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Warning Letter 320-21-13

December 1, 2020

Dear Mr. Cardona:

Your firm recently registered as a human drug manufacturer. The U.S. Food and Drug Administration (FDA) conducted testing of a consumer antiseptic rub drug product (also referred to as a consumer hand sanitizer), labeled as Soho Fresh Hand Sanitizer. This drug product was declared to be manufactured at your facility, Corporativo Bureli S.A. de C.V., FEI 3017066032, at Lazaro Cardenas No. 10 San Jeronimo, Tepetlacalco EDOMEX, Mexico. Following an attempt to import Soho Fresh Hand Sanitizer into the United States, it was detained and refused admission at the border.

The results of the FDA laboratory testing of a batch of this product detained at the border demonstrate that this drug product declared to be manufactured at your facility is adulterated within the meaning of section 501(d)(2) of the Federal Food, Drug, and Cosmetic Act (FD&C Act or the Act), 21 U.S.C. 351(d)(2), in that a substance was substituted wholly or in part therefor. In addition, this product is adulterated within the meaning of section 501(a)(2)(B) of the FD&C Act (21 U.S.C. 351(a)(2)(B)), in that the substitution demonstrates that the quality assurance within your facility is not functioning in accordance with Current Good Manufacturing Practice (CGMP) requirements.

In addition, this drug product is an unapproved new drug introduced or delivered for introduction into interstate commerce in violation of section 505(a) of the FD&C Act, 21 U.S.C. 355(a), and is misbranded under sections 502(j), (a), (e), (x), and (ee) of the FD&C Act, 21 U.S.C. 352(j), (a), (e), (x), and (ee). Introduction or delivery for introduction of this product into interstate commerce is prohibited under sections 301(d) and (a) of the FD&C Act, 21 U.S.C. 331(d) and (a). These violations are described in more detail below.

Adulteration Violations

Soho Fresh Hand Sanitizer, declared to be manufactured at your facility is labeled to contain 70% of the active ingredient ethyl alcohol (ethanol). However, FDA laboratory testing of a batch of this product detained at the border found that the product contained an average of <0.25% ethanol and an average of 70% methanol volume/volume. Therefore, this hand sanitizer drug product is adulterated under section 501(d)(2) of the FD&C Act in that the active ingredient, ethanol, was substituted wholly or in part with methanol, a dangerous chemical when in contact with human skin or ingested. Separate from the hand sanitizer drug product, Soho Fresh Rubbing alcohol was also declared as being manufactured at your facility and imported into the U.S. We are concerned about the potential for methanol substitution risk in this product as well, given the common manufacturing facility and active ingredient, alcohol.

Methanol is not an acceptable ingredient for hand sanitizers and should not be used due to its toxic effects. Skin exposure to methanol can cause dermatitis, as well as transdermal absorption with systemic toxicity. Substantial methanol exposure can result in nausea, vomiting, headache, blurred vision, permanent blindness, seizures, coma, permanent damage to the nervous system, or death. Although all persons using these products on their hands are at risk, young children who accidentally ingest these products, and adolescents and adults who drink these products as an alcohol (ethanol) substitute, are most at risk for methanol poisoning.

On September 15, 2020, FDA held a teleconference with your registered U.S. Agent, Registrar Corporation. We recommended you consider removing your firm’s hand sanitizer and rubbing alcohol drug products currently in distribution to the U.S. market. On September 16, 2020, FDA notified the public of the methanol contamination of your hand sanitizer drug products at the following website: https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-hand-sanitizers-consumers-should-not-use

You later explained you could not recall the hand sanitizer product as it was your first export and was refused admission. Your firm did not respond to subsequent correspondence from FDA.

In response to this letter provide the following:

• A detailed investigation into how the drug product described above, which was declared as manufactured at your facility and which was labeled as containing ethanol, was substituted in part or in whole with methanol.
• A list of all raw materials used to manufacture all of your hand sanitizer and rubbing alcohol drug products, including the suppliers’ names, addresses, and contact information.
• A list of all batches of any hand sanitizer and rubbing alcohol drug products shipped to the United States by your firm, and a full reconciliation of all material you distributed.
• Copies of the complete batch records for all batches distributed to the U.S.
• Provide a complete, comprehensive, and independent assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.

The substitution and contamination with methanol in a drug product declared or labeled as manufactured in your facility demonstrates that the quality assurance within your facility is not functioning in accordance with CGMP requirements under section 501(a)(2)(B) of the FD&C Act.¹

Unapproved New Drug and Misbranding Violations

Your Soho Fresh Hand Sanitizer 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 use in 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 as a consumer antiseptic hand rub.

Examples of claims observed on the Soho Fresh Hand Sanitizer product label that provide evidence of the intended uses (as defined in 21 CFR 201.128) of the product include, but may not be limited to, the following:

“Hand Sanitizer . . . Antibacterial . . . DRUG FACTS . . . Purpose . . . Antiseptic . . . Use To decrease bacteria on the skin that could cause disease . . . Directions “Thoroughly cover your hands with product and allow to dry without wiping.”

