Hye-In Jeong ¹, Kyeong-Han Kim ¹, Jae-Hee Won ², Gi-Un Sung ², Ji-Won Kim ³, Ji-eun Han ³, Angela Dong-Min Sung ³, Eun-Jung Park ⁴, Soo-Hyun Sung ^{3 *}

This study was conducted to development of hazardous materials management standards for the decoction type of personalized herbal medicines (PHMs).

This study was conducted in two stages. We searched documents about criteria to use words such as 'Herb', 'Herbal medicine', and 'Botanical Drug’ and summarized the results. We organized the committee consisted of seven experts, and held two meetings to reach an agreement on hazardous management standards of the decoction type of PHMs.

The seven documents were presented in the literature review and six items related to hazardous management standards of decoction were identified. The second expert meeting brought that a total of six items, including heavy metal, pesticide residues, sulfur dioxide, benzopyrene, mycotoxin, and micro-organism limits, were selected for safety management of decoction type of PHMs. Also, the criteria and test methods for each standard were suggested for monitoring the decoction type of PHMs.

The study suggested hazardous material management standards and criteria for the decoction types of PHMs. In the future, it would be necessary to conduct a pilot test to ensure the validity and credibility of the safety management standard and criteria. Furthermore, the government level safety management system should be introduced to verify the safety of decoction medicines.

hazardous materials management standard, personalized herbal medicine, decoction, Korean herbal medicine

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Herbal medicines (HMs) are defined as herbal preparations prepared by mixing two or more herbs extracted from animals, plants, or minerals [1, 2]. HMs have been in use for thousands of years across the world and recognized as to be safe to use [3]. While the HMs are considered to be safer compared to conventional medicine products, there have been cases of drug-induced liver injuries (DILI) and other adverse events with HMs [4]. As a result, the issue of safety of HMs is gaining more and more attention [5]. While some noted that the quality of the preceding studies on the safety issues of HMs is not of a satisfactory level and that the methods of the study had significant issues [6], now there is a wide-spread consensus that it is necessary to ensure the safety of HMs beyond a certain level, since they are now acknowledged as a type of medicine products. The manufactured herbal medicines (MHMs) that are recognized as medicine products are generally regulated by the Food and Drug Administration (FDA) [7]. These products are now required to be approved by the authorities and must be prepared in GMP-certified facilities [7]. In the case of the United States (US), new medicines are approved after going through a rigorous process of clinical trials in three stages by the FDA [8]. In the case of South Korea, the products which are mentioned in traditional texts of HMs are exempt from clinical trials and the requirement to submit toxicology test reports [7]. However, they are still required to prepare good manufacture practice (GMP)-certified facilities that are approved by the Korea Ministry of Food and Drug Safety (MFDS) [7]. In some countries where traditional medicine (TM) is being practiced (such as South Korea, China, and Taiwan, etc.), the patients are prescribed with personalized herbal medicines (PHMs) which are prepared and concocted at the TM clinics themselves [9]. A PHM is a personalized preparation that is prescribed based on the patient diagnosis at TM clinics, unlike the MHMs that are manufactured by a pharmaceutical company [9, 10]. Of the PHMs in use in South Korea, decoction formulations account for 54.8%, making them the most frequently used of all formulations in the country [11]. Also, the herbs to be used in a PHM must be of medical grades that conform with the hazardous material standards (e.g., heavy metals, pesticides, aflatoxins, sulfur dioxide, and benzopyrene) as designated by the Korea MFDS [12]. However, there can be safety concerns in the management and preparation of the PHMs, while non-medicinal herbs can also be used in preparing decoctions. As a result, there are difficulties in ensuring the safety of the final PHMs [13]. As for the previous studies, there have not been any studies on the safety management standards that could be applied to decoction type of PHMs in general except for some cases [14, 15] where the safety and efficacy were studied in individual prescriptions of decoction medicines. Traditionally, HMs have been used safely. Therefore, the safety issue of this type of medicine has not received much attention. However, the level of social demand for the safety of foods and medicines by the general public is increasing. It is now time to verify the safety of decoction medicines that are most frequently administered among HMs, which is a type of TMs. In this study, the researchers conducted literature reviews and interviews with experts, to establish the safety management standard for the hazardous materials test items, test criteria, and test methods for decoction type of PHMs. The purpose of this study is to establish such a safety management standard for decoctions and generate the basic data that could be used to monitor hazardous materials in decoctions.

