Hangzhou Glamcos Biotech Co., Ltd. - 692583 - 10/07/2024

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Warning Letter 320-25-02

October 7, 2024

Dear Ai Hong Ruan:

Your facility is registered with the United States Food and Drug Administration (FDA) as a manufacturer of over-the-counter (OTC) drug products. FDA has reviewed the records you submitted in response to our March 4, 2024 request for records and other information pursuant to section 704(a)(4) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) for your facility, Hangzhou Glamcos Biotech Co., Ltd., FEI 3017053743, at No 288 Xiufeng Road Tonglu County, Hangzhou, Zhejiang, China.

This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations, 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 products are 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, “disinpro multi-purpose ANTIBACTERIAL WIPES” is an unapproved new drug introduced or delivered for introduction into interstate commerce in violation of sections 505(a) and 301(d) of the Federal Food, Drug, and Cosmetic Act (FD&C Act,) 21 U.S.C. 355(a) and 331(d). This product is also misbranded under section 502(ee) of the FD&C Act, 21 U.S.C. 352(ee). Additionally, “disinpro multi-purpose ANTIBACTERIAL WIPES” and “Antibacterial Wet Wipes” are misbranded under section 502(f)(2) of the FD&C Act, 21 U.S.C. 352(f)(2). Introduction or delivery for introduction of misbranded products into interstate commerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C. 331(a). These violations are described in more detail below.

Following review of records and other information provided pursuant to section 704(a)(4) of the FD&C Act, significant violations were observed including, but not limited to, the following:

CGMP Violations

1. 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 (21 CFR 211.165(a)).

Based on the records and information you provided, you did not demonstrate you conducted adequate finished drug product testing on your drug products before releasing them for distribution.

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 your drug products conform to appropriate specifications before release.

2. Your firm failed to conduct at least one test to verify the identity of each component of a drug product. 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 211.84(d)(2)).

Your firm manufactured OTC drug products including antibacterial wet wipes used for reducing bacteria on skin. Based on the records and information you provided, you did not demonstrate you adequately performed identity testing on incoming components including, but not limited to, glycerin and propylene glycol, which are at high-risk of diethylene glycol (DEG) or ethylene glycol (EG) contamination. Identity testing for these and certain other high-risk drug components¹ include a limit test in the United States Pharmacopeia (USP) to ensure that the component meets the relevant safety limits for levels of DEG or EG. Because you did not perform sufficient identity testing, you failed to assure the acceptability of these components for use in manufacture of your drug products.

The use of ingredients contaminated with DEG or EG has resulted in various lethal poisoning incidents in humans worldwide. See FDA’s guidance document Testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and Other High-Risk Drug Components for Diethylene Glycol and Ethylene Glycol to help you meet the CGMP requirements when manufacturing drugs containing ingredients at high-risk for DEG or EG contamination at https://www.fda.gov/media/167974/download.

We also note your active pharmaceutical ingredient supplier does not appear to be registered with the FDA, and the information you provided does not indicate you have adequately qualified your raw material suppliers.

3. Your firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products and to use results of stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166(a)).

Based on the stability records and information you provided, you did not demonstrate the quality attributes of your drug products remain acceptable throughout the labeled expiry period. For example, you did not include active ingredient testing as part of your stability program.

Without appropriate stability studies, you do not have scientific evidence to support whether your drug products meet established specifications and retain their quality attributes through their labeled expiry.

4. Your firm failed to prepare batch production and control records with complete information relating to the production and control of each batch of drug product produced (21 CFR 211.188).

Based on the records and information you provided, your batch production records were inadequate. For example, your batch production records for OTC drug products lacked documentation that each significant step in the manufacture, processing, packing, or holding of the batch was accomplished.

Without adequate and complete batch records, you cannot assure the uniformity of your drug products from batch to batch and may impact your ability to adequately investigate any product deviations.

Unapproved New Drug Violations and Misbranded Drug Violations

Based on their labeled intended uses, “disinpro multi-purpose ANTIBACTERIAL WIPES” and “Antibacterial Wet Wipes” 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 consumer antiseptic rub drug products.

Examples from the “disinpro multi-purpose ANTIBACTERIAL WIPES” and “Antibacterial Wet Wipes” product labeling that provide evidence of the intended uses (as defined in 21 CFR 201.128) of these products include, but may not be limited to, the following:

“disinpro multi-purpose ANTIBACTERIAL WIPES”
“Drug Facts…Use: For handwashing to decrease bacteria on the skin. Kills 99.9% of germs.” [from the product label]

“Antibacterial Wet Wipes”
“Drug Facts…Use: For handwashing to decrease bacteria on the skin.” [from the product label]

Unapproved New Drug Violations

“disinpro multi-purpose ANTIBACTERIAL WIPES” 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 not the case for this product, 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 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 “disinpro multi-purpose ANTIBACTERIAL WIPES” 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) (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 in a consumer antiseptic rub.

