Amneal Pharmaceuticals, LLC – 709894

Delivery Method: VIA Electronic Mail Reference #: 320-25-104 Product: Drugs Recipient:

Recipient Name

Mr. Chintu Patel

Recipient Title

Co-Chief Executive Officer

Amneal Pharmaceuticals, LLC

50 Horseblock Road
Brookhaven, NY 11719-9509
United States

chintu@amneal.com Issuing Office: Center for Drug Evaluation and Research (CDER)

United States

Warning Letter 320-25-104

August 27, 2025

Dear Mr. Patel:

The United States Food and Drug Administration (FDA) inspected your drug manufacturing facility, Amneal Pharmaceuticals Private Limited, FEI 3018907202, located at 506 Survey No., near Sachana Kalyanpura Road Palli, Gujarat, India, from March 10 to 19, 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 April 3, 2025, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondences.

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).

Your firm failed to conduct an adequate investigation into recurring problems with visible particulate matter contamination. In 2024, your firm initiated an investigation when two batches of ropivacaine hydrochloride injection, supplied in polypropylene bags, exceeded your acceptance criteria for visual inspection. You identified the polypropylene bags as the source of the inordinately high levels of particulate contamination (predominately, white fibers). You performed an additional visual inspection and conducted a risk assessment that you believed justified releasing these batches. However, your risk assessment was inadequate as it minimized the severity associated with particle contamination in a sterile injectable drug product that can be administered into the epidural space. Your assessment failed to properly evaluate the potential impact of visible particulates on patient safety, as it did not adequately consider the route of administration and patient population receiving the product.

The presence of particulate matter in epidural injectable products can pose significant health risks to patients. These risks are of particular concern for patients receiving long-term epidural therapy. There is a reasonable probability that particulate matter in the epidural space may cause an epidural inflammatory process, epidural abscess, or meningitis. Depending on the location of the epidural injection, the particles could potentially cause damage to the spinal cord including spinal cord infarction or permanent nerve injury.

Your firm was aware of the risk of particulate contamination from the polypropylene bags purchased from your vendor for more than a year prior to your 2024 investigation. You had rejected several batches of a sterile drug product after investigating particulate contamination in late 2022 and early 2023. Your investigations found that the polypropylene bags were the source of the visible white fibers and noted difficulties in detecting these fibers when performing visual inspection. Notably, for multiple batches, your firm continued to detect visible fiber particles during acceptable quality limit inspections of limited sample sizes following performance of visual inspections.

However, you continued to use these polypropylene bags to produce sterile injectable drug products and did not implement appropriate corrective action and preventive action (CAPA) to prevent recurrence.

Based on your investigations into particulate contamination, you relaxed the “major defects” rate from no more than (NMT) (b)(4)% to NMT (b)(4)%, and the overall rejection limit from NMT (b)(4)% to NMT (b)(4)%. You implemented these significantly relaxed limits due to the high rate of particulate contamination in polypropylene bag lots received from your unreliable vendor. The inappropriately high tolerance for defective polypropylene bags accommodated the use of poor-quality polypropylene bags in the production of parenteral drug product batches.

It is unacceptable to increase lot acceptance specifications to excessive levels to enable use of unsuitable polypropylene bags received from your supplier.

In your response, you indicate that, on March 26, 2025, you filed a Field Alert Report for two lots of ropivacaine hydrochloride injection, USP, 500 mg/100 mL infusion bags due to particulate contamination. You also initiated a recall of these two lots on April 18, 2025. The company announcement was posted to the FDA website: https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/amneal-pharmaceutical-llc-issues-nationwide-recall-ropivacaine-hydrochloride-injection-usp. However, these actions were initiated only after FDA identified these problems during the current inspection.

You also indicate that you will be revising your major defect and total defect limits for polypropylene bag visual inspection from NMT (b)(4)% to NMT (b)(4)%, and NMT (b)(4)% to NMT (b)(4)%, respectively, and will reject batches that fail to meet your acceptable quality limit after visual inspection. These defect levels remain unacceptably high.

Furthermore, the health hazard assessment included in your response minimized the severity of risks associated with particle contamination in a sterile injectable drug product that can be administered into the epidural space.