To secure the safety of HMs, we conducted this study in the following order to develop the hazardous materials management standard. Firstly, we gathered the certified study reports that are related to herbs, HMs, HM products, botanical drugs, and botanical medicine extracts and summarized their results. This was followed by two meetings with experts based on the findings in the previous stage to develop the management standard.

In other to survey the official management standards related to HMs in South Korea and other countries, we searched the related documents on the safety standards of “herbs,” “herbal medicines,” “herbal medicinal products,” “botanical medicines,” and “botanical medicinal products, etc.” using the official government website of the MFDS under the Ministry of Health of South Korea. For gathering information from overseas sources, we also searched the websites of WHO, CODEX, and other official websites of the United States, Japan, China, and EU using keywords such as “herb,” “herbal medicine,” “botanical drug,” “food,” and “natural product,” etc. The terminology for natural-derived medicine is divided into four categories in the WHO guideline [16, 17]; (1) Herbs (crude plant material), (2) Herbal materials (whole plants or parts of medicinal plants), (3) Herbal preparations (the basis for finished herbal products), (4) Finished herbal products or herbal medicinal products. The results of the literature search were classified and organized according to the material type (herb and herbal material) and final product type (herbal preparation and finished herbal product).

To select the experts who will provide their opinions on the safety management standards for HMs, we contacted the experts who were working for the government agencies related to food or medicines, the professors who were participating in research projects related to foods or medicines at universities, or the experts in the private sectors providing consulting or working in the related private sectors concerning safety management standards. As for the government agencies, one expert from Korea Institute for Health and Social Affairs (KIHSA) and another from National Development Institute for Korean Medicine (NIKOM) participated in the meeting, while one faculty member of the school of Food Science and Biotechnology of Kyungpook National University joined the meeting to represent the academic sector. Lastly, as for the private sector, one representative expert from each of Daegu University Hazard Analysis and Critical Control Point (HACCP) Education Center, Korea Pharmaceutical Test & Research Institute, Food Hygiene Safety Institute, and KnA Consulting participated in the meeting.

The participants thoroughly reviewed the management items related to the safety of the decoction type of PHMs in South Korea and other countries before the meeting. The meeting was held as the participants were allowed to present any opinion they thought to be relevant. The meeting went on for two hours, and all of the participants were allowed to present their opinions. Afterward, the test items that are deemed to be essential for securing the safety of decoction medicines were identified based on the items presented by the experts. As a principle, the conclusion of the meeting was to be drawn with an unanimous agreement. For any items with disagreement, the discussions were to continue until an agreement was finally reached. With this, the items that are deemed essential for the decoction type of PHMs were identified among the items that were presented by the experts.

Concerning the items identified during the first meeting, the researchers summarized and presented the criteria and test methods suggested by the participating experts. All of the experts were advised to review the criteria and test methods thoroughly before the meeting. During the two-hour meeting, all of the participating experts were liberally allowed to give any opinion they deemed relevant regarding the criteria and test methods. Afterward, a step of finalizing the consensus on the criteria and test methods was taken. For any disagreements on the criteria or test methods, the participants continued discussing until an agreement was reached. With this, the criteria and test methods for each item for securing the safety of the decoction type of PHMs were decided.

