Ma Huateng’s two sessions made suggestions: pay attention to the integration of numbers and facts and build a government-led social emergency open platform

  In 2022, the National People’s Congress will be held, and Ma Huateng, deputy to the National People’s Congress and chairman and CEO of Tencent, intends to submit a number of written suggestions, covering the deep integration of digital technology and real economy, rural education and personnel training, the application and innovation of cultural and scientific achievements, the digital protection and inheritance of cultural heritage, the construction of social emergency network and the development of Guangdong-Hong Kong-Macao Greater Bay Area’s blue carbon (marine carbon sink).

On March 5, 2018, during the two sessions, Ma Huateng, a representative of the National People’s Congress, was interviewed in the "Representative Channel". Xinhua news agency data map

  Promote the digitalization of the entire chain of the cultural and art industry.

  The success of the Beijing Winter Olympics has demonstrated the cultural and scientific strength of China to the whole world. From 5G, ultra-high definition to virtual reality, the in-depth application of cultural and scientific achievements makes viewers turn from "online" to "present" and involuntarily "immerse" in it.

  As a practitioner in this field, Ma Huateng pointed out that the application of cultural scientific and technological achievements outside the cultural industry is getting richer and richer, and the spillover effect is beginning to appear. To this end, he suggested promoting the value spillover of cultural and scientific achievements in other industries, and transforming them in the fields of standards and patents to further enhance the ability of independent innovation in science and technology.

  In the field of cultural heritage protection, Ma Huateng suggested to promote the digitalization of the entire chain of the cultural and art industry, build a digital system of cultural heritage with full authenticity and interconnection, and form a new pattern of protection and inheritance with multiple collaborations.

  Promote the formulation of technical standards for digital transformation

  At present, digital technology and real economy are in a critical period of systematic and all-round integration — — With the technological innovation, the human-computer interaction interface is iterating, which gives birth to the development opportunities of a new generation of Internet. Traditional industries are activated by digitalization, and a large number of new platforms and formats have emerged; Governance modernization and digital public service models are constantly emerging, creating rich application scenarios and broad industrial opportunities for digital technology.

  However, "the integration of number and reality" also faces some problems. For example, the adaptability of technology application to the needs of different industries is not strong; It is difficult to get through different digital tools; Digital supply and demand are difficult to match, and there is a lack of large-scale docking platform.

  As a representative from the front line of digital science and technology industry, Ma Huateng has been actively making suggestions in promoting the digitalization process and developing the digital economy in China for many years. In view of the problems faced by the current "integration of number and reality", he suggested guiding digital technology enterprises to conduct research and development in core industries and key areas, promoting the formulation of technical standards for digital transformation, and improving the accuracy and effectiveness of digital upgrading support for "specialized and innovative" enterprises. In addition, it is necessary to study the key technologies and governance rules of the new generation Internet in a forward-looking way, and explore the Chinese scheme of coordinated development of digitalization and low carbon; Guide resource elements such as technology and capital to truly flow to the physical field; Summarize the advanced experience of promoting the digital construction of public services, and continuously increase the digital supply of public services to remote areas and special groups.

  Create an open platform for social emergency under the leadership of the government

  In the torrential rain in Henan Province and the flood disaster in Shanxi Province in 2021, Internet technology enterprises initially played a linkage effect in fund-raising, help-seeking information docking, localized volunteers, material deployment and other aspects through digital products and technologies such as public welfare platforms, multi-person collaborative online documents, and e-commerce platforms, highlighting the necessity of using digital support capabilities to build a social emergency network led by the government, with social coordination and public participation.

  Based on this, Ma Huateng proposed that Internet technology can be used to innovate safety publicity and education methods, improve public safety awareness and coping ability, create an open platform for social emergency under the leadership of the government, and effectively connect early warning information, emergency science popularization and rescue services. He suggested strengthening the integration of social emergency capacity building and grassroots governance, exploring ways to improve digital connectivity, and bringing a large number of localized groups such as community volunteers, takeaways, online car-sharing, drivers and couriers into the social emergency volunteer organization system, and accurately matching demand and supply through the dispatch mechanism.

  Improve the treatment of rural teachers and accelerate the development of rural-oriented vocational education

  For three consecutive years, Ma Huateng has submitted suggestions on rural revitalization. At the moment when talents are the foundation of rural revitalization, he focused on rural education and training in the two sessions in 2022 and put forward a number of suggestions to support rural talent training.

  In terms of educational facilities, Ma Huateng suggested strengthening the construction of rural small-scale schools and township boarding schools, constantly improving the treatment of rural teachers and creating a digital platform covering rural educational resources.

  Based on the demand of rural education, he suggested speeding up the development of rural vocational education, increasing the discipline construction in areas in short supply, such as old-age services and nursery services, and appropriately setting up courses such as breeding and garden art, so as to deepen the understanding and understanding of agricultural occupations among urban and rural teenagers and enhance their sense of belonging to the countryside. At the same time, Internet companies are encouraged to participate in the construction of talent practice bases, implement employment assistance, and guide school-enterprise cooperation to incubate advanced technologies and patents in the agricultural economy.

  Accelerate the development of blue carbon in Guangdong-Hong Kong-Macao Greater Bay Area and help carbon neutrality.

  Reducing carbon emissions and helping carbon neutrality are hot topics in recent years. During the past two sessions, Ma Huateng has been paying attention to ecological protection and green development, from the proposal to formulate the Nature Reserve Law to the proposal to coordinate the marine ecological restoration in Dawan District of Guangdong, Hong Kong and Macao and the construction of the Pearl River Estuary National Park.

  At the two sessions this year, Ma Huateng put forward suggestions on accelerating the development of blue carbon in Guangdong-Hong Kong-Macao Greater Bay Area. It is suggested that Guangdong-Hong Kong-Macao Greater Bay Area has the longest coastline and a complete marine ecosystem in China, as well as three coastal blue carbon systems, namely mangroves, seagrass beds and salt marshes, which have unique advantages in developing blue carbon.

