Capsule coating fails quality control
Capsule Coating Fails QualityControl
Testing the coating of a single drug capsule out of some 7 million manufactured falls far short of adequate quality control, FDA told Anabolic, Inc., of Irvine, Calif.
Acting on information from a competing manufacturer, FDA looked into Anabolic’s pancreatic drug, Pancrelipase Enteric Coated Capsules, and found serious inadequacies in the firm’s manufacturing practices. Anabolic recalled the drug in July 1989 and ceased production. Pancrelipase is used to treat pancreatic enzyme deficiency, usually seen in cystic fibrosis.
Anabolic began manufacturign the pancrelipase capsules in July 1988 under five labels for Econolab of Westland, Mich., delivering shipments directly to Econolab’s wholesalers in 13 states. The wholesalers then sold the drug to their customers, the largest of which was the federal government.
Early in 1989, United States Trading Corporation, an Econolab distributor in Los Angeles, won a $442,800 contract with the U.S. Department of Defense to supply that agency with pancrelipase capsules. In previous years, McNeil Pharmaceutical of Spring House, Penn., held the contract.
Federal agencies that procure medical products for the government receive advice about product quality from FDA. Consequently, when FDA’s Francis Flaherty, who directs this government-wide quality assurance program, met with DOD procurement officials on April 20, 1989, the United States Trading Corporation contract was discussed. McNeil had given DOD a report of tests performed on anabolic’s pancrelipase capsules by an independent laboratory (contracted by McNeil) and by Johnson & Johnson Products, Inc., McNeil’s parent company. The capsules were supposed to be specially coated so that they would pass through the stomach intact, releasing the active ingredients into the intestines. The Johnson & Johnson report claimed the coating on the Anabolic-manufactured capsules didn’t work. If that were true, the active ingredients would be destroyed by the stomach’s gastric fluid.
Flaherty quickly had samples of the capsules collected from DOD storage depots and sent to FDA’s Los Angeles laboratory for testing. He also asked the Los Angeles district office to inspect Anabolic’s manufacturing plant.
Visits to Anabolic from May 12 to June 8 by Dannie Rowland and Kirsten van der Kamp, FDA investigators from the Los Angeles district’s Santa Ana resident post, revealed significant short-comings. For instance, there were no written procedures for testing the stability of finished products, no documentation to show the coating operation was valid, and no routine review of quality control procedures or test results. Moreover, one lot that failed the firm’s potency testing was distributed anyway.
During the inspection, Anabolic agreed to re-test all nine lots manufactured and to recall any that were subpotent. Results of this testing and FDA’s testing of the DOD samples showed all were either subpotent or superpotent. More importantly, all were ineffectively coated, so patients taking the drug would not receive the expected therapeutic benefit.
Anabolic wrote Econolab on June 14 to recall the one lot initially found subpotent. The firm wrote FDA two days later to explain how it planned to correct the problems Rowland and van der Kamp had cited at the close of their inspection.
Investigators van der Kamp and Martina Santillanes made follow-up visits to Anabolic beginning June 23 to obtain further documentation of the problems with the pancrelipase capsules as well as additional shipping information. They found numerous deficiencies in the company’s packaging and shipping log, including figures that disagreed with invoices and entries that were missing, in the wrong column, out of sequence, or crossed out.
On June 26, anticipating multiple seizure requests from Flaherty, Sue Ann Williams, supervisory investigator at the Santa Ana post, requested FDA’s Boston, Brooklyn, Buffalo, Detroit, and Orlando district offices to collect samples from civilian wholesale customers in their districts. Several days later, sample requests were made to even more districts to visit additional civilian customers as well as military, Public Health Service, and Veteran’s Administration consignees.
Meanwhile, on June 29, Thomas Sawyer–FDA’s Los Angeles district compliance director–was assured by Anabolic that the firm would voluntarily recall all its pancrelipase capsules. With this assurance, there was no need to seize the product in distribution channels, so FDA suspended the nationwide sampling. Investigators Santillanes and van der Kamp returned to the firm and gathered the necessary product recall information.
Anabolic indeed wrote Econolab on July 3 to recall all lots of the drug. But FDA’s Williams reviewed the letter and found it inadequate. With the agency’s guidance, Anabolic wrote a new draft to include, among other items, directions to Econolab to have United States Trading recall all military shipments. This letter went out July 5. Anabolic sent Econolab a fourth recall letter on Aug. 25, extending the recall to the dispensing level.
Anabolic received two complaints from pharmacists that its pancrelipase capsules were ineffective and failed to adequately dissolve. In addition, FDA headquarters received reports from a physician concerning two cystic fibrosis patients treated with the capsules. The patients had become ill with symptoms such as abdominal cramps, gas, and greasy stool. The symptoms disappeared when the patients were taken off Anabolic’s drug and treated with another brand.
In a Sept. 19 letter to Anabolic, FDA spelled out 12 deficiencies–not “all-inclusive”–in the firm’s manufacturing practices. FDA also advised Anabolic to expect legal remedies such as injunction if the poor practices continued. So far, the firm has not resumed production of its pancrelipase capsules.
The federal contract with United States Trading Corporation was cancelled Nov. 17, and the firm reimbursed the government for the returned drugs.
FDA will monitor the recall to completion and will reinspect Anabolic to evaluate any possible corrections.
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