To expedite the establishment and refinement of a review and evaluation technical system suited to the characteristics of traditional Chinese medicine (TCM), and to guide applicants in the rational research and development of manufacturing processes for TCM compound formulations, the Center has organized the drafting of the "Technical Guidelines for the Study of Manufacturing Processes for TCM Compound Formulations," which has now been developed into a draft for comments. This draft is now publicly available on the Center's website to solicit a broad range of opinions and suggestions.

Technical Guidelines for the Study of Manufacturing Processes for TCM Compound Formulations
(Draft for Comments)

I. Overview 
These guidelines are intended to guide applicants in the study of manufacturing processes for TCM compound formulations using TCM decoction pieces as raw materials. Under the guidance of TCM theory, applicants should, based on clinical needs, prescription composition, drug properties, and dosage form characteristics, respect traditional medication experience, and integrate modern technology with actual production practices to conduct necessary research. The goal is to define the process route and specific process parameters, ensuring the process is reasonable, feasible, controllable, and that the drug quality is uniform and stable, thereby guaranteeing drug safety and efficacy.

These guidelines cover the following aspects: pre-treatment research, extraction, purification, concentration, and drying research, formulation research, packaging selection research, pilot-scale research, commercial-scale production research, process validation, etc.

Due to the complex composition of TCM compound formulations, numerous chemical components, weak foundational research, unclear active ingredients, and characteristics such as multi-target effects; different prescriptions have different compositions, and the same medicinal ingredients may require different processing techniques depending on the indication and clinical needs; there is a wide variety of preparation processes, technologies, and methods, with new technologies and methods continually emerging; the key considerations, research difficulties, and technical parameters to be determined for different preparation processes, methods, and technologies may all differ. Therefore, research on the manufacturing process for TCM compound formulations must adhere to TCM theory, respect traditional medication experience, follow general principles of drug research, utilize modern research findings, and comprehensively apply knowledge from relevant disciplines. Based on an analysis of the prescription composition, the relationships between medicinal ingredients, the physicochemical properties and pharmacological actions of the constituents, and considering the formulation process, production reality, environmental protection, and energy efficiency requirements, reasonable experimental design and evaluation indicators should be employed. The use of new technologies, new methods, and new excipients is encouraged.

TCM compound formulations containing non-decoction piece raw materials may refer to these guidelines for research.

II. Basic Principles and Requirements
(A) Respect Traditional Medication Experience
Research on TCM compound formulations should follow TCM theory and respect traditional medication experience. This research is based on the understanding of life, health, and disease in TCM, as well as on research exploration and data accumulation recorded in ancient and modern literature and actual clinical applications. Therefore, the more systematic and in-depth the preliminary literature research, and the more abundant the data accumulated in clinical applications, the better the core and focus of the research can be grasped.

(B) Quality by Design
Research on TCM compound formulations should be based on the "Quality by Design" (QbD) concept. The philosophy of drug quality management has evolved from "quality controlled by testing" and "quality controlled by process" to "quality controlled by design" (i.e., QbD), reflecting the importance of drug quality design. In the early stages of developing a TCM compound formulation, clinical value should guide the process. 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 mass transfer should be understood, and critical process parameters should be determined. Based on raw material characteristics and process conditions, a design space that meets product quality design requirements and ensures process robustness should be established, defining the control ranges for process parameters. Based on the design space, quality risk management should be established, and quality control strategies and a drug quality standard system should be defined.

(C) Holistic Quality Evaluation
The evaluation during the manufacturing process research of TCM compound formulations should reflect the holistic quality characteristics of the compound. Specific evaluation indicators should be selected based on the characteristics of the TCM compound, considering clinical application, formulation compatibility, chemical constituents, pharmacological effects, etc. Attention should be paid to the correlation with drug safety and efficacy.

The selected indicators should be comprehensive, scientific, objective, and as quantifiable as possible. They should objectively reflect changes in the relevant process steps, reflect the holistic nature, consistency, and the transfer pattern of active substances in the drug, ensuring process controllability. Evaluation indicators and acceptance criteria for intermediates and dynamic process control should be established. An environmentally friendly and cost-effective production process should be established and considered as a quality evaluation indicator.

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.

(D) Continuous Process Improvement
To ensure the uniformity and stability of product quality, continuous improvement of the process for TCM compound formulations is of great significance. The process routes and parameters determined at different research stages may have limitations due to factors like process conditions and batch scale. Therefore, verification and improvement through scale-up production are generally necessary. Pre-market validation under commercial production conditions is required to finalize the manufacturing process and parameters.

During the development of the manufacturing process for a new TCM compound formulation, provided that the process route and critical process parameters remain unchanged, process optimization research can be conducted before Phase III clinical trials. For process improvement research before market launch at different stages and after market launch, the "Technical Guidelines for Pharmaceutical Research at Different Stages of New TCM Drug Development" and the "Technical Guidelines for Post-Market Pharmaceutical Changes of Marketed TCM Drugs" can be referenced.

