Guideline ID：[Z]GPH2-1
Technical Guidelines for Research on Extraction and Purification Processes of Traditional Chinese Medicine and Natural Drugs
(Draft 2)
March 18, 002
Technical Guidelines for Research on Extraction and Purification Processes of Traditional Chinese Medicine and Natural Drugs
Overview
TCM and natural drugs have complex compositions. Generally, raw materials undergo extraction and purification to improve efficacy, reduce dosage, and facilitate formulation. These steps are unique to TCM and natural drug formulations. The rational and correct application of extraction and purification technologies directly affects whether raw material resources can be fully utilized and whether the therapeutic effects of the final products can be fully realized.
Concentration and drying processes are commonly required during extraction, purification, and subsequent formulation steps to meet the specifications for raw materials or intermediates. Therefore, these processes remain within the scope of this technical guidance principle.
Due to the complex composition and diverse effects of traditional Chinese medicines (TCMs) and natural drugs, coupled with the wide variety of processing methods and technologies—and the continuous emergence of new approaches—different techniques may require distinct research priorities, address unique challenges, and establish varying technical parameters. Therefore, research should follow general pharmaceutical principles while focusing on the specific characteristics of each product. It must respect traditional formulations, medication theories, and clinical experience, aiming to reveal the underlying mechanisms for evaluating the rationale behind process selection and its therapeutic benefits and risks for specific indications. Studies should be tailored to the drug's specific nature and aligned with actual production conditions to define precise process parameters. This ensures that the manufacturing process is scientific, rational, stable, and feasible, thereby guaranteeing product safety, efficacy, and consistent quality.
This guideline discusses the determination of methods and process routes, optimization of process conditions, application of experimental design methodologies, and establishment of evaluation criteria during the extraction, purification and concentration, and drying processes of Chinese herbal medicines and natural drugs.
Basic Content
1. Process Route
The extraction and purification process route for traditional Chinese medicines (TCMs) and natural drugs is a fundamental set of specifications defining the methods, conditions, and procedures used to ensure safety and efficacy. Based on clinical TCM usage, formula characteristics, and dosage form requirements, this route directly impacts drug safety and effectiveness, determines product quality, and influences large-scale manufacturability and economic viability. Consequently, the process route serves as the core foundation for the scientific rigor, rationality, and feasibility of TCM and natural drug production. Its design must adhere to principles that ensure the manufacturing process is scientific, advanced, and feasible.
Due to the complexity of ingredients in traditional Chinese medicine (TCM) and natural drugs, research on extraction, separation and purification, concentration, and drying processes should be based on an analysis of the prescription composition and relationships between individual herbs. This analysis must consider the physicochemical properties and pharmacological effects of the constituents in each herb. Process routes should be designed and method/condition screening performed by aligning the physicochemical properties of active components or fractions relevant to therapeutic effects with formulation requirements, large-scale production realities, and environmental regulations. The goal is to establish a stable process that is simple to execute and defined by clear conditions.
(I) Extraction and Purification Process
Extraction of Chinese herbal medicines and natural drugs should aim to recover the maximum amount of active ingredients or target specific components based on their properties. The selection of extraction solvents should avoid Class 1 and Class 2 organic solvents whenever possible.
Purification of traditional Chinese medicines (TCM) and natural drugs should be based on traditional TCM usage experience or the state, polarity, solubility, and other properties of confirmed active ingredients in the drug. The process must be scientifically designed, rational, stable, and feasible, employing a series of separation and purification techniques. The goal is to maximize the enrichment of active ingredients while removing inactive components.
Different extraction and purification methods each have unique characteristics and application ranges. The optimal process route and method should be selected through comparative testing, based on the physicochemical properties of the active constituents (or fractions) responsible for therapeutic effects or on findings from pharmacological studies.
(II) Concentration and Drying Processes
The concentration and drying processes should be selected based on formulation requirements, material properties, and factors affecting process performance to achieve the target specific gravity or moisture content, facilitating dosage form manufacturing. Key process steps, conditions, and critical parameters must be defined. Potential impacts during concentration and drying should be considered; for heat-sensitive components, thermal stability studies should be conducted to guide method selection and process optimization.
II. Process Conditions
After the preliminary process route is established, scientific and rational experimental design should be conducted to optimize process conditions for the selected methods. Process optimization must rely on accurate, simple, representative, and quantifiable comprehensive evaluation metrics and appropriate methodologies. In most cases, multiple factors influence the process; therefore, multi-factor, multi-level studies are required. For newly developed methods, feasibility and reliability assessments must be performed. Where necessary, the safety of materials used should be evaluated, and potential residues controlled. These methods may only be applied to research on Chinese medicine and natural drug preparations once sufficient evidence supports their safety and feasibility.
Selecting appropriate process methods, operating conditions, and equipment is critical for ensuring product quality, improving extraction efficiency, and maximizing economic benefits. Researchers should choose suitable processes and equipment based on the specific characteristics of each product. To ensure process stability and minimize batch-to-batch variability, the process flow and associated equipment must remain consistent.
