Fagron Group B.V.

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Fagron, Inc., FEI 1000174332, at 2400 Pilot Knob Road, Saint Paul, Minnesota (USA) from November 1 to November 18, 2021.

This warning letter summarizes significant deviations from current good manufacturing practice (CGMP) for active pharmaceutical ingredients (API).

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your API 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 December 10, 2021, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

During our inspection, our investigators observed specific deviations including, but not limited to, the following. 1. Failure to perform repackaging of API under appropriate CGMP to avoid potential cross-contamination.

During your API repackaging and relabeling operations, including highly potent drugs such as testosterone, estradiol, betamethasone, tamoxifen, and opioids, your firm failed to conduct adequate cleaning validation studies to demonstrate that your cleaning procedures for your (b)(4) non-dedicated “cabins” (production rooms) are adequate to prevent potential cross-contamination.

For example, your firm was unable to provide a completed cleaning validation study to support your current cleaning practices. During the inspection, you acknowledged that your 2008 cleaning validation study did not represent your current cleaning practices and your cleaning procedures needed to be revalidated. You provided your 2020 cleaning validation protocol’s cabin risk assessments in which Cabin (b)(4) was determined to be the worst case scenario for potential product carryover. Swabbing locations were identified based on risk level for contamination. You provided our investigators with preliminary results for niacin and progesterone (a potent compound) residue yielding carryover levels that significantly exceeded the allowable specification. Your firm informed investigators that you were in the process of conducting a supplemental validation.

Your firm failed to ensure that your equipment is adequately cleaned. For example, during the inspection, after the cleaning activities were documented as complete, our investigators observed visible powder residue on non-dedicated equipment ((b)(4) of the containment hood) following the repackaging of progesterone. Investigators also observed that the cleaning log for Cabin (b)(4) was (b)(4) during repackaging of lidocaine HCl, even though the cleaning activities had not been initiated. You later stated that an employee destroyed the cleaning log and were unable to provide a copy to our investigators.

In your response, you provided a follow-up cleaning validation report in which you only assessed the carryover of niacin swab samples but not progesterone, which was included in your initial cleaning validation. The lack of progesterone (b)(4) is concerning considering the failing residue results you provided to investigators would yield unacceptable levels of progesterone cross-contamination. Additionally, the niacin sample data you provided was limited to only the surfaces of (b)(4) containers even though you had detected unacceptable levels of drug residue in other areas of production that were not included in your current validation. Further, you stated that you are in the process of revising cleaning procedures including destruction steps for cytotoxic compounds. You also stated that you commit to performing additional cleaning validation activities and will evaluate the segregation of certain materials repackaged in specific rooms.

Your response is inadequate because you failed to demonstrate that your cleaning procedures are adequate to prevent cross-contamination of repackaged API. You did not conduct a comprehensive risk assessment to determine the potential cross-contamination of various API you distributed and failed to detail interim plans to ensure that your equipment is adequately cleaned while cleaning revalidation studies were in progress.

Inadequate removal of active ingredients and residues from manufacturing equipment during cleaning can result in cross-contamination of your API.

In response to this letter, provide:

• A comprehensive, independent retrospective assessment of your cleaning effectiveness to evaluate the scope of cross-contamination hazards. Include the identity of residues, other manufacturing equipment that may have been improperly cleaned, and an assessment whether cross-contaminated products may have been released for distribution. The assessment should identify any inadequacies of cleaning procedures and practices and encompass each piece of manufacturing equipment used to manufacture more than one product.

• A corrective action and preventive action (CAPA) plan, based on the retrospective assessment of your cleaning program, that includes appropriate remediations to your cleaning processes and practices, and timelines for completion. Provide a detailed summary of vulnerabilities in your process for lifecycle management of equipment cleaning. Describe improvements to your cleaning program, including enhancements to cleaning effectiveness, improved ongoing verification of proper cleaning execution for all products and equipment, and all other needed remediations.

• Appropriate improvements to your cleaning validation program, with special emphasis on incorporating conditions identified as worst case in your drug manufacturing operation. This should include but not be limited to identification and evaluation of all worst-case:

o drugs with higher toxicities o drugs with higher drug potencies o drugs of lower solubility in their cleaning solvents o drugs with characteristics that make them difficult to clean o swabbing locations for areas that are most difficult to clean o maximum hold times before cleaning

In addition, describe the steps that must be taken in your change management system before introduction of new manufacturing equipment or a new product.

• A summary of updated standard operating procedures (SOPs) that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment.

• A summary of all results obtained from testing retain samples from each batch for cross-contamination of potent compounds. If such testing reveals substandard quality drugs, take rapid corrective actions, such as notifying customers and product recalls.

Your investigations into out-of-specification (OOS) test results were inadequate. You failed to investigate OOS results or implement adequate CAPA. For example, your firm did not initiate an investigation into OOS bioburden counts from your water system (which is used as a drug component). Your test procedure stated that actions should include the review of historical data, (b)(4) sampling and testing frequency, identification of the microorganisms, and quarantine of the equipment used and drugs made since the last passing test result date. On June 5, 2020, production (b)(4) bioburden counts of approximately (b)(4) per milliliter (CFU/mL), which exceeds your firm’s action limit of no more than (b)(4) CFU/mL. You did not initiate an investigation.

