Catalent Indiana, LLC

The United States Food and Drug Administration (FDA) inspected your drug manufacturing facility, Catalent Indiana, LLC, FEI 3005949964, at 1300 South Patterson Drive, Bloomington, Indiana, U.S., from June 23 to July 14, 2025.

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 August 4, 2025, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

During our inspection, our investigators 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).

You failed to conduct adequate investigations into drug product failures and discrepancies. Your investigations frequently lacked data supporting the assigned root cause(s), were not adequately expanded to include all potentially affected drug products, were not formally or adequately documented in your deviation system, and/or did not assess the effectiveness of corrective actions taken. Your inadequate investigations often concluded that no drug product was impacted because finished sterile drug product test results (e.g., sterility, endotoxin, and environmental monitoring) were within specifications. For example:

Extrinsic Mammalian Hair

Beginning in August 2023, you observed more than 20 deviations related to extrinsic “mammalian hair” contamination in or around the stopper region of vials or (b)(4), including in direct contact with the drug product, from nearly (b)(4) batches of drug products following visual inspection. These deviations represented at least (b)(4) drug products for multiple customers. Mammalian hair is an extrinsic particle, could indicate microbial contamination and generally is considered to render the product adulterated. You did not initiate timely investigations in response to this contamination. Additionally, you did not identify trends, in part due to the limited search terms and timeframes specified in your procedures. Further, you failed to fully evaluate or implement effective corrective actions and preventive actions (CAPA) with your stopper suppliers to mitigate hair contamination.

Of note, your quality unit (QU) did not reject commercial batches associated with mammalian hair and released them for distribution to your customers after you attempted to cull out contaminated units. Despite your attempts to remove contaminated units, you continued to receive complaints from customers who observed mammalian hair contamination in drug products they received from you. Since Novo Nordisk acquired this facility, at least (b)(4) batches of finished drug product associated with mammalian hair contamination were also released to your customers.

Your initial investigations into contamination looked at potential sources in your facility but ultimately identified the contamination as likely originating from your stopper suppliers. While we recognize that you worked with your suppliers to reduce the likelihood of mammalian hair contamination events, we are concerned that Novo Nordisk released batches in which your customers found mammalian hair contamination. Notably, in a number of instances, your customers ultimately rejected batches after you distributed the batches to them.

Your response acknowledges the continued use of pre-shipment stopper samples (i.e., tailgate samples) for incoming quality control inspection and proposes revisions to procedures associated with your supplier qualification program. Additionally, you describe a specialized inspection protocol focused on inspecting (b)(4) stoppers from (b)(4) lots received from one of your suppliers, (b)(4), plant), and extending the protocol to your other stopper suppliers’ sites.

Your response is inadequate. You do not provide the revised supplier qualification program or the specialized incoming stopper inspection protocol and supporting data as evidence to ensure effective CAPAs were promptly initiated. While heightened testing for a limited amount of time or limited number of lots provides minimal short-term assurance, it cannot be sunsetted until you have adequate data to demonstrate your supplier(s) has adequately remediated routes of mammalian hair contamination.

Invalidated Media Fills

You failed to initiate timely and thorough investigations into unexplained batch terminations.

Since November 2023, you terminated more than five media fill batches representing (b)(4) Filling Line. Following two of the terminations for stoppering issues and an extrinsic particle, you failed to open a deviation or an investigation at the time of each failure, as required by your SOPs. During the inspection, you subsequently initiated one deviation record that reported the failure to initiate individual investigations for the two terminated media fills.

Your response indicates there was no impact to the SISPQ (Safety, Identity, Strength, Purity, Quality) of the terminated media batches or to any customer batches. You indicate these media fills were re-executed successfully with passing results.

Your response is inadequate. You do not provide the investigations with a root cause that justifies aborting and re-executing the media fills, nor do you provide the corrective actions taken for each terminated media fill to ensure effective CAPAs were promptly initiated. Additionally, you failed to initiate a deviation record to capture the lack of an investigation for each of the terminated media fills, resulting in an undercounting of the deviations for failure to follow your applicable SOPs.

In response to this letter, provide:

• A comprehensive, independent assessment of your overall system for investigating complaints, deviations, discrepancies, 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:o significant improvements in investigation competencies o root cause evaluation and scope determination o CAPA effectiveness o quality assurance oversight o written procedures o ensuring all phases of investigations are appropriately conducted.