(I) Optimization of Extraction and Purification Process Conditions
Different extraction methods and influencing factors affect extraction efficiency. Therefore, based on the chosen method and equipment, select appropriate influencing factors and determine extraction parameters. Typically, optimize the solvent and process conditions.
Purification processes for Traditional Chinese Medicines (TCMs) and natural drugs should be selected based on the purification objectives, the principles of available methods, and influencing factors. When selecting a purification method, consider the following: the intended dosage form and administration dose, the properties of active and unwanted components, requirements for subsequent formulation manufacturing, production feasibility, and environmental compliance. Evaluate potential influencing factors of the chosen method to select appropriate process conditions and define process parameters, ensuring process repeatability and drug quality stability. Conduct targeted studies to assess key indicators at each step, validating the rationality of the process. For commonly used methods such as water-ethanol precipitation, consider these factors: relative density of the concentrated extract, ethanol addition rate and stirring speed, ethanol concentration and volume (or final alcohol content), operating temperature, and precipitation duration.
(II) Optimization of Concentration and Drying Process Conditions
Maintain relative stability of drug components during concentration and drying processes. Since the methods, equipment, extent, and specific process parameters directly affect the stability of active ingredients in the solution, these factors should be studied and optimized in alignment with formulation requirements.
III. Evaluation Metrics
During process research, selecting appropriate evaluation criteria is critical for making reasonable judgments on experimental results. These criteria should be objective, quantifiable, scientific, and rational. When choosing specific indicators, consider the unique characteristics of traditional Chinese medicine (TCM) and natural medicines to ensure they accurately assess safety, efficacy, and controllability in a practical manner. In addition to chemical composition and biological indicators, environmental impact and process economics must also be factored into the overall evaluation.
(I) Evaluation Criteria for Extraction and Purification Processes
1. Single-Ingredient Preparations: Extraction and Purification. The target is a single chemical component; evaluation criteria should focus on method feasibility, stability, yield, and purity of the final product.
2, Effective Component Preparation
When selecting extraction and purification methods and their evaluation criteria for active fraction preparations, focus should be placed on the feasibility and stability of the methods, as well as the yield and purity of the resulting active fractions. It is recommended to ensure the basic stability of the extract's composition.
3. Single-ingredient or compound preparations (i.e., preparations containing non-active ingredients or active fractions)
The multi-component nature of formulations should be considered. When active ingredients are well-defined, they should serve as the primary evaluation metrics; when they are unclear, careful consideration is required in selecting appropriate indicators. Traditional usage experience and formulation theory must be valued, while acknowledging the current limitations in basic research regarding the substance basis and mechanisms of drug action. Blind purification should be avoided. At the same time, efforts should be made to improve formulation quality by employing comprehensive multi-indicator evaluation to meet clinical requirements.
When selecting specific evaluation indicators, considerations should be tailored to the characteristics of traditional Chinese medicines (TCMs) and natural drugs, as well as the specifics of each product. The goal is to identify indicators that allow for reasonable assessment of safety, efficacy, and controllability, ultimately yielding a manufacturing process that is scientifically sound, practical, and truly reflective of therapeutic effectiveness.
(II) Evaluation Criteria for Concentration and Drying Processes
During research, select appropriate evaluation indicators based on the specific variety and considering process and equipment characteristics. For drugs containing volatile or heat-sensitive active ingredients, also assess the retention of these components during concentration and drying.
IV. Experimental Design Methodology
During process research, selecting and defining process conditions requires scientific, objective, and quantifiable experimental methods and evaluation criteria to ensure valid and reasonable outcomes. When choosing specific evaluation metrics, consider the unique characteristics of traditional Chinese medicine (TCM) and natural drugs. Common experimental approaches include single-factor design and multi-factor design methods; the latter encompasses orthogonal design, uniform design, spherical symmetric design, and others.
The selection of key influencing factors and their levels is typically based on preliminary trial results. Specific choices should be determined according to the study context and the factors under investigation. However, it is essential to consider the applicability range of the method, ensure the rationality of factor and level settings, and prevent methodological errors or misuse—such as inappropriate factor/level selection, insufficient sample size, unreasonable indicator selection, flawed evaluation methods, or mismatched target populations. Proper handling and analysis of trial results must also be ensured, with appropriate selection of outcomes. Factor and level settings should be flexibly adapted to the characteristics of the subject under study.
Due to the diversity and complexity of processes, as well as unavoidable experimental errors in research, process optimization results should be validated through replication and scale-up trials.
During process optimization, consciously incorporate principles and methods of Design of Experiments (DOE), adopt advanced scientific design approaches and statistical data analysis techniques, and enhance the use of computer-aided design and analysis tools.
[Drafting Notes]
The extraction and purification processes of Traditional Chinese Medicine (TCM) and natural medicines directly determine the material basis for their therapeutic effects, influencing all aspects of safety, efficacy, and controllability. These processes are a critical component of TCM and natural medicine research. Due to the extreme complexity of components in TCM and natural medicines, combined with relatively weak foundational research, active ingredients are often undefined or present in very low concentrations. Furthermore, their therapeutic effects typically arise from the synergistic action of multiple components targeting various pathways. These factors significantly increase the challenges associated with extracting and purifying TCM and natural medicines.
