Notice from the National Medical Products Administration on the Release of Registration Categories and Data Requirements for Biological Products

　　(No. 43 of 2020)

　　Release date: 2020-06-30

　　To align with the implementation of the “Measures for Drug Registration Management,” the National Medical Products Administration has organized the development of the “Classification of Biological Product Registration and Requirements for Submission of Application Materials.” This document is hereby released, with the following clarifications:

　　I. Regarding the registration classification of biological products, the new regulations have been in effect since July 1, 2020.

　　II. Regarding the requirements for submission of biological product documentation, these shall take effect as of October 1, 2020. Prior to September 30, 2020, documentation may still be submitted in accordance with the original requirements.

　　Hereby notified.

　　Attachment: Registration Categories for Biological Products and Requirements for Submission of Application Materials

　　National Medical Products Administration

　　June 29, 2020

　　Attachment

Registration Categories and Data Submission Requirements for Biological Products 　

　　Biological products refer to preparations made using biological techniques, with microorganisms, cells, animal or human tissues and body fluids as starting raw materials, and intended for the prevention, treatment, and diagnosis of human diseases. To standardize the registration application and management of biological products, these products are classified into preventive biological products, therapeutic biological products, and in vitro diagnostic reagents managed as biological products.

　　Preventive biological products refer to vaccine-type biological products used for human immunization to prevent and control the occurrence and spread of diseases. These include vaccines included in the Immunization Program and vaccines not included in the Immunization Program.

　　Therapeutic biological products refer to biological products used for the treatment of human diseases, such as proteins, peptides, and their derivatives prepared from genetically engineered cells (e.g., bacteria, yeast, insects, plants, and mammalian cells) employing various expression systems; cell therapy and gene therapy products; allergen products; microbiome products; and bioactive products derived from human or animal tissues or body fluids, or prepared through fermentation. In vitro diagnostic reagents classified as biological products shall be managed in accordance with the regulations governing therapeutic biological products.

　　In vitro diagnostic reagents subject to biological product regulations include in vitro diagnostic reagents used for blood-source screening and in vitro diagnostic reagents labeled with radioactive isotopes, among others.

　　The classification of drug registration is determined at the time of filing the marketing application and will not be changed during the review process simply because other drugs have been approved for marketing domestically or internationally.

　　Part One: Preventive Biological Products

　　I. Registration Classification

　　Category 1: Innovative Vaccines: Vaccines that have not been launched either domestically or internationally.

　　1.1 A vaccine for a disease with no effective preventive measures.

　　1.2 New antigen formats developed on the basis of already marketed vaccines, such as novel recombinant gene vaccines, new nucleic acid vaccines, and new conjugate vaccines prepared based on existing polysaccharide vaccines.

　　1.3 Vaccines containing new adjuvants or new adjuvant systems.

　　1.4 Multivalent/multicomponent vaccines containing neoantigens or neoantigen forms.

　　Category 2: Improved Vaccines: Vaccines that represent improvements to existing vaccine products already marketed domestically or internationally, enhancing the new product’s safety, efficacy, and quality control capabilities, and offering clear advantages over the original products. These include:

　　2.1 A vaccine that modifies the antigen spectrum or serotype based on a product already marketed domestically or internationally and demonstrates clear clinical advantages.

　　2.2 Vaccines with significant technological improvements, including enhancements to the vaccine strain/cell substrate/manufacturing process/formulation, etc. (e.g., vaccines that have switched to a different expression system or cell substrate; vaccines that have replaced the original strain or undergone modifications to an already marketed strain; modifications to an existing cell substrate or target gene; conversion of non-purified vaccines into purified vaccines; conversion of whole-cell vaccines into component vaccines, etc.)

　　2.3 A new combination/multivalent vaccine composed of vaccines already available on the market that target similar pathogens.

