WARNING LETTER
BioLyte Laboratories, LLC
MARCS-CMS 603584 —
March 18, 2021
Delivery Method:
UPS Next Day
Product:
Drugs
Recipient:
Recipient Name
Kevin J. DeVisser
Recipient Title
Chief Executive Officer
BioLyte Laboratories, LLC
310 Northern Dr. NW
Grand Rapids
,
MI
49534
United States
Issuing Office:
Division of Pharmaceutical Quality Operations III
United States
March 18, 2021
WARNING LETTER
Case# 603584
Dear Mr. DeVisser:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, BioLyte Laboratories, LLC, FEI 3013171766, located at 310 Northern Dr. NW, Grand Rapids, MI, from December 9 to 18, 2019 and on February 13, 2020.
This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals and misbranding regulations for dietary supplements. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (21 CFR, parts 210 and 211) and 21 CFR 101, respectively. Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B). Introduction or delivery for introduction of adulterated products into interstate commerce is prohibited under sections 301(a) of the FD&C Act, 21 U.S.C. 331(a).
Your firm manufactures the products “
(b)(4)
Silver Gel,” “
(b)(4)
Silver Gel,” “
(b)(4)
Silver Gel with Aloe,” “
(b)(4)
Silver Liquid Supplement,” “
(b)(4)
Therapeutic Pain Gel,” “
(b)(4)
Pain Relief Cream,” and “
(b)(4)
Magnesium Oil Spray,” which are unapproved new drugs introduced or delivered for introduction into interstate commerce in violation of sections 505(a) and 301(d) of the FD&C Act, 21 U.S.C. 355(a) and 331(d). In addition, your “
(b)(4)
Silver Gel,” “
(b)(4)
Silver Gel,” “
(b)(4)
Silver Gel with Aloe,” “
(b)(4)
Silver Liquid Supplement,” “
(b)(4)
Therapeutic Pain Gel,” “
(b)(4)
Pain Relief Cream,” and “
(b)(4)
Magnesium Oil Spray” are also misbranded under section 502 of the FD&C Act, 21 U.S.C. 352. Introduction or delivery for introduction of misbranded products into interstate commerce is prohibited under sections 301(a) and 502 of the FD&C Act, 21 U.S.C. 331(a) and 352. These violations are described in more detail below.
Current Good Manufacturing Practice (CGMP) Charges
We reviewed your January 9, 2020, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.
During our inspection, our investigator observed specific violations including, but not limited to, the following.
1. Your firm failed to have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release (21 CFR 211.165(a)).
You released your over-the-counter (OTC) topical drug products without adequate quality control testing, including but not limited to the identity and strength of each active ingredient. For example, identity and potency testing is not performed for the active ingredient in your Topical Pain Relief drug product (Menthol 4%) before release.
Testing is essential to ensure that the drug products you manufacture conform to all pre-determined quality attributes appropriate for their intended use, including both chemical and microbiological specifications. Because you lacked testing of each batch of your drug products, you do not know whether they conform to finished product specifications and are suitable for release to consumers.
In your response, you stated that you were in the process of setting up testing with FDA registered laboratories that have the capability to test for identity and potency of your active pharmaceutical ingredients.
Your response is inadequate. You did not provide adequate justification for the limited testing you proposed in your response.
In response to this letter, provide:
A list of chemical and microbiological specifications, including test methods, used to analyze each batch of your drug products before a batch disposition decision.
Microbiological testing methods that are capable of recovering bioburden in your product and determining whether any microorganisms are objectionable relative to the product’s intended use, route of administration, and patient (i.e., consumer) population. The suitability of all test methods should be verified under actual conditions of use.
A commitment to testing each batch, using qualified methods to ensure conformance to finished product specifications before final disposition.
An action plan and timelines for conducting full chemical and microbiological testing of retain samples to determine the quality of all batches of drug product distributed within the United States and within expiry as of the date of this letter.
A summary of all results obtained from testing retain samples from each batch. If such testing reveals substandard quality drug products, take rapid corrective actions, such as notifying customers and product recalls.
2. Your firm failed to conduct at least one test to verify the identity of each component of a drug product. Your firm also failed to validate and establish the reliability of your component supplier’s test analyses at appropriate intervals (21 CFR 211.84(d)(1) and (2)).
You did not perform at least one specific identity test for each component used in production of your OTC and Homeopathic drug products. During the inspection, you stated that you do not perform identity testing of incoming drug components, nor verify or validate supplier’s test results as reported on the Certificates of Analysis (COAs).
