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Warning Letter 320-24-56

August 15, 2024

Dear Mr. Ferrari:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Intercos Europe S.p.A, FEI 1000181428, at Via Guglielmo Marconi 84, Agrate Brianza, from March 11 to 15, 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 April 5, 2024 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

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 manufactured over-the-counter (OTC) sunscreen drug products without adequately testing incoming raw materials including, but not limited to, glycerin for conformance with identity and other required specifications before their use in your OTC drug products. For example, you lacked an identity test to detect diethylene glycol (DEG) and ethylene glycol (EG) in all containers of all lots of glycerin before determining acceptability for use in manufacturing drug products intended for the U.S. market. The identity testing of glycerin includes a limit test per the United States Pharmacopeia (USP) to ensure it meets the relevant safety limits for the levels of DEG and EG.

You also relied on your suppliers’ certificate of analysis (COA) without establishing the reliability of their test analyses at appropriate intervals. Without adequate testing, you lack confirmation that the components conform to appropriate specifications before use in the manufacture of your drug products.

In your response, you state your raw material specifications will include all identification tests listed in the applicable monograph and you will review your related procedures. You also state you will analyze the (b)(4) incoming batch (b)(4) for conformance to your suppliers’ specifications, and you will analyze (b)(4) container of high-risk components.

Your response is inadequate. You lack updated procedures showing your corrective actions have been implemented. You also fail to demonstrate you have sufficiently established the reliability of your suppliers’ test results listed on their COAs. Additionally, you lack evidence showing you performed adequate testing on all containers of all lots of glycerin before its use in the manufacture of drug products. Furthermore, you did not provide a retroactive risk assessment of distributed products containing components at high-risk for DEG or EG contamination.

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 response to this letter, provide:

• A commitment to provide DEG and EG test results, no later than 30 calendar days from the date of this letter, from testing reserve samples for all lots of high-risk drug components used in the manufacture of drug products. Alternatively, if a reserve sample of a component lot is unavailable, perform reserve 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 (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 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 results obtained from testing all components to evaluate the reliability of the COA from each component manufacturer. Include your SOP that describes this COA validation program.
• A summary of your program for qualifying and overseeing contract facilities that test the drug products you manufacture.

2. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).

You failed to adequately investigate multiple microbial excursions of your (b)(4) system used to manufacture drug products. For example, the microbial results of (b)(4) sampled on July 26, 2023, exceeded your limit of (b)(4) cfu/g. You noted the result was likely due to a sampling error, but provided no assessment of your (b)(4) system, nor any evidence of the investigation leading to your conclusion. Additionally, despite this result, you performed no retrospective risk assessment of finished product manufactured with this (b)(4). During the inspection you stated there was no product impact because no microbial contamination was recovered from the finished product. However, microbial contamination is not uniformly distributed, and (b)(4) sample may not be representative of the type or level of contamination that may exist in other individual units of a batch.

Without investigations into microbial failure results in your (b)(4) system you cannot ensure that your (b)(4) meets minimum microbiological and chemical standards suitable for the manufacture of your drug products.

Our inspection also noted changes made to batch records without adequate explanation or investigation. You stated an investigation was not initiated because a supervisor made this change.

In your response, you state you will review several procedures, including but not limited to those related to your (b)(4) system and out-of-specification (OOS) investigations.

Your response is inadequate. You fail to provide a retrospective review of your (b)(4) system’s microbial results, and you lack a risk assessment of all products that may have been affected by the OOS results. Furthermore, you fail to identify the microbial species recovered from your (b)(4) samples.

In response to this letter, provide:

• Complete investigations into all (b)(4) test results that were above your microbial action limit (whether or not later invalidated) in the previous three years from the date of this letter. The investigations should detail your findings regarding the root causes of the contamination.
• A detailed risk assessment addressing the potentially hazardous effects of your (b)(4) system on the quality of all drug product lots within expiry currently in the United States. Specify actions that you will take in response to the risk assessment, such as customer notifications and product recalls.
• A comprehensive, independent assessment of the design and control of your firm’s (b)(4) system, with a detailed and thorough review of all microbiological hazards.
• A procedure governing your program for ongoing control and monitoring that ensures the (b)(4) system consistently produces (b)(4) that meets (b)(4), USP monograph specifications and appropriate microbial limits.
• A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, OOS results, and failures. Provide a detailed action plan to remediate this system. Your action plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, CAPA effectiveness, quality unit oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.
• A comprehensive review and remediation plan for your OOS result investigation systems. The CAPA should include but not be limited to addressing the following:

  o Quality unit oversight of laboratory investigations
  o Identification of adverse laboratory control trends
  o Resolution of causes of laboratory variation
  o Initiation of thorough investigations of potential manufacturing causes whenever a laboratory cause cannot be conclusively identified
  o Adequately scoping of each investigation and its CAPA
  o Revised OOS investigation procedures with these and other remediations

3. Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to ensure compliance with established specifications and standards (21 CFR 211.194(a)).

Your laboratory records did not include complete data to support the analysis performed. For example, your finished product test method for zinc oxide concentration requires the recording of solvent amounts used in sample preparation. However, solvent information, including lot numbers and quantities, was not documented. In addition, your procedure requires laboratory equipment to be operated at predetermined conditions, but it does not require peer review to verify these conditions and the data generated from your testing process.

Reliability of data is compromised when there is a failure to maintain complete records of the conditions and data associated with all tests. Furthermore, the lack of complete data compromises the quality unit’s (QU) ability to investigate discrepancies and exercise its function of ensuring compliance to applicable standards.

In your response, you state you will create a detailed checklist describing reagent preparation. You also state your COA and laboratory notebook will be signed by the analytical quality control manager before batch release.

Your response is inadequate. You fail to provide a comprehensive evaluation of your overall testing and documentation practices to assess the scope of your laboratory documentation deficiencies.

In response to this letter, provide:

• A comprehensive, independent assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.
• A comprehensive independent 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.

Data Integrity Remediation

Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. See FDA’s guidance document Data Integrity and Compliance With Drug CGMP for guidance on establishing and following CGMP compliant data integrity practices at https://www.fda.gov/media/119267/download.

We strongly recommend that you retain a qualified consultant to assist in your remediation. In response to this letter, provide:

• A comprehensive investigation into the extent of the inaccuracies in data records and reporting including results of the data review for drugs distributed to the United States. Include a detailed description of the scope and root causes of your data integrity lapses.
• A current risk assessment of the potential effects of the observed failures on the quality of your drugs. Your assessment should include analyses of the risks to patients caused by the release of drugs affected by a lapse of data integrity and analyses of the risks posed by ongoing operations.
• A management strategy for your firm that includes the details of your global corrective action and preventive action plan. The detailed corrective action plan should describe how you intend to ensure the reliability and completeness of all data generated by your firm including microbiological and analytical data, manufacturing records, and all data submitted to FDA.

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. 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 Intercos Europe S.p.A, Agrate Brianza 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 1000181428 and ATTN: Matthew Jensen.

Sincerely,
/S/

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