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Warning Letter 320-21-21

January 28, 2021

Dear Mr. Rodriguez:

Your firm is registered as a human drug manufacturer. The United States Food and Drug Administration (FDA) conducted testing of a consumer antiseptic rub drug product (also referred to as a consumer hand sanitizer), labeled as HEALTH & HAND GEL HAND SANITIZER. This drug product was manufactured at your facility, Simex logistics S.A. de C.V, FEI 3016774460, at Salvatierra No. 101 Fracc. El Puente, Celaya Guanajuato, Mexico 38060. Following an attempt to import this drug product into the United States, HEALTH & HAND GEL HAND SANITIZER was detained and refused admission at the border.

The results of the FDA laboratory testing of a batch (lot # 0720) of this product detained at the border demonstrate that HEALTH & HAND GEL HAND SANITIZER drug product manufactured at your facility is adulterated within the meaning of section 501(c) of the Federal Food, Drug, and Cosmetic Act (FD&C Act or Act), 21 U.S.C. 351(c), in that its strength, purity, or quality falls below that which it purports or is represented to possess. In addition, this product is adulterated within the meaning of section 501(a)(2)(B) (21 U.S.C. 351(a)(2)(B)), in that the subpotency and documents provided demonstrate that the quality assurance within your facility is not functioning in accordance with Current Good Manufacturing Practice (CGMP) requirements.

In addition, your HEALTH & HAND GEL HAND SANITIZER 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(a) and (ee) of the FD&C Act, 21 U.S.C. 352(a) and (ee). Introduction or delivery for introduction of such a 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

HEALTH & HAND GEL HAND SANITIZER, manufactured at your facility, is labeled to contain 70% of the active ingredient alcohol (ethanol). However, FDA laboratory testing of a batch of this product detained at the border found that this product contained an average of 51% ethanol volume/volume (v/v). This hand sanitizer drug product is adulterated under section 501(c) of the FD&C Act in that the active ingredient of ethanol is present at levels in the product lower than that which is declared on its labeling.

CDC recommends¹ that, if soap and water are not readily available, consumers use an alcohol-based hand sanitizer that contains not less than 60% alcohol (ethanol). This is the minimum active ingredient concentration of ethanol specified in the 1994 Tentative Final Monograph for Health-Care Antiseptic Drug Products (59 FR 31402), as further amended by “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).

On October 7, 2020, FDA held a teleconference with you and your registered U.S. Agent. We requested additional information concerning your CGMP operations, including test methods for your finished drug product. In your response, you provided information on the gel formulation used for the drug products you produce, as well as, third party testing conducted on 10 of the (b)(4) lots offered for importation. The third party testing conducted on “lot 0720”, the same as that tested by FDA, identified variability in the formulation. Specifically, the first sample from the upper layers of the bottle demonstrated subpotency (54%) and upon additional mixing of the sampe bottle you obtained a result of 68%. Your gel formulation does not appear to have uniform character and quality. Furthermore, you acknowledged that Simex released at least two of the (b)(4) lots to the U.S. market without performing finished product testing, a violation of 21 CFR 211.165.

In addition to the third party testing results, you offered details on the in-house testing that you are now using to test your drug products. The method of in-house testing uses a refractometer device that is unsuitable for the testing of finished hand sanitizers that contain materials other than ethanol and water in their matrix. Furthermore, you state that due to the “antiseptic nature of the product” there is no testing performed for objectionable microbiological contamination. Failure to adequately test prior to release or assure that the drug products have the identity, strength, quality and purity they purport or are represented to possess are violations of CGMP requirements. See 21 CFR 211.165 and 211.100.

Ultimately, you committed to recall all hand sanitizer drug products manufactured by your firm within expiration. You issued a voluntary recall on November 25, 2020. On November 10, 2020, FDA notified the public of the subpotency of your hand sanitizer drugs products at the following website: https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-hand-sanitizers-consumers-should-not-use.

