Introduction

Traditional Chinese medicine (TCM) has made outstanding contributions to our health and the treatment of many diseases, and this causes a global developmental upsurge. The research by Prof. Youyou Tu on the research of artemisinin treating malaria gained a Nobel Prize in Physiology or Medicine in 2015. As the milestone of the modernization of Traditional medicine, it has attracted global interests to many scientists on the investigation of TCM [1]. As the coronavirus disease 2019 (COVID-19) pandemic causes a significant global public health problem, TCM was used as a treatment for 91.5% of the COVID-19 cases in China, which showed promising results in improving symptoms and reducing disease deterioration, mortality and recurrence rates [2]. Three formulas (Qingfeipaidu Decoction, Huashibaidu Decoction and Xuanfeibaidu Decoction) developed from Chinese Classical Formula (经典名方, CCF) have been selected as general effective medicines for the treatment of COVID-19 and approved as new medicines in 2021 [3].

CCF are the prescriptions recorded in the medical records of the Qing Dynasty and before the Qing Dynasty and are still widely used, and they have definite curative effects and obvious characteristics and advantages [4]. The list of CCF should be promulgated by Chinese government and 100 CCF was promulgated in 2018 [5]. CCF are essential and supportive for the development of prescription theory. The prescription theory is based on the system of "principles, methods, formulas and medicine" (理法方药). After nearly two thousand years of continuous practical use, analysis, improvement and complement on theories, a tremendous amount of formula/prescription-related records have been accumulated. Some formulas with more precise therapeutic effects are widely used at a higher priority and considered as classical formula/prescription for the treatment of specific diseases. CCF are the essential formulas that have accumulated practical experience in the clinical application of Chinese medicine since thousands of years ago. With their remarkable therapeutic effects, they are currently still in use by medical doctors. It is a vital strategy to transform these Chinese treasures represented by CCF into high-quality products for easy to carry and use, which is a preferred shortcut for develo** TCM products and meets the needs of diversified medications.

The development of CCF pharmaceutical preparations (CCFPP) is a "green channel" for the drug development in China. Due to the complexity of TCM and its weakness in basic research for modernization, the success rate of new drug development from TCM is relatively low. Only five new drug applications were approved during 2014 to 2019, while forty new drug applications were approved from 2007 to 2013 [6]. The document "Opinions of the State Council on Reforming the Review and Approval System for Drugs and Medical Devices" [7] followed a series of reform policy documents that led to a sharp decrease in the number of new drug applications. The development of CCFPP has provided good ideas and opportunities for the development of new drugs from TCM. The core idea of CCF development is to refine the application of ancient and modern clinical practice and use it to design modernized pharmaceutical preparations with stable quality. For the application of CCFPP registration, the core advantage is that pharmacological research and clinical trial data are not needed. The research period of CCF is considerably shortened and the cost is drastically reduced.

The development and research of CCFPP have attracted a lot of attention to scientists, which has caused a large number of enterprises and researchers to invest in it. Meanwhile, the preliminary research, production and regulatory practice of China's formula granules (配方颗粒) have also provided a lot of experiences and references for the development of CCF in the past two decades.

The new version of the “Drug Administration Law” implemented in 2019 in China requires systematic research, quality control based on the whole manufacturing chain, quality traceability and adverse reaction monitoring for drug registration, which put forward new requirements for drug registration. The new law also emphasizes the responsibility of enterprises and other entities. There are still many gaps where policies have not yet been implemented for some specific CCF varieties. Although the authoritative role of expert consensus has been clarified, the specific determination criteria are still incomplete. The risks of CCF development are still high with policy factors, market capacity and uncertainty in the research process. Therefore, this study, was aimed to provide references for enterprises, researchers and relevant personnel of the governmental departments that are engaged in the development of CCF to speed up the develo** process of CCFPP.

Ideas for the development of CCFPP

Simplified Regulations on the Administration of Registration and Approval of Traditional Chinese Classical Formula Pharmaceutical Preparations (CCFPP) (referred to as Registration Regulations CCFPP) pointed out seven conditions that should be met for the application of CCFPP, which can be exempted from performing clinical trials [8]. When CCFPP meet the listed requirements, they can provide pharmaceutical and non-clinical safety research data for the registration of CCFPP without pharmacological research and clinical trial data. These seven regulations exclude the highly toxic Chinese medicine materials, thereby ensuring their safety. Besides, these regulations also limit the consistency of the formula composition, preparation method and administration methods recorded in ancient books of TCM, thereby ensuring the effectiveness and safety of the CCFPP.

