. Stock solution 

The initial raw material of the special immunity products is raw plasma or plasma components. The modified Cohn method or KistlerNitschmann method can be used to separate the special immunity products, and other methods can also be used for separation and purification, such as octanoate precipitation and chromatography. 

The separation and purification process adopted should ensure that the physicochemical and biological properties of the product and the biological activity of the Fc segment of IgG are well preserved. The production process must avoid or eliminate the pollution of microorganisms (bacteria, viruses) and their metabolites (pyrogens) to the maximum extent. It is necessary to strengthen the control of production process and consider the influence of the removal of filter AIDS and the selection of filter media on the products. It should be paid attention to that IgG fractions obtained by different separation methods may contain higher levels of IgA and IgM. At the same time, attention should be paid to the rationality of sterilization and filtration steps, and the integrity of the filtered membrane should be checked.

It is necessary to specify the amount of slurry for pre-clinical, clinical samples and market-scale samples. Generally, continuous production should be carried out, and the production capacity of each process step should be matched with each other, and the processing should be completed at one time. In each process step, it is the key to determine the process control parameters and scope and meet the requirements. When using ethanol and other precipitation methods, it is necessary to control the quality of ethanol and other reagents, and study the protein concentration, temperature, pH value, ionic strength, treatment time and so on, so as to define the acceptable limit range. In the process of dissolution and precipitation of plasma components, avoiding IgG coprecipitation is the key to improve the product yield, especially the key indexes such as temperature and adding time should be fully studied to investigate the influence on the key quality indexes such as protein purity and molecular size distribution. When chromatographic method is used, it is necessary to optimize chromatographic conditions and determine reasonable parameters according to the nature and concentration of protein in the product, such as the capacity of chromatographic column, ionic strength of feed solution and buffer solution, pH value of buffer solution, flow rate, contact time and temperature, etc. The determination of these parameters should be based on the research data of process development, and limit standards and allowable ranges should be formulated. At the same time, it is necessary to study the cleaning and regeneration (service life) of chromatographic resin, the load of chromatographic column and the extract, especially the use of chromatographic packing with potentially harmful ligands. It is necessary to pay attention to the volume, protein concentration, recovery rate and electrophoretic purity of each separation and purification step, and evaluate the process-related impurities (such as ethanol, sedimentation aid, IgA, aluminum, heavy metal ions, etc.) and product-related impurities.(such as polymers, etc.). If necessary, in order to prove the ability of the process to remove impurities, it may be necessary to use standard addition test to evaluate the ability of the process to remove some potential pollutants. If operations that may affect product quality, such as temporary storage and transportation of intermediate products, need to be supported by necessary stability research data.

Encourage the use of innovative and improved processes (including the improvement of ethanol separation process) to improve the utilization rate of plasma and improve the quality of special exemption products. In the early stage of process development, attention should be paid to the identification of key process parameters, the integrity of process control in different separation stages and the rationality of process parameter setting. If the applicant/holder has already marketed products with the same separation and purification process, and the existing process research data and control parameters can be used for reference, the process verification of three batches of new special exemption products should be carried out. 

Considering the preciousness of plasma resources, the pilot-scale research data suitable for clinical trials can also be used for the declaration of IND stage. However, when applying for NDA, it is necessary to have complete commercial scale research data.

2. Preparation 

Clarify single prescription and batch prescription, and explain the basis of rationality of preparation prescription. Auxiliary materials suitable for medical use should be used, and the stability of the supply chain should be ensured. For accessories from multiple suppliers, it is necessary to carry out full research. For brand-new excipients that have not been used in similar preparations at home and abroad, a comprehensive study should be carried out and related declarations should be made. No bacteriostatic agent shall be added to the special exemption products for intravenous injection. Because some cosolvents (such as polysorbate 80) have the potential risk of causing allergic reaction and hemolysis reaction, safety evaluation should be carried out. The preparation process (such as stirring speed) should be studied. In principle, the preparation of semi-finished products should come from a batch of stock solutions. If different batches of stock solutions are used to prepare semi-finished products, the possible risks should be evaluated.

The temperature of products, the duration of packaging, the temperature and humidity of packaging environment should be controlled. Special exemption products involving freeze-drying technology should have data such as freeze-drying process parameters and freeze-drying curves verified by commercial batches, indicating the influence of freeze-drying technology on product quality, especially on biological activity.

3. Process verification 

For the products exempt from intramuscular injection, it is necessary to determine the process flow and key process parameters before NDA declaration, and continuously produce three batches of products to verify the stability of the process, so as to provide a supporting basis for the products to go on the market. For the special exemption products for intravenous injection, the process flow and key process parameters should be determined as far as possible before the confirmatory clinical trial, and the stability of the process should be verified by continuous production of three batches. If there are differences between clinical trial samples and commercial scale batches in terms of production technology or site, it is suggested to carry out change research, and it is suggested to carry out research and exploration on the worst process conditions at an appropriate stage, and it is necessary to prove that qualified products can be produced under the determined process parameters and quality control limits. If multiple production sites or production lines are involved, verification research should be carried out. 

(III) Virus safety and virus removal/inactivation verification 

The detection of single plasma and mixed plasma should meet the requirements of China Pharmacopoeia, and the number of cases of mixed plasma should meet the sensitivity requirements of the kit/detection method. For anti-D immunoglobulin, the nucleic acid load of B19 virus in plasma should be ensured to be less than <104 IU/ml.

Because of the differences in the ability of inactivation/removal of lipid-coated and non-coated viruses by various methods, it is recommended to use two virus inactivation/removal methods with different mechanisms to carry out verification, and to clarify the technical conditions and control parameters of virus inactivation/removal process steps, including product uniformity, upper and lower temperature limits, inactivation time, filtration pressure/speed/temperature/solution composition/membrane integrity, etc. Attention should be paid to the rationality of setting the position of deactivation/removal process steps. When selecting virus removal/inactivation method, the effect of virus inactivation/removal should be balanced with product activity and general safety. 

