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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.
say
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)

Jiang Xin, who is domineering and tearing up her colleagues, is strong in returning to green tea and cutting short hair, is too queen-like.

The discussion of family and workplace in TV series Our Marriage has aroused a lot of enthusiasm. Women not only have to face the pressure from the workplace, but also shoulder the responsibility of supporting their families. How to balance career and family is a difficult puzzle for them.

Dong Sijia, played by Rulu, comes out with bgm. In the eyes of colleagues, she isA strong woman in real life. Work vigorously, pay attention to efficiency, is the leader in the team.

She is not a soft persimmon for anyone to hold. Her opponent wants to take away the project in her hand. A sentence "Experience and connections are more important" can block the opponent’s back road.

Subordinate ability is not good and love to snitch, she directly broke that little mind and let the other party leave.

If there is always a female leader who kills all sides in the workplace, there is no doubt that,Dong Sijia is slay’s presence in the audience..

Jiang Xin, who cut her hair short, is a bit more capable and domineering. In her memory, she is still the "Hua Fei Niangniang" who is not angry and powerful, and has the same majesty and gas field.

This domineering spirit has also continued to Xiao Shede. In education, she is a veritable tiger mother. She devoted all her efforts to cultivating her son, and that perseverance even gave in to the defeat of Nan Li, who always disliked her. Today’s "Our Marriage", different roles, speaking look is still so similar.

There will always be one in the workplace.The fearsome devil.They can be independent in their work and their business ability is a cinch. Looking at the appearance, you will feel that they are unreasonable. When you get close, you will find that there is a soft heart hidden under the hard appearance.

One second, I was still preparing for the roadshow with my colleagues, and the next second, I received a meeting notice from the leaders. When a phone call came, Dong Sijia was about to put down his work and rush to the company without stopping.

Subordinate don’t understand why she is so hard, she just said, "Work is sorrow and joy.",and then the figure disappeared in the downpour. No one can help you solve the problem, only you can rely on at the critical moment.

She seems to be strong, but in fact she has her own principles. After she hired Shen Comet, the partner hesitated and questioned whether Shen Comet was competent. Dong Sijia spoke of the dilemma of women’s survival in the workplace in a few words: if she is gentle, she will be questioned about her ability, and if she is strong, she will be criticized for unscrupulous means.

No doubt about employing people, no doubt about people. She recruited comet Shen because she valued each other’s ability, which had nothing to do with her background and partner. I have to say,If full-time mothers want to return to the workplace, they will inevitably face many difficulties. They need more professional ability and stronger inner strength to deal with possible problems..

Shen Comet has been a full-time mother for her children, and her husband Sheng Jiangchuan is too busy with work to ask about housework. The economy is not independent and can’t get the respect it deserves, so there are naturally more and more problems in life.

Unlike Shen Comet Sheng Jiangchuan’s husband and wife, Dong Sijia and Yuwen Li’s husband and wife are male and female. Dong Sijia is an executive of a financial company, with a successful career and a husband in the family. Everything is perfect and he is a "winner in life" in everyone’s eyes.

Her success can’t be separated from her husband’s full support. However, in others’ eyes, Yuwen Li is touched by his wife’s light, and she only needs to be a "full-time husband" with peace of mind at home.

At the reunion, someone took the opportunity to connote Yuwen Li, which sounded like praising his good eye and capable wife. In fact, it was somewhat disdainful and ironic that he was a "soft rice man". Looking at her husband being pointed at by others, Dong Sijia certainly has to support her husband. Liao Liao said a few words, and Rulu replied angrily to the uneasy and kind-hearted man for her husband, which was a perfect interpretation of domineering and protecting her husband.

Although I am grateful to my husband for his contribution to the family,Dong Sijia will still inevitably show her dissatisfaction with her husband’s career.. Yuwen Li wanted to find another job, but Dong Sijia blocked her husband’s way out on the grounds that he was "poor and disgraceful".

At this point, she is a sexual version of Sheng Jiangchuan. Unconsciously bringing work style into the family will inevitably suffocate people after a long time.

Every time he changes a play, Rulu will change his style. At first, the audience was attracted by the glamorous arrogance of Empresses in the Palace Huafei, and then they loved and hated Fan Shengmei in Ode to Joy, and then they avoided Tian Yulan’s tricks in Xiao Shede.

There are some similarities between Dong Sijia and Tian Yulan in Our Marriage. They are both housewives, but Dong Sijia’s husband is better at housekeeping than Tian Yulan, so that his wife has no worries.

It is said that every family has a difficult experience. If you want to do the homework of marriage well, both husband and wife should manage it carefully.A good marriage is to do addition to achieve the effect of 1+1 > 2.. Without a perfect marriage, getting along for a long time will naturally lead to contradictions. Take a step back from each other, regardless of who pays more, but Qi Xin should work together to run a good family.

A strong marriage is doomed not to last long. Passion retreats, and love and responsibility are the keynote of marriage management.

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Welcome to [Autohome Anqing Promotion Channel], we bring you the latest and not-to-be-missed promotion information. At present, the much-anticipated Toyota is giving back to consumers’ love with practical actions in the Anqing area, and its eye-catching price reduction promotion is underway. The maximum discount limit is as high as 35,000 yuan, which further reduces the already competitive starting price, and the minimum price is only 143,800 yuan. If you want to seize this rare car purchase opportunity, click the "Check Car Price" button in the quotation form to make your car purchase dream a reality at a more affordable price. Act quickly and strive to get your ideal car in the price reduction craze!

