To accelerate the establishment and improvement of a review and evaluation system tailored to the characteristics of traditional Chinese medicine (TCM), and to guide applicants in conducting rational research on the manufacturing process of TCM compound preparations, the Center for Drug Evaluation (CDE) has drafted the Technical Guideline on Process Research for Traditional Chinese Medicine Compound Preparations, which is now released as a draft for comments. The draft is hereby published on the CDE website to solicit opinions and suggestions from a wide range of stakeholders.

Technical Guideline on Process Research for Traditional Chinese Medicine Compound Preparations
(Draft for Comments)

I. Introduction
This guideline is intended to guide applicants in conducting process research for TCM compound preparations using TCM decoction pieces as raw materials. Under the guidance of TCM theory, applicants should conduct necessary research based on clinical needs, formula composition, drug properties, and dosage form characteristics, while respecting traditional medication experience and integrating modern technology with actual production practices. The aim is to establish a reasonable, feasible, and controllable process with clear process routes and specific parameters, ensuring product uniformity and stability, thereby guaranteeing the safety and efficacy of the drug.

This guideline covers the following aspects: pretreatment research, extraction, purification, concentration, drying research, formulation research, packaging selection research, pilot-scale research, commercial-scale production research, and process validation.

TCM compound preparations are characterized by complex compositions, numerous chemical components, limited basic research, unclear active ingredients, and multi-target effects. Different formulas may require different processing methods depending on the specific indications and clinical needs. There are various preparation processes, techniques, and methods, with new technologies and methods constantly emerging. The focus, challenges, and technical parameters to be determined may vary depending on the chosen process, method, and technology. Therefore, research on the manufacturing process of TCM compound preparations must adhere to TCM theory, respect traditional medication experience, and follow the general principles of drug research. It should utilize modern research findings, consider the relationship between the components of the formula and their physicochemical properties and pharmacological effects, and integrate relevant knowledge with production practices and environmental sustainability requirements. Reasonable experimental designs and evaluation indicators should be adopted. The use of new technologies, new methods, and new excipients is encouraged.

TCM compound preparations containing non-decoction-piece raw materials may refer to this guideline for research.

II. Basic Principles and Requirements
(1) Respect for Traditional Medication Experience
Research on TCM compound preparations should follow TCM theory and respect traditional medication experience. Such research is based on the TCM understanding of life, health, and disease, and is founded on historical records, modern literature, and accumulated data from clinical application. Therefore, the more systematic and in-depth the preliminary literature research, and the more sufficient the data accumulated during clinical use, the better the core focus of the research can be identified.

(2) Quality by Design (QbD)
Research on TCM compound preparations should be based on the concept of "quality by design." The evolution of pharmaceutical quality management concepts—from "quality by testing" to "quality by process control" and then to "quality by design"—reflects the importance of quality design. From the early stages of research, TCM compound preparations should be guided by clinical value. Based on an understanding of drug compatibility and clinical application, the process route and dosage form should be designed. Through experimental research, the product's critical quality attributes and the transfer of quality markers should be understood, and critical process parameters should be identified. Based on raw material characteristics and process conditions, a design space that meets product quality requirements and ensures process robustness should be established. Quality risk management, quality control strategies, and product quality standards should then be developed based on the design space.

(3) Holistic Quality Assessment
Evaluation during process research for TCM compound preparations should reflect the holistic quality characteristics of the formula. Specific evaluation indicators should be selected based on clinical application, formula compatibility, chemical components, and pharmacological effects. Attention should be paid to the correlation with drug safety and efficacy.

Selected indicators should be comprehensive, scientific, objective, and as quantifiable as possible, capable of objectively reflecting process variations, overall drug quality consistency, and the transfer pattern of active substances, ensuring process controllability. Evaluation indicators and criteria for intermediate products and dynamic process control should be established. Environmentally friendly and cost-effective manufacturing processes should be established and used as quality evaluation indicators.

The manufacturing process is closely related to production equipment. The concept that production equipment serves drug quality should be established, and equipment selection should meet the requirements of the manufacturing process.

