| Public Health Service Food and Drug Administration |
Los Angeles District |
Department of Health and Human Services
WARNING LETTER
CERTIFIED MAIL
RETURN RECEIPT REQUESTED
November 9, 2010
W/L 13-11
Mr. Eugene C. Ung, CEO
Ultimate Formulations, Inc., dba Best Formulations
17758 Rowland St.
City of Industry, CA 91748-1119
Dear Mr. Ung:
On March 17 through April 2, 2010, the U.S. Food and Drug Administration (FDA) inspected your dietary supplement manufacturing facility located at 17758 Rowland St., City of Industry, CA. Our investigators found significant violations of 21 CFR Part 111, Current Good Manufacturing Practice (cGMP) in Manufacturing, Packaging, Labeling, or Holding Operations for Dietary Supplements.
These violations cause your dietary supplement products identified in this letter 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 current good manufacturing practice regulations for dietary supplements. You may find the Act and the FDA’s regulations through links in the FDA’s home page at http:www.fda.gov.
The inspection revealed the following violations:
1) You failed to determine whether established product specifications for strength of the finished batches of your dietary supplements were met, as required by 21 CFR 111.73. You may verify that these specifications are met by testing or examining (1) every finished batch or (2) a subset of finished batches for each of the dietary supplements you manufacture [21 CFR 111.75(c)]. If you test a subset of finished batches, you must identify the subset using a sound statistical plan [21 CFR 111.75(c)]. Because you did not identify such a subset of finished batches, you must test every finished batch of the dietary supplements manufactured at your firm. However, you did not conduct finished product testing to verify established product specifications for strength for your finished dietary supplement products in softgel, tablet, capsule, powder and tea configurations, identified below, as required by 21 CFR 111.75(c). Your batch records, which FDA investigators reviewed during the inspection, revealed that your firm did not conduct finished product specification testing for strength for the following released finished dietary supplement products:
• (b)(4) - Fish Oil softgels
• (b)(4) – (b)(4) Zinc w/ Vit. D (b)(4) tablets
• (b)(4) – (b)(4) powder
• (b)(4) – Body Purifier capsules
• (b)(4) – (b)(4) Tea (b)(4)
• (b)(4) – (b)(4) Longevatrol – Resveratrol softgels
• (b)(4) – (b)(4) softgels
• (b)(4) – (b)(4) softgels
• (b)(4) – (b)(4) 153ml./5 fl. oz. softgels
• (b)(4) – 100% Black Currant Oil softgels
• (b)(4) – (b)(4) softgels
• (b)(4) – (b)(4) softgels
• (b)(4) – (b)(4) 180 softgels
• (b)(4) – Vit. A & D 10,000/400 softgels
• (b)(4) – (b)(4) Beta Carotene softgels
• (b)(4) – Vit. E400 IU (b)(4) softgels
• (b)(4) – (b)(4) softgels
In addition, batch records, reviewed during the inspection, revealed that your firm did not conduct finished product specification testing for composition for product (b)(4) oz. softgels.
We received your April 22, 2010 response to the FDA-483. In response to the violations described above, you stated that your firm will establish a “Quality Agreement” between your firm and customers, whereby your firm will provide customers with a “detailed checklist of all activities associating with manufacturing, holding, testing, and release of products” that will enable your firm “to segregate customers who will accept full responsibility of finished product analysis.” Further, you stated that for products “where customers are not able to perform analysis, [your firm] will start finished product testing for strength [and] composition (active ingredient) of two random lots per year of each product.” Your response is inadequate. As a dietary supplement manufacturer, you—not your customers—are responsible for ensuring that product specifications are met [21 CFR 111.1(a), 111.73, 111.75]. Your response does not address your failure to determine whether the specifications established under 21 CFR 111.70 are met, as required by 21 CFR 111.73.
2) Your firm’s master manufacturing records (MMR) for products (b)(4) – Phytomega sotfgels and (b)(4) failed to identify specifications for the points, steps, or stages in the manufacturing process where control is necessary to ensure the quality of the dietary supplements and that the dietary supplements are packaged and labeled as specified in your MMR, as required by 21 CFR 111.205(b)(1).
