Trilogy Laboratories, LLC MARCS-CMS 595087 — March 05, 2020

WARNING LETTER

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• Delivery Method: VIA UPS
• Product: Drugs

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• Recipient: Dr. Kristen K. Flaharty, PharmD; Owner; Trilogy Laboratories, LLC; 10060 Amberwood Rd., Suite 1; Fort Myers, FL 33913; United States

• Issuing Office: Office of Pharmaceutical Quality Operations, Division II; United States

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DATE: 3/5/2020

Case #: 595087

WARNING LETTER

Dear Dr. Flaharty:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility at Trilogy Laboratories, LLC, FEI 3012491944, located at 10060 Amberwood Road, Ste 1, Fort Myers, FL, from August 22 to 27, 2019.

This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (21 CFR parts 210 and 211).

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).

Additionally, your firm manufactures, repackages, distributes or sells, “AZUL Gly Sal Pads,” “AZUL Acne Defense Cream,” and “Azul DermaBright HQ Serum,” that are unapproved new drugs in violation of section 505(a) of the FD&C Act, 21 U.S.C. 355(a). Introduction or delivery for introduction of “AZUL Gly Sal Pads,” “AZUL Acne Defense Cream,” and “Azul DermaBright HQ Serum,” into interstate commerce is prohibited under section 301(d) of the FD&C Act, 21 U.S.C. 331(d).

Your firm also manufactures, repackages, distributes or sells, “AZUL Satin Eclipse Broad Spectrum SPF 32” that is misbranded under section 502(a) of the FD&C Act, 21 U.S.C. 352(a). “AZUL Gly Sal Pads,” “AZUL Acne Defense Cream,” and “Azul DermaBright HQ Serum,” are misbranded under section 502(c) of the FD&C Act, 21 U.S.C. 352(c). “Azul DermaBright HQ Serum,” “daily eclipse tinted Broad Spectrum SPF 30,” and “daily eclipse Broad Spectrum SPF 30” are misbranded under section 502(x) of the FD&C Act, 21 U.S.C. 352(x). Introduction or delivery for introduction of “AZUL Gly Sal Pads,” “AZUL Acne Defense Cream,” “Azul DermaBright HQ Serum,” “AZUL Satin Eclipse Broad Spectrum SPF 32,” “daily eclipse tinted Broad Spectrum SPF 30,” and “daily eclipse Broad Spectrum SPF 30” into interstate commerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C.

We reviewed your September 18, 2019, response to our Form FDA 483 in detail. Your response is inadequate because it did not provide sufficient detail or evidence of corrective actions to bring your operations into compliance with CGMP. Specifically, your response did not address the effect of these violations on the quality of your over the counter (OTC) drug products currently on the U.S. market and within expiry. During our inspection, our investigator observed specific violations including, but not limited to, the following.

CGMP Violations:

1. Your firm failed to perform, 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, and conduct appropriate laboratory testing for each batch of drug product required to be free of objectionable microorganisms (21 CFR 211.165(a) and (b)).

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)).

3. Your firm failed to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a))

Unapproved New Drug and Misbranding Violations

“AZUL Gly Sal Pads” and “AZUL Acne Defense Serum”

“AZUL Gly Sal Pads” and “AZUL Acne Defense Serum” are drugs as defined by section 201(g)(1)(B) of the FD&C Act, 21 U.S.C. 321(g)(1)(B), because they are intended for the diagnosis, cure, mitigation, treatment, or prevention of disease and/or as defined by section 201(g)(1)(C) of the FD&C Act, 21 U.S.C. 321(g)(1)(C), because they are intended to affect the structure or any function of the body. Specifically, these products are intended for use as acne drug products.

Examples of claims found on the products website, at “https://www.azulskinhealth.com,” that establish the intended uses (as defined in 21 CFR 201.128) of “AZUL Gly Sal Pads” and “AZUL Acne Defense Serum” include, but may not be limited to, the following:

“AZUL Gly Sal Pads” Website Labeling Claims:

“Extensively tested by Dr. Flaharty’s three daughters, these handy Gly/Sal pads contain therapeutic levels of glycolic and salicylic acid to help control acne break out . . . Glycolic Acid chemically exfoliates the skin. Helps penetrate deep into the skin to remove dry, dull skin layers . . . Salicylic Acid . . . is the prototypical anti-acne ingredient, working to prevent breakouts with its antimicrobial activity, and helps unclog pores with its keratolytic activity . . . Witch Hazel – Astringent and antioxidant that sooths [sic], heals and protects against free radicals.”