(4) Continuous Process Improvement
Continuous improvement of the manufacturing process is important to ensure product uniformity and stability. Process routes and parameters established at different research stages may have limitations due to process conditions and batch size. Therefore, verification and improvement are generally needed during scale-up. Pre-marketing validation under commercial-scale production conditions is required to finalize the manufacturing process and parameters.

For new TCM compound preparations, process optimization may be conducted before Phase III clinical trials, provided that the process route and critical parameters remain unchanged. For process improvements at different stages before marketing and after marketing, relevant guidelines on pharmaceutical research at different stages and on post-marketing pharmaceutical changes should be followed.

III. Main Content
(1) Pretreatment Research
Pretreatment methods for medicinal materials include cleaning, cutting, processing, pulverizing, sterilization, etc. The processing of decoction pieces should respect the processing methods used in clinical practice, meet the requirements of the TCM compound preparation design, and comply with the Technical Guideline on Decoction Piece Processing Research for New TCM Drugs. Based on the characteristics of the specific drug, dosage form, and formulation design, appropriate methods, equipment, process conditions, and parameters should be selected for pretreatment such as pulverization and sterilization, and corresponding quality control requirements should be established.

(2) Extraction, Purification, Concentration, and Drying Research
Due to the complex composition of TCM compound preparations, extraction and purification are generally required to retain active substances, remove inactive components, reduce dosage, and facilitate formulation. The proper use of extraction and purification technologies directly affects the utilization of medicinal resources and the full expression of therapeutic effects. During extraction, purification, concentration, and drying research, attention should be paid to TCM compatibility theory and traditional clinical experience (e.g., co-decoction, separate decoction, decocting first, decocting later), the correlation with drug efficacy and safety, the interaction of ingredients in the formula, and the transfer of quality markers from decoction pieces to intermediate products to the final product. Feasibility for large-scale production, as well as energy conservation and environmental friendliness, should also be considered.

1. Process Route

Different extraction, purification, concentration, and drying methods have their own characteristics and applicable scopes. The appropriate process route, methods, and evaluation indicators should be selected based on the process design objectives, combined with the physicochemical properties of drug components or active fractions related to efficacy and safety, pharmacodynamic study results, or existing literature.

Research on the selection of extraction, purification, concentration, and drying process routes should focus on:

Efficacy-related process route selection. For TCM formulas derived from clinically effective prescriptions, consideration may be given to the following aspects: 1) Clinical medication experience: Compare the chosen process route with the process route used in existing human experience (e.g., hospital preparations). If a different process route is used, comparison with the process used in clinical experience is generally recommended. 2) Pharmacodynamic or literature evidence: Pharmacodynamic studies may use the clinical dosage form (e.g., decoction) as a control, selecting appropriate pharmacodynamic models and key indicators to compare process routes. 3) Comparison of active substance basis: Compare the active substance basis with the clinical dosage form (e.g., decoction).

Safety-related process route selection. Safety should be assessed concurrently with efficacy screening. Considerations may include: 1) Adverse reactions reported during clinical use or in literature; 2) Safety indicators in animals during pharmacodynamic comparisons of different process routes; 3) Residues of toxic or harmful components; 4) Results of acute toxicity tests.

The more evidence supporting the rationality of the process route, the lower the risk of clinical trial failure. Sufficiently demonstrating the rationality of the process route from multiple perspectives can improve the success rate of new drug development. Attention should be paid to potential risks that may arise.

1.1 Extraction and Purification Processes

Extraction of TCM compound preparations should be based on a full understanding of traditional application methods, considering the characteristics of decoction pieces, properties of active components, and dosage form requirements. Attention should be paid to the transfer of active components, toxic components, extract properties, and other quality attributes. The use of Class I and II organic solvents as extraction solvents should be avoided whenever possible.

Purification of TCM compound preparations may be designed based on traditional experience or the existence state, polarity, solubility, etc., of confirmed active components. However, given the complexity of TCM compound preparations, the necessity and suitability of purification should be considered.

