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Warning Letter 320-22-18

June 27, 2022

Dear Ms. Flores:

Your firm registered as a human drug manufacturer. The U.S. Food and Drug Administration (FDA) conducted testing of consumer antiseptic rub drug products (also referred to as consumer hand sanitizers), labeled as EARTHS AMENITIES Hand Sanitizer and AGAVESPA skincare HAND SANITIZER. These drug products were listed as being manufactured at your facility, DDI Multinacional S.A. de C.V., FEI 3012510709, at Javier Espinoza No. Mz. 30 Lt 20, Col., Santa Martha Acatitla, Iztapalapa. Following an attempt to import EARTHS AMENITIES Hand Sanitizer and AGAVESPA skincare HAND SANITIZER into the United States, they were detained and refused admission at the border.

The results of the FDA laboratory testing of batches of these products detained at the border demonstrate that these drug products listed as being manufactured at your facility are 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, these products are 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, EARTHS AMENITIES Hand Sanitizer and AGAVESPA skincare HAND SANITIZER are unapproved new drugs 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 are misbranded under sections 502(j), (a), (e), and (ee) of the FD&C Act, 21 U.S.C. 352(j), (a), (e), and (ee). Introduction or delivery for introduction of such products 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

EARTHS AMENITIES Hand Sanitizer, listed as being manufactured at your facility, is labeled to contain 70% volume/volume (v/v) of the active ingredient alcohol (ethanol). However, FDA laboratory testing of a batch of this product detained at the border found that the drug product contained an average of 12% ethanol and an average of 60% methanol v/v. Additionally, the drug product AGAVESPA skincare HAND SANITIZER, is labeled to contain 70% v/v of the active ingredient alcohol (ethanol). However, FDA laboratory testing of a batch of this product detained at the border found that the drug product contained an average of 33% ethanol and an average of 35% methanol v/v. Therefore, these hand sanitizer drug products are 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.

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 June 29, 2020, FDA held a teleconference with you and Registrar Corporation, your registered U.S. Agent. We recommended you consider removing all of your firm’s hand sanitizer drug products currently in distribution to the U.S. market. On July 8, 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

On June 30, 2020, your firm responded that you were not recalling any product after a review of your product files as well as the technical information provided by your alcohol supplier, (b)(6).

You explained that you initiated analysis of a sample of the product, but while waiting for the results were not able to follow the agency’s instructions. You mentioned that because of the lack of alcohol in Mexico for the declared coronavirus contingency beginning in March 2020, all the authorized laboratories were closed so you could not test all specifications that you regularly evaluate. However, you explained your supplier justified the quality of the alcohol with the Certificate of Analysis according to the technical specifications of ethanol alcohol.

You further explained that issuing a press release or conducting a product recall was not feasible since you do not acknowledge any retail marketing of the product and were not aware of any finished product sold to individual customers in the U.S. You explained that the product purchased by the responsible exporter was only in the form of testing quantities for its eventual exportation, if viable, and in packs for professional use only.

In response to this letter provide the following:

• A detailed investigation into how the drug products described above, which were listed as being manufactured at your facility and which were labeled as containing ethanol, were substituted in part or in whole with methanol.
• A list of all raw materials used to manufacture all of your hand sanitizer drug products, including the suppliers’ names, addresses, and contact information.
• A list of all batches of any hand sanitizer 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.
• After a teleconference with the FDA on June 29, 2020, you explained you initiated analysis of a sample of the product, but you have not provided information regarding the analytical results to FDA. 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 listed as being 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

EARTHS AMENITIES Hand Sanitizer and AGAVESPA skincare HAND SANITIZER 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 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 they are intended to affect the structure or any function of the body. Specifically, these products are intended as consumer antiseptic rubs.

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

EARTHS AMENITIES Hand Sanitizer product label

“Hand Sanitizer[.]. . . Drug Facts . . . Uses ■ to help reduce bacteria on the skin.”

AGAVESPA skincare HAND SANITIZER product label

“HAND SANITIZER . . . Drug Facts . . .Uses ■ to help reduce bacteria on the skin.”