It is necessary to consider the potential interaction between inactivation steps, the influence of inactivation process on antibody integrity and clinical efficacy, whether new immunogens are formed and the risk of toxic residues that may be introduced. If the production process changes, which may affect the virus removal ability, it needs to be verified again. In addition, the samples used for inspection should be representative of the process. With the development of technology, some new methods of virus inactivation can also be applied in special exemption products, which need to be proved to be scientific and effective and fully verified.

If the products with the same process steps have been approved and registered, and the virus inactivation/removal process has been verified, the newly declared products will only change the mode of administration, and the products with the same production equipment, process and operation as the original products in commercial batches can not be subjected to virus inactivation/removal process repeatedly on the premise of meeting the relevant technical requirements such as Technical Methods and Verification Guidelines for Removing/Inactivating Viruses from Blood Products and Technical Guidelines for Pharmaceutical Change Research of Listed Biological Products.

In order to ensure the virus safety of the final product, we should consider the setting of plasma station from epidemiological data, strictly select plasma donors, screen plasma and manage the quarantine period, optimize the production process and add virus removal/inactivation steps, and evaluate the virus removal ability of the whole process steps of producing products. To evaluate the virus inactivation/removal ability of the production process and the maximum load of specific virus that may exist in the initial plasma, and to ensure the virus safety of the product to the greatest extent, it is necessary to ensure that the verification includes the worst case.

(D) Quality research and control 

1. Analysis of physical and chemical characteristics 

It is necessary to gradually improve the analysis of physical and chemical characteristics in combination with product types, preparation types and drug development stages. IND declaration can be made based on the preliminary research data of physical and chemical characteristics, and NDA declaration should be made by comparing the physical and chemical characteristics, including antibody integrity, antibody subtype distribution, circular dichroism analysis, etc.

2. Biological activity 

Biological activity research should be fully carried out, and it is suggested to study the correlation between binding titer and neutralization titer detection methods. From the aspects of supporting the rationality of the process and considering the influence of the process on the product, it is suggested to establish a method for detecting the biological function of Fc, and to study the sialic acid content of Fc segment in the development stage. Production technology, antibody titer, IgG polymer, IgG subclass, etc. will affect the results of biological function test of Fc. In addition, it is suggested to analyze the binding ability of Fc segment to immune cell surface receptors, the activation of complement function by Fc segment, and the regulation of phagocytosis.

3. Purity and impurities 

Attention should be paid to the components that affect the function of this kind of products, and the purity is generally not less than 95%. In addition to carrying out research on impurity residues and proving the ability of the process to remove impurities, the impurity level limits of batches at different stages (if there are clinical and commercial batches) should be set reasonably. It is suggested that a sensitive method should be used to control the content of impurity protein. 

Polymers produced during the preparation of special immunity products are related to anti-complement activity (ACA), and the content of IgG polymers should be controlled. In order to prevent patients with congenital IgA deficiency from causing serious allergic reaction after using special immunity products, the content of IgA should be controlled. The content of anti-A and anti-B hemagglutinin should be studied and the limit standard should be established to prevent hemolytic reaction caused by large amount of infusion. Encourage the detection of coagulation activator levels and establish standards. It is suggested that anti-D antibody detection should be carried out for intravenous special immunity products from special plasma sources. In addition, in order to prevent the risk of thrombosis, it is suggested to control the FXIa content of intravenous special immunity products and establish standards.

Encourage the detection of other miscellaneous proteins in blood, such as kallikrein activator, immunoglobulin M, transferrin, albumin, α1- antitrypsin, α2 macroglobulin, haptoglobin, α1- acidic glycoprotein, ceruloplasmin, fibrinogen, antithrombin III, plasminogen, fibronectin and C1 esterase inhibitor.

Special exemption products, especially those for intravenous injection, should also focus on the control of insoluble particles. Insoluble particles can not be metabolized in human body, and it is easy to induce thrombosis if they stay in tiny blood vessels. The content of aluminum should be controlled. Aluminum has potential risks to the central nervous system, bones and other organs, and this risk is related to the infusion dose.

4, quality analysis and standards 

The listed special exemption products should meet the requirements of China Pharmacopoeia, and the rationality of testing items should be fully considered for new special exemption products. Quality standards should be set reasonably according to the characteristics of products with different administration methods, such as intravenous special exemption products, and FXIa factor, aluminum ion and IgA content should be increased.

When applying for IND, special attention should be paid to antibody titer, harmful residues and other related testing items.

When applying for NDA, the quality standards of stock solution, semi-finished products (if any) and preparation should be reasonably drawn up based on the data of various research and development stages and stability inspection, on the basis of statistical analysis of multiple batches, combined with the requirements of China Pharmacopoeia and the situation of similar products, with emphasis on the quality control of potency, and more stringent internal control standards should be encouraged. Advanced and mature methods should be used for titer detection, and various complementary analysis methods should be encouraged for quality control in the early stage of research and development. If auxiliary materials such as maltose, polysorbate 80 and glycine are added to the preparation, it should be controlled in the quality standard of the preparation and its content range should be defined.

5, analysis method and methodology verification 

Combined with the characteristics of products, select a reasonable analysis method and carry out sufficient methodological verification to ensure the feasibility of the method.
At the time of IND declaration, at least the preliminary verification of antibody titer and harmful residue detection method should be completed.

When applying for NDA, a complete analysis method should be established and verified. Clarify the accuracy, precision (including repeatability, intermediate precision and reproducibility), specificity, detection limit, quantitative limit, linearity, range and durability of the determination method. Methods other than those in China Pharmacopoeia should be fully verified when applying for NDA. If the determination method is changed greatly, the scope of re-verification should be determined according to the degree of revision of the method.

