WARNING LETTER
Ardil Comercial S.R.L.
MARCS-CMS 612018 —
September 22, 2021
Delivery Method:
VIA UPS
Product:
Drugs
Recipient:
Recipient Name
Ms. Cecilia Ramirez
Recipient Title
Administrative Director
Ardil Comercial S.R.L.
Pastora Elida Km 19 No. 03, Apto. 1
11606
Santo Domingo
Dominican Republic
Issuing Office:
Center for Drug Evaluation and Research | CDER
United States
Warning Letter
320-21-59
September 22, 2021
Dear Ms. Ramirez:
Your firm registered as a human drug manufacturer. The United States Food and Drug Administration (FDA) conducted testing of a consumer antiseptic hand rub drug product (also referred to as a consumer hand sanitizer), labeled as Alcohol Isopropilico Hand Sanitizer Limar. This drug product was labeled as manufactured at your facility, Ardil Comercial S.R.L., FEI 3012644697, at Pastora Elida Km 19 No. 03, Apto. 1, Santo Domingo, 11606, Dominican Republic. Following an attempt to import Alcohol Isopropilico Hand Sanitizer Limar into the United States, it 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 this 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, Alcohol Isopropilico Hand Sanitizer Limar is an unapproved new drug in violation of section 505(a) of the FD&C Act, 21 U.S.C. 355(a), and is misbranded under sections 502(a), (c), (i)(1), (x) and (ee) of the FD&C Act, 21 U.S.C. 352(a), (c), (i)(1), (x) and (ee). 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). These violations are described in more detail below.
Adulteration Violations
Alcohol Isopropilico Hand Sanitizer Limar, labeled as manufactured at your facility, is labeled to contain 70% 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 an average of 48% IPA volume/volume (v/v), and an average of 16% ethanol 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, IPA, was substituted wholly or in part with undeclared ethanol.
On February 23, 2021, FDA held a teleconference with you and Registrar Corp, your registered U.S. Agent. During the call, we requested additional information concerning your CGMP operations, including test methods for your incoming active pharmaceutical ingredient, IPA, and finished product. As noted above, your hand sanitizer product labeled to contain IPA also contained ethanol. We requested information related to the investigation into how your hand sanitizer drug product was manufactured with a mixture of both IPA and ethanol. You acknowledged you were aware that the product was mislabeled and shipped to the United States. Following the teleconference, FDA sent multiple requests to your firm to provide additional information. Your firm has since exhibited a pattern of not providing adequate or complete responses to FDA’s requests for information regarding drug quality. In your response, you did not provide test methods for your incoming API or finished product to ensure appropriate identity test for IPA, as required under 21 CFR 211.84 and appropriate assay testing for finished product as required per 21 CFR 211.165. Without adequate testing of incoming raw materials and finished product you cannot assure that your drug products conform to appropriate standards of identity, strength, quality and purity. Your investigation provided lacked detailed information, including specific lot information.
On June 16, 2021, FDA held a second teleconference with you and Registrar Corp, your registered U.S. Agent to express concerns regarding your Alcohol Isopropilico Hand Sanitizer Limar packaged in a container that resembles a water bottle or beverage/drink container, commonly used by adults and children in the U.S. market. This hand sanitizer container has a similar shape, size, and function as a water bottle and can mislead children or adults into believing that the product is consumable water, which is of particular concern because hand sanitizers can be toxic if ingested. We recommended you consider removing lot 079932-4611-05-J of your hand sanitizer drug product distributed to the U.S. market. On June 16, 2021, FDA notified the public of your hand sanitizer drug product packaged in containers resembling a water bottle that presents increased risk of accidental ingestion at the following website:
https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-hand-sanitizers-consumers-should-not-use
On July 1, 2021, you issued a voluntary nationwide recall of one lot of Alcohol Isopropilico Hand Sanitizer Limar due to the hand sanitizer packaged in bottles that resemble drink containers, as noted on the following FDA website:
https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/ardil-comercial-issues-voluntary-nationwide-recall-limar-hand-sanitizer-packaged-4-oz-bottles?utm_medium=email&utm_source=govdelivery
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 which was labeled as containing IPA, was substituted in part with ethanol.
• 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 U.S. by your firm, and a full reconciliation of all material you distributed.
• Copies of the complete batch records for all batches distributed to the United States.
• Provide a commitment that you will test every lot of IPA and ethanol you receive for methanol content using the United States Pharmacopeia (USP) method in a CGMP compliant laboratory.
