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Warning Letter 320-23-19

July 25, 2023

Dear Mr. Sonaje:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Centaur Pharmaceuticals Private Ltd., FEI 3008861619, at Plot No.4, International Biotech Park, Phase-II, Hinjewadi, Pune, Maharashtra, India from January 30 to February 8, 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 February 28, 2023 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

During our inspection, our investigator 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 and maintenance procedures for non-dedicated (b)(4) equipment (b)(4), including your (b)(4) and (b)(4), are inadequate. Our inspection identified residues of what appeared to be different products on direct and indirect product contact surfaces, including those located inside (b)(4) systems, (b)(4) units (b)(4), and (b)(4). Your firm acknowledged that sections of the (b)(4), (b)(4), and (b)(4) have not been cleaned or examined for cleanliness since they were installed over 14 years ago. During the inspection, your analytical testing confirmed these residues contained multiple active ingredients. Furthermore, during the inspection, you collected residue samples at the end of placebo batches and subsequent cleaning, which also demonstrated active ingredient cross-contamination on surfaces.

(b)(4) over dirty surfaces can facilitate contamination of the drug being processed in an (b)(4). Robust design, cleaning, and maintenance of this and other equipment is critical to prevent cross-contamination.

The inspection also noted missing or faulty (b)(4) in (b)(4), as well as material back flow, which resulted in equipment contamination. For example, you stated the manually operated (b)(4) inside (b)(4) number CP/PT/(b)(4)-01 in (b)(4) Area (b)(4) is always in the open position. You also indicated the buildup of powder inside the (b)(4) and (b)(4) of this equipment was caused by the back flow of materials during equipment (b)(4).

As a result of these inspectional findings, you communicated with your client, Breckenridge Pharmaceutical, Inc., who initiated a recall of numerous batches of alprazolam tablets and clobazam tablets manufactured in your (b)(4). We also acknowledge the recall initiated by (b)(4) of (b)(4) tablets you manufactured.

In your response, you state all (b)(4) and (b)(4) used for multiple products have been taken out of service, and you have cleaned, replaced, and improved (b)(4) processing and cleaning equipment. You also indicate you have revised your cleaning procedures, and you explain that (b)(4) and (b)(4) are now appropriately inspected to verify cleanliness, which is recorded in your cleaning records. Further, you state you have manufactured placebo batches to assess the potential for cross-contamination of drug products. Through your testing of control and placebo batch samples, you conclude there is no product quality impact on commercially distributed batches of alprazolam tablets and clobazam tablets. You also state there is no risk to patients’ health and safety, and “no probability of contamination of material.”

Your response is inadequate. Cross-contamination is not uniform, and your testing of control samples and placebo batches failed to scientifically prove your products are free of contaminants from your visibly dirty equipment. Additionally, you state the active ingredient recovered after placebo batch manufacturing was from “mostly indirect contact surfaces.” You did not sufficiently address contamination recovered from product contact surfaces, and you failed to acknowledge that other locations and other sampling may reveal higher levels of contamination. FDA is aware of other instances where such lack of cleaning in (b)(4) handling has led to cross-contamination between drug products.

In response to this letter, provide:

• 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 assessment whether cross-contaminated products may have been released for distribution. The assessment should identify any inadequacies of 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 of your cleaning program, that 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.
• Appropriate improvements to your cleaning validation program, with special emphasis on incorporating conditions identified as worst case in your drug manufacturing operation. This should include but not be limited to identification and evaluation of all worst-case:

    o drugs with higher toxicities
    o drugs with higher drug potencies
    o drugs of lower solubility in their cleaning solvents
    o drugs with characteristics that make them difficult to clean
    o swabbing locations for areas that are most difficult to clean
    o maximum hold times before cleaning

In addition, ensure use of appropriate limits that take into account recovery study results and describe the steps that must be taken in your change management system before introduction of new manufacturing equipment or a new product.

• A summary of updated standard operating procedures (SOPs) that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment.
• A holistic review of cleaning procedures and the associated cleaning validation strategy for all manufacturing equipment to determine whether similar deficiencies exist.

2. 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 (d)).

Your quality unit (QU) failed to adequately implement the facility’s quality function and ensure quality oversight. For example:

A. Inadequate cleaning procedures

Your procedure to clean (b)(4) lacked sufficient requirements to clean (b)(4) and (b)(4), which had not been cleaned since they were installed more than 14 years ago. Also, your procedure for visually ensuring cleanliness of equipment failed to identify visible contamination.

In your response, you state that you have improved your standards for visual verification of (b)(4) equipment part cleanliness. The verification is then documented in the equipment cleaning record. You also indicate you have updated your cleaning procedures.

Your response is inadequate. You failed to provide evidence you have implemented CAPA measures to ensure written procedures are sufficiently written and reviewed for adequacy prior to implementing.

In response to this letter, provide:

• A comprehensive, independent 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

B. Inadequate Investigations

Your QU failed to adequately investigate extraneous peaks observed in long-term stability samples tested for dissolution by high-performance liquid chromatography (HPLC). Your investigation dated January 24, 2020, identified varying intensities in the peak response, and noted the peak eluted in some tablets, but not in others from the same batch. You determined the root cause to be interference from excipients used during manufacturing and concluded the peaks do not impact product quality. However, you provided no scientific explanation for this conclusion.

In your response, you describe further investigations that you performed, and conclude the inconsistent peaks were due to insufficient saturation of the filter used to prepare samples.

Your response is inadequate. You lacked an appropriate assessment of your procedures for investigating discrepancies. Furthermore, you failed to provide evidence that you have implemented sufficient corrective actions or interim controls to ensure investigations contain adequate root cause determination, CAPA, and effectiveness checks.

In response to this letter, provide:

• A comprehensive assessment of your overall system for investigating deviations, discrepancies, complaints, out-of-specification (OOS) 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 assurance oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.
• A detailed, independent assessment of all test methods to ensure they include specific instructions to ensure repeatability and system suitability, are supported by adequate validation (or verification, for United States Pharmacopeia (USP) compendial methods) studies and are appropriate for their intended use. The assessment should also determine whether test methods used in the stability program are stability-indicating. The scope of the assessment should encompass any tests conducted by your firm or its contract laboratories.

Drug Recall and Production Suspended

We acknowledge your commitment to temporarily suspend production and distribution of certain drugs intended for the U.S. market. In response to this letter, clarify which products you are continuing to manufacture and distribute to the U.S. market, and whether you intend to resume manufacturing drugs for the U.S. market at this facility in the future.

If you plan to resume manufacturing drugs for the U.S. market, notify this office before resuming your operations.

We also acknowledge recalls of alprazolam tablets and clobazam tablets manufactured at this facility that remain within expiry.

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), and 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 Plot No.4, International Biotech Park, Phase-II, Hinjewadi, Pune, Maharashtra 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 3008861619 and ATTN: Matthew Jensen, Compliance Officer.

Sincerely,
/S/

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