Submission of Compound Preparations Based on Classic Chinese Medicine Formulas
Document Requirements (Draft for Public Comment)
I. Submission Materials Items
(1) Overview Materials
1. Medication Name
2. Proof of Document
3. Prescription Source and Historical Development
4. Evolution of the Formula Principle
5. Clinical Applications
6. Summary and evaluation of key research findings
7. Draft Drug Label, Drafting Explanation, and References
8. Packaging and Label Design Proofs
(II) Pharmaceutical Research Data
9. Summary of Pharmaceutical Research Data
9.1 Summary of Key Research Findings
9.2 Analysis & Evaluation
9.3 “Standard decoction”Standard
10. Herbal medicine
10.1 Prescription Drug Taste
10.2 Medicinal Resource Assessment
10.3 Quality evaluation of medicinal herbs
10.4 Certificate of Analysis for Medicinal Herbs
10.5 References
11. Decoction Piece Processing
11.1 Processing of medicinal materials by origin
11.2 Determination of Processing Methods and Parameters
11.3 Quality Rating
11.4 References
12. Process Research
12.1 Prescription
12.2 Preparation Method
12.3 Dosage Form and Product Composition
12.4 Process Development Documentation
12.5 Process Validation
12.6 References
13. Test samples for nonclinical safety studies
14. Drug Standard Research
14.1 Overview of Pharmaceutical Standards
14.2 Drug Standard Project
14.3 Attention
14.4 Chemical Composition Analysis
14.5 Quality Research
14.6 Sample Inspection Report
14.7 References
15. Stability Study
15.1 Stability Summary
15.2 Stability study data
15.3 Packaging Material Selection
15.4 Post-Market Stability Studies
15.5 References
(3) Nonclinical Safety Study Data
16. Overview of Nonclinical Safety Studies
17. Safety Pharmacology Study Data and Literature
18. Single-dose toxicity study data and literature
19. Data on repeated-dose toxicity studies and literature
20. Special safety data and literature on hypersensitivity (local, systemic, and phototoxicity), hemolysis, local irritation (vascular, skin, mucosal, muscular, etc.), and dependency associated with local and systemic administration.
21. Genotoxicity study data and literature
22. Reproductive Toxicity Study Data and Literature
23. Carcinogenicity study data and literature
24. Dependency trial data and literature
II. Instructions for Preparing Application Materials
(I) Overview
1. Medication Name
Drug names include:
①Chinese Name;
②Pinyin Name
③Naming basis.
Traditional Chinese medicine compound formulas derived from ancient classic prescriptions (hereinafter referred to as“Classic Prescriptions”The name of the drug product shall, in principle, match the name of the prescription in ancient medical texts.
2. Proof of Document
Supporting documents include:
①Copies of the applicant's legally registered proof documents, "Drug Production License," and "Good Manufacturing Practice for Drugs" certification.
②Copy of the registration certificate or approval number for packaging materials (or containers) in direct contact with pharmaceutical products;
③Other supporting documents.
3. Prescription Source and Historical Development
The prescription composition, dosages of each ingredient, functions and indications, as well as the proposed administration and dosage should be clearly stated.
Clearly specify the source of the prescription (title and author), including the dynasty or period of origin. Provide the original text's record of herbal ingredients, processing methods, and dosages, along with the standardized names for each herb. Also include the original text's description of functions, indications, usage, and dosage. Attach the relevant excerpt from the original work as supporting documentation.
Provide a comprehensive review of the prescription's historical evolution, citing all relevant pharmacopoeia and literature with full references (including author, publication year, and edition).
4. Evolution of the Formula Principle
Apply TCM theory to analyze the etiology, pathogenesis, treatment principles, and methods of classic formula indications. Examine the formula's combination principles (such as Emperor, Minister, Assistant, and Guide) and the interrelationships among its ingredients. Systematically review the evolution of formula interpretations and corresponding treatment methods throughout history, citing relevant sources.
5. Clinical Applications
Apply the literature research method to systematically review past study results and clinical applications. Summarize and analyze existing clinical data reflecting the safety and efficacy of classic formulas, emphasizing their value in contemporary clinical practice. Additionally, provide a discussion on market prospects.
Ensure that cited references are authentic and relevant, clearly indicate their sources, and verify their credibility and reliability.
6. Summary and evaluation of key research findings
Provide a summary of the major study results by the applicant, along with an overall evaluation of the submitted product regarding safety, efficacy, and batch-to-batch consistency.
7. Draft Drug Label, Drafting Explanation, and References
Provide a draft of the drug package insert prepared in accordance with applicable regulations, along with explanatory notes for each section of the insert and relevant references on safety and efficacy.
Warning: This formula has a long history of clinical application in Traditional Chinese Medicine (TCM). This product is a prescription drug intended solely for use by TCM practitioners. Ingredients: List the prescription herbs and their dosages (equivalent to raw decoction pieces). Precautions: Specify the source of the prescription and its therapeutic indications. Therapeutic Indications: Use only TCM terminology consistent with records in ancient medical texts.[Pharmacology and Toxicology] This section should be drafted based on available toxicology study data, accompanied by a drafting rationale and supporting evidence.