In your response, you stated that your raw material receiving procedure would be modified to include identity testing of active pharmaceutical ingredients (API), and also stated that you had contracted a laboratory to perform identity testing of all future API received at your site.
Your response is inadequate. You did not address your failure to test all drug components, including both active and inactive ingredients used in your OTC and homeopathic drug products, for identity and other appropriate specifications before use. Further, your response did not address the failure to establish the reliability of your component supplier’s test analyses at appropriate intervals. You did not address the effect of this deficiency on the quality of all your distributed drug products.
In response to this letter, provide:
A comprehensive review of your material system to determine whether all suppliers of components, containers, and closures are each qualified and the materials are assigned appropriate expiration or retest dates. The review should also determine whether incoming material controls are adequate to prevent use of unsuitable components, containers, and closures.
The chemical and microbiological quality control specifications you use to test and release each incoming lot of component for use in manufacturing.
A description of how you will test each component lot for conformity with all appropriate specifications for identity, strength, quality, and purity. If you intend to accept any testing results on your supplier’s COA in lieu of testing each component lot for purity, strength, and quality, specify in detail how you will first establish the reliability and consistency of your supplier’s test results for these attributes through initial validation (followed by periodic re-validation). In addition, include a commitment to always conduct at least one specific identity test for each incoming component lot.
A summary of your program for qualifying and overseeing contract facilities that perform testing of the components you use in manufacturing your drug products.
A summary of results obtained from testing all components to evaluate the reliability of the COA from each component manufacturer.
A retrospective assessment of all drug product batches within expiry and in distribution within the United States, manufactured using components that were not adequately tested and controlled.
3. Your firm failed to establish a written testing program designed to assess the stability characteristics of drug products and to use results of such stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166(a)).
You do not have appropriate stability data to support the 3-year expiration date for the OTC Pain Relief drug product that you manufacture.
During the inspection, you provided evidence that you perform a visual, odor, and pH check of your finished drug product in your stability program. However, you failed to adequately demonstrate that the chemical, physical and microbiological properties of your drug products remain acceptable throughout the labeled 3-year expiry period. Therefore, there is inadequate assurance that your drug products can meet their label claims through their expiration period.
In your response, you stated that you were working with your client to determine a justifiable shelf life for this product, and you committed to test the drug product based on your standard real-time stability timeline as detailed in your updated stability procedure.
Your response cannot be fully evaluated because you did not include your stability study test results used to determine if each of your commercial drug products will meet specifications at the end of the labeled expiration period.
In response to this letter, provide:
A comprehensive assessment, corrective and preventive action plan to ensure the adequacy of your stability program. Your remediated program should include, but not be limited to:
o Stability indicating methods
o Stability studies for each drug product in its marketed container-closure system before you permit distribution
o An ongoing program in which representative batches of each product are added each year to the program to determine if shelf-life claims remain valid
o A detailed definition of the specific attributes to be tested at each station (timepoint)
All procedures that describe these and other elements of your remediated stability program.
Unapproved New Drug and Misbranding Charges
Unapproved New Drug Violations
Your “
(b)(4)
Silver Gel,” “
(b)(4)
Silver Gel,” “
(b)(4)
Silver Gel with Aloe,” “
(b)(4)
Silver Liquid Supplement,” “
(b)(4)
Therapeutic Pain Gel,” “
(b)(4)
Pain Relief Cream,” and “
(b)(4)
Magnesium Oil Spray” products are drugs under section 201(g)(1) of the FD&C Act, 21 U.S.C. 321(g)(1), because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease and/or intended to affect the structure or any function of the body. Examples of claims from your product labeling, including websites listed on your product labels, that provide evidence of the intended uses (as defined by 21 CFR 201.128) of your products as drugs include, but may not be limited to, the following:
“
(b)(4)
Silver Gel,”
“Used as an antimicrobial to help treat minor skin wounds, burns, infections . . .”
“
(b)(4)
Silver Gel”
“USEFUL FOR WOUNDS, BURNS, BANDAGES, AND MORE . . . TOPICALLY USED AGAINST INFECTIONS . . . TOPICALLY USED AGAINST SEVERAL SKIN CONDITIONS (Hives, Rashes, eczema, diaper rash).”
“The silver gel may reduce scarring, age spots, and may aid in healing of wounds, bed sores, burns, and diabetic ulcers.”
