WARNING LETTER
Grupo Yacana Mexico, S.A.S. de C.V.
MARCS-CMS 609824 —
January 26, 2021
Delivery Method:
VIA UPS
Product:
Drugs
Recipient:
Recipient Name
Ms. Sofia Corona Gonzalez
Recipient Title
Laboratory and Production Manager
Grupo Yacana Mexico, S.A.S. de C.V.
Av. Alfonso Reyes No. 714
Country la Silla Sector 4
67173
Guadalupe
,
N.L.
Mexico
Issuing Office:
Center for Drug Evaluation and Research | CDER
United States
Warning Letter 320-21-20
January 26, 2021
Dear Ms. Sofia Corona Gonzalez:
Your firm recently registered as a human drug manufacturer. The U.S. Food and Drug Administration (FDA) conducted testing of consumer antiseptic hand rub drug products (also referred to as consumer hand sanitizers) labeled as YACANA Alcohol Antiseptic 70% Topical Solution Antiseptic Hand Rub and YACANA Isopropyl Alcohol Antiseptic 70% Topical Solution Antiseptic Hand Rub. These drug products were labeled as manufactured at your facility, Grupo Yacana Mexico, S.A.S. de C.V., FEI 3015123543, at Av. Alfonso Reyes No. 714, Guadalupe (Country la Silla Sector 4), Nuevo Leon, Mexico. Following an attempt to import YACANA Alcohol Antiseptic 70% Topical Solution Antiseptic Hand Rub and YACANA Isopropyl Alcohol Antiseptic 70% Topical Solution Antiseptic Hand Rub into the United States, they were detained and refused admission at the border.
The results of FDA laboratory testing of batches of these products detained at the border demonstrate that the YACANA Alcohol Antiseptic 70% Topical Solution Antiseptic Hand Rub and YACANA Isopropyl Alcohol Antiseptic 70% Topical Solution Antiseptic Hand Rub drug products, labeled as 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.
The results of FDA laboratory testing of a batch of YACANA Isopropyl Alcohol Antiseptic 70% Topical Solution Antiseptic Hand Rub drug product, labeled as 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 represents to possess.
These products are also adulterated within the meaning of section 501(a)(2)(B) (21 U.S.C. 351(a)(2)(B)), in that the substitution and subpotency demonstrate that the quality assurance within your facility is not functioning in accordance with Current Good Manufacturing Practice (CGMP) requirements.
In addition, your YACANA Antiseptic 70% Topical Solution Antiseptic Hand Rub and YACANA Isopropyl Alcohol Antiseptic 70% Topical Solution Antiseptic Hand Rub 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 (a) and (ee) of the FD&C Act, 21 U.S.C. 352(a) and (ee). YACANA Antiseptic 70% Topical Solution Antiseptic Hand Rub is further misbranded under sections 502(j) and (e) of the FD&C Act, 21 U.S.C. 352(j), and (e). 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).
Adulteration Violations: Substitution
YACANA Alcohol Antiseptic 70% Topical Solution Antiseptic Hand Rub, 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 one batch of this product detained at the border found that the drug product contained on average 0.04% ethanol v/v and an average of 63% methanol v/v. FDA laboratory testing of another batch of this product detained at the border found on average 3.6% ethanol v/v and an average of 59% methanol v/v. FDA laboratory testing of a third batch of this product detained at the border found on average 0.6% ethanol v/v and an average of 49% methanol v/v.
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 accidently ingest these products, and adolescents and adults who drink these products as an alcohol (ethanol) substitute, are most at risk for methanol poisoning.
Additionally, YACANA Isopropyl Alcohol Antiseptic 70% Topical Solution Antiseptic Hand Rub, labeled as manufactured at your facility, is labeled to contain 70% (v/v) of the active ingredient Isopropyl Alcohol (IPA). However, FDA laboratory testing of a batch of this product detained at the border found that the drug product contained on average of 53% ethanol v/v and 0% (v/v) IPA.
Therefore, these hand sanitizer drug products are adulterated under section 501(d)(2) of the FD&C 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.