Establishment and verification of antibody titer detection methods: research on product-specific antibody titer detection methods and standards should be carried out before research and development. It is suggested to study the correlation between binding titer and neutralization titer detection methods. Try to use the method of China Pharmacopoeia, and try to choose the classic and industry-standard method for those not included in China Pharmacopoeia. Clarify the test operation flow, test parameters, preparation and calibration of work standards and criteria for judging results. According to the antibody titer detection method itself, select appropriate indicators to carry out methodological verification and establish verification scheme. Generally speaking, in terms of linearity, the correlation coefficient of neutralization titer determination method should meet the pre-set acceptable standards. In terms of accuracy, the ratio between the actual titer of neutralizing antibody and the theoretical titer of serum with different dilution times is 1, or the slope of regression line in covariance analysis is parallel. In terms of precision, the coefficient of variation should be controlled within 30% as far as possible. In terms of durability, it is necessary to investigate the effects of cell density (generation), neutralization virus dose, neutralization reaction conditions and time, and different positions of orifice plates on the test results. In order to study the influence of possible degradation products and degradation pathways on titer determination, the samples can be destroyed by accelerated methods such as strong light irradiation, high temperature and high humidity. Encourage the use of working standards as quality control, reduce test interference factors, and improve the accuracy and reliability of results.

Verification of detection methods for hazardous residues: Usually, hazardous residues are at trace level, and the sensitivity of detection methods determines the reliability of the results. Encourage the use of more advanced methods and instruments with higher sensitivity based on the methods in China Pharmacopoeia, and pay attention to distinguish the detection limits of instruments and methods. The obtained detection limit and quantitative limit data must be verified by samples with similar contents.
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Test process and detection limit results, including accuracy and precision verification data. The linear indexes such as recovery rate (%) and relative standard deviation (RSD%) should be listed as regression equation, correlation coefficient, residual square sum linear graph, etc. The range should be drawn up within 20% of the specified limit according to the preliminary measured data, and in general, various methods with different principles should be used to verify each other. Methodological verification of product-related impurities: Methodological verification shall be carried out according to the requirements of China Pharmacopoeia. If the commercial kit is used for residue detection, it is suggested to study the selection of detection kit (such as IgA detection), and the detection kit should explain the sensitivity, specificity, detection limit, quantitative limit and linear range. In general, the accuracy, precision, linear range, interference test, reference interval and other indicators of the kit should be verified. The variation coefficient of precision should be within 20%, the accuracy deviation should not exceed 10%, the linear range determination coefficient (R 2) should be ≥ 0.98, and the relative deviation of interference test should be less than 10%. Attention should be paid to identify the factors that affect the accuracy of the determination results during the release test of products, such as pH value, PK activity, ionic strength of product solution, reaction temperature, etc., which will affect the determination results of PKA, and low pH conditions may reduce the PKA activity of products. 

6, reference (standard)

The quality control reference of antibody titer should be established according to the requirements of relevant guiding principles. When applying for NDA, it is necessary to clarify the key information such as the source and quality control of reference materials, and the reference materials should be related to the samples used in clinical experiments, paying attention to the accuracy and traceability of assignment. If international/national standards are adopted, the information of standards used (source, batch, etc.) shall be specified. If it is a self-made reference, the preparation process, calibration and stability should be studied.

(5) Stability study 

Stability test runs through the whole product life cycle and is the basis for formulating product standards and expiration dates. The stability test should be carried out in accordance with the China Pharmacopoeia and the relevant guiding principles of stability research of biological products at home and abroad. In the declaration stage of IND, preliminary stability inspection can be conducted to ensure the quality of samples in clinical stage. Complete a comprehensive stability inspection before NDA declaration, select suitable packaging materials, define storage and transportation conditions, and formulate a reasonable validity period. The investigation of influencing factor test and accelerated test should be studied as far as possible until the product is unqualified. Long-term stability investigation should extend the observation time of products as much as possible. In general, the liquid dosage form should be placed upside down and upright for stability test. Products with different closed systems should be tested for stability respectively. If a new production site is introduced to produce intermediate products, unless there are other reasons, the stability research of intermediate products and finished products should be carried out. The activity of Fc segment is an important indicator of the effectiveness of this kind of products, so it is suggested to investigate the related stability. For the special exemption products in liquid dosage form, the thermal stability test should be carried out, and the visible foreign bodies should be checked. The results should meet the requirements of China Pharmacopoeia.

(6) Packaging and sealing container system 

The source and control standard of inner packaging materials should be clarified, and the compatibility and sealing of packaging materials should be studied in accordance with the relevant guiding principles such as Technical Guiding Principles for Compatibility Research of Chemical Injection with Medical Glass Packaging Container (Trial Implementation), Technical Guiding Principles for Compatibility Research of Chemical Injection with Plastic Packaging Materials (Trial Implementation) and the requirements of ICH related guidelines. Extracts, dissolved substances, sloughs, etc. shall meet the limit requirements. Pay attention to the influence of the extract of inner packing rubber stopper and glass bottle on the preparation. 

V. Explanation of nouns

1. Blood Products refer to therapeutic products derived from human blood or plasma, such as human albumin, human immunoglobulin, human coagulation factor, etc.

2. Human Normal Immunoglobulin (HNIG): also known as gamma globulin or multivalent immunoglobulin, is an immunoglobulin preparation separated from healthy human plasma by low-temperature ethanol protein separation method or other approved protein separation methods, including intravenous immunoglobulin, intramuscular immunoglobulin and subcutaneous immunoglobulin.

3. Specific human immunoglobulin (HIG): It is a high titer immunoglobulin preparation prepared from plasma containing specific antibodies. The sources of plasma include plasma with high titer antibody after the patient recovered from infection with a pathogen, and plasma containing specific antibodies by hyperimmune injection of healthy blood donors, that is, injection of vaccines or other antigens to make the injected people produce antibodies. Different from ordinary immunoglobulins, such preparations must have at least one high titer antibody for the prevention and treatment of specific diseases in clinic.

4. Anti-complement Activity (ACA): A substance in serum or tissue fluid that can nonspecific bind to complement and make it inactive, such as protease and ester. 

VI. References (omitted)

Chang’ an automobile Oula haomao

Changan Automobile Euler Good Cat is a brand owned by Great Wall Motor Group. The brand OLA was launched in 2018, focusing on new energy vehicles.