“
(b)(4)
Silver Gel with Aloe”
“For topical use,
(b)(4)
Silver Gel is used to resolve a wide variety of skin problems . . . ideal for cuts, burns, serious wounds . . . [s]ilver interferes with the energy sources of bacteria, virus and other microbes . . . [u]ltimately it kills bacteria and reduces viral replication.”
“Recommended uses . . . Wound care[,] Diaper rash[,] . . . Fungal infections . . ..”
“
(b)(4)
Silver Liquid Supplement”
“[C]an be used internally and topically to address a wide variety of health issues . . . demonstrates antiviral, antibacterial, and antifungal effects for virtually every surface and tissue in the body.”
“
(b)(4)
Therapeutic Pain Gel”
“Uses . . . For temporary relief of occasional: . . . minor aches and pains of muscles and joints associated with simple backache - arthritis – bruises - strains”
“
(b)(4)
is a gentle, clear, odourless, 97% natural pain relief gel for skin irritations, bruising, soreness, muscle strains, back pain, knee pain, and arthritis-related pain.”
“
(b)(4)
Pain Relief Cream”
“Pain Relief Cream with
(b)(4)
rejuvenating CBD” . . . Uses . . . For temporary relief of occasional: . . . minor aches and pains . . . Stiffness of muscles, joints and tissues”
“Arnica . . . It is known to reduce swelling and decrease pain . . . Belladonna . . . soothe joint pain and general nerve pain . . . Hypericum . . . treat wounds on the skin and improve tissue generation . . . Ruta Graveolens . . . known to treat neuromuscular problems such as joint paint (sic), strains, and arthritis . . . Bryonia . . . treat pain associated with sprains and bruises . . . Actaea Spicata . . . traditionally used for the treatment of various ailments such as rheumatism, inflammation, and nerve diseases . . . Actaea Racemosa . . . used in Native American culture to heal chorea, dropsy, lumbago, and other nervous disorders . . . Rhododendron Tometosum . . . used first and foremost as a first-aid remedy to prevent infection but also remedies bruises, insect stings and bites, puncture wounds, cuts, grazes, and scrapes . . . Rhododendron Chrysanthum . . . effective in healing conditions like splitting pain in the ligaments, joint tissue and cartilage as well as swelling and rheumatic pains . . . Salicylicum Acidum . . . know to treat rheumatism, coryza, psoriasis, acne, and general skin irritation . . . Bellis Perennis . . . used to treat bruises, muscle pain, cutaneous wounds, rheumatism, eczema, boils and skin inflammation . . . “
“
(b)(4)
Magnesium Oil Spray”
“Spray pain away . . . Magnesium Oil Spray . . . Research shows magnesium can ease stress, anxiety, muscle/joint pain, and headaches, and aid in promoting restful sleep. . . . Immediate Relief”
“This highly portable spray is a must-have post workout. Ultra-absorbent, odorless, and non-greasy, simply spray this magnesium chloride oil on your skin. . . . I am an athletic person and can tend to overuse and over do at time . (sic) . . . I feel confident that I have this product to help with the occasional flare up in my ankle . (sic) It alleviates the soreness rapidly” . . . I woke with a headache one morning and spray some on my temples and the headache went away immediately! I have very tense muscles in my neck and shoulders. I’ve tried so many different muscle rubs and creams, but this magnesium spray works better than anything I’ve ever tried! . . . No more joint pain . . . I have tendenitics/arthritis (sic) as a result of injurying (sic) the tendons on the thumb of my right hand years ago. Over the years I’ve had acupuncture treatments, and other ontiments (sic) to help with the pain that only offered temporary relief. . . . However, after using the magnesium spray, for the first time in years, I finally have relief from the persistent pain I’d wake up to in the mornings. . . . IT WORKS . . . I have achilles tendonitis and I spray it on before I go to bed. I am now able to sleep at night.””
External Analgesic Drug Products
Based on the above labeling claims, your products “
(b)(4)
Therapeutic Pain Gel,” “
(b)(4)
Pain Relief Cream,” and “
(b)(4)
Magnesium Oil Spray” are drugs intended for use as external analgesics. We are not aware of any adequate and well-controlled clinical studies in the published literature that support a determination that “
(b)(4)
Therapeutic Pain Gel,” “
(b)(4)
Pain Relief Cream”, or “
(b)(4)
Magnesium Oil Spray” are generally recognized as safe and effective (GRASE) for use under the conditions suggested, recommended, or prescribed in their labeling. Thus, these external analgesic drug products are “new drugs” within the meaning of section 201(p) of the FD&C Act, 21 U.S.C. 321(p). New drugs may not be introduced or delivered for introduction into interstate commerce without an approved application from FDA in effect, as described in section 505(a) of the FD&C Act, 21 U.S.C. 355(a), unless they are nonprescription drugs governed by and lawfully marketed under section 505G
1
of the FD&C Act, among other exceptions not applicable here. No FDA-approved application pursuant to section 505 of the FD&C Act, 21 U.S.C. 355, is in effect for any of these external analgesic products, nor are they nonprescription drugs eligible for marketing under section 505G of the FD&C Act, as described below. Accordingly, these products are unapproved new drugs marketed in violation of sections 505(a) and 301(d) of the FD&C Act, 21 U.S.C 355(a) and 331(d).
