Biological products are preparations that are manufactured from microorganisms, cells, animal- or human-derived tissues, body fluids etc. as starting raw materials making by biological technologies, used for prevent, treat and diagnose human diseases. To standardize the registration and management of biological products, biological products are classified as biological products for preventive, biological products for therapeutic and in vitro diagnostic reagents managed as biological products.
Biological products for prevention are biological products which are used for vaccine biological products for human immunization in order to prevent and control the occurrence and prevalence of diseases. Including immunization program vaccines and non-immunization program vaccines.
Biological products for therapeutic are biological products which are used for treat human diseases, such as proteins, polypeptides and their derivatives prepared from engineering cells (such as bacteria, yeast and insect, plant and mammalian cells) with different expression systems; cell and gene therapy products; allergen products; microecological products; biologically active products extracted from human or animal tissues or body fluids or prepared by fermentation. In vivo diagnostic reagents that are biological products shall be regulated as therapeutic biological products.
In vitro diagnostic reagents managed as biological products include in vitro diagnostic reagents used for blood source screening and radionuclide labeled in vitro diagnostic reagents,etc.
Drug registration classification is determined when apply for marketing. No changes will be made during the review process even if other drugs are marketed at home and abroad.
Part I Biological products for preventive
I. Registration classification
Type 1: innovative vaccines, domestically and overseas un-marketed vaccines:
1.1 Vaccines for the disease without effective prevention methods
1.2 Neoantigen forms developed on the basis of marketed vaccines, such as new recombinant vaccines, new nucleic acid vaccines, new conjugate vaccines prepared on the basis of marketed polysaccharide vaccines.
1.3 Vaccines containing neoadjuvants or neoadjuvant systems.
1.4 Multi-combined/polyvalent vaccines containing neoantigens or neoantigen forms.
Type 2: modified vaccines, vaccines with improved safety, effectiveness and quality controllability and obvious advantages that are obtained by modifying domestically or overseas marketed vaccine products:
2.1 Vaccines with obvious clinical advantages that are obtained by changing the antigen spectrum or type on the basis of domestically or overseas marketed products.
2.2 Vaccines with major technical improvements, including the improvements of the bacterial or viral strain/cell matrix/production process/dosage form of the vaccine. (For example, vaccines changed to other expression systems or cell matrixes; vaccines with changed or modified bacterial or viral strains; vaccines with modified cell matrixes or target genes; purified vaccines modified from non-purified vaccines; component vaccines modified from whole-cell vaccines.)
2.3 New multi-combined/polyvalent vaccines composed of marketed for similar vaccines.
2.4 Vaccines with obvious clinical advantages that are obtained by changing the administration route.
2.5 Vaccines with obvious clinical advantages obtained by changing the immunizing dose or immune procedure.
2.6 Vaccines with changed applicable populations.
Type 3: Domestically or overseas marketed vaccines:
3.1 Overseas marketed manufacturing on oversea, domestically un-marketed vaccines register for marketing.
3.2 Overseas marketed and domestically un-marketed vaccines register for domestic production and marketing.
3.3 Domestically marketed vaccines.
II. Requirements for registration documents
Please refer to the relevant acceptance review guidelines for supporting documents.
For the clinical trial application and marketing authorization registration application of the vaccine, the applicant shall prepare the registration documents in accordance with M4: Common Technical Documents (CTD) for the Registration Application of Human Drugs (hereinafter referred to as CTD). For the requirements for regional information 3.2.R, see the attachment.
Excepting to meet the CTD format, the application materials should also meet the requirements of the constantly updated relevant regulations and technical guidelines. According to the law of drug research and development, at different stages of application, pharmaceutical research, including process and quality control, is a progressive and perfect process. Different biological products also have their own pharmaceutical characteristics. If the applicant believes that it is not necessary to submit a certain study or certain studies required by the application materials, it should indicate that it is not applicable and provide a sufficient basis.
