Good Agricultural Practice for the Quality Assurance of Traditional...
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Chapter 5
Good Agricultural Practice for the Quality Assurance of Traditional Chinese Herbs Used in Dietary Supplements 1
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Frank S. C. Lee , Xiaoru Wang , and Lei Li
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Key Lab of Analytical Technology Development and the Standardization of Chinese Medicines, QingDao, China First Institute of Oceanography, State Oceanic Administration, QingDao, China 2
The quality control and standardization of traditional Chinese herbs (TCHs) commonly used in functional or therapeutic food products is a challenging task. The guidelines of Good Agricultural Practice (GAP) and Good Manufacturing Practice (GMP) are designed to standardize respectively the different operations involved. Although GMP guidelines have been well established in the manufacturing processes, the operational specifics of GAP guidelines in the agricultural production of herbal plants are still in the developmental stage. This contribution reviews the current status of GAP development in China.
Traditional Chinese herbs (TCHs) are gaining increasing popularity worldwide in the development of dietary supplements and pharmaceutical products. The quality control and standardization of TCHs is a challenging task because of (1) the large variations in the sources and properties of raw herbs, and (2) the wide diversity in process types and manufacturing conditions leading to the products. The Good Agricultural Practice (GAP) and Good Manufacturing 34
© 2008 American Chemical Society
In Functional Food and Health; Shibamoto, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2008.
35 Practice (GMP) guidelines are designed to address, respectively, the quality assurance issues involved in the above two areas. Although GMP guidelines have been well established in manufacturing processes, the scope and operational specifics of GAP guidelines in the agricultural production of herbal plants are still in the developmental stages. In recent years, the development of GAP-based farming in many countries including China is accelerating; and the adoption of GAP as an international standard for the marketing and trading of food or herbal products is gaining momentum in international communities.
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GAP and the "5P" Quality Assurance System The "5Ps" is the most widely accepted quality assurance system for the development and production of consumer products intended for therapeutic applications. These guidelines cover the entire lifecycle of a product from initial raw material supply, through the manufacturing processes, to the final stage of consumer consumption. Table I outlines the objectives and major activities of these guidelines. Of the 5Ps, Good Laboratory Practice (GLP) and Good Clinical Laboratory Practice (GcLP) safeguard the quality of laboratory and clinical testing. They are the gatekeeper at the front end of the product lifecycle during its research and developmental stages. At the other end is Good Supply Practice (GSP), which deals with product surveillance activities at the final stage. In between are Good Agricultural Practice (GAP) and Good Manufacturing Practice (GMP), which constitute the heart of the 5P system focusing on quality and safety issues during the manufacturing processes. For the manufacturing of synthetic chemicals with well defined properties, GMP is sufficient to safeguard the quality involved in the entire production chain from raw materials to the final products. For the agricultural production of natural product such as herbal plants, however, a different set of problems exists. Aside from internal factors such as the intrinsic properties of the herbs, the quality of the TCHs are affected also by external factors including the genetic variations of the plant species, environmental conditions and climate fluctuation. These external variables are hard to control because they vary from grower to grower, from crop to crop, and with the geographic locations of the production site. Thus, stability of the produce is more difficult to monitor and control, and benchmarking standards are more difficult to establish compared to synthetic drugs. It is against this background that GAP has been evolved. In recent years, the adoption of GAP as a quality standard for agricultural or food products is gaining increasing attention both in China and internationally (1-6). Although the overall 5Ps were designed originally for drug manufacturing, the general principle of these quality guidelines should be applicable to dietary supplement or health food products as well. By implementing quality standards from the farm to the factory, TCHs would be better prepared to meet the needs of
In Functional Food and Health; Shibamoto, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2008.
In Functional Food and Health; Shibamoto, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2008.
GAP-Good Agriculture Practice
Examination, Confirmation and quantification of active components in herbs.