Section 505G of the FD&C Act governs nonprescription drugs marketed without an approved application (commonly referred to as over-the-counter or “OTC” drugs), such as your “
(b)(4)
Magnesium Oil Spray” product.
2
Under section 505G, eligible nonprescription drug products need not have an approved application for lawful marketing, if certain conditions are met. However, your “
(b)(4)
Magnesium Oil Spray” product is not eligible for marketing without an approved application under section 505G. Specifically, your “
(b)(4)
Magnesium Oil Spray” product does not meet the applicable conditions of section 505G(a)(1) or (2) of the FD&C Act, 21 U.S.C. 355h(a)(1) or (2), under which nonprescription drugs marketed without an approved application are deemed GRASE and not considered “new drugs” by operation of law. Among these conditions is that a drug conforms with the general requirements for nonprescription drugs and that it conforms with the requirements for nonprescription use of a final monograph issued under 21 CFR part 330 or, for drugs classified in Category I for safety and effectiveness under a tentative final monograph (TFM), that a drug conforms with the proposed requirements of such TFM. Your “
(b)(4)
Magnesium Oil Spray” product does not meet these conditions, notably because the product's active ingredient, magnesium (as described below), was not an active ingredient in any applicable final monograph or TFM.
3
We note that your products “
(b)(4)
Therapeutic Pain Gel” and “
(b)(4)
Pain Relief Cream” are labeled as homeopathic drug products. Under section 201(g)(1) of the FD&C Act, 21 U.S.C. 321(g)(1), the term “drug” includes articles recognized in the official Homeopathic Pharmacopeia of the United States (HPUS), or any supplement to it. Homeopathic drug products are subject to the same statutory requirements as other drugs; nothing in the FD&C Act exempts homeopathic drugs from any of the requirements related to adulteration, misbranding, or approval. As noted above, your "
(b)(4)
Therapeutic Pain Gel” and “
(b)(4)
Pain Relief Cream” products are “new drugs” under section 201(p) of the FD&C Act and are not the subject of an FDA-approved application. Moreover, these products are not eligible to be marketed without an approved application under section 505G of the FD&C Act, because under the CARES Act, section 505G does not apply to homeopathic drugs.
4
Even if your “
(b)(4)
Therapeutic Pain Gel” and “
(b)(4)
Pain Relief Cream” products were governed by section 505G, they would not meet the conditions for marketing without an approved application under section 505G, notably because the products’ active ingredient cannabidiol (CBD), as described below, was not an active ingredient in any applicable final monograph or TFM.
5
CBD-containing drug products
Your products “
(b)(4)
Therapeutic Pain Gel” and “
(b)(4)
Pain Relief Cream” are labeled to contain CBD.
Although CBD is labeled as an inactive ingredient in the labels of your “
(b)(4)
Pain Relief Cream” and “
(b)(4)
Therapeutic Pain Gel” products, the labeling for these products clearly represent CBD as an active ingredient.
6
For instance, your product label for “
(b)(4)
Pain Relief Cream” features the statement, “Pain Relief Cream with
(b)(4)
rejuvenating CBD,” and the product label for “
(b)(4)
Therapeutic Pain Gel” features the statement, “CBD 560mg.” As noted above, CBD was not an active ingredient in any applicable final monograph or TFM, for purposes of establishing eligibility for lawful marketing without an approved application under section 505G of the FD&C Act.
Furthermore, even if CBD could be considered an inactive ingredient in a nonprescription drug product, that product would still need an approved new drug application to be legally marketed because the product would not be eligible for marketing under section 505G of the FD&C Act. In particular, such product would not meet the conditions under section 505G(a)(1) or (2), insofar as it would not conform with the general requirement in 21 CFR 330.1(e) that inactive ingredients must be safe and suitable.