If a section is not applicable, it may be omitted from the manual.
8. Packaging and Label Design Proofs
Submit draft packaging and label designs prepared in accordance with applicable regulations.
(II) Pharmaceutical Research
9. Summary of Pharmaceutical Research Data
The pharmaceutical research data summary is a conclusion, analysis, and evaluation of the pharmaceutical research results conducted by the applicant.
9.1 Summary of Key Research Findings
9.1.1 Prescription Drug Flavor and Herbal Resource Assessment
Clarify the source, origin, dosage form, administration method, and dosage of the prescription, along with its usage in recent and modern times.Briefly describe the newly established quality control methods and limits for prescription drugs.
Briefly describe the assessment of medicinal material resources.
9.1.2 Primary Processing of Medicinal Herbs and Decoction Slice Preparation
Ensure that the initial processing of medicinal materials and decoction slice preparation used for mass production at listing are consistent with the processes used in research.
9.1.3 Production Process
AfterBasis for the preparation of classic named formulas“Standard decoction”conduct research and development on the prescription, dosage, and decoction methods, and prepare it as“Standard decoction”Pharmaceutical research and comparative analysis should be based on the yield of paste, content, fingerprint profile, or characteristic fingerprint profile, consistent with“Standard decoction”Reach an agreement.
Define the preparation process of classical formula preparations and“Standard decoction”Consistency. If changes occur, the date, content, and rationale must be documented.
State the source of the legal standards for excipients. Briefly describe newly established quality control methods and acceptance criteria for excipients. For excipients without legal standards, indicate whether research and declaration were conducted in accordance with relevant technical requirements, and summarize the results.
Summarize the batch number, scale, and quality inspection results for the pilot production samples. Confirm whether the process is stable, reasonable, and feasible.
9.1.4 Drug Standards
Briefly describe the main components of the drug standard. Specify the batch count for content determination, the proposed content limits, and the rationale for their establishment. Indicate the source and purity of the reference standard.
Indicate whether non-statutory reference standards have been calibrated by the statutory authority.
9.1.5 Stability Study
Summarize the stability study results, including the number of batches tested, duration, methods, parameters evaluated and their outcomes, as well as packaging materials and containers in direct contact with the drug. Assess the product's stability, propose a shelf life, and define storage conditions.
9.1.6 Manual, packaging, label
Confirm direct-contact packaging materials and containers, including whether their registration certificate or approved number and drug standards are provided. Briefly describe the "Ingredients," "Description," "Specification," "Storage," "Packaging," and "Expiry Date" sections in the package insert, labeling, and packaging.
9.2 Analysis & Evaluation
Summarize findings from research on herbal resource assessment, preparation processes, quality control, and stability, analyzing the interrelationships among these results. Integrate insights from historical clinical application literature of classic formulas to evaluate correlations between pharmaceutical research outcomes and the drug's safety and efficacy. Assess process feasibility, quality controllability, and the stability of classic formula preparations.
9.3 “Standard decoction”Standard
Provide Approved“Standard decoction”Standard.
10. Herbal medicine
10.1 Prescription Drug Taste
Summarize the source, supporting documents, and applicable standards for each ingredient in the prescription in a list format. Example:
Table1. Prescription Drug Flavor List
Name | Standard (Pharmacopoeia, Ministry Standard) | Origin (up to county level) | Origin (Identification Basis, Identifier) | Collect time, batch, quantity, etc. |
Provide details on the medicinal material's origin (including family name, Chinese name, and Latin scientific name), part used, production area (latitude/longitude), harvesting period, processing and storage methods, and whether it is cultivated./Breeding (artificial production), variety, or cultivar name. ForA botanical origin identification report is required for all species that are easily confused with the target medicinal material.The raw material must have a fixed botanical origin and be selected in accordance with“Standard decoction”Herbs from the same botanical source.
Herbal materials sourced from wild resources must include information on ecological environment, morphological description, and growth characteristics.
When medicinal material quality varies significantly by origin, the source should be standardized., Promote the use of authentic medicinal materials. When material quality varies significantly depending on the harvest period, standardize the harvest timing.
Comply with the Good Agricultural and Collection Practices for Chinese Herbal Medicines (GAP) for planting, breeding, and production of Chinese herbal medicines.
10.2 Resource Assessment Report
Herbal resource assessment is the process by which a manufacturing enterprise scientifically evaluates the relationship between the projected consumption and availability of herbal resources over a specified period, based on its production capacity, as well as the potential impact of product manufacturing on the sustainable use of these resources. Enterprises should conduct herbal resource assessments and document data and conclusions at different stages: project initiation, development, and post-marketing.
Details on the content and conclusions of the herbal resource assessment are provided in the "Technical Guidelines for TCM Resource Assessment."