Section 505G of the FD&C Act addresses nonprescription drugs marketed without an approved application. 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, “disinpro multi-purpose ANTIBACTERIAL WIPES” 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. Specifically, the label states that “disinpro multi-purpose ANTIBACTERIAL WIPES” contain benzalkonium chloride at a concentration of 0.2%; however, benzalkonium chloride is only permitted at a concentration of 0.1% to 0.13%.

The introduction or delivery for introduction of this unapproved new drug product into interstate commerce violates sections 505(a) and 301(d) of the FD&C Act, 21 U.S.C. 355(a) and 331(d).

Misbranded Drug Violations

The “disinpro multi-purpose ANTIBACTERIAL WIPES” and “Antibacterial Wet Wipes” drug products are misbranded under section 502(f)(2) of the FD&C Act, 21 U.S.C. 352(f)(2), because the product labels do not include all of the applicable warnings required under 21 CFR 330.1(g). Specifically, the labels do not include the complete warning statement that reads, “If swallowed, get medical help or contact a Poison Control Center right away.”

Additionally, “disinpro multi-purpose ANTIBACTERIAL WIPES” is misbranded under section 502(ee) of the FD&C Act, 21 U.S.C. 352(ee), because this product 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 violates section 301(a) of the FD&C Act, 21 U.S.C. 331(a).

Additional Concerns

We note that the “disinpro multi-purpose ANTIBACTERIAL WIPES” and “Antibacterial Wet Wipes” drug products are marketed as “antiseptic wipes.” Antiseptic wipes generally refer to consumer antiseptic rub drug products that are not intended to be rinsed-off after use. However, the labels for both products suggests that they can be used as a consumer antiseptic wash. For example, both labels state, “For hand washing to decrease bacteria on the skin.” An antiseptic wipe drug product marketed under section 505G of the FD&C Act cannot also be a consumer antiseptic wash, as the directions for use conflict with each other and a wipe is not an acceptable dosage form for an antiseptic wash.²

Discrepancy in Information Provided

In response to FDA’s initial records request, you asserted that you have not manufactured drugs for the United States in three years. After FDA provided you information regarding shipments of drugs from your facility as recent as of January 8, 2024, you then provided the requested information. FDA is concerned that you may have falsely alleged that you do not manufacture, process, pack, or hold drugs for the United States.³

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 evaluate your operations and to assist your firm in meeting CGMP requirements. The qualified consultant should also perform a comprehensive six-system audit⁴ of your entire operation for CGMP compliance and evaluate 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.

Drug Production

In response to this letter, clarify whether you intend to continue to manufacture drugs for the U.S. market at this facility in the future.

If you plan to resume any manufacturing operations regulated under the FD&C Act, notify this office before resuming your drug manufacturing operations. You are responsible for resolving all deficiencies and systemic flaws to ensure your firm is capable of ongoing CGMP compliance. In your notification to the Agency, provide a summary of your remediations to demonstrate that you have appropriately completed all corrective action and preventive action (CAPA).

Conclusion

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.

FDA placed your firm on Import Alert 66-40 on September 30, 2024.

Correct any violations promptly. 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 any violations.

Failure to address any violations may also result in the FDA continuing to refuse admission of articles manufactured at Hangzhou Glamcos Biotech Co., Ltd. at No 288 Xiufeng Road Tonglu County, Hangzhou, Zhejiang, into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Articles under this authority that appear to be adulterated or misbranded may be detained or refused admission.

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 CDER-OC-OMQ-Communications@fda.hhs.gov. Identify your response with FEI 3017053743 and ATTN: Matthew Jensen.

Sincerely,
/S/

Francis Godwin
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research

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1 Components with higher risk of DEG or EG contamination compared to other drug components.

2 The permitted dosage forms for consumer antiseptic washes are set forth here: “Safety and Effectiveness of Consumer Antiseptics; Topical Antimicrobial Drug Products for Over-the-Counter Human Use,” Proposed Rule, 78 FR 76444 (December 17, 2013) and “OTC Safety and Effectiveness of Topical Antimicrobial Drug Products for Over-the Counter Human Use,” Final Rule, 81 FR 61106 (September 6, 2016).

3 See section IV of the FDA Guidance for Industry Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug or Device Inspection at https://www.fda.gov/media/86328/download.

4 i.e. Quality System, Facilities & Equipment System, Materials System, Production System, Packaging & Labeling System, and Laboratory Control System per FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations.