In a scathing letter to Wyeth, the US Food and Drug Administration (FDA) has vehemently criticised the drugmaker's manufacturing operations in Puerto Rico, accusing it of failing to report failures even when it was aware of them.
The good manufacturing practice (GMP) violations were discovered between November and December 2005 during the FDA's inspection of Wyeth's manufacturing facility in Guayama, affacting several drugs, including the company's Triphasil birth control pills, hormone replacement drug Prempro, Effexor depression tablets and several forms of the painkiller Advil.
Thanks to its low labour costs and its rich pool of expertise, Puerto Rico is a popular destination for pharmaceutical manufacturers, yet this development may hurt public confidence in drugmakers that offshore some of their production there.
Among the failures the FDA identified, the most embarrassing for Wyeth is the contamination of Tiphasil with an unknown substance and the subsequent handling of the issue.
The contamination was detected by Wyeth in batches of Triphasil tablets in June 2005 and initial investigations by the drug firm suggested that the contaminant was phenol, a packaging extractable originating from the ink used to print the package insert, which is considered to be quite toxic to humans via oral exposure.
But when the company carried out a laboratory investigation report (LIR) in August 2005, it concluded that the unknown peak in the specification results of the batches was not an impurity but an inaccurate observation.
Enter the FDA. During the agency's inspection of the site in November 2005, Wyeth changed its story, suggesting the unknown peak was Caprolactam, an extractable that potentially originated from the Nylon components used to pack Triphasil
In the following months the plot thickened as Wyeth continued to send mixed messages about the identity of the contaminant and to this day the FDA maintains that "the identity and the root cause of the peak are still unknown."
"No adverse effect to patients has been reported, there is no medical risk," Wyeth spokesman Doug Petkus told In-PharmaTechnologist.com.
"However, we have already recalled some of the product and we are cooperating with the FDA, we have made changes in the line clearance, on metal detectors, and we intend to take other steps as well."
Last week Wyeth issued a voluntary recall of 20 lots of Triphasil from wholesale distributors, still there has been no consumer recall and the FDA is concerned that the affected lots remain in the market.
But questions remain as to why Wyeth did not pursue the issue of the contaminant until it was raised by the FDA.
In fact, Wyeth failed to submit NDA Field Alert Reports (FAR) about the issue within 3 working days as the law dictates - it actually submitted them after five months, prompted by the FDA's inspection.
Whether this is the just the tip of the iceberg remains to be seen; FDA investigators have observed seventeen other examples, occurring between December 2003 and August 2005, where adequate investigations into unknown peaks were not performed, in drugs such as Ovrette, Zebeta, Alesse, Loette and Lo Gentrol.
The letter outlines further failures in cleaning and maintaining the packaging equipment, citing, among others, complaints reporting the presence of a screw and two washers inside a bottle of Inderal LA capsules.
Wyeth also failed to adequately inspect packaging and labelling equipment prior to its use to assure that all drug products have been removed from previous operations.
The FDA letter lists several incidents where product from previous lots was found in non-dedicated packaging lines, while filling and packaging operations were being performed.
In each of these cases, a complete line clearance had been performed between the processing of the two different products, and records indicated that discrepancies or deviations were not found.
In August 2005 for example, during a line clearance performed after the packaging of Advil caplets, two Advil liquid gel units were found under the conveyor belt leading to the in-line metal detector.
A similar line clearance was performed on this packaging line, prior to the packaging of Advil caplets, but no product was found during this clearance.
Wyeth's investigation into this incident determined that its procedures did not instruct operators to clean the conveyors leading to the in-line metal detector, so any product lodged in this section of the line would not have been discovered during the line clearance.
The FDA concludes its letter by pointing the finger to Wyeth's quality control unit for its "failure to assure that each deviation from drug manufacturing operations, impacting the identity, strength, quality and purity of your drug products, has been adequately investigated."
"Furthermore, your quality control unit has failed to assure that corrective actions have been determined and implemented to prevent the recurrence of these deviations," the FDA wrote.
Failure to make prompt corrections could result in regulatory action without further notice, warned the agency, including seizure, injunction and prosecution.
Wyeth will be aware that federal agencies are routinely advised of warning letters issued so that they may take this information into account when considering the award of government contracts.
The company now has two weeks to respond with specific steps it has taken to correct the violations.
Wyeth's other manufacturing plant in Puerto Rico, in Carolina, is not affected by the affair, yet it is not the first time the company has had a spat with the FDA.
In 2000 Wyeth had to fork out $30m after the FDA determined it was not meeting manufacturing standards at plants in Pennsylvania and New York.