安庆亚洲龙降价来袭！最新报价14.38万，今日钜惠

The exterior design of the Asian Dragon is unique and refined, which highlights the elegance and power of the Toyota brand. The front part of the face is made of bold and smooth lines, and the air intake grille is decorated with large areas of chrome to create a strong visual impact. The overall style blends movement and luxury, atmospheric without losing movement, and the details reflect the exquisite craftsmanship and quality assurance. This design not only attracts the eye, but also ensures that the vehicle is recognizable on the road.

安庆亚洲龙降价来袭！最新报价14.38万，今日钜惠

The Asian Dragon presents a streamlined profile with its elegant body proportions and refined side design. The 4990mm body length, 1850mm width and 1450mm height give it a solid visual impact. The wheelbase is up to 2870mm, ensuring the comfort of the interior space. The configuration of the front wheelbase of 1595mm and the rear wheelbase of 1605mm not only guarantees the driving stability, but also improves the handling. The tire specification is 215/55 R17, and it is matched with a fashionable wheel rim design, which not only strengthens the movement of the vehicle, but also adds a refined atmosphere to the overall shape.

安庆亚洲龙降价来袭！最新报价14.38万，今日钜惠

The interior design of the Asian Dragon shows a refined and practical style, focusing on the integration of comfort and technology. The center console is wrapped in a large area of soft materials, with a 10.25-inch high definition touch screen, which is easy to operate, intuitive interface and rich display information. The steering wheel is made of plastic material. Although it is not a high-grade material, it has a solid grip and supports manual up and down + front and rear adjustment, which is convenient for the driver to control. In terms of seats, the fabric seats provide good ride comfort. The main and passenger seats are equipped with front and rear adjustment, backrest adjustment and high and low adjustment functions to meet the needs of different drivers. Multimedia and charging interfaces are fully configured, including Type-C interfaces, to meet the charging and connection needs of passengers for electronic devices.

安庆亚洲龙降价来袭！最新报价14.38万，今日钜惠

[Engine] The Asian Dragon is equipped with a 2.0L L4 engine, capable of outputting a maximum power of 127 kilowatts, and has a peak torque of 206 Nm. It is matched with a CVT continuously variable transmission and simulates a 10-speed transmission, providing the driver with a smooth and efficient driving experience. This powertrain focuses on the balance of fuel economy and power performance, ensuring that the vehicle performs well in daily driving.

Overall, the Autohome owner was full of praise for the exterior design of the Asian Dragon, believing that the shark mouth design on its front face is very attractive, adding an extraordinary style to family travel. He emphasized the excellent performance of the Asian Dragon in terms of both practicality and appearance, making it stand out among many choices and become his ideal scooter. Whether it is the first time stunning or daily use, the Asian Dragon has met his expectations and undoubtedly added color to the owner’s travel life.

Avita entered Huawei’s channel, which is Huawei’s ＂own son＂？

The company has sold more than 10,000 cars for three consecutive months, which proves Huawei’s brand appeal and ability to attract money; and the increasing number of car companies that Huawei cooperates with proves that car companies also have "plans" for Huawei: they have taken a fancy to Huawei’s technology and its appeal.

This is a win-win logic. Huawei needs new business and growth points, and it also needs to give Hongmeng a new entrance. Car companies need to quickly cut into the track to let users recognize the brand as quickly as possible and gain market share.

As the partnership between Huawei and Cyrus gets better, and more and more car brands bear the "Huawei" brand, the question that plagues users has arisen: who is Huawei’s biological son?

From the user’s point of view, Wenjie was his biological son. The reason was very simple. For non-professionals who wanted to buy a car, Huawei’s blessing, Hongmeng system, and intelligent driving were all they could understand.

In the final analysis, these issues that confuse users are actually the result of Huawei’s internal "battle of routes" and the game between Huawei and various car companies.

After a period of discussion, the saying "Huawei does not make cars" has become well-known "old news". If you are interested in Huawei, you will know the rumors of that year. Ren Zhengfei once strongly said internally that whoever mentioned manufacturing would be transferred from his current position. What officially came out was a Huawei EMT resolution issued by Ren Zhengfei, saying that Huawei does not make complete cars, but focuses on ICT technology to help car companies make good cars.

Ren Zhengfei’s forceful statements and documents are a reassuring pill for automakers that see "Huawei" as a potential rival, and a solid foundation for Huawei to cooperate with other rivals: Huawei does not want and will not become their competitor.

At that time, it can be said that Huawei’s decision was very practical: the intelligent driving technology was still being rolled in, and the Hongmeng system had just been launched, which required a recognition time. What’s more, Huawei itself also had a lot of trouble, because of the change in form, the shortage of chips, and the mobile phone market share was forced to be handed over. – What Huawei needs to do is not to expand a new business to build cars, but how to recover its own decline and keep the company’s survival and development and the lives of employees.

With the passage of time and the expiration of documents, Huawei is gradually on the right track.

It can be said that building a car is the right thing, and doing the right thing is necessarily slow and difficult.

From within Huawei, how to "not build cars" is also a problem.

