Inspections, Compliance, Enforcement, and Criminal Investigations

Hillestad Pharmaceuticals USA, Inc. 4/17/13


Department of Health and Human Services logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration
Minneapolis District Office
Central Region
250 Marquette Avenue, Suite 600
Minneapolis, MN 55401
Telephone: (612) 334-4100
FAX: (612) 334-4142 


April 17, 2013
via UPS OVERNIGHT                                                      
Refer to MIN 13 – 16
Donald L. Hillestad
Hillestad Pharmaceuticals USA, Inc.
178 U.S. Highway 51 North
Woodruff, Wisconsin  54568
Dear Mr. Hillestad:
From July 25 – 27, 2012, an investigator from the Food and Drug Administration (FDA) conducted an inspection of your dietary supplement manufacturing plant at 178 U.S. Highway 51 North, Woodruff, Wisconsin. The inspection identified a number of significant violations of the Current Good Manufacturing Practice (CGMP) regulations 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 letters dated August 16, September 12, October 2, December 19, 2012, and February 27, 2013, responding to the form FDA-483, Inspectional Observations, which we issued on July 27, 2012. We address the adequacy of your responses following each of your remaining significant violations below.
Your significant violations include:
1.    You did not ensure that the tests or examinations you identify to demonstrate that you have met the established specifications are appropriate, scientifically valid methods, as required by 21 CFR 111.75(h)(1).  Specifically, you use (b)(4) for all identity testing; however, the method or your use of standard reference materials is inappropriate as follows: 
a.    You use (b)(4) for all identity testing based on the initial lot of product received of an ingredient without confirming the identity of the initial lot. The initial lot becomes your reference standard for future lots. 
b.    You have established a specification, Hit Quality Index (HQI) of at least (b)(4) as compared to the reference standard, for all incoming materials. However, when challenged, a sample of product was shown to have at least (b)(4) possible matches to the reference standards at a specificity of over (b)(4). Any of these (b)(4) could have been accepted as the tested material using the method and specifications established.
c.    You reported that almost all vitamins and minerals show a match at (b)(4) HQI or higher but you have never re-evaluated your specification limit or determined if a more stringent limit is appropriate.
d.    As previously stated, you use (b)(4) for all identity testing but you have not demonstrated that this is an appropriate test to identify probiotic species.  We note that the (b)(4) is limited in its capability to adequately identity live strains of organisms. 
We have reviewed your response and find it inadequate because you failed to provide documentation of the specific steps you will take to ensure compliance.
2. You did not verify that your finished batch of dietary supplement meets product specifications for identity, purity, strength, composition, and for limits on those types of contamination that may adulterate or that may lead to adulteration of the finished batch of the dietary supplement, as required by 21 CFR 111.75(c). Specifically, you have established specifications for strength and composition on your product, Acidophilus with Pectin; however, your means of verifying whether specifications are met are “based on input,” as in your operators have identified that they have added the ingredients to the batch of product. Ensuring that an ingredient is added to the batch of product does not provide adequate assurance that the finished product specifications are met. Furthermore, although you did conduct finished product testing on your Iron Tone Plus and Folic Acid Tablets for vitamin C content, you did not provide adequate documentation of your basis for determining that compliance with the specifications selected would ensure that your finished batch of the dietary supplement meets all product specifications, as required by 21 CFR 111.75(c)(3). For example, you did not provide documentation for your basis for determining that meeting the specification for vitamin C in your Iron Tone Plus product would ensure that the specifications for iron and vitamin E are met. Moreover, iron and vitamin E are likewise verified “based on input” which, as stated above, is not an appropriate finished product test. 
We have reviewed your response letter dated February 27, 2013, but we are unable to determine the adequacy of your response.  You state that you have discontinued your Acidophilus product and replaced it with a stronger Acidophilus product without pectin, and that you have established a specification for Acidophilus at the finished batch stage that you will verify through finished product testing.  However, you did not provide the established specification, nor did you provide an explanation of the finished product testing you plan to conduct.  We have also reviewed the blending study that you submitted with your February 27, 2013, response letter, but it does not address the components that are in the products that were reviewed during the inspection.  Furthermore, your blending study failed with respect to Biotin and you did not provide sufficient detail for us to review the study; therefore, your response is inadequate. 
We acknowledge that you indicated that your Garlic/Goldenseal/Echinacea and Naticor products cannot be tested at the finished batch stage due to interference, that these products are not currently being manufactured, and that prior to manufacturing the products in the future, you will prepare the necessary documentation exempting the product from verification testing under 111.75(d)(1). We note that our investigators will verify compliance under 111.75(d)(1) at the next inspection.
3. Your Master Manufacturing Records (MMRs) did not contain written instructions for the required elements necessary to ensure the quality of the dietary supplement, as required by 21 CFR 111.210. For example, your MMR for your Acidophilus with Pectin failed to include:
  1. Corrective action plans for use when a specification is not met, 21 CFR 111.210(h)(5);
  1. Procedures for sampling and a cross-reference to procedures for tests or examinations, 21 CFR 111.210(h)(2)].
We have reviewed your response and find it inadequate because you failed to provide a copy of the MMRs that include corrective action plans.
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). 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
Minneapolis District

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