　　2.4 Vaccines that alter the route of administration and offer clear clinical advantages.

　　2.5 Vaccines that involve changes to the immunization dose or immunization schedule and whose new dose or schedule offers clear clinical advantages.

　　2.6 Vaccines that change the applicable population.

　　Category 3: Vaccines already marketed domestically or internationally:

　　3.1 Submission for approval of vaccines manufactured overseas that have already been marketed abroad but not yet marketed domestically.

　　3.2 Vaccines already marketed overseas but not yet marketed domestically may be applied for approval to be manufactured and marketed domestically.

　　3.3 Vaccines already approved for marketing in China.

　　II. Requirements for Application Materials

　　The supporting documents shall refer to the relevant acceptance and review guidelines.

　　For applications for clinical trials and marketing authorization of vaccines, applicants shall prepare their submission documents in accordance with the “M4: Common Technical Document (CTD) for Human Pharmaceutical Registration Applications” (hereinafter referred to as the CTD). Refer to the attachment for the requirements under Regional Information 3.2.R.

　　In addition to meeting the requirements of the CTD format, the specific content of the submission documentation must also comply with the relevant regulations and technical guidance principles that are continuously updated. In accordance with the general principles of pharmaceutical development, pharmaceutical studies—including process development and quality control—progressively advance and become more refined at different stages of the application. Different biological products also have their own unique pharmaceutical characteristics. If the applicant believes that certain studies or a set of studies required in the submission documentation are not applicable, such cases should be clearly indicated as “not applicable,” along with sufficient supporting rationale provided.

　　The requirements for biological products in ICH M4 primarily apply to genetically engineered recombinant products. Given the specific characteristics of vaccine research, the following should also be taken into consideration:

　　Pharmaceutical aspects:

　　1. Considerations for Pharmaceutical Information on Different Types of Vaccines

　　Based on the ICH M4 basic framework, documentation—including information on production strains (viruses), process development, process descriptions, and quality attribute studies—should be submitted in accordance with the specific characteristics of the vaccine.

　　2. Considerations for Seed Batches and Cell Substrates

　　For vaccine submission data involving viral strains, the production-use strain data should be submitted in section 3.2.S.2.3.

　　In 3.2.S.2.3, the testing reports shall be re-verified by a third-party testing institution accredited by the Institute of Testing or the relevant drug regulatory authority for batches of microbial (viral) seed strains used in production and batches of cell substrate seed strains used in production.

　　3. Adjuvant

　　The adjuvant-related study data should be submitted in the following two sections: an overview of the adjuvant in Section 3.2.P; and complete pharmaceutical study information, including raw materials, manufacturing processes, quality attributes, analytical methods, and stability data, in Section 3.2.A.3.

　　4. Safety Evaluation of Exogenous Factors

　　The safety system analysis of exogenous factors should be conducted in accordance with the relevant technical guidelines. In general, conventional vaccines should comply with the requirements applicable to vaccine-related products, while recombinant vaccines may refer to the requirements applicable to recombinant therapeutic biological products.

　　The validation data for target virus inactivation is submitted under the Process Validation section 3.2.S.2.5.

　　The validation study for the removal/inactivation of non-target viruses was submitted under Section 3.2.A.2, Exogenous Factor Safety Assessment.

　　5. Multivalent/Multispecies Vaccine

　　For multivalent vaccines, the organization of the submission documents should take into account the differences in the manufacturing processes and quality control measures for each serotype component. If the differences are relatively minor, the information can be described in the same 3.2.S section; if the differences are significant, separate 3.2.S sections can be submitted individually.

　　When a product contains multiple components (e.g., combination vaccines or products supplied with diluents), a complete section on the original solution and/or formulation may be provided separately for each component.

　　Non-clinical research aspects:

　　1. Adjuvant

　　For adjuvants, if pharmacokinetic and toxicological studies are available, submit them in the corresponding sections according to the ICH M4 basic framework. The study contents regarding the type of adjuvant used, the necessity of adding an adjuvant, the rationale behind the adjuvant/antigen ratio, and the mechanism of action of the adjuvant should be submitted under Section 4.2.1.1, the main pharmacodynamic section.

