I. Overview

　　This guideline is mainly used to instruct the applicant to carry out studies on manufacturing process of compound preparations of TCMs with prepared slices/decoction pieces. The applicant should carry out necessary studies under guidance of TCM theories, based on clinical medication needs, formula composition, drug properties and characteristics of dosage form, showing respect for traditional medication experience, and in combination with modern technology and production practices, to specify process route and process parameters, so as to achieve reasonable and feasible manufacturing process, and consistent, stable and controllable product quality, thus to guarantee the safety and efficacy of TCMs.

　　This guideline covers the following contents: pre-treatment study, extraction, purification, concentration and drying study, preparation study, packaging study, pilot-scale study, commercial manufacturing study, and process validation, etc.

　　Compound preparations of TCMs are characterized with complex compositions, multiple chemical components and targets etc; different formulas are of different ingredients, and for the same ingredient, different processing may be applied for varied indications and clinical requirements; with the many existing preparation processes, technologies and methods, new technologies and new methods emerge constantly; and the key points that ought to be considered for different preparation processes, methods and technologies, those difficult points that ought to be studied, and the technical parameters that ought to be determined may all be different. Therefore, the study on manufacturing process of compound preparations of TCMs should not only follow TCM theories and show respect for traditional medication experience, but also follow the general laws of pharmaceutical investigation; based on modern research outcomes and the relationship between formula compositions and ingredients, the physiochemical properties and pharmacological action of the components contained in ingredients, considering the preparation process and manufacturing practice, environmental protection and energy-saving requirements, studies should be conducted using associated disciplinary knowledge, reasonable study design and evaluation indicators. It is encouraged to apply new technologies, new methods and new excipients conforming to product characteristics.

　　II. Basic Principles and Requirements

　　(I) Abiding by the traditional medication experience

　　Study on compound preparations of TCMs is based on knowledge of TCM in life, health and disease, and also based on records in ancient books and modern literature, as well as study, exploration and data accumulation from practical clinical application. Study on manufacturing process of compound preparations of TCMs should abide by TCM theories, and show respect for traditional medication experience. Therefore, the more systematic and deeper literature study in the preliminary phase and the more sufficient data accumulated in clinical application, the better the study core and key points can be grasped.

　　(II) Quality by design

　　Study on compound preparations of TCMs should be based on the concept of “Quality by design”. In the preliminary phase of manufacturing process study of compound preparations of TCMs, the process route and dosage form of TCMs should be designed as oriented by clinical value and on the basis of understanding formula compatibility, clinical application and other conditions, and tests and studies should be carried out to understand key quality attributes and quantitative and qualitative transfer of the product, and determine the key process parameters. In addition, design space that can meet product quality design requirements and has stable manufacturing process should be established in accordance with material properties and process conditions, etc., such as determining the control range of process parameters. Quality risk management should be carried out, and quality control strategy and drug quality standard system should be established in accordance with the design space.

　　(III) Holistic quality evaluation

　　Evaluation during the study on manufacturing process of compound preparations of TCMs should embody overall quality characteristics of compound preparations. Appropriate evaluation indicators should be selected in combination with characteristics of compound preparations of TCMs from aspects such as clinical application conditions, formula compatibility, chemical components contained, pharmacological and pharmaceutical effects, etc. Attention should be paid to the relevance to the safety and efficacy of drugs.

　　Indicators selected for study on manufacturing process should be comprehensive, scientific and objective, and should be quantifiable as much as possible. Such indicators should be able to reflect changes in relevant manufacturing processes, and also reflect integrity and consistency of drug quality as well as transfer law of active components, to guarantee controllability of the manufacturing process. Evaluation indicators and judgment criteria for intermediates/intermediate products and dynamic process control should be established. Environment-friendly and cost-effective manufacturing process should be established to serve as the quality evaluation indicators.

　　Manufacturing process and manufacturing equipment are closely related to each other. Therefore, the concept that manufacturing equipment serves the drug quality should be established, and the selection of manufacturing equipment should conform to the requirements for manufacturing process.

　　(IV) Constant improvement of manufacturing process

　　In order to guarantee homogeneity and stability of the product quality, it is of great significance to constantly improve the manufacturing process of compound preparations of TCMs. The processes and process parameters determined in various study phases may have certain limitations due to process conditions, batch sizes and other factors. Therefore, scale-up validation and improvement are g conducted, and validation of manufacturing conditions at commercial scale should be performed before marketing to determine the manufacturing process and process parameters.