From the cooperation model we have seen so far, there are three models for "Huawei does not build cars".

First, the standard supplier model, in which Huawei provides standardized components and acts as one of the suppliers.

Second, Huawei Hi mode. When it comes to the relevant parts of autonomous driving and intelligent cockpit, Huawei will conduct in-depth cooperation with the main engine factory. BAIC’s Extreme Fox α coefficient S Huawei Hi version belongs to this model. The car company cooperates with Huawei’s Xu Zhijun team. In short, this is the project team of Huawei TO B.

Third, Huawei smart selection model. Huawei leads the design of vehicles, user experience design, and fully configure Huawei’s intelligence system. The cooperation team of car companies is Yu Chengdong’s team, and this team is TO C.

In 2021, Yu Chengdong once summed up two models, "Xiao Xu goes east BCG, Lao Yu goes west to be well-off". BCG refers to the abbreviation of BAIC, Changan and GAC, and well-off is Sailis.

The second and third models, although both use Huawei’s intelligence system as a selling point, are fundamentally different for Huawei and car companies.

The second model, taking BAIC as an example, is mainly sold through BAIC’s own channels. Huawei’s "assistance" is relatively limited, and the exhibition cars that enter Huawei’s channels are only for display, not for test driving and sale.

In the third mode, we are familiar with Q & A, which not only uses Huawei’s system as a selling point, but also allows Q & A to directly penetrate Huawei’s channels and bundle with Huawei’s brand and sales.

These three modes, fed back to the product level, are the "source" that troubles users: all three modes are Huawei’s participation, and the depth is not the same. For example, some products use Huawei’s intelligent driving system, while others are not. However, from the user’s perspective, whoever is in Huawei’s store is Huawei’s own "baby".

Now entering the Huawei channel, there are a total of two brands, one is BAIC Extreme Fox, the other is Qinjie, and at the end of this year, Avita will also officially enter the Huawei channel and settle in the flagship stores in Beijing and Shenzhen.

This is certainly good news for Avita. After all, it has been two months since the official listing, and the data released by Avita is that the first batch of locked orders exceeded 5,000 vehicles within ten days.

This data, under the data of tens of thousands of people, is not good-looking. And in the media’s visit, in the offline store, only one made an order at home on October 13.

Entering the Huawei channel gave Avita, who was backed by three bosses, a solid endorsement: Huawei’s brand appeal has been verified.

However, according to the above classification, Avita and BAIC’s model are the same, and Huawei and cooperative car companies have adopted the "HUAWEI Inside model". Whether to sell it in Huawei’s flagship store or not, and how to sell it, is still a problem. How to balance the relationship between several brands is another problem that Huawei needs to solve.

Returning to the original question, who is Huawei’s biological son, it is necessary to answer another question, whether Huawei can build cars or not.

If Huawei did not build a car at that time, it was the most realistic decision to take into account the situation, but more than two years have passed, and the valid period of the document is still one year. At that time, if Huawei does not build a car, it will "not be able to, but not".

The reason is that we need to look a little higher and focus on Huawei’s new energy vehicle layout.

In terms of the layout of new energy vehicles, Huawei is still moving in two directions.

First, based on the positioning of automotive parts and software and hardware technology suppliers, we will infinitely promote vehicle solutions; second, with Huawei Hubble’s investment as a wing, we will continue to explore the technical limits of the new energy automotive industry and build strong chip barriers.

The first direction, which is the three models we mentioned just now, the second direction is forward-looking, exploring cutting-edge technologies and preparing for the next step.

Overall, Hubble’s investment focuses on the chip manufacturing industry chain, 5G industry chain, and automotive electronics, all of which are Huawei’s core businesses. The focus is on the integrated circuit semiconductor field, with a total of more than 70 companies. Coverage involves the entire chain of the chip industry (chip design, EDA manufacturers, packaging and testing, semiconductor materials and equipment) and other links.

"In the future, Huawei will be rooted in all aspects of semiconductors," Mr. Yu once said.

Take Huawei’s investment in Siripu as an example, automotive chips are one of Siripu’s three major tracks.

In 2018, Huawei’s contribution to Siripu’s revenue was only 1.70 million yuan, accounting for 1.5% of its total revenue. After accepting Huawei’s investment, its influence in the market has greatly increased. In 2019, Huawei’s contribution to sales reached 170 million yuan, accounting for 57.13% of total revenue. Today, Siripu’s total market value exceeds 30 billion.

After completing these investments, Huawei has actually created a semiconductor industry ecosystem for itself.

Not only investment, according to media reports, Huawei is also building its own fabrication plant, that is to say, if the progress is normal, these Huawei investment companies will be able to help Huawei get rid of the previous chip dilemma and give Huawei the advanced process automotive chips it needs.

As a car company executive once said at a media conference, "Huawei doesn’t build cars? I don’t believe it. Huawei builds cars, but sooner or later."

Which is Huawei’s own son? It is very likely that none of these brands are currently available.

New design language The new Tiggo 8 will be launched in the fourth quarter.

　　A few days ago, we learned from relevant channels that the new Chery Tiggo 8 (internal code T1D) will be launched in the fourth quarter of this year. According to the previous spy photos, the new car has been completely replaced with a new design language, and the whole car is more restrained than the current model. In terms of power, the new car will be equipped with a 1.6T turbocharged in-cylinder direct injection engine code-named F4J16, and its transmission is matched with a 7-speed dual-clutch gearbox.

