Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
Minneapolis District Office
250 Marquette Avenue, Suite 600
Minneapolis, MN 55401
Telephone: (612) 334-4100
FAX: (612) 334-4142
February 8, 2013
via UPS Overnight Delivery
Refer to MIN 13 – 12
Linda L. Graham
President and Owner
Beehive Botanicals, Inc.
16297 West Nursery Road
Hayward, Wisconsin 54843-7138
Dear Ms. Graham:
From July 23 – 25, 2012, an investigator from the Food and Drug Administration (FDA) conducted an inspection of your dietary supplement manufacturing plant at 16297 West Nursery Road, Hayward, Wisconsin. The inspection identified a number of significant violations of the Current Good Manufacturing Practice (CGMP) regulation for dietary supplements, Title 21, Code of Federal Regulations, Part 111, 21 CFR Part 111. These violations cause your dietary supplement products to be adulterated within the meaning of section 402(g)(1) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. § 342(g)(1), in that the dietary supplements have been prepared, packed, or held under conditions that do not meet the CGMP regulation for dietary supplements.
We received your letter dated August 13, 2012, responding to the form FDA-483, Inspectional Observations, which we issued on July 25, 2012. Overall, your response is inadequate. We have addressed each of your corrective actions below.
Your significant violations include:
1. You failed to establish required specifications for points, steps, or stages in the manufacturing process where control is necessary to ensure the quality of the dietary supplement, as required by 21 CFR 111.70. Specifically:
- You failed to establish component specifications for each component that you use in the manufacture of a dietary supplement, as required by 21 CFR 111.70(b). All components are approved for use in production without having specifications for purity, strength and composition.
- You failed to establish product specifications for the identity, purity, strength, and composition for each dietary supplement you manufacture, as required by 21 CFR 111.70(e). For example, you did not provide any finished product specifications for strength or composition for your products (b)(4) and (b)(4).
In addition, we note that manufacturers are responsible for more than establishing specifications. Once you have established the specifications under 21 CFR 111.70, you must determine whether the specifications have been met as required by 21 CFR 111.73 and 111.75.
Your August 13, 2012, response is inadequate for the following reasons:
(1) 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. The instrument you use for testing, (b)(4) does not provide purity, strength or composition analysis. For example, your BoneHealth product label lists Vitamin D at 600 IU per serving, Calcium at 1,000 mg per serving and Magnesium at 500 mg per serving. You cannot ensure meeting these labeled amounts without having created appropriate specifications and then performed the needed testing to ensure such specifications are met;
(2) While you have added specifications for the dietary ingredient into your MMR and BPR, you have not added the strength and composition of the finished dietary supplement. Your document, identified as “Finished Product Testing,” continues to only include (b)(4) testing, (b)(4) testing, (b)(4); and
(3) You have provided no timeframe in which the corrections will be completed.
2. You failed to ensure that the tests or examinations you used to determine whether the specifications are met are appropriate, scientifically valid methods, as required by 21 CFR 111.75(h)(1). Specifically:
- You use (b)(4) for all identity testing. However, you use (b)(4) of dietary ingredient received as the standard against which future lots are compared but, in approximately 80% or more of these ingredients, you have not confirmed that the reference materials are the biological material they purport to be prior to acceptance. You require that subsequent lots of ingredients match the initially set standard at a rate of (b)(4)% or greater. During the inspection different ingredients were shown to be capable of making such a match. Further, your procedure allows analysts to select a different lot of received ingredient as a comparison when the incoming material does not match well with the originally set standard.
Your August 13, 2012, response is inadequate because you specifically provided and pointed out an example of the (b)(4) analytical results for the dietary ingredient, Rhodiola Extract. However, the third party laboratory states that “The analytical method has not been verified or validated for this product by” that lab. You also provide the (b)(4) Chromatography for the same dietary ingredient but performed by a different lab. In this document, the lab states that the source for the Chromatography reference is the same lab as had performed the (b)(4) analysis. Information was not provided that demonstrates that the reference material was confirmed to be the actual botanical ingredient. Additionally, you did not provide a timeframe for when this correction would be completed.
