- Delivery Method:
- VIA UPS
Recipient NameMr. Alejandro Ortega
- Neoingenium Labs, SA de CV
Periferico Manuel Gomez Morin No. 6370
45010 Zapopan, Jal.
- Issuing Office:
- Center for Drug Evaluation and Research
Warning Letter 320-21-38
March 31, 2021
Dear Mr. Ortega:
Your firm recently registered as a human drug manufacturer. The U.S. Food and Drug Administration (FDA) conducted testing of a consumer antiseptic hand rub drug product (also referred to as a consumer hand sanitizer) labeled as cleansepure. This drug product was declared to be manufactured at your facility, FEI 3013359123 at Periferico Manual Gomez Morin No. 6370, Ciudad Granja, Zapopan, Mexico. Following an attempt to import cleansepure into the United States, it was detained and refused admission at the border.
The results of 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), 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, cleansepure 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)(1)(A), (c), (x), (b)(1), and (ee) of the FD&C Act, 21 U.S.C. 352(j), (a), (e)(1)(A), (c), (x), (b)(1), 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.
Cleansepure, declared to be 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 it contained an average of 9.6% ethanol and an average of 58% of methanol v/v. 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.
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 11, 2020, FDA held a teleconference with you and Mexus, Inc, 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 September 11, 2020, FDA notified the public of methanol contamination of your hand sanitizer at the following website: https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-hand-sanitizers-consumers-should-not-use.
On September 28, 2020, you provided correspondence stating that you do not manufacture cleansepure and that you believe a third-party is using your firm’s information to send this drug product without your knowledge and authorization. However, one of your consignees acknowledged your firm as the manufacturer of cleansepure and stated that it received this drug product from your firm. As of the date of this letter, you have yet to take market action based on FDA’s recommendation.
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.
• You stated in your September 28, 2020 correspondence that you plan to gather information on every raw material supplier for all lots of hand sanitizer product manufactured by your firm, and crossmatch the lots to the suppliers’ certificates of analysis and additional testing that was performed on those products. Further, you plan to crossmatch those lots with the product names, distributors/consignees and NDC numbers in each lot and against the import entries. Provide the summary of your findings. Include the raw material 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.
The substitution and contamination with methanol in a drug product declared 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, 21 U.S.C. 351(a)(2)(B).1
Unapproved New Drug and Misbranding Violations
Cleansepure 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 topical antiseptic.
Examples of claims observed on the cleansepure label that provide evidence of the intended use (as defined in 21 CFR 201.128) of the product include, but may not be limited to, the following:
“Drug Facts Purpose Antiseptic . . . Uses Hand Sanitizer to help reduce bacteria that potentially can cause disease. For use when soap and water are not available . . . Directions Place enough product on hands to cover all surfaces. Rub hands together until dry.”
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) or under 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 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 cleansepure 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 have 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 Rubs Proposed Rule). 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 section 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, cleansepure does not conform to the 1994 TFM, as further amended by the 2016 Consumer Antiseptic Rubs 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, cleansepure purportedly contains the active ingredient ethyl alcohol (ethanol) 70% v/v. However, as previously discussed, FDA laboratory analyses of a batch of this product detained at the border revealed that cleansepure contains ethanol in an amount that is less than the 70% v/v declared on the label and far less 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 the guidances setting forth FDA’s temporary policies for hand sanitizers during the COVID-19 public health emergency.3
FDA laboratory analyses also demonstrated that a batch of cleansepure contains significant concentrations of the undeclared ingredient methyl alcohol (methanol). Use of methanol as an active ingredient is not in conformance with the 1994 TFM, nor is methanol 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, cleansepure, is misbranded under sections 502(j), (a), (e)(1)(A), (c), (x), (b)(1), and (ee) of the FD&C Act, 21 U.S.C. 352(j), (a), (e)(1)(A), (c), (x), (b)(1), 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 or misleading. As noted above, cleansepure is labeled to contain ethyl alcohol 70% v/v. However, FDA laboratory analysis of a batch of this product demonstrates that the product contains a concentration of ethyl alcohol (ethanol) that is less than what is stated on the product label and contains a significant concentration 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 drug product to list methyl alcohol (methanol) as an ingredient on its label also causes it to be misbranded under section 502(e)(1)(A) of the FD&C Act, 21 U.S.C. 352(e)(1)(A).
Cleansepure is misbranded under section 502(c) of the FD&C Act, 21 U.S.C. 352(c), because the label fails to bear a complete statement of identity as required under 21 CFR 201.61. In the case of a drug that has an established name, the statement of identity must contain the established name and the general pharmacological action(s) or principal intended action(s) of the drug in the principal display panel. The label for this product fails to include the principal intended use of the drug as part of the statement of identity.
Furthermore, this product is misbranded under section 502(b)(1) of the FD&C Act, 21 U.S.C. 352(b)(1), because the product label does not contain the name and place of business of the manufacturer, packer, or distributor. Although the label contains the name of the distributor, Distribu LLC, it does not include the place of business of the distributor.
Further, this product 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 complete domestic address or domestic telephone number through which the responsible person (as described in section 760 of the FD&C Act) 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 cleansepure 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.
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 September 18, 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. 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 FD&C 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 CDER-OC-OMQ-Communications@fda.hhs.gov
Please identify your response with FEI 3013359123 and ATTN: Towanda Terrell.
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research
Registered US Agent:
1214 Beltway Pkwy
Laredo, TX 78045
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 February 10, 2021. 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 rubs) 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 presence of methanol in your hand sanitizer products declared as manufactured at your facility, a review of the drug product’s labeling further indicates that these products are 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.
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 cleansepure 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 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.