　　In the study on manufacturing process of new compound preparations of TCMs, under the condition of unchanged process route and key process parameters, study on optimization of manufacturing process can be carried out before confirmatory clinical trial. Studies in various pre-market phases and post-market studies on improvement of manufacturing process may be carried out in reference to relevant guidelines.

　　III. Main Contents

　　(I) Pre-treatment study

　　Pre-treatment methods of TCM crude drugs include cleansing, cutting, roasting and broiling, pulverization, and sterilization, etc. Study on processing of decoction pieces should show respect for processing technology of decoction pieces applied in clinical practices, conform to the needs for study design of compound preparations of TCMs, and conform to relevant technical requirements. In accordance with characteristics of specific medicines, requirements for dosage form and preparation design etc., , if pre-treatment such as pulverization and sterilization is required for decoction pieces, appropriate method, equipment, process conditions and parameters should be selected, and relevant quality control requirements should be determined.

　　(II) Study on extraction, purification, concentration and drying

　　Compound preparations of TCMs have complex ingredients, and therefore, in order to retain the active components as much as possible, reduce the dosage and facilitate the preparations, etc., extraction and purification are generally required. Reasonable and correct use of extraction and purification technologies has a direct relation to the performance of pharmaceutical effect and utilization of TCM crude drugs resources. Study on extraction, purification, concentration and drying of compound preparations of TCMs should center on the efficacy and safety of the medicines, lay emphasis on TCMs formula compatibility theory and traditional clinical application experience (e.g., combined decoction, separated decoction, decoct first, decoct later, etc.), pay attention to the interaction of ingredients, and quantitative and qualitative transfer of decoction pieces, intermediates/intermediate products and preparations, and also take feasibility, safety, energy saving, consumption reduction, environmental protection and other requirements for scale manufacturing into consideration.

　　1. Process route

　　Different extraction, purification, concentration and drying methods have their own characteristics and usages. Therefore, appropriate process route, method and evaluation indicators should be selected in accordance with the process design purpose, and in combination with physiochemical properties, pharmaceutical effect and safety study results of the components related to the therapeutic activity and safety, as well as existing literature reports.

　　Study on screening of process route should pay attention to:

　　Study on screening of process route related to efficacy. For compound preparations of TCMs originated from clinically effective formulas, the following aspects (including but not limited to) may be taken into consideration: 1) Clinical medication experience. Differences and similarities between the process route used and that of clinical medication (e.g., preparations of medical institutions, etc.) should be taken into consideration. If manufacturing process different from that of clinical medication is used, it is generally suitable to compare with the manufacturing process of clinical medication. 2) Pharmacodynamic test or literature references. In pharmacodynamic test, comparison study of process route can be carried out by selecting appropriate pharmacodynamic model and main pharmacodynamic indicators with clinical medication (e.g., decoction), etc. as the control. 3) Comparison of active components. For example, compare active components etc. when contrasting with clinical medication (e.g., decoction).

　　Study on screening of process route related to safety. Safety of the medicines should be studied when screening the efficacy. Consideration should be made from the following aspects (including but not limited to): adverse reactions and literature reports from preliminary clinical medication, comparison of animal safety indicators of different process routes with pharmacodynamics tests, toxic and harmful ingredients and single dose toxicity.

　　Rationality of manufacturing process is the basic work of study on manufacturing process of compound preparations of TCMs, and the more evidence supporting rationality of the process route, the more guarantee there is for study in later period. Attention should be paid to R&D risks that might be caused by irrational manufacturing process.

　　1.1 Extraction and purification process

　　Extraction of compound preparations of TCMs should be conducted on the basis of making full understanding of the traditional application mode, taking characteristics of decoction pieces, properties of active ingredients and requirements for dosage form into consideration, and paying attention to active ingredients, toxic ingredients and properties of extracts as well as quantitative and qualitative transfer of other quality attributes. Class I and Class II organic solvents should be avoided as the extraction solvent as much as possible.

　　For purification of compound preparations of TCMs, scientific, reasonable, stable and feasible manufacturing process can be designed in accordance with traditional TCM medication experience, or based on the existence state, polarity and solubleness, etc. of some active ingredients confirmed in the medicines. However, due to complexity of the ingredients in compound preparations of TCMs, the necessity and appropriateness of purification should be taken into consideration.