The biological products in ICH M4 mainly refer to genetically engineered recombinant products. According to the features of vaccine research, the following aspects shall also be taken into consideration:
Pharmaceutical aspect:
1. Consideration of the pharmaceutical documents for different types of vaccines
On the basis of the basic framework of ICH M4, the fungus (poisonous) species, process development, process description and quality characteristic research materials shall be submitted according to the characteristics of the vaccine.
2. Consideration of seed lot and cell matrix
For vaccine declaration materials involving fungus (poisonous) species the documents of the viral strain used for production shall be submitted in Section 3.2.S.2.3.
The review and verification report issued by the National Institutes for Food and Drug Control or a third-party verification agency recognized by the relevant drug regulatory agency for the seed lots of the viral strain and cell matrix used for production shall be provided in 3.2.S.2.3.
3. Adjuvant
The research documents related to the adjuvant shall be submitted in the following two sections: an overview of the adjuvant shall be provided in 3.2.P; the complete pharmaceutical research information shall be submitted in 3.2.A.3, including raw materials, process, quality attribute, test method and stability.
4. Safety evaluation of exogenous factors
The safety of exogenous factors shall be analyzed systematically accordance with the relevant technical guides. For traditionally vaccines, refer to the requirements for vaccines; for recombinant vaccines, refer to the requirements for recombinant therapeutic biological products.
The target virus inactivation verification materials shall be submitted in Section 3.2.S.2.5 Process Verification.
The nontarget virus elimination/inactivation verification study shall be submitted in Section 3.2.A.2 Safety Evaluation of Exogenous Factors.
5. Multi-combined/polyvalent vaccines
For polyvalent vaccines, to consider the method for organizing declaration materials according to the difference in production process and quality control between the various components. If the difference is small, they can be described in the same 3.2.S section; if the difference is big, it is recommended to provide different 3.2.S sections.
If the product contains multiple components (e.g. combined vaccines, or is supplied with diluent), it could separately provide a complete stock solution and/or preparation section for each component.
Non-clinical aspect:
1. Adjuvant
For the adjuvant, the pharmacokinetic and toxicological studies (if there are any) shall be corresponding part submission according to the basic framework of ICH M4; the research contents concerning the type of adjuvant used, the necessity of adding adjuvant, the rationality of the adjuvant/antigen ratio and the adjuvant mechanism shall be submited in Setion 4.2.1.1 Main Pharmacodynamics.
2. Multi-combined/polyvalent vaccines
The research contents concerning the rationality of the antigen ratio of the multi-combined/polyvalent vaccine and the cross protection activity of the antibody of the polyvalent vaccine shall be submitted in Section 4.2.1.1 Main Pharmacodynamics.
3. Others
Except for routine safety studies, other safety studies may be submitted in section 4.2.3.7 Other Toxicity Studies.
Clinical Trial aspect:
“The test report and trial production record of the test drug (including placebo)” shall be included in E3: 9.4.2 Identification of Research Products. The detailed documents shall be submitted in “16. Annex”, “16.1.6 The list of patients receiving the specific batch of test drugs/research products if more than 1 batch of drugs are used”.
Applicants should submit the clinical trial database on CD-ROM based on CTD when completing the clinical trial application for drug market registration. For specific requirements such as database format and related documents, please refer to the relevant guidelines for clinical trial data submission.
When an overseas applicant applies for conducting the clinical trial of a vaccine for minors in the territory of China, at least the overseas Phase I clinical trial data covering the target population shall be obtained. These provisions do not apply to vaccines urgently required to cope with major public health emergencies or other vaccines considered to be urgently required by the health administrative department of the State Council.
Part II Biological products for therapeutic
I. Registration classification
Type 1: innovative biological products, domestically and overseas un-marketed biological products for therapeutic
Type 2: modified biological products, biological products for therapeutic with improved safety, effectiveness and quality controllability and obvious advantages which are obtained by modifying domestically or overseas marketed products.
2.1 Biological products with obvious clinical advantages which are obtained by optimizing the dosage form and administration route on the basis of marketed products.