III. Main Content
(A) Pre-treatment Research 
Pre-treatment methods for medicinal materials include: cleaning, cutting, processing (paozhi), comminution, sterilization, etc. Research on decoction piece processing should respect the processing techniques used in clinical applications, meet the design requirements of the TCM compound formulation, and comply with the "Technical Guidelines for the Study of Decoction Pieces Used in New TCM Drugs." Based on the specific drug characteristics, dosage form, and formulation design requirements, if pre-treatment such as comminution or sterilization is necessary for the decoction pieces, appropriate methods, equipment, process conditions, and parameters should be selected, and relevant quality control requirements should be determined.

(B) Extraction, Purification, Concentration, and Drying Research 
TCM compound formulations have complex compositions. To retain active substances, remove inactive ones, reduce dosage, and facilitate formulation, extraction and purification are generally required. The rational and correct application of extraction and purification techniques directly affects the full utilization of medicinal resources and the full expression of therapeutic effects. During the research on extraction, purification, concentration, and drying of TCM compound formulations, attention should be paid to the compatibility theory of TCM formulations and traditional clinical application experience (such as co-decoction, separate decoction, decoct first, decoct later, etc.), the correlation with drug efficacy and safety, and the interaction between medicinal ingredients in the prescription, as well as the mass transfer from decoction pieces, intermediates, and final products. The feasibility of scale-up production, energy conservation, consumption reduction, and environmental friendliness should also be considered.

1. Process Route

Different extraction, purification, concentration, and drying methods each have their own characteristics and scope of application. The appropriate process route, method, and evaluation indicators should be selected based on the design purpose, combined with the physicochemical properties of the active ingredients or pharmacologically active fractions related to therapeutic effects and safety, pharmacodynamic test results, or existing literature.

Screening studies for extraction, purification, concentration, and drying process routes need to focus on:

Studies on process route screening related to efficacy. For TCM compounds derived from clinically effective prescriptions, consideration can generally be given, but is not limited to, the following three aspects: 1) Clinical medication experience: similarities and differences between the adopted process route and the process route of products with prior human use experience (e.g., hospital preparations). If a different production process is used, it is generally advisable to compare it with the process used for the product with prior human use experience. 2) Pharmacodynamic experimental basis or literature basis: Pharmacodynamic experiments can use the clinical administration form (e.g., decoction) as a control, selecting suitable pharmacodynamic models and primary pharmacodynamic indicators for comparative studies of process routes. 3) Comparison of pharmacodynamic material bases: Comparison with the clinical administration form (e.g., decoction) regarding the material basis, etc.

Studies on process route screening related to safety. The safety of the drug should be investigated concurrently with efficacy screening. Consideration can generally be given, but is not limited to, the following four aspects: 1) Adverse reactions reported during prior clinical use, literature reports, etc. 2) Animal safety indicators observed during pharmacodynamic experiments comparing different process routes. 3) Residual toxic or harmful components. 4) Acute toxicity test results.

The more evidence supporting the reasonableness of the process route, the lower the risk of failure in subsequent clinical trials. Fully demonstrating the rationality of the process route from multiple perspectives helps increase the success rate of new drug development. Potential development risks arising from this should be noted.

1.1 Extraction and Purification Process

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

The purification of TCM compound formulations can be based on traditional TCM medication experience or designed based on the state, polarity, solubility, etc., of some confirmed active ingredients to create a scientific, reasonable, stable, and feasible process. However, due to the complexity of components in TCM compound formulations, the necessity and appropriateness of purification should be considered.

1.2 Concentration and Drying Process

Based on the physicochemical properties of the materials and the requirements of the dosage form, and considering factors affecting concentration and drying efficiency, appropriate processes should be selected to ensure that the obtained product achieves the required relative density or water content, facilitating formulation. The main process steps, conditions, and factors to be investigated should be identified. The potential impact on unstable components during concentration and drying should be examined.

2. Process Conditions

After the preliminary process route is determined, scientific and reasonable experimental design and optimization should be conducted for the adopted technologies and methods. Process optimization should use accurate, simple, representative, and quantifiable comprehensive evaluation indicators and appropriate methods, examining multiple factors and levels based on preliminary experiments. The application of new technologies and methods is encouraged, but for newly established methods, research on their rationality and feasibility should be conducted.

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

In process condition studies, attention should be paid to the relationship between process parameters and product quality, and critical process parameters and their ranges should be identified.

