- Delivery Method:
- Via Email
Recipient NameChristopher T. Shieh
Recipient TitleGeneral Manager
- Ultra Chem Labs Corporation
1370 Valley Vista Drive
Diamond Bar, CA 91765
- Issuing Office:
- Division of Pharmaceutical Quality Operations IV
December 20, 2022
Dear Mr. Shieh:
The U.S. Food and Drug Administration inspected your drug manufacturing facility, Ultra Chem Labs Corporation, FEI 3011622931, at 4581 Brickell Privado Street, Ontario, California 91761-7828, from July 25 to July 27, 2022.
This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (21 CFR parts 210 and 211).
Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug product is adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).
In addition, PROTON ARMOR ANTI-MICROBIAL ALCOHOL-FREE FOAMING 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 section 502(j), (a), (e)(1)(A), and (ee) of the FD&C Act, 21 U.S.C. 352(j), (a), (e)(1)(A), 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.
We reviewed your August 1, 2022, response to our Form FDA 483 in detail. Although you mentioned that you discontinued the production and sale of your hand sanitizer drug product, your response is inadequate because you did not provide specific information or evidence of corrective actions to the observations identified during the inspection on our Form FDA 483.
During our inspection, our investigators observed specific violations including, but not limited to, the following.
1. Your firm’s quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22).
Your firm manufactures a consumer antiseptic hand rub drug product (also referred to as a consumer hand sanitizer), labeled as PROTON ARMOR ANTI-MICROBIAL ALCOHOL-FREE FOAMING HAND SANITIZER.1 Your quality unit (QU) approved the active ingredient, ULS 8357/(b)(4) (Anti-Microbial Shield) for use in your hand sanitizer without conducting an evaluation to determine its suitability for use in drug products. ULS 8357/(b)(4) contains (b)(4) methanol according to a safety data sheet (SDS) provided by your firm during the inspection. Your firm released hand sanitizer drug product batches formulated with ULS 8357/(b)(4) without determining the resulting methanol content of these drug products.
A review of your raw material specification sheet showed that your active ingredient contained between (b)(4) methanol. Based on your formulation, this would result in methanol content of your finished drug products between (b)(4) and (b)(4), an unacceptable level from a safety standpoint.
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, are most at risk for methanol poisoning.
On September 21, 2022, the FDA recommended that you test retain samples of your distributed batches of PROTON ARMOR ANTI-MICROBIAL ALCOHOL-FREE FOAMING HAND SANITIZER for methanol. You stated that you did not have any available product for testing.
On October 4, 2022, the FDA held a teleconference with you and we recommended you consider removing all adulterated batches of PROTON ARMOR ANTI-MICROBIAL ALCOHOL-FREE FOAMING HAND SANITIZER formulated with ULS 8357/(b)(4) currently in distribution from the U.S. market. We acknowledge you recalled after being notified of the unacceptable levels of methanol in your product.
On November 16, 2022, the FDA notified the public of the results in 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
Your QU also failed to ensure the following:
- To establish adequate procedures describing investigations, nonconformances, deviations, out-of-specifications, change controls, complaints, rejects, and returns (21 CFR 211.22(d)).
- Adequate training for your employees engaged in the manufacture, processing, packing, or holding of your hand sanitizer drug product (21 CFR 211.25(a)).
- Establishment of a stability program (21 CFR 211.137(a)).
- Retention of reserve samples for each batch of hand sanitizer drug product (21 CFR 211.170(b)).
- To prepare adequate batch control and production records for your hand sanitizer drug products (21 CFR 211.188).
Your firm’s quality systems are inadequate. See FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations for help in implementing quality systems and risk management approaches to meet the requirements of CGMP regulations 21 CFR parts 210 and 211, at https://www.fda.gov/media/71023/download.
In response to this letter, provide:
• A comprehensive assessment and remediation plan to ensure that your QU is given the authority and resources to function effectively. The assessment should also include, but not be limited to:
o A determination of whether procedures used by your firm are robust and appropriate.
o Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices.
o A complete and final review of each batch and its related information before the QU disposition decision.
o Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products.
2. Your firm failed to have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release; and your firm failed to conduct, for each batch of drug product, appropriate laboratory testing, as necessary, required to be free of objectionable microorganisms (21 CFR 211.165(a) and 21 CFR 211.165(b))
Your firm failed to conduct adequate release testing, including microbial testing, of your hand sanitizer drug product. You only conduct pH, viscosity, and clarity testing prior to release. Full release testing, including strength and identity testing of the active ingredient, must be performed before drug product release and distribution. Without adequate testing, you do not have adequate scientific evidence to assure that your drug products conform to appropriate specifications before release.
In response to this letter, provide a list of your chemical and microbial test methods and specifications used to analyze each batch of your drug products before making a batch disposition decision, and the associated written procedures.
3. Your firm failed to test samples of each component for identity and conformity with all appropriate written specifications for purity, strength, and quality. Your firm also failed to validate and establish the reliability of your component supplier’s test analyses at appropriate intervals (21 CFR 211.84(d)(1) and 21 CFR 211.84(d)(2)).