10.3 Quality evaluation of medicinal herbs
Conduct activities for medicinal herbs, processed slices, and“Standard decoction”Quality profile study, comprehensively considering medicinal materials-Decoction pieces-“Standard decoction”correlation, identify key quality attributes of the medicinal material, establish corresponding quality evaluation indicators and methods, and define a scientifically sound and reasonable quality standard for the medicinal material.
Quality profile refers to the overall description of a drug's quality attributes, considering both its safety and efficacy, and theoretically ensuring that the drug meets expected quality requirements. Quality attributes are physical, chemical, or biological properties that affect a drug's safety, efficacy, or consistency. Critical quality attributes (CQAs) are those quality attributes that have a significant impact on the drug's quality.
10.3.1 Quality Evaluation Metrics
MedicineQuality evaluation criteria for materials should correspond to the corresponding“Standard decoction”show a good correlation with quality and clinical efficacy, while meeting requirements for measurability, accuracy, durability, and low cost. EncourageDNAExploratory Research and Application of Barcoding and Bioactivity Assays.
Common quality evaluation criteria for medicinal herbs include:
（1Qualitative indicators, such as the original source of origin,Medicinal Part, Origin, Harvest Time, Post-Harvest ProcessingTraits, Effective/marker components, etc.;
（2) Quantitative metrics, such as effective/Active Ingredient ContentMoisture, impurities, pesticide residues, heavy metals and harmful elements, mycotoxinsWaitExternal contaminationLimited quantities, etc. If no testing is performed, provide a valid justification.
10.3.2 Standard
Prescription drug flavors must first comply with national drug standards, including《Chinese Pharmacopoeia》as well as the original Ministry-issued standards for Chinese medicinal materials. Additionally, enterprises must establish internal standards that meet or exceed national requirements.
Establishing enterprise standards must effectively control the quality of relevant Chinese herbal materials. If critical quality risk points identified during formulation quality evaluation cannot be controlled through existing material standards, those standards must be revised to include appropriate control methods and specifications. Submit a draft standard and its rationale; if new reference substances are required, provide both physical samples and written specifications along with supporting documentation, and file in compliance with applicable regulations. For exogenous impurities such as pesticide residues, mycotoxins, heavy metals, and harmful elements potentially present in herbal materials, establish control limits in accordance with relevant guidelines.
10.3.3 Quality Analysis
at least3not less than {0} from the following origins:15Analyze quality attributes of batch medicinal materials. Identify quality risk points related to origin, harvest period, and primary processing.
10.4 Certificate of Analysis for Medicinal Herbs
Inspection reports for prescription medicinal materials must be provided.
10.5 References
Provide source citations for references and documents.
11. Decoction Piece Processing
The preparation method for the medicinal slices must align with the ancient medical texts of the classic formula. Detailed documentation is required for raw material sourcing, initial processing, cleaning, slicing, and decoction, including key parameters of the preparation process route.
11.1 Processing of medicinal materials by origin
Describe the methods and key process parameters for processing medicinal materials at their origin. For fresh materials that undergo slicing or other treatments, explain the rationale and specify the post-processing specifications of the medicinal materials.
11.2 Determination of Processing Methods and Parameters
11.2.1 Herb Purification
For processed medicinal materials, describe the purification method used (e.g., sorting, winnowing, washing, sieving, trimming, cutting, scraping, peeling, removal of impurities, brushing, rubbing, grinding, pounding, extracting, or pressing). The purified materials must meet pharmaceutical standards.
11.2.2 Herb Slicing
For sliced medicinal materials, specify the slicing type and the basis for determining specifications. If softening is required prior to slicing, clearly define technical parameters such as softening duration, water absorption rate, temperature, and immersion equipment settings that could impact the loss or degradation of active ingredients.
11.2.3 Herbal Processing
Processed herbs must clearly specify the processing method (e.g.,stir-frying, roasting, baking, calcining, steaming, boiling, scalding, stewing, frost-making, and levigationFor specific processing parameters, if excipients are used in the heating process, clearly specify the source, type, quantity, and applicable standards of the excipients.A copy of the main text of the processing specification must be provided.
11.3 Quality Rating
Conduct activities for medicinal herbs, processed slices, and“Standard decoction”Quality profile study, comprehensively considering medicinal materials-Decoction pieces-“Standard decoction”Based on relevance, determine the critical quality attributes of the medicinal slices, establish corresponding quality evaluation indicators and methods, and define scientifically sound standards for the medicinal slices.
11.3.1 Quality Evaluation Metrics
Quality evaluation criteria for decoction pieces should correspond to the respective“Standard decoction”quality and clinical efficacy show good correlation, and are associated with corresponding“Standard decoction”The quality evaluation indicators for medicinal materials correspond well. Encouraging furtherDNAExploratory Research and Application of Barcoding and Bioactivity Assays.