2.1 Optimization of Extraction and Purification Process Conditions

Different extraction methods have different influencing factors. Therefore, the selection of influencing factors and determination of extraction parameters should be based on the extraction method and equipment used. Generally, factors such as solvent, number of extractions, and extraction time, as well as production equipment and process conditions, need to be selected and optimized. Mature and recognized optimization methods are commonly used; if new methods are used, their applicability should be considered.

Purification processes should be selected based on the purification objective, the principle of the method to be used, and the influencing factors. Consideration should generally be given to the physicochemical properties of the active ingredients intended to be retained and the inactive ingredients intended to be removed, the requirements of the dosage form and the formulation process, and the bridging to production conditions.

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

2.2 Optimization of Concentration and Drying Process Conditions

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

The concentration and drying process methods, main process parameters, and the determination of parameter ranges should be supported by relevant research data.

(C) Formulation Research

Formulation research for TCM compound formulations should select appropriate dosage forms, production processes, and equipment based on the properties and quantity of the intermediates obtained after extraction, purification, etc., combined with the characteristics of the indication, medication experience, and dosage form characteristics.

For the optimization of the formulation process, the main changes (including batch size, equipment, process parameters, etc.) and the supporting validation studies should be described.

1. Dosage Form Selection

Different dosage forms can lead to different drug effects, thereby affecting clinical efficacy and adverse reactions.

Dosage form selection should draw on prior medication experience, with the primary goal of meeting clinical needs. It should be based on a comprehensive analysis of the drug's physicochemical properties, biological characteristics, and dosage form features. Persuasive literature basis and/or experimental data should be provided to fully elaborate on the scientific basis, rationality, and necessity of the dosage form selection. 

Dosage form selection should primarily consider the following aspects:  

1.1 Clinical Needs and Patient Population

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

1.2 Properties and Quantity of Intermediates for Formulation

TCM active ingredients are complex, and their solubility, stability, and processes of absorption, distribution, metabolism, and excretion in the body vary. The appropriate dosage form should be selected based on the drug's properties. 

When selecting a dosage form, consider the prescribed quantity, the quantity and properties of the semi-finished product, the clinical dose, and the drug loading capacity of different dosage forms. 

1.3 Safety

Drug safety must be fully considered when selecting a dosage form. 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 attached to pre-formulation studies. Relevant research should be conducted based on understanding the drug's basic properties, dosage form characteristics, and formulation requirements. In dosage form selection and design, attention should be paid to incorporating new theories, methods, and technologies from related disciplines, and the development of new dosage forms is encouraged.

2. Formulation Composition Research

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

2.1 Pre-formulation Studies

Pre-formulation studies form the basis of formulation research. Their purpose is to ensure that the formulation composition and process are suitable for industrial production, guaranteeing rationality, feasibility, and batch-to-batch consistency during manufacturing. 

In pre-formulation studies for TCM compound formulations, the properties of the formulation raw materials should be investigated. For example, for raw materials used to prepare solid dosage forms, key properties to study include solubility, hygroscopicity, bulk density, flowability, stability, compressibility, etc.; for raw materials used to prepare oral liquids, key properties include solubility, pH, stability, taste, smell, etc. 

2.2 Excipient Selection

During the study of the formulation process, excipients should be selected, and the use of new excipients should be considered. All excipients used should meet pharmaceutical requirements, and new excipients should comply with relevant regulations.

Excipient selection should generally adhere to the following principles: meet the requirements for formulation, stability, and drug action; avoid adverse interactions with the drug; and avoid affecting the drug's assay. Given the characteristics of TCM compound formulations, such as reducing dosage and improving patient compliance, the formulation composition should achieve good formability with the smallest possible amount of excipients. 

2.3 Formulation Composition Screening

Formulation composition screening should consider the following factors: clinical requirements, properties of the formulation raw materials and excipients, and dosage form characteristics. Through screening studies, the formulation composition is preliminarily determined, and the types, grades, specifications, and quantities of excipients used are clarified. 

3. Formulation Process Research

Through formulation process research, the formulation composition is further refined and finalized, ultimately determining the formulation composition, process, and equipment, while paying attention to the stability of the formulation.

3.1 Formulation Process Requirements

Formulation process research should generally consider the selection of the formulation process route and preparation technology, pay attention to bridging laboratory conditions with pilot-scale and production scales, and consider the feasibility and adaptability of production-scale formulation equipment. 

Unit operations or key 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. During the formulation process, special attention should be paid to the uniformity of toxic drugs and drugs with small dosages but high activity. 

3.2 Formulation Technology, Formulation Equipment

During formulation research, specific formulation technologies and equipment can often significantly impact the formulation process and the types and quantities of excipients used. They should be selected appropriately.

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

(D) Packaging Selection Research
Packaging selection research for TCM compound formulations mainly refers to the selection of packaging materials and containers that come into direct contact with the finished drug product and semi-finished products during manufacturing (if applicable), as well as the selection of secondary packaging materials.

