WARNING LETTER
DEPQ Internacional S. de R.L de C.V.
MARCS-CMS 608871 —
March 18, 2021
Delivery Method:
VIA UPS
Reference #:
320-21-36
Product:
Drugs
Recipient:
Recipient Name
Mr. Daniel Alberto Alfaro Saldaña
DEPQ Internacional S. de R.L de C.V.
Prol. Calzada de Guadalupe 2830-A Col. Satélite Fco. I. Madero
78380
San Luis Potosí
,
S.L.P.
Mexico
Issuing Office:
Center for Drug Evaluation and Research
United States
Warning Letter 320-21-36
March 18, 2021
Dear Mr. Saldaña:
Your firm was recently registered as a human drug manufacturer. The U.S. Food and Drug Administration (FDA) conducted testing of healthcare personnel antiseptic rub drug products, labeled as Cleanhumans Hand Sanitizer, dgreen ADVANCED HAND SANITIZER ANTIBACTERIAL GEL and dgreen ADVANCED HAND SANITIZER Alcohol Free. These drug products were declared to be manufactured at your facility, DEPQ Internacional S. de R.L de C.V., FEI 3016788198, at Prol. Calzada de Guadalupe 2830-A Col. Satélite Fco. I. Madero, San Luis Potosí, 78380, Mexico. Following an attempt to import Cleanhumans Hand Sanitizer, dgreen ADVANCED HAND SANITIZER ANTIBACTERIAL GEL and dgreen ADVANCED HAND SANITIZER Alcohol Free into the United States, they were detained and refused admission at the border.
The results of the FDA laboratory testing of batches of these products detained at the border demonstrate that these drug products declared to be manufactured at your facility are adulterated within the meaning of section 501(c) of the Federal Food, Drug, and Cosmetic Act (FD&C Act or Act), 21 U.S.C. 351(c), in that their strength, purity, or quality falls below that which they purport or are 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 subpotency demonstrates that the quality assurance within your facility is not functioning in accordance with Current Good Manufacturing Practice (CGMP) requirements.
In addition, your Cleanhumans Hand Sanitizer, dgreen ADVANCED HAND SANITIZER ANTIBACTERIAL GEL and dgreen ADVANCED HAND SANITIZER Alcohol Free 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), and are misbranded under sections 502(a), and (ee) of the FD&C Act, 21 U.S.C. 352(a), and (ee). Cleanhumans Hand Sanitizer is further misbranded under section 502(x) of the FD&C Act, 21 U.S.C. 352(x). Introduction or delivery for introduction of such products into interstate commerce is prohibited under section 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
Cleanhumans Hand Sanitizer and dgreen ADVANCED HAND SANITIZER ANTIBACTERIAL GEL, declared to be manufactured at your facility, are labeled to contain 60% of the active ingredient ethyl alcohol (ethanol). However, FDA laboratory testing of batches of these products detained at the border found that the drug products contained a range of between 1.5-1.7% volume/volume (v/v) ethanol in four samples. These hand sanitizer drug products are adulterated under section 501(c) of the FD&C Act in that the active ingredient of ethanol is present at levels in the products lower than that which is declared on their 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 specified in the 1994 Tentative Final Monograph (1994 TFM) for Health-Care Antiseptic Drug Products (59 FR 31402), as further amended by the “Safety and Effectiveness of Health Care Antiseptics; Topical Antimicrobial Drug Products for Over-the-Counter Human Use; Proposed Amendment of the Tentative Final Monograph; Reopening of Administrative Record,” Proposed Rule, 80 FR 25166 (May 1, 2015) (2015 Health Care Personnel Hand Rub Proposed Rule).
Additionally, dgreen ADVANCED HAND SANITIZER Alcohol Free, declared to be manufactured at your facility, is labeled to contain 10% of the active ingredient benzalkonium chloride (BZK). However, FDA laboratory testing of batches of this drug product detained at the border found that the drug product contained an average of 0.7% and 1.5% weight/volume (w/v) BZK in two samples. These hand sanitizer drug products are adulterated under section 501(c) of the FD&C Act in that the active ingredient of BZK is present at levels in the products lower than that which is declared on their labeling.
While the drug products detailed above were shipped to the United States, information available to FDA demonstrated that all of your hand sanitizers were detained and refused admission at the border and did not enter the United States. Therefore, FDA did not recommend that you remove these products from the market.
On August 3, 2020, FDA notified the public of the subpotency of your hand sanitizer drugs products at the following webpage:
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 products described above, which were labeled as containing 60% ethanol, in fact contained a range of 1.5-1.7% v/v ethanol, respectively.
• A detailed investigation into how the hand sanitizer drug products described above, which were labeled as containing 10% BZK, in fact contained an average 0.7% and 1.5% w/v BZK in two samples, respectively.
• 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 of hand sanitizer drug products declared or 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
Cleanhumans Hand Sanitizer, dgreen ADVANCED HAND SANITIZER ANTIBACTERIAL GEL and dgreen ADVANCED HAND SANITIZER Alcohol Free 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 for use as health care personnel antiseptic hand rubs.