　　1.2 Concentration and drying process

　　In accordance with physiochemical properties of the materials, requirements for preparations, and factors influencing the concentration and drying effect, corresponding manufacturing process should be selected to enable the products obtained to reach required relative density and water content, etc., thus facilitating preparation of the final products. The main manufacturing process steps and process conditions as well as study factors need to be determined. The main ingredients should be studied, and attention should be paid to unstable ingredients.

　　2. Process conditions

　　Upon preliminary determination of the process route, scientific and reasonable test design and optimization should be performed for the process technologies and methods applied. Accurate, simple, representative and quantifiable comprehensive evaluation indicators and reasonable methods should be applied to optimize the manufacturing process, and multiple-factor and multi-level study should be performed based on pre-test. It is encouraged to apply new technologies and new methods, but for newly established methods, the rationality and feasibility study should be carried out.

　　Appropriate manufacturing process and equipment should be selected in accordance with specific product, and manufacturing process flow and the equipment used should be fixed.

　　Study on process conditions should pay attention to the relation between material properties, process parameters and the product quality, and key process parameters and their ranges should be determined.

　　2.1 Optimization of extraction and purification process conditions

　　Different extraction methods would have different factors influencing the extraction effect. Therefore, the selection of influence factors and determination of extraction parameters should be performed in accordance with the extraction method and equipment applied. Generally, it is required to select influence factors including solvent, extraction times and extraction duration etc., manufacturing equipment and process conditions, in order to optimize the extraction process. In addition, mature and well-recognized optimal selection method should be adopted, and the applicability of new method (if applied) should be taken into consideration.

　　The purification process should be selected in accordance with the purification purpose, principle of the method to be used and the influence factors. Generally, it is required to consider physiochemical properties of the active components to be reserved and the substances to be removed, the requirements of the dosage form to be made and the preparation process, as well as the bridging with manufacturing conditions.

　　Process parameters should be determined with references to tests, describing the test method, study indicators, and validation investigations etc. Determination of the ranges of process parameters should be supported by relevant study data.

　　2.2 Optimization of concentration and drying process conditions

　　The methods and degree of concentration and drying, equipment, process parameters and other factors have a direct influence on the stability of ingredients in the materials. Therefore, the process conditions should be studied and optimized in combination with the requirements of preparations.

　　The concentration and drying methods as well as main process parameters should be studied, and the determination of ranges of process parameters should be supported by relevant study data.

　　(III) Preparation study

　　During the preparation study compound preparations of TCMs, according to the properties and amount of medicinal substances for preparation process, and in combination with medication experience and indications, etc., appropriate dosage form, excipients, manufacturing process, and equipment should be selected.

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

　　1. Selection of dosage forms

　　Different dosage forms of the medicines may result in different pharmaceutical effects, thus affecting clinical efficacy and adverse reactions of the medicines.

　　Selection of dosage forms should reference the early medication experience to meet clinical medical needs based on the comprehensive analysis of physiochemical and biological properties, and dosage form characteristics, etc. of the medicines. The convictive references and experimental data should be provided to adequately elucidate the scientificity, rationality and necessity of the selection of dosage form.

　　The following aspects should be primarily considered for the selection of dosage forms:

　　1.1 Clinical needs and medication objects

　　It should be considered that different dosage forms may be applicable to different clinical symptoms, as well as the compliance and physiological conditions, etc. of medication objects.

　　1.2 Properties and amount of medicinal substances used for preparation process

　　Active ingredients of TCMs are complex, and the solubleness and stability of various ingredients are different during absorption, distribution, metabolism and excretion process in vivo. Therefore, appropriate dosage forms should be selected in accordance with the properties of medicines.

　　The formula amount, amount and properties of medicinal substances used for preparation process, clinical medication dosage, and loading quantity of different dosage forms, etc. should be considered for the selection of dosage forms.

　　1.3 Safety

　　The safety of medicines should be fully considered when the dosage forms are selected. Attention should be paid to possible safety hazards (including toxicity and side effects) caused by dosage form and administration route.

　　In addition, the study before formula design of medicinal preparations needs to be emphasized. Relevant studies should be carried out on the basis of understanding the basic properties, dosage form characteristics and preparation requirements of medicines. The theories, methods and technologies of relevant disciplines should be referenced during the selection and design of the dosage form.