Quality evaluation indicators for medicinal slices typically include:
（1）Qualitative indicators, such as herbal source, botanical origin, physical characteristics, and active constituents./marker components, etc.;
（2) Quantitative metrics, such as valid/Active Ingredient ContentMoisture, impurities, pesticide residues, heavy metals and harmful elements, mycotoxinsWaitExternal contaminationLimited quantities, etc. If no testing is performed, provide a valid justification.
11.3.2 Standard
Decoction pieces used in preparations of classic famous formulas must be processed according to the methods recorded in the original source and comply with the general processing standards of the current edition of the Chinese Pharmacopoeia.
Enterprise standards must be established that meet or exceed national standards. For proprietary Chinese medicine slice manufacturers, enterprise standards should effectively control the quality of these slices. If critical quality risk points identified during finished product quality evaluation cannot be adequately controlled due to missing indicators in the existing slice standards, those standards must be revised and improved by establishing appropriate control methods and indicators. A draft standard and its rationale must be provided. All other requirements remain consistent with those for medicinal materials.
11.3.3 Quality Analysis
Analyze based on enterprise standards for no less than3origin15Batch processed medicinal pieces; if the processed pieces have not been prepared in accordance with national standards, they shall undergo a minimum of [number] processing steps starting from the raw herbs.3from {0}15Conduct batch processing studies and quality analysis of decoction pieces. Document each stage and parameters of the processing technology, and establish internal control specifications or pharmacopoeial standards for decoction pieces.
11.3.4 Provide the inspection report for the medicinal slices.
11.4 References
Provide source citations for references and documents.
12. Process Research
The preparation of classic formula preparations shall, in principle, follow the methods recorded in ancient texts. Except for the shaping process, all other aspects must remain substantially consistent with the original formulation source.In process development, identify critical quality attributes (CQAs), critical material attributes (CMAs), and critical process parameters (CPPs). Use appropriate experimental designs to establish relationships between CMAs and CPPs with CQAs, enhancing the robustness of the manufacturing process.Establish corresponding process control methods to ensure consistent and traceable quality across batches.
12.1 Prescription:Provide1000Formula composition per dosage unit.
12.2 Method:
Conduct production trials using the enterprise's manufacturing equipment.3Based on data from pilot and validation batches produced using the enterprise's equipment and scale, combined with R&D batch data, comprehensively evaluate and determine all process parameters. Define quality control points and control methods for the production process, and establish a process specification.
Provide a process flowchart for the preparation of classic famous formulas and research data for each process step. Pharmaceutical research must be consistent with“Standard decoction”Perform comparative analysis.
12.2.1 Process Flow Diagram
Provide a complete, clear, and concise process flowchart based on the preparation steps. Include all process stages and specify key process parameters.
12.2.2 Detailed Preparation Method
Represented by pilot batches，Describe the process by unit operations (including packaging steps), specifying operating procedures, process parameters, and ranges. When describing each unit operation, focus on key process steps and parameters in light of different dosage forms and process characteristics.
12.3 Dosage Form and Product Composition:
（1Specify the dosage form and strength, with the amount of medicinal material per unit dose clearly stated under "strength." Present the prescription composition of unit-dose products in a table, listing each active ingredient and excipient along with their respective functions in the formulation and the applicable standards. Also list any solvents used during the manufacturing process that are ultimately removed.
Table2. Prescription composition for unit-dose products
Drugs and Excipients | Usage | Purpose | Standard |
Solvents used in the formulation process that are ultimately removed |
（2Describe the packaging materials and containers used for the product.
12.4 Process Development Documentation
Details on research content and requirements for processes such as extraction, concentration, and drying are provided in the "Technical Guidelines for Research on Extraction and Purification Processes of Traditional Chinese Medicines and Natural Drugs." Additionally, since production processes are closely tied to manufacturing equipment, a mindset that equipment serves drug quality should be adopted. Equipment selection must align with process requirements.
The objective of process development is to“Standard decoction”Maintain consistent quality attributes.Select at least three indicators, including yield rate, fingerprint similarity, content of multiple target components, and their transfer rates.must all“Standard decoction”Within the specified range.
12.4.1 Pre-processing technology for Chinese herbal decoction pieces
（1) Slicing
CNIf medicinal slices require cutting processing, the type and specifications of cutting must be clearly detailed. For materials that need softening prior to cutting, process parameters such as softening time, water absorption, temperature, and infiltration equipment must be specified to address any factors that could cause loss or degradation of active ingredients.
（2) Crush
If traditional Chinese medicine (TCM) decoction pieces require grinding, specify the grinding method and particle size with justification, and monitor powder yield. For herbs containing volatile components, control grinding temperature. For soft-textured herbs high in sugar, gum, or protein (e.g., animal-derived materials), select an appropriate grinding technique.
12.4.2 Process Extraction Research
The adopted process route shall be consistent with the traditional Chinese medicine manufacturing process of the classical formula.