1.2 Concentration and Drying Processes

Appropriate processes should be selected based on the physicochemical properties of the material and formulation requirements, considering factors affecting concentration and drying efficiency, to achieve the required relative density or moisture content for formulation. Key process steps, conditions, and investigation factors should be determined. Potential effects on unstable components during concentration and drying should be assessed.

2. Process Conditions

Once the process route is preliminarily determined, scientific and rational experimental design and optimization of the adopted processes and methods are necessary. Process optimization should use accurate, simple, representative, and quantifiable comprehensive evaluation indicators and appropriate methods, investigating multiple factors and levels based on preliminary experiments. The application of new technologies and methods is encouraged, but the rationality and feasibility of newly established methods should be studied.

Appropriate processes and equipment should be selected based on the specific product, and the process flow and equipment should be fixed.

During process condition research, the relationship between process parameters and product quality should be examined, and critical process parameters and their ranges should be determined.

2.1 Optimization of Extraction and Purification Conditions

Different extraction methods are influenced by different factors. Therefore, selection of influencing factors and determination of extraction parameters should be based on the chosen method and equipment. Factors such as solvent, extraction duration, and number of extractions, as well as production equipment and process conditions, generally need to be selected to optimize the extraction process. Established and recognized optimization methods are typically used; if a new method is applied, its suitability should be considered.

Purification processes should be selected based on the purpose of purification, the principles of the method, and the influencing factors. Generally, consideration should be given to the physicochemical properties of the active components to be retained and the inactive components to be removed, the requirements of the intended dosage form and formulation process, and the alignment with production conditions.

Determination of process parameters should be supported by experimental data, describing the experimental methods, evaluation indicators, and verification tests. The determination of parameter ranges should also be supported by relevant research data.

2.2 Optimization of Concentration and Drying Conditions

Factors such as the method, degree, equipment, and process parameters of concentration and drying directly affect the stability of components. Process conditions should be studied and optimized based on formulation requirements.

The concentration and drying methods, key process parameters, and their ranges should be studied, with parameter ranges supported by relevant research data.

(3) Formulation Research

Formulation research for TCM compound preparations should select the appropriate dosage form, manufacturing process, and equipment based on the properties and quantity of the intermediate product obtained after extraction and purification, considering the characteristics of the indication, medication experience, and dosage form attributes.

Optimization of the formulation process should focus on describing major changes (including batch size, equipment, process parameters, etc.) and the supporting validation studies.

1. Dosage Form Selection

Different dosage forms may lead to different therapeutic effects, affecting clinical efficacy and adverse reactions.

Dosage form selection should draw on prior medication experience and aim to meet clinical needs. It should be based on a comprehensive analysis of the drug's physicochemical properties, biological characteristics, and dosage form features. Convincing literature and/or experimental data should be provided to fully justify the scientific basis, rationality, and necessity of the chosen dosage form.

Key considerations for dosage form selection include:

1.1 Clinical Needs and Patient Population

Consider whether different dosage forms are suitable for different clinical conditions, as well as patient compliance and physiological conditions.

1.2 Properties and Quantity of the Intermediate Product

Since TCM contains complex components with varying solubility, stability, absorption, distribution, metabolism, and excretion profiles, the dosage form should be chosen based on the drug's properties.

The total formula amount, semi-finished product quantity and properties, clinical dosage, and the drug-loading capacity of different dosage forms should be considered when selecting the dosage form.

1.3 Safety

Safety must be fully considered during dosage form selection. Attention should be paid to potential safety risks (including toxicity and side effects) associated with the dosage form and route of administration.

Additionally, importance should be placed on pre-formulation studies. Research should be conducted based on understanding the drug's basic properties, dosage form characteristics, and formulation requirements. New theories, methods, and technologies from related disciplines should be considered, and the development of novel dosage forms is encouraged.