“AZUL Acne Defense Serum” Website Labeling Claims:

“This simple, yet effective formula combats acne and the environment that it thrives in. Pores are unclogged, sebum production is reduced and anti-inflammatory, antimicrobial and anti-bacterial ingredients . . . Salicylic Acid (2%) – Beta Hydroxy Acid (BHA), provides exfoliation preventing pore clogging and smoothing fine lines/wrinkles, stimulates new cell growth, reduces inflammation . . . Unireduce-r35 (Panthenyl Triacetate and farnesyl acetate) – Reduces sebum production on the skin after 28 days of use . . . Melaleuca Alternifolia (Tea Tree) Oil – provides antibacterial, anti-microbial, anti-fungal and antioxidant activities to protect and restore the skin . . . Cymbopogon Schoenanthus (Lemongrass) Oil – Antioxidant, antiviral, anti-bacterial, aromatherapeutic.”

OTC drug products intended for use as acne products, such as “AZUL Gly Sal Pads” and “AZUL Acne Defense Serum,” are subject to the Final Rule for Topical Acne Drug Products for Over-the-Counter Use (Acne Final Rule) (21 CFR Part 333 Subpart D). However, these products are not labeled or formulated in accordance with this final rule.

The labeling and formulation for as “AZUL Gly Sal Pads” and “AZUL Acne Defense Serum” are not consistent with the final rule referenced above. Specifically, the labels for as “AZUL Gly Sal Pads” and “AZUL Acne Defense Serum” do not distinguish active ingredients from inactive ingredients. Therefore, all of the labeled ingredients for “AZUL Gly Sal Pads” (Aqua (Water), Witch Hazel, Alcohol, Polysorbate 20, Glycolic Acid, Salicylic Acid, Glycerin, Acetone, Sodium Hydroxide) and for “AZUL Acne Defense Serum” (Aqua (Water), Glycerin, Salicylic Acid, Xanthum Gum, Farnesyl Acetate, Panthenyl Triacetate, Tocopheryl Acetate, Cymbopogon Schoenanthus (Lemongrass) Oil, Melaleuca Alternifolia (Tea Tree) Oil, Sodium Benzoate, Sodium Benzoate) are deemed to be represented as active ingredients, see 21 CFR 201.66(b)(2). Such products formulated and labeled as “AZUL Gly Sal Pads” and “AZUL Acne Defense Serum,” do not comply with the Acne Final Rule.

Furthermore, according to 21 CFR 201.66(b)(2), an “active ingredient” means 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 humans. Your website claims for “Gly Sal Pads,” further demonstrate that glycolic acid and witch hazel are “active ingredients” because these ingredients are intended to furnish pharmacological activity. The website labeling for “Gly Sal Pads” claims “contain therapeutic levels of glycolic and salicylic acid to help control acne break out” and “Witch Hazel – Astringent and antioxidant that sooths [sic], heals and protects against free radicals.” Neither Glycolic acid or Witch Hazel are permitted active ingredients in the Acne Final Rule. Furthermore, your “AZUL Gly Sal Pads” product includes indications such as antimicrobial and keratolytic activity, which are not indications set forth in the Acne Final Rule.

Similarly, your website claims for “AZUL Acne Defense Serum,” demonstrate that Unireduce-r35 (Panthenyl Triacetate and farnesyl acetate), Melaleuca Alternifolia (Tea Tree) Oil, and Cymbopogon Schoenanthus (Lemongrass) Oil, are “active ingredients” as defined in 21 CFR 201.66(b)(2), because these ingredients are intended to furnish pharmacological activity. The website labeling for “AZUL Acne Defense Serum” claims “Unireduce-r35 (Panthenyl Triacetate and farnesyl acetate) – Reduces sebum production on the skin after 28 days of use . . . Melaleuca Alternifolia (Tea Tree) Oil – provides antibacterial, anti-microbial, anti-fungal and antioxidant activities to protect and restore the skin . . . Cymbopogon Schoenanthus (Lemongrass) Oil – Antioxidant, antiviral, anti-bacterial, aroma-therapeutic.” These are not permitted active ingredients in the Acne Final Rule. Furthermore, “AZUL Acne Defense Serum” includes indications such as anti-inflammatory, anti-microbial, anti-bacterial, anti-fungal, and antiviral, which are not indications set forth in the Acne Final Rule.