"Good Cat" is one of the models of the brand, which is positioned in the small pure electric vehicle market, mainly for urban commuting and daily use. Its exterior design is fashionable and simple, while the interior pays attention to comfort and sense of technology. In terms of power, the good cat is equipped with a motor with a maximum power of 105 HP and a cruising range of more than 400 kilometers.

Generally speaking, Euler Good Cat is an environmentally friendly and energy-saving pure electric vehicle suitable for urban use.

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As a luxury sedan, the side lines of the Hongqi EH7 show the perfect combination of elegance and power. The body length reaches 4980mm, the width is 1915mm, the height is moderate at 1490mm, and the wheelbase reaches 3000mm, making the interior space spacious and comfortable. The front wheel base of 1645mm and the rear wheel base of 1655mm are set to ensure driving stability. The tire size is 245/50 R18, and it is selected with practical and delicate tires. With the wheel style that complements the body line, it gives the EH7 a unique sense of sports and luxury.

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In the interior design of Hongqi EH7, its refinement and luxury are immediately apparent. With a modern and traditional fusion style, the leather steering wheel feels delicate and supports manual up and down and front and rear adjustment, which is convenient for the driver to control accurately. The center is equipped with a 15.5-inch high definition central control screen, which integrates functions such as multimedia system, navigation and telephone, and also supports automatic speech recognition, which is convenient to operate. For the seat part, the seat material is a mix of imitation leather and leather/flip hair, which provides both comfortable touch and texture. The main and passenger seats can be adjusted in 4 or 2 directions, and are equipped with user-friendly functions such as heating, ventilation and headrest speakers. The driver’s seat is also equipped with electric seat memory to ensure the comfort of long-distance driving. In addition, the rear seats support proportional reclining, providing flexible storage space. Together, these configurations create a comfortable and technology-filled driving experience in the Hongqi EH7.

The Hongqi EH7 is equipped with a powerful engine with a maximum power of 253 kW and a maximum torque of 450 Nm, fully demonstrating the excellent performance and technological strength of the Hongqi brand. This engine undoubtedly provides the EH7 with surging power support and excellent driving experience.

To sum up, the Autohome owner has a lot of praise for the Hongqi EH7. He especially appreciates its sporty and stylish body design, as well as its eye-catching light group and unique logo at night. For this owner, the 4.98-meter body length and the new new energy logo have undoubtedly added to the charm of the vehicle. The Hongqi EH7 undoubtedly satisfies his pursuit of personality and quality and becomes his favorite car choice.

Cost-effective volume Wang Tiguan L 2024 listed IQ face value cost-effective full

  On November 1st, Tiguan L 2024 was launched, with a suggested retail price of 198,700 yuan — 247,000 yuan, of which 300TSI Zhixiang Edition is limited to 169,900 yuan, and there are different degrees of discounts when purchasing other editions.

Cost-effective volume Wang Tiguan L 2024 listed IQ face value cost-effective full _fororder_image001

  At the same time as the new model goes on the market, the sales of Tiguan L are also improving recently. According to the data, the Tiguan family delivered 17,902 vehicles in September, leading the joint venture SUV market. At the same time, Tiguan L also won the honor of being the first medium-sized SUV with more than 200,000 in the 2023 China Fuel Automobile Industry Customer Satisfaction Index (CACSI) evaluation, which brought super-value preference to consumers.

  High face value, strong smart price and better 330TSI R-Line, the more enjoyable version can be played.

  Tiguan L 2024 continues the Tiguan family’s IQ value double online, and focuses on the cost-effective advantage. Among them, the recommended retail price is lowered to 237,000 yuan, and the more enjoyable version of 330TSI R-Line brings a value-added experience with high value, high quality and high intelligence. It not only has a sporty front face made of R-Line sporty high-gloss black air intake grille and striking C-shaped chrome trim, but also adds a fashionable atmosphere with 19-inch R-Line aluminum alloy precision wheels and prismatic three-dimensional LED taillights.

  The 330TSI R-Line Enjoy Edition continues to highlight the ingenious manufacturing, high-standard configuration and full-scale details of Tiguan L 2024, satisfying every beautiful trip of users. Outside the car, all-LED headlights with automatic adjustment function, electric folding rear rearview mirror with parking automatic folding function, passenger rearview mirror with reverse automatic turning down function, and inner rearview mirror with automatic anti-glare, showing human care in details. In the car, the new 12-inch floating central control panel integrates intelligent voice, gesture from a distance, touch control and other functions, plus a 10.3-inch all-digital LCD instrument, R-Line leather multi-function steering wheel, 12-way electrically adjustable main and co-pilot seats and front row heating function, featuring a practical and comfortable, with LED ambient light, the advanced texture of driving comes to the fore.

Cost-effective volume Wang Tiguan L 2024 listed IQ face value cost-effective full _fororder_image002

  Intelligently, Tiguan L 2024 is fully equipped with Volkswagen IQ. Technology, both IQ. Drive intelligent driving butler helps to drive easily and free hands, and IQ. Smart car coupling makes the journey full of joy. For example, the 330TSI R-Line Enjoy Edition brings the intelligent king level of 200,000 yuan intelligent SUV with a number of high-value intelligent equipment. Such as IQ. 360 Panorama and PLA 3.0 intelligent parking system, which provide help for long-distance and short-distance, high-speed, ground, start-up, parking and other road conditions.

Cost-effective volume Wang Tiguan L 2024 listed IQ face value cost-effective full _fororder_image003

  Limited time 170,000 yuan Get Porsche same technology engine Tiguan L cost-effective full

  In addition, Tiguan L 2024 continues to focus on the demand of consumers for both power and economy, and further optimizes the price of the new 1.5T EVO II net efficiency engine version. At present, you can experience audi ag’s new "Golden Engine" with a limited time discount of 169,900 yuan.

  The 1.5T EVO II net effect engine has two core highlights: high efficiency and high economy. Its maximum power is 118kW and maximum torque is 250Nm, which can bring faster dynamic response and more lasting and abundant power output. Especially when stopping and accelerating and decelerating on the way to and from work, the power responds at any time. For long-distance driving, this engine accelerates by 3.8% per 100 kilometers, bringing a more enjoyable acceleration experience. Most notably, 300TSI Zhixiang Edition can also use No.92 gasoline, and its fuel consumption under WLTC comprehensive working conditions is as low as 6.6L/100Km, and CO2 emission is reduced by 10g/km, so the car economy is quite friendly.