The three documents that were identified through the search of South Korean databases were Korean pharmacopeia [1], the Korean herbal pharmacopeia [18], and the ‘quality control guideline for herbal or botanical medicine extracts’ [19]. The five documents identified through the search of overseas databases were the ‘guidelines for the regulation of herbal medicines in the South-East Asia region of world health organization (WHO)’ [16, 17], pharmacopoeia of the people’s Republic of China [20], Japanese pharmacopoeia [21], Japanese standards for non-pharmacopeial crude drugs [22], European pharmacopoeia [23], and the US botanical drugs development guidance for industry [24]. The literature review of the safety management standards related to the decoction type of PHMs resulted in the identification of six items, which included heavy metal, pesticide residue, sulfur dioxide, benzopyrene, mycotoxin, micro-organism limits (Table 1)

Based on the two suggestions below, it has been agreed to prepare standards for the management of hazardous substances based on ‘the quality control guideline for herbal or botanical medicine extracts’ . (1) The formula that was the most similar to decoctions was the herbal or botanical medicine extracts. Therefore, the ‘quality control guideline for herbal or botanical medicine extracts’ , which is the only standard with a guideline on herbal extracts, shall serve as the basis. (2) Since the purpose of this study is to suggest the management standard for the decoctions to be used in South Korea, the medical product management standard by Korean MFDS will be followed. As a result, five items of heavy metal, pesticide residues, sulfur dioxide, benzopyrene, micro-organism limits, and pH were identified. According to the WHO guideline [16, 17] and the European pharmacopoeia [23], mycotoxin was added to the list, as well. As a result of the 1st expert meeting, a total of six hazardous material management standard items were identified. The items of test and their rationale were as shown in (Table 2)

During the 2nd expert meeting, the test criteria and test methods for the pre-selected six standards identified during the 1st meeting were decided upon (Table 3)) As for the six items of heavy metal, pesticide residues, sulfur dioxide, benzopyrene, mycotoxin, and micro-organism limit, the standard for a formulation in Korean pharmacopeia that was similar to decoctions (e.g. herbal or botanical medicine extracts) were used as the reference. Since the WHO guideline [16, 17] and the ‘quality control guideline for herbal or botanical medicine extracts’ [19] were not legally binding, it was agreed that the test criteria and test methods were to be developed based on the legally binding standards of Korea pharmacopeia [1] and the Korean herbal pharmacopoeia [18].