3) Your firm’s MMR failed to establish controls and procedures to ensure that each batch of dietary supplements that you manufacture meets the specifications identified, as required by 21 CFR 111.205(b)(2), for the following products:
• (b)(4) Fish Oil softgels
• (b)(4) softgels
• (b)(4) tablets
• (b)(4) Iron Plus Folic Acid tablets
• (b)(4) Grape Seed 100 mg capsules
In response to these violations, you stated that your firm has “developed a plan to incorporate tests to determine finished product specification based on the Quality Agreement with [your] customers.” This response is not adequate. As noted above, you—not your customers—are responsible for ensuring that product specifications are met. Further, you are responsible for keeping a master manufacturing record that complies with the requirements set forth in 21 CFR 111.205.
4) Your firm failed to include the following required information in your MMR for the dietary supplements identified above in paragraphs 1 and 2:
• Written instructions, including specifications for each point, step, or stage in the manufacturing process where control is necessary to ensure the quality of the dietary supplement and that the dietary supplement is packaged and labeled as specified in the master manufacturing record [21 CFR 111.210(h)(1)];
• Written instructions, including 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 and that the dietary supplement is packaged and labeled as specified in the master manufacturing record [21 CFR 111.210(h)(3)];
• Written instructions, including corrective action plans for use when a specification is not met [21 CFR 111.210(h)(5)]. Specifically, you did not provide written corrective action plans for use for the following unmet specifications:
o Your firm manufactured two finished batches of product (b)(4) –Vitamin E400 IU w/Tocotrienols & Selenium, lots (b)(4), that did not meet the finished product specification for selenium (b)(4). Both lots were assayed and found to contain levels above the specifications; however, your records did not provide corrective action plans for use when this specification was not met.
o Your firm manufactured finished batches of product (b)(4) –Vitamin A & D 10,000/400, (b)(4), and Product (b)(4) – Beta-Carotene), (b)(4), that did not meet finished product specifications for size and shape configurations. These lots were found to contain different-sized softgels that were returned by your customer, as noted in product complaint reports (b)(4) and (b)(4) and your non-conforming reports (b)(4) and (b)(4), respectively. However, your records did not provide corrective action plans for use when this specification was not met.
In response to these violations, you stated that your firm will include the following instruction on each page of the batch record: “[N]otify Supervisor if out of range is obtained for explanation and corrective action” when a specification is not met. Your response does not adequately address these deviations.. Specifically, your attachments do not include written instructions to satisfy the MMR requirements under 21 CFR 111.210(h).
5) In addition, your MMR for the dietary supplements identified above in paragraphs 1 and 2 failed to include the following required information:
• A statement of theoretical yield of a manufactured dietary supplement expected at each point, step, or stage of the manufacturing process where control is needed to ensure the quality of the dietary supplement, and the expected yield when you finish manufacturing the dietary supplement, including the maximum and minimum percentages of theoretical yield beyond which a deviation investigation of a batch is necessary and material review is conducted and disposition decision is made [21 CFR 111.210(f)].
• Written instructions for manual operations that include (1) one person weighing or measuring a component and another person verifying the weight or measure [21 CFR 111.210(h)(3)(ii)(A)]; and (2) one person adding the component and another person verifying the addition [21 CFR 111.210(h)(3)(ii)(B)]. Specifically, the batch record for (b)(4) of your product (b)(4) Fish Oil softgels, indicates that component (b)(4) was weighed and verified on September 15, 2009, but added to the blend and verified on September 14, 2009, which would have been the day before. A component must be weighed and verified before it is added to the blend—not after it is added—because it is not possible to weigh and verify the amount of the component after it has been added to the blend.
6) When your dietary supplements failed to meet established specifications, your quality control personnel did not reject or reprocess these dietary supplements, nor did they approve a treatment, or in-process adjustment to ensure the quality of the finished dietary supplements and that the dietary supplements were packaged and labeled as specified in your MMR, as required by 21 CFR 111.77(a) and 111.113(b)(2).
