Miami University Department of Chemistry and Biochemistry - 623494 - 04/20/2022

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April 20, 2022

WARNING LETTER
Case # 623494

Dear Dr. Tierney:

The U.S. Food and Drug Administration (FDA) inspected your contract testing laboratory, at Miami University, FEI 3009095423, at 651 East High Street, Oxford, from November 1 to November 5, 2021.

This warning letter summarizes significant deviations from current good manufacturing practice (CGMP) for active pharmaceutical ingredients (API).

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your API 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 29, 2021, response to our Form FDA 483 in detail. We note that when the inspection was initiated, on November 1, 2021, Dr. Richard T. Taylor was the most responsible person onsite. However, during the inspection Dr. Taylor stated that he was no longer in the same role as on the first day of the inspection. Dr. David L. Tierney then stated that he became responsible for the testing performed by the laboratory only as of November 1, 2021.

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

1. Failure to exercise sufficient controls over computerized systems to prevent unauthorized access or changes to data, and failure to have adequate controls to prevent omission of data.

Your firm failed to implement adequate controls to ensure the integrity of data generated at your facility. Your firm is a contract testing laboratory that performs CGMP testing of crude heparin and active pharmaceutical ingredient (API) heparin sodium, USP. Testing performed by your firm, among other things, includes elemental impurity testing via (b)(4) and identity testing via (b)(4). (b)(4) testing of heparin includes analyzing samples for the presence of the contaminant Over-sulfated Chondroitin Sulfate (OSCS), of which historical contamination of heparin has been linked with adverse events, including death.

Immediately before the initiation of the FDA’s inspection, your firm, and the representatives from your heparin sodium, USP, customer, performed an audit. After reviewing the raw (b)(4) test data, your customer’s risk assessment determined that one of your student analysts had “falsified” data. Representatives from your firm, and from your customer, informed FDA investigators that this was the first time the (b)(4) and (b)(4) raw data was reviewed since you initiated CGMP testing at your firm. The falsification of (b)(4) data occurred from approximately 2018 to 2021 and consisted of an analyst entering arbitrary values for sample, spike, and correlation.

Furthermore, in addition to concerns about data falsification, additional data integrity concerns were identified, which include the following:

• All (b)(4) sample results were stored in an uncontrolled folder that could be manipulated by any user.
• The (b)(4) and (b)(4) equipment were used by numerous people at the University, including faculty members and graduate students. All users shared one master login for the (b)(4) which allowed for full administrative access.
• The (b)(4) raw data was not backed-up since CGMP testing began.
• The software that runs the (b)(4) did not have an audit trail.
• The Excel spreadsheet used to calculate spike recovery and final results for the (b)(4) analysis was uncontrolled.
• The software that runs the (b)(4) and (b)(4) equipment was not validated.
• Sample reprocessing was not formally documented, although your firm stated reprocessing did occur.
• In (b)(4) analyses, peaks of interest in the spectrum were chosen (b)(4) and were not covered by an established procedure.

In your response, you stated that the “data manipulation” was associated with a single analyst whose “motivation was exclusively to avoid the reanalysis of samples that did not pass system suitability requirements.” You also stated that the “data manipulation” was not performed to create results that conform to specification where they otherwise did not. However, we do not agree with your conclusion. All the elements identified in the risk exposure assessment for heparin are required to be quantified conclusively, in accordance with USP. A lack of conclusive, quantitative data for any of the elements reported indicates that the product has not been adequately analyzed for pharmaceutical quality. These system suitability failures, among other deficiencies, demonstrate that the results are not reliable, reportable, or suitable to support the quality of heparin drug or drug products. Therefore, you cannot conclude that the results generated were within, or failing, specification.

Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you analyze for your customers. 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/regulatory-information/search-fda-guidance-documents/data-integrity-and-compliance-drug-cgmp-questions-and-answers-guidance-industry.

We strongly recommend that you retain a qualified consultant to assist in your remediation. In response to this letter, provide the following:

A. A comprehensive investigation into the extent of the inaccuracies in data records and reporting which should include:

• (1) A detailed investigation protocol and methodology; (2) a summary of all systems to be covered by the assessment; (3) 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 the 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 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 the drugs you tested. 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 (CAPA) plan. Your strategy should include:

• 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, 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 the drugs you tested, such as notifying your customers, conducting additional testing, 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 status report for any of the above activities already underway or completed.

