China boasts more than 9,000 varieties of proprietary Chinese medicines, with dosage forms evolving from traditional preparations such as pills, powders, pastes, and elixirs to modern formulations including tablets, granules, capsules, and injections, thereby covering a broad spectrum of clinical applications. In 2017, the implementation of the Law of the People’s Republic of China on Traditional Chinese Medicine ushered in another significant opportunity for the development of TCM. As proprietary Chinese medicines are used directly in clinical practice, their quality is directly linked to clinical efficacy and safety; moreover, their production involves multiple stages, including raw medicinal materials, excipients, manufacturing processes, and packaging, resulting in numerous factors that can affect their quality and safety. To better ensure the safe and effective use of medicines by the public, the national drug regulatory authorities have conducted drug evaluation sampling inspections for over a decade, aiming to comprehensively assess the overall quality level and status of marketed drugs. These evaluations combine standard testing with exploratory research: standard testing entails comprehensive, item-by-item examination of drugs by inspection agencies in accordance with national pharmaceutical standards, serving as the foundation for drug quality assessment and the legal basis for administrative oversight; exploratory research, by contrast, is typically problem-oriented and seeks to identify and mitigate quality risks, with particular focus on issues related to drug safety, authenticity, efficacy, and quality consistency, thereby facilitating in-depth analysis of drug quality and further enhancing the level of quality control. This paper compiles data from the 2019 national drug sampling inspection report on proprietary Chinese medicines, summarizes and systematically organizes the major problems identified through case studies, and puts forward relevant recommendations for advancing the improvement of proprietary Chinese medicine quality.

In 2019, the national drug sampling inspection covered 37 varieties of traditional Chinese patent medicines, roughly the same number as in previous years. Among these, 20 varieties—including Anshen Bunao Capsules, Compound Ganmaoling Granules, Kuanchong Aerosol, and Zuogui Pills—were listed in the National Essential Medicines List (2018 Edition). The predominant dosage form was capsules, with additional coverage of tablets, pills, granules, syrups, oral liquids, injections, and decoction pastes, encompassing both traditional and novel dosage forms. The sampled products were sourced from all 31 provinces, autonomous regions, and municipalities directly under the central government, totaling 4,825 batches. Sampling was primarily conducted at distribution outlets, with supplementary sampling also carried out at manufacturing facilities and medical institutions. Testing was performed in accordance with standards set forth in the Pharmacopoeia of the People’s Republic of China, Ministry of Health–issued standards, State Drug Administration–issued standards, and supplementary testing methods issued by the State Drug Administration.

1. Standard Inspection

Standard testing provides a preliminary assessment of the current quality status of marketed pharmaceutical products and serves as a comprehensive review of the applicability of existing standards. Based on the feasibility of each test item for quality control and the issues identified during standard implementation, the integrated findings from exploratory research are conducive to further enhancing the level of quality control stipulated by these standards. Examination of the results from routine sampling and testing of proprietary Chinese medicines conducted between 2015 and 2019 indicates generally good quality, with a compliance rate consistently above 97% (Figure 3). In 2019, the compliance rate reached 99.4%, with non-compliant items primarily concentrated in assay and fill-weight variation, followed by disintegration time limit, extraneous organic impurities, and microbial limit tests.

2. Exploratory Research

Due to their complex formulations and diverse constituents, it is often difficult for existing standards to achieve comprehensive quality control over all herbal ingredients in proprietary Chinese medicines. Whether herbal ingredients not covered by the standards actually exist and how their quality should be assessed remain areas requiring exploratory research beyond routine standard testing. Such exploratory studies are guided by potential quality issues in both raw medicinal materials and finished preparations, leveraging advanced analytical techniques and methodologies to conduct in-depth investigations into aspects such as safety, efficacy, authenticity, and uniformity of quality. These studies serve as a robust complement to conventional quality assessment, helping to further enhance and refine testing standards and thereby improve the overall quality of proprietary Chinese medicines.

(1) Analysis of Quality Issues in Pharmaceutical Raw Materials

As the foundational raw material for the production of proprietary Chinese medicines, the quality of medicinal materials directly affects product quality. In particular, given the complex origins of these materials, factors such as harvest season, place of origin, storage conditions, and processing methods can all have a significant impact on their quality. Quality issues with medicinal materials primarily include adulteration and contamination, multiple botanical sources, dyeing, and the presence of exogenous toxic and harmful residues.