These topical antiseptic products are “new drugs” within the meaning of section 201(p) of the FD&C Act, 21 U.S.C. 321(p), because they are 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 these drug products as further described below). No FDA-approved application pursuant to section 505 of the FD&C Act, 21 U.S.C. 355, are in effect for these hand sanitizer products, nor are we aware of any adequate and well-controlled clinical studies in the published literature that support a determination that your EARTHS AMENITIES Hand Sanitizer and AGAVESPA skincare HAND SANITIZER drug products are GRASE for use under the conditions suggested, recommended, or prescribed in their labeling. 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).

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)(Consumer Antiseptic Rub Proposed Rule). Over the course of these rulemakings, benzalkonium chloride, ethyl alcohol, and isopropyl alcohol were classified as Category III for use as active ingredients in antiseptic rubs, 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 for safety or effectiveness in a TFM 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, EARTHS AMENITIES Hand Sanitizer and AGAVESPA skincare HAND SANITIZER do 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 do 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 labels, EARTHS AMENITIES Hand Sanitizer and AGAVESPA skincare HAND SANITIZER purportedly contain the active ingredient ethyl alcohol 70% v/v. However, as previously discussed, FDA laboratory analyses of a batch of each product revealed that EARTHS AMENITIES Hand Sanitizer and AGAVESPA skincare HAND SANITIZER contain a concentration of ethyl alcohol that is far less than the 70% v/v stated on its product label and far less than the amount of ethyl alcohol described in the 1994 TFM.² Such a product does not conform with the TFM and the applicable requirements for nonprescription drugs.

FDA laboratory analyses of a batch of each product also revealed that EARTHS AMENITIES Hand Sanitizer and AGAVESPA skincare HAND SANITIZER contain significant concentrations of the undeclared ingredient methyl alcohol (methanol). Use of methanol as an active ingredient is not in conformance with the TFM. 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.³

Additionally, these methanol-containing drug products, EARTHS AMENITIES Hand Sanitizer and AGAVESPA skincare HAND SANITIZER, are misbranded under sections 502(j), (a), (e) and (ee) of the FD&C Act, 21 U.S.C. 352(j), (a), (e) and (ee). They are misbranded under section 502(j) of the FD&C Act, 21 U.S.C. 352(j), because they are dangerous to health when used according to their 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.

These hand sanitizers are misbranded under section 502(a) of the FD&C Act, 21 U.S.C 352(a), because their labeling is false or misleading. As noted above, EARTHS AMENITIES Hand Sanitizer and AGAVESPA skincare HAND SANITIZER are labeled to contain ethyl alcohol 70% v/v. However, FDA laboratory analyses revealed that samples of these products contain little ethyl alcohol (ethanol) and instead contain significant concentrations of methyl alcohol (methanol), an ingredient that is not declared on the products’ labels.

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 products’ labels to disclose the presence of the methyl alcohol (methanol) in the products, causes these products to be misbranded under section 502(a) of the FD&C Act, 21 U.S.C. 352(a).

The failure of these products to list methyl alcohol (methanol) as an ingredient on their labels causes them to be misbranded under section 502(e)(1)(A) of the FD&C Act, 21 U.S.C. 352(e)(1)(A).

Lastly, these products are misbranded under section 502(ee) of the FD&C Act, 21 U.S.C. 352(ee) because EARTHS AMENITIES Hand Sanitizer and AGAVESPA skincare HAND SANITIZER 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 applications approved under section 505 of the FD&C Act, 21 U.S.C. 355.

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).

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 manufactured by your firm on Import Alert 66-78 on July 13, 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.

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 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 do so within 15 working days, state your reasons for delay and your schedule for completion.

Send your electronic reply to [email protected]

Identify your response with FEI 3012510709 and ATTN: Tamara Rosbury.

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

cc:
Registered U.S. Agent:
David Lennarz
Registrar Corp
144 Research Dr.
Hampton, VA 23666

____________________________

1 We note that your drug products also did not conform to any temporary policy FDA had implemented during the COVID-19 public health emergency. In March 2020, the Agency published three guidance documents to provide regulatory flexibility to certain firms to help meet the demand for alcohol-based hand sanitizer during the public health emergency. On December 31, 2021, these guidances were withdrawn, and firms must have ceased distribution, by March 31, 2022, of any remaining hand sanitizer products that were prepared under the temporary policies. See, 86 FR 56960, October 13, 2021.

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 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.