Inside USP: Traditional Chinese Medicines and Western Regulatory Paradigms

Traditional Chinese Medicine (TCM) is a collection of medical practices grounded in observational theory that originated thousands of years ago and continues to be widely practiced in China, among emerging populations and, increasingly, around the world. TCM is complex, in part because it is derived from physical, philosophical, cosmological, environmental, and cultural elements, as well as aspects of indigenous religion. Practices associated with TCM include acupuncture, massage, dietary therapy, and herbal medicines.

TCM faces regulatory challenges in the US and Europe. Regulatory options are available, and the US Pharmacopeial Convention (USP) and other international standards-setting bodies hope to develop compendial standards for discrete ingredients used historically in TCM. A portion of the USP annual scientific meeting held with the Chinese Pharmacopoeial Commission (ChP) in Tianjin, China, Nov. 6–7, 2008, addressed TCM and the opportunities for various Western compendia to include TCM ingredients in healthcare paradigms. This article focuses on herbal and botanical materia medica, drawing on presentations made at the meeting.

Regulatory options

TCM is espoused by the Chinese government; it is taught within dedicated TCM colleges and universities, practiced by TCM physicians, managed by TCM hospitals, and widely used by the Chinese populace. The singularly defined, authenticated ingredients that make up the complex TCM mixtures compounded by the practitioner for the patient fit into four categories recognized by the US Food and Drug Administration: pharmaceuticals, dietary supplements, foods or food ingredients, and cosmetics.

Options for incorporating TCM into US regulations are defined and, thus, may be viewed as restricted. The first limitation is that the herbal ingredient must be approved or allowed as a singular ingredient. Mixing and compounding can be performed but only with a defined set of approved (i.e., safe, singular) ingredients. The second limitation is how to regulate TCM. If one accepts the TCM assertion that an ingredient is curative or disease- or condition-preventive, then TCM immediately falls under applicable FDA drug regulations.

Although one might contend that FDA regulations are designed for recent allopathic drugs (synthetic chemically purified moieties), it is important to remember that the US has a 200-year history of standardizing drug products. The original USP of 1820 contained mostly botanically based decoctions, extracts, infusions, and tinctures (1). Improved opportunities have arisen for the development of botanical drugs.

In the US and Europe, the development of a drug (purified and/or botanical ingredients) must take place according to the paradigms of allopathic drugs. The prevailing US regulatory model is expensive and time-consuming, requiring many years of studies.

Manufacturers have concerns about patent protection and marketing exclusivity for finished TCM ingredients that undergo drug regulatory submission. Two regulatory alternatives may help resolve these issues: Treat the TCM ingredient as a dietary supplement or treat it as a food ingredient (most likely a functional food).

Food petitions and affirmations

In the US, food ingredients, functional or otherwise, must undergo one of two processes: the FDA-centric food additive petition (FAP) path or the more expedient and more cost-effective Generally Recognized as Safe (GRAS) affirmation path (2, 3). Opting not to submit an FAP would be in most manufacturers' best interests unless FDA or legal counsel requires doing so.

As is the case with drugs, FAP is a process that requires intensive safety testing and time- and money-consuming activities. The GRAS route affords the same level of acceptability for sales by manufacturers, use by end-product formulators, and consumer accessibility. GRAS certification can be based strictly on a vendor's self-affirmation and demonstration of safety. The latter are privately shared between the company or organization making the affirmation and the eventual user of the ingredient. A GRAS notification to FDA is optional and often of value to both selling and buying parties because it suggests that FDA does not disapprove the GRAS conclusion.

TCM's singular botanical ingredients, or, more likely, standardized extracts from singular botanical ingredients, are likely candidates for the GRAS process. Safety is fundamental and is demonstrated by appropriate animal studies linked to likely exposure scenarios and public acceptance, i.e., the general recognition, via peer-reviewed publications of the pivotal safety data. Many innovative companies are diligently developing safety packages for standardized botanical ingredients as they move toward GRAS affirmations and notifications (e.g., baby kiwi [Actinidia arguta], spirulina [Arthrospira platensis]) (4).

Options under the Dietary Supplement Health and Education Act

The complex regulatory status of TCM suggests parallels with dietary supplements and dietary supplement ingredients. Americans and other Western consumers typically link TCM herbal ingredients with dietary supplement herbal ingredients. Health food stores or the dietary supplement aisles at drug or grocery stores include a wide variety of botanicals, both in raw form and in concentrated or extracted fractions.

Current regulations for dietary supplements under the Dietary Supplement Health and Education Act of 1994 (DSHEA) provide the lowest barrier to market entry (5). In brief, submission of a new dietary ingredient (NDI) to FDA's Office of Nutritional Products, Labeling, and Dietary Supplements (ONPLDS) as a Notification (NDIN) requires a safety data package that is relatively straightforward.

DSHEA states that a dietary supplement that contains an NDI shall be deemed adulterated under section 402(f) of the Act [21 USC 342(f)] unless it meets one of two requirements: the dietary supplement contains only dietary ingredients that have been present in the food supply as an article used for food in a form in which the food has not been chemically altered; or a history of use or other evidence of safety establishes that the dietary ingredient when used under the conditions recommended or suggested in the labeling of the dietary supplement will reasonably be expected to be safe. Further, the manufacturer or distributor of the dietary ingredient or dietary supplement must provide FDA with certain safety information. Such safety information can include citations to published articles on the basis of which the manufacturer or distributor has concluded that a dietary supplement containing the dietary ingredient can reasonably be expected to be safe.

If a dietary ingredient has not been present in the food supply, vendors must show why they believe that consumption of an NDI can reasonably be expected to be safe under the conditions recommended in the labeling. FDA has not published guidance defining the specific information required to demonstrate safety but has made clear its position that there should be a "reasonable expectation of safety" when the product is used. The manufacturer is therefore responsible for determining what information provides the basis for the safety conclusion.

Standards for TCM–USP's role

Standardization of any new ingredient is of paramount importance. Appropriate specifications to demonstrate quality and purity (and impurities at acceptable levels) are critical in obtaining a successful response from a GRAS Expert Panel, from FDA's Center for Food Safety and Applied Nutrition during a follow-up GRAS Notification, or from ONPLDS in response to an NDIN.

Since its inception, USP has worked to provide accurate names for medicinal products, standardized procedures to test them, and reference standards that independent parties can use to ensure their identity, strength, and purity (1). In modern times, USP has asserted that "the elements of the monograph are sufficient to identify the compendial article and to control its quality in the marketplace. The activity can bring a private consensus developed between a regulatory agency and applicant into the open and allows public scrutiny and endorsement" (6). USP's expanding catalog of official reference standards enables dietary supplement, food ingredient, and pharmaceutical scientists worldwide to test an article in commerce against a reference standard or certified reference standard to ensure that the product is not adulterated (7).

USP also verifies the identity, strength, purity, and quality of dietary supplement finished products, dietary supplement ingredients, and pharmaceutical ingredients. Products and ingredients that pass USP verification requirements—including a GMP audit, product and ingredient testing, and manufacturing documentation review—are awarded use of the USP Verified mark, which helps assure consumers that products provide the expected value.

Conclusion

The USP–ChP annual scientific meeting brought together several experts to discuss the expanding use of TCM and associated regulatory issues. Modern research is ongoing in China and Western research facilities regarding the mechanisms of TCM's pharmacological action. USP will continue to exercise its role in developing TCM singular botanical ingredients via the dietary supplements and active drug and excipient moieties model.

James C. Griffiths, PhD, is vice-president of food, dietary supplements, and excipient standards at the US Pharmacopeial Convention, 12601 Twinbrook Parkway, Rockville, MD 20852-1709, jcg@usp.org

References

1. USP (Boston: Wells and Lilly, 1820).

2. FDA, Food Additive Petition Expedited Review—Guidance for Industry and Center for Food Safety and Applied Nutrition Staff (Rockville, MD, 1999), www.cfsan.fda.gov/~dms/opa-expe.html accessed Jan. 26, 2009.

3. FDA, Guidance for Industry: Frequently Asked Questions about GRAS (Rockville, MD, 2004), www.cfsan.fda.gov/~dms/grasguid.html accessed Jan. 26, 2009.

4. FDA, Numerical Listing of GRAS Notices (Rockville, MD, 2008), www.cfsan.fda.gov/~rdb/opa-gras.html accessed Jan. 26, 2009.

5. PL 103-417, Dietary Supplement Health and Education Act, 1994, www.fda.gov/opacom/laws/DSHEA.html accessed Jan. 26, 2009.

6. L. Bhattacharyya et al., "The Value of USP Public Standards for Therapeutic Products," Pharm. Res., 21, 1725–1731 (2004).

7. R.L. Williams et al., "Official USP Reference Standards: Metrology Concepts, Overview, and Scientific Issues and Opportunities," J.Pharm. Biomed. Anal., 40, 3–15 (2006).