  In this regard, he suggested that the basic investigation and testing of Greater Bay Area blue carbon ecosystem should be carried out and a data network system should be established. Based on this, we should strengthen marine cooperative protection and management, rebuild aquatic communities with high biomass and high carbon sink, and improve marine carbon cycle and carbon storage mechanism. At the same time, increase scientific research investment in key technologies of blue carbon, explore the pricing mechanism of blue carbon, and support ocean carbon sink trading.

  Southern Reporter Huang Huishi Jiang Lin

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)

Russia’s new arms plan submitted to Putin will cost 320 billion US dollars to focus on strategic nuclear forces.

        CCTV News:At the end of this year, Russia will release a new version of the National Armament Plan, which has been submitted to President Putin a few days ago, and the specific contents have not been made public.

        On December 15th, the new Russian National Armament Plan was formally submitted to President Putin, and the draft plan will be approved by Putin before the end of the year.

Russian President Vladimir Putin

        Although the specific content of the new armament plan has not yet been made public, there have been some clues. In late November, when Putin held the tenth series of meetings with army generals and defense industry representatives in Sochi, the task for the Russian army was — — We must ensure strategic deterrence, and if there are potential threats, we must eliminate them.

        Spend $320 billion on strategic nuclear forces.

        Bondarev, chairman of the Russian National Defense and Security Committee, said that Russia’s national armament plan for 2018-2025 will cost 19 trillion rubles, or about 320 billion US dollars, and the future development of military equipment will focus on high-precision strike weapons and strategic nuclear forces.

        Some American think tanks are also very concerned about Russia’s armament trends in the next few years. The University of Washington, USA, released the title on November 22nd.Report on Russia’s Military Modernization PlanThe equipment to be purchased by the Russian army in the next few years is analyzed, and it is considered that the development focus of the Russian trinity nuclear force by 2027 is basically clear:

sea

        existIn terms of nuclear forces at seaAfter 2021, Russia’s maritime nuclear forces will include six "Delta IV" class and eight "God of the North Wind" class ballistic missile strategic nuclear submarines (SSBN), which will be evenly distributed to the Northern Fleet and the Pacific Fleet.

air

        In terms of air nuclear powerRussian air nuclear forces are being upgraded, and modern Tu -95MS and Tu -160 bombers are being replaced with new engines and avionics, and weapons are being upgraded; The new long-range cruise missile Kh-101 with a range of up to 4,500 kilometers will replace KH-55; The construction of Tu -160 will also be restarted.

ground

        In terms of nuclear power on the groundAt present, there are three projects in progress, among which the "Boundary" project is the closest to completion, the next-generation well-launched intercontinental ballistic missile RS-28 "sarmat" will be deployed after 2020, and the launch test of the "Balguzin" missile train is expected to be carried out in 2019.

        "Balguzin" missile train project suspended

Missile train

        Surprisingly, the "Balguzin" missile train project, which had been highly anticipated before, has been dismounted. At the beginning of December, the Russian newspaper quoted a senior official of the Russian military-industrial complex as saying that the development plan of a new generation of "Balguzin" missile trains has been suspended and will not be restarted in the foreseeable future.

        For a long time, the "Balguzin" missile train has been regarded as a shadowy "nuclear arrow". Ota said that the system was originally planned to start service in 2019. Before 2020, the Russian strategic missile force will form five missile regiments equipped with train missile systems. Each regiment will be equipped with six Jarls strategic missiles, each of which can carry 3-4 nuclear warheads. The self-sufficiency of the missile train system can reach one month, and it can maneuver more than 1000 kilometers in one day, which can be hidden in railway branches or tunnels. Within 3 minutes of receiving the launch order, the strategic missile can enter the launch state.

        Media: Suspension of "Balguzin" or lack of money

pause

        At the beginning of February 2016, the British "Jane’s Defense Weekly" reported that due to Russia’s economic difficulties and tight budget, the high-profile missile train project would have to be cut off. At that time, it was denied by the Russian side, and the dismantling of the "Barguzin" missile train project was also considered to be related to financial pressure.

        New plan funds: 24 trillion rubles reduced to 19 trillion.

military expenditure

        The amount of funds for the arms program needs to be approved by the Russian Ministry of Finance. In response to the new version of the National Arms Program, Russian Defense Minister shoigu asked for 24 trillion rubles (about 400 billion US dollars) in the summer of 2016, and Finance Minister Silu Anoff only agreed to give half of it. A fierce dispute broke out between the two sides. By November this year, the final amount was 19 trillion rubles, which is still far from the expectations of the Russian Ministry of Defense.

17 Nissan Tourist 4.0 low-end, without sunroof, year-end discount

Hong Kong Xiaoyu: 180 2007 2516 (same as WeChat)

Appearance is important

  The appearance details of the 17 Nissan 4.0XE version are not very bright, but for a car, the appearance is important, but it is not the most concerned by potential buyers. Whether the off-road ability is strong enough and whether the ride is comfortable is much more important than the appearance. Attracted by the more majestic temperament of the huge body, on the basis of the hard style, it fully demonstrates its own unique charm.

  The 2017 large front air intake grille still has a large area of chrome-plated trim, and three silver trims have been added to the original all-black honeycomb grille. Black and silver trim are added around the fog lamps on both sides of the front, which is more textured as a whole.

  Configuration: 17 models, Middle East version Y62 4.0XE 7 seats 7 seats 18 wheels, bottom hanging 2 (four doors one-click lift) smart card, one-click start electric folding (black) intelligent four-wheel drive system (, multi-road condition selection) LSE + rear, uphill assistance, rhombus velvet seat, dual-zone automatic air conditioning, monitoring, front and rear open central armrest box (with refrigerator) multi-function steering wheel, central control leather hemming + door panel leather package

Transformation, smooth and full

  The interior of the 17 Nissan 4.0XE has both tranquility and functionality. It is still a three-row model. The interior materials are also more elegant, and the wood grain spline trim is more elegant. The planning of the central control part is comparatively luxurious, and the style of the standard Japanese luxury car, the BOSE sound is chosen by many mid-to-high-end cars. The thick image of Fanbo is still eye-catching in the vast traffic flow, and it is highly visual and offensive. The plain lines outline the original rough shape, coupled with the thick, pure off-road temperament.

