WARNING LETTER

Harmonic Nature S. de R.L. MI. MARCS-CMS 609367 — November 16, 2020

Delivery Method:: VIA UPS
Product:: Drugs

Recipient:: Recipient Name

Mr. Miguel Martinez; Recipient Title

Owner; Harmonic Nature S. de R.L. MI.; Lacandon 205
67150 Guadalupe, N.L.
Mexico

Issuing Office:: Center for Drug Evaluation and Research | CDER; United States

Warning Letter 320-21-11

November 16, 2020

Dear Mr. Martinez:

Your firm is 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 consumer hand sanitizer) labeled as Alcohol Antiseptic 75% Topical Solution Hand Sanitizer. This product is manufactured at your facility, Harmonic Nature S. de R.L. MI., Lacandon 205, Guadalupe, N.V., Mexico C.P. 67150. Following an attempt to import this drug product into the United States, Alcohol Antiseptic 75% Topical Solution 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 Alcohol Antiseptic 75% Topical Solution 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), 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) (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, Alcohol Antiseptic 75% 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 (a), (e), and (ee) of the FD&C Act, 21 U.S.C. 352 (a), (e), and (ee). Introduction or delivery for introduction of such a 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.

Adulteration Violations

The drug product Alcohol Antiseptic 75% Topical Solution Hand Sanitizer 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 0% ethanol and 38% 1-propanol 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 1-propanol, a dangerous chemical when in contact with human skin or ingested.

1-propanol, not to be confused with isopropyl or 2-propanol, is not a permitted active ingredient in hand sanitizers intended for the U.S. Exposure to 1-propanol may cause irritation to eyes, nose; throat; dry cracking skin; drowsiness, headache; ataxia, gastrointestinal pain; abdominal cramps, nausea, vomiting and diarrhea. Although all persons using these products on their hands are at risk, young children who accidentally ingest these products, and adolescents and persons with alcohol addiction who drink these products as an alcohol (ethanol) substitute, are most at risk for 1-propanol poisoning.

On August 12, 2020, FDA held a teleconference with you and 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 1-propanol contamination of your hand sanitizer drug products at the following website: https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-hand-sanitizers-consumers-should-not-use

On August 14, 2020, you announced a voluntary nationwide recall of all hand sanitizer drug products that were distributed to the U.S., which FDA posted at the following website: https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/harmonic-nature-issues-voluntary-nationwide-recall-hand-sanitizer-due-presence-1-propanol

In response to this letter provide the following:

• A detailed investigation into how the hand sanitizer drug products described above manufactured at your facility that are labeled as containing ethanol were substituted in part or in whole with 1-propanol.
• 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.
• Copies of the complete batch records for all batches distributed to the U.S.
• Details regarding your raw material identity testing of incoming active pharmaceutical ingredients and specifically how your test methods can distinquish between ethanol and 1-propanol.

The substitution and 1-propanol contamination in hand sanitizer drug products 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.¹

Unapproved New Drug and Misbranding Violations

Alcohol Antiseptic 75% 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 statements observed on the product label that provide evidence of the intended uses (as defined in 21 CFR 201.128) of the product include, but may not be limited to, the following:

“Drugs Facts . . . Uses■Hand Sanitizer to help reduce bacteria that potentially can cause disease. . . Directions■Place enough product on hands to cover all surfaces. Rub hands together 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 FD&C Act (which is not the case for this product, 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 this product, nor are we aware of any adequate and well-controlled clinical studies in the published literature that support a determination that your Alcohol Antiseptic 75% 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 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, three active ingredients (benzalkonium chloride, ethyl alcohol, and isopropyl alcohol) were classified as Category III for use as 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.

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, Alcohol Antiseptic 75% 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, Alcohol Antiseptic 75% Hand Sanitizer purportedly contains the active ingredient ethyl alcohol 75%. However, as previously discussed, FDA laboratory analyses revealed that samples of Alcohol Antiseptic 75% Hand Sanitizer contain 0% ethyl alcohol but instead contain significant concentrations of the undeclared ingredient 1-propanol. Such a product does not conform with the TFM or 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

Additionally, Alcohol Antiseptic 75% Hand Sanitizer, is misbranded under sections 502(a), (e), and (ee) of the FD&C Act, 21 U.S.C. 352(a), (e), and (ee).

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, Alcohol Antiseptic 75% Hand Sanitizer is labeled to contain ethyl alcohol 75%. However, FDA laboratory analyses revealed that samples of this product contain no ethyl alcohol but did contain significant concentrations of 1-propanol, 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. . . .” As such, the label representation that Alcohol Antiseptic 75% Hand Sanitizer contains the active ingredient ethyl alcohol when it does not, as well as the failure of the product label to disclose the presence of the 1-propanol 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 1-propanol as an ingredient on the 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 Alcohol Antiseptic 75% 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 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 these violations and for preventing their recurrence or the occurrence of other violations.

Note that FDA placed drugs labeled as 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 practice within the meaning of section 501(a)(2)(B) of the FD&C Act. 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.

After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done to correct your violations and to prevent their recurrence. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion. If you believe that your products are not in violation of the FD&C Act, include your reasoning and any supporting information for our consideration.

Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov.

Identify your response with FEI 3013318132 and ATTN: Marisa Heayn.

Sincerely,
/S/
Francis Godwin
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research

CC:
Registered US Agent
Mario Hidalgo
4712 N 12th St Apt 47
Mcallen, TX 78504-3604 US

___________________________

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 on March 27, April 15, June 1, and August 7 of 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 1-propanol in your hand sanitizer products, review of the formulations on your drug product labeling further indicate that such 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.

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 Alcohol Antiseptic 75% 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.