Cost-effective volume Wang Tiguan L 2024 listed IQ face value cost-effective full _fororder_image004

  As the pioneer of the domestic SUV market, the Tiguan L with IQ value double online is widely favored by users. According to the data, the Tiguan family delivered 17,902 vehicles in September, leading the joint venture SUV market, and now it has become the first choice for the 200,000-level joint venture SUV. The brand-new Tiguan L 2024 model continues to bring super-value preference to consumers. (Photo: provided by SAIC Volkswagen)

Driving and control experience of Yuntian -C in Han and Tang Dynasties: leapfrog luxury performance, comfortable sports are all satisfied!

On April 22nd, BYD Tang family ushered in the launch of a new model. The starting price of 219,800 yuan and the standard Yunqi -C made the new car extremely competitive. Taking the opportunity of this driving and control experience camp in Hantang Yunqi -C, Jiao Ge will take you to experience how fragrant the dual flagship of Hantang with Yunqi -C is!

Test drive evaluation

Beibu Gulf Airlines, a subsidiary of HNA Airlines, has been sailing for eight years to boost the high-quality development of Guangxi civil aviation.

Huang Bingzhu, correspondent of China Civil Aviation Network, reported that at 2: 18 a.m. on February 16th, the flight Jining-Nanning GX8960 of Beibu Gulf Airlines, a subsidiary of HNA Airlines, successfully landed at Nanning Wuxu International Airport, which marked the successful conclusion of Spring Festival travel rush in 2023 and also opened the prelude to the 8th anniversary of the establishment of Beibu Gulf Airlines. In the first Spring Festival travel rush after the adjustment of the epidemic policy, Beibu Gulf Airlines, which has been sailing for eight years, achieved a remarkable "good start": in 2023, Spring Festival travel rush carried out more than 3,800 flights, a substantial increase of 50% over the same period in 2022; Passenger traffic was 410,000 passengers, up 70% year-on-year, and many core business indicators such as single-day total revenue, single-day profit, double-machine hourly revenue and single-machine revenue all exceeded historical records …

Looking back on February 16, 2015, a passenger plane wearing a big red GX logo took off from Nanning Wuxu International Airport, and the first local airline in Guangxi, Beibu Gulf Airlines, officially set sail. Since its establishment eight years ago, Beibu Gulf Airlines has made vigorous efforts, practiced the corporate culture of "Party building is the soul", adhered to the development orientation of "based on Guangxi, serving the whole country and facing ASEAN", and sounded the clarion call of the times for a new journey of endeavor.

"From scratch" —— Guangxi local aviation realizes leap-forward development

Before the establishment of Beibu Gulf Airlines, due to economic and historical reasons, Guangxi lacked backbone airlines with local bases for a long time, which made it difficult to meet the growing air travel needs of Guangxi people. With the China-ASEAN Expo permanently settled in Nanning, Beibu Gulf Airlines came into being in February 2015 with the strong support of the Party Committee, government and Civil Aviation Administration of the autonomous region, and quickly entered the fast lane of steady development.


Beibu Gulf Airlines A320 passenger plane


Beibu Gulf Airlines newly introduced A320 passenger plane arrived at Nanning Wuxu International Airport.

In the eight years since its launch, the size of Beibu Gulf aviation fleet has increased from three at the initial stage to 28, from E190 single aircraft at the initial stage to E190-A320 dual aircraft fleet, with a total of 273 operating routes and 97 navigable cities, with over 200,000 flights, nearly 400,000 hours of safe flight and over 20 million passengers safely transported. At the same time, Beibu Gulf Airlines has always adhered to the principle of "people first, life first", fully implemented the general requirements of "change, dry and practical", introduced and implemented a series of safety management reforms, and increased safety management. Up to now, Beibu Gulf Airlines has not experienced serious symptoms or above. It has achieved the annual safety management objectives of the Civil Aviation Administration for eight consecutive years, and successfully passed the global civil aviation safety industry standard-International Air Transport Association Operational Safety Audit Certification (IOSA). The safety performance of safe operation is at the forefront of the industry and HNA Aviation Group.

"Gorgeous Turn" —— Guangxi local airlines resume flights to ASEAN to open up markets

On February 6, 2023, the departure hall of Terminal 2 of Nanning Wuxu International Airport was very lively. Beibu Gulf Airlines and Nanning Airport held the departure ceremony of the first delegation of Nanning = Bangkok route resumption and Guangxi’s resumption of outbound tourism. 159 passengers took flight GX8907 to Bangkok, Thailand, marking the official resumption of the operation of ASEAN international routes by Guangxi local airlines. At the beginning of the company’s establishment, Beibu Gulf Airlines took "facing ASEAN" as one of its development orientations, and actively prepared for international routes while steadily building a domestic route network. Since 2018, it has successively opened a number of domestic routes to and from Southeast Asian countries, such as Nanning = Siem Reap, Nanning = Singapore, Nanning = Bangkok, Nanning = Hanoi, Lanzhou = Singapore and Luoyang = Hanoi, making full use of the network layout of nearly 100 domestic routes during the peak period of Beibu Gulf Airlines. In 2019, the passenger throughput of Nanning Airport’s Southeast Asia route rose to 925,000 passengers, and Beibu Gulf Airlines contributed nearly one-third of the passenger transportation share.


The resumption ceremony of Beibu Gulf Airlines Nanning = Bangkok international route

In 2023, with the successive adjustment of the national entry-exit policy and international passenger flight control measures, Beibu Gulf Airlines GX8907/8 Nanning = Bangkok flight resumed smoothly on February 6, and it is planned to be encrypted from 1 flight per week to 4 flights per week on March 1, and the Nanning = Singapore route will be resumed on March 7. In order to meet the travel needs of more passengers, Beibu Gulf Airlines also offers the lowest domestic transit price only in 100 yuan, which can transit to and from Southeast Asia from 23 cities including Chongqing, Chengdu, Xi ‘an and Jinan via Nanning.