7
A suitable inactive ingredient generally provides a beneficial formulation function, such as a tablet binder or preservative, or improves product delivery (e.g., enhances absorption or controls release of the drug substance).
8
CBD has no known functional role as an inactive ingredient in a finished drug product. Additionally, an inactive ingredient should not exert pharmacological effects
9
and must be safe when used at the intended dosage.
10
CBD, however, has known pharmacological activity with demonstrated risks.
11
It is unknown whether the levels of CBD used in your “
(b)(4)
Pain Relief Cream” and “
(b)(4)
Therapeutic Pain Gel” products have pharmacological activity or pose any concern for safety events. Accordingly, CBD cannot be considered a safe and suitable inactive ingredient as required under 21 CFR 330.1(e). Moreover, as explained above, your “
(b)(4)
Pain Relief Cream” and “
(b)(4)
Therapeutic Pain Gel” products are labeled as homeopathic drug products and thus are ineligible for marketing without an approved application under section 505G of the FD&C Act.
Magnesium-containing drug product
Similarly, although your firm does not specifically list magnesium oil as an active ingredient on the label of your “
(b)(4)
Magnesium Oil Spray” product, the product labeling clearly represents magnesium as an active ingredient. For instance, the label includes the statement, “[r]esearch shows magnesium can ease stress, anxiety, muscle/joint pain, and headaches, and aid in promoting restful sleep.” Because as noted magnesium was not an active ingredient under any applicable final monograph or TFM, your "
(b)(4)
Magnesium Oil Spray” product would not meet the conditions for lawful marketing without an approved application under section 505G(a)(1) or (2). This product would also be ineligible for marketing without an approved application under section 505G(a)(1) or (2) because its labeling is inconsistent with the conditions applicable to OTC external analgesics, in that the product claims regarding easing of stress and anxiety reflect indications not included under the external analgesic TFM.
12
In addition to failing to meet the conditions for marketing under section 505G(a)(1) or (2) of the FD&C Act, your “
(b)(4)
Magnesium Oil Spray” product does not meet the other conditions under section 505G under which nonprescription drug products can be lawfully marketed without an approved application. Specifically, it does not satisfy the requirements under sections 505G(a)(3)
13
nor is its marketing permitted by an order issued under section 505G(b)(1).
14
Your “
(b)(4)
Therapeutic Pain Gel” and “
(b)(4)
Pain Relief Cream” products also cannot meet such other marketing conditions because they are inapplicable, given that these products are labeled as homeopathic drug products which, again, are not governed by section 505G.
For the above reasons, your “
(b)(4)
Therapeutic Pain Gel,” “
(b)(4)
Pain Relief Cream” and “
(b)(4)
Magnesium Oil Spray” products are unapproved new drugs marketed in violation of sections 505(a) and 301(d) of the FD&C Act, 21 U.S.C. 355(a), 331(d).
Silver-containing Drug Products
Based on their labeling, your products “
(b)(4)
Silver Gel,” “
(b)(4)
Silver Gel,” “
(b)(4)
Silver Gel with Aloe,” and “
(b)(4)
Silver Liquid Supplement” are drugs that contain silver as an active ingredient. Further, these products lack an approved application and are made available for purchase by consumers without a prescription, i.e., OTC. Accordingly, these products are subject to section 505G of the FD&C Act, which as noted above governs nonprescription drugs marketed without an approved application. Specifically, your silver products fall under section 505G(a)(5) of the FD&C Act, because under a final determination issued under 21 CFR part 330, as published in the Federal Register on August 17, 1999,
15
the Agency has determined that no silver containing OTC drugs are GRASE under section 201(p)(1) of the FD&C Act and that all such products are deemed to be new drugs and require an approved new drug application under section 505 of the FD&C Act to be lawfully marketed.
16
New drugs may not be introduced or delivered for introduction into interstate commerce without an approved application from FDA in effect, as described in section 505(a) of the FD&C Act, 21 U.S.C. 355(a), unless they are eligible to be marketed without an approved application under section 505G of the FD&C Act, among other exceptions not applicable here. No FDA-approved application pursuant to section 505 of the FD&C Act, 21 U.S.C. 355, is in effect for your firm’s “
(b)(4)
Silver Gel,” “
(b)(4)
Silver Gel,” “
(b)(4)
Silver Gel with Aloe,” “
(b)(4)
Silver Liquid Supplement,” “
(b)(4)
Therapeutic Pain Gel,” “
(b)(4)
Pain Relief Cream,” and “
(b)(4)
Magnesium Oil Spray” drug products. Nor are these products eligible to be marketed without an approved application under section 505G of the FD&C Act. Accordingly, these products are unapproved new drugs marketed in violation of sections 505(a) and 301(d) of the FD&C Act, 21 U.S.C 355(a) and 331(d).