2. Formulation Composition Research

Formulation composition research involves selecting suitable excipients and finalizing the formulation based on the properties of the formulation raw materials, dosage form characteristics, and clinical requirements. This is a crucial part of formulation research.

2.1 Pre-formulation Studies

Pre-formulation studies are the foundation for formulation research, aiming to ensure that the formulation and process are suitable for industrial production, ensuring rationality, feasibility, and batch-to-batch consistency.

In pre-formulation studies for TCM compound preparations, the properties of the formulation raw materials should be investigated. For example, for solid preparations, properties such as solubility, hygroscopicity, bulk density, flowability, stability, and compressibility should be studied. For oral liquid preparations, properties such as solubility, pH, stability, taste, and odor should be studied.

2.2 Excipient Selection

Excipients should be selected during formulation process research, with attention to the use of new excipients. All excipients must meet pharmaceutical requirements; new excipients must comply with relevant regulations.

The following principles should generally be considered when selecting excipients: meeting the requirements for formulation, stability, and action; avoiding adverse interactions with the drug; and not interfering with product testing. Considering the characteristics of TCM compound preparations, the formulation should aim to reduce dosage and improve compliance by achieving good formability with minimal excipient usage.

2.3 Formulation Screening Studies

Formulation screening should consider factors such as clinical requirements, the properties of formulation raw materials and excipients, and dosage form characteristics. Through screening, the formulation composition should be preliminarily determined, specifying the types, grades, specifications, and quantities of excipients used.

3. Formulation Process Research

Through formulation process research, the formulation design is further refined and finalized, determining the formulation, process, and equipment, while also considering product stability.

3.1 Formulation Process Requirements

Research on the formulation process should generally consider the selection of the process route and manufacturing technology, noting the bridging between laboratory conditions and pilot-scale/production scales, and ensuring the feasibility and suitability of large-scale production equipment.

Unit operations or critical processes should be investigated to ensure quality stability. The technical conditions for each step should be studied, and a detailed formulation process flow should be established. For drugs containing toxic components or potent drugs used in small quantities, special attention should be paid to uniformity during processing.

3.2 Formulation Technology and Equipment

Specific formulation technologies and equipment can significantly impact the formulation process, as well as the types and amounts of excipients used. These should be selected appropriately.

During formulation research, the impact of equipment type and process parameters on the critical quality attributes of the product should be evaluated. Diverse mathematical modeling methods can be used to study the correlation between process parameters and critical quality attribute evaluation indicators. A design space for critical process parameters and critical evaluation indicators of intermediates should be established, and corresponding process control technologies should be explored to reduce batch-to-batch quality variation, ensuring drug safety, efficacy, and quality stability. Advanced formulation technologies and corresponding equipment are important for improving formulation levels and product quality and should be given due attention.

(4) Packaging Selection Research
Packaging selection research for TCM compound preparations primarily involves the selection of packaging materials and containers that directly contact the drug, both for the final product and for intermediates (if applicable). It also includes research on secondary packaging materials.

Packaging materials and containers that directly contact the drug should be selected based on the results of stress testing and stability studies. The selection should comply with relevant requirements for such materials/containers and drug packaging labeling management.

Under certain special circumstances or when literature data is insufficient, compatibility studies between the drug and its immediate packaging materials should be strengthened, especially for liquid or semi-solid preparations containing organic solvents. On one hand, migration studies can determine whether components from the packaging material (especially additives) leach into the drug, causing quality changes. On the other hand, adsorption studies can assess whether adsorption/leaching leads to changes in drug concentration, precipitation, or other safety concerns. When using new packaging materials or specific dosage forms, additional special evaluation items should be included in the packaging selection research beyond the standard stability testing requirements.

(5) Pilot-Scale Research
After completing the laboratory-scale process research for a TCM compound preparation, process scale-up studies should be conducted under conditions substantially similar to production to provide a basis for commercial-scale process validation. Pilot-scale research validates and refines the laboratory process and is a necessary step to ensure process stability and operability. The bridging to commercial-scale production should be considered. Detailed process procedures should be established, and records should be maintained during pilot-scale research.

