Guideline Number: [Z]GPH3-1
Technical Guidelines for the Research of Traditional Chinese Medicine and Natural Drug Preparations
(Draft 2)
March 18, 002
Technical Guidelines for the Research of Traditional Chinese Medicine and Natural Drug Preparations
Overview
The formulation of Traditional Chinese Medicine (TCM) and natural medicine preparations influences the speed and extent to which these medicines exert their effects, directly impacting their safety, efficacy, and controllability. This guideline outlines the rationale for selecting TCM and natural medicine dosage forms, principles for developing formulations, research on manufacturing processes, and selection criteria for packaging materials in direct contact with the drug. It also discusses related issues. Since pre-treatment of raw materials, extraction and purification, quality studies, and stability studies are covered by separate guidelines, they are not addressed here; relevant work should follow those respective guidelines.
The fundamental principles of formulation research should be driven by clinical needs, integrating studies on extraction, separation, and purification to ensure safety, efficacy, manufacturing stability, and quality control. A well-designed formulation should meet the following criteria: high efficiency with rapid onset and long duration; low dose, low toxicity, and minimal side effects; and ease of production, transport, storage, portability, and administration.
Due to the complex composition and diverse pharmacological effects of traditional Chinese medicines (TCMs) and natural drugs, along with the wide variety of dosage forms, manufacturing processes, and technologies—further accelerated by rapid advancements in modern pharmaceutical technology—the key considerations, research challenges, and critical process parameters may differ depending on the specific method or technology employed. Therefore, based on the unique characteristics of each drug, researchers should draw upon traditional formulation principles, therapeutic theories, and practical experience, while integrating actual production conditions, to conduct necessary studies. This will help define precise process parameters that ensure the process is rational, feasible, stable, and controllable, thereby guaranteeing the safety, efficacy, and consistent quality of the final product. We recommend that researchers adopt new technologies, innovative processes, and advanced excipients in the development of TCM and natural drug formulations to drive pioneering research.
Basic Content
I. Dosage Form Selection
(I) Basis for Dosage Form Selection
Drugs must be formulated into specific dosage forms and administered via appropriate routes to reach the body and exert therapeutic effects. Variations in dosage forms can alter a drug's mechanism of action, onset speed, and toxicity profile, thereby impacting clinical efficacy. Therefore, selecting the optimal dosage form is critical to ensuring and enhancing therapeutic outcomes.
Form selection should be based on respecting traditional formulations, medication theories, and clinical experience, with the goal of meeting clinical medical needs. It requires comprehensive analysis of the drug's physicochemical properties, formulation characteristics, and biological factors.
The selection of dosage form should comprehensively consider all factors related to drug safety, efficacy, and quality controllability. The main aspects include:
1: Clinical Indications and Target Population
When selecting a dosage form, consider that different forms may be suited to different clinical needs. Also account for patient adherence and physiological factors such as age, sex, and weight.
2. Drug properties and prescription dosage
The active ingredients in Traditional Chinese Medicine (TCM) are complex, with varying solubility, chemical stability, and absorption, distribution, metabolism, and excretion profiles. The dosage form should be selected based on the drug's properties.
Due to variations in the quantity and nature of traditional Chinese medicine prescriptions, semi-finished products, and clinical dosages, different formulations accommodate varying amounts of medication; therefore, the appropriate formulation should be selected accordingly.
3: Drug Safety
When selecting a dosage form, safety must be carefully considered. No drug formulation is absolutely safe; however, the therapeutic benefits provided by the formulation should be weighed against potential risks. Prior human experience with the drug should also be thoroughly evaluated. Safety risks include toxicity and adverse effects.
4, Other factors
Consider the overall technical level and equipment of the pharmaceutical industry, the technical capabilities and production conditions of manufacturing facilities, market demand, and relevant issues in pharmacoeconomics.
Developers and submitting entities must prioritize dosage form selection, providing compelling literature and experimental data to substantiate its scientific basis, rationale, and necessity.
(II) Key Considerations
1 Prior formulation research should be given due attention. Based on a thorough understanding of the drug's fundamental physicochemical properties, dosage form characteristics, and formulation requirements, conduct research, analysis, and improvement supported by literature or experimental evidence to ensure the rationality and scientific validity of the selected dosage form.