Ensure the sustainable production of contamination-free herbs with controllable bioactivity and yield
Objectives
Acquire clinical data to quantify dose/response relationship
clinical trials of pre-marketing products
clinical testing for product registration
GCP-Good Clinical Practice
Ensure the quality, efficacy and safety of manufacturing products
Quality control of raw materials, in-plant process and final products
In-plant Product formulation and manufacturing
GMP-Good Manufacturing Practice
Enforcement of regulatory activities for commercial OTC or prescription products
Implementation of inspection, monitoring and reporting activities for commercial products
Surveillance of Finished products
GSP-Good sales(Supply) Practice
Priority Chinese medicinal herbs selected for 5Ps by Chinese Ministry of Science and Tech no logy (2000) include: Salvia Miltiorrhiza, Radix Astragoli, Radix Ophiopogonies, Bullbus Fritillariae Cirrhosea, Flos Chrysanthemi, Radix Glycyrrhizae, Radix Ginseng, Fructus Lycii, Herba Ephedrae, Radix Coicis, Radix Rehmanniae, Rhizoma Ligustici Chuanxiong, Radix Aconiti Praeparata, Rhizoma Gastrodiae, Cornu Cervi Pantotrichum, Radix Achyranthis Bidentatae, Rhizoma Pinelliae and Tuber Dioscoreae.
Bioassay, Chemical analysis and animal tests
Species Authentication, plant cultivation, and the processing of crude herbs
Laboratory biochemical assay and animal tests
GLP—Good Laboratory Practice
Major activities
Product preparation of raw development herbs or crude drugs Stage
QC/QA Guidelines
Table I. "5 Ps" Quality Assurance System for the Production of Medicinal Herbal Products
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37 increasingly discerning domestic consumers and international demand for botanicals. Table II outlines the major GAP-related regulatory activities took place in different countries in recent years. In the eighties and early nineties, GLP, GcLP and GMP guidelines have all been officially promulgated by SFDA in China (State Food and Drug Administration of China) (6). Meanwhile, the concept of GAP has evolved in Europe, Japan and North America during this period. In 1998, the U.S. Food and Drug Administration (USFDA) published regulations to ensure the microbial safety of fresh produce by defining the GAP and GMP guidelines that producers and handlers should follow (7). In year 2000, EAEM (European Agency for the Evaluation of Medicinal Products) announced official GAP guidelines for botanical dmgs and herbal products (8). Between year 2000 to 2002, scientists and governmental officials in China carried out extensive studies on the feasibility of implementing GAP in China (9-11). In June 2002, GAP for Chinese Crude Drugs (Interim) was passed into effect by SFDA (6). WHO (World Health Organization) also published guidelines on good agricultural and collection practices (GACP) for medicinal plants in 2003 (12).
GAP Certification System in China The GAP guidelines of China addresses quality and safety requirements for TCHs in areas including: (i) ecological and environment conditions of the production site; (ii) germ-plasma and propagation material; (iii) management for cultivation of medicinal plants; (iv) packaging, transportation and storage; and (v) managerial and technical aspects of quality management. The official GAP program for Chinese medicinal herbs started its trial period in ChinafromJune 1, 2002 (9). The GAP certificate, which is usually awarded to a private enterprise, is valid for 5 years. The follow-up monitoring activities are carried out by the expert teams organized by SFDA. In addition, provincial, city and regional FDA offices of China provide the needed assistance to handle the application and monitoring activities at the provincial or local levels. In the original regulation set out by SFDA in 1998, all manufacturers must comply with the Good Manufacturing Practice by April, 2004; while farms producing raw ingredients have until 2007 to meet the guidelines specified in Good Agricultural Practices. Work on GAP encompasses a wide range of topics in different disciplines. The type of work and major activities are described in ref 9, and also outlined in Table III. More than simply the implementation of a quality assurance system on existing practices, the current GAP program in China also calls or the application and development of updated technology for the modernization of traditional herb farming practices. On the other hand, the developed techniques have to be userfriendlyenough that they can be practiced by farmers on a routine basis. All the methods developed thus have to be standardized and documented in Standard Operational Procedures (SOPs); and personnel trainings are necessary to facilitate technology transfer.
In Functional Food and Health; Shibamoto, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2008.
38 Table II.
Regulatory Milestones Pertaining to GAP Development for Herbal Products
Regulatory initiated
Agency
Regulation/'Guidelines
Promulgated
(Year
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Published)
M i n i s t r y of Health of China (1982)
GMP Guidelines
M i n i s t r y of Health of China (1988)
GLP g u i d e l i n e s - R e g u l a t i o n s on Experimental Animals
SFDA (State Food and Drug Administration) of China [1932)
Regulations
US FDA (1998)
g u i d e l i n e s f o r the m i c r o b i a l s a f e t y of f r e s h produce d e f i n i n g the Good A g r i c u l t u r a l P r a c t i c e s (GAP) and Good Manufacturing P r a c t i c e s (GMP) g u i d e l i n e s that producers and handlers should f o l l o w .