"Transformation and rebirth" —— Guangxi local aviation management reform ushers in new opportunities for development

On December 8, 2021, Beibu Gulf Airlines officially joined Liaoning Fangda Group, integrating "party building as the soul" into the blood of enterprises, leading the development of enterprises with party building, continuously improving the decision-making power, innovation, productivity and cohesion of enterprises, taking party building as the "red engine" to drive the development of enterprises, managing enterprises with party building ideology, leading the development of enterprises with party building culture, and transforming the vitality of party building into the driving force for enterprise development. At the same time, Beibu Gulf Airlines accurately recognizes changes, scientifically adapts to changes, actively seeks changes, comprehensively introduces the advanced management experience of Liaoning Fangda Group to implement management changes, breaks the "wait, rely on, and want", practices "change, do, and be practical", implements an all-round "horse racing" mechanism, covering various professional lines such as safety, operation, service, and maintenance, and is performance-oriented and fully motivated.


Beibu Gulf Airlines appeared in the 2nd China-ASEAN Civil Aviation Cooperation Forum.

Beibu Gulf Airlines insists on intensive cultivation and strengthens the construction of route network system. While doing a good job in Nanning, it has set up overnight bases in Haikou, Changsha, Yichang and Yulin, and integrated the route network layout into the national strategies such as the construction of Hainan Free Trade Port, the development of the Yangtze River Economic Belt, the new land and sea passage in the west and Guangdong-Hong Kong-Macao Greater Bay Area, and actively promoted the recovery and development of the civil aviation market. In 2022, Beibu Gulf Airlines opened an overnight base in Yichang and new destinations such as Jingzhou and Wuhu, and made great efforts to build Nanning = Chongqing and Nanning = Jinan boutique routes, constantly optimizing the route network resources. In the winter and spring season, 14 routes including Yichang = Huizhou and Yichang = Qingdao were opened and 13 destinations were opened, and the route network layout was continuously expanded.

"Sincere Service" —— Polishing Guangxi Local Aviation Service Brand

Beibu Gulf Airlines "Qingxiu crew" was established in 2017. "Qingxiu" originated from Qingxiu Mountain, a famous scenic spot in Nanning. It takes the meaning of "clear and different, beautiful and not vulgar" and places a good expectation of "evergreen all the year round, always enterprising". This is a team of cabin service pacesetters who have been selected through various levels. The team members stand out from hundreds of flight attendants and are committed to building the air business card of the first local airline in Guangxi. Since its establishment, the flight crew has participated in many important activities such as China-ASEAN Expo, China-ASEAN Civil Aviation Cooperation Forum and important flight guarantee such as charter flights of Guangxi anti-epidemic medical team, and has successively won the honorary titles of "Youth Civilization" in Nanning and the first "Youth Civilization of Central and South China Civil Aviation". In addition, the crew participated in the design and development of the dining car fixing belt in the cabin, which can quickly fix the dining car in the cabin during bumps. This product has obtained the national patent certificate and has been fully promoted and implemented in Beibu Gulf air flights.


Beibu Gulf Airlines launched the theme flight of "Orchard in the Air" to promote Guangxi fruits.


The Beibu Gulf air crew carefully arranged the cabin atmosphere.

According to the concept of "sincere service" of Civil Aviation Administration, Beibu Gulf Airlines is committed to providing passengers with a more convenient, comfortable, efficient and pleasant high-quality travel experience by improving staff service awareness and strengthening subtle service innovation. Thanks to the joint efforts of all staff, Beibu Gulf Airlines has successively won honorary awards such as "Advanced Collective of National Transportation System in Fighting COVID-19 Epidemic", "Outstanding Contribution Collective of guangxi traffic Transportation Industry" and "TOP10′ Best Employer in Nanning by Zhaopin" in recent years, and its sincere service has been widely recognized by all sectors of society.


Guangxi Aid Qiong Medical Team arrived in Nanning by Beibu Gulf Airlines flight.


Beibu Gulf Airlines "Qingxiu Crew"

Winging for eight years will help Bagui take off and work together to build a dream and create a better future. Beibu Gulf Airlines will practice the corporate values of "four advantages", strive to build a service benchmark for local aviation enterprises in Guangxi under the guidance of the spirit of the 20th Party Congress, actively seize new opportunities for civil aviation development in the new era, and make unremitting efforts for the magnificent construction of Guangxi in the new era and the high-quality development of civil aviation in Guangxi. 

Industrial Consumer Finance: Value Symbiosis, Good and Far-reaching.

