Consumers are always reminded to read the label for important information about the drugs they use, but if the label is wrong, there could be serious consequences. That's why FDA's Good Manufacturing Practice regulations call for quality control procedures for labeling. A lack of such procedures led to five product recalls in four years by a New York drug manufacturer.
Superpharm Corp. of Central Islip, N.Y., a subsidiary of Orlove Enterprises, Inc., Hollywood, Fla., produces a variety of generic prescription and over-the-counter drugs. FDA's Brooklyn office became aware of the firm's labeling problems early in 1982.
The first mix-up involved a bottle labeled as aspirin that actually contained over-the-counter diet pills consisting of caffeine, phenylpropanolamine and ephedrine sulfate. During an inspection in April 1982, FDA learned the firm had not conducted an investigation of the mislabeling after receiving a complaint from the Veterans Administration. Because a patient taking diet tablets at the dosage recommended for aspirin could be exposed to potentially serious health hazards, what remained of the lot of aspirin, which had been distributed only to the Veterans Administrating Marketing Center in Illinois, was recalled the following June.
During a subsequent inspection, FDA found significant deviations from Good Manufacturing Practice regulations, including no written instructions for handling labels. The firm promised to make corrections.
In December 1982, Superpharm had another recall--this time because of a wrong expiration date on cyproheptadine HCl tables, a drug used to treat allergies. Again, the error resulted because there were no written instructions to the labeling clerk. In addition, the labels had not been checked by a supervisor before being used.
A comprehensive inspection in the spring of 1983 revealed that while most of the firm's other manufacturing deficiencies had been corrected, labeling problems had not. For instance, FDA's investigators spotted unlabeled bottles of two different drug products (quinine sulfate and methocarbamol) on the same bottling line.
Yet another recall was initiated in October 1983 when some bottles of 20-milligram isoxsuprine HCl tablets turned up with 10-milligram labels. (A wrong dose of this drug, used to treat blood circulation problems, could increase the chance of adverse reactions such as dizziness.) No one had noticed that the 10-milligram and 20-milligram labels had been mixed together when shipped from the parent company.
Because of Superpharm's continuing problems, FDA's Brooklyn office sent the firm a letter spelling out the deficiencies noted during earlier inspections. At a meeting in the Brooklyn district office in June 1984, the firm's officials promised to take corrective action, including tightening controls on the examination of incoming labels, revising written labeling procedures, and intensifying examination of finished drug products after labels were on.
That should have been the end of the story, but in August 1985 it happened again. Superpharm notified FDA of yet two more recalls involving mixed-up labels. One concerned bottles labeled as 25-milligram hydrochlorothiazide tablets (a diuretic), which actually contained 50-milligram strength tablets. The other concerned bottles labeled as isoxsuprine HCl tablets that actually contained dipyridamole tablets, medicine used to prevent or lessen anginal attacks. The errors were caught by an alert pharmacist.
In December 1985 a follow-up inspection of Superpharm again revealed labeling and other manufacturing deficiencies were continuing. However, at a January 1986 meeting with FDA at Superpharm's request, the firm's officials agreed to temporarily halt manufacturing operations while they took steps to avoid future mishaps. They agreed to hire a consulting firm to study the firm's operations and personnel and recommend actions to improve quality control. Superpharm also said it would add more qualified personnel, separate the various manufacturing processes, and tighten manufacturing procedures, particularly where packaging and labeling was performed.
In addition, the firm has agreed to test the new packaging/labeling controls to ensure they work before resuming production. For example, improper labels will be introduced into the system to see if line personnel detect the defect.
The firm resumed marketing in February 1986. FDA's reinspection in March found that improvements had been made and the firm was operating in compliance.
Heart Drug Problem Dissolves
Routine post-marketing tests by FDA's Los Angeles district laboratory revealed earlier this year that some drug tablets being prescribed for heart patients didn't dissolve properly. The result? The manufacturer, Duramed Pharmaceuticals, Inc., of Cincinnati, recalled nearly a million of their tablets.