Additionally, provide the following:

• A complete assessment of documentation systems used throughout your 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.

For further reference regarding heparin, see the guidance for industry Heparin for Drug and Medical Device Use: Monitoring Crude Heparin for Quality available online at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291390.pdf.

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

Your firm did not have an adequate quality unit (QU) or quality system in place to provide appropriate oversight of laboratory operations. Prior to communication from FDA asking if your firm was ready for FDA inspection, your firm did not have procedures in place and did not have an established QU to provide oversight over the CGMP testing performed by your firm. Additionally, during the course of the inspection, FDA investigators were informed that the Principal Investigator, who is the most responsible person at the firm, was changed on the first day of the FDA’s inspection. The previous Principal Investigator is now a consultant for the firm.

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.

It appears your firm attempted to create a quality system, and corresponding procedures, in a very short timeframe to comply with applicable requirements, after communication from FDA asking if your firm was ready for FDA inspection. In your response, and during our inspection, you provided over twenty recently created procedures including: Policy for CAPA, Root Cause Analysis, and Quality System Manual. However, all these procedures were created after the FDA initially contacted your firm, but also after you had provided test results used for CGMP purposes including release of drugs into interstate commerce. Although various procedures were provided during the inspection and in your firm’s response, these procedures appear to lack sufficient detail to be effective. Additionally, you did not provide evidence to demonstrate that your firm adequately implemented and follows the procedures.

In response to this letter, provide the following:

• A comprehensive assessment and remediation plan to ensure your QU is given the authority and resources to effectively function. The assessment should also include:
  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

3. Failure to ensure training is regularly conducted by qualified individuals and covers, at a minimum, the particular operations that each employee performs and CGMP as they relate to the employee’s functions.

You failed to ensure that laboratory personnel who performed CGMP testing were adequately trained in current good manufacturing practice requirements. CGMP testing is performed by both faculty members and graduate students at your facility. Your firm lacked the adequate documentation to demonstrate that laboratory personnel were adequately trained in their respective job functions.

In your response, and during our inspection, you provided training procedures entitled “Good Manufacturing Practices & Training” and “Employee Training,” both created approximately a week before the initiation of our pre-announced inspection. Your response is inadequate as your firm began CGMP testing prior to the generation of your procedures, and you failed to perform a retrospective assessment of previous laboratory personnel to demonstrate that they had the expertise or training to support the test results provided to your customers.

In response to this letter, provide the following:

• A comprehensive, independent assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.

• A retrospective assessment of previous laboratory personnel to demonstrate that they had the expertise to properly perform CGMP testing. The timeframe of this assessment should ensure that it includes CGMP testing of all drugs within expiry.

CGMP Consultant Recommended

Based upon the nature of the deviations we identified at your firm, we strongly recommend engaging 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.

API Testing Ceased/Suspended

We acknowledge your commitment to cease trace metal analyses and suspend (b)(4) testing operations of APIs at this facility. In response to this letter, clarify whether you intend to resume testing any drugs at this facility in the future.

If you plan to resume any CGMP testing, notify this office before resuming your operations.

Conclusion

The deviations cited in this letter are not intended to be an all-inclusive list of deviations that exist at your facility. You are responsible for investigating and determining the causes of any deviations and for preventing their recurrence or the occurrence of other deviations.

Correct any deviations promptly. Failure to promptly and adequately address this matter may result in regulatory or legal action without further notice including, without limitation, seizure and injunction. Unresolved deviations may also prevent other Federal agencies from awarding contracts.

Failure to address deviations may also cause FDA to withhold issuance of Export Certificates. FDA may withhold approval of new applications or supplements listing your firm as a drug 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 address any deviations.

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.

Please address your reply via email to: ORAPHARM3_RESPONSES@fda.hhs.gov

Attention: Tina M. Pawlowski, Compliance Officer
U.S. Food and Drug Administration
Division of Pharmaceutical Quality Operations III

Your written notification should refer to the Warning Letter above (WL #623494). If you have questions regarding the contents of this letter, please contact Tina M. Pawlowski at (313) 393-8217.

Sincerely,
/S/

Nicholas Lyons
Acting Program Division Director
Pharmaceutical Quality Operations Division III

Cc:
Courtney E. Stanton
President
Smithfield Bioscience Inc.
12150 Best Place
Cincinnati, Ohio 45241-1569