The material of solid wood feels excellent in the hand.

  Interior: The 17 Nissan 4.0 models use the four-wind wheel design commonly used in luxury cars. The thickness is relatively suitable, and the material of leather and solid wood is used, which makes it feel excellent to hold. In addition, the steering wheel is powerful and integrates audio, air conditioning control and Bluetooth car hands-free system, making it safer for drivers to drive and keep their hands on the steering wheel.

The overall style of the interior is luxurious

  The 17 Nissan Y62XE is a three-row model with a luxurious interior, DVD entertainment, uphill and downhill, and monitoring equipment. The new interior materials are also more elegant, using leather, aluminum and wood grain splines as embellishments, the overall interior style is luxurious, and the interior style still continues the home design, creating a relaxed and comfortable driving environment.

  Summary: The huge size of the Nissan Y62 makes it always have a feeling of "standing out from the crowd" on the road. Coupled with its low appearance rate, it causes passers-by to stop and watch from time to time. And as a large size, the luxury and comfort are also greatly improved. It is still the best partner for off-road and conquest. Introduced into the country mainly from the fourth generation model, many off-road players will buy and modify it. In everyone’s opinion, it is a pure model.

Hong Kong Xiaoyu: 180 2007 2516 (same as WeChat)

The Ministry of Transport has revised the regulations on taxi operation: driving a car online requires participating in the qualification examination

  People’s Daily Online, Beijing, September 9, according to the central government portal news, recently, the Ministry of Transport announced the newly revised "Regulations on the Management of Taxi Driver Qualifications" (Ministry of Transport Order No. 63 of 2016) and "Regulations on the Management of Tour Taxi Business Services" (Ministry of Transport Order No. 64 of 2016).

  The "Guiding Opinions on Deepening Reform and Promoting the Healthy Development of the Taxi Industry" (Guoban Fa [2016] No. 58), as the top-level design for deepening the reform of the taxi industry, clarifies the positioning of the taxi industry, and puts forward the overall reform ideas of "dislocation of new and old business formats, integrated development, and construction of a diversified and differentiated travel service system". It also requires strengthening the legal system to realize that the management, operation services and market supervision of the taxi industry have laws to follow and rules to follow. Following the top-level design of the "Guiding Opinions" and implementing the relevant requirements of the State Council on "streamlining administration and delegating powers, combining decentralization and management, and optimizing services", the two ministerial orders have made adaptable revisions in the aspects of industry development positioning, division and enterprise interests distribution, driver examination, registration, and further education.

  It is understood that the amendments to the two ministerial orders were solicited from local transportation authorities in early July this year. As an important supporting regulation for deepening the reform of the taxi industry, it will provide legal protection for promoting the transformation and upgrading of cruise cars, standardizing the operation of online car-hailing, and promoting the integrated development of new and old business models.

  Attachment: Interpretation of the "Regulations on the Administration of Taxi Driver Qualifications" and the "Regulations on the Administration of Cruise Taxi Business Services"

  What amendments have been made to the "Regulations on the Administration of Cruise Taxi Business Services"?

  According to the "Guiding Opinions of the General Office of the State Council on Deepening Reform and Promoting the Healthy Development of the Taxi Industry" (Guoban Fa [2016] No. 58) and the "Interim Measures for the Administration of Online Booking Taxi Business Services" (Ministry of Transport, Ministry of Industry and Information Technology, Ministry of Public Security, Ministry of Commerce, Administration for Industry and Commerce, State Administration of Quality Supervision, Inspection and Quarantine, State Internet Information Office Order No. 60 of 2016), the revised "Regulations on the Management of Tour Taxi Business Services" adjusted the scope of application and made a series of provisions on the positioning of the taxi industry, the distribution of interests between operators and drivers, etc. It is clear that taxis are an integral part of the urban comprehensive transportation system, a supplement to urban public transportation, and provide personalized transportation services for the public. The development of cruise taxis should be in line with the economic and social development of cities, and coordinated with the development of passenger transportation services such as public transportation. By clarifying the development orientation, efforts should be made to build a diversified and differentiated urban comprehensive transportation service system to better meet the travel needs of the people. In response to the problem of taxi "share money", cruise taxi operators are required to adjust the contract fee standards or quota tasks in a timely manner according to factors such as operating costs and freight changes, etc., to better build a business model of shared operational risks and reasonable distribution of benefits for enterprises and drivers, and accelerate the transformation and upgrading of traditional industries.

  II. What amendments have been made to the Regulations on the Administration of Taxi Driver Qualifications?

  The revised "Regulations on the Management of Taxi Driver’s Qualifications" clarify the scope of application, and the qualifications of taxi drivers include the qualifications of cruise taxi drivers and the qualifications of online booking taxi drivers, etc., and combined with the characteristics of the new business model of online car-hailing, the driver conditions, examination content, certificate types, registration management, further education and legal responsibility have been adjusted accordingly.

  III. Why should online car-hailing drivers be managed, and what aspects of the revision take into account the characteristics of online car-hailing?

  Regardless of whether it is online car-hailing or cruise car, it provides universal passenger transportation services for the public, and the driver is subject to access management according to law. This is the bottom line requirement of the industry management department to ensure transportation safety and service quality. The "Regulations on the Management of Taxi Driver Qualifications" are revised to fully consider the characteristics of online car-hailing, and actively support the development of new business models through "tailor-made" system design and management innovation. For example: Compared with cruise car drivers, the content of the online car-hailing driver’s test is simplified to the greatest extent, and its registration and cancellation are stipulated, which can be completed by the platform company reporting to the taxi administrative department where the issuing authority is located.

  IV. Are the application requirements for cruise car and online ride-hailing drivers the same?

  According to the revised "Regulations on the Administration of Taxi Drivers’ Qualifications", those who apply to participate in the taxi driver qualification examination shall meet the following conditions: obtain a motor vehicle driver’s license of the corresponding approved driving type and have more than 3 years of driving experience; no traffic accident crime, dangerous driving crime record, no drug abuse record, no driving record after drinking alcohol, and no record of 12 points in the last 3 consecutive scoring periods; no violent criminal record; other conditions stipulated by the urban people’s government. As a taxi driver,Whether it is a cruise or an online booking service, there is no difference in the application conditionsCreate positive conditions for fair competition between new and old business models.

  How to provide relevant proof materials such as no violent criminal record in the qualification examination conditions? Will it bring inconvenience to the parties?

  The revised "Regulations on the Administration of Taxi Driver Qualifications" makes it clear that those who apply to participate in the taxi driver qualification examination shall provide proof or commitment materials that meet the relevant provisions: (1) Motor vehicle driver’s license and photocopy; (2) No traffic crime, dangerous driving criminal record, no drug use record, no driving record after drinking, and no record of 12 points in the last 3 consecutive scoring periods; (3) No violent criminal record materials; (4) Identity certificate and photocopy; (5) Other certification materials stipulated by the city people’s government. At present, our Ministry is actively coordinating with the public security department to verify the commitment materials provided by the parties through information technology, so as to provide maximum convenience for the applicant parties.

  What are the differences between the content of the qualification examination for cruise and online taxi drivers?

  The revised "Regulations on the Administration of Taxi Driver Qualifications" makes it clear that: Taxi driver qualification examinations include national public subjects and regional subject examinations. The national public subject examination is a knowledge test with universal normative requirements for national taxi laws and regulations, professional ethics, service norms, and safe operation. The regional subject examination for the qualification of cruise taxi drivers is a knowledge test with regional service characteristics such as local taxi policies and regulations, human geography of business areas, and traffic routes. The regional subject examination for the qualification of taxi drivers by online booking is a knowledge test with regional norm requirements such as local taxi policies and regulations. The administrative department of taxis of local people’s governments at or above the district level may determine other examination contents on its own according to the regional service characteristics.

  What are the differences between the registration management of professional qualifications for cruise car and online ride-hailing drivers?

  The revised "Regulations on the Administration of Taxi Drivers’ Qualifications" basically retains the relevant requirements of the original registration regulations for cruise car drivers, and at the same time takes into account the characteristics of the new business model of online car-hailing, and stipulates that the registration and cancellation of online car-hailing drivers can be completed by reporting to the taxi administrative department where the licensing authority is located through the online car-hailing platform company.

  What optimization adjustments have been made in the further education of drivers?

  The revised "Regulations on the Administration of Taxi Driver Qualifications" on driver further education only put forward the result requirements of further education, and no longer make specific provisions on the method and process of further education, and make it clear that driver further education shall be organized and implemented by taxi operators, further implement the main responsibility of operators, and pay attention to the effectiveness of further education. At the same time, those who have not applied for registration for more than 3 years after obtaining the qualification certificate shall complete no less than 27 hours of further education before registration to better ensure service skills and professional quality.

Release the rules for the management of online car-hailing in many places: lower the entry threshold for vehicles and drivers

  Since September this year, a number of cities, including Quanzhou in Fujian and Lanzhou in Gansu, have been revealed to have relaxed their online car-hailing policies.

  Recently, Hangzhou, Zhejiang also launched a legislative hearing on the "Hangzhou Passenger Taxi Management Regulations (Revised Draft) ", planning to include online car-hailing in the management of passenger taxis, and adjust the vehicle standards and driver access standards for online car-hailing.

  Cheng Huiqiang, a researcher at the Development Research Center of the State Council, said in an interview with the surging news reporter that online car-hailing itself is one of the paths to deepen the reform of the taxi industry, and the policy adjustment according to local conditions reflects the government’s open and scientific attitude towards emerging business models. Because there is still a time difference between the implementation of online car-hailing policies in various places, the exploration of leading cities can provide reference for subsequent cities to formulate local online car-hailing rules.

  In July 2016, the "Interim Measures for the Management of Online Booking Taxi Business Services" was issued, which came into effect on November 1 of the same year. China took the lead in recognizing the legality of online car-hailing. Subsequently, detailed rules for the management of online car-hailing were issued in many places, many of which required drivers’ household registration and operating vehicle standards.

  Detailed rules for the management of online car-hailing in some cities

  Since September this year, Quanzhou and Lanzhou have been exposed to loosen the local version of the online car-hailing management rules. Hangzhou recently also held hearings on relevant policies.

  From the above-mentioned rule changes in the three cities, they mainly include the following:

  1.Lower the entry criteria for vehicle prices.

  Compared with the previous implementation details, Quanzhou, Lanzhou, and Hangzhou have all previously established minimum price standards for online car-hailing.

  Quanzhou originally required that the price of online car-hailing should not be less than 150,000 yuan, which needs to be more than 50% higher than that of mainstream taxis. Now it is adjusted to that the price of the vehicle should not be less than 1.2 times the price of the taxi. Lanzhou City will adjust the "online car-hailing price to be more than 140,000" to 1.5 times that of mainstream taxis.

  According to media estimates from the two places, thanks to this, the entry threshold for online car-hailing prices in the two places has dropped by more than 30% to 50%.

  2. Lower vehicle configuration standards.

  Previously, Quanzhou detailed rules required that online car-hailing must be equipped with positioning devices and emergency alarm devices with driving record functions, and must use the "Beidou" satellite positioning system. The new rules cancel the designated system and only require the same technical conditions.

  Lanzhou is in the new regulations.Deleted the relevant standards of "vehicle wheelbase 2700mm", "new energy vehicle wheelbase 2650mm or more", and "providing Internet wireless access, mobile phone chargers, paper towels, umbrellas, etc. for passengers to use".

  Hangzhou’s draft amendment simply cancels all the original vehicle wheelbases and pricing standards, and treats online car-hailing and taxis "equally."

  3. Lower the driver’s entry threshold.

  In the new regulations (draft) of Lanzhou and Hangzhou, both will obtain the city’s household registration or the city’s residence certificate as the entry threshold for online car-hailing drivers.The previous one-year time limit for obtaining a residence permit in this city has been removed.

  4. Reduce the difficulty of the exam.

  On September 8, the Ministry of Transport issued the "Notice on the Reform of the Taxi Driver Qualification Examination", which reduced the number of question bank questions from 1200 to 500, and the ratio of the number of question bank questions to the number of test paper questions did not exceed 10:1.

  5. Reduce administrative duplication of approval.

  Originally, if an online car-hailing platform wanted to settle in Quanzhou City, it had to submit an application to the Fujian transportation authority, which would review the platform’s online service capabilities. Now it is adjusted to be reviewed and identified by the platform company’s registration place to reduce duplicate certification.

  6. Reduce administrative intervention in the market.

  The original rules of Quanzhou City require that online car-hailing drivers cannot "marry one woman and two" and cannot connect to two or more online car-hailing platforms at the same time. The new regulations cancel this regulation and adjust it to the driver signing an agreement with the platform provider and acting in accordance with the agreement.

  It is worth noting that Hangzhou has also tried to incorporate online car-hailing into the management system of passenger taxis. To this end, Hangzhou has tried its best to conform to the existing taxi standards in terms of online car-hailing model access, and has proposed that the Hangzhou cruise taxi and online car-hailing exams will be implemented "two tests in one" and "two certificates in one". Drivers who pass the exam can not only drive online cars, but also drive taxis to achieve interactive flow.

  The gray operating state persists

  Regarding the adjustment of the new regulations on online car-hailing in many places, Surging News asked several online car-hailing platforms for their views, and the general response was: It is inconvenient to say more now.

  According to data from the Ministry of Transport, as of the end of July this year, 133 of the 338 cities above the prefecture level across the country have issued detailed implementation rules for online car-hailing, and 86 are publicly soliciting opinions.

  Some cities have been unable to issue detailed rules for the management of online car-hailing, and the slow progress of some online car-hailing platforms has led to the fact that online car-hailing drivers in many places are also in a state of gray operation.

  In August this year, Guizhou Metropolis Daily said that Anshun City has been unable to introduce new regulations on online car-hailing. In the face of the city-wide illegal operation of special projects, more than 4,000 online car-hailing cars in the city have become "illegal vehicles".

  At the same time, the number of cities where online ride-hailing platform companies have been allowed to land is not large.

  In July this year, according to the People’s Daily, there are more than 130 online car-hailing platform companies in the current market. As of now, 19 online car-hailing platform companies, including Didi Chuxing, Shenzhou Special Car, Shouqi Car, and Cao Cao Special Car, have obtained business licenses. Didi Chuxing, Shenzhou Special Car, Shouqi Car, Yidao, and Cao Cao Special Car have obtained business licenses in 22, 33, 29, 8, and 13 cities respectively.

Exclusive: "China Star" discontinued? The last flag of Hong Kong films falls

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The Ministry of Transport issued the "Measures for the Operation and Management of the Online Booking Taxi Supervision Information Interaction Platform"

  CCTV News:According to the website of the Ministry of Transport on July 22, the Ministry of Transport recently issued a notice on the issuance of the "Measures for the Operation and Management of the Online Booking Taxi Supervision Information Exchange Platform".

  The full text is as follows:

Measures for the operation and management of the online taxi reservation supervision information exchange platform

  Chapter 1, General Provisions

  Article 1: In order to strengthen the operation and management of the online booking taxi supervision information exchange platform (referred to as the online booking taxi supervision information exchange platform), standardize data transmission, improve the supervision efficiency of the online booking taxi industry, and create a good business environment, in accordance with the Interim Measures for the Management of Online Booking Taxi Business Services (Ministry of Transport, Ministry of Industry and Information Technology, Ministry of Public Security, Ministry of Commerce, State Administration of Market Regulation, Order No. 46 of 2019 of the Cyberspace Administration of China) and other relevant provisions, these Measures are formulated.

  The second article is that the online car-hailing supervision information exchange platform as mentioned in these measures includes the online car-hailing supervision information exchange platform at the industry level (referred to as the industry platform), the provincial-level online car-hailing supervision information exchange platform (referred to as the provincial platform), and the urban-level online car-hailing supervision information exchange platform (referred to as the urban platform).

  Article 3 These Measures shall apply to the data transmission, operation and maintenance, and data quality evaluation of the online car-hailing supervision information exchange platform.

  Fourth, the Ministry of Transport shall guide the operation and management of online car-hailing supervision information exchange platforms at all levels.

  The transportation authorities of all provinces and autonomous regions are responsible for the operation and management of provincial platforms, and guide and supervise the operation and management of urban platforms within their respective administrative regions.

  The municipal transportation authority directly under the Central Government and the municipal transportation authority divided into districts (referred to as the urban transportation authority) is responsible for the use, operation and maintenance management of the platform in the city.

  Each online ride-hailing platform company (including platforms that rely on Internet technology to provide information services and jointly provide online ride-hailing taxi services with online ride-hailing platform companies) is responsible for standardizing the operation management and data transmission of this platform in accordance with relevant regulations.

  Chapter 2, Data Transmission

  Fifth, the competent transportation departments of each city shall transmit the relevant license information of the company, vehicle and driver of the online car-hailing platform in real time through the transportation administration information system for the industry platform to share in real time. If the real-time sharing is not possible, the relevant license information of the company, vehicle and driver of the online car-hailing platform shall be entered and uploaded in a timely manner through the industry platform, and updated at least once a week in principle.

  Article 6 After obtaining the corresponding "Online Booking Taxi Business License", the online car-hailing platform company shall transmit basic static data such as the online car-hailing platform company, vehicles, drivers, and dynamic data such as order information, business information, positioning information, and service quality information to the industry platform from 0:00 the next day.

  Article 7: Online car-hailing platform companies shall strengthen the standardized management of data information, and the transmitted data related to online car-hailing operation services shall be directly connected to the industry platform and shall not be transmitted through third-party platforms or systems.

  Eighth, after the data of the online car-hailing platform company is transmitted to the industry platform, the industry platform forwards the data to the relevant provincial platform and city platform in real time. Local transportation authorities shall not require the online car-hailing platform company to transmit the same data repeatedly to the provincial platform or city platform.

  Article 9 The operation information data received by the industry platform shall be kept for a period of not less than two years.

  Article 10, the network about the car platform company shall establish and improve the working mechanism of data transmission, designate a special person responsible for data transmission, clear with the industry platform integration of the responsible person, business personnel and system technical personnel, and inform the industry platform. The above personnel information changes, should be informed in a timely manner.

  11Th Article: If an online ride-hailing platform company needs to suspend the operation of the online ride-hailing platform due to foreseeable reasons such as system transformation and server migration, it shall inform the industry platform 72 hours in advance.

  12Th, due to natural disasters, production safety accidents and other unforeseen emergencies caused by system failure, unable to transmit data normally, the online car-hailing platform company shall promptly inform the industry platform, and take effective measures to restore the normal operation of the system as soon as possible. After the system failure is eliminated, the online car-hailing platform company shall promptly retransmit the missed data and submit a written report on the handling.

  13Th Article: If an online car-hailing platform company has the potential to endanger the security of the industry platform system during the process of technology access and data transmission, the industry platform has the right to suspend technology access and data transmission; if losses are caused, relevant responsibilities shall be investigated according to law.

  Chapter III, Transmission Quality Requirements

  Article 14: Online ride-hailing platform companies shall ensure the integrity, standardization, timeliness, and authenticity of data transmission, and ensure the quality of data transmission.

  Article 15 The quality of the transmitted data meets the following requirements:

  (1) Data integrity: The data transmitted by the online car-hailing platform company shall comply with the relevant requirements of the "General Technical Requirements for Online Taxi Reservation Supervision Information Interaction Platform (Interim) ", ensure that the basic static data and dynamic data fields are complete and complete, and ensure that the full amount of data is transmitted without omission of information and fields.

  (2) Data standardization: The content of the data fields transmitted by the online car-hailing platform company shall comply with the relevant requirements of the "General Technical Requirements (Interim) of the Online Taxi Reservation Supervision Information Exchange Platform" in terms of element name, field name, data type, field length, value range, data accuracy, coding rules, etc.

  (3) Data timeliness: If the basic static data of the online car-hailing platform company changes, the data shall be transmitted to the industry platform within 24 hours after the change; order information, business information, service quality information, etc. shall be transmitted in real time, with a delay of no more than 300 seconds; positioning information shall be transmitted in real time, with a delay of no more than 60 seconds.

  (IV) Data authenticity: The data content transmitted by the online car-hailing platform company should be true and effective, the basic static data and dynamic data should be related to each other, and the logical relationship between the relevant data should be correct, true, and complete.

  Chapter 4, Transmission Quality Assessment

  Article 16 The industry platform regularly conducts an evaluation of the data transmission quality of online car-hailing platform companies, and the evaluation content includes data integrity, standardization, timeliness, authenticity, etc. The data transmission quality evaluation indicators and calculation methods of the online booking taxi supervision information exchange platform are shown in the attachment. The specific evaluation indicators and calculation methods will be updated according to the development of the industry.

  Article 17: Data transmission quality evaluation work is divided into monthly and annual evaluations, with monthly and annual evaluation cycles being every natural month and every natural year.

  Article 18 The data transmission quality evaluation results of online car-hailing platform companies are regularly announced by the industry platform, and the annual evaluation results are included in the quality and reputation assessment of taxi Enterprise Services. The industry platform regularly announces to the public the basic operation of the national online car-hailing industry, and the online car-hailing platform companies that do not transmit data to the industry platform as required.

  Encourage transportation authorities at all levels to make full use of the online car-hailing supervision information exchange platform at all levels to strengthen the monitoring and analysis of the operation of the online car-hailing industry and publicly release the analysis results to accept social supervision. Encourage local transportation authorities to rely on the online car-hailing supervision information exchange platform at all levels to improve law enforcement efficiency and enhance the precision and intelligence of regulatory law enforcement.

  Chapter 5, Operation and Maintenance

  19th Article, local transportation authorities shall clarify the responsible person and contact person for the use of the industry platform, and inform the industry platform; it is necessary to strengthen the application and opening management of the industry platform login account, and urge users to properly keep the account information and change the password regularly.

  Article 20 The competent departments of transportation at all levels shall, in accordance with the requirements of relevant national laws and regulations, strengthen the cyber security, data security and personal information protection management of the online car-hailing supervision information exchange platform, implement cyber security level protection, strengthen data transmission tracking, and regularly carry out security investigation. For discovered security risks and loopholes, timely rectification shall be made, and the whole process data security management system shall be established and improved. Necessary measures shall be taken to prevent data from being tampered with, destroyed, leaked or illegally obtained or illegally exploited.

  Article 21: All levels of online car-hailing supervision and information exchange platforms shall establish a platform system operation management and fault emergency response mechanism, conduct real-time monitoring of the operation of the system 7 × 24 hours a day, and deal with system failures in a timely manner.

  Article 22: Local transportation authorities may, in accordance with the needs of joint supervision of the online car-hailing industry, conduct technical docking with relevant information systems of other management departments to achieve information sharing.

  Article 23: Network link maintenance is carried out jointly by all levels of online car-hailing supervision information exchange platforms in accordance with the principle of hierarchical management. Network links between ministries and provinces (autonomous regions and municipalities directly under the Central Government) are jointly maintained by industry platforms, provincial platforms or municipal platforms directly under the Central Government; network links within provinces (autonomous regions) are maintained by provincial platforms and urban platforms.

  Chapter VI, Supplementary Provisions

  Article 24: Where private passenger car sharing business is conducted, data and information shall be transmitted in accordance with relevant local regulations.

  Article 25: Units responsible for the operation and maintenance of industry platforms shall do a good job in operation and maintenance, data transmission management, data security, etc., to ensure the safe and stable operation of the platform system, and shall not provide, process, and use relevant data information without authorization.

  Article 26 These Measures shall come into force on July 1, 2022.

NIO power exchange, it is difficult to ride a tiger

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  Source: Standard Business

  In the face of external doubts, NIO continued to exchange power up the ante.

  On November 21, NIO officially announced that,Signed a cooperation agreement with NIO in Chongqing, the two sides will cooperate in promoting the establishment of replacement battery standards, the construction and sharing of replacement networks, the research and development of replacement models, and the establishment of an efficient battery asset management mechanism to jointly promote the high-quality development and low-carbon transformation of the automotive industry.

  According to the agreement, Changan Automobile’s first exchangeable passenger car model that shares a battery pack with NIO is planned to be launched in 2025.

  After years of investment in the power exchange business, NIO has finally welcomed its first partner.

  The day before, NIO CEO Li Bin’s internal speech was a hot search. Li Bin said that the road to changing electricity is very difficult, but it is difficult and correct. "Everyone imagines changing electricity as if Amazon wanted to do Cloud as a Service in 2003. Cloud as a Service like Alibaba, Tencent, Amazon, Microsoft, etc., they lost many years before they finally achieved success."

  Three major controversies in the power exchange model

  In the new trend of car manufacturing, the biggest feature of NIO is the "power exchange mode".

  On October 26, NIO announced that NIO has deployed 2,000 power swap stations across the country, including 601 expressway power swap stations, opening up the high-speed power swap network in 6 vertical, 4 horizontal and 8 major urban agglomerations.

  As of November 20, NIO had a total of 2,103 power stations nationwide, and 798 new power stations were added this year. According to the plan, NIO will have a total of 2,300 power stations this year.

  For a long time, the outside world has been skeptical about NIO’s insistence on the power replacement model, mainly due to the investment, compatibility, rapid development of charging technology, and the necessity of power replacement.

  In terms of cost, at this year’s Shanghai Auto Show, NIO President Qin Lihong once said that the cost of a single station replacement is about 3 million yuan.

  Although the cost of each generation of NIO’s third-generation replacement stations is slightly different, based on a rough calculation of 3 million yuan per station, the fixed cost investment of all 2,000 replacement stations in NIO will reach RMB 6 billion. This does not include additional expenses such as site rental, personnel operation and electricity expenses. According to NIO’s goal of adding 1,000 replacement stations this year, the cost of building website alone is as high as 3 billion yuan.

  When will high-cost power stations become profitable? Shen Fei, vice-president of NIO, once said: "At present, each power station averages 35-36 orders per day. As long as it can handle 50-60 orders a day, the power station can break even."

  According to NIO official website data, the average number of daily power changes at the power station exceeds 60,000 times. 2,000 charging stations are equivalent to 30 times per station per day, lower than the earlier data of NIO Vice President Shen Fei.

  According to the calculation of the brokerage, when the power station reaches the break-even point, the utilization rate is about 20%, that is, each station needs to be serviced 88 times a day to barely make a loss. That is to say, more car companies need to develop power replacement in order to form a scale effect.

  Another issue with power replacement is compatibility.Chairperson Wang Chuanfu said at the 2022 annual general meeting that power replacement in the passenger car sector will not be the mainstream, and this model has standardization issues such as vehicle design, bulking, and structural safety.

  At present, there are several companies trying to lay out the power exchange model on the market, but generally the construction of power exchange stations is fragmented, and the industry is relatively scattered. Since 2020, relevant state departments have continued to promote the formulation of standards such as power exchange stations and power exchange battery packs. Minister of Industry and Information Technology Xin Guobin said at this year’s Global Power Battery Conference that it is necessary to guide social capital to invest rationally and avoid blind expansion and disorderly development. Promote the unification of standards such as battery size, power exchange interface, and communication protocol.

  As the main promoter of the power swap model, NIO is mainly used by NIO owners. At the China Electric Vehicle Hundred Forum held in April this year, Li Bin said that "the power swap service has reached the stage where it can be exported externally." He hopes that other companies can share and build a charging and swapping infrastructure with NIO, and revealed that existing car companies are discussing this matter with NIO.

  Only now has one company been finally finalized: Changan Automobile, but the real landing time will be in 2025.

  However, Li Bin believes that power replacement is a huge first-mover advantage of NIO, and it has reached the time node when it can be opened to the outside world. NIO will give the standard of next-generation battery packs to the whole industry. At present, NIO is still negotiating cooperation with 4 to 5 automobile companies.

  It’s hard to ride a tiger

  "The road to power replacement is very difficult." Li Bin said that NIO’s power replacement is equivalent to the large-scale investment of Cloud as a Service by Internet technology companies such as Amazon. Both need to establish a national network, and the investment scale is large and the investment cycle is long. Once it can serve external customers, the threshold for latecomers to enter will be very high.

  The problem is that power replacement is not a necessary option for new energy vehicles. Another opponent of the NIO power replacement model is charging technology, which is also the choice of most new energy vehicle companies.

  On August 16 this year, the global power battery leaderReleased a new 4C super fast charging battery based on lithium iron phosphate cathode material system, with a battery charge of 10 minutes and a battery life of 400 kilometers.

  At present, Tesla, Ideal, Xiaopeng, Great Wall, Geely, etc. are all deploying fast charging technologies. For example, Xiaopeng G6 uses 800V SiC silicon carbide high voltage technology and is equipped with a 3C ultra-fast charging battery pack, which can charge 300km in as little as 10 minutes. The Zhijie S7 jointly built by Huawei and Chery is matched with Huawei 800V high-voltage overcharging, which can be charged at a speed of 200 + km in 5 minutes, charged for 15 minutes, and has a battery life of 400 + km.

  Many people use the example of mobile phones to compare the charging of new energy vehicles. Ten years ago, most mobile phones could be replaced with batteries, but now they are basically not used.

  In other words, the rapid development of fast charging technology has impacted the meaning of the power exchange model itself. If fast charging basically achieves the same time as power exchange, what are the advantages of power exchange? Is Li Bin’s "Cloud as a Service" a false proposition?

  For a long time, Li Bin has used "long-term doctrine" to describe NIO. In 2019, Li Bin said, "NIO is still a company that has just been established for four years. You can’t ask a four-year-old child to support the family."

  In the first half of this year, Li Bin responded to the suggestion that he should save some money and do subtraction properly. "How long does it take to see our investment return? This is very important."

  This time, Li Bin used "large investment scale and long investment cycle" as the replacement model. The question is how much time is left for NIO in the market?

  NIO is now in a difficult situation to ride a tiger and continue to invest, the difficulties are obvious, Li Bin has said a lot, and when to make a profit is a problem. No more investment means admitting that the strategy is improper and may dissuade potential car owners who are keen on changing electricity.

  At present, smart electric vehicles are already a highly invaded market. On the one hand, leading car companies continue to raise funds, merge vertically and horizontally, and expand their power; on the other hand, new energy car companies such as Weimar, Aichi, and Byton below the waist have been in trouble this year.

  In the new energy sales rankings, the new car-making force "Wei Xiaoli" has been among the top ten for a long time, leaving Geely, Changan and many other established independent enterprises behind. Now, Geely, Changan, Chery, etc. have risen significantly in the new energy field, forming a large and powerful market impact on new car-making forces and joint venture brands.

  However, NIO is still in a state of continuous loss, and the construction of a service system centered on power exchange is also regarded as one of the culprits of NIO’s loss.

  Recently, a news of "NIO lost 76.40 billion in five and a half years" appeared on Weibo’s trending topic list and caused heated discussion. From 2018 to 2022, NIO’s net profit attributable to the parent was – 23.328 billion yuan, – 11.413 billion yuan, – 5.611 billion yuan, – 10.572 billion yuan and – 14.559 billion yuan respectively.

  In the first half of 2023, NIO lost 10.926 billion yuan in net profit, and the company has accumulated losses of 76.40 billion yuan in the past five and a half years.

  Due to the huge losses, there were rumors of NIO going bankrupt.

  Qin Lihong, co-founder and president of NIO, responded to the rumors of the company’s collapse at the Guangzhou Auto Show: "There are indeed a group of people on the Internet who can’t see how good NIO is, and they sing NIO down one after another. It can be predicted that 2024 is the peak year of tram shopping. After 24 years, NIO will know if it will fail!" "NIO will not go bankrupt, and there is absolutely no possibility of it going bankrupt. Please feel free to experience and buy NIO’s cars."

  From the current financial situation and investment in power replacement, NIO may still have a long way to go to achieve profitability.

Night reading, a man with a history of drug abuse was involved in theft and was caught while watching "Operation Ice Breaking". "Wayward Brother" carried 81 sacks 140,000 coins to buy a car

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"I paid 70,000 multiple car purchases, but now I don’t get the car, and I can’t even get this car purchase back." Recently, Mr. Su of Hechuan reported to the upstream news hotline 966966/upstream news APP that he was happy to buy a car, but he had such a thing. In order to get this car purchase back in the past few days, he has traveled back and forth to Chongqing several times.

Paid 70,000 down payment and was told there was no car

Last month, Mr. Su spotted an SUV at the Lynk & Co car sales showroom on Shixin Road in Jiulongpo District. On May 18, he deposited the down payment of 73,800 yuan into the account of the dealer Chongqing Century Jinye Automobile Sales Company. "At that time, the salesperson said that there was a 2019 model, and I paid for it." When Mr. Su handled the pickup, he found that the car that the other party planned to give him was not a 2019 model, but a 2018 model.

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Car purchase receipt.

"So I asked for a refund, and the other party agreed, but it never materialized." Mr. Su said that on May 23 and 24, he stayed at the 4S store for two days, but it was not properly resolved. The staff even said that the refund was not available, and the car could not be given even the old car. After that, Mr. Su went to the dealer to negotiate many times, but there was no result.

On the afternoon of May 27, the reporter and Mr. Su arrived at the 4S store. The light in the exhibition hall was dim, and the staff said that due to a power outage, they had a day off temporarily, and the person in charge was not there.

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There was a power outage in the 4S store on the day of the interview.

During the interview, several staff members kept quiet about the matter and refused to provide the contact information of the person in charge. After repeated inquiries from reporters, one staff member admitted that he had indeed said that he could refund Mr. Su. "How long will it take to get the money?" The reporter asked, but the staff member did not reply.

The security deposit of the second-level dealer cannot be recovered either.

In the interview, the reporter learned that several other car buyers and secondary dealers have encountered similar experiences.

"The car is not given, the money is not refunded, and I am not the only one who has been deceived by this 4S store. The most excessive thing is that the store is still operating normally in the morning." Mr. Su provided reporters with the contact information of another activist, who he said had raised a banner outside the store a few days ago.

"There is indeed such a thing, I am a second-level dealer in Rongchang, and I need a few display cars, so I ordered three cars in the store, signed the contract in April, and paid a 150,000 yuan security deposit." By mid-May, the activist said, the company asked them to return the cars to the store due to internal equity issues.

What he didn’t expect was that after returning three cars and going through all the formalities, he couldn’t get the security deposit back. "We’ve been here a few times, but the boss just dragged it on anyway, and then we called the police, and the police asked us to sue, but the process was too long." The activist said helplessly that he could only continue to urge the other party to refund the security deposit.

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A group of activists has been established.

Lawyers offer a variety of avenues for defending their rights

In the face of this situation, how should consumers protect their rights? Chongqing Zhitong (Liangjiang New District) Law Firm, lawyer Yue Hongwu, believes that there are many ways for consumers to protect their rights. First, consumers can directly negotiate with the manager, and if the company manager delays or has no right to resolve, they can directly consult with the company’s leaders. Second, if the negotiation fails, consumers can also seek help from the consumer rights association where the other company is located. Third, consumers can also file complaints and appeals with the local market supervision department. Fourth, consumers can also directly apply to arbitration institutions or people’s courts for arbitration and litigation, and at the same time take preservation measures to freeze and seal the company’s property and promptly protect their rights.

The lawyer said that in the case of Mr. Su, the car sales company violated the contract to provide other models of vehicles, and said that the company did not have such vehicles and refused to replace them, which was suspected of fraud. Mr. Li could actively take up legal weapons to safeguard his legitimate rights and interests.

Upstream News Reporter, Wang Yizhu, Text/Photo/Video

Upstream news hotline, channel: 966966, Upstream news APP reporting. New things, touching things, unjust things, welcome to tell upstream news. Once the news clues are adopted, rewards will be given as appropriate.

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