Misbranded Drugs
Your “
(b)(4)
Silver Gel,” “
(b)(4)
Silver Gel,” “
(b)(4)
Silver Gel with Aloe,” “
(b)(4)
Silver Liquid Supplement,” “
(b)(4)
Therapeutic Pain Gel,” “
(b)(4)
Pain Relief Cream,” and “
(b)(4)
Magnesium Oil Spray” products are misbranded drugs introduced or delivered for introduction into interstate commerce in violation of sections 502 and 301(a) of the FD&C Act, 21 U.S.C. 352 and 331(a).
As explained above, your “
(b)(4)
Magnesium Oil Spray,” "
(b)(4)
Silver Gel,” “
(b)(4)
Silver Gel,” “
(b)(4)
Silver Gel with Aloe,” and “
(b)(4)
Silver Liquid Supplement" products are nonprescription drugs subject to section 505G of the FD&C Act, 21 U.S.C. 355h, but do not comply with the requirements for marketing under that section, and are not the subject of an application approved under section 505 of the FD&C Act, 21 U.S.C. 355. Consequently, these products are misbranded under section 502(ee) of the FD&C Act, 21 U.S.C. 352(ee). In addition, your silver-containing products "
(b)(4)
Silver Gel,” “
(b)(4)
Silver Gel,” “
(b)(4)
Silver Gel with Aloe,” and “
(b)(4)
Silver Liquid Supplement" are misbranded under section 502 of the FD&C Act by virtue of 21 CFR 310.548(b).
17
Furthermore, your “
(b)(4)
Therapeutic Pain Gel” and “
(b)(4)
Pain Relief Cream” products are also misbranded under section 502(a) of the FD&C Act because the labeling of these products is false and misleading for several reasons. First, the labeling for your “
(b)(4)
Therapeutic Pain Gel” and “
(b)(4)
Pain Relief Cream” products identifies CBD as an inactive ingredient, but represents CBD as having purported active pharmacological properties such as pain relief, among others. Even if CBD could be considered an inactive ingredient in these products, the prominent featuring of CBD on the labeling on your “
(b)(4)
Therapeutic Pain Gel” and “
(b)(4)
Pain Relief Cream” products causes the products to be misbranded under section 502(a) of the FD&C Act, which deems a drug to be misbranded if its labeling is “false or misleading in any particular,” and under 21 CFR 201.10(c)(4). Under 21 CFR 201.10(c)(4), “[t]he labeling of a drug may be misleading by reason … [of] the featuring in the labeling of inert or inactive ingredients in a manner that creates an impression of value greater than their true functional role in the formulation.” Similarly, although the labeling for your "
(b)(4)
Magnesium Oil Spray” product does not specifically list magnesium oil as an active ingredient, your labeling claims represent magnesium as an active ingredient, as described above, and thus this product is also misbranded under section 502(a) of the FD&C Act and 21 CFR 201.10(c)(4).
Accordingly, your “
(b)(4)
Silver Gel,” “
(b)(4)
Silver Gel,” “
(b)(4)
Silver Gel with Aloe,” “
(b)(4)
Silver Liquid Supplement,” “
(b)(4)
Therapeutic Pain Gel,” “
(b)(4)
Pain Relief Cream,” and “
(b)(4)
Magnesium Oil Spray” products are misbranded drugs introduced or delivered for introduction into interstate commerce in violation of sections 502 and 301(a) of the FD&C Act, 21 U.S.C. 352 and 331(a).
Misbranded Dietary Supplements
Your
(b)(4)
Silver Liquid Supplement (even if not considered an unapproved new drug and/or a misbranded drug),
(b)(4)
Silver,
(b)(4)
Silver Water, and
(b)(4)
Silver products are misbranded dietary supplements under section 403 of the Act [21 U.S.C. 343] because they do not comply with the labeling requirements for dietary supplements as required by 21 CFR 101, as follows:
1. Your
(b)(4)
Silver and
(b)(4)
Silver Water products are misbranded within the meaning of section 403(e)(1) of the Act [21 U.S.C. 343 (e)(1)] in that the label fails to list the name and place of business of the manufacturer, packer, or distributor in accordance with 21 CFR 101.5.
2. Your
(b)(4)
Silver Liquid Supplement,
(b)(4)
Silver,
(b)(4)
Silver
(b)(4)
, and
(b)(4)
Silver products are misbranded within the meaning of section 403(q)(5)(F) of the Act (21 U.S.C. 343 (q)(5)(F)) in that the products do not present nutrition information on the labeling as required by 21 CFR 101.36 and 21 CFR 101.9. For example:
Your
(b)(4)
Silver Liquid Supplement,
(b)(4)
Silver,
(b)(4)
Silver
(b)(4)
, and
(b)(4)
Silver products labels fail to list the serving sizes which include 1 teaspoon twice daily for people under 75 pounds (lbs.) and 2 teaspoons twice daily for people over 75 lbs. If the product is for persons within more than one group, the quantitative amount and percent of Daily Value for each group shall be presented in separate columns in accordance with 21 CFR 101.36(b)(2)(iii)(E)
3. Your
(b)(4)
Silver,
(b)(4)
Silver
(b)(4)
, and
(b)(4)
Silver products are misbranded within the meaning of section 403(s)(2)(B) of the Act [21 U.S.C. 343(s)(2)(B)] because the product labels do not include a statement of identity as a “dietary supplement” as required by 21 CFR 101.3(g).
4. Your
(b)(4)
Silver and
(b)(4)
Silver
(b)(4)
products are misbranded within the meaning of section 403(y) of the Act [21 U.S.C. 343(y)] in that the label fails to bear a domestic address or domestic phone number through which the responsible person (as described in section 761 of the Act) may receive a report of a serious adverse event with such dietary supplement.
Additionally,
1. Your
(b)(4)
Silver Liquid Supplement,
(b)(4)
Silver,
(b)(4)
Silver
(b)(4)
, and
(b)(4)
Silver product labels bear the following statement: “DV (Daily Value) based on a 2,000 calorie diet.” This statement is only permitted when the percent of Daily Value is declared for total fat, saturated fat, total carbohydrate, dietary fiber, added sugars, or protein as required by 21 CFR 101.9(c) and 21 CFR 101.36(b)(2)(iii)(D).
2. Your
(b)(4)
Silver Liquid Supplement,
(b)(4)
Silver,
(b)(4)
Silver
(b)(4)
, and
(b)(4)
Silver product labels are using an incorrect version of the FDA disclaimer. This FDA disclaimer is only required when certain statements as mentioned in 21 CFR 101.93(f) are declared on the label.
CGMP consultant recommended
Based upon the nature of the violations we identified at your firm, we strongly recommend engaging a consultant qualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements. We also recommend that the qualified third party perform a comprehensive audit of your entire operation for CGMP compliance and evaluate the effectiveness of your corrective actions and preventive actions.
Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for fully resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance.
Any drug marketed by your firm must conform with all applicable requirements of the FD&C Act, including those outlined in the Unapproved New Drug and Misbranding Charges section of this letter.
Conclusion
The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the causes of any violations and for preventing their recurrence or the occurrence of other violations.
Failure to promptly correct any violations may result in legal action without further notice including, without limitation, seizure and injunction.
Failure to address violations of the FD&C Act may be cause for FDA to withhold approval of requests for export certificates and approval of pending new drug applications or supplements listing your facility as a supplier or manufacturer. We may re-inspect to verify that you have completed your corrective actions.
This letter notifies you of our findings and provides you an opportunity to address the above deficiencies. After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done since our inspection to address any violations and to prevent their recurrence. In response to this letter, you may provide additional information for our consideration as we continue to assess your activities and practices. If you cannot completely address violations within 15 working days, state your reasons for delay and your schedule for completion.
If you believe that your products are not in violation of the FD&C Act, include your reasoning and any supporting information for our consideration.
Please submit your response via email to ORAPHARM3_RESPONSES@FDA.HHS.GOV.
Attention: Brian D. Garthwaite, Ph. D.
Compliance Officer
U.S. Food and Drug Administration
Division of Pharmaceutical Quality Operations III
If you have any questions, please contact Dr. Garthwaite at
(612) 758-7132
.
Sincerely,
/S/
Art O. Czabaniuk
Program Division Director
Division of Pharmaceutical Quality Operations III
________________________________
1
Section 505G of the FD&C Act was added under title III, subtitle F ("Over-the-Counter Drugs") of the CARES Act, Pub. L 116-136 (March 27, 2020).
2
Your “
(b)(4)
Magnesium Oil Spray” is made available for purchase by consumers without a prescription.
3
We note that OTC drug products intended for external analgesic indications, such as the temporary relief of pain, were addressed in the Tentative Final Monograph (TFM) for External Analgesic Drug Products for Over-the-Counter Human Use (external analgesic TFM; 48 FR 5852, February 8, 1983). As noted above, magnesium was not included as an active ingredient under this TFM.
4
See section 3853(a) of the CARES Act, Pub. L. 116-136 (March 27, 2020).
5
See Tentative Final Monograph (TFM) for External Analgesic Drug Products for Over-the-Counter Human Use (external analgesic TFM; 48 FR 5852, February 8, 1983). As noted above, CBD was not included as an active ingredient under this TFM. 6 Under 21 CFR 201.66(b), an active ingredient is a component of a drug intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or function of the body.
7
21 CFR 330.1(e) requires that "the product contains only suitable inactive ingredients which are safe in the amounts administered and do not interfere with the effectiveness of the preparation or with suitable tests or assays to determine if the product meets its professed standards of identity, strength, quality, and purity".
8
See e.g., "Using the Inactive Ingredient Database" Guidance for Industry (July 2019), p. 1 at
https://www.fda.gov/media/128687/download
, and "Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients" Guidance for Industry (May 2005), pp. 1-2 at
https://www.fda.gov/media/72260/download
.
9
See e.g., 21 CFR 314.3(b) and 21 CFR 210.3(b)(7), which define an active ingredient as “any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man.” All other components of a finished drug product are considered inactive ingredients (see CFR 314.3(b), 21 CFR 210.3(b)(8)).
10
See 21 CFR 330.1(e).
11
For example, the labeling for Epidiolex (cannabidiol) prescription oral solution includes risks for the drug such as liver injury, interactions with other drugs or supplements, potential for male reproductive toxicity, somnolence, insomnia, diarrhea, decreased appetite, abdominal pain, upset stomach, changes in mood, irritability, and agitation. See
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/210365s005s006s007lbl.pdf
.
12
See Tentative Final Monograph (TFM) for External Analgesic Drug Products for Over-the-Counter Human Use (external analgesic TFM; 48 FR 5852, February 8, 1983). As noted above, easing of stress and anxiety were not indications included under this TFM.
13
Under 505G(a)(3) of the FD&C Act, drugs that were classified as Category III for safety or effectiveness in a TFM that is the most recently applicable proposal or determination issued under 21 CFR Part 330 -- and that were not classified as Category II for safety or effectiveness -- are not required to have an approved application under section 505 in order to be marketed, as long as they are in conformity with the relevant conditions of use outlined in the applicable TFM, including labeling conditions, and comply with all other applicable requirements for nonprescription drugs. Drugs containing magnesium as an active ingredient were not classified under any applicable TFM as Category III for safety or effectiveness. Thus, your “
(b)(4)
Magnesium Oil Spray” product does not meet the conditions under section 505G(a)(3) for lawful marketing absent an approved application.
14
Your “
(b)(4)
Magnesium Oil Spray” product is not the subject of an order issued under section 505G(b)(1) of the FD&C Act, 21 U.S.C 355h(b)(1), under which it is considered GRASE and can be lawfully marketed without an approved application.
15
See 64 FR 44653, 44658 (Aug. 17, 1999) establishing 21 CFR 310.548(a), which states in relevant part that "…there is a lack of adequate data to establish general recognition of the safety and effectiveness of colloidal silver ingredients or silver salts for OTC use in the treatment or prevention of any disease. These ingredients and salts include, but are not limited to, silver proteins, mild silver protein, strong silver protein, silver, silver ion, silver chloride, silver cyanide, silver iodide, silver oxide, and silver phosphate".
16
Id. at 21 CFR 310.548(b): "Any OTC drug product containing colloidal silver ingredients or silver salts that is labeled, represented, or promoted for the treatment and/or prevention of any disease is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act) for which an approved application or abbreviated application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application or abbreviated new drug application, such product is also misbranded under section 502 of the act".
17
See 64 FR 44653, 44658 (Aug. 17, 1999), establishing 21 CFR 310.548, which at 21 CFR 310.548(b) states that "Any OTC drug product containing colloidal silver ingredients or silver salts that is labeled, represented, or promoted for the treatment and/or prevention of any disease is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act) for which an approved application or abbreviated application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application or abbreviated new drug application, such product is also misbranded under section 502 of the act" (emphasis added).
Content current as of:
03/22/2021
Regulated Product(s)
Drugs