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Warning Letter 320-24-55

August 15, 2024

Dear Mr. Puvvala:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Eugia Pharma Specialities Limited (Unit III), FEI 3008461619, at Plot No.: 4, 34 to 48, EPIP, TSIIC, IDA-Pashamylaram, Patancheru (Mandal), Sangareddy, Hyderabad, Telangana, from January 22 to February 2, 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 February 26, 2024 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

1. 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)).

You failed to ensure the accuracy of data in records for both production and process simulations (media fills). Your procedure requires testing of all (b)(4). While you documented testing of all of the (b)(4), your operators did not test all of the (b)(4) used during manufacturing of sterile injectable drug products. Indeed, in videos retained, this practice was observed for three batches you manufactured. Your operators also did not appropriately document (b)(4) leaks and failures and performed inadequate (b)(4) monitoring. During the inspection, one of the (b)(4) that was not integrity tested failed after three attempts to perform integrity testing.

(b)(4) integrity is critical to preventing product contamination. Routine physical (b)(4) integrity tests should be performed. The monitoring and maintenance program should identify and eliminate any (b)(4) lacking integrity and minimize the possibility of placing a sterile product at risk.

Your operators also falsified environmental monitoring records for the ISO 5 and ISO 7 areas of multiple aseptic filling lines, including for viable active air samples and non-viable particle counts which were not collected in their documented location. Your operators used non-viable particle counts from a different time and place and altered the time to correspond to the desired results in the batch record. These systemic data integrity issues involved numerous production and quality assurance staff and were occurring at your facility for multiple months.

Your response indicates that you are revoking access for the involved employees to the aseptic area while you perform your investigation. However, your response did not adequately address how you plan to ensure individuals responsible for data integrity lapses are removed from positions where they can influence CGMP-related data anywhere in your facility. You also did not provide sufficient information to ensure the integrity of data throughout your production and process simulations.

Document control and data management is critical to CGMP to ensure the completeness, consistency, and accuracy of data. Data should be attributable, legible, contemporaneously recorded, original or a true copy, and accurate (ALCOA) to ensure complete and accurate records are evaluated by the quality unit (QU) to support batch release.

2. Your firm failed to prepare batch production and control records with complete information relating to the production and control of each batch of drug product produced (21 CFR 211.188).

You failed to ensure records for equipment cleaning, disinfection, and sterilization are complete and accurate. For example, operators documented in production records for three batches of sterile injectable drug products that the stopper (b)(4) bowl and cap (b)(4) bowl for your (b)(4) were cleaned and sterilized without performing these activities. Your operators also documented cleaning activities, such as disinfecting the (b)(4), in records without adequately following standard operating procedures and performing these operations.

Your response indicates that production and cleaning activities will be performed under supervision and will also include video review. However, your response is inadequate as it does not address how the video retention period will be sufficient for Quality Assurance to review video footage as part of batch release, in accordance with 21 CFR 211.180(a). Also, you did not adequately address how you will ensure that your equipment records will be controlled for accuracy and completeness.

Complete and accurate batch production and control records are necessary to ensure that manufacturing processes are consistently followed and reproducible. Additionally, incomplete manufacturing records deprive you of the ability to adequately investigate deviations.

Adequate cleaning of the (b)(4) interior is needed for effective decontamination using (b)(4) agents. Appropriate control and maintenance of (b)(4) is needed to minimize the risk to sterile product.

3. 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)).

You failed to ensure your operators adequately follow your written procedures for aseptic behaviors and interventions performed for manufacturing numerous sterile injectable drug products on multiple (b)(4) restricted access barrier system ((b)(4)-RABS) filling lines. For example, your operators were observed performing (b)(4) interventions when (b)(4) were available for use, directly contacting the filling line with their gloved hands, and blocking unidirectional airflow over open vials. Additionally, operators failed to adequately perform clearance of vials impacted by interventions, and there was a pattern of inadequate documentation and underreporting of interventions. For example, your operators failed to remove potentially impacted open vials from your (b)(4)-RABS when glass shards were generated during an intervention.

Your response states that interventions will be monitored and recorded from inside the aseptic filling area to ensure interventions are accurately recorded. Your response is inadequate because it does not adequately address how you will ensure your operators will follow your written procedures to reduce the excessive number of manually intensive interventions performed during manufacturing and ensure adequate clearance of open vials impacted by interventions.

Aseptic processes and procedures should be designed to minimize exposure of sterile articles to the potential contamination hazards of the manufacturing operation. Interventions, particularly those requiring opening (b)(4)-RABS (b)(4), during aseptic processing can increase the risk of product contamination. Supervisory personnel and the QU are responsible for ensuring operators follow established procedures for manufacturing sterile drugs products.

In response to this letter, provide your plan to ensure appropriate aseptic practices and cleanroom behavior during production. Include steps to better assure routine and effective supervisory oversight for all production batches. Also, describe the frequency of quality assurance oversight (e.g., audit) during aseptic processing and other operations.

4. 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 and to implement effective corrective actions and preventive actions (CAPA) to prevent recurrence of vial breakage during manufacturing of sterile injectable drug products. For example, your investigation into the media fill failure, which resulted in 124 contaminated units, concluded that vial breakage led to spilled media at the (b)(4) conveyor and contamination of the (b)(4) and (b)(4). The organisms identified were Staphylococcus epidermidis and Staphylococcus hominii. Notably, your investigation did not adequately consider the operators who performed the cleaning as the likely source of the contamination. Additionally, vial breakage and product spillage were subsequently observed at the same location during production of (b)(4) Injection demonstrating your investigation did not consider design flaws.

Your response states that you are remediating your investigation system, reinvestigating the media fill failure, and evaluating your surface sampling for environmental monitoring. Your response is inadequate because you failed to address how you will ensure appropriate interventions and vial clearance for glass breakage during manufacturing.

Well-documented, thorough, and scientifically sound investigations are necessary to identify the root cause and implement effective CAPA. It is essential to address potential contamination hazards in your manufacturing environment in a timely manner. Any adverse microbiological trends and potential routes of contamination should be identified promptly, allowing for implementation of appropriate follow-up measures to prevent contamination.

In response to this letter provide:

• 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 investigations trends, improves the CAPA program when needed, implements final QU decisions, and is fully supported by executive management.
• An assessment of changes implemented for your manufacturing processes and their effectiveness to prevent glass particles from entering your products.
• Your plan to ensure ongoing equipment and component qualification and continued verification of your filling process to prevent glass breakage during manufacturing.

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 test. 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 acknowledge that you are using independent third-party consultants to audit your operation and assist in meeting FDA requirements. In response to this letter, provide:

• A comprehensive investigation into the extent of the inaccuracies in data records and reporting. Your investigation should include:

    o A detailed investigation protocol and methodology; a summary of all laboratories, manufacturing operations, and systems to be covered by the assessment; and a justification for any part of your operation that you propose to exclude.
    o Interviews of current and former employees to identify the nature, scope, and root cause of data inaccuracies. We recommend that these interviews be conducted by a qualified third party.
    o An assessment of the extent of data integrity deficiencies at your facility. Identify omissions, alterations, deletions, record destruction, non-contemporaneous record completion, and other deficiencies. Describe all parts of your facility’s operations in which you discovered data integrity lapses.
    o A comprehensive retrospective evaluation of the nature of the testing/manufacturing/other data integrity deficiencies. We recommend that a qualified third party with specific expertise in the area where potential breaches were identified should evaluate all 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 CAPA plan. Your strategy should include:

    o A detailed corrective action plan that describes how you intend to ensure the reliability and completeness of all the data you generate including analytical data, manufacturing records, and all data submitted to FDA.
    o A comprehensive description of the root causes of your data integrity lapses including evidence that the scope and depth of the current action plan is commensurate with the findings of the investigation and risk assessment. Indicate whether individuals responsible for data integrity lapses remain able to influence CGMP-related or drug application data at your firm.
    o Interim measures describing the actions you have taken or will take to protect patients and to ensure the quality of your drugs, such as notifying your customers, recalling product, conducting additional testing, adding lots to your stability programs to assure stability, drug application actions, and enhanced complaint monitoring.
    o Long-term measures describing any remediation efforts and enhancements to procedures, processes, methods, controls, systems, management oversight, and human resources (e.g., training, staffing improvements) designed to ensure the integrity of your company’s data.
    o A commitment to have a qualified consultant conduct extensive annual audits, for at least 2 years, to assist in evaluating CAPA effectiveness after you have executed your data integrity remediation protocol.
    o Inform FDA if you will be hiring a Chief Integrity Officer who is fully empowered to receive anonymous complaints from employees reporting data integrity concerns and with the authority to ensure any potential breach is promptly investigated (by independent quality assurance function, along with expertise from outside entities whenever needed).
    o A status report for any of the above activities already underway or completed.

CGMP Consultant

The qualified consultant, as set forth in 21 CFR 211.34, should also perform a comprehensive six-system audit of your entire operation for CGMP compliance and evaluate the completion and efficacy of your CAPAs before you pursue resolution of your firm’s compliance status with FDA.

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. Your firm’s quality systems are inadequate. See FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations for help implementing quality systems and risk management approaches to meet the requirements of CGMP regulations 21 CFR, parts 210 and 211 at https://www.fda.gov/media/71023/download.

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 Eugia Pharma Specialities Limited, FEI 3008461619, at Plot No.: 4, 34 to 48, EPIP, TSIIC, IDA-Pashamylaram, Patancheru (Mandal), Sangareddy, Hyderabad, Telangana, 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).

We request you email CDER-OC-OMQ-Communications@fda.hhs.gov within 5 days of receipt of this letter to schedule a regulatory meeting. Identify your response with FEI 3008461619 and ATTN: Temeka Moore.

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 3008461619 and ATTN: Lynnsey Renn.

Sincerely,
/S/

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

cc: US Agent
Apexa Chudasama
Senior Director, Regulatory Affairs
Eugia US LLC
279 Princeton-Hightstown Road
East Windsor, NJ 08520
E-mail: achudasama@EugiaUS.com
E-mail: usagent@eugiaus.com

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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.