The suspect drug, dipyridamole, works by relaxing blood vessels and increasing the supply of blood and oxygen to the heart. FDA had tested two batches of the tablets for dissolution according to the standard U.S. Pharmacopeia method. One batch had been supplied by FDA's New York district office, the other by the Los Angeles office. Both batches failed. The way drugs dissolve is important, because they're formulated to release their active ingredients in a certain part of the body--the intestines, for example, as opposed to the stomach. If the drug doesn't dissolve properly, the patient may get too much or too little of the active ingredient.
After the lab test failures, FDA's Los Angeles office notified its Cincinnati counterpart of the results. On April 24, 1986, the Cincinnati office informed the firm of the problem.
An FDA investigator visited Duramed and learned that the product actually had been manufactured at a Westbury, N.Y., facility that Duramed no longer used. Thus, on-site examination of the manufacturing practices and processing equipment wasn't possible. Production records on the batches provided no clues as to why the tablets didn't dissolve properly.
Duramed conducted dissolution testing on its reserve samples for all lots that had similar expiration dates and dosage forms as the suspect batches and confirmed FDA's findings, but determined that no other lots were affected. So, on May 6, 1986, the firm voluntarily recalled all tablets of the defective lots from wholesalers nationwide, sending them letters requesting recall of the drug from pharmacies.
FDA's Cincinnati laboratory tested other Duramed products and found they met required standards. FDA determined that no other lots were affected and that Duramed's Cincinnati facilities were not deficient. The recall has been completed, but FDA is working with Duramed to determine whether the incident represented an ongoing problem or was an isolated incident.
A Deadly Hospital Gas Mix-Up
Argon is a gas with a variety of industrial uses, including arc welding, neon and fluorescent lights, lasers and Geiger counters. But the last place it should be is in a hospital operating room. Tragically, argon gas did get into the oxygen supply system of the Noble Army Hospital, Fort McClellan, Ala., causing the deaths of three patients--a soldier, a young woman, and an infant. The case against the firm whose product caused the deaths recently was concluded, with fines against the company and its stop officials.
When FDA's Atlanta office learned of the deaths on May 26, 1983, agency investigators immediately visited the hospital and learned that its oxygen supplier, Dixie Welding Supply Co., Inc., Attalla, Ala., had delivered and connected a tank containing argon to the hospital's central oxygen system. The tank, discovered by hospital officials, bore a partially obliterated oxygen label, as well as a sticker with "argon" handwritten on it.
The next day, an investigator visited Dixie Welding to find out how the mistake happened. He found the firm was breaking most of the rules for repacking medicinal gas.
Medical oxygen is regulated by FDA as a drug because it meets the definition of being a substance intended for prevention, diagnosis or treatment of disease and which affects the structure or function of the body. Medicinal gas repackers, like drug manufacturers, are required to follow FDA's Good Manufacturing Practices that set minimum requirements for packing, processing, storing and shipping their products.
Since many oxygen repackers also repack industrial gases, such as argon, special precautions must be taken to prevent mix-ups of industrial and medicinal containers. There are three different types of gas containers: cylinders, used for compressed gas in vapor form under high pressure; vessels, used to contain compressed gas in liquid form under low pressure; and cryogenic tanks, designated to hold liquid compressed gas--which may be dispensed in liquid or vapor form--at extremely low temperatures.
These containers have a number of valves, including an inlet valve to fill the container and a discharge valve to dispense the gas. Argon tanks have valves that are different from those on oxygen tanks. Theoretically, a properly "fitted" cryogenic argon tank cannot be hooked up to an oxygen delivery system such as that in a hospital. FDA's investigators found, however, that the tank delivered to the hospital had an argon inlet fitting and an oxygen outlet fitting.
The investigators also found that Dixie Welding failed to test every tank of gas it produced before release. The firm kept inadequate and incomplete batch records and failed to separate industrial and medicinal tanks.