　　2. Multivalent/Multi-dose vaccine

　　The content on the rationality of antigen ratios in multivalent/multi-component vaccines and the cross-protection activity of antibodies induced by multivalent vaccines should be submitted under Section 4.2.1.1, the main pharmacodynamic section.

　　3. Other

　　In addition to the routine safety studies, other safety studies can be submitted under Section 4.2.3.7, Other Toxicity Studies.

　　In terms of clinical trials:

　　The “Test Drug Inspection Report and Test Drug Manufacturing Records (including Placebos)” shall be categorized under “E3: 9.4.2 Labeling of Investigational Products.” Specific documentation should be submitted in “16. Appendix,” specifically under “16.1.6 List of Patients Receiving a Specific Batch of Investigational Drugs/Investigational Products if More Than One Batch is Used.”

　　When an applicant submits a marketing authorization application for a drug after completing clinical trials, it shall submit the clinical trial database in CD-ROM format based on the CTD. Specific requirements regarding the database format and related documents can be found in the relevant guidelines for the submission of clinical trial data.

　　For applicants based outside China who seek to conduct clinical trials of vaccines for minors within China, they must at least have obtained Phase I clinical trial data from overseas studies involving the target population. This requirement does not apply to vaccines urgently needed to respond to major public health emergencies or vaccines identified as urgently needed by the health authority under the State Council.

　　Part II: Therapeutic Biological Products

　　I. Registration Classification

　　Category 1: Innovative Biologics—Therapeutic biological products that have not been marketed either domestically or internationally.

　　Category 2: Improved Biologics: Therapeutic biological products that are improvements upon already-marketed products, either domestically or internationally, resulting in enhanced safety, efficacy, and controllability of quality, and possessing distinct advantages.

　　2.1 Biologics that are optimized in terms of dosage form, route of administration, and other aspects based on already marketed products, and that demonstrate clear clinical advantages.

　　2.2 Adding new indications and/or changing the patient population that have not been approved either domestically or internationally.

　　2.3 A biological product already available on the market, when combined with other similar products, forms a new combination product.

　　2.4 Biologics that represent significant technological improvements over already marketed products—such as those in which recombinant technology replaces biological tissue extraction techniques—or that exhibit clear clinical advantages due to modifications in amino acid sites or changes in expression systems and host cells compared to existing marketed products.

　　Category 3: Biologics already marketed domestically or internationally:

　　3.1 Submission for marketing approval of biological products manufactured overseas that are already marketed abroad but not yet marketed domestically.

　　3.2 Biologics that have already been approved for marketing overseas but not yet approved for marketing domestically may be submitted for approval to be manufactured and marketed domestically.

　　3.3 Biosimilars.

　　3.4 Other biological products.

　　II. Requirements for Application Materials

　　1. For clinical trial applications and marketing authorization applications for therapeutic biological products, applicants shall prepare their submission documents in accordance with “M4: Common Technical Document (CTD) for Human Medicinal Products” (hereinafter referred to as the CTD). The requirements for regional information 3.2.R are set forth in the attachment.

　　2. In addition to meeting the requirements of the CTD format, the specific content of the submission materials must also comply with the relevant regulations and technical guidance principles that are continuously updated. According to the general rules governing drug development, pharmaceutical studies—including process development and quality control—progressively advance and become more refined at different stages of the submission. Different biological products also have their own unique pharmaceutical characteristics. If the applicant believes that certain studies or a set of studies required in the submission materials are not applicable, such cases should be clearly indicated as “not applicable,” along with sufficient supporting rationale provided.

　　3. For biosimilar products, the content related to the quality similarity assessment can be submitted under “3.2.R.6 Other Documents.”