12.4.2.1 Extract process description
Describe the extraction process, key parameters, and scope.
12.4.2.2 Process Condition Evaluation
Provide the basis for determining key process parameters, including evaluation methods, assessment indicators, and validation studies for processes such as extraction. The determination of production process parameter ranges must be supported by relevant research data.
12.4.3 Concentrate
12.4.3.1 Concentration Process Description
Describe the concentration process method, key process parameters and ranges, and production equipment.
12.4.3.2 Concentration ProcessResearch
Provide concentrated process methodsBasis for determining key process parameters, including evaluation test methods, assessment indicators, and validation studies. The established ranges for production process parameters must be supported by relevant research data.
12.4.4 Dry
12.4.4.1 Drying Process Description
Describe the drying process method, key process parameters and their ranges, and production equipment.
12.4.4.2 Drying Process Research
Provide the drying process method and the rationale for determining key process parameters, including investigation methods, evaluation criteria, and validation studies. The determination of critical process parameter ranges must be supported by relevant research data.
12.4.5 Formulation Process
The dosage form should align with ancient records; formulations documented as decoctions may be produced as granules. For details on relevant research content and requirements, refer to the "Guidance Principles for Research on Preparations of Traditional Chinese Medicines and Natural Drugs."
12.4.5.1 Formulation Process Description
Describe the formulation process flow, key process parameters, and their ranges.
12.4.5.2 Pre-formulation studies (characterization of intermediates)
SubmitProvide detailed characterization data for intermediates. Establish and provide standards for intermediates.
12.4.5.3 Auxiliary Material Research
Provide detailed research materials on excipient selection.
12.4.5.4 Formulation Screening Study
Provide detailed formulation screening study data. Based on the screening, preliminarily determine the formulation composition and specify the type, grade, specification, and quantity of all excipients used.
12.4.5.5 Formulation Process Development
ProvideDetailed formulation process development documentation.
12.4.5.6 Formulation Characteristics
Analyze physicochemical properties related to formulation performance, such as moisture content and solubility.
12.4.5.7 Optimization of formulation process
Formulation process development should account for the feasibility and adaptability of large-scale manufacturing equipment. During formulation studies, specific technologies and equipment can significantly impact the process and the types and quantities of excipients used. It is essential to establish relationships between critical process parameters (CPPs), critical material attributes (CMAs), and critical quality attributes (CQAs), define acceptable ranges for variability, minimize batch-to-batch variation, and ensure the safety, efficacy, and quality consistency of the drug product.
ManufactureFor processes optimized during drug manufacturing, primarily describe key changes in the process development (including scale-up, equipment, and process parameters) along with relevant supporting validation studies.
Summarize sample data from representative batches developed during the R&D phase (including, but not limited to pilot-scale batches). Details must include: batch number, production date and location, batch size, intended use (e.g., stability studies), and analytical results (e.g., assay and other key quality attributes). As shown in the example below, when significant yield variations occur across different batches, analyze the root causes of these differences and assess their impact on critical quality attributes.
Table3. Batch Analysis Summary
Batch Number | Production Date | Place of Origin | scale | Yield | Sample Purpose | Sample Quality | |
Content | Other Metrics | ||||||
12.5 Process Validation
12.5.1 Manufacturer
Fill in as appropriate.
12.5.2 Prescribe
List the pilot-scale batch formulation composition in a table, specifying the standards applicable to each herb and excipient.
Prescription decoction pieces may be dosed using batch mixing (i.e., after quality homogenization of the decoction pieces). Requirements: Traceable quality of all decoction pieces used, and reasonable indicators for mixed-batch compounding (e.g., fingerprint profiles, extractives, and content of marker components).
Table4. Prescription Composition
Ingredients and Excipients | Usage | Standard |
used in formulation processes and finally remove the solvent |
12.5.3 Process Description
Describe the pilot batch sample process (including packaging steps) by unit operation, specifying procedures, parameters, and ranges.
12.5.4 Auxiliary materials and materials used during the production process
List all auxiliary materials, sources of materials used during production, supporting documents, and applicable standards. Example:
Table5. Auxiliary materials and materials used during production
Accessories | Specifications (or model) | Manufacturer/Supplier | Approval Number/Registration Certificate Number | Standard | …… |
Materials used in production | Specifications (or model) | Manufacturer/Supplier | Approval Number/Registration Certificate Number | Standard | …… |
Provide inspection reports for excipients and materials used during production from their manufacturers, as well as inspection reports issued by the formulation manufacturer for these excipients and materials.
If internal control standards are established for auxiliary materials, provide the internal control standards.
12.5.5 Key Production Equipment
Provide information on the major production equipment used.Such as model numbers, manufacturers, and key technical parameters of extraction tanks, concentration tanks, etc.; types and pore sizes of filtration cartridges; specifications of compounding and filling containers, etc.
12.5.6 Control of critical process steps and extracts (intermediates)
List all critical process steps and their control ranges for process parameters. Provide study results to support the rationale for defining these critical process steps and the reasonableness of their parameter control ranges.
