Abstract: Drawing on the 2020 Edition of the Chinese Pharmacopoeia and relevant literature, this paper discusses the newly introduced principles of species suitability in the “Technical Requirements for Quality Control and Standard Setting of Traditional Chinese Medicine Formula Granules” issued by the National Medical Products Administration in 2021. It also summarizes and categorizes certain medicinal materials that are not suitable for formulation into traditional Chinese medicine formula granules, while offering pertinent recommendations. The aim is to refine the quality standard requirements for traditional Chinese medicine formula granules and thereby promote the development of the formula granule industry.

Traditional Chinese medicinal decoctions are the primary dosage form in TCM; however, they suffer from drawbacks such as the inconvenience of preparation, carrying, and storage, as well as a lack of quality control. Standardized decoctions can, to a certain extent, serve as a substitute for raw herbal materials and represent an emerging dosage form; nevertheless, they still struggle to meet the demands of today’s fast-paced lifestyle. ^[1] Chinese herbal formula granules are prepared from traditional Chinese medicinal decoction pieces as raw materials through processes such as extraction, concentration, and drying, resulting in a new type of formulated medication characterized by standardized specifications, dosages, and quality standards. The introduction of single-herb formula granules has facilitated syndrome-based formulation in TCM, ensured the accuracy and efficacy of patient medication, aligned with the fast-paced lifestyle of modern individuals, and played a significant role in China’s fight against novel coronavirus pneumonia. To standardize quality control and methodological research for Chinese herbal formula granules, the National Pharmacopoeia Committee issued the “Technical Requirements for Quality Control and Standard Development of Chinese Herbal Formula Granules (Draft for Comments)” in 2016. ^[2] ; In November 2019, the “Public Notice on the Pilot Unified Standards for Varieties of Traditional Chinese Medicine Formula Granules” was issued. ^[3] , further standardizing the quality standards for 160 types of traditional Chinese medicine granular formulas; in 2021, the National Medical Products Administration formulated and issued the “Technical Requirements for Quality Control and Standard Development of Traditional Chinese Medicine Granular Formulas.” ^[4] , marking another significant milestone in the research, production, and clinical application of traditional Chinese medicine granular formulas.

In February 2021, the National Medical Products Administration and three other departments jointly issued an announcement on the termination of the pilot program for traditional Chinese medicine granular formulas. With this, the development of such formulations—spanning research and development, manufacturing, and clinical application—has come to a close after a 20-year pilot phase, thereby advancing their overall development and facilitating their large-scale clinical use. However, due to the unique characteristics of these formulations, certain medicinal materials are not entirely suitable for processing into granular forms. The “Technical Requirements for Quality Control and Standard Setting of Traditional Chinese Medicine Granular Formulas” addresses this issue by explicitly stipulating that “in principle, varieties whose natural properties make them unsuitable for preparation as granular formulas should not be processed into such formulations.” Nevertheless, the technical requirements do not specify which particular crude herbal slices or raw medicinal materials are ineligible for formulation into granules. This paper, drawing on the current state of research on traditional Chinese medicine granular formulas, explores this question.

1 Medicinal materials whose natural properties make them unsuitable for use in traditional Chinese medicine granular formulations.

1.1 Mineral medicine

Mineral medicines have a long history of use in China and are known for their sedative, tranquilizing, liver-soothing, and yin-nourishing effects, exhibiting great clinical flexibility. ^[5] Most mineral-based medicinal preparations typically contain heavy metals such as mercury, arsenic, and lead; improper use can readily cause severe damage to organs like the liver and kidneys, and may even result in death. ^[6] To eliminate or reduce the toxicity of mineral medicines, processing—such as purification, water-flying, dry-heat treatment, boiling, and repeated processing—is generally required. These processes are complex, and many of the traditional processing methods have since been lost. ^[7] Meanwhile, constrained by production processes and current technical requirements, the preparation of standardized decoctions from mineral medicinal materials presents considerable challenges. On the one hand, the lack of standardized and unified manufacturing protocols contributes to these difficulties; on the other hand, the unique characteristics of the raw materials mean that even slight variations in extraction and concentration conditions can readily alter the speciation of trace elements, thereby affecting therapeutic efficacy. For example, natural copper primarily consists of iron ions, especially ferrous ions; however, excessive temperatures during processing can lead to the formation of magnetic iron oxides, which in turn impede the dissolution of the active constituents. ^[8] When mirabilite is mixed with concentrated granules or used in the concentration-granulation process, it tends to dissolve incompletely and heat unevenly, which can lead to bumping. ^[9] In actual production, it is highly challenging to precisely control extraction time and temperature. Moreover, the low extract yield of mineral medicines also adversely affects the subsequent preparation of granules. ^[10] Therefore, most mineral-based traditional Chinese medicines are not suitable for formulation into TCM granules; see Table 1.

