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Warning Letter 320-24-51

July 11, 2024

Dear Mr. Dai:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Jiangsu Hengrui Pharmaceuticals Co., Ltd., FEI 3007373503, at 38 Huanghe Road, Economic and Technological Development Zone, Lianyungang, from January 8 to 16, 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 product 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 March 7, 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’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. For example, our inspection documented serious quality assurance (QA) deficiencies, such as discarded original CGMP records found stacked in a bag underneath a vehicle and in a nearby trash can, as well as your production manager’s unrestricted access to blank production batch records and other CGMP documents without QA issuance. Your 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 batch issuance procedures and data integrity principles.

Your production manager repeatedly accessed and printed uncontrolled blank copies of production records, media fill records, visual inspection records, process validation batch records, and cleaning validation records saved on his computer or through your document management system. When production employees reported an “error” in a record, your production manager printed a blank copy and had the employee transcribe the information on the new record and discarded the old record. There is no assurance that archived data is original or accurate.

In your response, you indicate you will perform a risk re-assessment on your document management software for better controls. You created new procedures for document destruction, revised existing procedures, and trained your employees on the new and revised procedures.

Your response is inadequate. Your response does not include a comprehensive assessment into employees creating new records to correct errors, and you do not identify the root cause or scope of the “errors” made with potential impact to CGMP documents and data.

In response to this letter, provide:

• A comprehensive assessment and remediation plan to ensure your QA department 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 QA 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 QA disposition decision
    o Oversight and approval of investigations and discharging of all other QA duties to ensure identity, strength, quality, and purity of all products
• Describe how senior and executive management supports QA and reliable operations, including but not limited to, timely provision of resources to proactively address emerging manufacturing/quality issues and to assure a continuing state of control.
• A complete assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed corrective and preventive action (CAPA) plan that comprehensively remediates your firm’s documentation practices to ensure you retain contemporaneous, attributable, legible, complete, original, and accurate records throughout your operation.
• Describe your plans to prevent manipulation and enhance control of all CGMP records. Specifically, describe your reconciliation and integrity improvements for all CGMP records that may be in loose form or otherwise vulnerable to manipulation. Based on an independent review by a qualified consultant, provide a gap analysis and specific CAPA measures you will take to safeguard integrity of records (e.g., recording data in logbooks, pre-paginated documents, and validated electronic systems).

2. Your firm failed to perform operations within specifically defined areas of adequate size and to have separate or defined areas or such other control systems necessary to prevent contamination or mix-ups in aseptic processing areas (21 CFR 211.42(c)(10)).

Inadequate Design of Facility

There is inadequate physical separation between Grade A and Grade B classified areas to ensure appropriate conditions for the aseptic manufacture of sterile drugs at your facility. For example, the “transitional” Grade A areas on either side of the (b)(4) conventional filling machine are where production employees transfer (b)(4) sterile equipment for assembly and (b)(4) vials of drug products for (b)(4). The transitional Grade A areas and surrounding Grade B areas are separated only by an (b)(4). This design does not provide adequate protection and can compromise the sterility of the (b)(4) drug products and the sterile equipment.

Additionally, your drug product contact equipment and utensils are sterilized and transferred (b)(4) through this Grade A and Grade B open air transition area which may compromise sterility.

Furthermore, you lacked smoke studies to demonstrate the airflow in the transition between the Grade A and Grade B areas outside of the filling machine. Thorough smoke studies are essential to evaluate and qualify your aseptic processing operations and ensure appropriate implementation of needed design remediations.

Lastly, the cart used to transfer (b)(4) drug product vials to the (b)(4), is open on both the front and rear sides. Air turbulence was visible in the smoke study video when the transfer cart moved through the Grade B area. Furthermore, during the transfer of (b)(4) vials, non-viable particles are not being monitored in the transfer cart, only a settling plate is used for environmental monitoring.

In your response, you commit to (b)(4) between the Grade A transitional area and the adjacent Grade B area on the (b)(4) of the filling machine to provide better protection. You acknowledge in your response that airflow in the areas between the Grade A transitional area and Grade B area are not characterized and you commit to evaluate these airflows through execution of smoke studies. You commit to (b)(4) sterilized equipment and validate the new loading patterns of the (b)(4) equipment.

Your response is inadequate. Although you commit to (b)(4) of the barrier of the Grade A laminar flow transition area you do not provide a risk assessment on the contamination hazards and lack of sterility assurance of having inadequate protection between the room Grade A area and Grade B area. In addition, the smoke study provided demonstrating the air visualization between the Grade A and Grade B areas is not dynamic and does not provide an operational view of the airflow during production. Furthermore, in your response and change control document you do not propose placing sterilization (b)(4) protection on all sterilized equipment transferred into the Grade A and Grade B transition areas.

In response to this letter, provide:

• Comprehensive risk assessment of all contamination hazards with respect to your aseptic processes, equipment, and facilities, including an independent assessment that includes, but is not limited to:
    o All human interactions within the ISO 5 area
    o Equipment placement and ergonomics
    o Air quality in the ISO 5 area and surrounding room
    o Facility layout
    o Personnel Flows and Material Flows (throughout all rooms used to conduct and support sterile operations)
• A detailed remediation plan with timelines to address the findings of the contamination hazards risk assessment. Describe specific tangible improvements to be made to aseptic processing operation design and control.

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 a consultant to audit your operation and assist in meeting FDA requirements. In response to this letter, provide:

A. A comprehensive investigation into the extent of the inaccuracies in data records and reporting. Your investigation should include:
• 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.
• 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.
• 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.
• A comprehensive retrospective evaluation of the nature of the testing and manufacturing 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.

B. 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.

C. A management strategy for your firm that includes the details of your global corrective action and preventive action plan. Your strategy should include these elements:
• 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.
• 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.
• 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.
• 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.
• A commitment to have a qualified consultant conduct extensive annual audits, for at least two years, to assist in evaluating CAPA effectiveness after you have executed your data integrity remediation protocol.
• Inform FDA if you will be hiring a Chief Integrity Officer who is fully empowered to maintain anonymity of employees who report data integrity concerns and with authority to investigate potential breaches.
• A status report for any of the above activities already underway or completed.

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 Jiangsu Hengrui Pharmaceuticals Co., Ltd., 38 Huanghe Road, Economic and Technological Dev Zone, Lianyungang, Jiangsu, China 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 3007373503 and ATTN: Erika V. Butler.

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.