　　Cash tiggo 8

　　Tiggo 7

　　"New Tiggo 8 spy photos"

　　According to the previous spy photos, although there are strict camouflage stickers attached to the head/tail of the new car, we found some clues through the details. For example, the new car adopts a design style similar to the new Tiggo 7, and its integrated front grille with big mouth replaces the upper and lower split front grille design of the current model. With the long and narrow headlights on both sides and the similar three-stage air intake below, the car looks younger and more fashionable.

　　As for the tail, the new car still uses temporary light sets, which has a certain gap with the official production car, so the reference value is not great. In terms of interior, the new car follows the current design style as a whole, and the three-spoke multi-function steering wheel and the suspended large-size central control LCD screen make the car look more fashionable and young.

　　In terms of power, according to the information taken by the vehicle, the new car will be equipped with a 1.6T turbocharged in-cylinder direct injection engine code-named F4J16, and its transmission is matched with a 7-speed dual-clutch gearbox. For more information about the new car, we will continue to pay attention.

Xu Lin, President of Sailisi Automobile Co., Ltd. (rotating)： Building a new energy car in China and creating a global smart car brand.

Acceptance speech:　

It is a great honor to be elected as "Top Ten Influential People of Chongqing Manufacturing Industry". I would like to thank the leaders of the Propaganda Department of the Municipal Party Committee, the Municipal Economic and Information Committee, the Chongqing Daily Newspaper Group and the upstream news for organizing this selection activity, and also thank the jury.The experts’ recognition of me!

Last month, Jin Kang New Energy Automobile Co., Ltd. was renamed Sailisi Automobile Co., Ltd., the headquarters of Xiaokang Group and related business clusters of Sailisi moved to a new location, and our customer M5 also achieved the fastest record of "delivering more than 10,000 cars in 87 days". These achievements can not be achieved without the care and support of leaders and partners from all walks of life.

We will continue to focus on the development of high-end smart cars and contribute to the transformation, upgrading and high-quality development of Chongqing’s automobile industry! thank you

Building a car: Sailis lays out two smart factories to develop new energy vehicles.

On December 23rd last year, Sailis Automobile Co., Ltd. (hereinafter referred to as "Sailis") officially released its high-end smart car brand AITO, and the first model M5 was delivered in March this year. By the end of May, the cumulative delivery exceeded 10,000 vehicles.

Wenjie M5 is produced in Sailisi Liangjiang Smart Factory, which meets the industrial 4.0 standard.

What standard is Industry 4.0?

Xu Lin said that the Sailisi Liangjiang Smart Factory, which was put into use in 2019, has the world-class high-standard intelligent manufacturing capability, and has achieved a high degree of automation and intelligence. It has more than 1,000 intelligent robots, 100% automation of key processes, and 24-hour online inspection, which effectively reduces labor costs while making manufacturing accuracy and product quality reach first-class standards. It was awarded the "Lighthouse Factory" in Chongqing in 2021.

In order to avoid the potential danger caused by battery PACK operation under high voltage of more than 300 volts, the production module in the battery pack workshop of Liangjiang Smart Factory is produced by automatic AGV, and the most advanced precision high-speed aluminum wire welding technology is adopted in the key welding process, which realizes automatic on-line monitoring of welding.

"Such a factory guarantees the rapid production and high-quality delivery of our vehicles," he said. In addition to Liangjiang Smart Factory, we are building a second smart factory in Fenghuang, Shapingba District, which is also built according to Industry 4.0 standard. It is expected to be completed and put into use in the second half of this year, with a maximum annual production capacity of 150,000 units.

R&D: Cross-border integration of Huawei and Cyrus creates three precedents.

On May 29th, the reporter went to the headquarters of Xiaokang Group in Shapingba District Enterprise Innovation Service Center.

New headquarters, new starting point.

"The relocation of the headquarters of Xiaokang Group and its related business clusters to new homes is a new stage of development for Celestial Automobile at a higher starting point, and it is also a new starting point for Celestial to make efforts to lead global intelligent enterprises." Xu Lin said.

In December 2017, Xu Lin was transferred from Chief Technology Officer of Xiaokang Group to Celes, and began to transform new energy vehicles from traditional car tracks.

Xu Lin said that traditional cars are different from the new forces of the Internet. Internet companies have certain inherent advantages in entering the new energy automobile industry. First, they have their own scientific and technological attributes, and they have certain advantages and persuasiveness in the intelligent aspects of vehicles, such as autonomous driving and intelligent cockpit. Secondly, many technology companies have their own relatively mature user circles and their own fans, so it is easier to find their target audience after the vehicle is built.

Traditional car companies have a complete vehicle supply and production system, and the established brand reputation, vehicle performance experience, technical strength and workmanship have occupied certain advantages.

At the same time, traditional car companies have accumulated many years of experience in vehicle chassis, power, interior and exterior design, and both adjustment and design are quite mature.

"Cyrus has a good partner, Huawei." He said that many people say that the cross-border integration of Huawei and Cyrus is a wonderful move. Combining the strengths of all parties, it will become a global intelligent leading enterprise in the future. I agree with this statement.

