WARNING LETTER
Limpo Quimicos, SA de CV
MARCS-CMS 608859 —
September 30, 2021
Delivery Method:
VIA UPS
Product:
Drugs
Recipient:
Recipient Name
Mr. Santiago Alvarado
Recipient Title
General Director
Limpo Quimicos, SA de CV
Privada Jose Silvestre Aramberri No. 149, Col. Solidaridad
66058
General Escobedo
,
N.L.
Mexico
Issuing Office:
Center for Drug Evaluation and Research | CDER
United States
Warning Letter
320-21-63
September 30, 2021
Dear Mr. Alvarado:
Your firm was 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 Andy’s Best ADVANCED HAND SANITIZER (678.28 FL OZ and 128 FL OZ) and NeoNatural gel Hand Sanitizer. These drug products were declared to be manufactured at your facility, Limpo Quimicos S.A. de C.V., FEI 3016628153, at Privada Jose Silvestre Aramberri No. 149, Col. Solidaridad General Escobedo Nuevo León. Following an attempt to import Andy’s Best ADVANCED HAND SANITIZER and NeoNatural gel 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 Andy’s Best ADVANCED HAND SANITIZER 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 or the “Act"), 21 U.S.C. 351(d)(2), in that a substance was substituted wholly or in part therefor.
The results of the FDA laboratory testing of a batch of NeoNatural gel Hand Sanitizer detained at the border demonstrate that this drug product declared to be manufactured at your facility is adulterated within the meaning of section 501(c) of the FD&C 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, 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 and subpotency demonstrate that the quality assurance within your facility is not functioning in accordance with Current Good Manufacturing Practice (CGMP) requirements.
Further, Andy’s Best ADVANCED HAND SANITIZER and NeoNatural gel Hand Sanitizer drug products 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). Andy’s Best ADVANCED 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). NeoNatural gel Hand Sanitizer 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 these 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
Andy’s Best ADVANCED HAND SANITIZER, declared to be 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 this product contained the following: an average of 1.1% ethanol v/v and an average of 63% methanol v/v; an average of 1.2% ethanol v/v and an average of 66% methanol v/v; and an average of 1.0% ethanol v/v and an average of 63% 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.
NeoNatural gel Hand Sanitizer, declared to be manufactured at your facility, is labeled to contain 70% v/v of the active ingredient alcohol (ethanol). However, FDA laboratory testing of this product detained at the border found that the drug product contained an average of only 32% v/v ethanol. The 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 recommends
1
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 as 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 July 8, 2020, FDA held a teleconference with you and Brand Name Distributors, LLC, your registered U.S. Agent, at the time. We recommended you consider removing all of your firm’s hand sanitizer drug product(s) currently in distribution from the U.S. market. On July 8, 2020, FDA notified the public of the methanol contamination 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
On July 23, 2020, you sent a communication to the FDA stating that you do not have any test results indicating methanol adulteration for any of your products exported from Mexico to the U.S. prior to May 19, 2020 and you also asserted that nothing entered the U.S. after May 19, 2020. However, you did not provide the methanol test results, and FDA records indicate that shipments of your products entered the U.S. after May 19, 2020. As of the date of this letter, you have yet to take a market action on all hand sanitizer drug products distributed both before and after May 19, 2020.
In response to this letter provide the following:
• In a communication to the FDA on July 7, 2020, you stated that your firm had undertaken an investigation and initiated corrective actions related to your facility’s manufacture of Andy’s Best ADVANCED HAND SANITIZER. However, you did not provide sufficient evidence for this assertion. Provide a detailed investigation into how the hand sanitizer drug product described above, which was declared as manufactured at your facility and labeled as containing ethanol, was substituted in part or in whole with methanol.
• A detailed investigation into how the NeoNatural gel Hand Sanitizer product described above, labeled as containing 70% ethanol, in fact contained an average of 32% ethanol.
• A list of all raw materials used to manufacture 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.
The subpotency and substitution of hand sanitizer drug products declared to be manufactured in your facility demonstrate 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
Andy’s Best ADVANCED HAND SANITIZER and NeoNatural gel 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 topical antiseptics.