Samples used for developing quality standards, stability studies, pharmacology/toxicology studies, and clinical studies should all be prepared using the process established through pilot-scale research. Through pilot-scale research, the control ranges for all critical steps and their parameters should be defined, the yield range of intermediates (e.g., extracts) should be determined, and issues related to process feasibility, occupational safety, environmental impact, and production costs should be identified to reduce drug development risks.

The technical parameters of pilot-scale equipment should be essentially consistent with those of production equipment. If pilot-scale samples are intended for clinical studies, they should be prepared in workshops that comply with Good Manufacturing Practice (GMP) requirements.

Due to the significant differences in production processes, equipment, workshop conditions, excipients, and packaging for different dosage forms, pilot-scale research should consider the characteristics of the dosage form, particularly how to adapt to production requirements.

The batch size for pilot-scale research should consider bridging to commercial-scale production, providing a basis for industrial production. Input quantity, intermediate yield, and final yield are important indicators of the feasibility and stability of the pilot-scale process. Generally, the input quantity for pilot-scale research should be at least 10 times the formulation quantity (calculated as per 1000 dosage units). For liquid preparations with a fill volume of 100 ml or more, the pilot scale should be appropriately increased. For preparations using whole medicinal powder, the input quantity may be appropriately reduced, but should still achieve the objectives of pilot-scale research. Intermediate and final yields should be relatively stable.

Pilot-scale research generally requires multiple batches to achieve process stability. For clinical trial applications, data from three stable pilot-scale batches is generally required, including batch numbers, input quantities, intermediate quantities, excipient quantities, final product quantities, yields, and ranges for quality transfer correlation and transfer rates.

(6) Commercial-Scale Production Research
Commercial-scale production research focuses on evaluating product uniformity and stability under large-scale conditions, particularly consistency with clinical trial samples, through comparison and assessment. Through this research, all process steps and their parameter control ranges suitable for commercial-scale production should be defined, and critical raw materials, intermediates, and quality risk points should be identified to ensure a robust, environmentally friendly, and economical process.

Compatibility with equipment and the smoothness and convenience of all production stages should be considered for commercial-scale production. Product quality consistency, uniformity, and production efficiency are important indicators for evaluating large-scale production.

Stability of commercial-scale production generally requires multiple batch runs. The correlation between process parameters and quality parameters, as well as quality variability, should be monitored during these runs. Records should be complete, standardized, and traceable.

(7) Process Validation
Validation of critical steps and critical process parameters should be completed before initiating clinical trials. Full process validation should be completed after clinical trials are finished and before submission for marketing authorization. The production environment for process validation must comply with GMP requirements, and production equipment should match the intended production scale.

For process validation, a validation protocol should be designed and executed according to the protocol. A process validation report should be prepared after completion. Appropriate indicators should be selected based on the pilot-scale or commercial-scale process. The validation protocol should be designed to assess the impact of personnel, equipment, materials, production environment, control measures, etc., on product quality under the intended production scale, process conditions, and parameters. If a design space or parameter range is proposed, the extremes of the proposed design space or parameter range should be tested during validation to verify process feasibility and product quality consistency.

The process validation protocol should include: purpose, scope, responsibilities and timeline, overview (description of the validation method and rationale, product description, process flow diagram, critical process steps, and critical process monitoring parameters), pre-validation checks (confirmation of required documents, personnel training, list of equipment and facilities used and their qualification, calibration verification of instruments), validation content (critical process parameters and operating ranges, sampling plan, testing methods and acceptance criteria for intermediates and finished products), and methods for recording and evaluating results. The process validation report should include: validation purpose and scope, description of execution, results summary and analysis, conclusion, deviations and corrective actions, appendices (including raw data), references (including protocol document number and version), and corrective and preventive actions for identified deficiencies.

IV. References
Omitted

V. Authors
Research Group for the Technical Guideline on Process Research for Traditional Chinese Medicine Compound Preparations (Draft for Comments)