Merck's response to FDA vaccine inspection inadequate; warning letter issued

At "Everything is fine at Merck?" I expressed skepticism about Merck's contention via a letter from the Sr. VP of Vaccine Manufacturing, John T. McCubbins, to the Philadelphia Inquirer that everything was basically OK in the Merck vaccine division.

Now, here is the word from the horse's mouth on the inspection and a warning letter issued on April 28. 2008. (A PDF of the warning letter is here, and HTML version is here.)

Merck Warning Letter

http://www.fda.gov/cber/faq/merckqa.htm

FDA's Electronic Freedom of Information Reading Room - Warning Letters and Responses

When did FDA first become aware of issues with Merck and Co described in the April 28, 2008 Warning Letter?

FDA conducted an inspection of Merck and Co.'s West Point, PA, facility between November 26, 2007, and January 17, 2008.

What issues did the agency identify during the inspection?

FDA investigators documented significant deviations from current good manufacturing practice in the manufacture of licensed vaccines, bulk drug substances and drug components. At the conclusion of the inspection, investigators issued a list of inspectional observations (FDA Form 483) to the firm, which included but was not limited to inadequate investigations of deviations and failure to maintain production and process controls. After determining that the firm's response to the FDA Form 483 was inadequate to address the serious deviations noted, FDA issued the Warning Letter. FDA is continuing its discussions with the firm on an ongoing basis.

Why did FDA issue this warning letter?

FDA's practice, depending upon the nature of a violation of regulations, is to give individuals and firms an opportunity to take voluntary and prompt corrective action before it initiates an enforcement action. Warning Letters are issued to achieve voluntary compliance and to establish prior notice. The use of Warning Letters and the prior notice policy are based on the expectation that most individuals and firms will voluntarily comply with the law.

Warning Letters are issued only for violations of regulatory significance. Significant violations may lead to enforcement action if not promptly and adequately corrected. A Warning Letter is the agency's principal means of achieving voluntary compliance with applicable laws and regulations.

What products are covered by this Warning Letter?

The Warning Letter covers U.S. licensed biologics manufactured by Merck at the West Point, PA facility, including but not limited to the following vaccines: Liquid PedvaxHIB®, RECOMBIVAX HB®, ProQuad®, Gardasil®, VAQTA®, and COMVAX®.

The FDA warning letter also addresses Merck's CEO's response to the inspection report and states:

... The deficiencies described in this letter are indicative of your quality control unit’s inability to fulfill its responsibility to assure the identity, strength, quality, and purity of your drug product and drug substance.

I should also note the FDA states "FDA does not believe that the issues identified will affect the safety of the vaccines manufactured by Merck. We will continue to review the progress made by the firm."

Is everything OK at Merck? I report, you decide.

Fortunately, the vaccines in question are apparently OK. This time.

Will they be as lucky next time?

Finally, Merck was sent the FDA warning letter because their response to the 483 inspection report was deemed inadequate by FDA.

We [FDA] acknowledge receipt of your [Merck's] written response dated February 15, 2008, which addresses the inspectional observations on the Form FDA 483 issued at the close of the inspection, and we have reviewed its contents. Corrective actions addressed in your letter may be referenced in your response to this Warning Letter; however, we believe that your response(s) did not provide sufficient detail to fully assess the adequacy of the corrective actions.

One wonders why "insufficient details" were provided. Was it complacency borne of habit, due to such matters in the past not getting the levels of public exposure (press, blogs etc.) and aggressive FDA response that they receive now? Or, in the face of downsizings, reorganizations, defections and loss of Merck's prior culture, does the vaccine division have enough expertise and resources to research, craft and execute a properly detailed, timely remediation plan?

It would be interesting if Mr. McCubbins shared with the media and/or bloggers the vaccine division Long Range Operating Plan and headcount projections from, say, five years ago, compared to today's. I doubt this would happen.

-- SS