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  5. Indoco Remedies Limited - 691594 - 12/16/2024
  1. Warning Letters

WARNING LETTER

Indoco Remedies Limited MARCS-CMS 691594 —

Delivery Method:
Via Email
Reference #:
320-25-23
Product:
Drugs
Recipient:
Recipient Name
Ms. Aditi Kare Panandikar
Recipient Title
Managing Director
Indoco Remedies Limited

Indoco House, 166, C.S.T Road
Kalina Santacruz (E)
Mumbai 400098
India

Issuing Office:
Center for Drug Evaluation and Research (CDER)

United States

Warning Letter 320-25-23

December 16, 2024

Dear Ms. Panandikar:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Indoco Remedies Limited, FEI 3005124189, at L 32 33 - 34 I D C Verna Industrial Road, Vasco Da Gama, Goa, India, from July 16 to 26, 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 August 15, 2024 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 record and justify any deviations from required laboratory control mechanisms (21 CFR 211.160(a)).

You lacked adequate controls to assure the reliability of microbiological testing results. For example:

A. Numerous non-viable dark particles were observed in (b)(4) plates used for microbiological analyses in your laboratory.

B. Non-viable dark particles were observed on filter (b)(4) used for (b)(4) microbiological testing.

C. Media plates prepared in-house did not consistently possess smooth surfaces needed to ensure maximum contact of test articles to facilitate the growth of any microbiological organisms present.

D. Analysts did not consistently ensure filter (b)(4) on media plates during microbiological testing needed to ensure maximum contact of filter (b)(4) to facilitate the growth of any microbiological organisms present.

In your response, you indicate you discontinued use of, and discarded, the implicated filter (b)(4) lot associated with the observed particulate matter and are attempting to identify an alternate vendor. You also performed a retrospective review of (b)(4) testing data, and you do not identify any similar instances of air bubbles being observed during testing. You conclude any incidence of failing to ensure filter (b)(4) on media plates during testing are “rare” and do not impact product quality.

Your response is inadequate. You do not holistically assess microbiological laboratory conditions and practices and their impact on the reliability of microbiological test results. Your retrospective review protocol to identify instances of (b)(4) filter (b)(4) during testing is insufficient as it relies on documentation of events that were not being recorded by your analysts. Additionally, the conclusion of the retrospective review stating there was no impact on product quality lacks scientific justification, in that contact between the filter (b)(4) and the media is essential for the growth and identification of any microbiological organisms on the filter (b)(4).

In response to this letter, provide:

  • 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 retrospective, independent review of all microbiological test data for products currently in the U.S. market and within expiry as of the date of this letter to assess the impact of the observed laboratory conditions and practices on the reliability of the microbiological test data. The review should include testing performed in support of qualification and validation activities currently relied upon to support the manufacture of drug products for the U.S. market.
  • A comprehensive, independent review of your material system to determine whether all suppliers of equipment and test supplies 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 equipment and test supplies.

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)).

Our review found deficiencies in video recordings of airflow (smoke) studies executed in the ISO 5 areas including on Line (b)(4) at the empty vial (b)(4) and the nozzle (b)(4). Specifically, the presence of excessive smoke prevented visualization of airflows. The inadequate visualization of airflow is a repeated from the 2023 inspection of your facility.

In your response, you commit to providing additional training to personnel responsible for the execution of airflow studies and to conduct new studies.

Your response is inadequate. Your previous actions taken to prevent recurrence were inadequate. You do not commit to reassessing your training program or the failure of previously implemented corrective action and preventive action (CAPA) to remediate the airflow studies. In response to this letter, provide:

  • An independent assessment of the training provided to personnel responsible for the execution of airflow study protocols.
  • An independent assessment of the CAPA effectiveness in response to previous adverse findings associated with your conduct of airflow studies. The assessment should include the determination of root cause(s), CAPA, and a description of how the CAPA effectiveness will be determined.
  • A revised Line (b)(4) airflow study protocol, completed protocol report, the airflow study videos, and an independent assessment of the aforementioned protocol, complete protocol report, and airflow study videos.

3. Your firm failed to establish an adequate system for maintaining equipment used to control the aseptic conditions (21 CFR 211.42(c)(10)(vi)).

Our review found unsuitable conditions in ISO 5 areas where aseptic processing is conducted. For example:

A. Rough metal surfaces and an incomplete (b)(4) were observed on the Line (b)(4) Restricted Access Barrier System (RABS) framework in the area above the stopper loading chute.

B. (b)(4) or (b)(4) were observed protruding through the interior of RABS (b)(4) on the Line (b)(4) RABS in the area above the stopper loading chute.

C. (b)(4) conduit was present with exposed wires and not properly secured to the adjoining surface in the Line (b)(4) filtration area.

You previously remediated the Line (b)(4) RABS in response to the unsuitable physical condition of Line (b)(4) RABS (b)(4) documented in the 2023 inspection of this facility. Your remediation activities failed to wholistically address the conditions of the Line (b)(4) RABS.

In your response, you report Lines (b)(4) were inspected for additional “uneven rough surfaces,” commit to inspecting Lines (b)(4) in the future, and updating procedures to require the inspection of areas for the presence of uneven and rough surfaces. You report an inspection of Lines (b)(4) for areas that are difficult to clean and identified a root cause for the electrical conduit not being properly secured as “improper verification” of the conduit. You also report the conduct of “Awareness Training” of personnel in your Engineering department.