HMs have been prescribed based on thousands of years of experience and the original pharmacological theories in TM. The decoction type of PHM, which is a type of extract prepared through the mixing and dispensing processes of herbs, has been most widely used throughout history and is still the most preferred formulations in China, South Korea, and Japan today [9]. While decoctions have been used for many years with a proven record of safety, the demand for the criteria for the efficacy and safety of decoctions and their regulations is increasing within the society [25, 26]. The TKM clinics of South Korea are required to use the medicinal herbs that conform to the hazardous material test criteria set by Korea MFDS in preparing decoctions. However, it is possible to use herbs that are not tested if these herbs are not included in the list of 601 registered herbs in Korean pharmacopoeia and the Korean herbal pharmacopoeia [1, 18]. Also, of these 601 medicinal herbs, there are only two items that have the criteria on benzopyrene, while 20 are regulated by the criteria for mycotoxin [1, 18]. As the test items for these medicinal herbs vary widely, the safety of the final decoction products has been questioned for years. For this purpose, the researchers conducted this study to secure the safety of the decoction type of PHMs, through the literature review and a process of consensus among experts. As for the criteria for hazardous materials for the medicinal herbs used in South Korea, Korean pharmacopoeia and the Korean herbal pharmacopoeia requires tests on heavy metal, pesticide residues, sulfur dioxide, mycotoxin, and benzopyrene, depending on the characteristics of each item [1, 18]. And, as for extracts, the ‘quality control guideline for herbal or botanical medicine extracts’ has been used as the basis of regulating the quality of extracts that are used as the raw material for herbal or botanical medicines [19]. As for the extract of raw materials, the required test items are, respectively, heavy metal, pesticide residues, sulfur dioxide, mycotoxin, and other remaining contaminants, while the extracts are to be tested for heavy metal, pesticide residues, solvent residue, and other remaining contaminants [19]. According to the Pharmaceutical Act of South Korea, different purity test requirements apply as outlined in the Korean pharmacopeia and the Korean herbal pharmacopeia [1, 18]. The micro-organism limit tests, in the meantime, cover the total aerobic bacteria, total fungal count, and specific micro-organisms (E. coli, salmonella, Pseudomonas aeroginosa, and Staphylococcus aureus), for the herbal or botanical medicine extracts [19]. As for heavy metals, Korean pharmacopoeia requires that the total heavy metal is tested or that lead, mercury, arsenic, and cadmium are tested individually [1]. International pharmacopeia or guidelines were also regulating chromium and copper. The heavy metals that were being regulated varied depending on the country. However, all countries were regulating arsenic and lead, while only China had the standard for the total heavy metal [20]. The heavy metal standards were in place in all countries for finished herbal products. And, only China and South Korea had heavy metal standards for herbal materials. Only South Korea had the standard for heavy metal in herbal or botanical medicine extracts. The literature review on domestic and overseas documents showed that the standards for pesticide residues covered dichloro diphenyl trichloroethane (DDT), benzene hexachloride (BHC), aldrin, dieldrin, and endrin. Europe and the US were regulating aldrin, dieldrin, and endrin, while Japan was regulating two pesticide residues. South Korea was regulating all five pesticide residues. As for sulfur dioxide, only South Korea had the standard to regulate chemicals as hazardous materials. HM materials are highly subject to the influence of the weather during the drying process. For this reason, it is a common practice to dry such materials indoors using coal as the fuel, instead of drying them outdoors under the sun. While this indoor drying process may be cheaper, it has been known to compromise health [27]. Therefore, it is necessary to set the testing criteria for monitoring sulfur dioxide. According to Korea pharmacopeia [1], only Rehmanniae Radix Preparata (熟地黃) and Rehmanniae Radi (地黃) had the standards for testing benzopyrene. A decoction type of PHMs is a type of extraction prepared by