The independent assessment should place special emphasis on reviewing your complaint system. Complaints from all customers (clients, healthcare professionals, patients) should be retrospectively reviewed to assess the system and to inform the development of an appropriate CAPA action plan. • An independent review of rejected vials for extrinsic particles, including an update on any analysis of retains performed by your firm related to customer complaints. • An independent assessment and remediation plan for your CAPA program. Provide a report that evaluates whether the program includes effective root cause analysis, ensures CAPA effectiveness, analyzes investigation trends, improves the CAPA program when needed, implements final quality assurance unit decisions, and is fully supported by executive management. • Your CAPA plan to implement routine, vigilant operations management oversight of facilities and equipment. This plan should ensure, among other things, prompt detection of equipment/facilities performance issues, effective execution of repairs, adherence to appropriate preventive maintenance schedules, timely technological upgrades to the equipment/facility infrastructure, and improved systems for ongoing management review.• A comprehensive review of root cause investigations for deviations related to mammalian hair found in your products, including incoming inspection activities and subsequent CAPA activities. Provide supporting documents including data generated and effectiveness evaluations.• A comprehensive, independent review of root cause investigations for media fill batch terminations since November 2023 and subsequent CAPA activities. Provide supporting documents, including data generated and effectiveness evaluations. In addition, regarding the terminated media fill due to the extrinsic particle contamination, provide identification of the extrinsic particle and whether it is associated with the mammalian hair contamination events.• The most updated status on your supplier quality investigations for stoppers and any remediation efforts.

2. Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)).

Visual Inspection Program

Your firm has not established adequate provisions to address individual defect types, nor do you trend defects at the individual level from (b)(4) visual inspection. Instead, your firm relied on limits established for three general criticality categories (i.e., critical, major, minor).

Your response indicates your firm will establish quality monitoring limits for individual defect types using existing defect data, such as hair, glass, and atypical particulate.

Your response is inadequate. You do not adequately explain how you will adopt a more vigilant oversight of batch data, including a timely and appropriate response whenever extrinsic matter is identified in your sterile drug products.

(b)(4) Contamination Hazards

Your firm found that the “most probable root cause” of an environmental monitoring failure of a (b)(4) sample was equipment surfaces that were occluded during (b)(4) decontamination, and that the route of contamination occurred during execution of an atypical intervention involving (b)(4) changes and (b)(4). These parts are integral to stopper seating in the (b)(4). Your own risk assessments advise against interventions that can disturb potentially occluded surfaces. In another case of apparent insufficient (b)(4) exposure, your firm named occluded surfaces on wrapped (b)(4) within the (b)(4) as the potential cause of contamination of (b)(4) used to install (b)(4).

Additionally, as part of post-filling environmental monitoring activities, the (b)(4) are sampled using (b)(4) contact plate, sampling (b)(4) with one sweeping sampling motion. With this method, you are unable to attribute contamination events to specific (b)(4). Also your firm’s use of contact plates is not as effective as using swab methods. These factors increase the risk of failing to detect microbial contaminants for these critical product-contacting surfaces.

Your response is inadequate. We acknowledge your firm plans to expand swab sampling to all processing lines to replace use of contact plates to sample irregular surfaces. However, your firm does not commit to performing a thorough re-evaluation of your (b)(4) to more comprehensively identify and reduce any exposure to occluded surfaces and high-risk interventions that may pose a contamination hazard.

Deficient Stopper Evaluation

Your firm was inappropriately relying on pre-shipment samples of (b)(4) stoppers. Although you recognized stoppers as a possible contributing factor for contamination with mammalian hairs in finished drug products in July of 2024, a limited, enhanced sampling strategy for one of your suppliers was not implemented to monitor incoming stoppers until May 2025. Your data indicated that while stoppers from (b)(4) were the primary source of extrinsic particles, they were not the only source of foreign matter. So, while you increased sampling oversight at (b)(4), you did not increase it for other stopper suppliers. You did not address enhanced or comparative sampling of stoppers from your other suppliers. We acknowledge you increased sampling from other suppliers as a corrective action after this inspection.

Your response is inadequate. You indicate that you initiated an expanded incoming quality control inspection protocol for stopper batches to evaluate their quality. However, you did not provide the protocol, nor did you specify how your other suppliers will be included in the expanded protocol. Additionally, you did not include an assessment to increase the initial sample size or to tighten the ANSI inspection levels, given the criticality of the stopper defect. Further, you indicate that future batches found during visual inspection of finished drug products would undergo a re-inspection followed by tightened acceptable quality limit to ensure defective units would be removed. However, you did not provide the procedure for reinspection.