We encourage the use of suitable (b)(4) visual inspection methods for particulates to augment the 100% (b)(4) visual inspection program. (b)(4) methods should be rigorously studied and qualified to assess their capability and robustness under various conditions, including machine settings, container-closure sizes, defect types, product characteristics, and other variables. In addition, any use of (b)(4) particulate inspection as an adjunct method does not supplant the need for 100% (b)(4) visual inspection. It is essential that a final visual inspection program ensures reliable detection of not only particulates, but various other defects (e.g., container or closure abnormalities, cracks, volume, crimping issues, atypical (b)(4), discoloration, bubbles, and any other appearance defects).

It is important that significant quality defects, including visible particulate contamination, are appropriately evaluated and investigated. Visible particulates in injectable products should be avoided through appropriate preventive measures built into your process design and production controls.

In response to this letter, provide:

• A comprehensive 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 unit (QU) oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.
• A comprehensive, independent review of your materials system, including but not limited to:
  o An evaluation of all suppliers of materials (components, containers, and closures) to determine if they are reliable and appropriately qualified.
  o An assessment of all materials to determine whether they are consistently of acceptable quality.
  o A review to ensure assigned expiration or retest dates are appropriate (supported by data).
  o An assessment of the adequacy of the supplier qualification program, and its selection, qualification, and disqualification provisions.
• Based on a thorough review, provide a summary of your systemic CAPA to remediate the vendor qualification program and prevent use of unsuitable components, containers, and closures.
• A commitment to have a third-party review your firm’s defect categorization pertaining to the visual inspection program, including defining critical, major, and minor defects.
• 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.

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.

• Identification of interim steps and controls to ensure lots being produced and distributed into U.S. commerce are essentially free of visible particulate matter.
• Revision of your risk assessment procedures to ensure thorough evaluation of potential patient impact, and address factors including but not limited to route of administration, patient population, and particle characteristics.
• Training for all relevant personnel on revised policies, procedures, and other associated items.

2. Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160(b)).

During our inspection, we observed the preparation and reading of bacterial endotoxin tests and identified numerous deficiencies:

• Failure to completely discharge the micropipette solution during preparation of water for injection samples, which may compromise the accuracy and reproducibility of the test results.
• Transfer of gel-clot sample tubes from the incubator to the waste container in a single rapid motion during microbiological analysis, without the crucial pause required to inspect the firmness of the gel for endotoxin detection.
• The analyst responsible for the (b)(4) verification of the gel-clot assessment was unable to adequately observe or verify the process due to the primary microbiologist’s rapid assessment. Despite this basic deficiency, the secondary analyst signed off on the verification.
• Inadequate documentation practices when recording sample results of bacterial endotoxin tests for water for injection, including non-contemporaneous documenting of negative sample results and assigning a passing result to a positive control sample prior to the actual observation and confirmation of the result.

In your response, you state that you revised various procedures, provided associated training, retested reserve samples of potentially impacted drug products, and purchased new equipment to increase laboratory automation.

Your response is inadequate due to its limited scope, which primarily addressed the specific deficiencies identified during the FDA inspection. You did not conduct a comprehensive evaluation to determine if similar deficiencies exist in other laboratory operations or address additional opportunities for laboratory equipment automation.

It is imperative that your organization conducts a more thorough and systemic review of all laboratory processes, testing methodologies, equipment capabilities, and documentation practices to ensure compliance with CGMP and prevent recurrence of similar issues in the future.

In response to this letter, provide:

• A comprehensive 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 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.

Quality Unit Authority

Significant findings in this letter indicate that your QU is not fully exercising its authority and/or responsibilities. Your firm must provide the QU with the appropriate authority and sufficient resources to carry out its responsibilities and consistently ensure drug quality.

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.

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. 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 Amneal Pharmaceuticals Private Limited, FEI 3018907202, located at 506 Survey No., near Sachana Kalyanpura Road Palli, Gujarat, India, 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.1 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 3018907202 and ATTN: CDR Frank Verni, Compliance Officer.

Sincerely,
/S/

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

cc: 

Mr. Sandeep Raktate, President (Operations)
Sandeep.Rakate@amneal.com

_______________

1 Under program enhancements for the Generic Drug User Fee Amendments (GDUFA) reauthorization for fiscal years (FYs) 2023-2027, also known as the GDUFA III Commitment Letter, your facility may be eligible for a Post-Warning Letter Meeting to obtain preliminary feedback from FDA on the adequacy and completeness of your corrective action plans.

Source