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Delivery Method: VIA UPS Reference #: 320-25-17 Product: Drugs

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Recipient:

Recipient Name

Mr. Ernesto Leonelli

Recipient Title

CEO

Eurosirel S.P.A

Viale Europa 30 20090 Cusago MI Italy

Issuing Office: Center for Drug Evaluation and Research (CDER)

United States

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Warning Letter 320-25-17

November 20, 2024

Dear Mr. Leonelli:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Eurosirel S.P.A., FEI 3015892095, at Viale Europa 30, Cusago, Milan, from May 20 to 24, 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 June 11, 2024 response to our Form FDA 483 in detail.

CGMP Violations

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 topical drug products including (b)(4) and pain patches. You failed to perform adequate identity testing of each component lot used in the manufacture of your drug products. You also relied on your suppliers’ certificate of analysis (COA) without establishing the reliability of your component suppliers’ test analyses at appropriate intervals.

Glycerin

You failed to adequately test each shipment of each lot of glycerin for identity, a component at higher risk of diethylene glycol (DEG) and ethylene glycol (EG) contamination. We note that glycerin is included in the formulation of your pain patches. Identity testing for glycerin and certain other high-risk drug components1 includes a limit test in the United States Pharmacopeia (USP) to ensure 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.

In your response, you state you will perform identification tests on all active ingredients listed on in the “drug fact.” Your response is inadequate. You did not describe appropriate identity testing for each lot of your incoming components, including a limit test for high-risk components such as glycerin. Additionally, you did not provide details about how you will verify the reliability of your suppliers’ COA at appropriate intervals. Further, you did not address potential impact to drug products already distributed to the United States that are within expiry.

2. Your firm failed to establish an adequate quality control unit with the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging materials, labeling, and drug products (21 CFR 211.22(a)).

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

• Appropriate written records of major equipment cleaning, maintenance, and use (21 CFR 211.182).
• Complete batch and control records for each batch of drug product (21 CFR 211.188).

Your QU is responsible for fully exercising its authority and responsibilities. FDA is concerned that your QU may not be conducting appropriate oversight regarding CGMP operations.

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.

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 audit 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.

Cosmetics Manufactured for Distribution in the United States

In addition, we note that some of the products you manufacture may be regulated as cosmetics, as defined in section 201(i) of the FD&C Act (21 U.S.C. 321(i)). Any cosmetics you manufacture must comply with applicable statutory and regulatory requirements, including the FD&C Act. A cosmetic is deemed adulterated under section 601(c) of the FD&C Act (21 U.S.C. 361(c)) if it has been prepared, packed, or held under insanitary conditions whereby it may have become contaminated with filth, or whereby it may have been rendered injurious to health. Some of the conditions that cause the drug products you manufacture to be adulterated may also cause any cosmetic products you manufacture to be adulterated. Under section 301(a) of the FD&C Act (21 U.S.C. 331(a)), it is a prohibited act to introduce or deliver for introduction into interstate commerce a cosmetic that is adulterated.

Further, your facility may be subject to requirements of the Modernization of Cosmetics Regulations Act of 2022 (MoCRA). Information on MoCRA requirements may be found at https://www.fda.gov/cosmetics/cosmetics-laws-regulations/modernization-cosmetics-regulation-act-2022-mocra.

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. 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 refusing admission of articles manufactured at Eurosirel S.P.A., at Viale Europa 30, Cusago, Milan 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 may be detained or refused admission, in that the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351(a)(2)(B).

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 3015892095 and ATTN: Daniel W. Brisker.

Sincerely, /S/

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

CC: Registered U.S. Agent: William A. Clementi Chief Executive Officer Clementi & Associates, Ltd. bill@clementi@clempharma.com

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