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10/26/2023
WARNING LETTER
CASE# 660268

Dear Mr. Arneson:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Brenntag Great Lakes, LLC, FEI: 2126821, at N59W14765 Bobolink Avenue, Menomonee Falls, WI 53051-5901, from April 26 to May 5, 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 drugs 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. 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 investigator observed specific violations including, but not limited to, the following.

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

Your firm manufactures over-the-counter (OTC) hand sanitizer drug product, (b)(4) 70% Hand Sanitizer Solution, as well as non-drug products including Class 2 solvents and industrial chemicals, including automotive brake parts cleaner using the same equipment. This was noted during a previous inspection and as a corrective action you stated you would discontinue the use of non-dedicated blending tank equipment in the manufacture of OTC drug products. However, our investigator observed that you continued to use non-dedicated blending tank equipment to manufacture OTC drug products. In your response, you explained that while there was a decision to discontinue using non-dedicated tanks, the decision was not effectively communicated to the production team.

It is unacceptable as a matter of CGMP to continue manufacturing drugs using the same equipment that you use to manufacture these non-pharmaceutical products due to the risk of cross-contamination. Inadequate removal of active ingredients and product residues from surfaces of non-dedicated manufacturing equipment can lead to contamination of drug products subsequently manufactured on that equipment.

In response to this letter, provide:

• Confirmation of whether you will discontinue manufacturing drugs on shared equipment in your facility and implement appropriate controls to prevent cross-contamination.
• If you intend to continue manufacturing both pharmaceutical and non-pharmaceutical products at your facility, provide a plan to show how you will maintain appropriate separation with dedicated manufacturing equipment for your pharmaceutical manufacturing and industrial product manufacturing operations.
• A review of your production records (e.g. tank logbooks) to determine if other drug products within expiry were made on non-dedicated equipment, and if so, provide a risk assessment for all drugs you have previously produced on equipment shared with industrial products. For each product, assess the risk of potential contamination due to the shared equipment, and provide your plans for addressing the product quality and patient safety risks for any product still in distribution, including potential recalls or market withdrawals.

2. 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:

• Adequate procedures to ensure the QU has the authority to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated (21 CFR 211.22(a)).
• Adequate written procedures for production and process controls (e.g., mixer speed for (b)(4) Hand Sanitizer Solution) (21 CFR 211.100(a)).
• Appropriate control over computer systems (21 CFR 211.68(b)).
• Performance of periodic product reviews (21 CFR 211.180(e)).

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.

• An assessment of each drug product process to ensure that there is a data-driven and scientifically sound program that identifies and controls all sources of variability, such as your production processes, and will consistently meet appropriate specifications and manufacturing standards. This includes, but is not limited to, evaluating suitability of equipment for its intended use, sufficiency of detectability in your monitoring and testing systems, quality of input materials, and reliability of each manufacturing process step and control.
• Timelines for completed process performance qualification for marketed drug products for which a state of control has not been adequately/fully established.

Repeat Observations at Facility

In previous inspections ending on September 10, 2014 and August 2, 2019, FDA cited similar CGMP observations. You proposed specific remediation for these observations in your response. Repeated failures demonstrate that executive management oversight and control over the manufacture of drugs is inadequate.

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 audit¹ 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.

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.

Your response should refer to Case # 660268. 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.

Sincerely,
/S/

Nicholas F. Lyons
Director of Compliance
Division of Pharmaceutical Quality Operations III

For

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

Cc:
Kaoni N. Rhodes
Regional Health, Safety, Quality and Environmental Manager
Brenntag Great Lakes, LLC
4420 N. Harley Davidson Avenue
Wauwatosa, WI 53225

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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.