Adulteration Violations: Subpotency
YACANA Isopropyl Alcohol Antiseptic 70% Topical Solution Antiseptic Hand Rub, labeled as manufactured at your facility, is labeled to contain 70% (v/v) of the active ingredient isopropyl alcohol (IPA). However, FDA laboratory testing of a batch of this product detained at the border found that it contained 61% IPA (v/v) and 0.7% ethanol (v/v). This hand sanitizer drug product is adulterated under section 501(c) of the FD&C Act in that the active ingredient of IPA is present at levels in the product lower than that which is declared on its labeling. CDC recommends
1
that, if soap and water are not readily available, consumers use an alcohol-based hand sanitizer that contains not less than 70% IPA. This is the minimum active ingredient concentration of IPA specified in the 1994 Tentative Final Monograph for Health-Care Antiseptic Drug Products (59 FR 31402), 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).
On August 12, 2020, FDA held a teleconference with you and Pragmatic Compliance LLC, 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. FDA notified the public of the subpotency and methanol contamination of your hand sanitizer drug products at the following webpage:
https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-hand-sanitizers-consumers-should-not-use
On August 18, 2020, you issued a voluntary nationwide recall of all your hand sanitizer drug products due to the presence of undeclared methanol (Wood Alcohol) and subpotent ethanol, as noted on the following webpage:
https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/grupo-yacana-mexico-sas-de-cv-issues-voluntary-nationwide-recall-all-lots-yacana-hand-sanitizer-due
In response to this letter provide the following:
• A detailed investigation into how the drug products described above, which were labeled as manufactured at your facility and which were labeled as containing ethanol or IPA, were substituted in part or in whole with methanol or ethanol, respectively.
• A detailed investigation into how the hand sanitizer drug products described above, which were labeled as containing 70% IPA, in fact contained an average of 61% IPA (v/v).
• A list of all raw materials used to manufacture all of your hand sanitizer drug products, including the supplier’s 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 hand sanitizer drug products labeled as manufactured in your facility, as well as the subpotency of hand sanitizer 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 FD&C Act.
2
Unapproved New Drug and Misbranding Violations
YACANA Antiseptic 70% Topical Solution Antiseptic Hand Rub and YACANA Isopropyl Alcohol Antiseptic 70% Topical Solution Antiseptic Hand Rub 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 for use as consumer antiseptic rubs.
Examples of claims observed on the YACANA Antiseptic 70% Topical Solution Antiseptic Hand Rub and YACANA Isopropyl Alcohol Antiseptic 70% Topical Solution Antiseptic Hand Rub product 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:
“Drug Facts…Uses…Hand Sanitizer to help reduce bacteria that potentially can cause disease…”
“Directions…Place enough product to cover all surfaces, rub hand together until dry…”
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 their 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 products, 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 either of these drug products, nor are we aware of any adequate and well-controlled clinical studies in the published literature that support a determination that your YACANA Antiseptic 70% Topical Solution Antiseptic Hand Rub and YACANA Isopropyl Alcohol Antiseptic 70% Topical Solution Antiseptic Hand Rub drug products are GRASE for use under the conditions suggested, recommended, or prescribed in its 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 FDA’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, 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 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, YACANA Antiseptic 70% Topical Solution Antiseptic Hand Rub and YACANA Isopropyl Alcohol Antiseptic 70% Topical Solution Antiseptic Hand Rub do not conform to the 1994 TFM, as further amended by the 2016 Consumer Antiseptic Rub proposed, 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 label, YACANA Antiseptic 70% Topical Solution Antiseptic Hand Rub purportedly contains the active ingredient ethyl alcohol (ethanol) 70% v/v. However, as previously discussed, FDA laboratory analyses of batches of these products detained at the border demonstrated that YACANA Antiseptic 70% Topical Solution Antiseptic Hand Rub contains ethanol in a concentration that is less than the 70% stated on its product label and far less than the amount of ethanol described in the 1994 TFM.
3
Such a product does not conform to the TFM or 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
FDA laboratory analyses of batches of this product detained at the border revealed that batches of YACANA Antiseptic 70% Topical Solution Antiseptic Hand Rub contain 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 consistent with the formulations described in the guidances setting forth FDA’s temporary policies for hand sanitizers during the COVID-19 public health emergency. 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.