The transformation of new energy automobile industry shows a trend of borderless integration, and ecological development and mutual win-win are more important, and the cross-border alliance between automobile enterprises and technology companies is bound to be further strengthened. The cooperation between Cyrus and Huawei is also the general trend, and the pragmatic values of "customer-centered, quality first" are the consensus of the two sides, and the two sides have already started cooperation in 2019.

At present, Celestial and Huawei, through the mode of mutual empowerment and in-depth cooperation, further promote cooperation in the field of intelligent terminals around technologies, products and channels, jointly create high-performance and intelligent mobile travel solutions, and integrate the digital world into every car.

Both Cyrus and Huawei are "technology houses" that focus on technology research and development. Huawei is a global leader in scientific and technological innovation and is committed to building a smart world with the Internet of Everything.

Cyrus also pays attention to the investment in research and development, and has mastered more than 1,000 new energy-related technology patents. It is also the first enterprise in China to master the core three-electricity technology and have the qualification to produce new energy vehicles. It is precisely because they have the same pursuit in the technical field that the cooperation between the two sides is quite effective.

Huawei has more than 5,000 experience stores in China and 730 million smartphone users, which can provide a huge traffic portal for the sales of intelligent products.

"The cross-border integration of our joint business with Huawei has created three precedents." Xu Lin said: First, it has created a precedent for the deep integration of new energy automobile enterprises and ICT technology enterprises; The second is to create a precedent for cars to enter mobile phone stores for sale, and realize the first channel interoperability between technology brands and automobile brands in the world; The third is to create a precedent for the release of mobile phones and cars together.

Planning: The M7 will be mass-produced soon, and a number of mid-to-high-end smart models will be available in five years.

Recently, Celestial Phoenix Smart Factory is working overtime for the final debugging stage.

"Wenjie M5 is produced in Liangjiang Smart Factory, and the upcoming Wenjie M7 will be produced in Phoenix Smart Factory." Xu Lin said. The M7 is positioned as a "luxury smart large electric SUV" and will be officially released soon.

"For the M7, which is about to be mass-produced, there has been a solid foundation and good reputation laid by the M5 before, and with the technical support of Huawei, we think the future can be expected." 　

At present, Chongqing’s automobile industry has a huge scale and outstanding industrial advantages. Sailis will actively respond to the strategy of building a world-class automobile industry cluster in Sichuan and Chongqing, closely follow the new round of scientific and technological revolution and the trend of "new four modernizations" of automobiles, and accelerate the digital transformation of enterprises.

"We will still adhere to the concept of self-sustaining technology, maintain an open and cooperative mentality, actively cooperate with outstanding enterprises in relevant chains, promote the optimization of the whole industrial chain, and jointly promote the development of the new energy automobile industry." He said that Cyrus will firmly promote the automobile energy transformation and create a smart mobile life, adhere to the in-depth cooperation with Huawei, and strive to become a global smart car brand enterprise. In the next five years, it will plan a variety of mid-to-high-end smart models to meet the needs of more users.

Xu Lin said that in the future, Sailis will still take users as the center, define car functions based on user usage scenarios, define configuration and technical solutions based on functions, and divide cars into hardware bases, software bases and application layers to gradually realize "software-defined cars" and realize "pluggable hardware, programmable scenes, ecology on demand and self-evolution of the system".

Why is it difficult to protect consumers’ rights and interests？

A few days ago, a car blogger posted that his friend bought an AITO Wenjie M5, and due to the epidemic prevention and control, licensing in special areas and the continuous high temperature, he informed the store to pick up the car later. But not long after, AITO issued her an order invalidation notice, saying that the order was invalid and the deposit would not be refunded.

This notification letter pointed out that it has been more than 10 working days since the consumer was notified to pick up the car, and the remaining car purchase money has not been received so far. According to the AITO Car Subscription Agreement, it is regarded as having given up buying a car.

In this regard, the consumer believes that he has not signed this agreement and has not agreed on the time of car purchase. Interface News tried to contact the consumer and got no response.

The relevant person in charge of Huawei’s automobile brand told the interface news that after discovering the complaint, the user center tried to communicate with the consumer, but it was not able to contact him yet.

"Our new delivery specialist didn’t hand over the work well and didn’t understand the previous communication situation. He directly sent an order invalidation notice, which was not in accordance with the standard process." The person in charge said that the consumer’s order was not cancelled and the deposit was not confiscated.

　

As a high-end new energy brand jointly built by Cyrus and Huawei, AITO currently sells models of Wujie M5 and Wujie M7, among which the first pure electric model, Wujie M5 EV, was released on September 6th, and the reservation was started. On the first day of listing, the order volume of M5 EV has exceeded 30,000.

However, with the increase of orders, the disputes between AITO and consumers began to increase. The interface news noticed that in the relevant complaint platform, most of AITO’s complaints were linked to the deposit, and focused on the non-refundable deposit and the sales concealment to induce the order.

A consumer complained that when he paid the deposit, the sales did not clearly tell whether the deposit could be refunded and the time limit for withdrawal; Another consumer told the interface news that he applied for a refund during the hesitation period of the deposit, but the refund process took a long time and waited for nearly three months. On the complaint platform, many consumers have been waiting for a refund for more than two months.