This hand sanitizer product is a “new drug” within the meaning of section 201(p) of the FD&C Act, 21 U.S.C. 321(p), because it is not generally recognized as safe and effective (GRASE) for use under the conditions prescribed, recommended, or suggested in its labeling. New drugs may not be introduced or delivered for introduction into interstate commerce without prior approval from FDA, as described in section 505(a) of the FD&C Act, 21 U.S.C. 355(a), unless they are lawfully marketed under section 505G of the FD&C Act (which is not the case for this product, as further described below). No FDA-approved application pursuant to section 505 of the FD&C Act, 21 U.S.C. 355, is in effect for this drug product, nor are we aware of any adequate and well-controlled clinical studies in the published literature that support a determination that your Soho Fresh Hand Sanitizer drug product is GRASE for use under the conditions suggested, recommended, or prescribed in its labeling. Accordingly, this product is an unapproved new drug marketed in violation of sections 505(a) and 301(d) of the FD&C Act, 21 U.S.C 355(a) and 331(d).

We note that over-the-counter (OTC) topical antiseptic products had been the subject of rulemaking under the Agency’s OTC Drug Review. In particular, such products were addressed in a tentative final monograph (TFM) entitled “Topical Antimicrobial Drug Products for Over-the-Counter Human Use; Tentative Final Monograph for Health-Care Antiseptic Drug Products,” Proposed Rule, 59 FR 31402 (June 17, 1994) (1994 TFM), as further amended by the “Safety and Effectiveness of Consumer Antiseptics; Topical Antimicrobial Drug Products for Over-the-Counter Human Use; Proposed Amendment of the Tentative Final Monograph; Reopening of Administrative Record,” Proposed Rule, 81 FR 42912 (June 30, 2016). Over the course of these rulemakings, benzalkonium chloride, ethyl alcohol (ethanol), and isopropyl alcohol were classified as Category III for use as active ingredients in consumer antiseptic rub products, meaning that additional safety and effectiveness data are needed to support a determination that a drug product containing one of these active ingredients would be GRASE for use as a consumer antiseptic rub.

Section 505G of the FD&C Act, addresses nonprescription drugs marketed without an approved application. Under 505G(a)(3) of the FD&C Act, drugs that were classified as Category III in a TFM for safety and effectiveness that is the most recently applicable proposal or determination for such drug 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 the active ingredient, and comply with all other applicable requirements.

However, Soho Fresh Hand Sanitizer does not conform to the 1994 TFM, as further amended by the 2016 Consumer Antiseptic Rub proposed rule, nor any other TFM, proposed rule, or final rule, and does not meet the conditions under section 505G(a)(3) of the FD&C Act for marketing without an approved application under section 505.

According to the product label, Soho Fresh Hand Sanitizer purportedly contains the active ingredient ethyl alcohol 70%. However, as previously discussed, FDA laboratory analyses revealed that a sample of Soho Fresh Hand Sanitizer detained at the border contains ethanol in an amount that is less than the 70% declared on the label and less than the amount of ethanol described in the 1994 TFM. Such a product does not conform with the TFM and the applicable requirements for nonprescription drugs², nor is it consistent with the formulations described in FDA’s temporary policies for hand sanitizers during the COVID-19 public health emergency.³ FDA laboratory analyses revealed that a sample of Soho Fresh Hand Sanitizer detained at the border contains significant concentrations of the undeclared ingredient methyl alcohol (methanol). Use of methanol as an active ingredient is not in conformance with the TFM, nor is it included in the formulations described in FDA’s Temporary Policy for Preparation of Certain Alcohol-Based Hand Sanitizer Products During the Public Health Emergency (COVID-19) Guidance for Industry. Furthermore, methanol is not acceptable as an inactive ingredient in hand sanitizers. As previously discussed, methanol has significant and sometimes fatal toxic effects and, therefore, does not meet the requirements under 21 CFR 330.1(e) that a product’s inactive ingredients be safe and suitable.⁴

Additionally, this methanol-containing drug product, Soho Fresh Hand Sanitizer, is misbranded under sections 502(j), (a), (e), (x), and (ee) of the FD&C Act, 21 U.S.C. 352(j), (a), (e), (x), and (ee). It is misbranded under section 502(j) of the FD&C Act, 21 U.S.C. 352(j), because it is dangerous to health when used according to its labeling as a hand sanitizer. As previously stated, skin exposure to methanol could lead to systemic absorption, and substantial methanol exposure can potentially result in, among other things, blindness, permanent nervous system damage, and even death.

