- Delivery Method:
- VIA UPS
Recipient NameCleman Agami
- Botanicals Internacional S.A. de C.V.
Ave. de la Luz No. 73-B
Parque Industrial la Luz
54716 Cuautitlan Izcalli, Méx.
- Issuing Office:
- Center for Drug Evaluation and Research | CDER
Warning Letter 320-21-22
February 3, 2021
Dear Cleman Agami:
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 inatek HAND SANITIZER. This drug product was labeled as manufactured at your facility, Botanicals Internacional S.A. de C.V., FEI 3010166858, at Ave. de la Luz No. 73-B, Parque Industrial la Luz, Cuautitlan Izcalli. Following an attempt to import this drug product into the United States, inatek HAND SANITIZER 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 inatek HAND SANITIZER drug product, labeled as manufactured at your facility, is adulterated within the meaning of section 501(d)(2) of the Food, Drug, and Cosmetic Act (FD&C Act or 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, inatek HAND SANITIZER 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), and (ee) of the FD&C Act, 21 U.S.C. 352(j), (a), (e), 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.
inatek HAND SANITIZER, a drug product labeled as manufactured at your facility, is labeled to contain 70% volume/volume (v/v) of the active ingredient ethyl alcohol (ethanol). However, FDA laboratory testing of batches of this product detained at the border found that the product contained an average of 75% (v/v) methanol and an average of 0.2% (v/v) ethyl alcohol, which is 0.3% of the amount of ethyl alcohol described on the label. Therefore, this hand sanitizer drug product is adulterated under section 501(d)(2) of the Act in that the active ingredient of 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.
While the contaminated drug products detailed above were shipped to the United States, information available to FDA indicated that all of your inatek HAND SANITIZER products were detained and refused admission at the border and did not enter the United States. Therefore, FDA did not contact you to recommend that you remove these products from the market. FDA placed drugs and drug products manufactured by your firm on Import Alert 66-78. FDA notified the public of the methanol contamination of your drugs at the following website:
In your July 17, 2020 correspondence to FDA and in subsequent correspondence, you state that you discovered the methanol contamination in drug products as a result of your own independent investigation, and you believe the source of the contamination was isolated to one supplier. However, you initially released the contaminated drug products from your firm for subsequent distribution without exercising adequate controls to ensure that the necessary quality attributes were met for both your finished drug products and their raw materials.
In response to this letter provide the following:
• An updated investigation into how the drug product described above, which was labeled as manufactured at your facility and labeled as containing ethanol, was substituted in part or in whole with methanol. Include an analysis of all CGMP failures under 21 CFR 210 and 211 that contributed to the distribution of dangerous material, and specific corrective action and preventative actions (CAPA) for each.
• 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.
• A list of all raw materials used to manufacture all of your hand sanitizer drug products, including the suppliers’ names, addresses, and contact information. In addition, explain how your quality systems were unable to detect the multiple manufacturing failures associated with the contaminated drugs, from receipt of raw materials to final release of drug products.
The substitution and methanol contamination in hand sanitizer drug products 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 Act.1
Unapproved New Drug and Misbranding Violations
inatek 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 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 product 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 . . . Antiseptic [.] Use: hands (sic) sanitizer to help decrease bacteria on the skin . . . Direction: Put enough product in your palm to cover hands and rub hands together briskly until dry….”
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 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 hand sanitizer product, nor are we aware of any adequate and well-controlled clinical studies in the published literature that support a determination that your inatek 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, 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 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, inatek 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, inatek HAND SANITIZER purportedly contains the active ingredient ethyl alcohol 70%. However, as previously discussed, FDA laboratory analysis revealed that a sample of inatek HAND SANITIZER contained an average of 0.2% ethyl alcohol, which is far less than the 70% of ethyl alcohol declared on the label and far less than the amount of ethanol described in the 1994 TFM. Such a product does not conform to the TFM and other applicable requirements,2 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 analysis of a batch of this product detained at the border also revealed that a sample of inatek HAND SANITIZER contains a significant concentration 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
Finally, this methanol containing drug product, inatek HAND SANITIZER, is misbranded under sections 502(j), (a), (e), and (ee) of the FD&C Act, 21 U.S.C. 352(j), (a), (e), 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, inatek HAND SANITIZER is labeled to contain ethyl alcohol 70%. However, FDA laboratory analysis revealed that a sample of this product contains less ethyl alcohol (ethanol) than indicated on the labeling and instead 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), 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). Lastly, this product is misbranded under section 502(ee) of the FD&C Act, 21 U.S.C. 352(ee) because inatek 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).
We acknowledge the statement in your letter to FDA on July 17, 2020 that you had retained a “qualified GMP consultant to review the company’s quality system and procedures.” However, you have not provided the identity of this entity or written documentation of its qualifications to demonstrate how it is adequate to assist your firm in regaining compliance.
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 August 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. 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.
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
Identify your response with FEI 3010166858 and ATTN: Philip Kreiter.
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research
Registered US Agent:
144 Research Drive
Hampton, VA 23666
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 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 hand sanitizer products labeled as manufactured at your facility, a review of your drug product labeling indicates that this 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.
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 inatek 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.