First GMP Warning Letter Reflects FDA's List Of Major Concerns

FDA's first warning letter concerning dietary supplement good manufacturing practices advises Coats International Holdings to follow written procedures, improve documentation and conduct appropriate identity tests.

The violations listed in the letter posted May 3 on FDA's Web site echo recent observations made by senior agency supplement program official Carl Reynolds on common GMP compliance problems (¹ (Also see "FDA's Reynolds Marks Top GMP Trouble Spots As Deadline Looms" - Pink Sheet, 10 May, 2010.)).

FDA submitted the letter March 30 to Dallas-based Coats, an aloe product manufacturer. In addition to listing GMP violations, officials said the firm's corrective actions taken after FDA's inspection, conducted Sept. 1-18, 2009, were inadequate.

Firms "that are doing something similar" to the violations in the warning letter "should also take care to make corrections," an FDA spokesperson told "The Tan Sheet."

Reynolds told industry stakeholders April 28 at the SupplySide East tradeshow and conference in Secaucus, N.J., to refer to FDA's compliance guidelines for supplements, available on the agency's Web site, for clarity. The guidelines detail focus areas for GMP inspections, and dictate major GMP violations that likely will draw warning letters.

Major areas outlined in the compliance document deemed warning letter-appropriate include: lack of batch records, lack of quality control review or quality control procedures, failure to establish specifications for raw material for dietary ingredients or failure to conduct identity tests, lack of master manufacturing records and "significant plant deficiencies."

Some of these issues occurred in Coat's inspection.

The letter said Coats failed to conduct at least one appropriate test or examination to verify the identity of a dietary ingredient used to manufacture two aloe products for the company Herbalife.

Many of the violations related to a failure to document information.

FDA said the firm did not follow its written procedure for collecting representative samples of each component and does not have documentation to explain the rationale for raw material specifications.

The FDA letter instructed Coats to respond in writing within 15 days with specific steps taken to correct the violations.

Failure to comply could lead to enforcement, including the seizure of violative products and an injunction against the firm.

In an interview, Coats President and CEO Billy Coats said the firm replied to the warning letter, made corrections FDA called for and submitted appropriate documentation. The firm awaits FDA's reply.

However, Coats said the one issue that "is still on the table" is establishing an appropriate identity test for aloe. He said he is working with four other companies on an aloe identity test.

Coats said the firm has made products for Herbalife for 15 years and has operated for 49 years.

John Venardos, worldwide regulatory, government & industry affairs with Herbalife, said his firm is conducting its own independent tests and plans to meet with FDA and Coats to review the testing results. "We hope that addresses all of their concerns," he said.

At SupplySide, Reynolds said the agency had issued one warning letter related to GMPs, but did not identify the target.

The senior advisor in FDA's Division of Dietary Supplement Programs said he expects some firms will not be ready to comply with the GMPs by the final deadline in five weeks.

The June 2007 GMP final rule gave firms with 500 or more employees a year to comply and those with 20 to 499 employees until June 2009. Smaller firms must comply by June 25 (² (Also see "FDA Will Rev GMP Inspections Of Medium Supplement Firms, After A Pause" - Pink Sheet, 11 May, 2009.)).

First Warning Provides Example

Hyman, Phelps and McNamara attorney Wes Siegner said the letter should show other supplement firms they need to establish standard operating procedures before FDA arrives to inspect.

Firms need to "know how to handle FDA inspections if they have not already trained for that," Siegner said in an e-mail.

He said warning letters that FDA makes available "need to be parsed carefully" to see how the agency will interpret "vague terms" in the GMP regulations.

Siegner, who discussed the letter in a May 10 FDA Law Blog post written with HP&M colleague Ricardo Carvajal, also said firms should self-audit to help avoid the problems FDA says it found with Coats.

When GMP implementation is completed, he expects FDA will focus more on enforcement, which could mean more severe actions than warning letters.

Expect "a significant number of warning letters over the next year, followed by possible injunctive actions after that phase - possibly even without warning letters if FDA sees some very bad facilities," Siegner said.

