Shiva Analyticals Private Limited - 707857 - 07/23/2025

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Warning Letter 320-25-96

July 23, 2025

Dear Mr. Nagaraj Ranganathan:

The United States Food and Drug Administration (FDA) inspected your contract testing laboratory, Shiva Analyticals (India) Private Limited, FEI 3006192929, located at Plot 24D (P) and 34D KIADB Industrial Area, Hoskote, Bangaluru, Karnataka State, 562114, India, from January 20 to 24, 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, the drug products you tested 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 13, 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).

Your firm did not adequately investigate out-of-specification (OOS) results. Your investigations into laboratory incidents and OOS results lacked adequate scientific rationale to support root cause determinations and did not extend into previously analyzed batches. New test results were used as the basis for invalidating OOS results without also performing an adequate root cause investigation.

In addition, our inspection found that your firm did not take adequate effective corrective action and preventive action (CAPA) to reduce specific recurring human errors that have contributed significantly to the number of laboratory incidents and OOS investigations in the past 3 years.

In your response, you acknowledge that standard operating procedures (SOPs) for handling OOS results and laboratory incidents are inadequate to effectively evaluate trends, identify causes, and enable implementation of suitable holistic CAPA. You also acknowledge that there was no procedure to assess human errors and that had contributed to significant trends not being assessed by your quality unit (QU). You commit to improve CAPA effectiveness based on your newly implemented trend evaluation program.

Your response is inadequate because you do not adequately address how you will ensure that laboratory OOS results are adequately investigated using scientifically sound and appropriate procedures for retesting, hypothesis testing, re-sampling, and root cause analyses.

For more information about handling failing, out-of-specification, out-of-trend, or other unexpected 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/media/158416/download.

As a contract laboratory, you must comply with the CGMP regulations that apply to operations you perform, including but not limited to, those that address the operations of your quality control unit, laboratory, investigation system, and documentation system.

FDA considers contractors as extensions of manufacturer’s own facility. Your failure to comply with CGMP may affect the quality, safety, and efficacy of the products you test for your clients. It is essential that you understand your responsibility to operate in full compliance with CGMP, and to inform all your customers or clients of significant problems encountered during the testing of their drugs. Your clients (e.g., drug manufacturers, application sponsors), in turn, must provide you with all the scientific data and information needed to support reliable testing and method implementation.

For additional information refer to FDA Guidance for Industry Contract Manufacturing Arrangements for Drugs: Quality Agreements (https://www.fda.gov/media/86193/download).

In response to this letter, provide:

• A retrospective, independent review of all laboratory incident investigations and OOS results for all finished product tests. Identify any products which may be intended for the United States for the last 3 years 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.
  o For all OOS results found by the retrospective review, identify any potential root cause and indicate if your customer was notified of the failure. Include the original test, date of test, testing result, customer, and reason for initiating an investigation.
  o The written response from your customers following notification of the testing failure(s).
• An independent assessment of your overall system for investigating deviations, incidents, complaints, OOS 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, scope determination, root cause evaluation, CAPA effectiveness, QU oversight, and written procedures.
  o Address how your firm will ensure all phases of investigations are appropriately conducted.
  o Revised OOS investigation procedures with these and other remediations.
  o Informing clients of batches for which the invalidation of an OOS result may not be adequately supported by your investigation.

2. Your firm failed to establish adequate written responsibilities and procedures applicable to the quality control unit and to follow such written procedures applicable to the quality control unit (21 CFR 211.22(d)).

Your QU failed to ensure the reliability and integrity of analytical testing data. For example, our investigators observed many torn and discarded original CGMP documents inside your main waste disposal area. These discarded original documents included, but were not limited to, analytical balance weighing printouts, pH meter printouts, and analytical method verification records. The discarded balance printouts were observed containing test weights that were different from those weights documented in testing of raw materials and finished products (including those intended for the U.S. market).

Additionally, during the evaluation of audit trail review for your MassLynx software, our investigator documented that your laboratory analysts performed hundreds of entries related to “Add/Modify/Delete peaks,” and “Alter existing file on disk” user privileges between January 16, 2022, and January 23, 2025.

Data integrity is critical throughout the CGMP data lifecycle, including in the creation, modification, processing, maintenance, archival, retrieval, and transmission of data. Customers rely on the integrity of the laboratory data that you generate to make decisions regarding drug quality.

It is important to maintain strict control over electronic data to ensure that any additions, deletions, or modifications of information in your electronic records are authorized and appropriately documented.

In your response, you identify lack of quality oversight and lack of procedures for the proper control of CGMP documents as root causes for these deficiencies. You state that you are performing a protocol-based study to review the sample and system audit trails.

Your response is inadequate. You do not provide a scientific evaluation of whether discarded data may have caused reported test results to fail drug product specifications.

Your firm’s quality systems are inadequate. See FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations for help in implementing adequate Quality Unit (QU) in your laboratory operation to meet the requirements of CGMP regulations 21 CFR, parts 210 and 211 at https://www.fda.gov/media/71023/download.

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 Oversight and approval of investigations.
• A complete and independent assessment of documentation systems used throughout your laboratory operations to determine where documentation practices are insufficient. Include a detailed CAPA plan that comprehensively remediates your firm’s documentation practices ensuring you retain attributable, legible, complete, original, accurate, contemporaneous records throughout your operation.
• An 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.

CGMP Consultant Recommended

Based upon the nature of the violations we identified at your firm, we strongly recommend that your firm 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 violations that exist at your facility. You are responsible for investigating and determining the causes of these violations and for preventing their recurrence or the occurrence of other violations.

Correct any violations promptly. FDA may withhold approval of new applications or supplements listing your firm as a drug contract testing laboratory until any violations 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.

Failure to address any violations may also result in the FDA refusing admission of articles manufactured by your clients and tested at Shiva Analyticals (India) Private Limited, 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 appears 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. 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 3006192929 and ATTN: Joan Johnson.

Sincerely,
/S/

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