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Warning Letter 320-25-32

January 23, 2025

Dear Mr. Shen:

The U.S. Food and Drug Administration (FDA) inspected your contract testing laboratory, Center for Instrumental Analysis of China Pharmaceutical University, FEI 3005037448, at Zhongyang Road, No. 24 Tongjiaxing Road, Nanjing, Jiangsu, from September 18 to 20, 2024.

This warning letter summarizes significant deviations from Current Good Manufacturing Practice (CGMP) for active pharmaceutical ingredients (APIs).

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, the APIs 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 September 23, 2024 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

During our inspection, our investigators observed specific deviations including, but not limited to, the following.

1. Failure to have laboratory control records that include complete data derived from all laboratory tests conducted to ensure your API and intermediates complies with established specifications and standards.

Your firm is a contract testing laboratory that analyzes APIs and intermediates, including samples of crude (b)(4), (b)(4), and (b)(4) USP, for the presence of (b)(4) using ¹H Nuclear Magnetic Resonance spectroscopy (NMR).

Your firm failed to ensure that laboratory testing records were complete. For example, your test record of samples, “(b)(4) (USP) Experiment Records” for Lot (b)(4) contained only two lines of numbers with no explanation headers or titles. During the inspection, you explained that these numbers represented the testing date, lot number, and processing data for (b)(4) samples you analyzed for your customers. Further, the testing records did not document sample preparation, the test procedure(s), and system suitability. Additionally, not all the testing records were reviewed by a second person prior to the results being shared with your customers.

Your firm also failed to ensure that laboratory records were readily available during the inspection. You informed our investigators that your (b)(4) ¹H NMR testing data before November 2023 were stored on external hard drives. However, when our investigators requested to review this data, you stated that it might be difficult to locate the data because there were many archived hard drives and only the archiving personnel could retrieve the data. As a result, you did not provide any CGMP data stored on the external hard drives for review during the inspection. We acknowledge that you provided limited data after the inspection.

Additionally, your firm failed to ensure that your computerized systems, such as the computers used to control to the NMR equipment, and to store raw data files or process data, have adequate controls in place to prevent unauthorized access or changes to data. The NMR equipment was also used for academic teaching and research, and it appears that various users shared one login ID with full administrative access.

In your response, you acknowledge your failure to keep adequate records and have now established procedures outlining requirements for laboratory documentation and sample tracking. You also state that you implemented user management settings on your computerized system and completed the system validation.

Your response is inadequate because the procedures appear to lack sufficient detail to be effective. Moreover, you did not consider a retrospective review and risk assessment to evaluate the potential impact of the inadequate documentation and lack of access controls, along with their associated risks, on the validity of your test results.

In response to this letter, provide:

• A complete assessment of documentation systems used throughout your laboratory operations to determine where documentation practices are insufficient. Include a detailed corrective action and preventive action plan that comprehensively remediates your firm’s documentation practices to ensure you retain attributable, legible, complete, original, accurate, contemporaneous records throughout your operation.
• A risk assessment summarizing the potential impact of inadequate documentation on product quality, and a commitment to notify customers of any deficiencies.
• A risk assessment summarizing the potential impact of lack of access controls of the computers and NMR equipment on product quality, and a commitment to notify customers of any deficiencies.

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.

2. Failure of your quality unit to ensure that drugs are appropriately tested and the results are reported.

You failed to establish a quality unit (QU), including defining responsibilities and procedures applicable to a QU. Additionally, when asked during the inspection whether you track any deviations and laboratory errors, you responded that you only provide testing results. Your laboratory director stated that the firm is not involved in CGMP activities, however, your customers used your data for CGMP purposes.

Without an adequate QU and quality system in place, there is inadequate assurance that controls are implemented to ensure that your CGMP testing operations are performing in a state of control.

In your response, you state that you established a quality department and provided supporting documentation, including standard operating procedures. Your response is inadequate as your procedures appear to lack sufficient detail and comprehensive coverage of all the systems supporting your CGMP testing operations.

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 A complete and final review of the laboratory record for each sample and its related information before the QU disposition decision.
  o Oversight and approval of investigations and discharging of all other QU duties to ensure validity of the laboratory test results without having negative impact on identity, strength, quality, and purity of your customers’ drug products.
• A comprehensive, independent assessment of your change management system. This assessment should include, but not be limited to, your procedures to ensure changes, such as changes to or deviations from a validated test method, are justified, reviewed, investigated, and approved by your QU. Your change management program should also include provisions for determining change effectiveness.

An adequate QU overseeing all elements of CGMP is necessary to consistently ensure drug product quality. Your firm’s quality systems are inadequate. See FDA’s current thinking on quality systems in the FDA guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations at https://www.fda.gov/media/71023/download for help in implementing quality systems and risk management approaches.

Drug Testing Ceased

We acknowledge your commitment to cease all drug testing services for the U.S. market. In response to this letter, clarify whether and when you intend to resume drug testing for the U.S. market at this facility in the future.

If you plan to resume any CGMP operations regulated under the FD&C Act, notify this office before resuming your operations. You are responsible for resolving all deficiencies and systemic flaws to ensure your firm is capable of ongoing CGMP compliance.

Responsibilities of a Contract Testing Lab

FDA considers contractors as extensions of the manufacturer’s own facility. Your failure to comply with CGMP may affect the quality, safety, and efficacy of the drugs you test for your customers. It is essential that you understand your responsibility to operate in full compliance with CGMP, and that you inform all your customers of any out-of-specification results or significant problems encountered during the testing of these drugs.

CGMP Consultant Recommended

Based upon the nature of the deviations we identified at your firm, you should engage a consultant qualified to evaluate your operations 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

Correct any deviations promptly. FDA may withhold approval of new applications or supplements listing your firm as a manufacturer until any deviations are completely addressed and we confirm your compliance with CGMP. We may re-inspect to verify that you have completed corrective actions to any deviations.

Failure to address any deviations may also result in the FDA refusing admission of articles manufactured by your customers and tested at the Center for Instrumental Analysis of China Pharmaceutical University, at Zhongyang Road, No. 24 Tongjiaxing Road, Nanjing, Jiangsu, 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 deviations 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 3005057567 and ATTN: Emily Wu.

Sincerely,
/S/

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