With the steady drumbeat of Form 483s, Warning Letters and Untitled Letters sent by the US Food and Drug Administration (FDA) to pharmaceutical, medical device and dietary supplement manufacturers, it can be difficult to remember that those aren't the only life science industries FDA regulates-a fact that was brought into clear view last week when the agency sent a New Kersey-based veterinary pharmaceutical company an Advisory Action Letter.
Rare Letter, Common Problems
Such letters are sent exclusively by the Center for Veterinary Medicine (CVM), but rarely so. To date, CVM has only sent one letter in 2013, and since 2008 has only sent 14-far fewer than the number of Warning Letters sent by FDA, which can exceed that total in a single week.
But if the letters are few and far between, the reasons they are sent to manufacturers are decidedly common. A letter sent by CVM to Phibro Animal Health Corporation on 22 May 2013 cites the company for manufacturing Type A medicated articles, which FDA defines as a mixture of one or more drug substances with a vehicle or vehicles for consumption.
In the case of Phibro, FDA's inspection of the company's Teaneck, N.J. facility found that the company was manufacturing products in violation of current good manufacturing practices (CGMPs) for veterinary pharmaceuticals. Interestingly, the Advisory Action Letter-similar in form and function to a Warning Letter-cites a complaint that FDA has been focusing on heavily in recent weeks: Contractor management.
The letter says the company regularly failed to submit Field Alert Reports (FARs) under 21 CFR 514.80(b)(1). FARs are used to alert FDA when products are found to have been manufactured outside of approved specifications (OOS), and are required to be submitted to FDA within three days of a company receiving OoS findings. Phibro allegedly failed to do this in several instances, going as far as to "invalidate the original test results by repetitive retesting" to get the result it wanted, FDA wrote. In 2011 alone, FDA alleged the company had 140 OOS results, of which dozens were retested and subsequently released.
Such retesting is permitted, but not without a proper investigation and an assignable cause, two criteria FDA said the company did not meet. "Accordingly, the actions taken often did not prevent recurrence of the problems." This left regulators "concerned about the lots affected," saying the retesting was an "indication that [the] firm's contract manufacturer does not have a well-controlled manufacturing process."
And if that was the first indication that the manufacturing process had problems, FDA wrote that the second was a pervasive "insect issue" that had not been investigated to determine its impact on its product's stability. The company's response to FDA's Form 483-a notice of deficiencies-apparently did not include correct and preventive actions (CAPA) meant to prevent insect infestations in the future, earning another rebuke from regulators.
A Common Complaint
The observations culminate in a now-familiar warning to the company: A sponsor cannot contract out its responsibility, and must provide assurances that a final product meets required standards and specifications.
"Your firm is ultimately responsible for the quality of your products," FDA explained. "Regardless of who manufactures and tests your products, you are required to ensure these products meet predefined specifications prior to distribution and that they are manufactured in accordance with the Act, and its implementing regulations, including CGMP regulations for Type A medicated articles."
That language is similar to that used in five Warning Letters sent in May 2013 to dietary supplement manufacturers, in which FDA wrote that, "Although your firm may contract out certain dietary supplement manufacturing operations, it cannot, by the same token, contract out its ultimate responsibility … to comply with dietary supplement CGMPs."
Concluding its letter to Phibro, FDA said it believed the company needs to implement an effective audit system at its contract facilities to ensure its products are manufactured to CGMPs. "Without such a quality feedback system in place, the Quality System cannot provide the basic assurance of product quality."
FDA: Advisory Action Letter