Examples of claims observed on the Andy’s Best ADVANCED HAND SANITIZER 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:
“HAND SANITIZER . . . . . .
Drug Facts
. . .
Use
Hand Sanitizer to help reduce bacteria on skin. . . .
Directions
Put a [sic] enough product in your palm to cover hands and rub hands together briskly until dry . . .”
Examples of claims observed on the NeoNatural gel Hand Sanitizer 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
. . .
Use
: Hand Sanitizer to help reduce bacteria on skin. . . .
Directions
: Put enough product in your palm to cover hands and rub hands together briskly until dry.”
These hand sanitizer 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) 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 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 Andy’s Best ADVANCED HAND SANITIZER and NeoNatural gel 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 Rubs Proposed Rule). Over the course of these rulemakings, three active ingredients (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 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, Andy’s Best ADVANCED HAND SANITIZER and NeoNatural gel Hand Sanitizer do not conform to the 1994 TFM, as further amended by the 2016 Consumer Antiseptic Rubs Proposed Rule, nor any other TFM 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, Andy’s Best ADVANCED HAND SANITIZER and NeoNatural gel Hand Sanitizer purportedly contain 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 Andy’s Best ADVANCED HAND SANITIZER and NeoNatural gel Hand Sanitizer contain concentrations of ethanol in concentrations that are less than the 70% stated on the labels and far less than the amount of ethanol described in the 1994 TFM.
3
Such products do not conform with the TFM or other applicable requirements, nor are they consistent with the formulations described in FDA’s temporary policies for hand sanitizers during the COVID-19 public health emergency.
4
FDA laboratory analyses also demonstrated that batches of Andy’s Best ADVANCED 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 1994 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.
5
Additionally, this methanol-containing drug product, Andy’s Best ADVANCED 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 or misleading. As noted above, Andy’s Best ADVANCED HAND SANITIZER is labeled to contain ethyl alcohol 70% v/v. However, FDA laboratory analyses of batches 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 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 the 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 the 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).
Additionally, NeoNatural gel 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, NeoNatural gel Hand Sanitizer is labeled to contain ethyl alcohol (ethanol) 70% v/v. However, FDA laboratory analyses of a batch of this product demonstrate that the product contains a concentration of ethanol that is far less than what stated on its product label.
Thus, the misleading representation of the concentration of the active ingredient ethyl alcohol in the NeoNatural gel Hand Sanitizer labeling causes this product to be misbranded under section 502(a) of the FD&C Act, 21 U.S.C. 352(a).
Lastly, Andy’s Best ADVANCED HAND SANITIZER and NeoNatural gel Hand Sanitizer are misbranded under section 502(ee) of the FD&C Act, 21 U.S.C. 352(ee), because the products 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 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
We acknowledge the statement in your response dated July 7, 2020 that you retained a “GMP Drug Consultant” for “GAP Analysis and 21 CFR OTC Drugs Quality Program.” 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 drugs and drug products manufactured by your firm on Import Alert 66-78 on July 15, 2020. 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 CDER-OC-OMQ-Communications@fda.hhs.gov
Identify your response with FEI 3016628153 and ATTN: Rory Geyer.
Sincerely,
/S/
Francis Godwin
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research, FDA
CC:
Registered U.S. Agent
Brand Name Distributors
Luciano Escobedo
luciano@infotrade.com.mx
Brand Name Distributors
Carolina Hernandez
carolina.hernandez@infotrade.com.mx
____________________________________
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 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 a 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 testing results detailed above that demonstrate the subpotency and substitution of the hand sanitizer products declared as manufactured at your facility, a review of the purported formulations on drug products’ labeling further indicates 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 handwashes and healthcare personnel handwashes an alcohol concentration of “60 to 95 percent by volume in an aqueous solution denatured according to Bureau of Alcohol, Tobacco and Firearms regulations in 27 CFR part 20.” 59 FR at 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 Andy’s Best ADVANCED HAND SANITIZER and NeoNatural gel Hand Sanitizer are not consistent with the formulations 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:
10/05/2021
Regulated Product(s)
Drugs