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WARNING LETTER

Natco Pharma Limited MARCS-CMS 672564 —


Delivery Method:
Via Email
Reference #:
320-24-32
Product:
Drugs

Recipient:
Recipient Name
Mr. Rajeev Nannapaneni
Recipient Title
Vice Chairman and CEO
Natco Pharma Limited

Natco House Road No: 2, Banjara Hills
Hyderabad 500034
India

Issuing Office:
Center for Drug Evaluation and Research | CDER

United States

Secondary Issuing Offices

United States


Warning Letter 320-24-32

April 8, 2024

Dear Mr. Nannapaneni:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Natco Pharma Limited, FEI 3004540906, at Kothur Village Rangareddy, Telangana, India, from October 9 to 18, 2023.

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 November 8, 2023 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 clean, maintain, and, as appropriate for the nature of the drug, sanitize and/or sterilize equipment and utensils at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements (21 CFR 211.67(a)).

Your cleaning procedure for your non-dedicated (b)(4) equipment is inadequate. Our investigators observed residue inside the (b)(4) and throughout the (b)(4) of two non-dedicated (b)(4), identified as VS/034 and T/020, and labeled as “cleaned.” You confirmed the presence of multiple active pharmaceutical ingredients (APIs) with values higher than your allowable limit when you sampled and tested these residues. You swabbed similar areas of other (b)(4) equipment and also identified residues of various API throughout the (b)(4).

In your response, you state a potential cause for API residues found in (b)(4) equipment is due to higher (b)(4). Further, your assessment concluded (b)(4) tablets manufactured in the (b)(4) VS/034 are not contaminated with other API residues. Additionally, your response mentions that in August 2022, you implemented a (b)(4) cleaning process to clean the (b)(4) upstream of your (b)(4). However, this cleaning process was implemented for only 3 of the (b)(4) used in drug production.

Your response is inadequate. Cross-contamination is not uniform, and your testing of control samples and placebo batches failed to scientifically prove that your products are free of contaminants from your visibly dirty equipment. You do not sufficiently address contamination recovered from product contact surfaces, and you fail to acknowledge that other locations and other sampling may reveal high levels of contamination. Your reserve sample testing alone is insufficient to determine the scope of the cross-contamination issue and mitigate risks associated with it. A failure to adequately clean (b)(4) units may lead to cross-contamination between drug products.

You do not provide interim control of equipment cleaning for the remaining (b)(4) used to manufacture your drug products. You have not submitted your finished drug products test results to determine the impact of cross-contamination observed during the inspection.

Your response also fails to address the presence of unknown peaks obtained from swab samples collected from the (b)(4) of (b)(4).

In response to this letter, provide the following:

  • A comprehensive, independent retrospective assessment of your cleaning effectiveness to evaluate the scope of cross-contamination hazards. Include the identity of residues, other manufacturing equipment that may have been improperly cleaned, and an expanded assessment to determine whether cross-contaminated product batches may have been released for distribution. The assessment should identify any inadequacies in cleaning procedures and practices and encompass each piece of manufacturing equipment used to manufacture more than one product.
  • A corrective action and preventive action (CAPA) plan, based on the retrospective assessment, includes appropriate remediations to your cleaning processes and practices, and timelines for completion. Provide a detailed summary of vulnerabilities in your process for lifecycle management of equipment cleaning. Describe improvements to your cleaning program, including enhancements to cleaning effectiveness; improved ongoing verification of proper cleaning execution for all products and equipment; and all other needed remediations.

    o In addition to this holistic remediation, provide specific CAPA activities that are being undertaken to effectively remediate the conditions that caused the specific cross-contamination incidents discussed above. Provide an independent review by your consultant that determines the effectiveness of your CAPA, including but not limited to:

 A list of all enhancements to cleaning and maintenance procedures including specific frequencies and locations to be cleaned in all relevant equipment (e.g., (b)(4)).
 Identify any other sources of cross contamination other than (b)(4) equipment, (b)(4) and (b)(4).
 Determine the adequacy of your analytical methodology to identify residual carryover.
 Your investigations into the unknown (unidentified) peaks detected in your reserve samples.
 Supporting evidence to demonstrate that the challenges identified during your study, such as interference of product matrix and co-eluting peaks, were adequately resolved.
 Adequacy of scope of the investigation and its related CAPA.

2. Your firm failed to thoroughly investigate any 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’s investigations into unexplained discrepancies were inadequate. Your quality unit (QU) failed to thoroughly investigate all finished product batches and components associated with unexplained discrepancies. For example:

  • Your investigation related to missing batch record pages for (b)(4) mg powder batch (b)(4) lacked evidence to support your conclusion. (b)(4) critical manufacturing steps were recorded 25 days after production. You concluded that the most probable cause was the inattention of your manufacturing operators.
  • Your firm initiated an investigation due to missing sample weight balance printouts of (b)(4) Tablets batch (b)(4). You changed the sample weight 22 days after analysis. You concluded that the most probable cause was analyst error.

You concluded your investigations without a root cause determination supported by evidence or initiating CAPA.

The inspection also documented questionable practices regarding the disposition and destruction of CGMP records by employees.

In your response, you commit to conduct a review of all investigations from January 2021 to the end of 2023. Your response also indicates you hired a third-party consultant to perform an assessment of your documentation system.

Your response is inadequate. Your response does not include the protocol followed and lacks a comprehensive assessment into the type and extent of records destroyed.

In response to this letter, provide the following:

  • A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, out-of-specification (OOS) results, discrepancies, failure, and records management system. Provide a detailed action plan to remediate your quality system. Your action plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, CAPA effectiveness, quality assurance unit oversight, and written procedures. Address how your firm will ensure that all phases of investigations are conducted appropriately.
  • An independent assessment and remediation plan for your CAPA program. Provide a report that evaluates whether staff possesses proper investigation competencies, effectively conducts root cause analysis, and assures CAPA effectiveness. Also, determine whether your quality system ensures you regularly review investigation trends, implement improvements to the CAPA program when needed, ensure appropriate quality unit decision rights, and receive full executive management that promotes timely lifecycle manufacturing improvements.
  • Submit a full report of the holistic assessment for the inadequacy of investigations and lacking CGMP documentation control for all batches produced from January 2021 until the end of 2023 intended for the U.S. market.

Drug Production Suspended

We acknowledge your commitment to temporarily suspend production of all drugs manufactured on all dedicated and non-dedicated (b)(4) equipment for the U.S. market while you remediate the CGMP violations.

If you plan to resume any manufacturing operations regulated under the FD&C Act, notify this office before resuming your drug manufacturing operations. You are responsible for resolving all deficiencies and systemic flaws to ensure your firm is capable of ongoing CGMP compliance. In your notification to the Agency, provide a summary of your remediations to demonstrate that you have appropriately completed all CAPA.

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 Natco Pharma Limited at Kothur Village Rangareddy, 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 3004540906 and ATTN: Rafael E. Arroyo.

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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