In response to this letter provide the following:
• Your plans to reformulate your drug product.
• A remediation plan that better assures ongoing management oversight throughout the manufacturing lifecycle of all drug products. Provide a more data-driven and scientifically sound program that identifies sources of process variability, and assures that manufacturing including both production and packaging operations meet appropriate parameters and quality standards. This includes, but is not limited to, evaluating suitability of equipment for its intended use, ensuring quality of input materials, determining the capability and reliability of each manufacturing process step and its controls, and vigilant ongoing monitoring of process performance and product quality.
• A detailed program for designing, validating, maintaining, controlling and monitoring each of your manufacturing processes that includes vigilant monitoring of intra-batch and inter-batch variation to ensure an ongoing state of control. Also, include your program for qualification of your equipment and facility.
• A list of appropriate chemical and microbial test methods and specifications used to analyze each lot of your components and drug product before making a lot disposition decision, and the associated written procedures.

The subpotency of active ingredient ethanol in this drug product declared as manufactured at your facility and the documents you provided demonstrate that the quality assurance within your facility is not functioning in accordance with CGMP requirements under section 501(a)(2)(B) of the Act.²

Unapproved New Drug and Misbranding Violations

HEALTH & HAND GEL 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 for use as a consumer topical antiseptic.

Examples of claims observed on the HEALTH & HAND GEL 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 . . . Drug Facts . . . Purpose . . . Antimicrobial . . . Use(s) . . . Helps reduce bacteria on the skin that could cause diseases . . . Directions ∙ Place enough product in the palm of your hands to thoroughly cover your hands. ∙ Rub hands together briskly until product is completely absorbed and hands are dry.” (product label)

This topical antiseptic 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 HEALTH & HAND GEL 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 “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, three active ingredients (benzalkonium chloride, ethyl alcohol (ethanol), and isopropyl alcohol) were classified as Category III for use 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 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, HEALTH & HAND GEL 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, as added by the CARES Act, for marketing without an approved application under section 505.

According to the product label, HEALTH & HAND GEL HAND SANITIZER purportedly contains the active ingredient ethyl alcohol 70%. However, as previously discussed, FDA laboratory analyses of a batch of this product detained at the border demonstrated that HEALTH & HAND GEL HAND SANITIZER contains ethanol in a concentration that is less than the 70% stated on its product label and less than the amount of ethanol described in the 1994 TFM.³ Such a product does not conform with the TFM or the applicable requirements, nor is it consistent with the formulations described in the guidances setting forth FDA’s temporary policies for hand sanitizers during the COVID-19 public health emergency.⁴

Additionally, this drug product, HEALTH & HAND GEL HAND SANITIZER, is misbranded under sections 502(a) and (ee) of the FD&C Act, 21 U.S.C. 352(a) and (ee).

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 or misleading. As noted above, HEALTH & HAND GEL HAND SANITIZER is labeled to contain ethyl alcohol 70%. However, FDA laboratory analyses of a batch of this product demonstrate that the product contains a concentration of ethyl alcohol (ethanol) that is less than what is stated on the product label. Thus, the misleading representation of the concentration of the active ingredient ethyl alcohol (ethanol) in the product causes this product to be misbranded under section 502(a) of the FD&C Act, 21 U.S.C. 352(a).

Lastly, this product is misbranded under section 502(ee) of the FD&C Act, 21 U.S.C. 352(ee) because HEALTH & HAND GEL HAND SANITIZER 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 any 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 November 17, 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 practice within the meaning of section 501(a)(2)(B) of the FD&C Act. Drugs and drug products that appear to be adulterated or misbranded may be detained or refused admission 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 a 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 address any 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 3016774460 and ATTN: Tamara Ely.

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

CC:
Registered U.S. Agent
Aldo Martinez
1600 University Blvd
Brownsville, Texas 78520
[email protected]

_________________________

1 https://www.cdc.gov/handwashing/hand-sanitizer-use.html

2 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 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 subpotency of ethanol in hand sanitizer products manufactured at your facility, a review of your drug product labeling further indicates that the product is not prepared consistent with FDA’s temporary policy set forth in the guidance. Therefore, this product does 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.

3 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.

4 See, e.g., Temporary Policy for Preparation of Certain Alcohol-Based Hand Sanitizer Products During the Public Health Emergency (COVID-19). Because HEALTH & HAND GEL HAND SANITIZER is not consistent with the formulations described 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.