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July 8, 2022

In reply, refer to CMS 621842

WARNING LETTER

Dear Ms. Martin-Buresh and Mr. Buresh:

The U.S. Food and Drug Administration (FDA) conducted an inspection of your facility, located at 1601 NE Hemlock Avenue, Redmond, Oregon, on September 20, 2021, through September 24, 2021. The inspection revealed serious violations of FDA’s regulations for Current Good Manufacturing Practice (CGMP) in Manufacturing, Packaging, Labeling, or Holding Operations for Dietary Supplements, under Title 21, Code of Federal Regulations (CFR), Part 111 (21 CFR Part 111). These violations cause your dietary supplement products, including Stress Guard, Aller-Aid, Eyes Love Lutein, TumeriPro, Prostate Health, Kids Tranquil Child, Kids Echinacea Goldenseal, CountToZen, Milk Thistle Elixir, Ashwagandha Gingko, Sleep Better, Hawthorn, Bilberry, Cordyceps, and Black Cohosh 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 they have been prepared, packed, or held under conditions that do not meet CGMP requirements for dietary supplements. You may find the Act and FDA regulations through links on FDA’s home page at www.fda.gov.

We received your email correspondence dated October 15, 2021, December 15, 2021, February 11, 2022, April 12, 2022, and June 8, 2022, written in response to the Form FDA 483, Inspectional Observations, issued to you at the close of the inspection. We address your responses below, in relation to the noted violations.

Your significant violations of CGMP requirements are as follows:

1. You failed to establish product specifications for the identity, purity, strength, and composition of the finished batch of the dietary supplement, 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 to ensure the quality of the dietary supplement, as required by 21 CFR 111.70(e). Specifically, you have not established specifications for the strength and composition of the dietary ingredients in the formulation of your Kids Tranquil Child and Eyes Love Lutein.

We have reviewed your responses dated October 15, 2021, and December 15, 2021, in which you communicated your plan to update all finished product specifications and provide progress updates to FDA. Neither of these responses included revised specifications for the products referenced in the relevant observation.

In your response dated February 11, 2022, you stated that you have updated specifications for 30 finished dietary supplements; however, you provided specifications for only one product not referenced above, as an “example” (Oat Straw Tops c/s COG 4 oz). For this product, the identity specification relied on microscopy, but no characteristic morphology was provided. You also claimed there is no scientifically valid method for determining strength, and that composition is determined by weighing the bag of product; these specifications are not adequate.

In your response dated April 12, 2022, the Finished Product Specification sheet for Eyes Love Lutein, which you provided as an example, is inadequate because it does not contain a strength specification for the dietary ingredient Organic Bilberry Fruit. Also, the specification sheet described the “Genus & species” of this product as Pullulan capsules; this particular descriptor does not apply to your finished product and also would be inaccurate even if applied to the Organic Bilberry Fruit dietary ingredient because “pullulan” is a starch used to make capsules.

In your latest response, dated June 8, 2022, you provided specifications for your product Ashwagandha - Organic, which you described as an “[e]xample of a master specification that has been recently updated.” The specifications provided in this document are inadequate for the reasons we describe below. For the identity specification, you listed organoleptic techniques in conjunction with microscopic analysis or (b)(4) analysis. You stated, “[i]dentify using microscopic analysis and verify that results confirm the presence of relevant diagnostic characters as described on the product specific Form 354 Microscopic Analysis Report (the standard for the ingredient).” However, your response dated December 15, 2021, included only a blank template Form 354. No completed Form 354 with the standard characteristics of Ashwagandha was provided to serve as a “standard” for comparing the sample. You mentioned (b)(4) as an alternative identification method, but you provided no (b)(4) conditions and no description of how a reference standard will be procured for the analysis. You stated, “Potency is undiluted ingredient, and no scientifically valid method exists for testing this product specification.” Potency is the strength of the ingredient, and common high performance liquid chromatography (HPLC) methods exist for testing the strength of Ashwagandha. Also, you previously stated that you will continue to use input as a strength “test” method in cases where no other strength test method is available. Testing by input is not an acceptable method.