But criminal cases linked to GMP violations are unlikely. "The possibility of any criminal prosecutions is very low, barring some significant safety problems along the lines of the recent peanut situation," he said.

Marc Ullman, an attorney with New York-based Ullman, Shapiro and Ullman, said ingredient identity test issues FDA finds in GMP inspections likely could lead the agency to take harsher action.

"There is going to come a point ... that the warning letters are going to start saying, 'You don't do the identity testing on incoming dietary ingredients, therefore we consider all products manufactured in your facility'" from a certain day on are adulterated.

Ullman said FDA still is "acknowledging there is still a bit of a learning curve," but likely will not allow firms too many chances to learn "they really mean it.'"

According to FDA, Coats' quality control program omitted a periodic review of calibration records for instruments and controls. The firm did not have documentation detailing quality control personnel's approval of products released or rejected, FDA said.

FDA said the master manufacturing record for manual operation did not include written instructions of one person verifying the addition of a component to a product or of one employee signing off for another.

Nor did the record include corrective action plans to take when a specification goes unmet, a problem Reynolds identified as common.

Ullman said the warning letter highlights the importance of documentation.

"We see it repeatedly hammered home in this warning letter - if it is not in writing, it didn't happen," Ullman said. "If the writing doesn't exist that you are actually following your written procedures, it didn't happen."

In their blog post, Siegner and Carvajal called the warning letter "a timely reminder that failure to comply with any required step, including even the signing of a required document, causes the products at issue to be adulterated and therefore wrongfully marketed."

Siegner and Carvajal also said that such violations to the Food, Drug and Cosmetic Act are misdemeanor criminal violations.

"Although the federal government has seldom brought such actions in recent decades, there are signs the agency may be considering bringing such cases again against senior management to emphasize the need to comply" with the act's requirements, they wrote.

The agency announced in March its strategy to increase misdemeanor prosecutions and hold corporate officers responsible for the issues accountable (³ (Also see "FDA Targets Executives With Powerful Misdemeanor Strategy" - Pink Sheet, 26 Apr, 2010.)).

FDA also said Coats' master manufacturing record, batch production records and corrective action plans were incomplete. FDA said the master manufacturing record, for example, did not include corrective action plans to take when a specification goes unmet.

Treat A 483 Like A Warning Letter

To get ahead of GMP issues, Reynolds has stressed firms should read the rule language and know what is expected and to take corrective actions as soon as possible.

However, FDA said Coats inadequately addressed potential GMP violations identified in the 483 at the conclusion of the September 2009 inspection.

FDA said the firm's response did not adequately address identity test concerns the agency had and did not provide what new test would be implemented.

Similarly, FDA found the firm's other corrective action plans were inadequate, often because the firm did not include documentation of any changes.

Ullman said firms should treat responses to 483s as if they were warning letters to ensure their corrective action plans are adequate.

Further, he said firms should deal with corrective actions as the inspection takes place, pointing out that Coats' inspection occurred over 17 days. An inspector "is going to tell you what they see and they are going to make comments and oral observations."

Firms should "get a hold of your consultant or your counsel and deal with some of the things as your investigator comments on them," he said.

Daniel Fabricant, VP of scientific and regulatory affairs with the Natural Products Association, said firms also should take advantage of the "debrief" period at the end of an inspection, during which he said firms can discuss inspection findings with inspectors.

Ullman agreed. "It's an opportunity to interact," he said, adding that firms can acknowledge, own and aim to correct mistakes.

Firms can provide documentation on corrections to the investigator within 24 hours, "and have it sitting there at the investigator's desk before they sit down and do a formal write-up," he said.

Fabricant said firms can help ensure their corrective actions are adequate by enlisting a third party.

It is important for a firm to "stay on top of the agency" and current with all the information, after submitting corrective action plans or follow-up correspondence, he said. "Commit to the corrective action. And then follow up."

- Katie Stevenson ( ⁴ [email protected] )