Specifically, your firm's quality control personnel approved the release of two finished batches of product (b)(4) – Vit. E400 IU with Tocotrienols & Selenium softgels, lots (b)(4) and (b)(4), when finished product specifications for selenium (b)(4), were not met, as referenced in investigations (b)(4) and (b)(4), each referencing selenium test results that exceeded specification levels (b)(4), respectively). It is your firm’s responsibility to reprocess, treat, or adjust dietary supplements that do not meet established specifications or reject the supplements to ensure that they are not released [21 CFR 111.77(a), 111.113(b)(2)].
In response to this violation, you stated that your firm employed a third party contractor to check products for “leakers and other defects while the investigation of OOS (out of specification) was still ongoing.” Further, you stated that the product was “released based on Quality Inspector evaluation to indicate no physical defects found in this product.” Your response does not adequately address on what basis you can release finished dietary supplements that fail to meet established specifications. Your firm cannot release for distribution a finished batch of dietary supplements that does meet established specifications unless your quality control personnel approve a treatment, an in-process adjustment, or reprocessing that will ensure the quality of the finished dietary supplement and that the supplement is packaged and labeled as specified in your MMR [21 CFR 111.77(a), 111.113(b)(2)].
7) Your firm’s quality control personnel failed to conduct a material review and make a disposition decision when an established specification was not met, as required by 21 CFR 111.113(a)(1). Specifically, your finished product analysis report for product (b)(4) – Vit. E400 IU w/ Tocotrienols & Selenium softgels, lots (b)(4) and (b)(4), indicated that when you failed to meet an established specification for selenium, your quality control personnel did not conduct a material review and make a disposition decision; instead your quality control personnel changed the specification for the selenium overage from (b)(4) to (b)(4). In addition, you must keep documentation, at the time of performance, of any material review and disposition decision conducted by your quality control personnel [21 CFR 111.140(b)(2)].
9) Your quality control personnel failed to review and approve decisions about whether to investigate a product complaint, the findings, and follow-up action of any investigation performed, as required by 21 CFR 111.560(b), for the following products:
• (b)(4): your product complaint report (b)(4) indicates that a customer complained because the dietary ingredient, (b)(4) when assayed by your customer, did not meet the labeled claim. However, according to your product complaint form, quality control personnel did not review and approve decisions about whether to investigate the product complaint and no findings were recorded on the form. Further, you firm’s customer service failed to follow your standard operating procedure, (b)(4) in that the product complaint report was not forwarded to your quality control personnel, as required by 21 CFR 111.553.
• (b)(4): your product complaint report (b)(4) indicates that a customer complained because yeast counts were out of specification when analyzed by your customer. However, according to your product complaint form, quality control personnel did not review and approve decisions about whether to investigate the product complaint and no findings were recorded on the form. Further, you firm’s customer service failed to follow your standard operating procedure, (b)(4), in that the product complaint report was not forwarded to your quality control personnel, as required by 21 CFR 111.553.
• (b)(4) – Black Currant: your product complaint report (b)(4) indicates that a customer complained because the dietary ingredient, (b)(4), when assayed by your customer, did not meet the labeled claim. However, according to your product complaint form, quality control personnel did not review and approve decisions about whether to investigate the product complaint and no findings were recorded on the form. Further, your firm’s customer service failed to follow your standard operating procedure, (b)(4), in that the product complaint report was not forwarded to your quality control personnel, as required by 21 CFR 111.553.
This letter is not an all-inclusive list of violations at your facility. It is your responsibility to ensure that your establishment and the products you market comply with the Act and its implementing regulations.
Failure to promptly correct the violations specified above may result in enforcement action without further notice. Enforcement action may include seizure of violative products and/or injunction against the manufacturers and distributors of violative products.
In addition, we note the following:
• Your MMR for your dietary supplement products indentified above in paragraph 3 did not include a description of packaging and a representative label, or a cross-reference to the physical location of the actual or representative label, as required by 21 CFR 111.210(g). In your April 22 response, you stated that you will include actual labels to your executed batch record. Under 21 CFR 111.210(g), you must include a description of packaging and a representative label or a cross-reference to the physical location of the label in your MMR and not in your batch record.