　　4. For antibody-drug conjugates or modified products, the pharmaceutical study data for small-molecule drugs may be submitted either as a complete set of study data following the CTD format and content requirements, or all the pharmaceutical study data may be submitted under “3.2.S.2.3 Material Control.”

　　5. For combination products or multi-component products, a complete section on the original solution and/or formulation may be submitted separately for each component.

　　6. For cell and gene therapy products, pharmaceutical study data may be submitted in the corresponding sections for the drug substance and/or drug product, based on the product characteristics. For items that are not applicable, “Not Applicable” may be indicated. For example, pharmaceutical study data for plasmids and viral vectors—key raw materials—may be submitted in their entirety under the “3.2.S.2.3 Material Control” section, following the format and content requirements of the CTD.

　　7. When an applicant submits a drug registration application after completing clinical trials, it shall submit the clinical trial database in CD format based on the CTD. Specific requirements regarding the database format and related documents can be found in the relevant guidelines for submitting clinical trial data.

　　8. Ordinary or specific human immunoglobulin and human albumin, which are exempt from clinical trials as stipulated, can be directly submitted for marketing approval.

　　9. In vitro diagnostic reagents of the biological products category shall prepare submission documents according to the CTD format.

　　Part 3: In Vitro Diagnostic Reagents Managed as Biological Products

　　I. Registration Classification

　　Class 1: Innovative in vitro diagnostic reagents.

　　Category 2: In vitro diagnostic reagents that have already been marketed both domestically and internationally.

　　II. Requirements for Application Materials

　　In vitro diagnostic reagents can be directly submitted for market approval.

　　(1) Overview

　　1. Product Name

　　2. Supporting Documents

　　3. Description of the patent status and ownership status

　　4. Purpose and Justification for the Project

　　5. Self-assessment report

　　6. Product Instructions and Drafting Notes

　　7. Packaging and Label Design Drafts

　　8. Application materials for the approval of generic drug names (if applicable)

　　(2) Summary Table of Key Research Information

　　9. Basic Product Information

　　10. Analysis of Performance Information Summary

　　11. Summary of Clinical Trial Information

　　(3) Research Materials

　　12. Research data on primary raw materials

　　13. Research data on major process procedures and test methods

　　14. Reference Values (Range) Determination Data

　　15. Analyze performance evaluation data

　　16. Stability Study Data

　　17. Manufacturing and verification records, production processes (i.e., manufacturing and verification procedures)

　　18. Clinical trial data

　　III. Instructions for the Application Materials Items

　　(1) Summary Section

　　1. Product Name: The product name may include the generic name, the trade name, and the English name simultaneously. The generic name shall comply with relevant naming principles, such as those outlined in the Chinese Pharmacopoeia.

　　2. Supporting Documents: Submit the supporting documents in accordance with the requirements of the “Guidelines for Acceptance and Review of In Vitro Diagnostic Reagents.”

　　3. Description of the patent status and ownership status, as well as a statement confirming that the patent does not infringe upon the rights of others.

　　4. Rationale and Basis for the Project: This includes relevant domestic and international literature and data on the research, development, production, and use of this product.

　　5. Self-assessment report

　　5.1 Intended Use of the Product: The intended use of the product, along with background information on clinical indications related to its intended use, such as the incidence of these clinical indications and susceptible populations, as well as relevant clinical or laboratory diagnostic methods.

　　5.2 Product Description: Product name, packaging specifications, methods employed, instruments used for testing, and a summary and evaluation of the product’s key research findings.

　　5.3 Instructions Regarding Biosafety: Since the primary raw materials used in in vitro diagnostic reagents may be prepared by processing or adding certain substances to materials derived from various animals, pathogens, human tissues, body fluids, or radioactive isotopes, researchers should provide detailed explanations of the protective measures adopted for these raw materials to ensure the safety of users and the environment during transportation and use.