FDA has found each of the examples of revised finished product specifications that you have sent us in your responses to be inadequate.

2. You failed to ensure that the tests and examinations that 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 did not have appropriate, scientifically valid methods to ensure that the identity specification for each component that you use in the manufacture of a dietary supplement is met. Furthermore, you did not have appropriate, scientifically valid methods to ensure that your identity and strength specifications for your finished dietary supplement are met. For example:

a. Specifications for “potency herb strength” for the total of all the dietary ingredients in liquid dietary supplements such as Kids Echinacea Goldenseal, CountToZen, and Milk Thistle Elixir are verified by calculation and input into the batch. Relying solely on the amount input is not a valid scientific method of confirming that specifications for strength of the finished batch are met.

b. Fourier transform infrared spectroscopy (FTIR) is used as part of the identity and composition testing for bulk blends such as those for Stress Guard, Aller-Aid, Eyes Love Lutein, TumeriPro, Prostate Health, Kids Echinacea Goldenseal, CountToZen, and Milk Thistle Elixir. During the inspection, you stated that FTIR methodology cannot identify the presence of individual dietary ingredients included in these products.

c. Your acceptance criteria for identity testing of (b)(4) botanical components by FTIR is (b)(4)% match to the reference standard. Your results of the identity testing of Nettle (b)(4) lot (b)(4) for Aller-Aid and Cordyceps (b)(4) lot (b)(4) for Cordyceps showed the tested material has greater than (b)(4)% match to the reference standard of the component and several other components (Catnip tops have an 86.38% match, (b)(4) have a 86.25% match, (b)(4) has a 86.09% match, Calendula Flower has an 86.02% match, Yarrow Flower has a 85.12% match and Thyme Leaf has a 84.92% match), with no differentiation of the standard and the other components. There is no assurance that your FTIR methodology provides the requisite specificity and that it is scientifically valid for identifying (b)(4) botanicals.

You stated in your October 15, 2021, response that for dietary supplements, “[c]omposition and strength will be determined by calculation and input where current and generally available analytical methods do not exist to establish product specification testing.” You may exempt one or more product specifications from verification requirements under 21 CFR 111.75(c)(1) if you determine and document that the specifications you select for determination of compliance with specifications are not able to verify that the production and process control system is producing a dietary supplement that meets the exempted product specification and there is no scientifically valid method for testing or examining such exempted product specification at the finished batch stage, in accordance with 21 CFR 111.75(d)(1). In such a case, you must document why, for example, any component and in-process testing, examination, or monitoring, and any other information, will ensure that such exempted product specification is met without verification through periodic testing of the finished batch. However, you have not prepared such documentation to exempt any of these specifications from finished product verification. In your response, you also included a revised master manufacturing record (MMR) with finished product specifications for TumeriPro. You determined the identity and strength of all dietary ingredients in the TumeriPro product (turmeric, bromelain, and citrus bioflavonoids) using HPLC methodology. However, your response is inadequate because you did not provide appropriate, scientifically valid methods for the testing of all your finished dietary supplements.

Your February 11, 2022, response stated that you are reducing your use of FTIR for identification testing and restricting its use to only those raw materials or components that are purified substances with a purity of at least (b)(4)% and where validation requirements are met. You further indicated that you are moving towards HPLC and (b)(4) to test to specifications for any remaining raw materials and components. Your response is inadequate because you did not provide an appropriate, scientifically valid method to ensure that the identity and strength specifications for all of your finished dietary supplements are met.

In your response dated April 12, 2022, you stated that you will significantly reduce the use of FTIR for identification testing, and instead plan to use HPLC, (b)(4), and microscopic analysis where applicable. Your response is inadequate because you provided no specific (b)(4) or HPLC methodology or reference standard information to ensure that the identity and strength specifications for all your finished dietary supplements are met for each specific dietary supplement. Furthermore, you continue to maintain that you will determine the composition and strength of some of your dietary supplements by calculation and input. Your response is inadequate because input is not a valid test method to determine strength.