① Adulteration and Mislabeling: In recent years, with the intensified implementation of drug quality inspection and sampling programs and the ongoing strengthening of regulatory oversight by drug administration authorities, instances of pure counterfeit products being fraudulently marketed have become relatively rare. However, due to resource shortages or price considerations, adulteration and cross-contamination involving expensive and high-value medicinal materials—as well as closely related species—continue to occur. A comprehensive analysis of the 2019 Quality Assessment Report on proprietary Chinese medicines reveals that adulteration primarily affects two such categories: deer antler and donkey-hide gelatin. Currently, the quality of deer antler on the market is highly variable, with inconsistent grading and frequent instances of substandard material being passed off as superior. Specifically, domesticated reindeer antler and elk antler are often used as substitutes for genuine deer antler or deliberately adulterated to mimic it, with reindeer antler (Rangifer tarandus) being the most common culprit. Using liquid chromatography–mass spectrometry and employing reindeer-specific peptide markers as analytical indicators, the competent authorities detected reindeer-derived components in certain batches of Dingkundan products, indicating a potential risk of using reindeer antler as a substitute for or adulterant in deer antler formulations. As for donkey-hide gelatin, due to tight supplies of donkey hide and soaring prices, several enterprises have been found in recent years to use cattle hide or horse hide as raw materials in production. Liquid chromatography–mass spectrometry analyses revealed that certain batches of Dingkundan contained equine-derived oligopeptides A, while some batches of Fukangbao Oral Liquid were found to contain ingredients derived from horse hide and pig hide, suggesting adulteration of donkey-hide gelatin. Adulteration and cross-contamination are particularly prevalent among closely related species that are difficult to distinguish, as well as among medicinal materials with similar external characteristics or names but originating from different sources—for example, Ophiopogon japonicus and Ophiopogon delavayi, Bupleurum chinense and Bupleurum tibeticum, and Lonicera japonica and Lonicera fulvotomentosa. Given the complexity of proprietary Chinese medicine formulas and their constituent ingredients, determining whether adulteration or cross-contamination has occurred typically requires precise and highly sensitive methods and technologies that exploit differences in characteristic marker compounds between authentic and counterfeit products. For instance, using liquid chromatography–mass spectrometry and leveraging Ophiopogon delavayi–specific marker saponins such as delavayiside B and short-stemmed Ophiopogon–specific marker saponins like short-stemmed saponin C, it was discovered that certain batches of Kunbao Wan, Qingre Bawei preparations, and Xia’er Yanbian Granules contained adulterated Ophiopogon delavayi, suggesting possible substitution of Ophiopogon delavayi for Ophiopogon japonicus or contamination of Ophiopogon japonicus with Ophiopogon delavayi. Similarly, by analyzing the characteristic bupleurum saponin K in Bupleurum tibeticum, it was found that certain batches of cold-and-cough-relief formulations and Ruxue Neixiao Liquid exhibited adulteration or cross-contamination with Bupleurum tibeticum. Furthermore, using saponin markers specific to Lonicera fulvotomentosa, it was detected that certain batches of Xia’er Yanbian Granules and Jinqi Hypoglycemic Preparations contained gray-felted honeysuckle saponin E, indicating cross-contamination of Lonicera japonica with Lonicera fulvotomentosa. In addition, it has been found that certain batches of Dahuang Chong Wan use non-pharmacopoeial species such as Phrynosoma or suspected stone leeches as substitutes for medicinal leeches; certain batches of Kuanchong Aerosol employ volatile oils extracted from non-standard Australian sandalwood and other sandalwood varieties instead of the officially listed sandalwood oil; some batches of Niuhuang Jiedu Pian exhibit carbonate reactions in both the product itself and the gypsum raw material, suggesting adulteration or falsification of the gypsum; and certain batches of Dahuang Chong Wan and Shenshuaining Tablets contain adulterated North China or Hetao rhubarb.

Adulteration primarily involves the inclusion of non-medicinal parts, affecting raw medicinal materials such as Ephedra, Honeysuckle, Scutellaria, and Eupolyphaga. In the formula for Wind-Cold Cold Granules, the standard specifies that the medicinal part of Ephedra is the dried herbaceous stem; however, inspection of the raw materials submitted by manufacturers reveals that some batches contain woody stems—non-medicinal parts. In the formula for Pediatric Pharyngeal-Flat Granules, Honeysuckle, certain batches from one manufacturer were found to be adulterated with non-medicinal stems and leaves. For Dahuang–Chongwan, the standard stipulates that the medicinal part of Scutellaria is the root; yet samples provided by one manufacturer were found to contain mixed rootstock. Regarding Eupolyphaga, the standard defines the medicinal part as the dried female insect, but some manufacturer-provided samples were found to include male insects and a significant amount of sand adhering to the insect bodies. For Licorice, the standard specifies the root and rhizome as the medicinal parts; nevertheless, some samples were found to contain aerial parts, and there was considerable variation in diameter among samples from different manufacturers. As for Fried Bitter Almonds, some manufacturer-provided samples were not peeled, containing impurities such as pebbles and almond shells, and even adulterated with peach kernels.