mixing and processing herbal materials. However, in TM, the herbal materials go through additional processes, such as frying or burning, to maximize the efficacy in treatment [28]. During this additional processing, benzopyrene may be generated. Therefore, it is necessary to regulate this substance by setting a standard for it. The standards on mycotoxin are based on aflatoxin, which is known to be of the highest toxicity. When compared based on the requirements on total aflatoxin, South Korea, Europe, and Japan had a stricter standard compared to the US. However, the detailed items of these standards varied among countries. As for South Korea, the requirement for all botanical medicines was total aflatoxin 15 ppb or less and aflatoxin B1 10 ppb or less. For other countries, the standards varied depending on the types of products. The range of total aflatoxin was between 10 and 20 ppb. In South Korea, the herbal or botanical medicine extracts were being regulated for the contamination by micro-organisms that were not regulated for herbal materials using micro-organism limit tests. The standards covered the total aerobic bacteria, total fungi, and specific micro-organisms (E. coli, salmonella, pseudomonas aeroginosa, and staphylococcus aureus). China had the standards for herbal extracts covering total aerobic bacteria and total fungi. The specific bacteria were not being regulated. The WHO guideline contains somewhat relaxed criteria for the hot water extracts of botanical drugs covering total aerobic bacteria and total fungi compared to the requirements in effect in South Korea. However, the WHO was recommending the regulation of clostridium and shigella, which were not being regulated in South Korea. The United States and Europe had the standard for total aerobic bacteria and total fungi in raw materials and finished products that were plant-based. Europe also had an additional set of criteria for specific micro-organisms (E. coli and salmonella). A total of seven documents were identified through the search of international search. The result of the literature review showed that only South Korea had quality management standards for herbal or botanical medicine extracts as a medicine product. The expert meeting brought that a total of six items, which were, respectively, heavy metal, pesticide residues, sulfur dioxide, benzopyrene, mycotoxin, and micro-organism limits, were identified as the hazardous materials in a decoction type of PHMs. However, while the said guideline also contained the management criteria for the solvent for extracting, these were dismissed as deemed irrelevant to decoction medicines, which are extracted using hot water. Finally, the six items below are finalized as the hazardous material management standard for decoctions; (1) individual heavy metals (lead, arsenic, mercury, and cadmium), (2) pesticide residues (five pesticides of organic chlorine types), (3) sulfur dioxide, (4) mycotoxin (total aflatoxin and aflatoxin B1), (5) benzopyrene, (6) micro-organisms (total aerobic bacteria, total fungi, E. coli, salmonella, pseudomonas aeroginosa, and staphylococcus aureus). The strength of this review is that it is the first study that provided the hazardous material test items and criteria for the decoction types of PHMs and can be used as the basis for introducing a safety management system for the decoction types of PHMs by the government in the future. The limitations of this review are as follows; First, this study is found wanting in terms of the credibility of the experts who selected the test items and criteria (there was no sampling) or their representativeness (only a handful of experts). Second, the literature review was limited to the data that were in English or Korean language. Therefore, the databases from the countries which have been using traditional decoction medicines were not included in the study. Finally, no pilot tests to apply the criteria set in this study were conducted. In the future, it would be necessary to conduct a pilot test to ensure the validity and credibility of the test items, criteria, and methods, as well as their field relevance. Especially, a sufficient number of decoction monitoring, public hearings and gathering of the opinions from the field would have to be conducted. Finally, it would be necessary for the government to introduce the decoction safety management program so that the people of the country may use proven decoction medicines.