2.2 Biological products with newly added domestically and overseas unapproved indications and/or changed applicable populations.
2.3 New compound products composed of marketed biological products.
2.4 Biological products with major technical improvements made on the basis of marketed products, such as recombinant technology replaces biological tissue extraction technology; it has obvious clinical advantages after changing amino acid sites or expression systems and host cells compared with products already on the market.
Type 3: Domestically or overseas marketed biological products:
3.1 Overseas marketed manufacturing in oversea, domestically un-marketed biological products register for marketing.
3.2 Overseas marketed and domestically un-marketed biological products register for domestic production and marketing.
3.3 Biosimilars.
3.4 Other biological products
II. Requirements for registration documents
1.For the clinical trial application and marketing authorization registration application of the biological product for therapeutic, the applicant shall prepare the registration documents in accordance with M4: Common Technical Documents (CTD) for the Registration Application of Human Drugs (hereinafter referred to as CTD). For the requirements for regional information 3.2.R, see the attachment.
2.In addition to the CTD format requirements, the contents of the registration documents shall meet the requirements of the relevant up-to-date regulations and technical guidelines. According to the law of drug research and development, pharmaceutical study, including process and quality control, is a gradually progressive and improved process in different registration stages. Different biological products have different pharmaceutical characteristics. A sufficient basis for support is required if applicant considered unnecessary to submit one or some of the studies requested for the registration and should be indicated that it is not applicable.
3. For biosimilars, the content about quality similarity evaluation can be submitted in 3.2.R Other Documents.
4. For antibody-drug conjugates or modified products, a complete set of pharmaceutical research materials for small molecule drugs can be submitted separately according to the CTD format and content requirements, or all the pharmaceutical research materials can be submitted in 3.2.S.2.3 Material Control.
5. For compound or multicomponent products, it could separately provide a complete stock solution and/or preparation section for each component.
6. For cell and gene therapy products, the pharmaceutical research documents can be provided under the corresponding item for the stock solution and/or preparation according to the product features and the inapplicable items can be marked with “not applicable”. For example, for the pharmaceutical research documents of the plasmid and viral vector in the key raw materials, the complete pharmaceutical research documents can be submitted partially under 3.2.S.2.3 Material Control according to the CTD format and content requirements.
7.Applicants should submit the clinical trial database on CD-ROM based on CTD when completing the clinical trial to apply registration for marketing. For specific requirements such as database format and related documents, please refer to the relevant guidelines for clinical trial data submission.
8. Intramuscular injections of general or specific human immunoglobulin, human serum albumin, etc. that are exempted from clinical trials as required by the regulations can be directly submitted for marketing application.
9. For in vivo diagnostic reagents that are biological products, the registration documents shall be prepared in accordance with CTD.
Part III In vitro diagnostic reagents managed as biological products
I. Registration classification
Type 1: Innovative in vitro diagnostic reagents;
Type 2: Domestically or overseas marketed in vitro diagnostic reagents.
II. Requirements for registration documents
In vitro diagnostic reagents can be directly submitted for marketing application.
(I) Overview
1. Product name
2. Certification document
3. Patents and their ownership status
4. Purpose and basis of subject establishment
5. Self-evaluation report
6. Instructions for use and drafting notes
7. Sample manuscripts of package and label
8. Approval application documents for the generic name of the drug (if applicable)
(II) Summary table of main research information
9. Basic information of the product
10. Summary of analysis performance information
11. Summary of clinical trial information
(III) Research documents
12. The research data on the main raw materials
13. The research data on the main processes and test methods
14. Reference value (range) determine data
15. Analysis performance evaluation data
16. The documents of stability study
17. Manufacturing and testing records, manufacturing process (manufacturing and testing procedures)
18. Clinical trial documents
III. Description of submission documents
(I) Overview part
1. Product name: The product name may include generic name, trade name and English name. The generic name shall comply with the relevant naming rules specified in Chinese Pharmacopoeia.