• We question the appropriateness of the component specification range for selenium in your product (b)(4) – Vit. E400 IU w/ Tocotrienols & Selenium softgels. As noted in your Laboratory Investigation Checklist and Report for lots (b)(4) and (b)(4) (tracking (b)(4) and (b)(4)), the specification range for this product is (b)(4) to (b)(4) per softgel. Your batch formulation records for this product list (b)(4) as the selenium “claim” for this product. In this context, “claim” appears to refer to the amount of selenium per softgel declared or claimed on the finished product label. A dietary supplement with a label declaration of an added nutrient, including selenium, is misbranded unless the nutrient content is at least equal to the value for that nutrient declared on the label [21 CFR 101.9(g)(4)(i)]. Therefore, the lower limit of the component specification range for selenium for your Vit. E400 IU w/ Tocotrienols & Selenium product must be at least 25 mcg to prevent the product from being misbranded [21 CFR 101.9(g)(4)(i)]. Currently, the upper limit of the component specification range for selenium for this product is (b)(4). If your Vit. E400 IU w/ Tocotrienols & Selenium product is labeled as containing 25 mcg of selenium per softgel but contains (b)(4) your product would be misbranded under section 403(a)(1) of the Act because the label would be false and misleading [see 21 CFR 101.9(g)(6)]. Further, please be advised that your quality control personnel must perform operations that include approving or rejecting all processes, specifications, written procedures, controls, tests, and examinations, and deviations from or modifications to them, that may affect the identity, purity, strength, or composition of a dietary supplement, to comply with 21 CFR 111.105(a).
• You purchase (b)(4) from a supplier for use in your product (b)(4) - Fish Oil softgels. Traditional (b)(4) does not contain more than trace amounts of lovastatin, if any. Therefore, your component specification for (b)(4), which provides for up to (b)(4), indicates that your (b)(4) - Fish Oil product is intended to contain (b)(4) manufactured with enhanced or added lovastatin. Lovastatin is the active pharmaceutical ingredient in (b)(4), which are FDA-approved drugs used to treat patients with primary hypercholesterolemia (high cholesterol). Section 201(ff) of the Act [21 U.S.C. § 321(ff)] specifically excludes from the dietary supplement definition articles that are approved as new drugs under section 505 of the Act [21 U.S.C. § 355], unless the article in question was marketed as a dietary supplement or food before its approval as a drug. 21 U.S.C. § 321(ff)(3)(B). FDA approved (b)(4) as a new drug on (b)(4) neither lovastatin as a single ingredient, nor any (b)(4) product manufactured and promoted for lovastatin content, was marketed as a dietary supplement or as a food before that date. Therefore, lovastatin's approval as a new drug preceded its marketing as a food or dietary supplement, and products containing (b)(4) manufactured to contain enhanced or added lovastatin are excluded from the definition of a dietary supplement under section 201(ff)(3)(B) of the Act. If your RYR CoQ10 - Fish Oil product contains (b)(4) with enhanced or added lovastatin, it would be excluded from the dietary supplement definition and could not be marketed as a dietary supplement. FDA's interpretation of the exclusion in 21 section 201(ff)(3)(B) of the Act and the agency's conclusion that a lovastatin-enhanced (b)(4) product was not a dietary supplement were upheld in litigation involving a product called (b)(4)
Please advise this office in writing within 15 days from your receipt of this letter of the specific steps you have taken to correct the violations noted above and to ensure that similar violations do not occur. Your response should include any documentation necessary to show that correction has been achieved. If you cannot complete all corrections before you respond, state the reason for the delay and the date by which you will complete the corrections.
Your response should be sent to:
Mr. Blake Bevill
Director, Compliance Branch
Food and Drug Administration
Los Angeles District Office
19701 Fairchild
Irvine, CA 92612
If you have any questions about the content of this letter, please contact Dr. William Vitale, Compliance Officer, at 949-608-2919.
Sincerely yours,
/s/
Alonza E. Cruse
District Director
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