Dyno Manufacturing, Inc. - 700785 - 04/09/2025

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Warning Letter 320-25-63

April 9, 2025

Dear Ms. Boofer:

The United States Food and Drug Administration (FDA) inspected your drug manufacturing facility, Dyno Manufacturing, Inc., FEI 3017219182, at 2 Fox Industrial Dr., Madison, IL 62060-1155, from October 28 to November 1, 2024.

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 reviewed your November 21, 2024 response to our Form FDA 483 in detail.

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

1. 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 manufactures over-the-counter (OTC) hand sanitizer and antibacterial hand soap drug products without adequate assurance of the quality of raw materials. For example, you did not adequately test incoming raw materials, including identity testing of each shipment of each component lot (e.g., ethanol, glycerin, propylene glycol) used in the manufacture of your OTC drug products. You stated that you were aware of the legal requirement for testing components, but accepted the at-risk components based on their suppliers’ certificate of analysis (COA).

Glycerin

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.

Ethanol

You failed to adequately test your incoming ethanol, used as an active ingredient, for methanol. During the inspection, you indicated that your supplier tests ethanol for methanol prior to shipment. You relied on your suppliers’ COA, and you have not established the reliability of your component suppliers’ test analyses at appropriate intervals. In addition, the supplier’s COA for ethanol did not include test results for methanol.

Without adequate testing you do not have scientific evidence that your raw materials 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.

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 at: https://www.fda.gov/media/173005/download.

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 of 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 your program for qualifying and overseeing contract facilities that test the drug products you manufacture.
• 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 (SOP) that describes this COA validation program.
• A commitment to provide DEG and EG test results, no later than 30 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 corrective actions and preventive actions (CAPAs) 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.
• Methanol testing for all hand sanitizer batches released and distributed in the United States within expiry.

2. Your firm failed to assure that the drug product bore an expiration date that was supported by appropriate stability testing (21 CFR 211.137(a)).

You failed to establish a stability testing program to support the expiry of your distributed drug products. You did not perform any stability studies for your OTC hand sanitizer and antibacterial hand soap drug products to support their assigned (b)(4) expiry period. Also, you did not have an approved stability program procedure at the time of inspection.

In your response, you commit to drafting stability protocols for all your hand sanitizer and antibacterial soap products and qualifying a contract laboratory to utilize their stability chambers for your stability studies. Your interim remediation is to test “representative retain samples” of your marketed products for assay to show stability under ambient conditions.

Your response is inadequate. Your interim remediation of testing your “retain samples” for assay does not address other critical quality attributes for drug stability, including microbiological and impurity testing.

In response to this letter, provide:

• Your plan for continuing stability studies for your drug products through expiry, including detailed timelines. This plan should also include an assessment of the stability of drug product currently on the U.S. market.
• Your stability data to demonstrate that the chemical, purity, and microbiological properties of your drug products will remain within specification throughout their expiry period.
• Your action plan to address any product quality or patient safety risks for your drug products in U.S. distribution, including potential customer notifications and recalls.
• A comprehensive, independent assessment and CAPA plan to ensure the adequacy of your stability program. Your remediated program should include, but not be limited to:
  o Stability indicating methods.
  o Stability studies for each drug product in its marketed container-closure system before distribution is permitted.
  o An ongoing program in which representative batches of each product are added each year to the program to determine if the shelf-life claim remains valid detailed definition of the specific attributes to be tested at each station (timepoint).
  o All procedures that describe these and other activities of your remediated stability program.

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)).

You failed to validate your production and process controls. You did not have assurance that you are capable of consistently manufacturing your drug product with defined quality attributes. Your firm lacked a process validation program and data to support fundamental process parameters such as mixing speed, time, and temperature.

From October 2022 to 2024, you manufactured approximately (b)(4) batches of liquid OTC hand sanitizer and antibacterial hand soap drug products using unvalidated processes.

Additionally, you did not perform equipment qualification studies, and the inspection documented that cleaning validation studies have not been completed for your drug product manufacturing equipment. You have not established evidence to show your equipment functions and operates as expected or that your cleaning processes for this equipment prevents product contamination.

In your response, you commit to completing process validation studies and equipment qualification activities, however, your response is inadequate because you do not provide product impact assessments for ongoing manufacturing and distributed drug products.

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 include intensive monitoring and testing throughout each significant process stage to characterize intra-batch variation and evaluate batches to 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 the FDA's guidance for industry, Process Validation: General Principles and Practices for general principles and approaches that the 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 (PPQ), and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.
• A timeline for performing PPQ for each of your marketed drug products. Also include an explanation how you will ensure proper satisfactory PPQ studies are performed prior to future distribution of any drug products.
• A risk assessment for the distributed drug product(s) produced without performing any process validation studies.
• Process performance protocol(s), and written procedures for qualification of equipment and facilities.
• 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.

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 adequately exercise its authority and responsibilities including, but not limited to, implementing effective procedures and conducting adequate oversight. For example, you failed to ensure the following:

• Establishment of written records describing the evaluation of quality standards of each drug product at least annually to determine the need for changes in drug product specifications, manufacturing, or control procedures (21 CFR 211.180(e)).
• Establishment of adequate written procedures defining QU responsibilities and controls (21 CFR 211.22(d)).
• Appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records as required by 21 CFR 211.68(b).

In your response, you initiated a CAPA to complete annual product reviews for all your liquid OTC hand sanitizers and antibacterial hand soaps manufactured. You also state under your effectiveness criteria, you will review and address data trends and implement CAPAs as appropriate based on your findings.

Your response is inadequate. You do not provide information on how you will ensure annual product reviews will be completed routinely for all your drug products.

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

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. 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 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 CDER-OC-OMQ-Communications@fda.hhs.gov. Identify your response with FEI 3017219182 and ATTN: Sai Dharmaraj.

Sincerely,
/S/

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