In response to this letter, provide:

• A remediation plan that better assures ongoing management oversight throughout the manufacturing lifecycle of all drug products. Provide a more data-driven and scientifically sound program that identifies sources of process variability, and assures that manufacturing (including both production and packaging) operations meet appropriate parameters and quality standards. This includes, but is not limited to, evaluating suitability of equipment for its intended use, ensuring quality of input materials, determining the capability and reliability of each manufacturing process step and its controls, and vigilant ongoing monitoring of process performance and product quality.• The procedure(s) and/or policy that address the oversight of batch data whenever extrinsic matter is identified in your sterile drug products. • The protocol and results to date for the expanded incoming quality control inspection of stoppers from all suppliers to evaluate their quality and confirm they are free of visible particulate.• The re-inspection protocol for finished drug products with heightened acceptable quality limit.• The protocol and results to date for the implementation of swab sampling for (b)(4) for all active filling lines.• A review of (b)(4) exposure to decontamination methods as well as permitted interventions, including: o a retrospective historical review of routine interventions and atypical interventions to determine their riskso a comprehensive identification of locations in (b)(4) that are not reliably exposed to (b)(4) decontamination (i.e., occluded surfaces)o your plan to reduce occluded surfaces, where feasibleo review of currently permitted interventions and elimination of high-risk interventions entailing equipment manipulations during production campaigns that expose the ISO 5 environment to surfaces not exposed to a validated decontamination processo redesign of any intervention that poses an unacceptable contamination risk.• A comprehensive risk assessment of all contamination hazards with respect to your aseptic processes, equipment, and facilities, including an independent assessment that includes, but is not limited to:o material flows (throughout all rooms used to conduct and support sterile operations)o (b)(4) setup procedures and practices, and preparation for decontamination o equipment placement and ergonomicso (b)(4)o (b)(4) integrity• A detailed remediation plan with timelines to address the findings of the contamination hazards risk assessment. Describe specific tangible improvements to be made to aseptic processing operation design and control.

During our inspection, it was observed that your firm was inappropriately relying on pre-shipment, or tailgate, samples of stoppers. These samples upon which you used to make quality decisions were shipped directly from your stopper supplier to you for analysis. Samples for the testing of quality attributes are to be taken at your facility from containers after receipt to ensure they are representative of the components in question.

For more information about sampling and testing of representative samples to ensure suitability prior to use in manufacturing, see FDA’s current guidance document Questions and Answers on Current Good Manufacturing Practice Requirements | Control of Components and Drug Product Containers and Closures at https://www.fda.gov/drugs/guidances-drugs/questions-and-answers-current-good-manufacturing-practice-requirements-control-components-and-drug.

We recognize that Novo Nordisk acquired the Catalent facility after contamination events had started to occur. And we recognize that Novo Nordisk is investing significant resources into this facility. However, we are concerned that release of potentially contaminated drug products continued to occur well after the Novo Nordisk acquisition. While you continue efforts to remediate this facility, we recommend you analyze quality assurance oversight structures at other Catalent facilities purchased as part of the acquisition. Additionally, representatives of Novo Nordisk informed FDA (b)(4). We ask that you provide a timeline for this streamlining of operations and coordinate with the CDER’s Drug Shortages Staff, as appropriate.

FDA held a teleconference with your firm on September 26, 2025. During this call, FDA informed you that our inspection revealed that the drug products produced at Catalent Indiana, LLC, determined to contain extrinsic mammalian hairs do not meet CGMP requirements and are considered adulterated. Your firm initially released adulterated batches for distribution based on your assertion that product testing results were adequate. After discussions with FDA during the teleconference, Novo Nordisk made a commitment to contact your customers regarding recall of their drug products. As a result, recalls were initiated for (b)(4) on (b)(4), (b)(4) on (b)(4), and (b)(4) on (b)(4).

After you submit your response to this warning letter, we recommend you reach out to this office to arrange for a teleconference to discuss your corrective and preventive actions in detail. Please direct your request to Christina Reyes at christina.reyes@fda.hhs.gov and cc: CDER-OC-OMQ-Communications@fda.hhs.gov.

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.

If you are considering an action that is likely to lead to a disruption in the supply of drugs produced at your facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately, at drugshortages@fda.hhs.gov, so that FDA can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuances or interruptions in your drug manufacture under 21 U.S.C. 356C(b). This also allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products.

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 days1 . 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 3005949964 and ATTN: Carrie A. Hughes.