List the quality control standards for intermediates, including items, methods, and limits. Provide method validation data where necessary. Clearly specify the yield range for intermediates (e.g., extracts).
12.5.7 Production Data
Must be continuous3Stable batch data, including batch number, input quantity, semi-finished product quantity, auxiliary material quantity, finished product quantity, and yield rate.
12.5.8 Final Inspection Result
Provide finished product self-inspection results. For herbs related to sample assay, submit the raw material data used and the sample assay data, and calculate the transfer rate.
12.6 References
Provide source citations for references and documents.
13. Test samples for nonclinical safety studies
Samples for nonclinical safety studies shall be manufactured at pilot scale or larger. Provide the raw materials, manufacturing process, quality standards, test reports, and batch production records used to prepare these samples.
14. Drug Standard Research
14.1 Overview of Pharmaceutical Standards
To effectively control quality across all stages of classical formula preparation, conduct comprehensive quality profiling of herbs, processed pieces, and finished preparations. Identify critical quality attributes to ensure batch-to-batch consistency and traceability of the final products.
Standard research should comply with“Technical Requirements for the Development of Quality Standards of Traditional Chinese Medicine in the Pharmacopoeia of the People's Republic of China”as stipulated in.Classical formula preparations must establish standards for medicinal herbs, intermediates, and finished products simultaneously, along with“Standard decoction”Compare; quality level must not be below“Standard decoction”Requirements. A draft quality standard is required.and the explanatory notes, and provide drug reference standards and relevant materials.
14.2 Drug Standard Project
Drug standards include, but are not limited to: appearance and physical properties, identification, assay, fingerprint or characteristic profile analysis, testing, and general requirements for dosage forms.
14.3 Key Considerations:
14.3.1 Basis for Drug Standard Development:Drug standard items should correspond to“Standard decoction”The preparation process and clinical efficacy are well-correlated, while meeting the requirements for measurability, accuracy, durability, and low cost.Explain the rationale for each quality control item. Summarize the basis for selecting inspection methods and establishing limits, as well as the considerations and justification for excluding items from the standard.
14.3.2 Measures to ensure stability and uniformity across different batches of pharmaceutical products: Establish fingerprint or characteristic profiles, and encourage exploratory research on bioactivity testing to comprehensively reflect overall product quality through analysis. Quality specifications in pharmaceutical standards, such as assay limits, should have reasonable ranges, typically determined based on actual assay results from multiple test batches.
14.3.3 Reference Standard: If a reference standard from the Chinese Pharmacopoeia is used during the development of the classical formula, specify its source and provide the accompanying specification sheet and batch number. If a self-prepared reference standard is used, submit documentation certifying that it has been standardized by the National Institutes for Food and Drug Control (NIFDC).
14.4 Chemical Compositionand key quality attributesResearch
14.4.1 Literature Review on Chemical Composition Research
Provide literature on the chemical constituents of raw materials and decoctions from classic famous formulas. Analyze and explain the key chemical components and their physicochemical properties related to extraction processes, manufacturing, and product performance.
14.4.2 Research data on chemical component confirmation
SubmitExperimental data for chemical studies of classic formulae, including systematic chemical component research (extraction, isolation, structural identification), analytical study data, and related spectra.
14.4.3 Documentation on Critical Quality Attributes
Provide experimental data specifying the determination methods and limits for physicochemical and biological activity indicators that impact safety, efficacy, and batch-to-batch consistency.Analyze and explain the critical quality attributes (CQAs) of preparations based on classic ancient formulas.and its influencing factors。
Table6. Summary of Key Quality Attributes for Classical Famous Prescription Preparations
Project (AsxxIngredients | Quality Standards (e.g., upper and lower limits of content) | |
Key quality attributes related to efficacy | ||
Key Quality Attributes Related to Security | ||
Process-related Critical Quality Attributes | ||
Other Key Quality Attributes |
14.5 Quality Research
SubmitExperimental and literature data for quality research. Typically includes the following:
（1) Analysis Methods: Specify the testing methods for each item listed in the drug standards.
Table7. Test methods for items in pharmaceutical standards
Project Evaluation | Detection Method | Limit Requirements | Test Basis |
Traits | |||
Verify | |||
moisture | |||
Solubility/Clarity | |||
Content | |||
Feature Map | |||
Check | |||
Other Projects |
（2Validation of Analytical Methods
① Method validation for inclusion in standard projects
Provide method validation data and corresponding analytical chromatograms in accordance with the relevant guidelines of the current edition of the Chinese Pharmacopoeia, item by item.
② Method validation for non-standard analytical methods
Provide method validation data and corresponding analytical chromatograms in accordance with the relevant guidelines of the current edition of the Chinese Pharmacopoeia, item by item.