Two stages for the development of CCFPP

The Registration Regulations of CCFPP pointed out that the development of CCFPP is divided into two stages: the research and development (R&D) of the CCF Material Reference (MR, 物质基准) and the R&D of pharmaceutical preparation based on the CCFMR to ensure that the key quality attributes of CCFMR and CCFPP are consistent [8] (Fig. 1). The CCFMR is a reference for the production process optimization and quality evaluation of the CCFPP. It refers to the standards of medicinal substances in CCF that are prepared based on the preparation methods recorded in the ancient medical books, and it is called standard decoction (标准汤剂) for water decoction preparation. It is an intermediate reference for the transformation of TCM from traditional individualized preparation to industrial pharmaceutical products. The involvement of CCFMR in the development of CCF ensures that the clinical efficacy of the pharmaceutical preparations is not decreased, their toxicity is not increased, and their product quality is stable and consistent.

Fig. 1
figure 1

The guidance for the development of Chinese Classical Formula pharmaceutical preparations (CCFPP). The standard decoction or the material reference of CCF is a reference for the optimization of the production process and quality evaluation of the CCFPP

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To further ensure the safety of CCFPP, non-clinical safety studies with Good Laboratory Practice (GLP) specifications should be done for the application of the CCFPP according to the Registration Classification and Application Requirements for Traditional Chinese Medicines [9] and the Registration Regulations of CCFPP. Non-clinical safety research together with sufficient clinical practical experience of CCF can further ensure the safety of CCFPP.

The development of CCFMR

The concept of CCFMR has gone through a long period of demonstration. The concept of standard decoction (标准汤剂) was first proposed for the development of Japanese Kampo (汉方制剂) in 1986 [10]. The standard decoction is the chemical and biological base for the development of Japanese Kampo to ensure good product quality. Because Japanese Kampo preparations are mainly derived from CCF, the concept of "standard decoction" proposed by Japan is worth learning for the industrialization of CCF in China. Therefore, the concept of "standard decoction" was introduced as a reference for production and quality management of CCFPP. In April 2016, Prof. Shilin Chen proposed the concept of "standard decoction of medicinal material decoction pieces" [11, 12]. In August 2016, the concept of "standard decoction" was applied in the quality control of granules of decoction pieces in the Technology for Quality Control and Standard-setting of Traditional Chinese Medicine Granules of Pieces (Draft for Solicitation of Comments) promulgated by the National Pharmacopoeia Commission [13]. Subsequently, the National Medical Products Administration in China (NMPA) adopted the concept of standard decoction in the Registration Regulations of CCFPP (Draft for Comments) promulgated in October 2017. The concept of CCFMR was then adopted in the Registration Regulations of CCFPP, which was finally promulgated in June 2018. Although the name of CCFMR has been changed to different names, such as "standard decoction", "standard Jianye", "key samples", but their essence is the same, namely the reference for CCFPP.

Key issues for the establishment of CCFMR

The preparation of CCFMR is based on the preparation methods recorded in the ancient medical books but it is a big difficulty in develo** CCF. There are no success cases for referencing, and the officials has not published declaration guidelines yet. There are also uncertainties in relation to policies, healthcare market and R&D process. There are four main issues, including the origins of the medicinal materials, processing methods of the decoction pieces, dosages, and the preparation methods of the CCFMR (Fig. 2). These key common issues are needed to be verified by comprehensive consideration of the ancient records with modern clinical applications, and some of them may need be confirmed by the scientific research evidence. The quality of CCFMR is also needed to be evaluated with modern quality control methods, which is important as a reference for the R&D of CCFPP [14].