The firm also lacked written procedures for labeling controls, batch testing, and conducting product recalls and had released tanks of gas with incorrect or conflicting labeling. Finally, the firm lacked written specifications for equipment maintenance and cleaning and failed to properly train and supervise employees.
Because of the seriousness of these violations and to prevent other fatal mixups, on June 2, 1983, at FDA's request, the U.S. Attorney's office in Birmingham obtained a temporary restraining order against the firm, ordering Dixie Welding to cease operations until it could demonstrate compliance with Good Manufacturing Practices.
FDA also instituted criminal proceedings against the firm, Kenneth C. Williams, president, and David E. Davis, vice president. On March 26, 1986, in the U.S. District Court for the Northern District of Alabama in Birmingham, all three defendants pleaded guilty to two counts of adulteration: manufacturing drugs under conditions that failed to conform with FDA's GMP regulations, and shipment of a gas purported to be oxygen but which failed to meet the U.S. Pharmacopeial standard for medicinal oxygen.
Magistrate R. Macey Taylor fined each defendant $1,000 per count for a total of $6,000. No prison sentence was imposed.
Toxic Tea--Part II
Tea can be exotic or herbal, relaxing or refreshing, but it had better not be poisonous. When FDA found one firm's tea contained a toxic alkaloid, the legal wheels started turning, the investigation broadened, and eventually not one but two firms had to destroy $390,000 worth of their toxic teas.
Two years ago, U.S. marshals seized over $340,000 worth of herbal teas in Utah, Texas and Ohio because the teas contained Lobelia inflata L., an herb classified by FDA as an unsafe food additive. The manufacturer, Nature's Sunshine Inc. of Spanish Fork, Utah, contested the seizures, which had been requested by FDA's Denver district office. (See "Pretty but Poisonous" in the Investigators' Reports in the May 1985 FDA Consumer.)
The district office had initially sent an investigator to inspect the firm after getting a tip from U.S. Customs that large amounts of the herb were being shipped into the country. While investigating this information, the district also got complaints from several customers who had drunk the teas and then complained of nausea, indigestion, vomiting and diarrhea. The investigator found that many of the teas contained lobelia, which is reputed to help digestive and kidney problems and to ease tension. However, lobelia contains the poisonous alkaloid lobeline, which can cause the symptoms described by the customers, and it was on FDA's list of poisonous plants. The district therefore initiated the seizures.
Several months later, the district office learned that another firm, Murdock International, Inc., springville, Utah, was also manufacturing lobelia products, primarily teas made with ground lobelia and a lobelia extract in an alcohol base. The district arranged for state authorities to embargo two lots of the teas until they could be seized. However, the agency did not want to take any further action until the Nature's Sunshine case came to trial.
In October 1985, the district office asked Murdock International to voluntarily discontinue marketing and distributing products containing lobelia until the Nature's Sunshine case was decided in court (the trial date had been set for April 1986). The firm declined this offer and, in the meantime, it continued to sell the lobelia products.
Then, in January 1986, Nature's Sunshine decided not to contest the seizures. The company had already removed lobelia from its teas and agreed to the destruction of the teas that had been seized.
So the district office sent another letter to Murdock International, inviting the firm to follow the example set by Nature's Sunshine. FDA warned that it was still prepared to go to court--this time with Murdock International, if necessary.
The firm agreed to destroy the embargoed products--over 3,315 bottles and 680 pounds of lobelia. The president of the firm agreed to remove lobelia from his herbal teas by June 30, 1986. FDA district staff decided to hurry the process by taking samples of the tea from stores across the country for evidence in possible seizures. The firm then managed to rid its products of lobelia by the middle of May. The firm also destroyed another 3,000 bottles of the product at the plant.
Now, no products produced by either Nature's Sunshine or Murdock International contain the poisonous lobelia.
COPYRIGHT 1986 U.S. Government Printing Office
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