Thus, as formulated and labeled, “AZUL Gly Sal Pad” and “AZUL Acne Defense Serum” do not comply with the final rule described above. Furthermore, we are not aware of sufficient evidence to show “AZUL Gly Sal Pad” and “AZUL Acne Defense Serum” as formulated and labeled, are generally recognized as safe and effective. Therefore, these products are new drugs within the meaning of section 201(p) of the FD&C Act, 21 U.S.C. 321(p). As new drugs, “AZUL Gly Sal Pad” and “AZUL Acne Defense Serum” may not be legally marketed in the United States absent approval of an application filed in accordance with section 505(a) of the FD&C Act, 21 U.S.C. 355(a). “AZUL Gly Sal Pad” and “AZUL Acne Defense Serum” are not the subject of FDA-approved applications; therefore, the current marketing of these products violates section 505(a) of the FD&C Act, 21 U.S.C. 355(a). Introduction or delivery for introduction of such products into interstate commerce is prohibited under section 301(d) of the FD&C Act, 21 U.S.C. 331(d).

“AZUL Gly Sal Pad” and “AZUL Acne Defense Serum” are also misbranded because they are not labeled in accordance with the “Drug Facts” labeling requirements described in 21 CFR 201.66. Specifically, the product labels fail to include a Drug Facts panel. Therefore, these products are misbranded under section 502(c) of the FD&C Act, 21 U.S.C. 352(c), because the information that is required to appear on the labeling is not prominently placed thereon with such conspicuousness and in such terms as to render it likely to be read and understood by the ordinary individual under customary conditions of purchase and use.

The introduction or delivery for introduction of misbranded drugs into interstate commerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C. 331(a). Therefore, the marketing of “AZUL Gly Sal Pad” and “AZUL Acne Defense Serum” violate this provision of the FD&C Act.

“AZUL DermaBright HQ Serum”

“AZUL DermaBright HQ Serum” is a “drug” as defined by section 201(g)(1)(B) of the FD&C Act, 21 U.S.C. 321(g)(1)(B), because it is intended for the diagnosis, cure, mitigation, treatment, or prevention of disease, and/or under section 201(g)(1)(C) of the FD&C Act, 21 U.S.C. 321(g)(1)(C), because it is intended to affect the structure or any function of the body. Specifically, this product is intended for use as a skin bleaching drug product.

Examples of claims found on the product website, at “https://www.azulskinhealth.com,” that establish the intended uses (as defined in 21 CFR 201.128) of “AZUL DermaBright HQ Serum” include, but may not be limited to, the following:

“AZUL DermaBright HQ Serum” Website Labeling Claims:

“Hydroquinone (2%) - Skin lightener, inhibits melanin production . . . Brightenyl (Diglucosyl Gallic Acid) – Restores even skin tone by blocking the melanogenesis process at several levels and by protecting the skin and preventing its inflammation. 4x times more potent than vitamin C, 60x more efficient than kojic acid. Visible results after only 28 days . . . Kojic Acid – Inhibits melanin production by inhibiting tyrosinase, provides gradual and continual skin lightening to relieve skin discolorations . . . Azelaic Acid – Inhibits tyrosinase activity to reduce pigmentation spotting, anti-bacterial, antiinflammatory . . . Lactic Acid – An Alpha Hydroxy Acid (AHA) that hydrates and exfoliates, reducing wrinkles and pigmentation discolorations . . . Salicylic Acid – A Beta Hydroxy Acid (BHA), provides exfoliation and preventing pore clogging and smoothing fine lines/wrinkles, stimulates new cell growth, reduces inflammation . . . Ascorbic Acid (Vitamin C) – antioxidant, strengthens collagen, assists in lightening, provides antiwrinkle effects, smooths skin texture.”

OTC drug products such as “AZUL DermaBright HQ Serum” intended for skin bleaching, are also being evaluated as part of the OTC Drug Review. They have been proposed to be classified as generally recognized as safe and effective and not misbranded under the Tentative Final Monograph (TFM) for Skin Bleaching Drug Products (47 FR 39108, September 3, 1982) if they meet each condition in the TFM and each general condition in 21 CFR 330.1. Pending the promulgation of a final rule, the agency generally does not intend to pursue regulatory action against products marketed in accordance with the conditions proposed in the TFM and each general condition in 21 CFR 330.1 unless a particular product poses a public health concern. Such marketing, however, is subject to the risk that a final rule may require reformulation and/or relabeling or FDA approval through the “new drug” procedures of the FD&C Act (section 505). However, “AZUL DermaBright HQ Serum” is not labeled and formulated in accordance with the conditions proposed in the TFM for Skin Bleaching Drug Products for the reasons explained below.

As referenced above, according to 21 CFR 201.66(b)(2), an “active ingredient” means 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 humans. Although your firm does not specifically list Brightenyl (Diglucosyl Gallic Acid), Kojic Acid, Azelaic Acid, Lactic Acid, Salicylic Acid, and Ascorbic Acid, as active ingredients, your website claims for these specific ingredients demonstrate that these are “active ingredients” because the ingredients are intended to furnish pharmacological activity. The website labeling for “AZUL DermaBright HQ Serum,” claims “Brightenyl (Diglucosyl Gallic Acid) – Restores even skin tone by blocking the melanogenesis process at several levels and by protecting the skin and preventing its inflammation. 4x times more potent than vitamin C, 60x more efficient than kojic acid. Visible results after only 28 days . . . Kojic Acid – Inhibits melanin production by inhibiting tyrosinase, provides gradual and continual skin lightening to relieve skin discolorations . . . Azelaic Acid – Inhibits tyrosinase activity to reduce pigmentation spotting, anti-bacterial, anti-inflammatory . . . Lactic Acid – An Alpha Hydroxy Acid (AHA) that hydrates and exfoliates, reducing wrinkles and pigmentation discolorations . . . Salicylic Acid – A Beta Hydroxy Acid (BHA), provides exfoliation and preventing pore clogging and smoothing fine lines/wrinkles, stimulates new cell growth, reduces inflammation . . . Ascorbic Acid (Vitamin C) – antioxidant, strengthens collagen, assists in lightening, provides anti-wrinkle effects, smooths skin texture.” These active ingredients are not proposed active ingredients in the TFM for Skin Bleaching Drug Products. Furthermore, “AZUL DermaBright HQ Serum” includes indications such as anti-bacterial, anti-inflammatory, and prevents pore clogging, which are not proposed indications in the TFM for Skin Bleaching Drug Products.

Furthermore, we are not aware of any adequate and well controlled clinical trials in the published literature that support a determination that “AZUL DermaBright HQ Serum” is generally recognized as safe and effective for its labeled indications. Additionally, we are not aware of a similar OTC product as formulated and labeled that was available in the United States market on or before the inception of the OTC Drug Review.

“AZUL DermaBright HQ Serum,” as labeled, is therefore a new drug within the meaning of section 201(p) of the FD&C Act because it is not generally recognized among scientific experts as safe and effective for the drug uses described in its labeling. “New drugs” may not be introduced or delivered for introduction into interstate commerce unless an application approved by FDA under section 505 of the FD&C Act is in effect for the drug. “AZUL DermaBright HQ Serum” is not the subject of an approved new drug application; therefore, marketing this product in the United States is prohibited under section 301(d) of the FD&C Act, 21 U.S.C. 331(d) and violates section 505 of the FD&C Act.

“AZUL DermaBright HQ Serum” is also misbranded within the meaning of section 502(c) of the FD&C Act, 21 U.S.C. 352(c), because the label fails to bear a statement of identity as required under 21 CFR 201.61. The label for this product fails to include the established name and general pharmacological category(ies) or principal intended action(s) of the product.

Additionally, “AZUL DermaBright HQ Serum” is misbranded under section 502(x) of the FD&C Act, 21 U.S.C. 352(x), because the product’s label fails to disclose a domestic address or domestic telephone number through which the responsible person may receive a report of a serious adverse event with such drug. Please note that section 201(k) of the FD&C Act states that “ [t]he term ‘label’ means a display of written, printed, or graphic matter upon the immediate container of any article; and a requirement made by or under the authority of the FD&C Act that any word, statement, or other information appear on the label shall not be considered to be complied with unless such . . . also appears on the outside container . . . .” Therefore, the domestic address or domestic telephone number must appear on the immediate container label as well as on the outside container label if one exists.

The introduction or delivery for introduction of a misbranded drug into interstate commerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C. 331(a). Therefore, the marketing of “AZUL DermaBright HQ Serum” violates this provision of the FD&C Act.

“AZUL Satin Eclipse Broad Spectrum SPF 32,” “daily eclipse tinted Broad Spectrum SPF 30” and “daily eclipse Broad Spectrum SPF 30”

“AZUL Satin Eclipse Broad Spectrum SPF 32,” “daily eclipse tinted Broad Spectrum SPF 30,” and “daily eclipse Broad Spectrum SPF 30,” are “drugs” as defined by section 201(g)(1)(B) of the FD&C Act, 21 U.S.C. 321(g)(1)(B), because they are intended for the diagnosis, cure, mitigation, treatment, or prevention of disease, and/or under section 201(g)(1)(C) of the FD&C Act, 21 U.S.C. 321(g)(1)(C), because they are intended to affect the structure or any function of the body. Specifically, these products are intended for use as sunscreen drug products.