Recently, the policy on consumer finance has been continuous, and the development of the industry has attracted much attention. The tide is just the time to sail. As the first consumer finance company controlled by a joint-stock commercial bank in China, Industrial Consumer Finance has always adhered to the concept of the parent bank Industrial Bank, insisting on "lending with sincerity" and practicing Pratt & Whitney, rooting in Bamin and spreading its branches and leaves to all corners of the country.
Up to now, the company’s exhibition area has covered more than 50 major economically developed cities in China, with accumulated loans exceeding 330 billion and accumulated customers exceeding 21 million. The compliance foundation has been continuously built, the service quality and efficiency have been steadily improved, the digitalization level has advanced by leaps and bounds, and the corporate image and brand have been deeply rooted in the hearts of the people.
Consumer finance is for the people and promotes development from the perspective of the masses.
If you have a goal in your heart and a direction under your feet, the more you know, the more you will do. At present, China’s financial and economic structure has undergone tremendous changes, from the previous investment to the current consumption-driven. After vicissitudes and changes in the consumer market, consumer finance has emerged from the booming consumer market, and its position in economic development has become increasingly important. Following the Central Economic Work Conference, the General Administration of Financial Supervision once again stressed: "To promote the consolidation and enhancement of the economic recovery, we must accelerate the development of consumer finance."
To be broad and subtle. Small and micro groups are "capillaries" in economic development, so consumer finance should help the economy grow steadily, and in the final analysis, it should take meeting the people’s growing needs for a better life as the starting point and the end result. Xingye Consumer Finance has always been committed to improving the consumption power and quality of life of domestic residents and helping the development of the real economy. It adheres to inclusive finance’s initial intention, adheres to the service concept of "standing on credit and lending with sincerity", and features differentiated operations at the grassroots level. It cooperates with each other online and offline, making consumer finance deeper, more detailed and more refined, innovating consumer financial products and services in diversified consumption scenarios, and striving to make development "temperature" and people’s happiness "texture".
Taking serving the new citizens as an example, doing a good job in financial services for the new citizens is a necessary measure to satisfy people’s yearning for a better life and promote the common prosperity of all people. Under the guidance of the Action Plan of Xingye Consumer Finance Co., Ltd. on Serving the Financial Needs of "New Citizens", Xingye Consumer Finance focuses on the new citizen groups, based on the three product systems of "family consumption loan", "talent development plan" and "career development plan", fills the gap, strengthens the position and provides excellent service, and sends the mind to the "doorstep" and the warmth to the "heart". "New citizens generally have financial qualification defects such as insufficient collateral assets and lack of credit information. On the basis of adhering to offline pro-nuclear and pro-visit, we linked online big data portraits, accurately positioned demand, and always paid attention to the practical difficulties of new citizens. By covering diversified and universal consumer financial products such as life consumption, further education and employment, we provided them with pure credit, unsecured installment loan services and exclusive service programs to help new citizens start a better city life." Industrial consumer finance staff said.
A branch and a leaf always care about the situation, and show their responsibility with "value symbiosis"
Seek good and far-reaching, and both righteousness and benefit will last for a long time. Xingye Consumer Finance inherits the parent bank’s genes, and in combination with the requirements of the regulatory authorities, while striving for its own healthy, sustained and steady development, it takes the initiative to assume more social responsibilities, and pays attention to putting back social and humanistic care into the connotation of sustainable development of enterprises through every good deed within its power.
The "Xingcai Plan", which has been launched for three years, is the "sustainable development sample" of Xingye’s consumer finance exploration. The project gives priority to public welfare, and "let every aspiring young person go to school and study hard" is the initial intention of Xingcai Plan. In addition to providing loans for higher education, a total of 1.5 million yuan has been donated for the revitalization of rural talents, which is used to set up the "Xingcai Plan Scholarship and Scholarship". Among them, scholarships have been distributed to 195 college students with financial difficulties, of which rural registered students account for 68.6%; Scholarship funds are specially designed to reward educators who work in rural primary schools and make important contributions to rural revitalization.
In addition to scholarships, Xingye Consumer Finance also relies on the Xingcai Plan to unite with the government and schools to build a public welfare base for the inspirational growth of talents, give full play to the linkage role of the government, society and industry, make use of the existing resource advantages, pay attention to the shaping of students’ inspirational character and the cultivation of correct employment values, help college students become the human resources needed by the market and society, and further broaden and extend the rising channels of graduates, so that it is better to give them a sword than a stick.
Embroider Gankun at the head of the tide, and drive the engine with "digital intelligence technology"
In the era of digital intelligence, the business logic of consumer finance is undergoing fundamental changes, from the competition of capital and price to the competition of ecology and technology, and the role of science and technology is accelerating from supporting and ensuring to leading development. Under this background, Xingye Consumer Finance took the lead in formulating the information technology plan in the 14th Five-Year Plan, and according to the strategic goal of "building a financial technology weapon to enable the company to develop at a high speed and with high quality", it planned a blueprint for digital architecture, covering the whole life-cycle consumer credit service, optimizing financial supply by relying on digital tools, and fully empowering business development and management, and the picture of "Digital Xingye" slowly unfolded.
In promoting high-quality development, Industrial Consumer Finance has broken the geographical limitations of physical outlets with the help of digital technologies such as the Internet, big data and artificial intelligence, and its service radius and coverage have been greatly expanded; Build automated and standardized risk identification, anti-fraud, post-loan collection and operation systems, and gradually improve operational efficiency; Identify and quickly respond to customers’ personalized service needs, and realize the networking of the whole business process, the automation of loan approval decision-making, and the normalization of 7×24-hour uninterrupted service. In terms of consumer rights protection, Industrial Consumer Finance actively explored the cross-domain cooperation of "digital finance+smart justice", put into operation the blockchain electronic deposit system, realized the data docking between the court case handling and the financial business system, reduced the burden of consumers’ proof, effectively realized data protection and consumer rights protection, and built a more efficient post-loan disposal channel to effectively resolve financial risks. At present, through the blockchain electronic deposit system and the Quanzhou Intermediate People’s Court, the company has realized the electronic deposit of credit in the whole process and cycle, automatically generating and submitting litigation materials in batches with one button, and has handled more than a thousand cases cumulatively, forming a good demonstration effect.
With its strong scientific and technological innovation ability and high service level, Xingye Consumer Finance won the "Tianji Award of Outstanding Consumer Finance Company in 2023" and was selected as the case of "Outstanding Brand Value Consumer Finance Platform in 2023".
Take root down and grow up. In the future, Societe Generale’s consumer finance will actively integrate into and serve the new development pattern, and stride towards high-quality inclusive finance with a more high-spirited attitude.
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The captain broke the news: Tottenham Hotspur will not be in harmony, Watford will change coaches again, and Neymar will be reimbursed for the season.

"Captain broke the news" on March 11th.

[Kawasaki striker adjusts defense for the fifth consecutive game]

Kawasaki striker announced the starting lineup of this round of Japanese jobs. Due to the injury of foreign aid central defender Jahir, the team used different five sets of defense combinations in the opening four rounds of league matches and one UFJ Cup, but Kawasaki striker never finished zero in previous games.

The first round: Yamamoto Shirai, Jahir, Cheya Shintaro, Sasaki Xu.

The second round: Shangen Shilai, Shancun Heye, Da Nan Tuomo, and Orange Tian Jianren.