1.2 Precious medicine

The growth duration and resource availability of Chinese medicinal materials directly influence their prices. Certain herbs with unique therapeutic properties are highly sought after, leading to scarcity and high costs; when these herbs are processed into formulated granules, they inevitably face challenges such as limited raw-material supply and elevated production costs. Moreover, some precious herbs require only small doses to produce significant therapeutic effects and are specified in the 2020 edition of the Chinese Pharmacopoeia or in classical materia medica texts as being intended for single-use. Such herbs are likewise unsuitable for formulation into granules, as shown in Table 2.

1.3 Toxic medicinal materials requiring special processing

Traditionally, the toxicity of Chinese medicinal materials is classified into three categories: highly toxic, toxic, and slightly toxic. ^[11] Modern classification, based on the site of action, divides these effects into central nervous system toxicity, cardiovascular toxicity, gastrointestinal toxicity, hepatorenal toxicity, and toxicity affecting the skin, mucous membranes, and muscles; see Table 3. Such medicinal materials generally require special processing to reduce their toxicity, and dosage and administration vary from person to person. For example, the Chinese herbal medicine Fuzi: the 2020 edition of the Chinese Pharmacopoeia specifies that it should be decocted first and for a prolonged period; moreover, studies have shown that when Fuzi is administered in high doses, it must be boiled in boiling water for more than 3 hours. ^[12] However, the current “Technical Requirements for Quality Control and Standard Setting of Traditional Chinese Medicine Formula Granules” generally stipulates a decoction time of about 30 minutes per decoction; for herbs with a harder texture or those used for tonification, the decoction time may be appropriately extended. Prolonged decoction, therefore, clearly does not comply with the technical requirements. Although the toxicity of Phytolacca is markedly reduced after vinegar boiling, this processing method conflicts with the water-based solvent specified in the current technical requirements. Consequently, such herbs are not suitable for formulation into traditional Chinese medicine formula granules.

1.4  Medicinal materials with high extract yield and high viscosity that affect the shaping process

The extract yield refers to the mass of liquid or dry extract obtained per unit mass of crude medicinal material under a specified extraction process. It is an important production-management indicator in the extraction process and is closely related to product quality and cost. At the same time, extract yield has a significant impact on active ingredient content. However, a high extract yield also necessitates a corresponding increase in excipients for tableting, which raises the clinical dosage of traditional Chinese medicine granules and can easily lead to waste of resources and production costs. Moreover, excessive viscosity may result in an excipient-to-extract ratio exceeding 1:1, thereby failing to meet relevant regulatory requirements. For certain herbs, an excessively high extract yield often indicates intense extraction conditions and prolonged extraction times, which can transform aromatic herbs that disperse outward and ascend to those with heavy flavor and turbid qi that tend to descend, thus compromising therapeutic efficacy. ^[20] Because traditional Chinese medicine formula granules require the medicinal materials to be extracted and concentrated before being processed together with the corresponding excipients, the quality of the resulting extract can affect the subsequent use of the excipients and may easily compromise the product. Therefore, such medicinal materials exhibit poor compatibility with traditional Chinese medicine formula granules.

1.5  High-purity crystalline medicinal materials

High-purity crystalline medicinal materials are typically obtained by crystallizing extracts from plant stems and leaves; they exhibit aromatic properties and are readily volatile and sublimable, such as borneol, menthol, and camphor. These compounds can enhance the permeability of the blood–brain barrier and are commonly used in traditional Chinese medicine as “assistant” or “guide” herbs in formula combinations, albeit in small clinical doses. ^[21-22] Due to the preliminary extraction and crystallization processes they have already undergone, these materials exhibit high purity, making subsequent secondary extraction extremely challenging. Such medicinal materials are typically insoluble in water but readily soluble in organic solvents; the solvents used do not meet the pharmaceutical-grade water requirements stipulated in the technical specifications for traditional Chinese medicine formula granules, and their mixing with excipients necessitates complex processing. Consequently, these materials are also unsuitable for formulation into traditional Chinese medicine formula granules.

