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  5. Auto-Chlor System LLC - 641808 - 12/20/2022
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WARNING LETTER

Auto-Chlor System LLC MARCS-CMS 641808 —

Delivery Method:
VIA Electronic Mail
Product:
Drugs
Recipient:
Recipient Name
Mr. Johnathan Koth
Recipient Title
Manufacturing Plant Manager
Auto-Chlor System LLC

3045 Commerce Way
Hapeville, GA 30354-1240
United States

Issuing Office:
Division of Pharmaceutical Quality Operations II

United States

DATE: 12/20/2022

Case #: 641808

WARNING LETTER

Dear Mr. Koth:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Auto-Chlor System LLC, FEI 3010164603, at 3045 Commerce Way, Hapeville, from July 5 to 18, 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 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, HAND KLEEN FOAMING INSTANT 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(ee) of the FD&C Act, 21 U.S.C. 352(ee). Introduction or delivery for introduction of such 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.

We reviewed your August 8, 2022, response to our Form FDA 483 in detail. Your response is inadequate because it did not provide sufficient detail or evidence of corrective actions to bring your operations into compliance with CGMP.

During our inspection, our investigators observed specific violations including, but not limited to, the following.

1. Your firm failed to establish and follow written procedures for cleaning and maintenance of equipment (21 CFR 211.67(b)).

Your firm is currently registered as a drug manufacturer and manufactures over-the-counter (OTC) hand rub1 drug products (also referred to as a consumer hand sanitizer) including HAND KLEEN FOAMING INSTANT HAND SANITIZER, as well as non-drug products including industrial cleaners. It is unacceptable as a matter of CGMP to continue manufacturing drugs using the same equipment that you use to manufacture industrial cleaners or other non-pharmaceutical products due to the risk of cross-contamination. Our investigator also observed inadequate cleaning and maintenance of your drug manufacturing equipment.

Inadequate removal of active ingredients and drug product residues from surfaces of non-dedicated manufacturing equipment can lead to contamination of drug products subsequently manufactured on that equipment.

2. 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 211.84(d)(2)).

You failed to test your incoming components for identity before using the components to manufacture your drug products. This includes not testing incoming ethanol, used as an active ingredient, for methanol. Additionally, you relied on certificates of analyses from unqualified suppliers for specifications such as purity, strength, and quality. By not analyzing your components for identity, purity, strength, and quality, you failed to ensure that your incoming components meet appropriate specifications.

In addition, you confirmed that your firm uses (b)(4) water as a component for manufacturing drug products. Your firm has not shown that the (b)(4) water that you use for component water is suitable for aqueous-based dosage form drug product manufacturing, and, at a minimum, meets the USP purified water monograph and appropriate microbial limits. You confirmed to our investigators that no testing of this (b)(4) water has been performed, and you also lack procedures regarding water specifications, testing, or handling of water.

Furthermore, you manufacture drugs that contain ethanol. The use of ethanol contaminated with methanol has resulted in various lethal poisoning incidents in humans worldwide. See FDA’s guidance document Policy for Testing of Alcohol (Ethanol) and Isopropyl Alcohol for Methanol, Including During the Public Health Emergency (COVID-19) to help you meet the CGMP requirements when manufacturing drugs containing ethanol at https://www.fda.gov/media/145262/download.

As a manufacturer, you have a responsibility to sample, test, and examine drug components before use to assure adequate quality, including testing for the presence of methanol in ethanol, before use in production.

3. Your firm failed to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a)).

Your firm has not established that your processes used to manufacture hand sanitizer drug products are validated. In addition, you could not provide evidence that equipment qualification had been performed on your equipment.

Process validation evaluates the soundness of design and state of control of a process throughout its lifecycle. Each significant stage of a manufacturing process must be designed appropriately and assure the quality of raw material inputs, in-process materials, and finished drugs. Process qualification studies determine whether an initial state of control has been established. Successful process qualification studies are necessary before commercial distribution. Thereafter, ongoing vigilant oversight of process performance and product quality is necessary to ensure you maintain a stable manufacturing operation throughout the product lifecycle.

See FDA’s guidance document Process Validation: General Principles and Practices for general principles and approaches that FDA considers appropriate elements of process validation at https://www.fda.gov/media/71021/download.

4. 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 quality unit (QU) did not provide adequate oversight for the manufacture of your drug products. For example, your QU failed to ensure the following:

  • Employees are trained and remain familiar with CGMPs (21 CFR 211.25(a)).
  • Appropriate testing for the identity and strength of the active ingredients was performed and reviewed before release for each batch of drug product (21 CFR 211.165(a)).
  • Appropriate testing of each batch of drug product to be free of objectionable microorganisms (21 CFR 211.165(b)).
  • Establishment of an adequate, ongoing stability program (21 CFR 211.166(a)).
  • Performance of annual product reviews (21 CFR 211.180(e)).
  • To prepare adequate batch control and production records for your hand sanitizer drug products (21 CFR 211.188).
  • Thorough investigations for out-of-specifications results, complaints, deviations, and other discrepant results per an adequate written and approved procedure (21 CFR 211.192).