Examples of claims observed on the product labels, that establish intended uses (as defined in 21 CFR 201.128) of the products include, but may not be limited to, the following:

“AZUL Satin Eclipse Broad Spectrum SPF 32,”
     “Broad Spectrum SPF 32”

“daily eclipse tinted Broad Spectrum SPF 30”
     “Broad Spectrum SPF 30”

“daily eclipse Broad Spectrum SPF 30”
     “Broad Spectrum SPF 30”

The labeling for such drugs, like all OTC drugs, must comply with all of the requirements of section 502 of the FD&C Act and all pertinent regulations found in Title 21 of the Code of Federal Regulations (21 CFR). However, your products do not meet these requirements for the reasons described below.

“AZUL Satin Eclipse Broad Spectrum SPF 32” is misbranded under section 502(a) of the FD&C Act, 21 U.S.C. 352(a), because the product’s labeling is false and misleading. The product’s immediate container is labeled “SPF 32,” the outer box container is labeled “SPF 34,” and during the inspection, Dr. Flaharty provided the SPF testing that was performed during R&D for the product in which she stated, “the SPF testing revealed an SPF of 33.” Therefore, both the immediate container and outer carton are false and misleading because they are not consistent with the actual SPF testing conducted for the formulation of the product.

“daily eclipse tinted Broad Spectrum SPF 30,” and “daily eclipse Broad Spectrum SPF 30” are misbranded under section 502(x) of the FD&C Act, 21 U.S.C. 352(x), because the product labels fail to disclose a domestic address or domestic telephone number through which the responsible person may receive a report of a serious adverse event with such drug. Please note that section 201(k) of the FD&C Act states that “[t]he term ‘label’ means a display of written, printed, or graphic matter upon the immediate container of any article; and a requirement made by or under the authority of the FD&C Act that any word, statement, or other information appear on the label shall not be considered to be complied with unless such . . . also appears on the outside container . . . .” Therefore, the domestic address or domestic telephone number must appear on the immediate container label as well as on the outside container label if one exists.

The introduction or delivery for introduction of misbranded drugs into interstate commerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C. 331(a). Therefore, the marketing of “AZUL Satin Eclipse Broad Spectrum SPF 32,” “daily eclipse tinted Broad Spectrum SPF 30,” and “daily eclipse Broad Spectrum SPF 30,” violate this provision of the FD&C Act.

Drug Production Ceased

We acknowledge your commitment to cease production of drugs at this facility. In response to this letter, clarify whether you intend to resume manufacturing any drugs at this facility in the future.

If you plan to resume manufacturing drugs for the U.S. market or contract out the manufacture of drug products, notify this office in writing before resuming your operations.

Because these violations are significant, it is urgent that corrective action is taken as soon as possible. FDA will contact your firm to schedule a face-to-face regulatory meeting between your firm and Agency officials. The purpose of this meeting is to ensure your firm is taking prompt actions to correct the violative conditions found during the 2019 inspection discussed in this Warning 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 these violations and for preventing their recurrence or the occurrence of other violations.

Correct the violations cited in this letter promptly. Failure to promptly correct these violations may result in legal action without further notice including, without limitation, seizure and injunction. Unresolved violations in this warning letter may also prevent other Federal agencies from awarding contracts.

FDA may also withhold approval of requests for export certificates and approval of pending new drug applications or supplements listing your facility as a supplier or manufacturer until the above violations are corrected. We may re-inspect to verify that you have completed your corrective actions.

After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done since our inspection to correct your violations and to prevent their recurrence. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.

Your written notification should refer to case # 595087.

Please electronically submit your reply, on company letterhead, to Jamillah Selby, Compliance Officer, at ORAPHARM2_RESPONSES@fda.hhs.gov. In addition, please submit a signed copy of your response to jamillah.selby@fda.hhs.gov and Compliance Branch Director at john.diehl@fda.hhs.gov.

If you have questions regarding the contents of this letter, you may contact Jamillah Selby via phone at 214-253-5218 or email at jamillah.selby@fda.hhs.gov.

 

Sincerely,
/S/

Monica R. Maxwell
Program Division Director
Office of Pharmaceutical Quality Operations,
Division II

Cc: Jessica Sapp Interim Executive Director Department of Health Florida Board of
Pharmacy, 4052 Bald Cypress Way, Bin C-04 Tallahassee, Florida 32399-3258