SFDA of China (2000)
A r t i c l e (2000) 157 published emphasizing the importance of well managed TCM ( T r a d i t i o n a l Chinese Medicines) herb Farms, and the requirements f o r F i n g e r p r i n t i n g of CM I n j e c t i o n f l u i d products.
Secretary of States of China (2000)
published r e g u l a t i o n s p r o h i b i t i n g the c o l l e c t i o n and s a l e s of w i l d l i c o r i c e , ephedra s i n i c a s t a p t
European Agency f o r the E v a l u a t i o n of Medicinal Products (2000)
GAP g u i d e l i n e s f o r b o t a n i c a l drugs and herbal products
SFDA (2002)
Issuance of GAP r e g u l a t i o n f o r Medicinal Plants and Animals
SFDA (2003)
GAP c e r t i f i c a t i o n system s t a r t s operation-certificate valid for 5 years; s t a t u s followed and monitored by SFDA
XJHO (2003)
published g u i d e l i n e s on good a g r i c u l t u r a l and c o l l e c t i o n practices (GACP) f o r m e d i c i n a l plants i n 2D03 (Uorld Health Organization, 2003)
approval
on r e g i s t r a t i o n and
of New CM drugs (GCP, GLP)
In Functional Food and Health; Shibamoto, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2008.
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Table III. Scope of GAP Work Area of work
Major Activities
Objectives
Environmental monitoring and impact assessment
Collection and analysis of environmental quality parameters for air, water and soil; the development and application of environmental friendly practices for pest prevention; environmental impact assessment of the production site.
Ensure the meeting of environmental quality standards, the absence of potential sources of contaminants including natural or man-made toxins^ollutants, heavy metals, and pesticides/herbicides residues, and the sustainable development of the production site and the surrounding area.
Selection, identification and
Seed selection and preservation; Plant species identification through DNA fingerprinting and chemical compositional fingerprinting
Establish the authenticity and correct genetic identity ofthe plant species
Plantation, cultivation and harvesting technology
Standardized production based on modem science in combination with traditional wisdom; pest prevention; specified fertilizers; best harvest time determination.
Establish standardized farming practice to grow quality and safe produce
Processing, storage and transportation
harmonize traditional method with modem science for the field and factory processing of raw p lant, and the storage and transport of crude products after primary treatment
Establish modernized and standardized field and factory processing technology for the preparation of contaminationfree crude herbal products
Management, training and documentation
Establish SOPs (Standard Operation Procedures) for the technical operations including site selection, environmental monitoring, cultivation practices, quality control and primary processing; Establish management systems including product registration, personnel training; SOP documentation and updating, and facility maintenance
Establish standardized technical manuals, managerial systems quality control procedures and qualified personnel for GAP operation.
authentication of plant species
In Functional Food and Health; Shibamoto, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2008.
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40 In the application of GAP certificate, the species should have completed at least one growth cycle. Documented information should include site selection and selection criteria, historical data, scale of production, and environmental conditions of the surrounding area. In cultivation practice, information should include species authentication/identification, speciation of wild or cultivated varieties, Details of the GAP program defined by SFDA can be found in ref (14) seeding and growth conditions, harvest practice, fertilization, pest prevention, and field and farm management practices. Also to be included are management and operation practices involved in quality control and assessment methods, personnel training and maps showing detailed cultivation area and experimental farms (scale, production yield and scope). Besides regular GAP studies, work also emphasize ways to: (l).maintain ecological balance and the sustainable development of environment and (2) develop and optimize the transition from wild to cultivated farming. Since the inauguration of the GAP program in 2004, a series of TCH farms have already been awarded the GAP certificates issued by SFDA of China. Based on published information from SFDA (tf), the location of these farms and the herbs which had received GAP certifications from 2004 to 2006 are summarized in Table IV. These certificates were awarded to the sponsoring party of the program which is usually a business enterprise. The technical work of the program is carried out by a working team of experts and professionals, generally from a research institution or university. For our purpose here, only the locations of the GAP farms are listed in the table while the names of the private companies are omitted. Also listed in Table IV are the locations of "genuine" herbs as specified in Chinese Pharmacopoeia (2005). The concept of "genuine herbs" (75) is rooted deeply in traditional Chinese medicines, meaning that only species grown in specific geographic locations are the authentic species with the best quality. The GAP farms are in general, but not always, located in sites with the reputed "genuine herbs".