Fig. 2
figure 2

Key issues for the establishment of Material Reference of Chinese Classical formula (CCFMR). The preparation of MR is based on the preparation methods recorded in the ancient books, but there are four main issues, including the origins of the medicinal materials, processing methods of the decoction pieces, dosages, and the preparation methods

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Origin of the medicinal materials

“Origin” is the systematic summary of the species, effective parts, and habitat of the medicinal materials. The varieties and medicinal parts of some Chinese medicine have changed with time due to the facts that it has been used for a long history of thousands of years and the original plants of the same family and genus have similar morphology of the variety of species, and some records on the morphology given by the ancient books are too simple. Thus, it is necessary to clarify the historical origins and changes of the source of Chinese medicine material through the research on origin to determine their varieties and medicinal parts for the development of CCF, and to accurately pass the medical experience to others and ensure good safe use of medicine. There are 159 types of Chinese medicine materials involved in 100 CCF. The medicinal parts comply with the Chinese Pharmacopoeia (ChP) for most of the Chinese medicine materials, and most of those are from their original habitat [15]. An essential purpose in the research of origin is to identify species and avoid using substitute and adulterated medicine. Chinese medicine substitutes refer to the medicine with the same taste, meridian entry (归经), function and indications as the original Chinese medicine. Chinese adulterated medicine refers to the Chinese medicinal products whose sources or medicinal parts do not meet the criteria of ChP or other statutory drug standards, including the confusion of species, medicinal parts, and intentional fraud. Chinese medicine substitutes and adulterated medicine can interfere with the correct usage of the original Chinese medicine. To avoid the influences by the substitute and adulterated medicines, researchers will use textual research of the ancient records to trace the change of their origins and combine this with modern technology, like DNA barcoding [16], trait identification [17], or Q-marker to identify the original Chinese medicine materials [18].

Several main methods for the textual research of origin are Materia Medica Research, Botanic (animal, mineral) Taxonomy Research, Molecular Identification Research, and Chemical Identification Research. Materia Medica Research reviews the literature on material medica and its traits to verify the name, origin, and habitat of different Chinese medicine materials in each era. The basic operation process of the textual research on material medica includes the acquisition of drug characteristic information and proof of the origin. The acquisition of characteristic information mainly includes three key phases: reviewing, sorting out and selecting literatures. The molecular identification of Chinese medicine is mainly based on the characteristics of macromolecules (protein and nucleic acid), which can be divided into protein and nucleic acid identification. At present, the main methods of molecular identification of Chinese medicine are DNA barcode identification, specific polymerase chain reaction method, population genetic analysis, and molecular lineage geographical analysis. Chemical identification research on Chinese medicine is a method that targets the analysis of characteristic chemical compounds in Chinese medicine materials.

Processing method verification

Most of the Chinese medicine used in the CCF have been processed (Paozhi). Paozhi refers to the processing medicinal materials, which allow them to store easily, meet their clinical needs and improve their clinical efficacy. Most of the processing methods that were recorded in those 100 CCF are specifically stipulated in the ChP. However, more research is needed to study the processing methods that are not regulated or not consistent with the methods in the ChP. The main processing method in the CCF is to remove the unrelated parts of the medicinal materials. Simultaneously, slicing and the use of additional material processing (with auxiliary materials) are also widely used in the processing of CCF. The processed medicinal materials are called decoction pieces, whereas the unprocessed medicinal materials are called fresh drug. The existence of fresh drugs reflects the diversity of paozhi methods and the distinctive characteristics of prescription in CCF. For toxic Chinese medicine materials, the control of their toxic components is achieved through Paozhi, but more proofs are still needed for the safety use of toxic Chinese medicine materials [19].

Paozhi technologies are widely recorded in ancient medical books. However, some of them contain unclear information, confusing words, and non-accurate records, so some double-textual research or more research are needed to resolve these problems to standardize the specific details for processing [20]. Besides, there are only a few descriptions on the quantification of the Paozhi technologies in the ancient records. Even though there are some descriptions, most of them are subjective judgments, quantifying the Paozhi technologies is a big challenge in the research field. The same Paozhi technologies used may have different processing steps, so textual research on Paozhi should also compare the medicinal experience from the ancient books in different dynasties. Simultaneously, looking at the effects of each medicinal material in the prescription can help to trace back the original method and clear purpose of the Paozhi, which can provide more reliable evidence for the Paozhi method verification of CCF. Take Dachengqi Decoction as an example, the function of this decoction is to regulate the gastrointestinal tract. After Dahuang is processed with wine, its medicinal properties can be changed, and the heat of the triple energizers can be removed, which help to restore the health of the gastrointestinal tract. Therefore, in this prescription, the original paozhi method of Dahuang should be processed with wine.

Dosage verification

Dosage is an important factor influencing the safety and effect of CCF. The dosage and ratio between each medicinal material determine its clinical efficacy. As the measurement unit in ancient times is different from modern times, the standard dosage of each CCF cannot be determined directly. Therefore, it is necessary to verify the dosage to achieve the standardization of the current dosage, which is important to ensure the safety and stability of the current dosage for the development of CCF.