The substitution of hand sanitizer drug product labeled as manufactured in your facility, in addition to the deficiencies in your response to the information we requested during the June 16, 2021 teleconference, 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 Isopropilico Hand Sanitizer Limar 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 for use as a consumer topical antiseptic.
Examples of claims observed on the Alcohol Isopropilico Hand Sanitizer Limar product label and labeling 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:
“Antibacterial . . . Drug Facts . . . Antimicrobial Uses hand sanitizer to help reduce bacteria on the skin”
This topical antiseptic 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 drug product, nor are we aware of any adequate and well-controlled clinical studies in the published literature that support a determination that your Alcohol Isopropilico Hand Sanitizer Limar 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 “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 (ethanol), and isopropyl alcohol) were classified as Category III for use 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 section 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.
According to the product label, Alcohol Isopropilico Hand Sanitizer Limar purportedly contains the active ingredient isopropyl alcohol 70%. However, as previously discussed, FDA laboratory analyses of a batch of this product detained at the border demonstrated that Alcohol Isopropilico Hand Sanitizer Limar contains isopropyl alcohol in a concentration that is less than the 70% stated on its product label and less than the amount of isopropyl alcohol described in the 1994 TFM.
2
Furthermore, the analyses revealed that the product contained concentrations of the undeclared ingredient, ethanol. Ethanol as a sole active ingredient, is permitted for use in a consumer topical antiseptic rub. However, ethanol in combination with isopropyl alcohol was not proposed for use as consumer drug products. Further, 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 with the TFM or the 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.
3
Additionally, Alcohol Isopropilico Hand Sanitizer Limar is misbranded under sections 502(a), (c), (i)(1), (x) and (ee) of the FD&C Act, 21 U.S.C. 352(a), (c), (i)(1), (x) and (ee).
It 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 Isopropilico Hand Sanitizer Limar is labeled to contain isopropyl alcohol 70% v/v. However, FDA laboratory analysis of batch of this product demonstrate that the product contains concentrations of isopropyl alcohol less than that stated on its product label but contains ethanol even though the product label does not include ethanol as an ingredient. Thus, the misleading representations of the concentration of the active ingredient isopropyl alcohol on the Alcohol Isopropilico Hand Sanitizer Limar labeling cause this product to be misbranded under section 502(a) of the FD&C Act, 21 U.S.C. 352(a).
Alcohol Isopropilico Hand Sanitizer Limar contains labeling information both in English and Spanish. Dual language labeling with English and another language is permissible when labeled in accordance to 21 CFR 201.15 and not otherwise false or misleading. Please note, 21 CFR 201.15 states that “all words, statements, and other information required by or under authority of the act to appear on the label or labeling shall appear thereon in the English language” . . . and “if the label contains any representation in a foreign language, all words, statements, and other information required by or under authority of the act to appear on the label shall appear thereon in the foreign language.” The labeling for Alcohol Isopropilico Hand Sanitizer Limar is misbranded under section 502(c) of the FD&C Act, 21 U.S.C. 352(c), because it is not labeled in accordance to 21 CFR 201.15. For example, the label does not include a “Drug Facts” panel in the Spanish language.
Alcohol Isopropilico Hand Sanitizer Limar is in a 4 fluid ounce container that resembles a drinking water bottle customarily purchased by U.S. consumers. Section 502(i)(1) of the FD&C Act, 21 U.S.C. 352(i)(1), provides that a drug is misbranded if “its container is so made, formed, or filled as to be misleading . . .” As such, your clear, colorless hand sanitizer that fills a 4 fluid ounce container resembling plastic bottles ordinarily used to package drinking water is misbranded under section 502(i)(1) of the FD&C Act, 21 U.S.C. 352(i)(1).
Alcohol Isopropilico Hand Sanitizer Limar 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 Alcohol Isopropilico Hand Sanitizer Limar 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 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 June 30, 2021, 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 FD&C 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.
Please identify your response with FEI 3012644697 and ATTN: Tamara Rosbury.
Sincerely,
/S/
Francis Godwin
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research
cc:
Registered U.S. Agent
Registrar Corp
144 Research Drive
Hampton, VA 23666
USA
________________________________
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 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 sample results detailed above that demonstrate the substitution of hand sanitizer products manufactured at your facility, a review of the purported formulations on the drug products’ labeling further indicates 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 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.
3
See, e.g., Temporary Policy for Preparation of Certain Alcohol-Based Hand Sanitizer Products During the Public Health Emergency (COVID-19). Because Alcohol Isopropilico Hand Sanitizer Limar is not consistent with the formulations described 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.
Content current as of:
10/05/2021
Regulated Product(s)
Drugs