Manufacturing Practices of Dietary Supplement Companies Andrea M. Bieser and Steven B. Hess Introduction According to the Dietary Supplement Health and Education Act of 1994, dietary supplements are considered safe unless they are proven unsafe by FDA.[1] Thus, manufacturers of supplements have largely been free to regulate themselves. The supplement industry follows the good manufacturing practices (GMPs) used for food (although FDA is planning to issue dietary supplement GMPs by 2003). A company may choose -- or not choose -- to operate under pharmaceutical GMPs, which are far more rigorous than food GMPs. Some companies may have internal self-auditing procedures or may undergo voluntary audits by the National Nutritional Foods Association (NNFA). NNFA was established in 1936 and comprises 4000 retailers, manufacturers, and suppliers of the natural products industry. This association tracks regulatory and legislative issues that may have an impact on the industry, and its department of science and quality assurance is responsible for certifying the GMPs of NNFA members and for conducting the "TruLabel Program," begun in 1990. The TruLabel Program seeks to ensure the quality of dietary supplements by conducting annual random tests of NNFA members' products. If a test finds a deficiency in a product's ingredients, the member must correct the problem or be expelled from NNFA. All members will have been audited at least once by 2002.[2] Another important organization a dietary supplement company may belong to is the Institute for Nutraceutical Advancement (INA). This is an international alliance of 30 dietary supplement companies that sponsor the Methods Validation Program for standardizing the laboratory analysis of raw materials used in manufacturing natural products and the measurement of active ingredients. INA includes committee representatives from the American Botanical Council (ABC), the American Herbal Pharmacopoeia, the American Herbal Products Association (AHPA), the Herb Research Foundation, and FDA.[3] The purpose of this study was to survey dietary supplement companies to determine their manufacturing practices so that this information could be used in selecting brands for sale at a health system's wellness center and outpatient pharmacies. Background Evanston Northwestern Healthcare (ENH) is a private, nonprofit, 675-bed integrated health care system in suburban Chicago with a level 1 trauma center providing medical, surgical, and critical care. ENH operates three inpatient pharmacies, five outpatient pharmacies, three oncology clinic pharmacies, an anticoagulation clinic, and a newly opened wellness center, home to the health system's integrative medicine program. The integrative medicine committee investigated sources of dietary supplements so that reliable products could be selected for sale at the wellness center. Methods ENH's integrative medicine committee, composed of two pharmacists and a physician with a fellowship in integrative medicine, evaluated 20 dietary supplement companies from November 1999 to June 2000. The companies were selected on the basis of (1) their involvement in INA's Methods Validation Program, (2) their membership in the Corporate Alliance for Integrative Medicine (a group of 10 manufacturers and suppliers interested in funding clinical trials at major universities and in developing educational programs for medical personnel), (3) their current inventory at ENH's outpatient pharmacies, or (4) their leading brandname status. The committee developed survey questions based on common concerns from clinicians regarding dietary supplements and discussions with a leading expert on pharmacognosy at the University of Illinois at Chicago. The questions were also formulated after consulting the "Checklist for Credentialing Botanical/Herbal Suppliers" in the November 1998 issue of The Integrator, a publication from Integrative Medicine Communications.[4] Integrative Medicine Communications provides clinician, consumer, and business information related to integrative medicine. It has an 80-member board of peer-reviewing health professionals and is not sponsored by any dietary supplement manufacturer.The survey questions addressed important aspects of manufacturing, quality control, suppliers, formulations, clinical trial involvement, and professional association membership. All members of the integrative medicine committee agreed on the questions selected for the survey. The companies selected were surveyed by telephone or e-mail or through onsite visits.Results A total of 14 companies responded to the survey (response rate, 70%). Most responded via telephone and e-mail; five were visited at their manufacturing facilities.Table 1 lists the questions and summarizes the findings. Specific company responses are not presented because of confidentiality agreements. A plurality of the companies (43%) were independent, and more than a third were family run. More than half were not an FDA-registered drug-manufacturing facility. Eight companies followed food GMPs, and six followed pharmaceutical GMPs. All the companies had an inhouse quality assurance program staffed by 5 to 70 individuals with various credentials. To measure labeled ingredients, all the companies used high-pressure liquid chromatography, and some used Fourier transform infrared spectroscopy, atomic absorption spectrometry, mass spectrometry, gas-liquid chromatography, thin-layer chromatography, and ultraviolet spectrometry. Some tested, in addition, for pesticides, microbial contamination, heavy metals, and other contaminants. All the companies quarantined raw or extracted material before quality assurance release. Some companies performed finished-product verification, and all retained samples of each product. Most of the companies that did extractions had a selection process in place requiring raw materials to be accompanied by certificates of origin and authenticity, certificates of analysis, results of analyses for contaminants, summaries of suppliers' quality control and quality assurance programs, or other relevant information. One company based its selections solely upon business relationships. Five companies did their own extractions, and one did not use extracted materials for its products. The remaining companies chose an extraction supplier on the basis of reputation, compliance with standards, and the reliability or reproducibility of the certificates of analysis. Almost all of the companies (93%) made standardized extracts. In addition, four made freeze-dried products, and two made whole-herb powders.Ten companies standardized their products on the basis of clinical research; others based standardization on what competitors were doing. Lot numbers and expiration dates were used by 10. Almost two thirds of the companies based their formulations on clinical research, and none had entered FDA's investigational new drug process. Nine companies conducted or funded clinical studies of their products. Those that did not carry out trials pointed to funding as the main hindrance. Almost all the companies were members of NNFA, INA, AHPA, or ABC, and some belonged to the Consumer Health Products Association or the Council for Responsible Nutrition. Discussion There are important operational differences among dietary supplement companies that can affect the quality of the final product. Since dietary supplements are not pharmaceuticals, it is not surprising that most companies were not FDA-registered drug-manufacturing facilities. However, some companies followed pharmaceutical GMPs even though they were not manufacturing pharmaceuticals. This shows a willingness to adhere to higher standards that may improve the overall quality and integrity of the final product.All 14 companies surveyed had quality control or assurance programs, although the number of people staffing these programs and their scientific qualifications varied. There was good uniformity among the companies in the testing equipment used for quality control. However, depending on the product, it can be important to know whether appropriate testing for contaminants was performed. Certain raw and extracted materials may have been purchased without certification that they were free of unacceptable levels of heavy metals, pesticides, and herbicides. In addition, quarantining is crucial to prevent contaminated, damaged, or unintended materials from entering the manufacturing process. Other quality-related checks have to do with finished-product verification and sample retention. Finished-product verification was done only with certain products and formulations, and mostly for standardized products. Formulations containing multiple vitamins, minerals, and herbs are difficult and expensive to analyze after manufacturing. All the companies surveyed did retain samples in case of a problem with a certain formulation. When the companies chose raw material or extraction suppliers, they usually had a selection process. This process involves different requirements for different companies, including certain certificates accompanying the materials, reliable certificates of analyses, and adherence to quality assurance guidelines. Within the selection process lie the guidelines for confirmatory tests of raw materials and testing for reliability of the certificates of analysis. As in any industry, there are inexpensive suppliers and expensive suppliers. Dietary supplement companies generally will not release the names of their suppliers.Almost all the companies made standardized extracts, with some also manufacturing freeze-dried products. There is controversy as to whether standardizing or freeze-drying is necessary. Most clinical trials have been carried out with standardized extracts. So, most standardization among companies is based on clinical research. Also, a majority of the companies based their formulations on clinical research. This is important because competitors may change formulations by one particular ingredient without scientific evidence to support the addition of that ingredient. The sole reason for this is to prevent mimicking a competitor's product. Since pharmacognosists, botanists, and chemists in this field have not agreed that standardization is absolutely necessary, it is not surprising that one of the companies surveyed did not standardize its products. Instead, it may be more important to know, for example, the suppliers of certain plants or plant parts and what processing they have undergone.Lot numbers and expiration dates are important for shelf-life determinations and product recalls. A majority of the companies used lot numbers and expiration dates. In addition, over half funded or conducted clinical trials on their products. This makes good sense, since many dietary supplements are being used for diseases and in disease prevention. However, none of the companies had entered the investigational new drug process. Finding funding for clinical trials in the supplement industry is certainly much more difficult than in the drug industry. All the companies belonged to industry-related organizations, some of which audit their members to ensure compliance with industry standards. Limitations of this study include the small sample, the selection of only reputable supplement companies, and the unstructured data-collection method. In addition, company-specific responses could not be reported because of confidentiality agreements. Those companies that voluntarily followed pharmaceutical GMPs, standardized and formulated their products according to research, used lot numbers and expiration dates, and enrolled their products in clinical trials were considered to offer superior brands suitable for sale at ENH's wellness center and outpatient pharmacies. Any pharmacy business or health system considering the marketing of dietary supplements is advised to use this or a similar evaluation process before selecting a product line for sale. Conclusion Dietary supplement companies differed with respect to the GMPs they followed, how standardization of a product was determined, the use of lot numbers and expiration dates, whether to formulate based on research, and whether they subjected their products to clinical trials. All the companies used some sort of quality assurance process. [Am J Health-Syst Pharm 58(21):2066-2069, 2001. © 2001 ASHP, Inc.] From this article July 3, 2002 The Nation via Alternet.org HealthCanada Press Release, 6/18/03 Council for Responsible Nutrition, 1/05 ConsumerLab.com Drops Lawsuit Against CRN Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. 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