5
According to its label, YACANA Isopropyl Alcohol Antiseptic 70% Topical Solution Antiseptic Hand Rub purportedly contains the active ingredient isopropyl alcohol 70% v/v. However, as previously discussed, FDA laboratory analyses revealed that batches of these products detained at the border contain isopropyl alcohol, which is less than the 70% stated on its product label and less than the amount of isopropyl alcohol described in the 1994 TFM. Furthermore, the analyses revealed that the product contained concentrations of an undeclared ingredient, ethanol. Ethanol as a sole active ingredient is permitted for use as a consumer or health care personnel antiseptic hand rub. However, even if ethanol was intended to be the only active ingredient for the product, the concentrations of the undeclared ingredient is below the concentration allowed under the TFM. Such a product does not conform to the TFM or 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.
Additionally, YACANA Antiseptic 70% Topical Solution Antiseptic Hand Rub is misbranded under sections 502(j), (a), (e), and (ee) of the FD&C Act, 21 U.S.C. 352(j), (a), and (e). YACANA Isopropyl Alcohol Antiseptic 70% Topical Solution Antiseptic Hand Rub is misbranded under sections 502(a) and (ee) of the FD&C Act, 21 U.S.C. 352(a) and (ee).
YACANA Antiseptic 70% Topical Solution Antiseptic Hand Rub 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. The failure of this product to list methanol as an ingredient on its label also causes YACANA Antiseptic 70% Topical Solution Antiseptic Hand Rub to be misbranded under section 502(e)(1)(A) of the FD&C Act, 21 U.S.C. 352(e)(1)(A).
YACANA Antiseptic 70% Topical Solution Antiseptic Hand Rub and YACANA Isopropyl Alcohol Antiseptic 70% Topical Solution Antiseptic Hand Rub are misbranded under section 502(a) of the FD&C Act, 21 U.S.C 352(a), because their labeling is false or misleading. 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. . ..” As noted above, of YACANA Antiseptic 70% Topical Solution Antiseptic Hand Rub is labeled to contain ethanol 70% v/v. However, FDA laboratory analyses of batches of this product demonstrate that the product contains a concentration of ethanol that is far less than the 70% stated on the product label and instead contains significant concentrations of methanol, an ingredient that is not declared on the product labels. Similarly, as noted above, Yacana Isopropyl Alcohol Antiseptic 70% Topical Solution Antiseptic Hand Rub is labeled to contain isopropyl alcohol 70% v/v. However, FDA laboratory analyses of batches of this product demonstrate that the product contains isopropyl alcohol, which is less than the 70% stated on its product label and contains ethanol even though the product label does not include ethanol as an ingredient. Thus, the misleading representation of the concentration of active ingredient ethanol and the failure of the product label to disclose the presence of the methanol in the product, causes YACANA Antiseptic 70% Topical Solution Antiseptic Hand Rub to be misbranded under section 502(a) of the FD&C Act, 21 U.S.C. 352(a).
Lastly, YACANA Antiseptic 70% Topical Solution Antiseptic Hand Rub and YACANA Isopropyl Alcohol Antiseptic 70% Topical Solution Antiseptic Hand Rub are misbranded under section 502(ee) of the FD&C Act, 21 U.S.C. 352(ee) because they 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 they are 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).
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 August 20, 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 3015123543 and ATTN: Philip Kreiter.
Sincerely,
/S/
Francis Godwin
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research
CC:
Registered U.S. Agent
Mr. Jerry Doane
Pragmatic Compliance LLC
15815 SW 11th Court Rd.
Ocala, FL 34473
USA
_______________________________
1
https://www.cdc.gov/coronavirus/2019-ncov/hcp/hand-hygiene.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 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 substitution and contamination of methanol in hand sanitizer products labeled as manufactured at your facility, as well as the subpotency of hand sanitizer products labeled as manufactured at your facility, a review of the drug products’ labeling further indicate that these 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.
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 YACANA Antiseptic 70% Topical Solution Antiseptic Hand Rub and YACANA Isopropyl Alcohol Antiseptic 70% Topical Solution Antiseptic Hand Rub are not consistent with the formulations described in these guidances, they do 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.
5
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.
Content current as of:
02/02/2021
Regulated Product(s)
Drugs