FDA Warns Wyeth over Manufacturing Quality at Puerto Rican Plant

FDA Demands Action on Manufacturing Shortcomings

The U.S. FDA yesterday published a warning letter (dated 8 May) that it had sent to U.S. drug-maker Wyeth, informing the company of a series of failures at its manufacturing site in Puerto Rico. The letter followed an inspection of the facility that the agency carried out between 7 November and 15 December last year, which found that a number of the company's products were not packaged under proper conditions.

The letter (the full text of which is available at the FDA's website) stated that,

'[Wyeth's]…manufacture, processing, packaging or holding of the human drug products Triphasil -21 & 28 tablets, Prempo 0.625/2.5mg & 0.45/1.5mg tablets, Advil (liquid Gels, Caplets, Gel Caplets), Effexor tablets, Duofeln tablets, Gestodene tablets, Caltrate 600mg + D tablets and Inderal LA 60mg tablets violated the Current Good Manufacturing Practice.'

The agency listed five deficiencies that it had observed at Wyeth's manufacturing plant during the inspection:

• Wyeth's failure to thoroughly investigate or correct signs of possible contamination within batches of Triphasil (levonorgestrel and ethinyl estradiol tablets - triphasic regimen). According to the agency, five months after the contaminant was detected in these batches of Triphasil, Wyeth identified that it was in fact an extractable compound originating from the Nylon components used to pack the Triphasil drug product.
  
  
• The FDA also highlighted Wyeth's failure to clean and maintain the packaging equipment at appropriate intervals, in order to prevent contamination that would alter the safety, identity, strength, quality of the drug products being manufactured. The letter then cited a number of examples of customer complaints regarding foreign metal objects - including screws and washers - that had been found in some of the company's bottled products.
  
  
• The agency also noted that Wyeth had failed to adequately inspect packaging and labelling equipment prior to its use, to ensure that all drug products had been removed from previous operations. The FDA cited several incidents of products from previous lots being found on the company's non-dedicated packaging lines while new lots were being packaged.
  
  
• Wyeth was also criticised for being slow to report problems and failing to submit New Drug Application (NDA) Field Alert Reports within the required three working days of significant chemical, physical or other changes or deterioration of a distributed product being detected.
  
  
• Finally, the agency condemned the failure of Wyeth's quality control unit to review production records to assure that errors had not occurred, and to fully investigate errors that had occurred during the manufacturing process.

The FDA's most stinging censure was reserved for Wyeth's quality control unit. The agency stated that all of the deficiencies that it identified in the letter were indicative of the unit's failure to assure that 'each deviation from…[Wyeth's] manufacturing operations, impacting the identity, strength, quality and purity of…[Wyeth's]…drug products,…[had] been adequately investigated'.

Wyeth stated that some of the contaminants of Triphasil that the agency highlighted in its letter, which included phenol, were caused by the normal migration of the chemical from packaging to product, according to Reuters. The report also cited a Wyeth spokesman as stating that the company had recalled some lots of Triphasil already, and was working with the FDA on the problem. He then added that had been no reports of these problems having any impact on patient safety and product efficacy. In its warning letter, the FDA gave Wyeth 15 working days from receipt of the letter to notify the agency of the specific steps that it had taken to correct the noted manufacturing violations.

Outlook and Implications

Observers were split on the impact that these manufacturing problems would have on Wyeth's business. While none of the issues relate specifically to problems with the manufacture of Wyeth's best-selling products, being mainly being confined to Triphasil, the severity of the impact will be heavily contingent on the FDA's regulatory response. It is conceivable, as noted by an analyst cited by the Reuters News Service, that the agency could decide to take a hard line with Wyeth and delay all non-critical NDAs from the company. This could have a serious detrimental effect on Wyeth's business by delaying the launch of a number of new products - most notably, and critically, desvenlafaxine,  the follow-on product to anti-depressant Effexor (venlafaxine).

However, while this is definitely the worst-case scenario, the warning letter does demonstrate that the FDA intends to keep a close watch on Wyeth's manufacturing processes. The company must now prove to the regulatory authority that it has got its ship in order, or the consequences could be severe.

Find out more about Same-day Analysis