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  5. Higley Industries, Inc. - 669170 - 02/22/2024
  1. Warning Letters


Higley Industries, Inc. MARCS-CMS 669170 —

Delivery Method:
UPS Next Day

Recipient Name
Mr. Lance R. Hummel
Recipient Title
Higley Industries, Inc.

2330 Industrial Parkway SW
Dyersville, IA 52040-8748
United States

Issuing Office:
Division of Pharmaceutical Quality Operations III

United States

Secondary Issuing Offices

United States

February 22, 2024

CASE# 669170

Dear Mr. Hummel:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Higley Industries, Inc., FEI 3002984417, at 2330 Industrial Parkway SW, Dyersville, IA 52040-8748, from September 19 to September 21, 2023.

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).

We acknowledge receipt of your response and subsequent correspondence to our Form FDA 483.

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

1. 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 adequately test samples of your incoming components before using the components to manufacture your over-the-counter (OTC) drug products. You also relied on your suppliers’ certificate of analyses (COA) without establishing the reliability of your component suppliers’ test analyses at appropriate intervals.


You failed to adequately test your incoming ethanol, used as an active ingredient, for methanol. 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 to help you meet the CGMP requirements when manufacturing drugs containing ethanol at https://www.fda.gov/media/173005/download.


You failed to adequately test your incoming components at high-risk of diethylene glycol (DEG) or ethylene glycol (EG) contamination for identity before using them to manufacture your drug products. This includes, but is not limited to, testing of glycerin you used in manufacturing your drug products to determine its appropriate identity. Identity testing for glycerin and certain other high-risk drug components 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 identity testing on each shipment of each lot using the USP identification test that detects these hazardous impurities, you failed to assure the acceptability of these components for use in the 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.


Your firm uses water from your (b)(4) water system as a component for manufacturing drug products. Your firm has not demonstrated that the water is suitable for use and meets the USP (b)(4) water monograph.

In your response, you commit to sampling and testing the identity and strength of raw materials as third-party results will be compared to the COA and water quality will be monitored and tested routinely. Your response is inadequate because you failed to specify how you will establish the reliability of your third party’s test results.

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.

In response to this letter, provide:

  • A description of how you will test each component lot 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 lot 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 revalidation. In addition, include a commitment to always conduct at least one specific identity test for each incoming component lot. In the case of glycerin, propylene glycol, and certain additional high-risk components we note that this includes the performance of parts A, B, and C of the USP monograph.
  • The chemical quality control specifications you use to test each incoming lot (including high-risk drug components) to determine acceptability for use in manufacturing.
  • 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.
  • A summary of results obtained from testing all components to evaluate the reliability of the COA from each component manufacturer. Include your standard operating procedure that describes this COA validation program.
  • A summary of your program for qualifying and overseeing contract facilities that test the drug products you manufacture.
  • A commitment to provide DEG and EG test results, no later than (b)(4) calendar days from the date of this letter, from testing retains for all lots of high-risk drug components used in the manufacture of drug products. Alternatively, if a retain of a component lot is unavailable, perform retain sample testing of all implicated finished drug product batches for the presence of DEG and EG.
  • A full risk assessment for drug products that are within expiry which contain any ingredient at risk for DEG or EG contamination (including, but not limited to, glycerin). Take prompt and appropriate actions to determine the safety of all lots of the component(s) and any related drug product that could contain DEG or EG, including customer notifications and product recalls for any contaminated lots. Identify additional appropriate CAPA that secure supply chains in the future, including, but not limited to, ensuring that all incoming raw material lots are from fully qualified manufacturers and free from unsafe impurities. Detail these actions in your response to this letter.
  • A procedure for your water system monitoring that specifies routine microbial testing of water to ensure its acceptability for use in each batch of drug products produced by your firm.
  • The current action/alert limits for total counts and objectionable organisms used for your (b)(4) water system. Ensure that the total count limits for your (b)(4) water are appropriately stringent in view of the intended use of each of the products produced by your firm.
  • A procedure governing your program for ongoing control, maintenance, and monitoring that ensures the remediated system consistently produces water that meets (b)(4) Water, USP monograph specifications and appropriate microbial limits.

2. 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)).

You failed to adequately validate your processes and qualify the equipment used to manufacture your PSSI E-SAN Alcohol Antiseptic 80% Topical Solution Hand Sanitizer. During the inspection, you told the investigator that any filling line could be used to manufacture hand sanitizer. However, you were unable to provide documentation of process validation.

In your response, you acknowledged that you “failed to establish control procedures that monitor the output and validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of the in-process material and the drug product,” and commit to validating the manufacturing process and implement in-process equipment qualification procedures. Your response is inadequate because you did not provide sufficient detail or evidence to demonstrate implementation of adequate corrective actions.

An adequate ongoing program for monitoring process control ensures stable manufacturing operations and consistent drug quality. 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.

In response to this letter, provide:

  • A detailed summary of your validation program for ensuring a state of control throughout the product lifecycle, along with associated procedures. Describe your program for process performance qualification, and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.
  • A timeline for performing appropriate process performance qualification (PPQ) for each of your marketed drug products.
  • Include your process performance protocol(s), and written procedures for qualification of equipment and facilities.
  • Provide a detailed program for designing, validating, maintaining, controlling and monitoring each of your manufacturing processes that includes vigilant monitoring of intra-batch and inter-batch variation to ensure an ongoing state of control. Also, include your program for qualification of your equipment and facility.

3. 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 OTC drug products. For example, your QU failed to ensure the following:

  • Adequate evaluation of product quality before batch release (e.g., Quality Manual designated the Shipping Clerk with final authority to review and approve drug product for release) (21 CFR 211.22(a)).
  • Adequate batch production and control records that include documentation of the accomplishment of each significant step in the manufacture, processing, packing, or holding of the batch, for each batch of drug product (21 CFR 211.188(b)).
  • Adequate written procedures for test methods and sampling plans (21 CFR 211.160(b)).
  • Establishment of an adequate, ongoing stability program (21 CFR 211.166(a)).
  • Performance of periodic (i.e., at least (b)(4)) product reviews (21 CFR 211.180(e)).

In your response, you acknowledge that your QU failed to review and approve drug product production and control records for compliance with all procedures before batch release and distribution, and that you updated your QU procedures. Your response is inadequate because you did not provide sufficient detail or evidence to demonstrate implementation of adequate corrective actions.

An adequate QU overseeing all manufacturing operations is necessary to consistently ensure drug quality. Your firm’s quality systems are inadequate. 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.

In response to this letter, provide:

  • A comprehensive assessment and remediation plan to ensure your QU is given the authority and resources to effectively function. 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.

  • A complete assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed corrective actions and preventive actions (CAPA) plan that comprehensively remediates your firm’s documentation practices to ensure you retain attributable, legible, complete, original, accurate, contemporaneous records throughout your operation.

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 (b)(4)1 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.


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.

Your response should refer to Case # 669170. Please address your reply via email to: ORAPHARM3_RESPONSES@fda.hhs.gov

Attention: Brian Nicholson, Compliance Officer
U.S. Food and Drug Administration
Division of Pharmaceutical Quality Operations Division III

If you have questions regarding the contents of this letter, please contact Compliance Officer, Brian Nicholson at (630) 207-9337.


Jeffrey D. Meng
Program Division Director
Office of Pharmaceutical Quality Operations Division III

cc: Project Clean
Normand Frechette, President and CEO
12 James St N, Suite 202
Hamilton, ON L8R 2J9,


1 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.

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