② Multiple origin issues: In the Hongjin Xiaojie series of prescriptions, black ants are not listed in the Pharmacopoeia of the People’s Republic of China (2015 edition); however, they are included in the Uygur Medicine Volume of the Pharmaceutical Standards of the Ministry of Health of the People’s Republic of China, as well as in the local medicinal material standards of Guangxi, Hunan, Yunnan, and Zhejiang provinces (autonomous regions). Specifically, the Uygur Medicine Volume of the Pharmaceutical Standards of the Ministry of Health lists the dried bodies of Formica fusca Linnaeus, an insect of the family Formicidae. The 1996 edition of the Guangxi Zhuang Autonomous Region Standard for Chinese Medicinal Materials and the 2009 edition of the Hunan Province Standard for Chinese Medicinal Materials both specify that the source is the dried bodies of Polyrhachis dives Smith, an ant species belonging to the family Formicidae. The 2017 edition of the Zhejiang Province Standard for Chinese Medicinal Materials designates the dried bodies of Polyrhachis vicina Roger, another ant species in the family Formicidae. As for woodlice, they are not listed in the Pharmacopoeia of the People’s Republic of China (2015 edition); yet they are included in the local medicinal material standards of Hunan, Hubei, Jilin, Shandong, Shanghai, and Jiangsu provinces (municipalities). The Jilin Province Pharmaceutical Standards stipulate that the source is the dried bodies of Porcellio sp., a woodlouse belonging to the family Porcellionidae. The 2002 edition of the Shandong Province Standard for Chinese Medicinal Materials specifies that the source is the dried bodies of Armadillidium vulgare (Latreille), a pill bug of the family Armadillidiidae. The 2012 edition of the same standard, however, defines the source as the whole dried body of either Armadillidium vulgare (Latreille), a common pill bug (also known as a woodlouse), or Porcellio scaber Latreille, a woodlouse of the family Porcellionidae. Other local medicinal material standards likewise list the whole dried body of Armadillidium vulgare (Latreille), a pill bug of the family Armadillidiidae, as the source.

③ Dyeing: Traditional Chinese medicine products that are dyed often use harmful synthetic dyes, posing serious health risks to consumers. Consequently, the national drug regulatory authorities have successively approved a series of supplementary testing methods as the technical basis for identifying such problematic products, in order to rigorously crack down on dyed counterfeit products. Over the past five years, illegal dyeing has been effectively curbed. In 2019, sampling inspections still revealed traces of synthetic dyes in a few product varieties: for example, 808 Scarlet was detected in certain batches of Dahuang Chongwan; Acid Red 73 was found in some batches of Qingre Bawei Wan; Auramine O was detected in certain batches of Kunbao Wan; and Lemon Yellow was found in individual batches of Yuxuebi Capsules and Yuxuebi Granules.

④ Residues of exogenous toxic and harmful substances: These residues primarily include heavy metals and harmful elements, mycotoxins, pesticide residues, and sulfur dioxide residues, all of which can directly compromise the safety of pharmaceutical products. According to quality analysis reports on proprietary Chinese medicines in recent years, some preparations exhibit elevated levels of heavy metals and harmful elements—namely lead, cadmium, arsenic, mercury, and copper—with particular concerns regarding lead, arsenic, and mercury. In 2019, Dahuang Chongwan and Kunbao Wan were found to contain excessive residues of heavy metals and harmful elements, notably lead and mercury, posing potential safety risks that must not be overlooked and warrant further stringent control measures.

Due to their carcinogenic, genotoxic, and teratogenic effects, mycotoxins pose significant health risks. In some traditional Chinese medicinal materials, fungal contamination may occur as a result of storage conditions and other factors, thereby drawing increasing attention to the issue of mycotoxin residues. Recent years have generally shown that risk control for mycotoxin residues, such as aflatoxins, has been effective; in 2019, no mycotoxin residues were detected in any of the proprietary Chinese medicine products tested. However, mold was observed in licorice samples provided by one manufacturer for Dahuang Chongwan pills, and mold growth was noted in Jin Guolan samples supplied by another manufacturer for Xia’er Yanbian granules, both of which warrant close attention. Furthermore, continued vigilance is needed regarding mycotoxin issues in formulations and preparations that contain herbs prone to aflatoxin contamination, such as Chenpi, Suanzaoren, and Tui Bie Chong.