In your response, you acknowledged that CAPAs (including (b)(4) investigations) are "(b)(4)" and stated that you would conduct a retrospective analysis of results and determine appropriate actions. You failed to perform an investigation into the failing results to evaluate potential root causes, assess risk to patient safety and product quality, determine the scope and magnitude of the discrepancies, and implement and verify effectiveness of CAPAs.

Inadequate investigations may result in not identifying or mitigating the root causes of nonconformances and does not ensure consistent production of safe and effective drugs.

For more information about handling failing, OOS, out-of-trend, or other unexpected analytical results and documentation of your investigations, see FDA’s guidance document Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/investigating-out-specification-test-results-pharmaceutical-production. In response to this letter, provide:

• A retrospective, independent review of all invalidated OOS (including in-process and release/stability testing) results for U.S. products currently in the U.S. market and within expiry as of the date of this letter and a report summarizing the findings of the analysis, including the following for each OOS: o Determine whether the scientific justification and evidence relating to the invalidated OOS result conclusively or inconclusively demonstrates causative laboratory error. o For investigations that conclusively establish laboratory root cause, provide rationale and ensure that all other laboratory methods vulnerable to the same or similar root cause are identified for remediation.

• For all OOS results found by the retrospective review to have an inconclusive or no root cause identified in the laboratory, include a thorough review of production (e.g., batch manufacturing records, adequacy of the manufacturing steps, suitability of equipment/facilities, variability of raw materials, process capability, deviation history, complaint history, batch failure history). Provide a summary of potential manufacturing root causes for each investigation, and any manufacturing operation improvements.

• 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. Failure of your quality unit to exercise its responsibility to ensure the API manufactured at the facility are in compliance with CGMP.

Your quality unit (QU) failed to perform several critical functions to ensure that the API you repackage and distribute meets CGMP requirements. For example, investigators observed computers connected to CGMP-related laboratory equipment that allowed changes to or deletion of data generated to support the release of drugs without restriction.

In addition, during the inspection you acknowledged that your QU did not qualify the contract laboratories you used to support product release due to resource issues. This is a repeat observation from your 2017 inspection.

In your response, you stated you will evaluate and implement the necessary actions to ensure that your equipment used in CGMP-related operations is compliant with 21 CFR Part 11. We acknowledge your commitment to qualify your contract laboratories and immediately hire additional QU personnel to support supplier qualification.

Your response is inadequate because simply addressing laboratory equipment deficiencies is insufficient to achieve overall CGMP compliance. These steps are only effective if you establish and follow appropriate procedures and systems that ensure your QU reviews all production and control data and associated audit trails as part of the batch release process. Further, you failed to assess how the deficiencies noted above may have affected drug quality or identified how additional personnel will adequately remediate your QU deficiencies.

An adequate QU overseeing all CGMP operations is necessary to ensure consistent drug quality.

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 o Also describe how top management supports quality assurance and reliable operations, including but not limited to timely provision of resources to proactively address emerging manufacturing/quality issues and to assure a continuing state of control.

• 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 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 Certificates of Analysis (COA) instead of testing (b)(4) for strength, quality, and purity, specify how you will robustly establish the reliability of your supplier’s results through initial validation as well as (b)(4) re-validation. In addition, include a commitment to always conduct at (b)(4) specific identity test for (b)(4) incoming component lot.

• 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.

FDA considers the expectations outlined in ICH Q7 when determining whether API are manufactured in conformance with CGMP. See FDA’s guidance document Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients for guidance regarding CGMP for the manufacture of API at https://www.fda.gov/media/71518/download.

Based upon the nature of the deviations we identified at your firm, we strongly recommend engaging a consultant qualified to evaluate your operations 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.

The deviations cited in this letter are not intended to be an all-inclusive list of deviations that exist at your facility. You are responsible for investigating and determining the causes of any deviations and for preventing their recurrence or the occurrence of other deviations.

Correct the deviations cited in this letter promptly. Failure to promptly correct these deviations may result in legal action without further notice including, without limitation, seizure and injunction. Unresolved deviations in this warning letter may also prevent other Federal agencies from awarding contracts.

Failure to address deviations may also cause FDA to withhold issuance of Export Certificates. FDA may withhold approval of any new applications or supplements listing your firm as a drug manufacturer until any deviations are completely addressed and we confirm your compliance with CGMP. We may re-inspect to verify that you have completed your corrective actions.

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 deviation 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.

Please address your reply via email to: ORAPHARM3_RESPONSES@fda.hhs.gov

Attention: Tina M. Pawlowski, Compliance Officer U.S. Food and Drug Administration Division of Pharmaceutical Quality Operations III

Your written notification should refer to the Warning Letter Case Number above (#624255). If you have questions regarding the contents of this letter, please contact Tina M. Pawlowski at (313) 393-8217.