TheTraceback Investigation

Traceback InvestigationOnce the groundwork had been laid and the legal hurdles surmounted, the traceback investigation was launched in earnest. Initially, Selanikio and Pulham suspected that contaminated propylene glycol might be the chemical culprit as in the 1990 Nigerian epidemic of renal failure and the 1990 Bangladesh outbreak.

The two men went to the Pharval facility, trying to identify the ingredients used in the manufacture of lots CI, C2, and C3 of Afebril and Valodon. They were able to obtain samples of the leftover propylene glycol used in these lots, but the company’s records and retain samples were incomplete for many of the other ingredients in the acetaminophen syrup. In the wake of its own 1938 DEG crisis, the US had adopted stringent good manufacturing practice (GMP) standards. At a US firm, it would have been relatively easy to locate raw materials on shelves and match them with the appropriate paperwork. At Pharval, however, the documentation was limited.
Selanikio and Pulham then turned to the facility itself to try to pinpoint a source or route of contamination. In their inspection report they documented many lapses in quality control—from filthy production floors and dirty production surfaces to a poorly maintained ingredient storeroom where powders were not kept in sealed canisters and the contents of top canisters could easily drift into bottom canisters. Bottles were dusty and their ingredients were exposed to the open air. In the ingredient store room, some storage drums of raw materials were labeled with the country of origin—for example, China or Brazil—but they were missing lot numbers. The scale used to measure active ingredients looked more like a supermarket scale than a pharmaceutical scale. When the investigators asked how it was calibrated, they could not understand the Creole response until they saw what the workers were referring to—a “little plastic tub.” This object, weighing exactly 14 pounds, was the company’s only apparent means of calibration.

The С DCs National Center for Environmental Health and the FDA’s Forensic Lab in Cincinnati immediately began analyses of samples collected at Pharval by Selanikio and Pulham. The CDC lab found that the quality control retain samples were contaminated with DEG. Propylene glycol samples, however, were not contaminated. The FDA laboratory compared the retain samples with the patient samples, attempting to determine the likelihood that the problem drug was counterfeit. Analyses of the product composition, glass, paper, labels, and glue all indicated that the two products were produced at the same time and virtually eliminated any possibility that the patient samples were counterfeit.
When Selanikio and Pulham returned to Pharval on Saturday, June 29, they learned that Everglade, an independent US laboratory hired by Boulos, had reached similar conclusions. The Miami laboratory had found 20% DEG in Pharval’s Afebril and Valodon samples. Consulting with Pharval officials, Pulham and Selanikio determined that the propylene glycol could not be the sole or even the main source of the problem. Even if DEG had been substituted for 100% of the propylene glycol, this ingredient constituted only 12% of the company’s “recipe” for acetaminophen syrup and could not account for the 20% level of DEG contamination found in the samples. According to the company’s production records, only glycerin was present in quantities sufficient to account for a contamination level of 20% or more. But the independent laboratory, Everglade, had detected only trace amounts of DEG in the glycerin sample it had tested. Only when the Atlanta CDC lab, Everglade, and the FDA’s forensic lab compared their testing methodologies was an error detected. Everglade then retested its samples and found that the glycerin was indeed contaminated with DEG.

Convinced at last that its product had caused the epidemic, Pharval responded by initiating its own recall of the contaminated products about a week after the government’s recall had begun.

The investigators quickly discovered that virtually all of the contaminated glycerin had already been used by Pharval. (Several other Pharval products were found to contain lesser levels of DEG, and ultimately Pharval recalled 17 of its glycerin-containing products.) The single remaining glycerin drum showed no address or phone number. The investigators tried to identify the supplier through the Certificate of Analysis that should have accompanied the glycerin shipment, indicating that the product had been tested for purity and strength.