In this study, the researchers developed a set of safety management standards for the decoction type of PHMs, which included individual heavy metals, pesticide residues, sulfur dioxide, mycotoxin, benzopyrene, and micro-organisms. In the future, it would be necessary to verify the field relevance and applicability of the test items, criteria, and methods by monitoring the decoction medicines prescribed by actual TM clinics.

The authors declare that there are no conflicts of interest regarding the publication of this paper.

This study was supported by a grant from the Project of National Development Institute of Korean Medicine, Accreditation of External Herbal Dispensaries of Traditional Korean Medicine Clinics, funded by the Korea Ministry of Health.

1. Korea Ministry of Food and Drug Safety. Korean Pharmacopoeia, 11th edition. Korea Ministry of Food and Drug Safety (Osong); 2017.
2. World Health Organization. General guidelines for methodologies on research and evaluation of traditional medicine. World Health Organization (Geneva); 2000.
3. Pan SY, Litscher G, Gao SH, Zhou SF, Yu ZL, Chen HQ, et al. Historical perspective of traditional indigenous medical practices: the current renaissance and conservation of herbal resources. Evid Based Complement Alternat Med. 2014;2014:1-20.
4. Pittler MH, Ernst E. Systematic review: hepatotoxic events associated with herbal medicinal products. Aliment Pharmacol Ther. 2003;18(5):451-71.
5. Cheon CH, Park JS, Park SJ, Kweon KT, Shin YC, Ko SG. Necessity of adverse event reporting system through the trend of internet news about safety of herbal medicine. Kor J Oriental Preventive Medical Society. 2011;15(2):131-43.
6. Yun YJ, Shin BC, Lee MS, Cho SI, Park JH, Lee HJ. Systematic review of the cause of drug-Induced liver injuries in Korean literature. J Korean Oriental Med. 2009;30(2):30-45.
7. Choi DW, Kim JH, Cho SY, Kim DH, Chang SY. Regulation and quality control of herbal drugs in Korea. Toxicology. 2002;181-182:581-6.
8. Ciociola AA, Cohen LB, Kulkarni P. How drugs are developed and approved by the FDA: Current Process and Future Directions. Am J Gastroenterol. 2014;109(5):620-3.
9. Pusan National University. A study on establishment of foundation for strengthening the health insurance coverage of herbal medicine (decoction). National Health Insurance Service (Wonju); 2018.
10. Ryu JY, Park JY, Sung ADM, Sung SH. The utilization of traditional herbal medicine for treatment in traditional Korean medicine clinics. IntechOpen (London); 2019.
11. Korea Ministry of Health and Welfare, National Development Institute of Korean Medicine, Gallup Korea. 2017 years national survey for usage and consumption of traditional herbal medicine. National Development Institute of Korean Medicine (Seoul); 2018.
12. Korea Ministry of Food and Drug Safety. 2016 Ministry of Food and Drug Safety white paper. Ministry of Food and Drug Safety (Osong); 2015.
13. Association of Traditional Korean Medicine. Development and implementation of the safety management strategies for non-medicinal herbs. National Development Institute of Korean Medicine (Gyeongsan); 2019.
14. Kim TK, Jung WS, Park SW, Cho KW, Kim YB. Comparison of efficacy and safety between Chunghyul-dan (HH-333) and Atorvastatin (Lipitor). Korean J Orient Int Med. 2003;24(4):837-45.
15. Kim YM, Choi HY, Kim JD. Studies on oral toxicity of Eumcheonyijin-tang in rats. J Korean Oriental Med. 2000;21(3):199-208.
16. World Health Organization. Guidelines for the regulation of herbal medicines in the South-East Asia region: developed at the regional workshop on the regulation of herbal medicines. Regional office for South East Asia (New Delhi); 2003.
17. World Health Organization. National policy on traditional medicine and regulation of herbal medicines, Report of a WHO global survey. World Health Organization (Geneva); 2005.
18. Korea Ministry of Food and Drug Safety. Korean Herbal Pharmacopoeia, 4th edition. Korea Ministry of Food and Drug Safety (Osong); 2013.
19. Korea Ministry of Food and Drug Safety. A quality control guideline for herbal or botanical medicine extracts. Korea Ministry of Food and Drug Safety (Osong); 2015.
20. Pharmacopoeia Committee of China Ministry of Health. Pharmacopoeia of the People’s Republic of China, 16 edition. China Medical Science Press (Beijing); 2015.
21. Japan Ministry of Health, Labor and Welfare. Japanese Pharmacopoeia, 16th edition. Ministry of Health, Labor and Welfare (Tokyo); 2016.
22. Japan Ministry of Health, Labor and Welfare. Japanese standards for non-pharmacopoeial crude drugs. Ministry of Health, Labor and Welfare (Tokyo); 2015.
23. Council of Europe. European Pharmacopoeia, 18th edition. Council of Europe (Strasbourg); 2015.
24. US Center for Drug Evaluation and Research. Botanical Drug Development Guidance for Industry. US Center for Drug Evaluation and Research (Silver Spring); 2016.
25. Jang IS, Yang CS, Lee SD, Han CH. A review of herbal medicinal products associated with toxic events in Korea. J Korean Oriental Med. 2007;28(1):1-10.
26. Man SC, Durairajan SSK, Kum WF, Lu JH, Huang JD, Cheng CF, et al. Systematic review on the efficacy and safety of herbal medicines for Alzheimer's disease. Journal of Alzheimer's Disease. 2008;14(2):209-23.
27. Seoul National University. Risk management of sulfur dioxide residue in herbal medicine. Korea Ministry of Food and Drug Safety (Osong); 2004.
28. Cho YK, Kim JS, Yoon SH, Ryu BH, Ryu KW. The effects of Strychni Ignatii Semen on toxicity levels and gastrointestinal tract. Korean J Orient Int Med. 2002:23(1):107-16.