FDA-APPROVED L-TRYPTOPHAN MANUFACTURING PROCEDURES RECOMMENDED

FDA-APPROVED L-TRYPTOPHAN MANUFACTURING PROCEDURES RECOMMENDED by Tyson & Associates in an Aug. 11 submission to Rep. Henry Waxman's (D-Calif.) Energy & Commerce/health subcommittee. The Tyson & Associates report, based on a literature review of L- tryptophan safety studies and the eosinophilia myalgia syndrome (EMS) epidemic in 1989, concludes that FDA can "assure the entrance of safe, non-contaminated [L-tryptophan] into the marketplace" by approving the manufacturing procedures "that are not case-associated" with EMS. Once FDA establishes manufacturing procedures for L- tryptophan, the report recommends, "any alterations in those procedures or new procedures [would have to] go through [an] approval process." Tyson & Associates also suggested that high- performance liquid chromatography "analysis must be added to the USP specifications for this amino acid" and that manufacturers of safe L-tryptophan be allowed to continue to manufacture the product by the same processes and market it. The report was submitted to Rep. Waxman as follow-up testimony to a July 29 health subcommittee hearing on dietary supplements ("The Tan Sheet" Aug. 2, p. 6). Titled "Safety of Amino Acids in Human Subjects: A Review, "the retrospective literature evaluation concludes that "excluding the [L-tryptophan-related EMS] epidemic of 1989, history . . . supports the safety of amino acids as determined by the lack of [serious] side-effects reported despite availability of products." According to the report, the episodes of EMS can be traced to L- tryptophan supplied by Japanese manufacturer Showa Denko. Tyson & Associates maintained that the safety of L-tryptophan is supported by the fact that "91% of EMS cases were reported during or after May 1989, despite [the product] being available in the marketplace for approximately 25 years (1974-1989)." If concern about the identity of the contaminant "is used to keep [L-tryptophan] off the market, then logic would dictate that no manufactured [L-tryptophan should be sold in any form," including the enteral and parenteral formulas which currently contain the ingredient, Tyson & Associates asserted. The report also questions the rationale for restricting access to L-tryptophan until the contaminant involved in the EMS epidemic is identified. Tyson & Associates maintained that the EMS epidemic is analogous to the Toxic Oil Syndrome epidemic that occurred in Spain in 1981, which affected approximately 20,000 people and caused 350 deaths. "No specific contaminant has been identified nor has a proper animal model been found despite 12 years of research" on the rapeseed oil that was sold and ingested as cooking oil, the report states. "Based on current EMS research," the report speculates that "it is likely that the actual cause or identification of specific contaminant(s) responsible for EMS will never be identified." To further support the theory that L-tryptophan made by Showa Denko was solely responsible for the EMS epidemic, Tyson & Associates reported that some EMS patients ingested the product "in amounts less than the adult human requirement for this amino acid." Other studies cited by Tyson & Associates suggest that EMS patients who were switched to L-tryptophan not made by Showa Denko following the onset of EMS either saw a remission of their symptoms or complete resolution. Tyson & Associates also referred to a Mayo Clinic "personal communication" that traced EMS-associated L-tryptophan in a psychiatric practice in South Carolina to Showa Denko. In addition, Tyson cited reports that contaminated L-tryptophan from two German pharmaceutical companies was reported to be linked to Showa Denko and that nine out of 10 EMS cases in Canada were traced to L-tryptophan purchased in the U.S. "The only reason Canada did not have an EMS problem is because the only supplier of [L-tryptophan] in Canada, ICN, obtained their [L-tryptophan] from [Japanese supplier] Ajinomoto and not Showa Denko," the report concludes. Tyson indicated that Showa Denko may have inadvertently created a situation in which its L-tryptophan product was susceptible to contamination; prior to the EMS outbreaks, Showa Denko had altered its manufacturing process with a new strain of bacterium (Bacillus amyioliquifaciens, strain V), a 50% reduction in the amount of powdered activated carbon, and a partial bypass of a reverse osmosis membrane filter, according to a 1990 article cited in the Tyson & Associates report. In a June 18 Federal Register notice on the regulation of dietary supplements, FDA said that it intends to call for data on safety and intended uses of amino acids, as well as support for claims made for amino acids ("The Tan Sheet" June 21, p. 8). The call for data was prompted by the findings of an FDA task force on dietary supplements, which suggested that amino acids be classified as drugs. In the notice, FDA stated that the EMS epidemic "was caused by several factors and is not necessarily related to a contaminant in a single source of L-tryptophan." The agency added that more than 1,500 cases of EMS, including 38 deaths, had been associated with L-tryptophan-containing supplements in 1989. Tyson asserted in the report that the L-tryptophan safety issue is "not whether the [product] was a prescription drug or sold as a dietary supplement," but "whether a company bought [L- tryptophan] from the implicated manufacturer, as did some pharmaceutical companies in the U.S. and abroad." The report states that the Showa Denko product "was found to be negative for bacteria, viruses, radioactivity, and 37 inorganic elements," and was, in fact, "USP grade." The report also says that "unique chromatograph differences were found between the various . . . manufacturers" of implicated L-tryptophan. Tyson & Associates cited an HPLC analysis conducted by Edward Belongia, MD, et al. for an article appearing in the Aug. 9, 1990 issue of the New England Journal of Medicine; the article concluded that "bulk-tryptophan samples from Showa Denko demonstrated a total of 33 peaks, each representing a trace chemical constituent other than tryptophan." In addition, three Lewis Rat studies mentioned in the Tyson report observed distinct pharmacological differences between implicated and non-implicated L-tryptophan. "Implicated [ingredient] produced histologic signs of inflammation, similar to that found in EMS, whereas [control L-tryptophan] did not" in one of the studies, Tyson & Associates said. A manufacturer of biochemical products for the medical profession, Hawthorne, Calif.-based Tyson & Associated markets L- tryptophan and other amino acids. Although Tyson & Associates -- like other manufacturers -- withdrew its L-tryptophan product from the supplement marketplace following the 1989 epidemic, its product was not implicated in the contamination.