Your response is inadequate. You do not:

  • Evaluate the training of personnel responsible for inspection activities.
  • Perform a comprehensive assessment of all lines and equipment therein to ensure appropriate design and suitability of materials of construction and equipment.
  • Comprehensively assess procedures governing equipment design to ensure appropriate user requirements are established.
  • Assess the quality unit’s (QU) role in assuring the suitability of the facility and equipment therein.

In response to this letter, provide 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. Explain how you will use qualified third-party consultant(s) to assist you in development, execution, and assessment of CAPA effectiveness for these activities.

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).

Your investigations into product quality defect complaints are not consistently and scientifically supported and rely on flawed analyses to reach conclusions on product quality impact. For example:

A. Your investigation into complaints of dispensing tip (nozzle) blockage associated with (b)(4) solution USP (b)(4)% ((b)(4)) and (b)(4) and (b)(4) solution USP, (b)(4)mg/ml and (b)(4)mg/mL ((b)(4)) concluded the tip blockage phenomena was due to improper storage by patients. You stated the ensuing exposure of product solutions to air resulted in the (b)(4) excipient in the formulations forming a film or precipitating and blocking the dispensing tips. Your investigation is deficient for reasons including, but not limited to:
1. Neither of the scientific publication sources cited in your investigation support your root cause.
2. Your experimental study compared the effect of atmospheric exposure of a freshly prepared solution by your research and development group against samples of innovator product that expired approximately 2.5 years earlier.

B. Your investigations into complaints of (b)(4) and (b)(4) drug products missing tips or being received empty by patients were repeatedly determined to have no impact on product quality. This conclusion conflicts with the finished product quality attributes for fill volume.

In your response, you report your (b)(4). You also report the revision of your complaint handling procedure and your plan to evaluate the function of equipment used to detect missing container closure system components.

Your response is inadequate. You do not provide sound scientific data or other relevant information supporting your conclusion that atmospheric exposure of (b)(4) in these products is solely responsible for the tip blockage complaints. You also did not adequately address empty units being received by patients.

In response to this letter, provide:

  • A scientifically sound investigation into the tip blockage issue. The investigation should identify root cause(s), CAPA, and the mechanism(s) for determining CAPA effectiveness.
  • An independent evaluation of your product quality complaint handling procedures and practices including relevant procedures and practices used by contracted third parties that perform complaint handling activities on your behalf. The independent evaluation should include identification of all deficiencies, assignment of appropriate CAPA, and the mechanism(s) for determining CAPA effectiveness.

5. Your firm failed to establish an adequate quality unit and the responsibilities and procedures applicable to the quality control unit are not in writing and fully followed (21 CFR 211.22(a) and 211.22(d)).

Warning and error messages in the Empower Message Center included in your chromatography data software are not reviewed. For example, during the 20-day period between December 26, 2023, and January 15, 2024, the following error messages were registered in the Empower Message Center:

A. Approximately 33 instances of “Injection --- cannot be altered. It belongs to a sample set which is currently being acquired”

B. Approximately 60 instances of “User Abort”

C. Approximately 18 instances of “Stop Flow key was pressed”

The procedures governing chromatography analyses do not require the review of all audit trail data. Your personnel were unaware of the requirement to review the Empower Message Center data in Plant (b)(4) analyses during the inspection. The error and warning messages in the Empower Message Center can be an indicator of problems with equipment and method suitability.

In your response, you report revisions to the procedures governing chromatography analyses in Plant (b)(4) and Plant (b)(4) to require the review of data in the Empower Message Center. You also report the conduct of a “comprehensive review” of data in the Empower Message Center in Plant (b)(4) and Plant (b)(4) and corresponding risk assessments. You also indicate you do not review the Empower Message Center as required by your procedure governing chromatography analyses in Plant (b)(4).

Your response is inadequate. Your review of data in the Empower Message Center failed to identify unexpected discrepancies including approximately 32 of the 33 instances of “Injection --- cannot be altered. It belongs to a sample set which is currently being acquired” messages generated between December 26, 2023, and January 15, 2024, were associated with the same user. You also did not identify and investigate the relatively high number of “User Abort” messages generated over the same timeframe.

In response to this letter, provide an independent, retrospective assessment of Empower Message Center data for the last three years from the initial date of inspection and a report summarizing the findings of the analysis. The analysis should include trending of pertinent data including, but not limited to, specific users, methods, and equipment.

Repeat Violations at Facility

In a previous inspection, dated February 20 to February 28, 2023, FDA cited similar CGMP violations. You proposed specific remediation for these violations in your response. Repeated failures demonstrate that executive management oversight and control over the manufacture of drugs is inadequate.

Ineffective Quality System

Significant findings in this letter demonstrate that your firm does not operate an effective quality system in accord with CGMP. In addition to the lack of effective management oversight of your laboratory operations, we found your QU is not enabled to exercise proper authority and/or has insufficiently implemented its responsibilities. Executive management should immediately and comprehensively assess your company’s global manufacturing operations to ensure that your systems, processes, and products conform to FDA requirements.

CGMP Consultant Recommended

Based upon the nature of the violations we identified at your firm, you should engage a consultant qualified 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 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 Indoco Remedies Ltd., L 32 33 - 34 I D C Verna Industrial Road, Vasco Da Gama, Goa, 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 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 3005124189 and ATTN: Jason F. Chancey.

Sincerely,
/S/

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

_________________

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.

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