　　5.4 Other: This includes information on the approval status of similar products both domestically and internationally. It also covers the technical approaches and clinical applications adopted by the relevant products, as well as any differences between the product being applied for registration and its counterparts at home and abroad. For innovative diagnostic reagent products, applicants must provide documented evidence establishing the relationship between the target analyte and the intended clinical indications. Applicants shall establish a scientific committee to conduct a comprehensive review of the product’s R&D process and results, ensuring the scientific rigor, completeness, and authenticity of the data. Applicants shall also submit a self-assessment report on the research data.

　　6. Product Instructions and Drafting Notes: The product instructions shall comply with relevant requirements and be prepared with reference to applicable technical guidance principles.

　　7. Packaging and Label Design Samples: The labels on the product’s outer packaging shall include the generic name, the marketing authorization holder, the name of the manufacturing enterprise, the product batch number, and precautions. The product’s generic name, trade name, and English name may also be indicated simultaneously.

　　For various components in in vitro diagnostic reagent products—such as calibrators, quality control materials, and cleaning solutions—their packaging and labels shall indicate both the Chinese name and batch number of each component. If components with different batch numbers within the same product batch cannot be interchanged, both the product batch number and the batch numbers of the individual components must be clearly indicated.

　　8. Application materials for the approval of generic drug names (if applicable)

　　(2) Summary of Key Research Information

　　9. Basic product information: applicant, marketing authorization holder, manufacturing address, packaging address, etc.; test methods and instruments used for testing, etc.

　　10. Summary of Performance Information Analysis: The key performance indicators analyzed include the limit of detection, analytical specificity, measurement range, assay accuracy (for quantitative assays), within-batch precision, between-batch precision, storage conditions, and shelf life, among others.

　　11. Summary of Clinical Trial Information: Includes clinical trial institutions, clinical study protocols, total sample size, sample sizes at each clinical site, sample information, clinical study results, as well as basic information on other testing methods or diagnostic reagent products used.

　　(3) Research Materials

　　12. Research data on primary raw materials

　　12.1 Radioisotope-labeled products: solid-phase carriers, antigens, antibodies, radioisotopes, quality control materials, reference standards (calibration standards), and enterprise reference materials, etc. Study data on the source, preparation, and quality control of these products shall be provided. For quality control materials, reference standards (calibration standards), and enterprise reference materials, additional study data on assigned values or traceability shall also be provided.

　　12.2 Immunological-based products—including solid-phase carriers, color-developing systems, antigens, antibodies, quality control materials, and enterprise reference materials—shall be accompanied by study data on their sources, preparation methods, and quality control procedures. For quality control materials, reference standards (calibration standards), and enterprise reference materials, additional study data on assigned values or traceability shall also be provided.

　　12.3 Pathogen Nucleic Acid Detection Kit: Primers, probes, enzymes, dNTPs, nucleic acid extraction, separation, and purification systems, color development systems, quality control materials, internal standards, and enterprise reference materials, etc. Supporting documentation regarding the source, preparation, and quality control of these components shall be provided. For quality control materials, internal standards, and enterprise reference materials, additional experimental data demonstrating their assigned values or traceability shall also be provided.

　　13. Research data on major process procedures and test methods

　　13.1 Radioisotope-labeled products: including coating of solid-phase carriers, radioisotope labeling, sample collection and processing, establishment of reaction systems, and research on quality control methods.

　　13.2 Immunological-based products: These include the coating of solid-phase carriers, color-developing systems, sample collection and processing, establishment of reaction systems, and research on quality control methods.

　　13.3 Pathogen Nucleic Acid Detection Kit: Research on sample processing, sample volume, reagent volume, nucleic acid isolation/purification procedures, establishment of reaction systems, quality control methods, and testing methodologies for different applicable instrument models.

　　14. Data for determining reference values (ranges): Measure negative samples, samples at the lowest detection limit, and other relevant samples; after performing statistical analysis on the measurement results, determine the reference values (ranges), and specify the confidence level and confidence interval.