An adequate QU overseeing all manufacturing operations is necessary to consistently ensure drug quality. See FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations for help 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.

Unapproved New Drug and Misbranding Violations

Examples of claims observed on the HAND KLEEN FOAMING INSTANT HAND SANITIZER label that provide evidence of the intended uses2 (as defined in 21 CFR 201.128) of the product include, but may not be limited to, the following:

“HAND KLEEN FOAMING INSTANT HAND SANITIZER . . . Drug Facts . . . Active Ingredient . . . Benzethonium Chloride 0.20% w/w . . . Purpose . . . Antiseptic handwash. . . Uses . . . For handwashing to decrease bacteria on the skin. . . Directions . . . Apply a small amount to palm · Briskly rub, covering hands with product until dry. . .” [from your HAND KLEEN FOAMING INSTANT HAND SANITIZER label]

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 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 HAND KLEEN FOAMING INSTANT HAND SANITIZER 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 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). We note that the active ingredient benzethonium chloride was classified as Category III for use as an active ingredient in a consumer antiseptic wash. However, benzethonium chloride was determined to be ineligible for evaluation under the OTC Drug Review for use as an active ingredient in consumer antiseptic rubs.

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, HAND KLEEN FOAMING INSTANT HAND SANITIZER does not conform to the 1994 TFM, as further amended by the 2016 Consumer Antiseptic Rubs Proposed Rule [and the 2013 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.

As previously noted, statements on the product label for HAND KLEEN FOAMING INSTANT HAND SANITIZER suggest that this product is intended to be both a consumer antiseptic wash and consumer antiseptic rub. However, benzethonium chloride (in any concentration) is not an active ingredient permitted for use in consumer antiseptic rubs under the 1994 TFM. A product cannot also be labeled as a handwash with directions in the labeling that pertain to use as a hand rub under the 1994 TFM.

Lastly, this product is misbranded under section 502(ee) of the FD&C Act, 21 U.S.C. 352(ee), because HAND KLEEN FOAMING INSTANT 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.

CGMP Consultant Recommended

Based upon the nature of the violations we identified at your firm, if your firm intends to resume manufacturing drugs for the U.S. market, you should engage a consultant qualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements. The qualified consultant should also perform a comprehensive audit of your entire operation for CGMP compliance and evaluates the completion and efficacy of any identified corrective actions and preventive actions before you pursue resolution of your firm’s compliance status with FDA.

Outsourcing to Contract Manufacturers

We acknowledge your commitment to cease production of drugs at this facility, to outsource the manufacturing of all FDA products to a private labeling company, and to ensure appropriate corrections are completed at the new manufacturer. If you plan to resume or outsource the manufacturing of drugs, notify this office before resuming your operations.

Drugs must be manufactured in conformance with CGMP. FDA is aware that many drug manufacturers use independent contractors such as production facilities, testing laboratories, packagers, and labelers. FDA regards contractors as extensions of the manufacturer.

You are responsible for the quality of your drugs regardless of agreements in place with your contract facility. You are required to ensure that drugs are made in accordance with section 501(a)(2)(B) of the FD&C Act to ensure safety, identity, strength, quality, and purity. See FDA’s guidance document Contract Manufacturing Arrangements for Drugs: Quality Agreements at https://www.fda.gov/media/86193/download.

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.

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 FDA to withhold issuance of Export Certificates. 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 Jose R. Lopez, Compliance Officer, at ORAPHARM2_RESPONSES@fda.hhs.gov. In addition, please submit a signed copy of your response to joser.lopez@fda.hhs.gov and ronda.loyd-jones@fda.hhs.gov.

Your written notification should refer to case # 641808.

If you have questions regarding the contents of this letter, you may contact Jose R. Lopez via (787) 729-8603 or joser.lopez@fda.hhs.gov.

Sincerely,
/S/

Monica R. Maxwell
Program Division Director
Office of Pharmaceutical Quality Operations,
Division II

_______________________________

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 were present. These circumstances included preparation of hand sanitizer products using only the ingredients and formulas set forth in the guidance. Because Auto-Chlor System LLC 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 We note that your HAND KLEEN FOAMING INSTANT HAND SANITIZER drug product’s labeling contains conflicting information regarding whether it should be used as consumer antiseptic rub/consumer antiseptic wash or 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., “Apply a small amount to palm · Briskly rub, covering hands with product until dry”). This product, however, does not conform to the requirements for either a consumer antiseptic rub or a consumer antiseptic wash, as further described below.

 
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