This hand sanitizer is misbranded under section 502(a) of the FD&C Act, 21 U.S.C 352(a), because its labeling is false and misleading. As noted above, Soho Fresh Hand Sanitizer is labeled to contain ethyl alcohol 70%. However, FDA laboratory analyses revealed that a sample of this product contains little ethyl alcohol (ethanol) and instead contains significant concentrations of methyl alcohol (methanol), an ingredient that is not declared on the product label. Section 201(n) of the FD&C Act, 21 U.S.C. 321(n), provides that “in determining whether the labeling or advertising is misleading there shall be taken into account . . . not only representations made or suggested . . . but also the extent to which the labeling or advertising fails to reveal facts material in the light of such representations or material with respect to consequences which may result. . ..” Thus, the misleading representation of the concentration of active ingredient ethyl alcohol (ethanol) and the failure of the product label to disclose the presence of the methyl alcohol (methanol) in the product, causes this product to be misbranded under section 502(a) of the FD&C Act, 21 U.S.C. 352(a). The failure of this product to list methyl alcohol (methanol) as an ingredient on its label causes it to be misbranded under section 502(e)(1)(A) of the FD&C Act, 21 U.S.C. 352(e)(1)(A).

Furthermore, Soho Fresh Hand Sanitizer is misbranded under section 502(x) of the FD&C Act, 21 U.S.C. 352(x), because the product 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.

Lastly, this product is misbranded under section 502(ee) of the FD&C Act, 21 U.S.C. 352(ee) because Hand Sanitizer Gel is a nonprescription drug subject to section 505G of the FD&C Act, 21 U.S.C. 355h, but does not comply with the requirements for marketing under that section and is not the subject of an application approved under section 505 of the FD&C Act, 21 U.S.C. 355.

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).

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 evaluate your operations and to assist your firm in meeting CGMP requirements if your firm intends to resume manufacturing drugs for the U.S. market. We also recommend that the qualified consultant perform a comprehensive audit of your entire operation for CGMP compliance and that the consultant evaluates the completion and efficacy of your corrective actions and preventive actions before you pursue resolution of your firm’s compliance status with FDA. Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance.

Conclusion

The violations cited in this letter are not intended to be an all-inclusive list of violations associated with your drug products. You are responsible for investigating and determining the causes of these violations and for preventing their recurrence or the occurrence of other violations.

Note that FDA placed all drugs and drug products listed as manufactured by your firm on Import Alert 66-78 on September 24, 2020, as the methods used in and controls used for the manufacture, processing, packing, or holding of these products do not appear to conform to current good manufacturing practices within the meaning of Section 501(a)(2)(B) of the FD&C Act. Your drugs and drug products may be subject to detention without physical examination.

All drugs and drug products manufactured by your firm may remain listed on this import alert until there is evidence establishing that the conditions that gave rise to the appearance of the violation have been resolved, and the Agency has confidence that future entries will be in compliance with the Act. This may include an inspection prior to the Agency considering the appearance of adulteration to be addressed.

If you decide you want to manufacture drugs for the United States in the future, request a Regulatory Meeting to discuss corrective actions.

After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done 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. 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.

Send your electronic reply to [email protected]

Identify your response with FEI 3017066032 and ATTN: Tamara Rosbury.

Sincerely,
/S/
Francis Godwin
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research

CC:
Mr. Jorge Bermudez Cardona
[email protected]

Registered U.S. Agent:
Sarah Gurganus
Registrar Corporation
144 Research Drive
Hampton, VA 23666
[email protected]

__________________________________

1 Due to an increased demand for alcohol-based hand sanitizers during the COVID-19 pandemic, FDA published the Guidance for Industry: Temporary Policy for Preparation of Certain Alcohol-Based Hand Sanitizer Products During the Public Health Emergency (COVID-19) on March 19, 2020, and subsequently updated the guidance several times, most recently on August 7, 2020. This guidance communicates the Agency’s temporary policy that we do not intend to take action against firms for CGMP violations under section 501(a)(2)(B) of the FD&C Act if such firms prepare alcohol-based hand sanitizers for consumer use (or for use as a health care personnel hand rub) during the public health emergency, provided certain circumstances described in the guidance are present. These circumstances include preparation of hand sanitizer products using only the ingredients and formulas set forth in the guidance. In addition to the violative sample results detailed above that demonstrate the substitution of hand sanitizer products declared as manufactured at your facility, a review of the formulations on the drug products’ labeling further indicates that such products are not prepared consistent with FDA’s temporary policy set forth in the guidance. Therefore, these products do not fall within the Agency’s temporary policy not to take action against firms manufacturing hand sanitizer products for violations of section 501(a)(2)(B) of the FD&C Act.

2 The 1994 TFM, which does not distinguish between antiseptic hand washes and rubs, proposed for antiseptic hand washes and healthcare personnel hand washes an alcohol concentration of 60 to 95% by volume in an aqueous solution: 59 FR 31442. Later amendments to the 1994 TFM distinguished between antiseptic hand washes and rubs, and between consumer and healthcare personnel antiseptics, but did not change the alcohol concentration originally proposed in 1994.

3 See, e.g., Temporary Policy for Preparation of Certain Alcohol-Based Hand Sanitizer Products During the Public Health Emergency (COVID-19). Because Soho Fresh Hand Sanitizer is not consistent with the formulations in these guidances, it does not fall within any temporary Agency policy not to take action against firms manufacturing hand sanitizer products for violations of section 505 of the FD&C Act.

4 An inactive ingredient used in over-the-counter (OTC) monograph drugs must meet the requirements of 21 CFR 330.1(e), which requires, among other things, that inactive ingredients must be safe in the amount administered.