　　15. Analyze performance evaluation data

　　15.1 includes items such as the limit of detection, analytical specificity (including selection of anticoagulants, interference from endogenous interfering substances, and interference from samples associated with relevant diseases), detection range, measurement accuracy, within-batch precision, between-batch precision, and comparative studies with already approved and registered products. For nucleic acid detection products for pathogenic microorganisms, consideration should also be given to the detection of samples representing major domestic subtypes or genotypes. Regarding the limit of detection, the confidence level and the corresponding confidence interval should be specified.

　　15.2 Multiple batches of products should be used to evaluate the performance of the aforementioned items. By conducting statistical analysis on the performance evaluation results from multiple batches of products, product standards can be established to effectively control the stability of both the production process and product quality.

　　15.3 If the registration application includes different packaging specifications or if the product is applicable to different models, test data demonstrating the evaluation of the aforementioned items must be provided for each packaging specification or for each model. However, if the different packaging specifications differ only in fill volume, it is not necessary to provide the evaluation data for the aforementioned items.

　　15.4 For nucleic acid detection products for pathogenic microorganisms, if pooled samples are used for testing, the analytical performance should be evaluated separately for both individual test samples and pooled test samples.

　　15.5 Description of quality standards and the basis for their determination.

　　16. Stability Study Data: This includes stability study data for at least three batches of samples, stored under actual storage conditions and in opened-vial conditions until after the expiration date. Accelerated degradation studies should be provided when necessary.

　　17. Manufacturing and Verification Records, Manufacturing and Verification Procedures

　　Photocopies of production and self-inspection records for at least three consecutive batches of products.

　　Manufacturing and Testing Procedures: Refer to the current edition of the Chinese Pharmacopoeia.

　　18. Clinical trial data

　　18.1 Conduct clinical trials at least in three domestic clinical institutions, and provide the clinical trial protocol and the clinical trial plan.

　　18.2 Provide a complete clinical trial report.

　　18.3 Detailed information on the clinical trial, including trial data for all clinical samples, as well as basic information on other testing methods or diagnostic reagent products used, such as the testing methods, source of the diagnostic reagent products, product instructions, and registration approval status.

　　18.4 Total sample size of the clinical study:

　　Radioisotope-labeled products: at least 500 cases.

　　Products based on immunological methods: at least 10,000 cases.

　　Pathogen nucleic acid detection products: at least 100,000 cases.

　　18.5 When conducting comparative studies using commercially available products, samples with inconsistent measurement results must be further confirmed using third-party products.

　　18.6 For nucleic acid detection products for pathogenic microorganisms: If pooled samples are used for testing, statistical analysis should be performed separately on the results obtained from individual sample testing and from pooled-sample testing.

　　18.7 Applicants from overseas shall provide clinical trial data completed abroad, a summary report on clinical use abroad, and clinical trial data completed within China.

　　Attachment: M4: Regional Common Technical Document (CTD) for Human Drug Registration Applications

　　Information

　　Attached

M4: General Application for Human Drug Registration

　　Regional Information on the Technical Documentation (CTD)

　　

　　3.2.R Regional Information

　　3.2.R.1 Process Validation

　　Provide process validation plans and reports.

　　3.2.R.2 Batch Records

　　When submitting a clinical trial application, provide batch production and inspection records that represent the manufacturing process of the clinical trial samples.

　　At the time of the marketing application, provide batch production and testing records for key clinically representative batches as well as at least three consecutive batches at the proposed commercial-scale validation batch size.

　　Provide the inspection reports for the above-mentioned batches.

　　3.2.R.3 Analytical Method Validation Report

　　Provide an analytical method validation report, including typical chromatograms.

　　3.2.R.4 Stability Map

　　Typical profiles for stability studies.

　　3.2.R.5 Comparability Plan (if applicable)

　　3.2.R.6 Other