1.6  Medicinal materials containing poorly soluble active ingredients

The major active constituents of certain medicinal materials are highly lipophilic and poorly soluble in highly polar solvents, resulting in low extraction efficiency via water-based methods. Consequently, industrial extraction typically employs organic solvents, which do not comply with the current technical requirements for quality standards of traditional Chinese medicine granular formulations. Therefore, such medicinal materials are not suitable for preparation as TCM granular formulations; see Table 4.

2 Medicinal materials that, for special reasons, are not suitable for formulation into traditional Chinese medicine granules.

2.1 Medicinal materials whose quality standards are difficult to control

Unified and clearly defined standards for medicinal materials are of paramount importance for strengthening the supervision and management of their quality. Certain medicinal materials have not yet been included in the 2020 edition of the Chinese Pharmacopoeia, or although they once had official pharmacopoeial standards, these standards have since been progressively abolished by the National Medical Products Administration, such as Aristolochia and Guanmutong, which contain aristolochic acid. ^[31] . For certain medicinal materials, the current quality standards are relatively low, with quality control primarily relying on macroscopic characteristics of the raw herbs or processed slices. Once these materials are formulated into granules, however, their quality can no longer be assessed based on the granules’ macroscopic appearance—for example, Jiaomu and Zihéchē. Jiaomu is first recorded in the “Ben Cao Jing Ji Zhu” and is a locally customary medicinal material in Gansu Province; its current quality standard is specified in the Gansu Provincial Standards for Chinese Medicinal Materials (2009 edition), which includes only descriptions of macroscopic features and microscopic identification. ^[32] However, Zihéchē is not included in either the 2015 or 2020 editions of the Chinese Pharmacopoeia; the 2010 edition of the Pharmacopoeia provides only descriptions of its external characteristics, such as appearance and shape, but lacks control parameters for identification, testing, and assay. ^[33] . Some medicinal materials have relatively low specificity in their quality standards; for example, Schisandra chinensis (northern schisandra) and Schisandra sphenanthera exhibit extremely high similarity, differing only in the content of their constituent components. ^[34] Once these herbs are processed into formulated granules, it becomes difficult to exercise effective quality control. For such medicinal materials, the quality of the resulting traditional Chinese medicine formulated granules cannot be reliably assured; therefore, it is recommended that they not be formulated into granules, as shown in Table 5.

2.2  Medicinal materials that use special solvents in the extraction process

The “Technical Requirements for Quality Control and Standard Setting of Traditional Chinese Medicine Formula Granules” explicitly stipulates that the extraction solvent shall be pharmaceutical-grade water, thereby bringing the process closer to that of traditional water-decocted preparations. However, water extraction of certain medicinal materials can increase their toxicity, such as those containing colchicine or saponins. Colchicine inhibits the formation of spindle fibers during cell division, thereby blocking mitosis; it also strongly irritates the urinary and digestive systems. Moreover, colchicine is highly soluble in water, so it readily migrates from the herbal material into the solvent during aqueous extraction. ^[40] Medicinal materials containing saponins exert a certain inhibitory effect on respiration and often require reaction with acetic acid to form acetates, thereby reducing their toxicity. ^[41] Common medicinal materials containing colchicine include Fritillaria cirrhosa and Paris polyphylla, while those rich in saponins mainly include Phytolacca acinosa, Achyranthes bidentata, and Akebia quinata.

2.3 Medicinal materials under special management

“Poisonous, psychotropic, and anesthetic” traditional Chinese medicinal products are special categories of TCM; due to their unique properties, their storage, custody, and use are subject to corresponding regulatory controls. The most common psychotropic and anesthetic herbs include ephedra and poppy husk. Poppy husk is further divided into raw poppy husk and honey-fried poppy husk, both of which must be used in accordance with prescribed formulas and may not be sold or used individually on the market. ^[42] Ephedra contains ephedrine and pseudoephedrine, which can stimulate the central nervous system and are therefore easily illicitly converted by criminals into methamphetamine. Consequently, regulations stipulate that “compound preparations containing ephedrine alkaloids with a unit-dose ephedrine alkaloid content exceeding 30 mg shall be classified as prescription drugs subject to prescription-only dispensing.” ^[43] Due to the specific nature of their policies and therapeutic effects, such medicinal materials are not suitable for formulation into traditional Chinese medicine granules.