In your latest response, dated June 8, 2022, you provided specifications for your Ashwagandha - Organic finished product. You continue to maintain that you will determine the strength of some of your dietary supplements by input. Your response is inadequate because input is not a valid test method to determine strength.

3. Your quality control personnel failed to reject a component or dietary supplement when an unanticipated occurrence took place during the production and in-process control systems that results in or could lead to the adulteration of a component or dietary supplement, as required by 21 CFR 111.113(b)(1).

Specifically, when allergen, filth, and other foreign materials were detected in components for dietary supplements during visual examination, your quality control personnel failed to reject the lot of the component. For the following components that contained visible foreign materials, your records (OWH Material Review/Re-Work Forms #119-06) indicated that if the components came to your facility in multiple bags of the same lot, in some cases you rejected the material in the bags that contained visible pieces of foreign material and approved the material in the other bags. In other cases, you appear to have approved bags of component material after (b)(4) removing the foreign materials and using visual confirmation that all foreign material was removed. Your records indicate that allergens, filth, and other foreign materials were detected in the following components for which your quality control personnel approved a portion of the lot and your firm used it in production:

• Wheat and rock foreign material were detected in Ashwagandha Root COG (b)(4) component lot (b)(4); a portion of the lot was approved and released by your QC personnel and appears to have been used in the manufacturing of Ashwagandha Gingko Capsules and Stress Guard Capsules.
• Tree nut shells, peanut shell, corn, rodent feces, and seed foreign material were detected in Ashwagandha Root COG (b)(4) component lot (b)(4); a portion of the lot was approved and released by your QC personnel and appears to have been used to manufacture Ashwagandha Ginkgo, Sleep Better, and Stress Guard products.
• Walnut and corn foreign material were detected in Hawthorn Berry COG Whole component lot (b)(4); a portion of the lot was approved and released by your QC personnel and appears to have been used to manufacture Hawthorn products.
• Tree nut shell, glass, hard plastic, and rodent feces foreign material were detected in your Bilberry Fruit (b)(4) Whole component lot (b)(4); a portion of the lot was approved and released by your QC personnel and appears to have been used to manufacture Eyes Love Lutein and Bilberry products.
• Glass, an AA battery, and tree nut shell foreign material were detected in your Black Cohosh Root component lot (b)(4); a portion of the lot was approved and released by your QC personnel and appears to have been used to manufacture Black Cohosh products.

Your investigation for Milk Thistle Seed COG Whole component lot (b)(4) contaminated with wheat grains demonstrates that (b)(4) removing the visible allergen from the component does not necessarily completely remove the allergen from the component. The material tested positive for gluten after the manual removing of visible grains. Note that foreign materials, such as allergens, broken glass, and rodent feces, may not be evenly distributed in the components and that the presence of visible foreign material may be an indicator of gross contamination. Removing the visible foreign material may not ensure the absence of contaminants.

Your response dated October 15, 2021, stated that you would revise your procedures for inspection and handling of major food allergens, a corrective action that is not broad enough to address all the concerns listed above. You stated that you would include justifications for inspections when you release part of a lot and reject another part of the same lot. However, we cannot evaluate the adequacy of your response because you did not provide revised procedures along with your response.

Your December 15, 2021, response documented allergen material found during an incoming inspection of whole valerian root from (b)(4) lots. However, your response did not document how many bags were in the lots and where the sample was selected from to form a representative sample per your SOP C-048, “Raw Material Inspection.” Per the material review form, the samples from (b)(4) lots were (b)(4) as a composite sample for testing at a third-party lab. The SOP does not address composite sampling of (b)(4) lots. Also, the SOP section on partial rejection does not identify Quality Control as responsible to make the determination that the material can be accepted for use in manufacturing. The SOP also does not provide that Quality Control will verify cleanliness and the absence of allergens by swabbing equipment.

