NWL Netherlands Services B.V. - 701206 - 04/01/2025

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Warning Letter 320-25-59

April 1, 2025

Dear Mr. Duivenvoorden:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, NWL Netherlands Services B.V., FEI 3003696942, at Amperestraat 12, Hillegom, Zuid-Holland, Netherlands, from October 14 to 18, 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 8, 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 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).

Your investigations lacked sufficient root cause determinations, corrective actions and preventive actions (CAPAs), and assessment of all potentially affected batches. For example, you did not adequately investigate repeated out-of-limit (OOL) results for microbial content in your (b)(4) system. You used (b)(4) generated from your (b)(4) system as a major component of drug products. In 2024, you obtained seven OOL events, at least two with results as high as 10,000 colony-forming units (CFU)/mL. After the first OOL event, your firm’s response to subsequent OOL events was limited to reviewing (b)(4) system test results from the day before and after, along with relying on finished product test results.

You have not shown that you can consistently produce (b)(4) suitable for the manufacture of pharmaceutical products. At a minimum, your (b)(4) must meet the United States Pharmacopoeia (USP) monograph for (b)(4) with appropriate microbial limits. It is essential that you effectively control, maintain, and monitor the system to ensure it consistently produces (b)(4) suitable for pharmaceutical use.

In your response, you indicate that individual investigations with impact assessments will be created when you obtain OOL results. You also indicate that your quality lead will review and document (b)(4) results on a (b)(4) basis. Furthermore, you commit to training your quality team on when to report and escalate an OOL result.

Your response is inadequate. It fails to provide a comprehensive retrospective risk assessment into the microbial content of (b)(4) used for production of drug products and evaluate the full scope and impact of OOL results. Furthermore, you do not provide any supporting documentation about the CAPAs that were described, such as updated procedures and training records.

In response to this letter, provide:

• A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, out-of-specification 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 assurance oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.
  o Include your updated investigation procedures and a clear description of how investigations are initiated, documented, and completed.
• A detailed risk assessment addressing the potential effects of the observed (b)(4) system failures on the quality of all drug product batches currently in U.S. distribution or within expiry. Specify actions that you will take in response to the risk assessment, such as customer notifications and product recall.

2. 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)).

Your firm failed to perform identity testing of each component lot used in the production of your over-the-counter drug products, including (b)(4), your active pharmaceutical ingredient. You also relied on the certificates of analysis (COAs) from your suppliers and failed to establish the reliability of each of your component suppliers’ test analyses at appropriate intervals.

In your response, you acknowledge the need to update your procedure to require testing of incoming materials, such as (b)(4), for impurities (e.g., (b)(4)).

Your firm’s response is inadequate. You fail to provide a specification for impurities, such as (b)(4), in your incoming materials. Without appropriate testing of components and ingredients, you cannot ensure the quality and safety of your drug products.

(b)(4)

You manufacture multiple drugs that contain (b)(4). The use of (b)(4) contaminated with (b)(4) has resulted in various lethal poisoning incidents in humans worldwide. See FDA’s guidance document (b)(4).

In response to this letter, provide:

• 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.
• The chemical and microbiological quality control specifications you use to test and release each incoming lot of component for use in manufacturing.
• 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 re-validation. In addition, include a commitment to always conduct at least one specific identity test for each incoming component lot.
• A comprehensive assessment of the risk to drug product quality for the batches manufactured using (b)(4) that did not undergo incoming identity testing that remain within shelf-life in the U.S. market.
• (b)(4) testing for all (b)(4) drug product batches released and distributed in the United States within expiry.

3. Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records (21 CFR 211.68(b)).

Your laboratory equipment used to generate analytical data for finished drug product release lacked restricted access and sufficient controls. There was no assurance that your systems had the appropriate controls to prevent data deletion and record modifications. For example, you did not establish unique usernames and passwords, and laboratory staff had administrator rights allowing uncontrolled access to delete or modify high performance liquid chromatography (HPLC), gas chromatography (GC), and fourier transform infrared spectroscopy (FTIR) files. Furthermore, your firm did not adequately maintain backups of data generated by your laboratory equipment.

It is important to maintain strict control over CGMP electronic data to ensure that all additions, deletions, or modifications of information in your electronic records are authorized and appropriately documented. Without complete and accurate records, you cannot ensure your firm makes appropriate batch release, stability, and other decisions that are fundamental to ongoing assurance of drug product quality.

In your response, you state that your firm’s quality lead will perform a (b)(4) review of software systems and data to confirm there have been no unauthorized editing or deletion of files. You also indicate that you will create a procedure to identify the required access rights for each job function.

Your response is inadequate. Your response fails to provide a comprehensive review of your system for identifying deleted or modified data.

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, independent assessment of computer system performance and security. Provide a report that identifies vulnerabilities in the design and controls, and a thorough CAPA plan for each of your laboratory computer systems, which addresses the following elements:
  o A list of all hardware (both standalone and networked) and software used by your laboratory.
  o Identify and evaluate vulnerabilities in performance and security of all of these computer systems, including but not limited to, their configurations, administrative rights, password controls, audit trails capabilities, and state of implementation for each system, qualification/validation status, deviation history, backup capabilities, network requirements, completeness of data records, suitability of current hardware/software for its intended use(s), change management, and management oversight.
  o Detail the associated user privileges for each system.
  o Specify user roles and associated user privileges for all staff levels who have access to the laboratory computer system, and provide organizational affiliations, responsibilities, and titles. Clearly specify all staff who have administrator privileges.
  o Fully describe how you will ensure segregation of firm personnel involved with laboratory testing from those with administrator rights. For all staff roles that are permitted to have administrative rights, specify the scope and type of privileges.
  o Assess each system to determine if unique usernames and passwords are used.
  o Evaluate policies and procedures regarding computers and data governance, with special emphasis on audit trails, prohibiting data deletion, and appropriate modifications of results. Specify how your firm prevents data deletion and undocumented/inappropriate modifications of data. Also describe how you ensure original data and information is always preserved. Provide your procedures for audit trail review.
  o Provide requirements for data retention and backup for all laboratory systems.
• Summarize your interim controls to assure reliable performance and security while your CAPA plan is being implemented.

CGMP Consultant Recommended

Based upon the nature of the violations we identified at your firm, we strongly recommend engaging a consultant qualified to evaluate your operations 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 NWL Netherlands Services B.V. Zuid-Holland, Netherlands, 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 3003696942 and ATTN: Yasamin Ameri

Sincerely,
/S/

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