2.4  Medicinal materials with non-uniform origins

The botanical origin of Chinese medicinal materials has a significant impact on their quality and therapeutic efficacy, making the precise identification of such origins crucial for quality control and new drug development. However, some medicinal materials suffer from confusion regarding their botanical origins and lack of standardized criteria, which complicates subsequent processing. For example, Liu Jinu is classified into Northern Liu Jinu and Southern Liu Jinu; the former is derived from the plant Yin Xing Cao, which belongs to the Scrophulariaceae family. Siphonostegia chinensis The dried whole herb of Benth., the latter being derived from the Asteraceae plant Artemisia annua. Arfemisia anomala The dried whole herb of S. Moore is listed in the 2020 edition of the Chinese Pharmacopoeia only as North Liu Jinu, whereas the 2015 edition of the Zhejiang Provincial Standard for Processing of Traditional Chinese Medicinals includes only South Liu Jinu, indicating that South Liu Jinu is the commonly used medicinal material in this province. ^[44] Meanwhile, different regions have varying regulations regarding the source of the medicinal herb Liu Jinu. ^[45] The issue of taxonomic confusion in the botanical origins of ethnic medicinal materials is also particularly prominent, as shown in Table 6. Such materials are difficult to quality-control, and their quality becomes even more challenging to ensure once they are processed into traditional Chinese medicine granules.

3 Conclusion

Traditional Chinese medicine granular formulations represent a significant trend in the modernization of TCM. They not only preserve the essential characteristics of traditional herbal decoction pieces, enabling physicians to apply syndrome differentiation and individualized treatment with appropriate modifications based on clinical evidence, but also eliminate the cumbersome process of decocting, allowing for direct dissolution in water for rapid onset, reliable efficacy, and enhanced safety and hygiene. These advantages bode well for their future development. However, research on granular formulations has revealed that certain medicinal materials, due to their inherent properties or other specific factors, are unsuitable for processing into such formulations. The “Technical Requirements for Quality Control and Standard Setting of Traditional Chinese Medicine Granular Formulations” provides guiding provisions on this issue; although these represent an improvement over the “Draft Technical Requirements for Quality Control and Standard Setting of Traditional Chinese Medicine Granular Formulations (for Public Comment),” they still lack detailed elaboration. This paper discusses these gaps, aiming to stimulate further attention within the industry and thereby promote the development of the granular formulation sector.

Because certain medicinal materials are unsuitable for formulation into granules, clinicians sometimes encounter situations in clinical practice where the required crude herbs do not have corresponding granular formulations—for example, in classic renowned formulas such as Dachengqi Tang and Fuzi Lizhong Tang, which call for Mangxiao and Fuzi, respectively. Mangxiao, being a mineral-based herb, is not appropriate for granule preparation, while Fuzi, due to its significant toxicity, requires special processing, thus failing to meet the technical guidance requirements for Chinese herbal granules. In actual clinical application, physicians should be well-informed about Chinese herbal granules before prescribing; therefore, it is recommended to provide relevant training for clinicians to prevent repeated prescription modifications during medication use.

For certain crude herbal materials that are not suitable for formulation into traditional Chinese medicine granules, special processing methods may be employed: for example, precious medicinal materials can be directly pulverized and granulated; for materials containing volatile constituents, the volatile oils can be extracted first and then incorporated into the herbal extract prior to granulation; and for extracts of materials with high starch and mucilage content, techniques such as macroporous resin adsorption or membrane separation can be used during filtration. ^[46] Based on the absorption of traditional Chinese medicine theories, Japan has developed a formulation model comprising “compound granules plus single-herb granules.” Compound granules are formulated from time-honored classic prescriptions by renowned TCM masters, while single-herb granules refer to granular formulations prepared by extracting and concentrating a single herbal ingredient. ^[47] This formulation approach is more flexible and can, to a certain extent, mitigate situations where the selected varieties are not well suited.

Among the 160 publicly announced quality standards for traditional Chinese medicine granular formulations, some exhibit insufficient specificity, which hinders the accurate identification of their authenticity and quality. Examples include granules of raw Rehmannia root and processed Rehmannia root; white peony root, red peony root, and stir-fried white peony root; as well as kudzu root and pueraria root granules. When these ingredients are used in decoction pieces, their authenticity can be verified through macroscopic characteristics; however, once they are formulated into granules, such visual features are lost, rendering the existing standards non-specific and making it difficult to control the quality of the raw materials used in production. Consequently, it is challenging to detect and prevent fraudulent or improper ingredient substitution in these types of granular formulations. Therefore, it is recommended to establish specific quality standards for these easily confused granular formulations. Until such standards are in place, it is advisable not to permit their commercialization as finished products, so as to ensure the quality of traditional Chinese medicine granular formulations and promote the healthy development of the industry.