Future Development and Challenges With a full GMP/GAP certification scheme in place, and with both industrial and agricultural sectors understanding what is required of them, progress is being achieved at a rapid rate. Quality has been improved because raw materials via the GAP system are being controlled; and supply of raw materials also becomes more stable with less price fluctuation. High quality and contaminant-free raw material produced under GAP principles is a pre-requisite for the making of quality and safe Chinese medical products based on modern GMP production.
In Functional Food and Health; Shibamoto, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2008.
In Functional Food and Health; Shibamoto, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2008.
Tianma
Taizishen
Renshen Saqi
Huangqi Maidong
Guanghuoxiang
Danshen
Danggui
Chuanxiong
Banlangen
Baizhi
Chinese name of Herb (pinYing)
+
Rhizoma chuanxiong Radix angelicae sinensis Radix salviae miltiorrhizae Herba pogostemonis Radix astragali Radix ophiopogonis Radix ginseng Radix notoginseng Radix pseudostellariae Rhizoma
Radix angelicae dahuricae Radix isatidis
Latin Name of herb
+
root and
root
root root
root root
entire grass
root
root and stem root
root
root
Functional part of herb
Yun Nan, Si Chuan
Jiang Su
Ji Lin, Hei Long Jiang Yun Nan , Guan Xi
Shan Xi, Inner Mongolia Si Chuan, Zhe Jiang
Guang Dong, Hai Nan
Shan Xi, SiChuna
Hangzhou, Zhe Jiang province ; Sui Ning, Si Chuan province An Guo, He Bei province, Nan Tong, Jiang Su province Guan Xian, Si Chuan, Yun Nan , He Bei Gan Su, Shan Xi
Location of genuine herb defined in Chinese Pharmacopoeia*
Table IV. GAP Herbs Certified in China**
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2006
2006
2004 2005
2006 2004
2006
2004
In process
2006
2006
Year SFDA GAP certificate Recv'd 2006
Continued on next page.
Shan Xi
Gui Zhou
Inner Mongolia Ya An San Jiu Co in SiChuna Ji Ling Yun Nan
Tian Shi Li Co., Shan Xi Guang Dong
Gan Su
Si Chuan province Bai Yun Shan, Fu Yang Si Chuan
Location of GAP Farm in China*
In Functional Food and Health; Shibamoto, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2008.
Fructus corni Fineleaf Schizonepeta Herb Bungeanae Corydalis Herb Folium Ginkgo Radix Polygoni Multiflori Radix Platycodi
Radix Codonopsis Semen Coicis
Herba Gynostemmatis Pentaphylli Fructus Gardeniae Herba Artemisiae Annuae
Shanzhuyu Jingjie
Dangshen Yiyiren
Jiaogulan
Zhizi Qinghao
Jiegeng
Yinxingye Heshouwu
Kudiding
Yuxingcao
Radix panacis quinquefolii Herba houttuyniae
Xiyangshen
+
Latin Name of herb
Chinese name of Herb (pinYing)
whole grass
Jiang Xi Unspecified or unknown
Unspecified or unknown
root fruit
fruit whole grass
Jiang Su He Nan, Hu Bei, Guang Xi, Guang Dong, Gui zhou, Si chuan , Jiang Su Shan Dong, Jiang Su, An Hui, Zhe Jiang, Si Chuan Shan Xi Unspecified or unknown
Gan Su, Shan Xi, Shan Xi, Shan Dong
whole grass leaf root
He Nan Jiang Su, Zhe Jiang, Jiang Xi, Hu Be, He Bei
fruit whole grass
Jiang Xi Chong Qing, Si Chuna
2005 2005 Shan Xi Zhe Jiang (Zhe Jiang Tai Shun) Shan Xi
2004 2004
2005
2005 Shan Dong
2006 2005
2006 2006
2004
Jiang Su Gui Zhou
Ya An San Jiu Co. He Nan He Bei
Unspecified or unknown
whole grass
2006
Ji Lin
Unspecified or unknown
root
Year SFDA GAP certificate Recv'd 2004
He Bei
Location of GAP Farm in China*
Functional part of herb
Location of genuine herb defined in Chinese Pharmacopoeia*
Table IV. Continued
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In Functional Food and Health; Shibamoto, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2008.