Standards organizations such as the US and British Pharmacopeias require that drug manufacturers test all excipients for purity, grade, potency, and heavy metal contamination. If a manufacturer has a long-running and well-established relationship with a supplier, it may test excipients only sporadically and rely more heavily on Certificates of Analysis, but the burden of proof is on the manufacturer to ensure the safety and potency of all raw ingredients. Pharval’s quality control chief later received the Certificate of Analysis for the glycerin, nearly a year after the shipment had arrived. It was clear that Pharval had never tested the glycerin or even checked for a Certificate of Analysis.

The CDC identified and contacted the Haitian distributor from which Pharval had purchased its raw ingredients—Chemical Trading and Consulting (CTC), headquartered in Reinfeld, Germany CTC representatives confirmed having sold Pharval the propylene glycol used in Afebril and Valodon. Checking their records again, they found they had also supplied Pharval with the glycerin through a Haitian distributor that had received 72 drums on June 27, 1995. The crisis began to assume international dimensions, however, when CTC representatives told investigators that although they could readily identify the manufacturer of the propylene glycol sold to Pharval, they could not identify the manufacturer of the glycerin. CTC had received the glycerin from a Dutch trader, VOS, a subsidiary of a large German chemical conglomerate, Helm AG. In one conversation with Pharval officials, CTC officials mentioned, almost parenthetically, that they had heard that there were problems with Chinese glycerin but insisted CTC did not buy from China at all.

By Monday afternoon, July 1, the FDA’s Forensic Chemistry Center had completed its analysis of the glycerin samples it had received and concluded that it was not USP grade glyc erin, but was contaminated with 24% DEG. The acetaminophen syrup made by Pharval, as a result, had a 12% to 20% contamination level.

At this point in the investigation, the FDA took over the international traceback of the contaminated glycerin. Based on the information provided by CTC, the FDA sent a drug specialist from its Philadelphia office, Ann deMarco, to VOS to determine the manufacturer of the glycerin and to find out whether any other drums of contaminated product may have been distributed. On Friday, July 4, deMarco arrived at VOS, where she determined that the company was not the original source of the glycerin shipped to Pharval. Documentation obtained at VOS showed that VOS had served as a broker and had received the contaminated glycerin from Metall-Chemie in Hamburg, Germany. VOS personnel informed deMarco that the company had also purchased a second lot of glycerin from Metall-Chemie, which was stored in a warehouse in Rotterdam. deMarco collected product samples from this shipment and forwarded them to FDA’s Forensic Chemistry Lab for analysis. Documentation provided by VOS showed that both the glycerin sold to Pharval and the glycerin in storage in Rotterdam had been shipped from Xingang, China. Analysis of the second shipment found the same profile of contamination as in the glycerin that had been shipped to Haiti.

Since it was critical to determine the source of this material, deMarco set out for Germany to visit Metall-Chemie. She determined that Metall-Chemie, also a broker, had arranged the purchase of the contaminated glycerin from a Chinese trader, Sinochem International. Personnel from Metall-Chemie explained how they had photocopied their company letterhead onto the Certificate of Analysis provided by Sinochem in order to obliterate the identity of the supplier. They explained that bulk chemical traders do this routinely to protect their role as middlemen. In the

case of the glycerin that had reached Pharval in Haiti, neither the Certificate of Analysis nor the product labeling indicated the manufacturer or country of origin.
Although the labeling and the Certificate of Analysis indicated that the glycerin shipped to Haiti met the strict standards of the US Pharmacopeia (USP), all personnel that deMarco interviewed at Metall-Chemie and VOS denied knowing that the glycerin was contaminated and failed to meet USP requirements. A Dutch journalist later reported that a sample of glycerin from the lot shipped to Haiti had been tested by an independent laboratory shortly after shipment and was found to be only 53.9% pure. (USP standards for glycerin call for 98% purity.) This discovery became the basis for several lawsuits, although it is not clear who requested the testing.