Interface News called a Huawei experience store as a consumer, and the car sales consultant of the store told Interface News that you can pay a deposit through online channels such as Huawei Mall to buy a brand car. The sales reminder, within 72 hours without confirming the lock order, the deposit can be refunded.

"Now, the M5 pure electric version has just been listed, and there is still a small order stage. You can pay 1000 yuan’s intention to reserve the rights and interests first, and the small deposit can be refunded at any time."

When asked about the deposit contract, the seller said that an electronic version of the contract would be issued when the deposit was paid. However, it was not until the final payment that the reporter noticed a line of small-print reminders, asking for the approval of the AITO Automobile Subscription Agreement and the AITO Automobile Privacy Policy. These two agreements will not pop up automatically, and consumers need to read and understand them themselves.

According to "AITO Automobile Subscription Agreement", 72 hours after the subscription deposit is paid belongs to the hesitation period. During the hesitation period, the subscription agreement can be terminated by unilateral notice. When the notice is delivered, all the subscription deposit paid will be refunded. Beyond the hesitation period, it is deemed that the unilateral termination right has not been exercised or waived, and the subscription deposit will not be refunded.

The above agreement also emphasizes the terms of the offline car purchase contract. The agreement requires consumers to go to the designated user center to sign the car purchase contract and pay the remaining car purchase price within 10 working days after receiving the notice. If it is not signed within the time limit, AITO has the right to decide to cancel the order and deduct the deposit paid.

Lawyer Gu Pan of Beijing Dacheng (Xi ‘an) Law Firm said in an interview with Interface News that the signed subscription agreement is a formal sales contract and is binding on both parties.

During the period of repentance agreed in the contract, the consumer notifies the merchant to return the deposit without a lock, and the merchant shall return the deposit according to the contract, otherwise the merchant will constitute a breach of contract; On the other hand, if the consumer fails to pay the final payment within the time limit stipulated in the contract, he will also be liable for breach of contract. Therefore, when buying bulk consumer goods such as automobiles, consumers should carefully browse the contract and understand the specific terms.

"If the seller makes false propaganda and misleading, causing misunderstanding among consumers, then the misled party can demand to terminate the contract and return the paid fees through litigation."

Gu Pan stressed that in practice, it will be more difficult for consumers to prove that they have not been informed or misled in advance, so it is necessary to pay attention to fixed evidence. When returning the deposit within the prescribed time limit, you should also remember to keep the written notice evidence to safeguard your rights and interests.

Zhang Xiang, a special expert of China Bolian think tank, told the interface news that the current car reservation system started from Tesla, and new forces have started booking processes such as small booking and big booking. Car owners who order in advance can enjoy more rights and pick up the car first.

"Most of the new car-making forces have a policy of free refund of the deposit. Only when they are about to go bankrupt or have no cash on their accounts will they not get the deposit back."

Zhang Xiang believes that it takes a long time for the brand to refund the deposit. On the one hand, the process cycle of refunding the deposit is really long, on the other hand, it also reflects Huawei’s lack of attention to consumer rights. "The contract does not clearly state the time requirement for refund, and the seller will naturally delay."

Eye injury, mental injury, financial injury … Children can’t do homework without electronic products？

　　In August this year, the Ministry of Education and other eight departments jointly issued the "Implementation Plan for Comprehensive Prevention and Control of Children and Adolescents’ Myopia" (hereinafter referred to as the "Implementation Plan"), which made it clear that the teaching time using electronic products should not exceed 30% of the total teaching time in principle, and paper homework should be used in principle. However, according to a survey conducted by reporters in the past two months, some schools rely too much on electronic products to assign homework, making it the carrier of "sea tactics". Parents are tied to homework like "teaching assistants", and even the absurd phenomenon of "parents working overtime, children can’t do homework" appears.

　　"Children can’t do homework without a tablet."

　　"The first thing to do when I get home from work every day is to see what homework the teacher has arranged on the APP, as if I were reading." Mr. Wang, a parent of a first-grade student in a public primary school, said that there are 80 calculation questions in a day just for mathematics. "Did the child read a fake first grade?"

　　Half a month, the reporter looked through the APP mentioned by Mr. Wang, which listed various subjects such as Chinese, mathematics and English. After finishing the homework, it can be submitted online. After the teacher reviews it, it will be returned immediately, and parents will teach the children to correct it before uploading it.

　　In this way, using software on mobile phones, tablet computers and other devices to arrange homework has become a routine operation in more and more schools, and some schools have relied too much.

　　Mr. Shen, a parent of a third-grade elementary school student, said that the school not only requires children to do it online, but also requires parents to read it themselves and then upload it. "Every night like ‘ Teaching assistant ’ Similarly, once you are on a business trip or work overtime, your child’s homework will be abolished. After all, your grandparents are not very good at playing tablets. "

　　A reporter who talked for half a month found that homework depends on electronic products. One of the main reasons is that some schools are still keen on "super-class teaching" and "sea tactics".

　　A principal of a public primary school told reporters that according to the curriculum standards, school-age students are provided with exercise books and other teaching AIDS in addition to textbooks, but often these standards can not meet the requirements of some schools to "pull up".

　　The Ministry of Education has repeatedly stressed that there is no written homework in the first and second grades of primary schools, but many schools use electronic equipment to violate the rules in disguise.

