Precision Analitica Integral S.A. de C.V. MARCS-CMS 609784 —
- Delivery Method:
- VIA UPS
Recipient NameMr. Alan Williams
- Precision Analitica Integral S.A. de C.V.
Calle De Minas 501 Bodega 21
Alvaro Obregon, CDMX
- Issuing Office:
- Center for Drug Evaluation and Research | CDER
Warning Letter 320-21-25
February 5, 2021
Dear Mr. Williams:
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 CleanCare nogerm ADVANCED HAND SANITIZER. This drug product was labeled as manufactured at your facility, Precision Analitica Integral, FEI 3016855928, at Calle Minas 501 Bodega 21-22, Col. Lomas de Becerra Alc. Alcaro Obregon, Ciudad de Mexico, Mexico. Following an offer for import of this drug product into the United States, CleanCare nogerm ADVANCED HAND SANITIZER 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 the CleanCare nogerm ADVANCED HAND SANITIZER drug product labeled as 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. 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, CleanCare nogerm ADVANCED 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), (x), and (ee) of the FD&C Act, 21 U.S.C. 352(j), (a), (e), (x), 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.
CleanCare nogerm ADVANCED HAND SANITIZER, a drug product labeled as manufactured at your facility, is labeled to contain 75% volume/volume (v/v) of the active ingredient ethyl alcohol (ethanol). However, FDA laboratory testing of a batch of this product detained at the border found that the product contained an average of 40% ethanol v/v and an average of 28% 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 August 6, 2020, FDA held a teleconference with you and ESPMEX, LLC, your registered U.S. agent1. We recommended you consider removing all of your firm’s hand sanitizer drug products currently in distribution to the U.S. market. On August 7, 2020, FDA notified the public of the methanol contamination of your hand sanitizer drug product at the following website: https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-hand-sanitizers-consumers-should-not-use
As of the date of this letter, you have yet to initiate a recall on hand sanitizer products manufactured by your firm and distributed to the United States. However, FDA is still concerned regarding the quality of your hand sanitizer products.
In response to this letter provide the following:
• In a letter a respresentative of your U.S. Agent, ESPMEX, LLC, sent to FDA on July 21, 2020, ESPMEX, LLC provided the results of its investigation into how your hand sanitizer was contaminated with methanol. However, this investigation failed to provide a justification for why your firm failed to perform raw material (ethyl alcohol) or finished product testing for the CleanCare nogerm ADVANCED HAND SANITIZER imported to the U.S. Provide an updated, detailed investigation into your failure to perform raw material or finished product testing on your drug products.
• A list of all raw materials used to manufacture all of 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.
• In August 2020, you provided copies of batch records for certain batches of hand sanitizers distributed to the U.S. Provide copies of the complete batch records for all batches distributed to the U.S.
• During the August 6th teleconference with the Agency, you stated that your current supplier was adequate. However, on June 17, 2020 your U.S. Agent, ESPMEX, LLC, had indicated that your supplier may have been involved in contaminated material at another facility. In a communication on August 14, 2020, your counsel later stated that your U.S. Agent was initially incorrect. FDA remains concerned regarding your supplier qualification program. Provide details regarding your supplier qualification program and how it is compliant with human drug CGMP.
The substitution and contamination with methanol in 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 FD&C Act.2
Unapproved New Drug and Misbranding Violations
CleanCare nogerm ADVANCED 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 as a consumer antiseptic hand rub.
Examples of claims observed on the CleanCare nogerm 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:
Drug Facts . . . Purpose Antimicrobial . . . Uses: Hand Sanitizer to help reduce bacteria on 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.”
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 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 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 CleanCare nogerm ADVANCED 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 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). 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, CleanCare nogerm ADVANCED HAND SANITIZER does 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 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, CleanCare nogerm ADVANCED HAND SANITIZER purportedly contains the active ingredient ethyl alcohol (ethanol) 75%. However, as previously discussed, FDA laboratory analyses of a batch of this product detained at the border demonstrate that CleanCare nogerm ADVANCED HAND SANITIZER contains a concentration of ethanol that is far less than the 75% declared on the label. Such a product does not conform with the TFM and other applicable requirements,3 nor is it consistent with the formulations described in FDA’s temporary policies for hand sanitizers during the COVID-19 public health emergency.4
FDA laboratory analyses of a batch of this product detained at the border also revealed that a sample of CleanCare nogerm 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 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 an OTC drug product’s inactive ingredients be safe and suitable.5
Additionally, this methanol-containing drug product, CleanCare nogerm 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, CleanCare nogerm ADVANCED HAND SANITIZER is labeled to contain ethyl alcohol 75%. However, FDA laboratory analysis of a batch of this product demonstrate that the product contains a concentration of ethyl alcohol (ethanol) that is far less than what is stated on the product label 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 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 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). Furthermore, 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 domestic address or domestic telephone number through which the responsible person 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 CleanCare nogerm ADVANCED 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 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 listed as 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 3016855928 and ATTN:CDR Frank Verni.
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research
Registered US Agent
Ernesto Casillas, Director
Samuel Casillas, Director ESPMEX, LLC
3923 Purple Plum Ct
Las Vegas, NV 89147-8078
Mr. Benjamin L. England, Esq.
Benjamin L. England & Associates
810 Landmark Drive, Suite 126
Glen Burnie, MD 21061
1 Under section 510(i)(1) of the FD&C Act, 21 U.S.C. 360(i)(1), you are required to submit registration information annually by electronic means for each foreign establishment you own or operate, engaged in the manufacture, preparation, propagation, compounding, or processing of a drug that is imported or offered for import into the United States, and include the name of the United States Agent. As a drug manufacturer, it is your responsibility to ensure complete and accurate registration information.
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 presence of methanol in your hand sanitizer product, a review of your drug product labeling further 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.
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 CleanCare nogerm ADVANCED 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.
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.