Your firm failed to conduct any testing on the components used to manufacture your hand sanitizer drug product. This includes your active ingredients, benzalkonium chloride (BZK) and ULS 8357/(b)(4). Additionally, your firm accepts components from your suppliers without establishing the reliability of your suppliers’ test analyses, and without obtaining your suppliers’ certificate of analysis (COA).
Without adequate testing, you do not have scientific evidence that the components conform to appropriate specifications prior to use in the manufacture of your drug products. As a manufacturer, you have a responsibility to sample, test, and examine drug components before use in production to assure adequate quality.
In response to this letter, provide:
- A comprehensive, independent review of your material system to determine whether all suppliers of components, containers, and closures, are each qualified and the materials are assigned appropriate expiration or retest dates. The review should also determine whether incoming material controls are adequate to prevent use of unsuitable components, containers, and closures.
- The chemical and microbiological quality control specifications you use to test and release each incoming batch of components for use in manufacturing.
- A description of how you will test each component batch for conformity with all appropriate specifications for identity, strength, quality, and purity. If you intend to accept any results from your supplier’s COA instead of testing each component batch for strength, quality, and purity, specify how you will robustly establish the reliability of your supplier’s results through initial validation as well as periodic re-validation. In addition, include a commitment to always conduct at least (b)(4) specific identity test for each incoming component batch.
- A summary of results obtained from testing all components to evaluate the reliability of the COA from each component manufacturer. Include your SOP that describes this COA validation program.
- A summary of your program for qualifying and overseeing contract facilities that test the drug products you manufacture.
Unapproved New Drug and Misbranding Violations
PROTON ARMOR ANTI-MICROBIAL ALCOHOL-FREE FOAMING 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 for use as a consumer topical antiseptic. Please note that “PROTON ARMOR ANTI-MICROBIAL ALCOHOL-FREE FOAMING HAND SANITIZER” will refer to all varieties and sizes of this product listed2.
Examples of labeling claims observed on the PROTON ARMOR ANTI-MICROBIAL ALCOHOL-FREE FOAMING HAND SANITIZER product labels and labeling 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:
“24 HOUR GERM PROTECTION . . . POWERED BY EXTENDED MICROBIAL PROTECTION . . . PROTON ARMOR ANTI-MICROBIAL ALCOHOL-FREE FOAMING HAND SANITIZER . . . Drug Facts . . . Active ingredient . . . Benzalkonium Chloride 0.13% . . . ULS 8357 0.33% . . . Purpose . . . Antimicrobial . . . Anti-Microbial Shield . . . Uses . . . For hand washing to decrease bacteria on the skin.” [from your PROTON ARMOR ANTI-MICROBIAL ALCOHOL-FREE FOAMING HAND SANITIZER product labels]3
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 the 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 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 PROTON ARMOR ANTI-MICROBIAL ALCOHOL-FREE FOAMING HAND SANITIZER 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. Additionally, OTC consumer antiseptic washes were addressed in “Safety and Effectiveness of Consumer Antiseptics; Topical Antimicrobial Drug Products for Over-the-Counter Human Use,” Proposed Rule, 78 FR 76444 (December 17, 2013) (Consumer Antiseptic Washes Proposed Rule) and “OTC Safety and Effectiveness of Topical Antimicrobial Drug Products for Over-the-Counter Human Use,” Final Rule, 81 FR 61106 (September 6, 2016).
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, PROTON ARMOR ANTI-MICROBIAL ALCOHOL-FREE FOAMING HAND SANITIZER does not conform to the 1994 TFM, as further amended by the 2016 Consumer Antiseptic Rub proposed rule and the Consumer Antiseptic Washes 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.
The Drug Facts panel indicates that ULS 8357 0.33% is an active ingredient intended for use as an “Anti-Microbial Shield,” an ingredient not permitted by the aforementioned rulemakings. Evaluation of the Safety Data Sheet collected during the inspection for ULS 8357, indicates that ULS 8357 is composed in part with methyl alcohol (methanol). The use of ULS 8357, that is composed in part with methanol as an active ingredient is not in conformance with the 1994 TFM. Furthermore, ULS 8357 that is composed in part with 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 suitable4.
In addition, according to the product label, PROTON ARMOR ANTI-MICROBIAL ALCOHOL-FREE FOAMING HAND SANITIZER indicates that it provides “24 HOUR GERM PROTECTION.” Time-specific extended efficacy claims may lead to a false sense of security for the general public that may result in infrequent hand washing. Furthermore, this labeled intended use goes beyond merely describing the general intended use of topical antiseptics as set forth in the 1994 TFM, as amended by the 2016 proposed rule5.