Attempts to trace the contaminated glycerin within China proved inconclusive. The glycerin was reportedly made not by a pharmaceutical company but by a fine chemical manufacturing plant, which was said to have manufactured the product according to specifications for a USP grade product. Only the invoice stamp indicated that the product met USP standards, and there was no record of an analysis having been conducted before shipment from the factory The inspectors discovered that the firm had ceased production at the site, had moved its operations, and was making a different product. No production records were available, and the Chinese officials noted that they did not normally keep production records past two years. The investigation did not reveal when or where the contamination occurred, although the firm’s officials did tell investigators that the product had been produced by fermentation, rather than by chemical synthesis as had been previously assumed.

In Haiti, however, a vigorous investigation was launched to account for the disposition of the entire shipment of 72 drums of glycerin. Sixty-two of the 72 drums had been sold to Pharval by the Haitian distributor. The search for the last 10 drums of presumably contaminated glycerin required extensive investigative work, which went on alongside the ongoing recall effort.

Investigators found that the Haitian distributor had stored the 10 drums of Chinese glycerin not sold to Pharval along with four drums of glycerin from Brazil in his own factory. The factory had scanty records, but investigators determined that 12 of the 14 drums had been sold to 11 local pharmacies in Haiti. FDA and CDC investigators visited nine of the pharmacies and learned that most of the glycerin had been sold for use as a moisturizer or hair tonic, both topical applications. One pharmacy did sell some as a laxative, but none of the pharmacists had received any complaints. Unfortunately, there were no records of sale and there was no remaining product to be sampled, closing that part of the investigation.

The last two drums of glycerin were sold to another Haitian pharmaceutical company. This company used the glycerin in the manufacture of 15 liquid products, not including any acetaminophen preparations; none of their product formulations required more than 10% glycerin. Residues from the first drum tested negative for DEG, but there were no remains to test from the second drum. Dr. O’Brien and the CDC team speculate that this second drum, if it were contaminated, might account for some of the eight identified cases of renal failure for which they could demonstrate no exposure to either Valodon or Afebril.

The FDA followed up its active investigations by sending San Juan drug investigator Jorge Guadalupe back to Haiti to conduct a two-week training course on good manufacturing practices and recall procedures for the Ministry of Health. Later, under the sponsorship of the WHO, a Haitian Ministry of Health pharmacist came to the United States for two months of intensive training in photography, sample collection, evidence development, report writing, lab techniques, and good manufacturing practices.
In an unusual epitaph to an excellent investigation, the investigative team learned that even if Pharval had used a recommended method of testing, it would not necessarily have detected the contamination. Virtually all pharmacopeias worldwide, including that of the United States, recommended that infrared spectrometry be used in testing glycerin. CDC and FDA lab experts, however, determined that this method does not detect DEG contamination in glycerin. The only other method recommended as a test for glycerin purity, gasAiquid chromatography, was expensive. Poor countries, the investigators realized, would never be able to afford this methodology. In an amazing “small world” story, a solution was reached. While stationed in Botswana in 1996, one of O’Briens former classmates and a fellow EIS Officer (Class of 1994), Thomas Kenyon, MD MPH, heard a BBC broadcast about the Haitian epidemic. He e-mailed O’Brien about the work that his father had done at the FDA in developing a simple and inexpensive kit to test chemicals and raw materials for purity. Alan Kenyon, PhD, a physical chemist who had worked for 38 years at Monsanto, was 80 years old at the time of the Haitian crisis and still volunteering at the St. Louis FDA lab, working on thin layer chromatography. Dr. Kenyon had spent the summer of 1995 working with an international group of college students to refine a method of detecting DEG contamination in glycerin. Finalizing the research with the help of visiting scholars from Australia,

Shanghai, and Singapore, Dr. Kenyon and his team developed an inexpensive and portable test kit for DEG in glycerin and made it available to the WHO, which is making some modifications prior to distributing it. Mean while, US officials hope that the Hait¬ian tragedy will serve as a springboard for international efforts to tighten control over bulk drug ingredients and fine chemical shipments. In 1997, a first step was achieved when an international workshop on DEG contamination was held, raising awareness of the problem among health officials and prompting some countries to make changes in their export procedures for drug excipients and fine chemicals.

Category: Health

Tags: Diethylene Glycol, Renal Failure

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