（3Analysis of Exogenous Contaminants
For possibleImpurities such as pesticide residues, heavy metals, arsenic salts, fungal toxins, solvent residues, and resin residues; analyze their sources of formation, and establish control limits in accordance with relevant guidelines.Provide justification for whether final quality standards are controlled and the limits of such control.
14.6 Sample Inspection Report
Provide continuous during production declaration3Inspection report for the sample batch.
14.7 References
Provide source citations for references and documents.
15. Stability Study
15.1 Stability Summary
Summarize the sample details, testing conditions, parameters evaluated, and results of the stability studies conducted. Based on these findings, propose the storage conditions and shelf life. Example:
（1) Test Sample
Table8. Sample Status
Batch Number | |||
Specifications | |||
Source of Ingredients and Execution Standards | |||
Production Date | |||
Test Start Time | |||
Place of Origin | |||
BatchNote | |||
Packaging/Appearance of the sealing system (e.g., packaging material type, physical form, and color) |
NoteStability studies must be conducted using pilot-scale or larger samples.
（2Research Content
Table9. Routine Stability Study Results
Project | Placement Condition | Inspection Period | Project Evaluation | Analysis method and verification | |
Stress Testing | High Temperature | ||||
High Humidity | |||||
Lighting | |||||
Other | |||||
Conclusion | |||||
Accelerated Testing | |||||
Long-term study | |||||
Conclusion | |||||
Form Instructions:
1Influence factors study“Conclusion”Summarize which factors (e.g., light, temperature, humidity) the sample is sensitive to or stable against. This serves as a basis for evaluating storage conditions.
2）“Methodology and Validation”It must be stated whether the method employed is a validated method listed in the pharmacopoeia. If the method used differs from that listed in the pharmacopoeia, or if the pharmacopoeia does not include this item, the location of the method validation documentation within the submission dossier shall be clearly indicated in the table above.3Conclusion
Table10.Stability Study Conclusions
Inner packaging | |
Storage Conditions | |
Expiration Date | |
Note regarding relevant content in the user manual |
15.2 Stability study data
Provide specific results of the stability study in a tabular format, and attach relevant charts from the stability study.
15.2.1 Stress Testing
Table11. Stress Testing
Batch No.: (One batch of samples) Bulk: Specifications:
Project Evaluation | Limit Requirements | Light Test450 0 Lux(Heaven) | High-Temperature Test 60℃(Heaven) | High Humidity Test 92.5%RH(Heaven) | ||||||
0 | 5 | 10 | 0 | 5 | 10 | 0 | 5 | 10 | ||
Traits | ||||||||||
Verify | ||||||||||
moisture | ||||||||||
Solubility/Clarity | ||||||||||
Content | ||||||||||
Other Projects | ||||||||||
Note: Requirements for stress testing are detailed in the "Technical Guidelines for Stability Studies of Traditional Chinese Medicines and Natural Drugs."
15.2.2 Accelerated Testing
Table12. Accelerated Testing
Batch Number1: (3 batches) Batch No.: Specification: Packaging: Inspection Conditions:
Project Evaluation | Limit Requirements | Time (Months) | ||||
0 | 1 | 2 | 3 | 6 | ||
Traits | ||||||
Verify | ||||||
moisture | ||||||
Solubility/Clarity | ||||||
Content | ||||||
Other Projects | ||||||
Note: Requirements for accelerated testing are detailed in the "Technical Guidelines for Stability Studies of Traditional Chinese Medicine and Natural Medicines."
15.2.3 Long-term study
Table13. Long-term study
Batch Number1: (3 batches) Batch: Specification: Packaging: Test Conditions:
Project Evaluation | Limit Requirements | Time (months) | |||||||
0 | 3 | 6 | 9 | 12 | 18 | 24 | … | ||
Traits | |||||||||
Verify | |||||||||
moisture | |||||||||
Solubility/Clarity | |||||||||
Content | |||||||||
Other Projects | |||||||||
Description:For long-term testing requirements, refer to the "Guiding Principles for Stability Studies of Traditional Chinese Medicines and Natural Drugs."
15.3 Packaging Material Selection
（1）Packaging Type, Source, and Related Documentation:
Table14. Packaging materials
Project | Packaging Container | AccessoriesNote2 |
Packaging TypeNote1 | ||
Packaging Material Manufacturer | ||
Packaging Registration Certificate Number or Approval ID | ||
Validity period of packaging material registration certificate | ||
Packaging Material Quality Standard Number |
Note1: For packaging type, specify the structural material and dimensions.
For example,Aluminum-plastic blister packaging, composed of:3.2VC/Aluminum,3.2VC/3.2E/3.2 VDC/Aluminum、3.2VC/3.2VDC/Aluminum
ReplyPouch packaging composed of: polyester/Aluminum/Polyethylene composite film bags, polyester/Low-density polyethylene composite film bags.
Note2: The "Accessories" column in the table must include all packaging components that directly contact the drug.
Provide packaging inspection reports (from the packaging manufacturer or supplier).