In your responses dated April 12, 2022, and June 8, 2022, you did not address this specific observation; therefore, we cannot assess further progress towards compliance.

4. You failed to verify that the laboratory examination and testing methodologies are appropriate for their intended use, as required by 21 CFR 111.320(a). Specifically, you did not verify that your testing of components and dietary supplements for microbial contamination does not interfere with the reliability of the microbial test methods. Additionally, you did not verify that the in-house prepared media used for microbial testing are appropriate for their intended use.

We have reviewed your response dated October 15, 2021, in which you stated you will update your procedures, forms, and train employees. We cannot evaluate the adequacy of your response because you did not include evidence of these corrective actions for review.

Your December 15, 2021, response stated that you are using USP and AOAC approved methods, and that no suitability testing is required for those AOAC methods because they have already been established as suitable for use with dietary supplements. You further indicated that you verified this approach after consulting with third-party experts. However, you did not provide the criteria for suitability. Therefore, FDA cannot determine that your methodology can accurately determine the microbial counts.

Your February 11, 2022, response did not include verification that testing of components and dietary supplements for microbial contamination does not interfere with the reliability of the microbial test methods.

Regarding your response dated April 12, 2022, you stated that your firm performed a side-by-side comparison of Petrifilm, USP, and FDA BAM methods for microbial testing. You stated that you determined the data indicated that the (b)(4) method was most suitable for your product. However, you did not provide any data, so we cannot evaluate the adequacy of your response at this time. When using methodology for microbial testing, it is important to verify that the dietary supplement powder is not inherently inhibiting microbial growth, which would invalidate the test method.

In your June 8, 2022, response, you provided SOPs for your microbiological testing of your finished dietary supplement products. We find your response inadequate because your procedures do not include a control for verification that the dietary supplement powder is not inherently inhibiting microbial growth.

This letter is not intended to be an all-inclusive statement of violations that may exist in connection with your products. You are responsible for investigating and determining the causes of any violations and for preventing their recurrence or the occurrence of other violations. It is your responsibility to ensure that your firm complies with all requirements of federal law, including FDA regulations.

This letter notifies you of our concerns and provides you an opportunity to address them. Failure to adequately address this matter may result in legal action including, without limitation, seizure and injunction.

In addition to the violations identified above, we offer the following comment:

Your firm includes expiration dates on the labels of the dietary supplement products including Stress Guard, Aller-Aid, Prostate Health, TumeriPro, and Eyes Love Lutein. During the inspection, you informed our investigators that your firm had organoleptically examined the products at expiration and used this examination to justify the listed expiration date. You stated that you do not have data supporting the expiration dates listed on the product labels. You asserted in your responses dated October 15, 2021, and December 15, 2021, that GMP regulations do not require expiration dating or a stability program. Your February 11, 2022, response stated that the SOP 080, “Expiration Date Determination” was revised and that the nonconformances that were the subject of this observation have been fully addressed. You did not provide a revised procedure along with your response, and you did not include additional corrections in your responses dated April 12, 2022, and June 8, 2022. Since you have elected to use a “Best By” and “Use By” date on your products, the date that you place on a product label should be supported by data that demonstrates the product’s shelf life [See 72 Fed. Reg. 34752, 34856 (June 25, 2007)].

Please notify FDA in writing, within 15 working days of receipt of this letter, of the specific steps you have taken to address any violations. Include an explanation of each step being taken to prevent the recurrence of violations, as well as copies of related documentation. If you cannot complete corrective actions within 15 working days, state the reason for the delay and the time within which you will do so. If you believe that your products are not in violation of the Act, include your reasoning and any supporting information for our consideration.

Please send your reply to the Food and Drug Administration, 22215 26th Avenue SE, Suite 210, Bothell, Washington, 98021, to the attention of Tracy K. Li, Compliance Officer. If you have any questions concerning this letter, you can contact Ms. Li at (425) 302-0428.

Sincerely,
/S/

Miriam R. Burbach
District Director
Program Division Director