2 When selecting and designing dosage forms, leverage new theories, methods, and technologies from related fields to encourage the development of novel formulations.
3 Based on the specific properties of each drug and clinical needs, while respecting traditional usage patterns and dosage forms, fully integrate new advancements in modern formulation research. Develop and innovate new dosage forms that ensure safety, enhance efficacy, and improve clinical convenience.
4 Traditional Chinese Medicine (TCM) and natural drugs are primarily administered orally or topically, based on accumulated clinical experience. Therefore, when selecting the injectable dosage form—given the lack of human usage history and the complexity of TCM and natural drug components—special attention must be paid to their safety, efficacy, and quality control.
Provide comprehensive research materials and test data.
5: For dosage form modifications of drugs that already have national standards, changes should be made based on a comprehensive and systematic evaluation of the existing dosage form's application. A comparative study between the old and new dosage forms must be conducted to fully justify the necessity of the modification and the rationale for selecting the new form.
II. Formulation Development
Formulation development involves selecting suitable excipients and finalizing the drug formulation based on the properties of intermediates, dosage form characteristics, and clinical usage requirements. It is a core component of pharmaceutical research.
(I) Pre-formulation Studies
Pre-formulation studies form the foundation of formulation development, ensuring drug stability and efficacy while aligning the formulation and process with industrial manufacturing requirements. Before finalizing a formulation, pre-formulation studies should be conducted based on the specific characteristics and requirements of each dosage form. For traditional Chinese medicine (TCM) and natural product formulations, in addition to understanding the physicochemical properties of active ingredients, it is essential to evaluate the physicochemical properties of semi-finished products. These properties significantly influence the selection of processing methods, excipients, and equipment, largely determining the ease or difficulty of solidifying the formulation. For example, semi-finished products intended for solid dosage forms require assessment of solubility, hygroscopicity, flowability, compressibility, and bulk density. For liquid oral dosage forms, key properties include solubility, pH, stability, odor, and taste.
1 For single-component drugs, studies should be conducted on physicochemical properties, stability, formulation characteristics, and drug-excipient interactions.
2. Drugs composed of active fractions should have a thorough understanding of the physicochemical properties and formulation characteristics of these fractions. For critical parameters such as solubility, purity of active components, stability, and interactions with excipients, supporting literature or experimental study data must be provided.
3 Complex formulations contain multiple ingredients, making them difficult to fully understand. However, their key characteristics should be clear and well-defined.
(II) Selection of Auxiliary Materials
Excipients do more than just enable dosage form formation; they can alter the physicochemical properties of drugs, modulate drug release in vivo, and impact or even change clinical efficacy, safety, and stability. The application of new excipients provides a foundation for improving formulation quality and developing new dosage forms and formulations. In research on formulation processes, priority should be given to selecting excipients and exploring the use of new ones.
Excipients should generally be selected based on the following principles: they must support formulation and stability, not cause adverse interactions with the drug, and avoid interfering with qualitative or quantitative analysis. Given the characteristics of traditional Chinese medicines (TCM) and natural drugs, excipient selection should also aim to reduce dosage volume and improve patient compliance. In addition to meeting formulation requirements, attention should be paid to minimizing excipient quantities; an optimal formulation achieves the best physical properties using the least amount of excipients. All excipients used must comply with pharmacopoeial standards.
(III) Excipient Formulation Screening Study
The formulation screening study should be conducted using scientific and appropriate experimental methods and evaluation criteria, based on the properties of the drug and excipients and the characteristics of the dosage form. The following factors should be considered: clinical requirements, physicochemical properties of the active ingredient, excipient properties, physicochemical properties of the intermediate product, dosage form characteristics, patient compliance, potential interactions between the active ingredient, intermediate product, and excipients, and the impact of excipients on the physical, chemical, and biological stability of the active ingredient. If necessary, stress tests can be performed to evaluate interactions between the main drug (e.g., active ingredient or active fraction) and excipients, as well as the effects of light, oxygen, heat, and humidity on the stability of the active ingredient. The formulation screening study must clearly define the type, grade, specification, and quantity of each excipient used.