（2Describe the rationale for packaging material selection. Primary packaging materials in direct contact with drugs must comply with the "Interim Measures for Administration of Drug Packaging Materials and Containers," the "Detailed Rules for Drug Packaging and Labeling" (Interim), and other relevant regulations, with supporting registration certificates and quality standards provided. When selecting primary packaging materials, conduct literature reviews on similar drugs and their packaging to demonstrate feasibility, and evaluate these choices based on drug stability studies.
（3Describe the supporting studies conducted on the selected packaging materials. In special cases or when literature is insufficient, enhanced compatibility testing between the drug and the primary packaging materials should be performed. When introducing new packaging materials, in addition to the standard stability tests required during material selection, specific additional assessments must also be included.
15.4 Post-Market Stability Studies
When declaring production, you must commit to the post-market production of the first3Conduct long-term stability testing on retained samples of the product, and ensure that at least one batch produced each year is included.1Conduct long-term stability testing on retained samples of each product batch.
Provide a follow-up stability study plan.
15.5 References
Provide source citations for references and documents.
(3) Nonclinical Safety Studies
16. Overview of Nonclinical Safety Studies
Non-clinical safety studies of classic formula preparations shouldIn accordance with the current technical requirements for nonclinical safety studies of traditional Chinese medicine compound preparations,ApprovedGLPCertified InstitutionProceedMust be strictly enforcedGLPGuidelines。The nonclinical safety review should provide a comprehensive and critical evaluation of the nonclinical safety assessment for the drug under application.
16.1 Summary of Nonclinical Safety Studies
Provide a concise summary of the main findings from nonclinical safety studies, organized in the following order: Overview of Nonclinical Safety Studies, Safety Pharmacology Studies, Single-Dose Toxicity Studies, Repeat-Dose Toxicity Studies, Genotoxicity Studies, Reproductive Toxicity Studies, Carcinogenicity Studies, and Formulation Safety Studies.Irritation, hemolysis, and allergenicity tests), other toxicity studies, discussion of study results and conclusions, with a summary table attached.
16.2 Overview and Conclusions
Perform a comprehensive assessment of nonclinical safety studies. Analyze results from individual nonclinical safety trials, evaluate the interrelationships among these results, and assess species- and sex-specific differences. Based on this analysis of all available nonclinical safety data, determine whether the data support the marketing application for the proposed product.
17. Safety Pharmacology Study Data and Literature
Conduct safety pharmacology studies as needed. Literature reviews may be used in lieu of experimental studies.
18. Single-dose toxicity study data and literature
Single-dose toxicity studies can be conducted in at least one animal species.
19. Data on repeated-dose toxicity studies and literature
CanFirst, conduct a repeat-dose toxicity study in rodents. If significant toxicity is observed, proceed with a repeat-dose toxicity study in non-rodent species. If the intended population includes children, provide data from juvenile animal repeat-dose toxicology studies corresponding to the relevant pediatric age groups.
20. Special safety data and literature on sensitization (local, systemic, phototoxicity), hemolysis, and local irritation (vascular, skin, mucosa, muscle, etc.) associated with local and systemic administration.
If the formulation is administered via non-oral routes (e.g., transdermal, mucosal, or cavity), submit special safety study data tailored to the route and formulation characteristics. This includes: toxicity at the site of administration (e.g., irritation, local hypersensitivity) and systemic toxicity (e.g., systemic hypersensitivity, hemolysis).
21. Genotoxicity study data and literature
If abnormal hyperplasia is observed in repeated-dose toxicity studies, or if the formulation contains ingredients suspected of high genetic toxicity, submit appropriate genetic toxicity study data based on the specific circumstances.
Drugs intended for people of childbearing potential that may affect the reproductive system or its functions—including those for treating sexual dysfunction, promoting spermatogenesis, enhancing fertility, maintaining pregnancy, perinatal use, and agents with hormonal activity or cytotoxic effects—must undergo genetic toxicity testing. Prior to market approval, a standard battery of genetic toxicity tests must be completed. If suspicious or positive results are observed, additional relevant studies should be conducted.
22. Reproductive Toxicity Study Data and Literature
Drugs intended for use in women of childbearing potential that may affect the reproductive system or its functions (e.g., drugs for sexual dysfunction, spermatogenesis promotion, fertility enhancement, pregnancy maintenance, perinatal use, or those with hormonal activity or cytotoxic effects), as well as drugs showing positive results in genotoxicity tests or demonstrating significant reproductive toxicity in repeated-dose toxicity studies, shall provide appropriate reproductive toxicity study data based on specific circumstances.
23. Carcinogenicity study data and literature
If cytotoxicity, abnormal promotion of organ growth, or positive results in genotoxicity studies are observed during repeat-dose toxicity tests or other toxicity studies, carcinogenicity studies shall be conducted. Carcinogenicity data should generally be provided prior to market approval.
24. Dependency trial data and literature
Drugs with potential for dependence should undergo drug dependence testing.