　　2. Study on formulas of preparations

　　Study on formulas of preparations is a process for screening appropriate excipients and determining formulas of preparations based on the properties of medicinal substances used for preparation process, dosage form characteristics and clinical medication requirements, etc. Study on formulas of preparations is an important content of preparation study.

　　2.1 Pre-formula study of preparations

　　Pre-formula study of preparations is the basis of the study on preparation process, for the purpose of enabling the preparation formula and preparation process to adapt to requirements for industrialized manufacturing, and guaranteeing the rationality, feasibility and inter-batch consistency of manufacturing.

　　In the pre-formula study of compound preparations of TCMs, the properties of medicinal substances used for preparation process should be studied. For example, for solid preparations, dissolution characteristics, moisture absorption, fluidity, stability and compressibility, etc. of the medicinal substance for preparation process should be mainly studied; and for oral liquid preparations, dissolution characteristics, acid-base property, stability, smell, and odor, etc. of the medicinal substance for preparation process should be mainly studied.

　　2.2 Selection of excipients

　　In the study of preparation process, of excipients should be selected. The excipients used should conform to the medicinal requirements, and new excipients should also conform to the relevant requirements.

　　Selection of excipients should generally take the following principles into consideration: meet the requirements of preparation process, stability and action characteristics of final products, have no adverse interaction with active components, and avoid the influence on drug testing. Considering the characteristics of compound preparations of TCMs, reducing the administration dosage and improving the medication compliance, the preparation formula should be able to obtain good preparations with as little amount of excipients as possible.

　　2.3 Study on screening of formulas of preparations

　　Study on screening of formulas of preparations should take the following factors into consideration: requirements for clinical medication, properties of the medicinal substances and excipients used for preparation process, and dosage form characteristics, etc. Through the study on formula screening, the formula composition of preparations is preliminary determined, and the types, models, specifications and amounts, etc. of the excipients used are clarified.

　　3. Study on preparation process

　　Through the study on preparation process, the formula design can be further improved, and the preparation formula, process and equipment are finally confirmed. In addition, it is required to pay attention to the stability of preparations.

　　3.1 Requirements for preparation process

　　Study on preparation process should generally take selection of preparation process and preparation technology into consideration, pay attention to bridging between the laboratory conditions and the pilot scale and manufacturing, and consider the feasibility and adaptability of commercial manufacturing equipment.

　　Unit operation or key process should be studied to guarantee the stability of quality. The technical conditions of each process should be studied to determine the detailed preparation process. During the preparation process, special attention should be paid to the homogeneity of toxic ingredients and medicines with small dosage but strong activity.

　　3.2 Preparation technology and preparation equipment

　　During the study of preparations, specific preparation technology and equipment may always have a great influence on the preparation process as well as the category and amount of the excipients used, so they should be correctly selected.

　　During the study of preparations, influences of equipment type and process parameters on key quality attributes of preparations should be emphatically studied. The diversified mathematical modeling methods can be used to carry out correlation studies among the properties of medicinal substances used for preparation process, process parameters, and evaluation indicators of key quality attributes, establish the design space for key material attributes, key process parameters and key evaluation indicators of medicinal substances used for preparation process, and explore corresponding process control technology, to reduce the inter-batch quality difference, guarantee the stability of drug quality, and then guarantee the safety and efficacy of drugs. Advanced preparation technology and corresponding preparation equipment are important aspects for improving the preparation level and product quality, which should also be paid attention.

　　(IV) Study on selection of package

　　Study on selection of package of compound preparations of TCMs mainly refers to the study on selection of packaging materials (containers) in direct contact with finished preparations and intermediates/intermediate products (if applicable), and also includes the study on selection of secondary packaging materials (containers).

　　Packaging materials (containers) in direct contact with drugs should be selected in accordance with influence factors and the stability study results of the product. Selection of packaging materials (containers) in direct contact with drugs should conform to relevant requirements of packaging materials (containers) in direct contact with drugs, drug packaging and label management, etc.