2. Certification document: The certification document shall be submitted in accordance with the Requirements for the Guidelines for the Acceptance Review of In Vitro Diagnostic Reagents.
3. A description of the patents and their ownership status, as well as a statement of no infringement of the patent rights of any third party.
4. Purpose and basis of subject establishment: including the domestic and overseas research and development, marketing status, its manufacturing and using status. relevant literatures
5. Self-evaluation report
5.1 The intended use of the product: the intended use of the product, the background information of the clinical indication related to the intended use, such as the incidence rate and susceptible population of the clinical indication, as well as the relevant clinical or laboratory diagnosis method.
5.2 Product description: product name, packaging size, used methods, test instruments. Summary and evaluation of the main research results of the product.
5.3 Notes on biosafety: Since the main raw materials of the in vitro diagnostic reagent may be prepared from pathogen, animal- or human-derived tissues and body fluids or radioactive isotope with or without the addition of some substances, to ensure the safety of the user and environment during the transportation and use of the product, the protective measures taken for these raw materials shall be stated by the researcher.
5.4 Others: including the domestic and overseas marketing approval status of similar products. The technical methods to be used on relevant products and the clinical using situation, the similarities and differences between the registered product and similar products on domestic and overseas, etc. For new diagnostic reagent products, the literatures on the relationship between the test and the intended clinical indications shall be provided. The applicant shall establish a scientific committee to conduct a comprehensive review of the R & D process and results to ensure the scientificity, integrity and authenticity of the data. The applicant shall also submit a self-inspection report for the research documents.
6. The instructions for use shall meet the relevant requirements and shall be prepared by reference to the relevant technical guidelines.
7. Sample manuscripts of package and label: The label on the outer package of the product shall include generic name, marketing authorization holder, manufacturer name, product batch number and precautions. The generic name, trade name and English name of the product can be indicated at the same time. The Chinese names and batch numbers of the constituents of the in vitro diagnostic reagent product, such as calibrator, quality control material and cleaning liquid, shall be indicated on the package and label. If different batches of constituents of the same batch of products are not interchangeable, the batch numbers of the various constituents shall be indicated in addition to the product batch number.
8. Approval application documents for the generic name of the drug.( If applicable.)
(II) Summary of main research information
9. Basic information of the product: applicant, marketing authorization holder, production address, packaging address. Test methods, test instruments and so on.
10. Summary of analytical performance information: The main analytical performance indexes include the limit of minimum detection, specificity, range, accuracy (quantitative determination of products), precision in batch, precision between batches, preservation and validity period, etc.
11. Summary table of clinical trial information: including clinical trial institution, clinical study protocol, total sample size, the number of samples by each clinical unit, sample information, clinical study result, the other test methods used or the basic information of other diagnostic reagent products.
(III) Research documents
12. The research data of the main raw materials
12.1 Radionuclide labeled products: solid phase carrier, antigen, antibody, radionuclide, quality control material, standard substance (calibrator) and enterprise reference. The research materials of their sources, preparation and quality standards shall be provided. For quality control products, standard products (calibration products), reference products by enterprise, should also provide value or traceability of research documents.
12.2 Products based on immunological methods: solid phase carrier, color development system, antigen, antibody, quality control products and reference products by enterprise and so on. The research documents of their sources, preparation and quality standards shall be provided. For quality control products, standard products (calibration products), reference products by enterprise, should also provide value or traceability of research documents.
12.3 Nucleic acid detection kits for pathogenic microorganisms: primer, probe, enzyme, dNTP, nucleic acid extraction and separation/purification system, color development system, quality control products, internal standard and enterprise reference. The research materials of their sources, preparation and quality standards shall be provided. For the quality control material, internal standard and reference products by enterprise, the valuing or traceability test materials shall also be provided.
13. The research documents of the main processes and test methods
13.1 Radionuclide labeled products: the researches of the coating of the solid phase carrier, the labeling of radionuclide, sample collection and treatment, sample size, the amount of each constituent of the reagent, reaction conditions and quality control method.