During formulation screening studies, to reduce trial-and-error, improve efficiency, and achieve optimal results, experiments can be planned using various statistical methods based on preliminary trials. Examples include single-factor comparison, orthogonal design, uniform design, or other suitable approaches. Additionally, exploring computer-aided design (CAD) for pharmaceutical formulation optimization is a promising avenue.
3. Research on Formulation Process
Formulation development is the process of processing semi-finished products or crude drug powders obtained after extraction and purification with excipients, following the scope of formulation research. It involves screening based on appropriate evaluation criteria to select and finalize suitable excipients, manufacturing techniques, and equipment, ultimately producing a specific dosage form. Essentially, formulation development implements the formulated design and further refines it by selecting the optimal formulation, manufacturing technology, and equipment.
(I) Principles to Consider in Formulation Process Development
Formulation process development should consider the selection of process routes and preparation technologies, ensuring alignment between laboratory conditions and pilot-scale/production stages, while evaluating the feasibility and adaptability of large-scale manufacturing equipment.
The unit operations, critical process parameters, and batch-to-batch quality must be evaluated to ensure operational reproducibility and the stability of chemical composition and quality. Detailed documentation on the formulation manufacturing process flow and technical basis for each step's conditions must be provided. During formulation, uniformity must be maintained. Special consideration is required in the prescription design, process route selection, and equipment choice when handling toxic drugs or highly potent drugs with low dosage.
Investigational medicinal products for clinical trials shall be manufactured in facilities that comply with the requirements of Good Manufacturing Practice (GMP), and the manufacturing process must strictly adhere to GMP standards.
(II) Selection of Evaluation Criteria for Formulation Process Development
Selecting evaluation metrics for formulation process studies is critical to ensuring that formulation development meets its intended objectives. Metrics should be tailored to the specific characteristics of each drug, considering factors such as formula design, excipient selection, manufacturing technology, and equipment optimization. Evaluation metrics may include chemical, pharmacological, or production-related parameters. Researchers can choose appropriate metrics based on the drug's properties, dosage form characteristics, manufacturing processes, and available equipment.
Evaluation criteria should be objective and quantifiable. Quantitative metrics are critical for formulation design, screening, and manufacturing. For instance, key indicators for tablet processing include powder flowability, physicochemical changes upon blending with excipients, compressibility, and hygroscopicity. In the case of oral solid dosage forms, dissolution testing may also be required.
(III) Formulation Technology and Equipment
Formulation screening and dosage form development require specific formulation technologies and equipment. New technologies and corresponding equipment are critical for advancing traditional Chinese medicine (TCM) formulations and improving product quality. During formulation research, the choice of technology and equipment can significantly influence the development route, as well as the types and quantities of excipients used. Therefore, it is essential to carefully evaluate the selection and application of emerging formulation technologies and equipment during dosage form development studies.
Maintaining fixed process parameters and equipment ensures process stability, minimizes batch-to-batch quality variation, and guarantees the safety, efficacy, and consistent quality of pharmaceutical products.
IV. Selection of Packaging Materials in Direct Contact with Drugs
When selecting packaging materials that directly contact the drug, conduct literature reviews on similar drugs and their packaging to demonstrate feasibility. Evaluate these selections in conjunction with drug stability studies. Ensure compliance with the Interim Measures for Management of Drug Packaging Materials and Containers, the Interim Detailed Rules for Drug Packaging and Labeling, and other relevant requirements. Provide corresponding registration certificates and quality standards.
In special circumstances or when documentation is insufficient, enhanced compatibility testing between the drug and direct-contact packaging materials should be conducted. For new packaging materials or specific dosage forms, in addition to standard stability studies, appropriate specialized compatibility assessments must also be included during material selection research.
[Drafting Note]
Research on traditional Chinese medicine (TCM) and natural drug formulations affects the speed and extent of their therapeutic action, directly impacting safety, efficacy, and controllability. This research holds a critical position in new drug development and constitutes a key component of pharmaceutical studies submitted during drug registration applications. Due to the complex composition of TCMs and natural drugs, coupled with relatively weak foundational research, active ingredients are often unclear or present at extremely low levels. Their pharmacological effects typically arise from the combined action of multiple components targeting multiple sites, significantly increasing the complexity of formulation research.