　　Mr. Shen’s children attended a well-known public primary school in a coastal area, but in the past two years, almost all the homework done by children through tablet computers was one grade higher. Now children in the third grade have been exposed to the teaching content of the fourth grade. "Paper exercise books are not required because they are too simple for children."

　　Some teachers and parents report that homework APP helps to improve the efficiency of teachers’ correcting homework, evaluation and feedback, especially to make English and other language subjects lively and interesting. It can also analyze children’s weak knowledge points through big data, but if it is not used properly, it will easily become an electronic big question bank, which will increase the burden on students.

　　Electronic homework, labor-saving or tiring?

　　The original ink-scented exercise books have become tablet computers and mobile phones, and even the original extracurricular practice of hands, feet and brains is also inseparable from electronic products.

　　Ms. Liu, the parents of primary school students, said that the school-based curriculum requires children to show the places they have been in the summer in the form of tabloids, and take turns to give speeches after school starts. But tabloids must be made on the computer in PPT or PDF format, and then printed. "The implication is that parents can do it."

　　Computers, tablets, printers and point readers … … More and more families’ children’s rooms are filled with electronic products for learning needs. What makes parents anxious is not only that the equipment costs money, but also that the children hurt their eyes and worry about their children.

　　"I really don’t understand why homework like tabloids and paintings that give play to children’s imagination and potential must be done through computers?" Mr. Lu, a parent of primary school students, said that parents have been controlling the time when their children use electronic products, but for homework, parents have nothing to say if their children stare at the screen again.

　　"As soon as a child takes a tablet, it is necessary to prevent him from playing games and watching videos." Mr. Shen said that the couple can rack their brains, such as registering all the video applications on the tablet as members, so that even if they are not with their children, they can check whether their children have watched other videos through "history" on their mobile phones.

　　A primary school class teacher told reporters that the most frustrating thing for parents and teachers is that children will gradually use some homework apps to search for answers to questions online, making people unable to tell whether they really understand or plagiarize.

　　Building an information-based campus, not at the expense of children’s eyesight.

　　In fact, whether it is homework or extracurricular practice, more and more parents and children are exposed to electronic products not because of interest, but because of school requirements. Intelligent learning APPlications such as homework app are very common, and some applications have become an integral part of some local education administrative departments and schools to build information-based campuses and digital classrooms.

　　Take a well-known APP commonly mentioned by interviewed parents as an example. It is said that the APP has completed the C round of financing of 100 million US dollars in February this year, and entered 70,000 schools in more than 400 cities in 31 provinces, autonomous regions and municipalities directly under the Central Government. More than 30 million primary school teachers and students are using this app to arrange and submit homework.

　　A central primary school in Luwan, Huangpu District, Shanghai has added the use of tablet computers in seven or eight courses, such as Chinese and mathematics, but the school’s myopia rate is low, and some classes even have no myopia.

　　President Wu Rongzhen said that the school insisted on not using all kinds of apps to arrange homework. "Electronic products used in schools are generally controlled within 15 minutes, but as homework assignments, time cannot be controlled. Once dependence is formed, it is a bad thing."

　　It is understood that some apps adopt a business model of free use of homework function and personalized counseling fee. For example, various courses of online learning must be paid for.

　　The founder of an online education platform said that homework APPs usually drain first, and then make money. The reason why they aim at homework is because it is a hard rule of the school every day, and the user’s viscosity is high. To some extent, it is what this kind of app is most willing to see that teachers and children form dependence.

　　Yu Jianbo, assistant dean of massive open online course Research Institute of Shanghai Jiaotong University, believes that everything has advantages and disadvantages. Schools should use electronic products and application software appropriately. It is more important to learn how to use them scientifically and reasonably.

　　Wu Zunmin, a professor at the Education Department of East China Normal University, said that all localities should make detailed regulations according to local conditions when implementing the Implementation Plan. For example, it is suggested that students in the lower grades of primary schools should not be assigned homework grafted on electronic products except written homework. (Half-monthly talk with reporter Pan Xu and Wu Zhendong)

＂Training Shuai＂ is controversial. Where is the national football team going？

Reporter Han Bing reports With the national football team’s 1-1 draw with Australia, the top 12 matches ended in six rounds, which ushered in an interval of more than two months. With four rounds left, China is 11 points behind the top Saudi Arabia, 7 points behind the second Japanese and 6 points behind the third Australian, and the qualifying probability is basically zero. After the game, head coach Li Tie also held a 32-minute press conference, which was a comprehensive summary of the first six rounds. Unfortunately, Li Tie’s "personal summary", as before, has caused widespread controversy. The next day, Li Tie continued to publish pictures and texts on social networks, which once again set off a wave of public opinion.

Against the background that the Top 12 Competition has come to an end, facing the unspeakable outstanding achievements of the national football team and various controversies caused by the words and deeds of head coach Li Tie, the China Football Association must give an explanation to the national football team, the relevant parties in the league and the fans who love China football as soon as possible.

Earlier, the media said that the renewal of the contract between the Football Association and Li Tie was to "train handsome" for the 2026 World Cup qualifiers. After six games before the Top 12, from tactics to employing people, and then to the controversy that triggered off-court public opinion storm, it became a question whether it is necessary for Li Tie to continue to "practice". The probability of qualifying is almost zero. Under the background that the remaining four top 12 games next year are only meaningful for training, it is necessary to have a clear conclusion from whether the coach will stay or not, how to use the naturalized players, and whether the Chinese Super League will continue to make way for the top 12 games. After all, the national football team is about to prepare for the 2023 Asian Cup, followed by the 2026 World Cup qualifiers. It is not too late to make up for the coach’s choice. Now, the national football team will have at least three years to bring a new atmosphere to the new coach.