3. Your Master Manufacturing Records (MMRs) do not contain all the elements required under 21 CFR 111.210. Specifically, your MMRs for (b)(4) failed to include:
- Specific actions necessary to perform and verify points, steps, or stages in the manufacturing process where control is necessary to ensure the quality of the dietary supplement, 21 CFR 111.210(h)(3), such as mixing/blending instructions, times, and equipment, and acceptable capsule weight range during in-process checks.
- Corrective action plans for use when a specification is not met, 21 CFR 111.210(h)(5).
- A statement of any intentional overage amount of a dietary ingredient, 21 CFR 111.210(e).
Your August 13, 2012, response is incomplete. You have not provided a timeline for the completion of this corrective action. Furthermore, the specific written instructions required by 21 CFR 111.210(h)(3) are not included in your submitted revised MMR record; the correction only appears in the revised standard operating procedures.
4. You failed to establish and follow laboratory control processes that are reviewed and approved by quality control personnel to include use of criteria for selecting standard reference materials used in performing tests and examinations, as required by 21 CFR 111.315(d). Specifically:
- You failed to establish any criteria (i.e., characterization) to establish a reference standard. You use (b)(4) of dietary ingredient received as the standard against which future lots are compared but, in approximately 80% or more of these ingredients, you have not confirmed that the reference materials are the biological material they purport to be prior to acceptance nor have you qualified these materials as a standard. Further, your procedure allows analysts to select a different lot of received ingredient as a comparison when the incoming material does not match well with the originally set standard.
5. You failed to provide documentation of your material review and disposition decision and follow-up, as required under 21 CFR 111.140(b)(3), that included a description of your investigation into the cause of the deviation from the specifications or of the unanticipated occurrence, 111.140(b)(3)(ii), and an evaluation of whether or not the deviation or unanticipated occurrence resulted in or could have led to a failure to ensure the quality of the dietary supplement or a failure to package and label the dietary supplement as specified in the master manufacturing record, 21 CFR 111.140(b)(3)(iii). Specifically:
- A result of the finished product testing results for (b)(4) Capsules lot #27110000N688.1B had a result of (b)(4) of (b)(4) MPN/g. The specification for (b)(4) is less than (b)(4) MPN/g. You performed retesting of samples which confirmed the result and released the product. However, there was no documentation to describe how the retest samples were collected and your investigation did not identify any possible root causes.
6. Your quality control personnel failed to meet the requirements under 21 CFR 111.123(b)(3) for approving and releasing a finished batch of dietary supplements. Specifically, your firm released (b)(4) Capsules lot #27110000N688.1B which did not meet the specification for (b)(4).
This letter may not list all the violations at your facility. You are responsible for ensuring that your facility operates in compliance with the Act and all applicable FDA regulations, including the CGMP regulation for dietary supplements. We may take further action if you do not promptly correct these violations. For instance, we may take further action to seize your products and/or enjoin your firm from operating.
You should notify this office in writing within 15 working days of receipt of this letter of the steps that you have taken to correct the above-listed violations and to assure that similar violations will not recur. If corrective action cannot be completed within 15 working days, please state the reason for the delay and the timeframe within which the corrections will be made.
Section 743 of the Act, 21 U.S.C. § 379j-31, authorizes FDA to assess and collect fees to cover FDA’s costs for certain activities, including re-inspection-related costs. A re-inspection is one or more inspections conducted subsequent to an inspection that identified non-compliance materially related to a food safety requirement of the Act, specifically to determine whether compliance has been achieved. Re-inspection-related costs means all expenses, including administrative expenses, incurred in connection with FDA’s arranging, conducting, and evaluating the results of the re-inspection and assessing and collecting the re-inspection fees,
21 U.S.C. § 379j-31(a)(2)(B). For a domestic facility, FDA will assess and collect fees for re-inspection-related costs from the responsible party for the domestic facility. The inspection noted in this letter identified non-compliance materially related to a food safety requirement of the Act. Accordingly, FDA may assess fees to cover any re-inspection-related costs.
Address your reply to the U.S. Food and Drug Administration, 250 Marquette Avenue, Suite 600, Minneapolis, MN 55401, Attention: Tyra S. Wisecup, Compliance Officer.
Michael Dutcher, DVM