Inadequate 483 Response

MINNEAPOLIS FDA has sent Beehive Botanicals Inc. a warning letter detailing the company's inadequate response to the 483 good manufacturing practice (GMP) inspection report that cited numerous violations, including failure to set and verify key specifications and to adequately test ingredients and finished products.

The GMP inspection at Beehive took place in July 2012 at the company's Hayward, WI, facility, and inspectors noted several key violations involving missing specifications and testing procedures. Beehive sent its response to the 483 inspection report on Aug. 13, 2012, but FDA's warning letter to Beehive on Feb. 8, 2013 detailed why this response was inadequate.

Specifically, the agency noted the testing instrument use by Beehive for testing does not provide purity, strength or composition analysis. "Composition cannot be verified by 100% of formulation unless the components and dietary ingredients used in the formulation have been verified to meet specifications which would result in 100% of the labeled amounts," FDA reminded the company. While the company added dietary ingredient specs to its master manufacturing record (MMR) and batch production record (BPR), specs for strength and composition of finished supplements were not also added. The company also failed to provide a timeframe for when corrections would be made.

For the testing performed by Beehive, the company failed to determine and ensure the methods used for analysis were scientifically valid, FDA said. According to the agency's warning letter, Beehive failed to confirm, prior to acceptance, reference materials for 80 percent of ingredients used are what they are supposed to be. There was also inconsistent lot comparisons made in verifying incoming lots to a verified standard.

Further, FDA noted Beehive's MMRs for several products did not specify actions required to perform and verify in-process controls, such as for blending/mixing instructions and equipment, and capsule weight range. MMRs also did not include corrective action plans for out-of-spec products and a statement of any intentional overages. Similarly, there was a lack of documentation on how retest sampling is conducted, and quality control personnel at the facility did not meet GMP requirements for approving and releasing finished product batches.

FDA provided the usual 15 working days for Beehive to notify FDA of the steps taken to correct the GMP violations, reminding the company further enforcement actions may be taken, including seizure and injunction.

UPDATE:

Beehive's attorney, Marc Ullman, parter at Ullman, Shapiro & Ullman, confirmed the company previously had been certified through NSF International's GMP certification program. "The company is flabbergasted that they could successfully complete NSF's GMP program and still receieve a warning letter like this," he stated.

As for addressing FDA concerns, Ullmann reported the company has had communications with FDA and is working hard to address the agency's concerns. To this end, it has brought in additional consultants and is confident the GMP concerns wiill be adequately resolved.

In response to the situation, NSF International provided additional details on Beehive's history in the NSF GMP program and how it communicates on FDA inspections and warning letters.

Ed Wyszumiala, general manager for dietary supplement and food certification programs at NSF, explained FDA's GMP inspection program for dietary supplements has evolved since its debut a few years ago, with the agency increasingly strict in its interpretations of the regulation and requirements. "With a public health and safety mission, NSF takes its public health role seriously and has been at the forefront in monitoring the FDA developments to help both manufacturers and auditors react to the evolving FDA GMP inspection program," he assured. "This includes working with the FDA to update the NSF audit checklist, to train NSF auditors to incorporate current FDA interpretations and to incorporate feedback from FDA inspections into the NSF audit checklist and auditor training."

Wyszumiala further explained the NSF GMP Registration is, as opposed to product certification, a consultative audit process highly dependent on open, transparent communication.

In fall 2011, NSF conducted a two day, annual/full audit of Beehive's facility, resulting in findings consistent with the previous NSF audits as well as the then current FDA inspections of Beehive Botanicals. " In April 2012, NSF conducted a one-day monitoring audit, where NSF learned that the three previous FDA audits had not resulted in any Form 483 findings or, in other words, that the FDA believed Beehive Botanicals was in compliance with the then FDA GMP inspection program," Wyszumiala said, adding FDA inspected Beehive again in July 2012 and apparently issued Form 483 findings, but NSF was not provided a copy of the Form 483 finding. "Thereafter, without the benefit of the Form 483 findings, NSF conducted its annual/full audit in October 2012, which identified many of the same issues that the FDA subsequently identified in the February 2013 warning letter. In other words, many months before NSF knew of the FDA findings, NSF on its own, in accordance with its audit checklist and trained auditors, made most of the same findings as the FDA. NSF required Beehive Botanicals to make corrective actions, which it did in October 2012. We are unsure whether the corrective actions required by NSF were shared with the FDA."

Wyszumiala noted because the FDA GMP inspection program is evolving, a manufacturer cannot use prior inspections as the final barometer for continued GMP compliance. "Here, had NSF received a copy of the Form 483 finding, NSF would have been better able to help Beehive address specific issues and findings in a timely manner, and perhaps avoid the FDA warning letter issued seven months later," he reasoned."This is why manufacturers are encouraged to immediately advise NSF of any regulatory inspections, resulting Form 483 findings and warning letters. The lesson here is that it is in everyones interest to share FDA inspection reports with your GMP auditor and allow NSF to assist in responding to corrective actions."