Xihonghua
Yuxingcao Flower
whole grass whole grass
whole grass
root
Originated in Spain and Ho land, now cultivated in Shanghai, Zhe Jiang,He Nan, Beijing and Xin Jiang
Unspecified or unknown Unspecified or unknown
Guang Dong, Fu Jian
Si Chuan, Hu Bei
Pinging and Latin names are listed in Chinese Pharmacopoeia, 2005 edition *For locations of "genuine herbs" and "GAP Farms", only the name of the province in China is listed ** Based on published data by SFDA from year 2004-2006 (6)
+
Herba Andrographis Herba Erigerontis Herba Houttuyniae Stigma Croci
Chuanxinlian
Dengzhanxixin
Rhizoma Coptidis
Huanglian
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2004 in process in process
Si Chuan Ya An Shanghai
2004
2004
Yun Nan
Chong Qing, Si Chuna Guang Dong
44 The critical challenge of GAP establishment is the difficulty involved in the quality control and standardization of herbal plants. The two main problems are the lack of scientific-based conventions to define and standardize quality, and the lack of comprehensive toxicological data. To date, although GMP guidelines have been well established in manufacturing processes, the GAP for efficacy assurance and safety of Chinese herbal plants used for functional foods and dietary supplements is still in the development stage requiring continuing research.
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References 1.
2.
3.
4.
5.
6. 7. 8.
9. 10. 11.
Lee, F.S.C., et al., Development of Good Agriculture Practice and Quality Index for Danshen (Radix Salviae Miliorrhizae) from Zhong Jiang, Sichuan", Program code UIM/6 funded by Hong Kong Innovation and Technology Fund (ITF) and New World Bioscience, Ltd., 2000-2003. For program details, refer to website www.itf.gov.hk. Xiaoru Wang, et al, GAP programs on Licorice (Radix Glycyrrhiza,), Taizishen (Pseudostellaria heterophylla (Miq.) Pax.) and Alisma (Alisma gramineum Lej.). For program details, refer to SFDA website www.sfda.gov.cn. Lee, F.S.C.; Wang, X. Key Analytical Technologies for the Quality Control of Chinese Medicinal Herbs Produced according to GAP Guidelines, Xiamen University Press, Xiamen, China, 2002. Wang, X.; Lee, F.S.C.; Li, L. Eds., Key Technologies for the Quality Control of Chinese Medicinal Herbs, Chemical Industry Publishing House, Beijing, China, 2006. For general discussion of technical issues involved in Quality Control and GAP studies, see, for instance, relevant articles in J. Research and Practice of Chinese Medicines, Special issue, 2004, Vol. 18. For regulatory and research activities, refer to official webside of SFDA: www.sfda.gov.cn. For details, refer to U.S. FDA issued final GMP regulations, 2003 EMEA/HMPWG/18/99/ Draft on the document "Good Agriculture Practice (GAP) from the European Herbs Growers and Producers Association, 5 August 1998 Ren, D.Q.; Zhou, R.H. An Operational Manual for the Implementation of GAP, China Agriculture Publishing, 2003. Zhou, R.H. J. Med. Plants, 1998, 13, 254. Chang, N.P.; Shiao, X.; Lin, R.C. Research and Information on Traditional Chinese Medicine, 2001, 3, 15.
In Functional Food and Health; Shibamoto, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2008.
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12. WHO Publication, Guidelines on Good Agricultural and Collection Practices for Medicinal Plants, http://www.who.int/medicines/library/trm/medicinalplants/agricultural.shtml 13. Hu, S.L. Study of Chinese Genuine Herbs, Chinese Medicine Publishing, Inc., 1997.
In Functional Food and Health; Shibamoto, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2008.