Dosage is a comprehensive reflection of the treatment concepts from the ancient clinical doctors, which passes on their unique therapeutic thoughts, medication habits and the historical background of the prescriptions. The main factors that determine the dosage include: (1) the type of disease determines the primary medicine and dosage used in the prescriptions; (2) the age and physical conditions of the patients determine the overall dosage; (3) the prescription dosage form also has special requirements for the dosage; (4) the historical factors and medication habits in ancient times have a direct impact on the dosage.

The CCF are derived from the ancient records in the medical books of the past dynasties. Most of them are intuitive descriptions of the subjects, dosages, preparation methods, and there is lack of accurate data. The verification of the dosage is the verification of the quantity of medicinal materials. Due to the shortcomings of TCM inheritance, the dosage of medicinal materials is often considered confidentially, so there are many difficulties in verifying the dosages of some CCFs. In addition, CCF have a relatively large time span, the dosage of their original prescriptions has changed due to some errors in spreading and modification by clinical physicians, and the measurement units used in different dynasties are different [4). The content of each step is elaborated below.

Fig. 4
figure 4

Critical steps for develo** Chinese Classical Formula pharmaceutical preparations (CCFPP). There are three main steps in the development of CCFPP, optimization of the preparation methods, development of the quality analysis methods and quality standards, and safety evaluation

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Preparation techniques

The research of CCFPP should aim at producing CCFPP with same quality as the CCFMR. The research contents include studying and determining the technical processes and parameters (ranges) of the pre-treatment, extraction, solid–liquid separation, concentration, drying and preparation molding of CCFPP. Furthermore, it should complete commercial-scale production process verification and draw up detailed operating procedures. Due to the limitation of historical technologies, the traditional preparation methods of CCF are relatively rough and individualized. The development of new drugs is based on the large-scale industrial production. Many parameters in the manufacturing process can be gradually optimized in the pilot study to achieve the goal that the key quality attributes of the CCFPP are consistent with the those determined by the CCFMR, while realizing the rational use of Chinese medicine resources. In the pilot research and large-scale industrial production, water should be kept as the extraction solvent for decoction. Other preparation processes can be changed according to the requirements of large-scale production equipment, such as the amount of water, the number of extractions, the extraction time, the filtration method, the concentration method, the drying method, and the preparation method.

Quality is another important factor for optimizing the preparation process to ensure process stability and reduce the fluctuation range of preparations. Clarifying the upper and lower limits of the control range, including paste yield, transfer rate and other indicators of process, is important to ensure the stability of the preparation production process. It is also important to ensure the uniformity and stability of the preparation quality. The relevant administrative departments in China stated that the acceptable fluctuation range of the main testing indicators for the preparation quantity is 70–130% in average. For indicators outside this range, it is required to analyze the reason by correlation analysis between medicinal materials, decoction pieces, preparation intermediates and CCFPP.

The composition of Chinese medicine is complex, and its therapeutic effects are the joint effects of multiple components. When the composition ratios of different components are the same or similar, their therapeutic effects will be similar. Therefore, when exploring the process parameters for CCFPP, the composition ratios between different components must be compared. Importantly, the composition ratios should be consistent with the CCFMR.

Quality evaluation and stability test

The holistic quality standard of the preparation is important to measure the quality of the product. The methods of quality control should strengthen with specific identification and multi-component quality control. It should at least include the extraction rate, quantitative determination of the characteristic components and their transfer rate, and fingerprint/characteristic map. The fingerprint/characteristic map should clarify the requirements of similarity, relative retention time and relative peak area. The main components should be identified as much as possible in the fingerprint/characteristic map. At the same time, factors related to safety should be paid attention.

A scholar Prof. Dai proposed that the development process of quality control methods and standards for CCFPP can be divided into three steps (Fig. 5) [24]. Firstly, the medicinal materials and decoction pieces are tested according to the existing quality evaluation methods and standards in the ChP to select the qualified raw materials. Secondly, with the CCFMR as the object, a holistic quality control method should be developed, which can detect all the medicinal materials in the formula. The key quality attributes and key quality indicators can also be selected by correlation analysis of the medicinal materials, decoction pieces, intermediates and CCFPP. With the key quality attributes, holistic quality control methods can be established for CCFPP, and its quality standard can be established according to the quality data of different batches of CCFPPs. The medicinal materials from which the index components are derived from can be confirmed by correlation analysis between CCFMR and decoction pieces. If the determined quality indicators/index is different from the index components in the existing quality evaluation methods of the medicinal materials in the ChP, a new quality control method with the new index component for medicinal materials and decoction pieces should be developed by the third step. Finally, with the determined quality indicators, optimized quality control methods for raw materials and decoction pieces should be developed. With the new analysis methods, decoction pieces and medicinal material are analyzed to determine the required quality standards of decoction pieces to meet the standards of CCFPP [23]. These new quality control methods and quality standards of raw materials and decoction pieces can be used as internal quality control methods and standards in enterprises to ensure the quality of CCFPP.

Fig. 5
figure 5

The development process of holistic quality control methods for Chinese Classical Formula pharmaceutical preparations (CCFPP) based on the whole manufacture process. The holistic quality control methods include the quality control from medicinal materials—decoction pieces Chinese Classical Formula pharmaceutical material reference (CCFMR) — Chinese Classical Formula pharmaceutical preparations (CCFPP) with key quality control index

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The validity period of CCFPP should be determined based on the results of long-term test. In general, the data of 6-month accelerated stability test and 18 months long-term stability test should be provided. After the drug is put on the market, the stability test should be continued.

Non-clinical safety evaluation

After long-term clinical practice tests and accumulated experiences, prescriptions with poor efficacy and safety have been gradually eliminated, while CCF with safety and definite efficacy have been used until today. To enable CCF to meet the needs of patients, the NMPA in China have issued relevant regulations, clarifying that “for CCF preparations that meet the requirements, they can provide pharmacy and non-clinical safety research data without reporting pharmacological research and clinical trial data". This is aimed to simplify the registration and approval procedures to promote the development of Chinese medicines. However, there are concerns about this as simplified registration may reduce the requirements for drug safety and lead to medication risks.

Safety evaluation for simplified registration and approval of CCF

CCF are derived from ancient medical records and have a long-term basis from clinical application. The safety and effectiveness have been confirmed by clinical practice, so it is reasonable to implement simplified registration and approval for them. Misuse of medicinal materials, improper processing, unreasonable long-term medication, improper compatibility and inconsistent use of medicine are the main reasons for the occurrence of adverse reactions in recent years [21]. To avoid the potential safety problems caused by the simplified registration and approval, the NMPA in China has established regulations on the selection of prescriptions and has also set requirements for simplified registration of CCF, including formulations, preparation methods, routes of administration, dosages of drugs, therapeutic effects and indications, applicable populations, and qualifications of manufacturers in many aspects. Besides, each CCF preparation needs to conduct non-clinical safety studies that follow GLP standards to systematically, objectively and comprehensively evaluate the safety of CCFPP to ensure the safety of clinical medications. In this case, only the prescriptions listed in the ACFD are eligible for simplified registration and approval. The prescriptions selected in this directory should meet the requirements of "widely used, definite therapeutic effects, obvious characteristics and advantages, sufficient records and evidence in medical records from ancient times, sufficient clinical and experimental research reports in modern literatures, further clinical studies of Chinese medicine and widely recognized by authoritative experts, described in various Chinese medicine textbooks" and other requirements.

The context of safety evaluation for CCFPP

The long-term clinical application and reasonable formulation of the CCF could reduce the toxicity of Chinese medicine to achieve relatively mild effects. However, due to the use of many new technologies in the modern Chinese medicinal preparations, there are significant changes in the routes of administration, dosage forms and material bases. Some changes are unknown, especially when the contents of key ingredients are significantly increased, their pharmacological effects may be significantly enhanced, and the adverse reactions may also be increased. Therefore, CCFPPs should be tested for safety evaluation, including acute and long-term toxicity studies.

The pre-clinical safety evaluation of the CCFPPs can be selectively conducted according to the specific conditions of the drug itself. For example, the safety test can be conducted as needed, and the toxicity of a single dose can be tested in a single type of animal. For toxicity test, repeated doses test can be firstly conducted with repeated doses in one type of animal (rodent). When toxicity is found, further studies are needed to test the toxicity with repeated doses in other kinds of animals (non-rodent). Special toxicity tests, such as genetic toxicity test, reproductive toxicity test, carcinogenic test and dependence test, are all needed when evidences suggest that they should be conducted (preliminary experimental results and literature reports). This requires a systematic summary and evaluation of the current safety information of the prescriptions before conducting the research. Therefore, making an experimental design and a research plan are necessary and should be based on the characteristics of the prescriptions.

