Bionateo Sp. z.o.o. MARCS-CMS 614651 —
- Delivery Method:
- VIA UPS
Recipient NameMr. Dominik Wojciechowski
- Bionateo Sp. z.o.o.
Ul. Chocimska 6
- Issuing Office:
- Center for Drug Evaluation and Research | CDER
Warning Letter 320-22-04
November 4, 2021
Dear Mr. Wojciechowski:
Your firm is recently 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 ALTAIO HAND SANITIZING GEL. This drug product was listed as being manufactured at your facility, Bionateo Sp. z.o.o, FEI 3017231855, at Ul. Chocimska 6, Kalisz, Wielkopolskie. Following an attempt to import ALTAIO HAND SANITIZING GEL 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 listed as being manufactured at your facility is adulterated within the meaning of section 501(a)(2)(B) of the FD&C Act (21 U.S.C. 351(a)(2)(B))1, in that the contamination demonstrates that the quality assurance within your facility is not functioning in accordance with Current Good Manufacturing Practice (CGMP) requirements.
In addition, ALTAIO HAND SANITIZING GEL 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 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.
ALTAIO HAND SANITIZING GEL, listed as being manufactured at your facility, is labeled to contain 80% volume/volume (v/v), of the active ingredient alcohol ethyl alcohol (ethanol). However, FDA laboratory testing of a batch of this product detained at the border found that the drug product contained impurities at unacceptable levels. Methanol impurity levels were found to be between 625 ppm to 2,500 ppm. Testing also found approximately 0.88% (v/v) undeclared isopropanol in your hand sanitizer.
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 April 22, 2021, FDA held a teleconference with you and Magic Play LLC, your registered U.S. Agent. During that meeting, we requested additional information concerning your CGMP operations, including test methods for your incoming active pharmaceutical ingredient (ethanol) and test methods for your finished drug product testing. 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, or meeting deadlines for FDA’s information requests. For example, you have not provided FDA with all requested information, such as assay results and the specific testing methods used by your firm. Such testing and documentation thereof is required by 21 CFR 211.165.
On May 26, 2021, 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
In response to this letter, provide the following:
• A detailed investigation into how the hand sanitizer drug product described above, which was listed as manufactured at your facility and which was labeled as containing 80% ethanol, was contaminated with methanol and isopropanol.
• 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 United
• A complete, comprehensive, and independent assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.
The contamination with methanol of hand sanitizer drug products listed as being 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.
Unapproved New Drug and Misbranding Violation
ALTAIO HAND SANITIZING GEL 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 ALTAIO HAND SANITIZING GEL 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:
“Drug Facts…Purpose: Antiseptic…Use[s]…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 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) 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 drug product, nor are we aware of any adequate and well-controlled clinical studies in the published literature that support a determination that your ALTAIO HAND SANITIZING GEL 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.
However, ALTAIO HAND SANITIZING GEL does not conform to the 1994 TFM, as further amended by the 2016 Consumer Antiseptic Rubs 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.
FDA laboratory analyses demonstrated that the product contained 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 methanol 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.2 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.3
Additionally, this methanol-containing drug product, ALTAIO HAND SANITIZING GEL, 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).
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. According to the product label, ALTAIO HAND SANITIZING GEL purportedly contains the active ingredient ethyl alcohol 80%. However FDA laboratory analyses of a batch of this product detained at the border demonstrated that ALTAIO HAND SANITIZING GEL contains ethanol in a concentration that is less than the 80% stated on its product label but above the amount allowed under the 1994 TFM.4 Additionally, ALTAIO HAND SANITIZING GEL contains isopropyl alcohol and methyl alcohol (methanol), that are 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 isopropyl alcohol and 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 isopropyl alcohol and methyl alcohol (methanol) as ingredients on its label causes also 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, ALTAIO HAND SANITIZING GEL 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 complete 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 ALTAIO HAND SANITIZING GEL 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.
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 7, 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 3017231855 and ATTN: Bryce Hammer.
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research
Registered U.S. Agent
Magic Play LLC
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 testing results detailed above that demonstrate the contamination of the hand sanitizer product listed as being manufactured at your facility, a review of the drug product’s labeling further indicates that this product is a gel and therefore 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.
2 See, e.g., Temporary Policy for Preparation of Certain Alcohol-Based Hand Sanitizer Products During the Public Health Emergency (COVID-19). Because ALTAIO HAND SANITIZING GEL 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.
3 An inactive ingredient used in 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.
4 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 denatured in accordance with Bureau of Alcohol, Tobacco and Firearms regulations. 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.