Unexo Lifesciences, Private Limited - 688163 - 11/06/2024

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Warning Letter 320-25-11

November 6, 2024

Dear Mr. Bansal:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Unexo Life Sciences, Private Limited, FEI 3013514280, located at B16, Sector 4, Bawana Industrial Area, New Delhi, Delhi, 110039 India, from May 1 to 14, 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 June 04, 2024 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

1. Your firm’s quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22).

Your firm failed to provide adequate oversight and ensure the reliability of data related to the quality of finished drug products manufactured at your facility. Your quality assurance (QA) department was not exercising its basic responsibilities for the oversight and control over the adequacy and reliability of all CGMP data at your facility. In addition, your QA department is responsible for ensuring your employees understand and adhere to data integrity principles.

A. You 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). For example, batch production records were found torn in plastic bags on your rooftop. Among the torn records were missing batch production records that you were not able to locate during the inspection for your drug product, (b)(4) Patch, batches (b)(4) which were intended for the U.S. market. The torn records also included duplicate incomplete batch production records with the same batch numbers and issuance dates as the batch records already provided to the investigators, such as (b)(4) Patch batch (b)(4) and (b)(4) Patch batch (b)(4) also intended for the U.S. market.

Your executive management admitted to not having all the batch records for the released drug products and batch production records were “retrospectively prepared” to provide to the investigators.

In your response, you commit to investigate the retrospectively created batch records and perform assessments regarding your data integrity practices and capabilities of your quality unit (QU) organization to meet CGMP compliance and “sustain a quality culture”. In addition, you indicate you reconciled batch records for all batches manufactured ((b)(4) batches) for the U.S. market within expiry, and these records are under review by a qualified independent consultant. You state batches (b)(4) will be rejected and destroyed.

Your response is inadequate. You do not share in detail how you will detect and investigate for non-contemporaneously prepared records. Considering you created records during the inspection, FDA is concerned regarding the validity of your reconciled records generated at your facility for all products within expiry. Additionally, you do not provide a rationale for only rejecting and destroying select batches, and you do not include adequate assurance the batches in U.S. distribution are consistently manufactured to ensure the products are safe and effective.

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

B. You failed to ensure that laboratory records included complete data derived from all tests necessary to ensure compliance with established specifications and standards (21CFR211.194(a)). You lacked raw data to support the product testing for released drug products. For example, your internal test report for (b)(4) Patch product, batch (b)(4), was missing the individual results for assay, patch weight, peel strength analysis and rolling ball analysis. Your quality management acknowledged you did not have the data for the peel strength and rolling ball analyses for batch (b)(4), and provided no explanation when asked how you released the batch without the data.

In your response you state that you initiated a deviation to investigate instances where the raw data is not available, and have a third-party consultant perform a comprehensive assessment on data integrity practices at your site. Also, as part of your current controls, you explain the analyst checks the raw data and results against the specification for compliance, while the laboratory manager verifies preparations, analyzed results, and approves the individual test.

Your response is inadequate. You do not provide a copy of your initiated deviation with a detailed investigation plan for identifying incomplete laboratory records. You do not provide sufficient details describing how data integrity deficiencies will be detected and documented by your third-party consultant. Additionally, it is unclear whether your raw data review process has adequate oversight by your QA to ensure ALCOA (attributable, legible, contemporaneously recorded, original or a true copy, and accurate) principles are followed throughout your laboratory operations.

Reliability of data is fundamentally compromised when there is a failure to record or maintain complete and accurate records of test results, or conditions associated with all tests. Furthermore, the lack of reliable data compromises the QA’s ability to exercise its function of ensuring compliance to applicable standards.

C. Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records (21 CFR 211.68(b)). For example, your QC analyst had the ability to manipulate results, dates, and images of in-house and vendor stamp approvals on component certificate of analyses (COAs) from third-party contract laboratories, including the means to duplicate the stamp approval across multiple COAs for components, such as (b)(4), lot (b)(4), lot (b)(4).

In your response, you explain the analyst involved with access to unauthorized test data was removed from regular duties, however, your response is inadequate because it does not explain in detail how appropriate controls will be implemented for maintaining data integrity and defining user privileges for computer systems, including measures for appropriate oversight and maintenance of data and results from third-party contract laboratories.

Customers rely on the integrity of the laboratory records you create, approve, and manage. It is important to maintain strict control over CGMP electronic data to ensure that all additions, deletions, or modifications of information in your electronic records are authorized and appropriately documented.

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 manufacture. 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 an independent third-party consultant 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 assessment of all raw data and results in which your QC analyst(s) had the ability to manipulate results, dates, and images of in-house and vendor stamp approvals for data integrity inaccuracies and deficiencies.
    o A comprehensive retrospective evaluation of the nature of the 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 corrective action and preventive action (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 QA function, along with expertise from outside entities whenever needed).
    o A status report for any of the above activities already underway or completed.

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

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 production and 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.

2. 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)).

Our investigators observed unclean air conditioner vents above production areas that include the (b)(4) machine in which (b)(4) drug products are exposed to the air flowing from the unclean vents.

In your response, you state the air conditioners are used to cool and recirculate the air from the air-handling unit, and you commit to investigate the cleaning deficiency for all your air conditioners in the facility.

Your response is inadequate because it does not include a copy of the investigation and corrective actions indicated. Also, your response is unclear because it does not specify if you intend to identify the residue on the unclean air conditioner vents and evaluate your cleaning procedures. Additionally, you do not provide an assessment of previously manufactured drug products or testing of reserve samples from impacted batches.

In response to this letter, provide:

• A copy of your initiated deviation, UDF/PRD/2024/024.
• A copy of your cleaning procedure and most recent cleaning verification studies of the air conditioners at your facility.
• 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 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, 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 that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment.
• 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.

Access to Information During Inspection

During the inspection, the only computer alleged to have all the electronic CGMP data, which was not backed up, was not available because the QC analyst took the computer home and could not be reached after multiple attempts. Additionally the QC manager’s computer was requested to review COAs and test procedures, however, when the laptop was provided all recent files and drives were apparently deleted before being presented to the investigators. This limited FDA’s access to records for inspection to evaluate the CGMP compliance status of your facility.

Additionally, you reported your QC analyst was receiving COAs from your third-party contract laboratory in Word format via WhatsApp on his personal cell phone, and he confirmed to have deleted all the received COAs. You do not have appropriate controls to assure integrity and traceability of your COAs from your third-party contract laboratories.

When an owner, operator, or agent delays, denies, limits, or refuses an inspection, the drugs may be deemed adulterated under section 501(j) of the FD&C Act. See FDA’s guidance document Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug or Device Inspection at https://www.fda.gov/media/86328/download.

Production Suspended and Drug Recall

We acknowledge your decision to temporarily cease the manufacturing of products made at your facility intended for U.S. distribution.

On October 8, 2024, FDA held a teleconference with you recommending you initiate a voluntary recall of all batches of drug product manufactured from your facility in distribution and intended for the U.S. market that remain within expiry.

On October 9, 2024, you committed to a voluntary recall of certain drugs due to the significant CGMP violations. Provide an update on your efforts to initiate the recall.

In response to this letter, clarify whether you intend to resume manufacturing drugs for the U.S. market at this facility in the future.

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 corrective actions and preventive actions (CAPAs).

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.

(b)(4)

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 continuing to refuse admission of articles manufactured at Unexo Life Sciences, Private Limited, located at B16, Sector 4, Bawana Industrial Area, New Delhi, Delhi 110039, 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 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 3013514280 and ATTN: Sai Dharmaraj.

Sincerely,
/S/

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