The third round: Yamamoto Shirai, Jahir, Dainan Tuomo, Sasaki Xu.

UFJ Cup: Matsunaga Hirohito, Yamamura Kazuyoshi, Dainan Tuomo, Sasaki Hiroshi

The fourth round: Yamamoto Shirai, Yamamura Heye, Dainan Tuomo, Sasaki Xu.

[bielefeld Sports director+coach dismissed]

In the last round, bielefeld led by 3 goals, and was tied by Brunswick 3-3. The relegation situation is still in jeopardy. On the second day after the game, Sports director Arabi, who has served for 12 years, was dismissed. A day later, the second head coach of the team this season, Shernin, was also fired. Scherning started coaching the team last September, with a total of 6 wins, 3 draws and 10 losses in the league, which is slightly better than his predecessor, but still can’t help the team out of trouble. Bielefeld immediately announced the new head coach, Ke Ginart, who coached in low-level leagues most of the time, only coached Sandhausen for two years in the Bundesliga in 2018-2020, and led the team to the 10th place in the Bundesliga in the whole season.

[There are 4 players suspended from the Australian Super League in this game]

In the Australian Super League match between the Central Coast sailors and MacArthur FC, four players from both sides were suspended and could not play. The Central Coast Mariners are without the No.2 striker winger En Kololo (5 goals in 18 rounds), the main central defender Kartak (2 assists in 16 rounds) and the short-term substitute striker Morais Che (2 rounds). MacArthur, on the other hand, lacked the main winger Noon (4 assists in 15 rounds), which was his second consecutive suspension. MacArthur was forced to adjust his formation in the last round because of the lack of corresponding substitutes on the wing.

[After the Champions League exit, Tottenham Hotspur will not be in harmony]

In the second leg of the Champions League quarter-final which ended on March 9, Beijing time, Tottenham drew 0-0 with AC Milan at home, and the total score was eliminated 0-1. Brazilian striker Risalesson served as a substitute in this game and was replaced in 70 minutes. After the game, Rishalison said in an interview that he didn’t understand why he came off the bench, and no one told him the reason. Later, he even compared this season to "relying on defense". (After Rishalison joined Tottenham Hotspur, the Premier League still scored 0 goals, and the only two goals were in the Champions League)

At the pre-Premier League press conference of Tottenham Hotspur against Nottingham Forest, Kong Di was naturally asked relevant questions, and "Kong Ertui" also spoke bluntly, directly indicating that Rishalison’s metaphor was correct, and pointed out that Rishalison’s words were somewhat self-centered. This time, Rishalison and Kong Di fired at each other, reflecting that there are some problems in Tottenham’s dressing room at present.

[Menxing’s main goalkeeper continues to be injured]

In the 22nd round of Bundesliga, Mainz beat Menxing 4-0, and Omlin, the main goalkeeper of Menxing, was injured and left the game. He will continue to be injured in this round. In addition to Omlin, 21-year-old German goalkeeper Olshovsky of Menxing team is also in a state of recovery, and the only goalkeeper the team can rely on is 34-year-old Cipel. Last week, at one time, all four famous men in Menxing were absent from training due to injury. Fortunately, Cipel’s injury is not serious, and he can continue to play in this round of competition.

[Watford changes coach again]

Watford announced this week that bilic, the team’s former head coach, was dismissed. This is the second time that the team has changed coaches this season. bilic took office only last October. Watford has only won one game in the last eight rounds of the Championship, and has fallen to the 10th place in the standings. At this node, he decisively chose to change coaches again, striving to hit the top six in the standings and get a play-off seat. Waterford’s new coach is Wilder, who has previously coached English teams such as Northampton, Sheffield United and Middlesbrough. During the coaching of Sheffield United, Wilder led the team to win the British Championship runner-up in the 2018/19 season and won the 9 th place in the Premier League in the following season.

[Neymar season reimbursement]

In the Ligue 1 match about three weeks ago, Paris narrowly beat Lille 4-3 at home. Neymar made a cross in the match, but left in the 51st minute due to injury. This week, Paris Saint-Germain officially announced that Neymar will undergo surgery to repair the ligament of his right ankle and confirm the reimbursement for the season. This season, Neymar made 20 appearances in Ligue 1, contributing 13 goals and 11 assists. Since the World Cup, it has been difficult for the three stars in Paris to get together because of injuries and holidays, which led to a decline in their record, including the Champions League, which was eliminated by Bayern this week.

[Niol’s new coach took office in the first battle]

Niol, a French team, recently announced the appointment of a new coach, Bernade Simondi, and signed a contract until the end of this season. Simondi has been away from French football for more than 20 years. In recent years, he has spent most of his time coaching in West Asian and African countries, and has coached Moroccan U23, Qatari U23, Burkina Faso, Guinea and other national teams.

Niol has experienced two official coaches and an acting coach before. At present, the team ranks at the bottom of French B with a record of 6 wins, 5 draws and 13 losses. However, it is only 4 points away from Bo, a safe area, and there is still hope of relegation. After Simondi takes office, Acting Coach Giomogo will return to teaching assistant position to continue coaching the first team.

[Even hit, Dortmund is short of people on the sidewalk]

Dortmund has been continuously affected by injuries recently, especially the lack of people on the sidewalk. At present, Dortmund’s usual 4-5-1, three starting candidates on the wing, Brandt (23 rounds, 8 goals and 4 assists), Adeyemi (16 rounds, 3 goals and 2 assists) and Royce (15 rounds, 4 goals and 4 assists), are reported to be unable to play in the Ruhr Derby. Brandt was injured against Chelsea, Adeyemi has not yet returned, and Royce is suspected of playing with a cold. Among them, Brandt is very important in the current Dortmund lineup. Before losing in the Champions League, he won 10 consecutive games. Brandt all started and directly participated in 6 goals.

"official website in the Bundesliga" predicted that Dortmund’s two starting wingers were Reina and Mullen, and the complete prediction was as follows: korbel, Ryerson, Jule, Schlotterbeck, Guerrero, Ozcan, emre can, Bellingham, Reina, Alai and Mullen.