This guideline is formulated in accordance with the "Administrative Measures for Drug Registration" (Trial) to align with the updated requirements of the revised "Drug Administration Law" and its "Implementation Regulations," and to adjust relevant drug registration regulations in line with WTO principles. It aims to establish a scientific drug R&D and evaluation system suited to China's national conditions, explore the intrinsic laws of drug research, achieve systematic integration between drug research and technical review, and promote sustainable and healthy development of the field.
Based on the "Specifications for Drafting and Revising Drug Research Technical Guidelines" issued by the Center for Drug Evaluation, a project team was established at the Center. The team studied and referenced foreign technical guidelines, incorporated content from the "Guidelines for New Traditional Chinese Medicine Drug Research" (Ministry of Health Pharmaceutical Administration 1993 Edition) and "Technical Requirements for New Traditional Chinese Medicine Drug Research" (SFDA 999 Edition), and considered general principles of formulation research alongside the current status of domestic formulation development. This process led to the first draft of this guideline.
After internal review by the Center, the first draft was submitted to a deliberation meeting attended by representatives from four key groups: Center project team members, drug evaluation experts, drug development and manufacturing entities, and provincial drug administration and inspection departments. Based on feedback from this group, the first draft was revised to produce the second draft of this guideline.
During extraction, purification, and subsequent formulation processes, operations such as concentration and drying are often required to meet specifications for the material or semi-finished product used in formulations. Therefore, this technical guidance primarily addresses extraction, purification, concentration, and drying in the development of preparations derived from traditional Chinese medicines and natural drugs.
Attendees agreed that extraction and purification are unique process steps in traditional Chinese medicine and natural drug formulations. The rational and correct application of these technologies directly determines whether medicinal resources can be fully utilized and whether the therapeutic effects of the formulations can be maximized.
Given the complexity of methods and technologies involved in extraction, purification, concentration, and drying, a detailed discussion of each aspect is not feasible. The delegates agreed that this guideline will focus on the following areas during the R&D of extraction, purification, concentration, and drying processes for traditional Chinese medicines and natural drugs: determination of methods and process routes, optimization of process conditions, application of experimental design methodologies, and establishment of evaluation criteria.
Experts believe that traditional Chinese medicines (TCMs) and natural drugs contain complex components. Research on extraction, separation and purification, concentration, and drying processes should be based on:
- Analysis of the prescription composition and relationships between individual herbs in compound formulas;
- Study of physicochemical properties and pharmacological effects of components within each herb;
- Consideration of physicochemical properties of active ingredients or fractions relevant to therapeutic effects;
- Requirements for formulation preparation;
- Practical realities of large-scale production;
- Environmental protection standards.
Process routes must be designed, methods and conditions screened, and standardized procedures established that are simple, reproducible, and clearly defined. Targeted experiments should evaluate key indicators at each step to assess process rationality. Potential influencing factors of applied methods must be studied to select optimal conditions, define parameters, and ensure process reproducibility and drug quality stability.
Selecting appropriate extraction and purification methods, process conditions, and equipment is critical for ensuring product quality, improving extraction efficiency, and maximizing economic benefits. Attendees agreed that researchers should choose suitable processes and equipment based on the specific characteristics of each product. They emphasized that to ensure process stability and minimize batch-to-batch variability, the process flow and associated equipment must be standardized.
Delegates engaged in extensive discussions on evaluation criteria, concluding that the selection and extraction of these criteria are closely tied to the rationality of purification processes. For components or fractions with well-defined active ingredients, criteria should primarily focus on these active elements. However, for compound preparations—which are more complex—the multi-component nature of their effects must be considered when selecting extraction methods and corresponding indicators. When active ingredients are clearly identified, they generally serve as appropriate indicators. In cases where active ingredients remain unclear, careful consideration is required regarding how to ensure retention of efficacy during extraction and purification, as well as how to guarantee the safety and effectiveness of the final preparation.
While traditional medicinal experience should be valued, one must also acknowledge the current limitations in basic research, including insufficient understanding of the substance basis and mechanisms of drug action; thus, blind purification should be avoided. At the same time, efforts should be made to improve preparation quality by adopting a multi-criteria comprehensive evaluation approach to meet clinical requirements. Further discussion and research on the selection of evaluation criteria are recommended. Specifically, when choosing evaluation criteria, it is essential to consider the unique characteristics of traditional Chinese medicines and natural drugs, as well as the specifics of each variety. The goal is to identify scientifically sound, practical, and realistic criteria that can reliably assess safety, efficacy, and controllability—ideally through a multi-indicator comprehensive evaluation. This will help establish processing methods that are not only scientific, reasonable, and feasible but also truly reflect the therapeutic effects of the drugs.
Author
Research Team for the Technical Guidelines on Extraction and Purification Processes of Traditional Chinese Medicines and Natural Drugs