The World Cup qualifiers are the most important events of the national football team. It is hard to understand how to "train handsome" in such an important event. After all, even if the national football team originally had a low probability of qualifying for strength reasons, it is not the reason to "train handsome" with the most important events. What’s more, in terms of preparation, training, personnel selection, tactics and contingency, Li Tie has shown his incompetence as a national football coach, which has also caused more unnecessary disputes outside the stadium. If the national football team wants to make a breakthrough in the local Asian Cup in 2023 and the World Cup qualifiers in 2026, it should make a decision and make a choice early.

The great controversy caused by Li Tie’s use of naturalized players has proved that he misjudged the ability of naturalized players, which directly affected the national football team’s record and led to the complete disillusionment of the qualifying hope that there was still a chance. Regardless of foreign or local handsome, nationality is not an amulet, but whether it has the ability to make the national football performance go up a storey still higher is the key. It is an act of putting the cart before the horse to deprive the national football team of the most important growth opportunity just for the sake of "training handsome", and the China Football Association must root out the root cause.

If the coach’s ability is insufficient, we can still give Li Tie more time. However, Li Tie’s prejudice against naturalized players failed to maximize the strength of the national football team, which also directly affected the performance of the national football team. In the face of his mistakes in employing people, tactics and coping with emergencies, Li Tie failed to take the initiative in many statements. Instead, he blamed the poor performance of the national football team on many objective factors, such as losing the home court, long-term training, naturalized players’ physical condition and so on, without the sense of responsibility and overall situation that the national football coach should have.

What’s more, when the national football team almost lost the hope of qualifying because of his personal mistakes, and the public opinion and fans were extremely dissatisfied, Li Tie, as the coach of China national team, repeatedly posted inappropriate pictures and texts on social networks, causing even greater public controversy. Even when the outside world was generally dissatisfied with the performance of the national football team, advertisements were posted on the homepage of personal social networks, and pictures suspected of infringing on the rights and interests of national football sponsors were deleted after being pointed out by the media. Judging from the action of deleting pictures, Li Tie released Weibo, who was suspected of product placement, the day after the top 12 competition. It was definitely not approved by relevant parties, and the advertising behavior suspected of infringing the rights and interests of the official equipment sponsors of the China Football Association was even more unacceptable to public opinion and fans. Li Tie caused such a huge controversy inside and outside the stadium, with poor performance and shirking responsibility. Is he still suitable to continue as the coach?

China Football Association must also face more thorny problems caused by the Top 12 matches, including the resumption of the Super League, whether the Super League will continue to make way for the Top 12 matches next year, and how to deal with the messy wage crisis in the Super League. All these require the Football Association to take the attitude of being responsible for football in China, assess the situation, and come up with a solution that conforms to the objective laws of football as soon as possible and can minimize the negative impact on all parties concerned.

In a word, it is the eventful autumn of football in China, and more than two months have been reserved for the Football Association in the Top 12. For the future of football in China, it is time for the Football Association to make a decision. ???

Italian team’s naturalization tactics, fierce harvesting of Argentine wool

Italy has always been a traditional strong team in the world football, but in recent years, the degree of talent decline in Italy is also obvious to the naked eye, especially his recent record in Italy is complicated. Although he won the European Cup in 2021, the team was eliminated from two World Cup qualifiers, and failed to qualify for the 2010 and 14 World Cups. Even the current coach of Italy, Mancini, once said, "Now Italian children don’t play football, and I can’t see young people playing football in the streets." Because of this, Italy chose naturalization tactics as a last resort.

As a country with a close relationship with Italy in history, Italian coach Mancini Argentina has naturally become the primary target of Italian naturalized players. Nearly 30 million of Argentina’s 44 million people are of Italian descent, making it the largest ethnic group in Argentina, among which Matteo Reggit is a successful model.

Matteo Reggit was born in Buenos Aires, Argentina on April 29th, 1999. He has dual nationality of Italy and Argentina. In March 23rd, Italian coach Mancini confirmed that he would call up Reggit. On March 18th, Reggit was selected into the Italian national team list. On March 24th, he made his debut in the European Cup and scored his first goal in the national team. In the second round, Reggit scored in a row, and his performances of two goals attracted Italian teams. Reggit, although he is an Italian shirt, can’t speak Italian, and he has no experience in European teams, but his grandfather was an Italian immigrant, so he has Italian descent.

Reggie’s excellent performance gave coach Mancini a taste of sweetness. It is also planned to naturalize 10 young Argentine players: 22-year-old riverbed striker beltran, 21-year-old Boca defender valentini, 24-year-old Salzburg midfielder Capaldo, 22-year-old Ranus striker Dehlavi and 17-year-old sarsfield striker Prestianni, 22-year-old independent competitive midfielder Pozo, 19-year-old Rosario central midfielder infantino, 21-year-old Newell boy midfielder Foza, 23-year-old Newell old boy striker Gianni and 19-year-