Furthermore, statements on the PROTON ARMOR ANTI-MICROBIAL ALCOHOL-FREE FOAMING HAND SANITIZER label provide evidence that the product is intended for use as a handwash, with claims such as “For hand washing to decrease bacteria on the skin,” and as a consumer antiseptic rub, with claims such as “Pump a small amount of foam into palm of hand . . . Rub thoroughly over all surfaces of both hands for 15 seconds.” However, such a combination that suggests the product can be simultaneously used both as a wash (to be rinsed off), and as a rub (to be left-on) is not in conformity with the most current applicable TFMs or proposed rules for these monograph products. Accordingly, this product does not meet the conditions under section 505G(a)(3) of the FD&C Act for marketing without an approved application under section 505.
Additionally, this methanol-containing drug product, PROTON ARMOR ANTI-MICROBIAL ALCOHOL-FREE FOAMING HAND SANITIZER, is misbranded under sections 502(j), (a), (e)(1)(A), and (ee) of the FD&C Act, 21 U.S.C. 352(j), (a), (e)(1)(A), 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. 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 failure of the product label to disclose the presence of the 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 drug product to list methyl alcohol (methanol) as an ingredient on its label 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).
Lastly, this product is misbranded under section 502(ee) of the FD&C Act, 21 U.S.C. 352(ee), because PROTON ARMOR ANTI-MICROBIAL ALCOHOL-FREE FOAMING 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, you should engage a consultant qualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements if your firm intends to resume manufacturing drugs for the U.S. market. The qualified consultant should also perform a comprehensive audit of your entire operation for CGMP compliance and evaluate the completion and efficacy of any identified corrective actions and preventive actions before you pursue resolution of your firm’s compliance status with the FDA.
Drug Production Ceased
We acknowledge your commitment to cease production of drugs at this facility. However, your firm continues to be registered as a drug manufacturer. In response to this letter, clarify whether you intend to resume manufacturing any drugs at this facility or another in the future.
If you plan to resume manufacturing drugs, ensure that adequate corrective actions are in place and notify this office to schedule a meeting before resuming your operations.
The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the causes of any violations and for preventing their recurrence or the occurrence of other violations.
Correct any violations promptly. Failure to promptly and adequately address this matter may result in regulatory or legal action without further notice including, without limitation, seizure, and injunction. Unresolved violations may also prevent other Federal agencies from awarding contracts.
Failure to address violations may also cause the FDA to withhold issuance of Export Certificates. The FDA may withhold approval of new applications or supplements listing your firm as a drug manufacturer until any violations are completely addressed and we confirm your compliance with CGMP. We may re-inspect to verify that you have completed corrective actions to address any violations.
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 complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.
Send your electronic reply to ORAPHARM4_Responses@FDA.HHS.GOV or mail your reply to:
CDR Steven E. Porter, Jr.
Director, Division of Pharmaceutical Quality Operations IV
U.S. Food & Drug Administration
19701 Fairchild Road
Irvine, California 92612-2506
Please identify your response with unique identifier 641742.
If you have any further questions, please contact Mariza Jafary, compliance officer, by email at Mariza.Jafary@fda.hhs.gov or by phone at (949) 608-2977.
CDR Steven E. Porter, Jr.
Director, Division of Pharmaceutical Quality Operations IV
1 Due to an increased demand for alcohol-based hand sanitizers during the COVID-19 pandemic, the 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. The guidance was withdrawn effective December 31, 2021 (86 Fed Reg at 56960). This guidance communicated the agency’s temporary policy that we did not intend to take action against firms for CGMP violations under section 501(a)(2)(B) of the FD&C Act if such firms prepared 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 included preparation of hand sanitizer products using only the ingredients and formulas set forth in the guidance. Because Ultra Chem Labs Corp. hand sanitizer drug products were not consistent with the formulations described in these guidances, they did 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.
2 PROTON ARMOR ANTI-MICROBIAL ALCOHOL-FREE FOAMING HAND SANITIZER (1.7 fl oz and 1 US GAL sizes), PROTON ARMOR ANTI-MICROBIAL ALCOHOL-FREE FOAMING HAND SANITIZER green tea & aloe (1.7 fl oz size), PROTON ARMOR ANTI-MICROBIAL ALCOHOL-FREE FOAMING HAND SANITIZER with green tea & aloe essence (32 fl oz size).
3 We note that your PROTON ARMOR ANTI-MICROBIAL ALCOHOL-FREE FOAMING HAND SANITIZER labeling contains conflicting information regarding whether it should be used as a consumer antiseptic wash or a consumer antiseptic rub. The term “hand sanitizer” generally refers to consumer antiseptic rubs, and the Drug Facts Label of your product both indicates that the product is to be used for handwashing (presumably with water) and suggests that it should be used without water (i.e., “Rub thoroughly over all surfaces of both hands for 15 seconds. No rinsing required.”). The PROTON ARMOR ANTI-MICROBIAL ALCOHOL-FREE FOAMING HAND SANITIZER product, however, does not conform to the requirements for either a consumer antiseptic rub or a consumer antiseptic wash, as further described below.
4 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.
5 The 1994 TFM covers health care antiseptics that are indicated for use to help reduce bacteria that potentially can cause disease and health care and consumer antiseptics that are indicated for use to decrease bacteria on the skin. 59 FR at 31443.