13.2 Products based on immunological methods: including the researches of the coating of the solid phase carrier, color development system, sample collection and treatment, establishment of reaction system and quality control method.
13.3 Nucleic acid detection kits for pathogenic microorganisms: the researches of sample treatment, sample size, amount of reagent, nucleic acid separation/purification process, establishment of reaction system and quality control method, as well as the researches of the test methods for different applicable models.
14. Reference value (range) determination documents: The reference value (range) shall be determined, the power and confidence interval shall be stated after the testing of the negative samples, minimum detection limit samples, and the statistical analysis of the test results.
15. Analytical performance evaluation documents
15.1 These include the limit of minimum detection, specificity (including selection of anticoagulant agent, interference of endogenous interfering substance, interference of relevant disease samples), range, accuracy, precision in batch, precision between batches, the comparison study with approved registration products. For nucleic acid detection products of pathogenic microorganisms, the testing of the samples of main domestic subtypes or genotypes shall also be taken into consideration. For the limit of minimum detection, the power and confidence interval shall be stated.
15.2 The above-mentioned performance evaluations shall be carried out using multiple batches of products. The product specification shall be drawn out after the statistical analysis of the performance evaluation results of multiple batches of products, in order to effectively control the production process and the stability of product quality.
15.3 If the registration application covers different packaging specifications or if the product is suitable for different models, each packaging specification product is required, or to carry out the above evaluation on the different models and provide test documents. Different packaging specifications are only different in the amount of packaging, then there is no need to provide evaluation information for the above items.
15.4 For nucleic acid detection products for pathogenic microorganisms, if mixed samples are used for detection, the single and mixed test samples shall be respectively evaluated for analytical performance.
15.5 The quality standards and their determination basis shall be stated.
16. The documents of stability study: including the stability study data of at least three batches of samples under actual storage conditions and open-bottle conditions until the expiration date, accelerated destructive test data should be provided if necessary.
17. Manufacturing and testing records, manufacturing and testing procedures:
Copies of production and self-inspection records for at least three consecutive batches
Manufacturing and testing procedures: refer to the current edition of Chinese Pharmacopoeia.
18. Clinical trial documents
18.1 The clinical trial shall be done in at least 3 domestic clinical institutions, the clinical trial agreement and protocol shall be provided.
18.2 Providing completely clinical trial report .
18.3 The detailed materials of the clinical trial, including the trial materials of all the clinical samples and the basic information of the other test methods or other diagnostic reagent products used, such as the test method, the source of the diagnostic reagent product, the instructions for use and registration approval of the product.
18.4 The total number of subjects used in the clinical study:
Radionuclide labeled products: at least 500 cases.
Products based on immunological methods: at least 10000 cases.
Nucleic acid detection products for pathogenic microorganisms: at least 100 thousand cases.
18.5 When carrying out comparison study with marketed products, the samples with nonconforming test results shall be further confirmed with third party products.
18.6 For nucleic acid detection products for pathogenic microorganisms, if mixed samples are used for detection, the single and mixed sample test results shall be respectively statistically analyzed.
18.7 The overseas applicant shall provide the overseas clinical trial documents, the summary report of overseas clinical applications and the domestic clinical trial documents.
Attachment:
M4: Common Technical Documents (CTD) for the Registration Application of Human Drugs
Regional information
3.2.R Regional information
3.2.R.1 Process verification
The process verification scheme and report shall be provided.
3.2.R.2 Batch record
For clinical trial application, the batch production and inspection records representing the process of the clinical trial samples shall be provided;
For marketing authorization application, the batch production and inspection records of the key clinical batches and at least three consecutive marketing scale validation batches shall be provided;
The testing reports of these batches shall be provided.
3.2.R.3 Analysis method validation report
The analysis method validation report shall be provided, including the typical chromatogram.
3.2.R.4 Stability chromatogram
The typical chromatogram of stability study shall be provided.
3.2.R.5 Comparability protocol (If applicable)
3.2.R.6 Others