Examples of claims observed on the Cleanhumans Hand Sanitizer, dgreen ADVANCED HAND SANITIZER ANTIBACTERIAL GEL and dgreen ADVANCED HAND SANITIZER Alcohol Free product labels and labeling that provide evidence of the intended use (as defined in 21 CFR 201.128) of the products include, but may not be limited to, the following:
“Use[s]. . . Health care personnel hand rub to help reduce bacteria that potentially can cause disease.”
These topical antiseptic 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 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 Cleanhumans Hand Sanitizer, dgreen ADVANCED HAND SANITIZER ANTIBACTERIAL GEL and dgreen ADVANCED HAND SANITIZER Alcohol Free drug products are GRASE for use under the conditions suggested, recommended, or prescribed in its 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 “Safety and Effectiveness of Health Care Antiseptics; Topical Antimicrobial Drug Products for Over-the-Counter Human Use; Proposed Amendment of the Tentative Final Monograph; Reopening of Administrative Record,” Proposed Rule, 80 FR 25166 (May 1, 2015). 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 health care personnel antiseptic hand 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 health care personnel antiseptic hand 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, Cleanhumans Hand Sanitizer, dgreen ADVANCED HAND SANITIZER ANTIBACTERIAL GEL and dgreen ADVANCED HAND SANITIZER Alcohol Free do not conform to the 1994 TFM, as further amended by the 2015 Health Care Antiseptics Proposed Rule, nor any other TFM, proposed rule, 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, Cleanhumans Hand Sanitizer and dgreen ADVANCED HAND SANITIZER ANTIBACTERIAL GEL purportedly contain the active ingredients ethanol, 60%, citric oil extracts, 1% and chlorhexidine gluconate,1%. Similarly, according to the product label, dgreen ADVANCED SANITIZER Alcohol Free purportedly contains the active ingredients benzalkonium chloride,10%; citric extracts,15% and chlorhexidine gluconate, 5%. Neither chlorhexidine gluconate, citric oil extracts, nor citric extracts are permitted as a sole ingredient or in combination with other ingredients, like ethanol or benzalkonium chloride, for use as consumer or health care personnel antiseptic hand rub drug products. Such products do not conform with the TFM or the applicable requirements, nor are they 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
Furthermore, with regard to dgreen ADVANCED HAND SANITIZER ANTIBACTERIAL GEL, we note that ethanol at concentrations of 60% through 95%, as a sole active ingredient, is permitted for use as a consumer or health care personnel antiseptic hand rub. However, even if ethanol was the only active ingredient for the product, FDA laboratory analyses revealed that samples of dgreen ADVANCED HAND SANITIZER ANTIBACTERIAL GEL contains a concentration of ethanol that is far less than the 60% stated on its product label and also contains far less than the amount of ethanol described in the 1994 TFM.
4
Such a product does not conform with the TFM or the applicable requirements for nonprescription drugs, 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.
5
Additionally, these hand sanitizers are misbranded under section 502(a) of the FD&C Act, 21 U.S.C 352(a), because their labeling is false and misleading. As noted above, Cleanhumans Hand Sanitizer and dgreen ADVANCED HAND SANITIZER ANTIBACTERIAL GEL are labeled to contain ethanol, 60%. However, FDA laboratory analyses of batches of these products demonstrate that the products contain concentrations of ethanol that is significantly far less than that stated on their respective product labels. Likewise, dgreen ADVANCED HAND SANITIZER Alcohol Free is labeled to contain benzalkonium chloride, 10%. However, FDA laboratory analysis batches of this product demonstrate that the product contains concentrations of benzalkonium chloride that is far less than that stated on its respective product label.
Furthermore, these products are misbranded under section 502(ee) of the FD&C Act, 21 U.S.C. 352(ee), because Cleanhumans Hand Sanitizer, dgreen ADVANCED HAND SANITIZER ANTIBACTERIAL GEL and dgreen ADVANCED HAND SANITIZER Alcohol Free 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.
Lastly, Cleanhumans Hand Sanitizer 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.
The introduction or delivery for introduction of a misbranded drug into interstate commerce 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 July 31, 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 the 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: 3016788198 and ATTN: Rory Geyer.
Sincerely,
/S/
Francis Godwin
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research
CC:
Registered U.S. Agent
Biokaab Inc.
Daniel Fosado
1312 Houston Street Ste. 111
Laredo, TX 78040
USA
__________________________________
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 sample results detailed above that demonstrate the subpotency of hand sanitizer products declared as manufactured at your facility, a review of the purported formulations on the 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 use of more than one active ingredient for such products is not consistent with the applicable TFM for consumer and health care personnel antiseptic hand rubs. Therefore, Cleanhumans Hand Sanitizer, dgreen ADVANCED HAND SANITIZER ANTIBACTERIAL GEL and dgreen ADVANCED SANITIZER Alcohol Free go beyond the conditions outlined in their applicable TFM and as such they are not eligible for marketing without an approved application.
4
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% 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.
5
See, e.g.,
Temporary Policy for Preparation of Certain Alcohol-Based Hand Sanitizer Products During the Public Health Emergency (COVID-19)
. Because Cleanhumans Hand Sanitizer, dgreen ADVANCED HAND SANITIZER ANTIBACTERIAL GEL and dgreen ADVANCED HAND SANITIZER Alcohol Free are 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.
Content current as of:
03/23/2021
Regulated Product(s)
Drugs