Packaging materials and containers that come into direct contact with the drug should be selected based on the results of drug stress testing and stability studies. The selection of such materials and containers should comply with relevant regulations concerning packaging materials/containers in direct contact with drugs and drug packaging labeling.

In certain special cases or when literature information is insufficient, the compatibility between the drug and the packaging material in direct contact with it should be strengthened, especially for liquid or semi-solid formulations containing organic solvents. On one hand, based on migration studies, it can be determined whether components from the packaging material (especially additives) might leach into the drug, causing quality changes. On the other hand, based on adsorption studies, it can be determined whether the concentration of the drug changes or precipitates form due to adsorption/leaching by the packaging material, raising safety concerns. For new packaging materials or specific dosage forms, additional specific tests should be included in the packaging selection study beyond the items required for stability testing.

(E) Pilot-Scale Research 
After completing the series of laboratory-scale process studies for the TCM compound formulation, process scale-up should be conducted under conditions comparable to production to provide a foundation 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 at production scale. Pilot-scale research should consider bridging to commercial-scale production. A detailed process procedure should be established during pilot-scale research, and records should be kept.

The samples used for establishing quality standards, stability studies, pharmacology/toxicology studies, and clinical studies should all be prepared using the process defined through pilot-scale research. Through pilot-scale research, the control ranges for all critical steps and their process parameters, as well as the yield range of intermediates (e.g., extracts), should be clarified. Issues related to process feasibility, occupational safety, environmental protection, and production costs should be identified to mitigate risks in drug development.

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

Since the production processes, equipment, workshop conditions, excipients, and packaging used vary significantly depending on the dosage form, pilot-scale research should be tailored to the specific dosage form, particularly focusing on how to adapt to the characteristics of production.

The batch size for pilot-scale research should consider bridging to commercial-scale production studies and provide a basis for industrial production. Batch size, semi-finished product yield, and finished product yield are important indicators for evaluating the feasibility and stability of pilot-scale research. Generally, the batch size for pilot-scale research should be at least 10 times the formulation quantity (calculated based on 1000 dosage units). Liquid formulations with a fill volume of 100 ml or greater should have appropriately larger pilot scales; formulations containing whole medicinal powder may use a smaller pilot batch size, but must still achieve the objectives of pilot-scale research. Semi-finished product yield and finished product yield should be relatively stable.

Pilot-scale research typically requires multiple batches to achieve process stability. For clinical study applications, data from generally 3 stable pilot-scale batches should be provided, including batch numbers, input quantities, semi-finished product quantities, excipient quantities, finished product quantities, yields, and mass transfer correlation and transfer rate ranges.

(F) Commercial-Scale Production Research
Commercial-scale production research focuses on the uniformity and stability of product quality under scaled conditions, especially the consistency with the quality of samples used in clinical studies, and involves comparison and evaluation. Through this research, all process steps and their parameter control ranges suitable for commercial-scale production should be clarified, and raw materials, intermediates, and quality risk points should be identified to ensure a robust, environmentally friendly, and economical process.

Commercial-scale production should focus on equipment compatibility and the smoothness and convenience of all production stages. Product quality consistency, uniformity, and production efficiency are important indicators for evaluating scaled production.

Stability of commercial-scale production typically requires multiple batches. During the experiments, attention should be paid to the correlation between process parameters and quality parameters, as well as quality variability. Relevant records should be complete, standardized, and traceable.

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

When conducting process validation, a process validation protocol should be designed, and validation should be performed according to the protocol. A process validation report should be generated after completion. Based on the pilot-scale or commercial-scale process, appropriate indicators should be selected, and a validation protocol designed to investigate the impact of personnel, equipment, materials, production environment, and control measures on product quality under the intended production scale, process conditions, and parameters. If a design space or process parameter range is established, process validation should include testing at the extremes of the proposed design space or parameter range to verify process feasibility and product quality consistency.

The process validation protocol should include: objective, scope, responsibilities, division of labor, and timeline; overview (description of the validation method used and justification for its selection, product description, process flow diagram, critical process steps, and critical process monitoring parameters, etc.); pre-validation checks (confirmation of required documents, confirmation of personnel training, list of participating equipment and facilities and their qualification status, confirmation of instrument calibration, etc.); validation content (critical process parameters and operating ranges, sampling plans, testing methods and acceptance criteria for intermediates and finished products, etc.); methods for recording and evaluating results, etc. The process validation report should include: validation objective and scope, description of experiment implementation, summary and analysis of results, conclusions, deviations and corrective actions, appendices (including raw data), references (including validation protocol document number and version), and corrective and preventive actions for identified deficiencies.

IV. References
Omitted

V. Authors
Research Group for the "Technical Guidelines for the Study of Manufacturing Processes for TCM Compound Formulations (Draft for Comments)"