　　Under some special conditions or conditions with insufficient literature materials, the study on compatibility between drugs and packaging materials (containers) in direct contact with drugs should be strengthened. Especially for liquid preparations or semi-solid preparations containing organic solvents, on the one hand, it is possible to study whether ingredients in the packaging materials (especially additive ingredients in the packaging materials) will seep into the drugs to cause changes of product quality in accordance with the migration experimental results; and on the other hand, it is possible to study whether the adsorption/exudation of packaging materials could cause changes in drug concentration and precipitation, etc., thus leading to safety concerns in accordance with the adsorption test results. For new packaging materials (containers) in direct contact with drugs or packaging materials (containers) of specific dosage forms, , not only the stability test should be carried out, but also appropriate study items should be added.

　　(V) Pilot-scale study

　　Pilot-scale study is the validation and improvement of rationality of laboratory process, and is an inevitable procedure for guaranteeing that the process can reach manufacturing stability and operability. After completing a series of studies on manufacturing process of compound preparations of TCMs, scale-up study should be carried out under the conditions which are basically consistent with the manufacturing conditions, to provide a basis for realizing the validation of manufacturing process at commercial scale. Pilot-scale study should take bridging with manufacturing at commercial scale into consideration. During the pilot-scale study process, the specific process procedures should be formulated, and proper records should be kept.

　　Through the pilot-scale study, the key steps, control range of key process parameters and yield range of intermediates/intermediate products (e.g., extracts, etc.) are explored, and the problems existing in process feasibility, labor protection, environmental protection and manufacturing cost, etc. are discovered, so as to provide a basis for manufacturing at commercial scale.

　　The pilot-scale study equipment should generally have consistent working principle with the manufacturing equipment, and the main technical parameters should be basically consistent. Pilot-scale study samples, if used in clinical trials, should be prepared in workshops conforming to conditions in the Good Manufacturing Practice (GMP).

　　Since for different dosage forms of drugs, the manufacturing process, equipment, workshop conditions, excipients and packaging, etc. differ greatly, the dosage form should be considered in pilot-scale study, and in particular, how to carry out work by adapting to manufacturing characteristics should be taken into consideration.

　　Feeding amount of pilot-scale study should take bridging with study on manufacturing at commercial scale into consideration, to provide a basis for manufacturing at commercial scale. Feeding amount, yield rate of intermediates/intermediate product and rate of finished products are important indicators for measuring the feasibility and stability of pilot-scale study. Feeding amount of pilot-scale study should meet the purpose of pilot-scale study. Yield rate of intermediates/intermediate product and rate of finished products should be stable relatively.

　　Generally pilot-scale study involves multiple batches to reach the purpose of stable process.

　　(VI) Study on manufacturing at commercial scale

　　Study on manufacturing at commercial scale mainly involves the homogeneity and stability of product quality under large-scale condition, especially the consistency of quality of samples used in clinical trials, which also covers comparison and evaluation. Through the study, all process steps and control ranges of process parameters applicable to manufacturing at commercial scale are specified, the decoction pieces, intermediates/intermediate product, and quality risk points are clarified, and the stability, environmental protection and economy of manufacturing process are guaranteed.

　　Manufacturing at commercial scale should pay attention to its match with the equipment, as well as fluency and convenience of various manufacturing procedures. Homogeneity and stability of product quality and manufacturing efficiency are important indicators for measuring large-scale manufacturing.

　　Stability of manufacturing at commercial scale generally should be performed through multiple batches. During the test, the process parameters and quality attribute relationship should be noticed, and the fluctuation of quality should be concerned. Relevant records should be improved, standardized and traceable.

　　(VII) Process validation

　　Validation of key processes and key process parameters should be completed before carrying out clinical trials, and complete process validation should be performed before applying for marketing authorization. Manufacturing environment for process validation should conform to the requirements of Good Manufacturing Practice (GMP), and the manufacturing equipment should match with the proposed manufacturing scale.

　　The process validation should be performed according to the designed protocol, and a process validation report should be formed afterwards. For the pilot-scale process or manufacturing at commercial scale, appropriate indicators should be selected, the process validation protocol should be designed, and the influence of personnel, equipment, materials, manufacturing environment, management and control measures, etc. on product quality are studied under proposed manufacturing scale, process conditions and parameters. If the design space or range of process parameters has been proposed, the extreme value of the proposed design space or the range of process parameters should be studied in the process validation, to validate the feasibility of manufacturing process and the consistency of product quality.

　　Note: In the event of any discrepancy between the English and Chinese versions, the Chinese version shall prevail.