The development of technical guidelines for TCM and natural drug formulations plays a vital role in guiding rational dosage form selection, optimizing formulation design, establishing appropriate manufacturing processes, and standardizing overall formulation research practices. To align with the "Drug Registration Management Measures" and based on the "Guidelines for Drafting and Revising Drug Research Technical Guidelines (Trial)" issued by the Center for Drug Evaluation, a project team was established to study and reference relevant international guidelines. The team also incorporated content from the "Guidelines for New TCM Drug Development" (Ministry of Health Pharmaceutical Administration 1993 Edition) and "Technical Requirements for New TCM Drug Development" (SDA1 999 Edition). Considering general principles of formulation research and the current domestic landscape, the first draft of these guidelines was developed.
Following internal review by the Center, the first draft was presented for deliberation by an advisory group comprising representatives from the Center's project team, drug evaluation experts, development and production entities, provincial drug regulatory bureaus, and drug inspection agencies. Based on feedback from this group, the first draft was revised to produce the second draft of the guidelines.
This guideline aims to reflect both the scientific nature of drug research and its practical relevance for researchers and regulatory applicants.
This guidance primarily covers two areas: dosage form selection and formulation manufacturing processes. It outlines the fundamental principles for studying traditional Chinese medicine (TCM) and natural drug formulations, including criteria and principles for selecting dosage forms, formulation development research, manufacturing process research, and selection of primary packaging materials that directly contact the drug. Relevant issues are also discussed. Since pre-processing of raw materials, extraction and purification, quality studies, and stability studies are covered in separate guidance documents, they are not addressed here. For these aspects, please refer to the applicable guidelines.
Given the importance of dosage form selection and the current state of formulation research, this guideline requires that developers and applicants prioritize dosage form selection, provide compelling literature support and experimental data, and thoroughly explain the scientific rationale, appropriateness, and necessity of the chosen dosage form.
Pre-formulation studies are the foundation of formulation development. In the development of formulations for Chinese herbal medicines and natural drugs, it is essential to understand not only the basic physicochemical properties of the active ingredients but also those of the semi-finished products (intermediates). The physicochemical properties of these intermediates significantly influence the selection of processing methods, excipients, and equipment, and largely determine the feasibility of finalizing the dosage form. This guideline emphasizes that, to some extent, formulation process development for Chinese herbal medicines and natural drugs constitutes formulation research on the intermediates. It clarifies the requirements for the physicochemical properties of intended excipients and addresses interactions between the drug and excipients, providing a scientific basis for formulation design and process development.
Formulation screening should be conducted using scientific and rational experimental methods and evaluation criteria, based on the properties of the drug and excipients and the characteristics of the dosage form. This process should define the type, grade, specification, and quantity of each excipient used. To minimize trial-and-error, improve efficiency, and achieve optimal results, this guideline recommends employing various statistical methods—such as single-factor comparison, orthogonal design, uniform design, or other suitable approaches—to plan experiments based on preliminary studies. Additionally, computer-aided design (CAD) for formulation optimization is a promising avenue worth exploring.
The research team, considering the current state of domestic formulation development and production, thoroughly discussed key areas in formulation process research. They emphasized that formulation process studies should account for the selection of process routes and preparation technologies, ensure seamless integration between laboratory conditions and pilot-scale/production operations, and evaluate the feasibility and adaptability of large-scale manufacturing equipment. Unit operations, critical processes, and batch-to-batch quality must be carefully assessed to ensure operational reproducibility and stability of chemical composition and product quality. The team recommended that formulation screening and process optimization adopt evaluation metrics tailored to each drug's specific characteristics. It was recognized that formulation technologies and equipment play a vital role in the research and production of traditional Chinese medicine and natural drug formulations. During formulation development, priority should be given to selecting and applying new technologies and advanced equipment. All participants agreed that standardizing process parameters and using consistent equipment enhances process stability, minimizes batch-to-batch variability, and ensures drug safety, efficacy, and quality consistency.
After discussion, the research team agreed that greater emphasis should be placed on selecting packaging materials for drug formulations in the registration process, and systematic studies on the compatibility of drug packaging materials with formulations should be initiated.
Regarding the legal source of auxiliary materials and related management issues, the guidelines do not provide detailed clarification at this time.
Author
Research Team for the "Technical Guidelines for the Study of Traditional Chinese Medicine and Natural Drug Preparations"