According to quality inspection reports from recent years, the situation regarding pesticide residues has generally improved. In 2019, only a few batches of Zuogui Wan were found to contain relatively high levels of chlorothalonil residues. Going forward, continued vigilance is warranted with respect to pesticide residues in Chinese medicinal materials that are particularly susceptible to pest and disease infestation, as well as in proprietary Chinese medicines formulated using whole powdered medicinal materials.

Sulfur fumigation is a traditional processing method for Chinese medicinal materials, which can enhance appearance and prevent insect infestation and mold growth; however, improper or excessive fumigation can lead to excessive residual sulfur dioxide. Overall data from 2019 indicate that risk control for sulfur dioxide residues has been effective, with no instances of detected sulfur dioxide residues.

(2) Auxiliary Material Issues

In 2019, honey and preservatives were identified as excipient-related issues in certain proprietary Chinese medicine products. For Kunbao Pills, honey is used as an excipient; testing revealed that, in some batches from certain manufacturers, the amount of refined honey added during formulation may be insufficient, and in a few cases the sucrose content exceeded the permissible limit. In addition, liquid chromatography–mass spectrometry screening for 43 veterinary drugs detected several such substances in the refined honey excipient of some manufacturers; according to the Ministry of Agriculture and Rural Affairs’ “2019 Monitoring Plan for Veterinary Drug Residues in Animals and Animal Products,” all of these are prohibited from being detected in honey. Furthermore, testing of Ruhu Neixiao Liquid showed that certain manufacturers’ products exceeded the permitted levels of preservatives.

(3) Production Process-Related Issues

The selection of raw medicinal materials and the manufacturing process are critical control points for ensuring the quality of proprietary Chinese medicines. In recent years, routine drug inspections have revealed that, for certain medicinal ingredients not explicitly specified in the standards, there are instances of failure to use the prescribed ingredients, failure to adhere to the formulated quantities, use of substandard materials, or non-compliance with the approved manufacturing procedures. In 2019, abnormal large amounts of starch granules were detected in certain batches of Dahuang Chongwan pills; analysis suggests this may have resulted from insufficient viscosity of the honey excipient during pill-forming, leading to the addition of starch as a binder or disintegrant. Microscopic examination of Compound Chuanshenlian Tablets revealed microscopic characteristics of roadside green herb powder in some batches, indicating potential issues with extraction and ingredient addition that deviate from the established manufacturing process. For Cold Soft Capsules, the prescription includes Jingjie Sui and Peppermint; using five common characteristic constituents as analytical markers and applying GC–MS/MS screening, it was found that certain manufacturers’ products may have omitted these key ingredients. Testing of Compound Cold Granules for acetaminophen, caffeine, and chlorphenamine maleate showed that some manufacturers’ samples may exhibit instability in the addition of chemical pharmaceuticals. In Tripterygium Glycosides Tablets, ethanol and chloroform levels in certain batches from some manufacturers exceeded regulatory limits, indicating excessive residues of organic solvents. Due to variations in manufacturing processes and the quality of raw medicinal materials among different enterprises, significant differences exist in the compositional profile and active ingredient content across products from different manufacturers—for example, in Wind-Cold Cold Granules, Kunbao Pills, and Qingre Bawei Capsules. Furthermore, certain products have been found to contain added or contaminated chemical drugs: for instance, some batches of Shuanghuang Anti-inflammatory Tablets tested positive for acetaminophen, while some batches of Anti-inflammatory Analgesic Ointment may have failed to add belladonna fluid extract according to the prescribed manufacturing procedure, potentially resulting in the intentional addition of atropine sulfate.

(4) Issues with Packaging and Packaging Materials

In recent years, as pharmaceutical sampling and inspection have been continuously carried out, the impact of packaging materials on the quality of dosage forms has gradually attracted attention. In 2019, an inspection of the packaging materials for Niuhuang Jiedu Pian revealed that solvent residues—ethyl acetate in some medicinal composite films and, in others, toluene—exceeded the limits specified in the 2015 National Standards for Pharmaceutical Packaging Materials. Consequently, batches from certain manufacturers were found to be non-compliant, underscoring the need to pay close attention to the quality and safety of packaging materials. Furthermore, an inspection of the packaging materials for Yiqi Fumai Injection disclosed the presence of 6-tert-butyl-4-methylphenol (BHT) and p-octylphenol (PTOP) in some samples, indicating that PTOP from the rubber stoppers had partially migrated into the drug product. Based on the BHT usage limit established in the U.S. FDA’s Chemical Substances Toxicity Database, the PTOP levels in the finished formulation were determined to be within the acceptable range.