International administration for the registration of Traditional herbal medicine

"World Health Organization (WHO) Traditional Medicine Strategy 2014–2023" by the WHO pointed out that Traditional and alternative medicine can be found in almost every country around the world, and its demand is growing. Herbal medicine is essential for the implementation of Traditional medicine. As its safety and effectiveness have been confirmed to a certain extent in ancient times, many countries and regions have given specific simplified requirements for the application of registration of Traditional herbal medicines according to their respective circumstances.

The recognition criteria for General Kampo Formula is the basis for the research and production of Kampo medicine in Japan. Under this circumstance, within the range mentioned in the regulation, when only water is used as the extraction solvent, any companies can independently determine the compatibility of medicinal materials, select dosage forms, formulate process and quality standards, and directly produce the products without pharmacological and clinical researches [10]. For Kampo medicine that was not included in the “Recognition criteria for General Kampo Formula” but was approved for production from 1968 to 2015, other companies only need to conduct the process and quality standards studies when applying for production without the needs of providing pharmacological and clinical research data if there are no added solvents other than water in the formulas.

According to the characteristics and uses of Traditional herbal medicine in European Union countries, the European Parliament stipulates that registered enterprises within the European Community can be exempted from conducting clinical and pre-clinical experiments when applying for the registration of Traditional herbal medicine if the products can meet the listed requirements, including oral, topical or inhaled Traditional herbal preparations that do not require clinical physicians to diagnose, prescribe and supervise with certain specifications and dosages. The medicine needs to have at least 30 years of medication history before the registration, including at least 15 years of use history in the European Community, sufficient data showing the traditional and safe use of the product under certain conditions, and confirmed pharmacological efficacy [19].

In the United States, the United States Food and Drug Administration (FDA) allows the application of new medicine under the over-the-counter drug (OTC) monograph system or new drug application (NDA) if their safety and effectiveness are approved as some botanical products and they have been used for a long time in the United States. However, clinical research data are needed for the application for botanical drug marketing under the OTC monograph system and NDA application system. Among them, the safety information provided by the human use history of botanicals should also be considered. Considering the characteristics of botanical medicine, the United States FDA reduces the technical requirements for the first clinical trials, so for most botanicals at this stage, the characteristics of the botanicals (chemical composition, manufacturing and quality control) are not required for guarantee. Simultaneously, for the plant products that are legally listed on the market as supplementary food, pre-clinical pharmacological and toxicological research are also not required when applying for the first clinical trials if there are no safety issues and the dosage is roughly the same [20].

Pharmaceutical research and safety

Following the requirements of Chinese 6.1 categories new medicine from Drug Regulation Management Measures and other related policies, toxicological research is needed to provide 7 types of experimental research data: (1) Summary of toxicological research data. (2) Acute toxicity test data and literature reviews. (3) Long-term toxicity test data and literature reviews. It is also necessary to consider whether the following research data are needed according to the specific circumstances of the research project: (4) Safety test data and literature reviews on allergy (local, systemic and photosensitive toxicities), hemolytic and local irritation and dependency (vascular, skin, mucous membrane and muscle) that are related to local and systemic administration. (5) Genetic toxicity test data and literature reviews. (6) Reproductive toxicity test data and literature reviews. (7) Carcinogenicity test data and literature reviews. Considering the characteristics of CCF and strict screening procedures, only 1–3 types of experimental research data are required under normal circumstances. If necessary, 1–3 more types of individual experimental research data or all other experimental research data should be supplemented.

Conclusions

As a vital part of the clinical prescriptions, CCF are the primary support for all the prescription science and even for the theoretical system of TCM. The long-term practice has provided evidences to show their clinical efficacy and low safety risks. Combining ancient and modern applications and standardizing their preparation methods are key considerations for the development of CCF. Expert consensus might also be a good approach to solve the major issues of the modernization of CCF, including the origin of the medicinal materials, processing methods, dosages, and preparation processes. The modernization of CCF by the pharmaceutical industry has become mature, the R&D of CCF is expected to promote the development and improvement of the theoretical system of prescriptions and benefit more to the patients in a broader range.