2022年4月20日，FDA发布的警告信显示，美国FDA于2021年11月1日至11月5日检查了迈阿密大学合同检测实验室。

本警告信总结了原料药生产严重违反CGMP的行为：由于你们的原料药生产、加工、包装或保存的方法、场所或控制不符合CGMP要求，你们的原料药根据FDCA的501(a)(2)(B)以及21 U.S.C.351(a)(2)(B)被认为是掺假药品。

WARNING LETTER
Miami University Department of Chemistry and Biochemistry
迈阿密大学化学与生物化学系
MARCS-CMS 623494 —
APRIL 20, 2022
Recipient:
Dr. David L. Tierney
Principal Investigator
Miami University Department of Chemistry and Biochemistry
651 East High Street, Room 160
Oxford, OH 45056
United States
Issuing Office:
Pharmaceutical Quality Operations Division III


United States


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.
美国FDA于2021年11月1日至11月5日检查了你们位于牛津651 East High Street的迈阿密大学（FEI 3009095423）合同检测实验室。
This warning letter summarizes significant deviations from current good manufacturing practice (CGMP) for active pharmaceutical ingredients (API).
本警告信总结了原料药生产严重违反CGMP的行为。
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).
由于你们的原料药生产、加工、包装或保存的方法、场所或控制不符合CGMP要求，你们的原料药根据FDCA的501(a)(2)(B)以及21 U.S.C.351(a)(2)(B)被认为是掺假药品。
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.
我们审核了你们于2021年11月29日给FDA483缺陷的回复，我们注意到2021年11月1日开始检查，Dr. Richard T. Taylor是该场所最高负责人，但是在检查期间，Dr. Taylor声称他自检查的第一天开始就不再是负责人了。然后Dr. David L. Tierney说他自2021年11月1日开始成为实验室负责人。
During our inspection, our investigators observed specific deviations including, but not limited to, the following.
在检查期间，我们检查员发现的具体缺陷包括但不限于：
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. 未对计算机化系统进行足够控制，防止未经授权访问或修改数据，无充分控制以防止数据的删除。
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.
你公司未实施充分控制措施确保你们场所产生的数据完整性。你公司是一个合同检测实验室，执行肝素粗品和USP肝素钠API的CGMP检测。你公司所执行的检测包括有对肝素进行的XX方法元素杂质检测和XX方法鉴别测试，包括检测样品中是否有硫酸软骨素（OSCS）污染物，该污染物之前曾经发生过导致死亡的不良事件。
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.
在FDA开始检查前不久，你公司和你们的USP肝素钠客户代表进行了一次审计。在对原始XX检测数据进行审核后，你们客户经过风险评估后确认你们有一名学生化验员“捏造”了数据。你公司和客户代表通知了FDA检查员，这是你们在你公司开始CGMP检测之后对XX和XX原始数据进行的首次审核。XX数据伪造发生在约2018至2021年期间，包括有化验员录入随意捏造的样品数值、加标值和相关数据。
Furthermore, in addition to concerns about data falsification, additional data integrity concerns were identified, which include the following:
另外，除了数据伪造担忧外，还发现有其它数据完整性问题，包括以下：
All (b)(4) sample results were stored in an uncontrolled folder that could be manipulated by any user.
所有XX样品结果均保存在一个任何用户均可修改的不受控文件夹中
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.
XX和YY设备在大学里有无数人使用，包括教职员工和研究生。所有用户均共用一个总的登录账号，该账号具有管理员所有权限
The (b)(4) raw data was not backed-up since CGMP testing began.
XX原始数据自CGMP检测开始后未进行备份
The software that runs the (b)(4) did not have an audit trail.
运行XX的软件没有审计追踪
The Excel spreadsheet used to calculate spike recovery and final results for the (b)(4) analysis was uncontrolled.
用于计算XX分析加标回收率和最终结果的EXCEL表格不受控
The software that runs the (b)(4) and (b)(4) equipment was not validated.
运行XX和YY设备的软件未经过验证
Sample reprocessing was not formally documented, although your firm stated reprocessing did occur.
样品重新处理没有正式记录，虽然你公司声称未进行重新处理
In (b)(4) analyses, peaks of interest in the spectrum were chosen (b)(4) and were not covered by an established procedure.
在XX分析中，光谱图涉及的峰被选择XX，且不在既定程序中
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.
在回复中，你们声称“数据捏造”只涉及到单个化验员，其“动机是避免重新分析未通过系统适用性要求的样品”。你们还声称“数据捏造”并不是想要为本不符合质量标准的样品创建合格结果。但是我们并不认同你们的结论。在肝素风险暴露评估中发现的所有元素均要按USP进行检测，获得可得出确定结论的定量结果。缺少支持时报告的任何元素定量数据均表明产品未经过足够的药品质量分析。系统适用性失败（除其它缺陷外）表明这些结果不可靠，不是可报告结果，不适合用于支持肝素API或制剂的质量。因此，你们无法得出结论说所得结果符合或不符合质量标准。
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.
你们的质量体系不能充分保证数据准确性和完整性，无法支持你们为客户所分析药品的安全性、有效性和质量。参见FDA指南文件“数据完整性和符合药品CGMP”，指导建立并遵守CGMP符合性数据完整性规范要求。
We strongly recommend that you retain a qualified consultant to assist in your remediation. In response to this letter, provide the following:
我们强烈建议你们聘请一位具备资格的顾问，协助你们进行补救。在回复本函时请提交以下资料：
A. A comprehensive investigation into the extent of the inaccuracies in data records and reporting which should include:
A. 对数据记录和报告的不准确程度进行全面调查，其中应包括：
(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.
(1) 详细的调查方案和方法学；(2) 评估涵盖的所有系统的摘要；(3) 提议排除任何操作部分的理由。
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.
对现任和前任员工进行访谈，以确定数据不准确的性质、范围和根本原因。我们建议这些面谈由合格的第三方进行。
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.
对你设施中数据完整性缺陷程度的评估。识别缺失、修改、删除、记录销毁、非同步完成记录和其他缺陷。写明发现有数据完整性问题所有操作。
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.
对检测数据完整性缺陷的性质进行全面回顾性评估。我们建议在识别出潜在违规的领域，由拥有特定专业知识的合格第三方应评估所有数据完整性失误。
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.
B. 对所发现的缺陷对所检测药物质量的潜在影响的风险评估。评估应包括分析因数据完整性问题所影响药物放行对患者造成的风险，还要分析正在进行的操作带来的风险。
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:
C. 公司的管理战略，包括全球纠正措施和预防措施 (CAPA) 计划的详细信息。策略应包括：
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.
详细的纠正措施计划，说明你们打算如何确保所生成的所有数据（包括分析数据和提交给 FDA 的所有数据）的可靠性和完整性。
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.
全面说明数据完整性问题的根本原因，包括目前的行动计划的范围和深度与调查和风险评估结果相称的证据。写明负责数据完整性问题的个人是否仍然能够影响你公司的 CGMP 相关或药物申报数据。
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.
说明已采取或将要采取的措施以保护患者和确保所检测的药物质量的临时措施，例如通知客户、进行更多检测和加强投诉监控。
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.
写明所有补救工作和改进程序、流程、方法、控制、系统、管理监督和人力资源（例如培训、人员配备改进）的长期措施，旨在确保你公司数据的完整性。
A status report for any of the above activities already underway or completed.
已进行或已完成的上述任何活动的状态报告。
Additionally, provide the following:
另外，请提交以下资料：
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.
对整个实验室操作中使用的文件系统进行完整评估，以确定文件管理不足的地方。包括一份详细的 CAPA 计划，全面纠正公司的文件操作，以确保在整个操作过程中保留可追溯的、清晰的、完整的、原始的、准确的、同步的记录。
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.
更多关于肝素的参考文件参见行业指南《药物和医疗器械用肝素：肝素粗品质量监测》。
2. Failure of your quality unit to ensure that drugs are appropriately tested and the results are reported. 你们质量部门未能确保药品经过恰当检测并报告结果。
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.
你公司没有适当的质量部门 (QU) 或质量体系来对实验室操作进行适当的监督。在与 FDA 沟通询问你公司是否准备好接受 FDA 检查之前，你公司没有适当的程序，也没有建立 QU 来监督你公司执行的 CGMP 检测。此外，在检查过程中，FDA 调查人员获悉，作为公司最负责人的首席调查员在 FDA 检查的第一天就被换了。以前的首席研究员现在是你公司的顾问。
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.
如果没有适当的 QU 和质量体系，则无法充分保证实施控制以确保您的 CGMP 测试操作在受控状态下执行。
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.
在与 FDA 沟通询问你公司是否已准备好接受 FDA 检查后，贵公司似乎试图在很短的时间内建立一个质量体系和相应的程序以符合适用的要求。在公司回复中以及在我们的检查期间，你公司提供了 20 多个最近创建的程序，包括：CAPA 政策、根本原因分析和质量体系手册。但是，所有这些程序都是在 FDA 最初与你公司联系之后创建的，而且也是在您提供用于 CGMP 目的的测试结果（包括将药物放行到州际贸易中）之后创建的。尽管在检查期间和你公司的回复中提供了各种程序，但这些程序似乎缺乏足够的细节使得有效实施。此外，你们没有提供证据证明你们公司充分实施并遵守了这些程序。
In response to this letter, provide the following:
在回复本函时请提交以下资料：
• A comprehensive assessment and remediation plan to ensure your QU is given the authority and resources to effectively function. The assessment should also include:
• 一项全面的评估和补救计划，以确保公司 QU 获得有效运作的权力和资源。评估还应包括：
o A determination of whether procedures used by your firm are robust and appropriate
o 确定你公司使用的程序是否健全和适当
o Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices
o QU对整个运营过程进行监督的规定，以评估对适当做法的遵守情况
o A complete and final review of each batch and its related information before the QU disposition decision
o 在 QU 处置决定之前对每批及其相关信息进行完整和最终审查
o Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products
o 监督和批准调查，履行所有其他 QU 职责，以确保所有药品的鉴别、含量、质量和纯度

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. 未能确保由具备资格的人员定期进行培训，并至少包括每位员工要执行的特定操作，及员工职责有关的CGMP知识
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.
你们未能确保执行 CGMP 测试的实验室人员接受了CGMP要求的充分培训。CGMP 测试由你公司所在机构的教职员工和研究生进行。你们公司缺乏足够的文件来证明实验室人员在各自的工作职能方面接受过充分的培训。
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.
在你们的回复中，以及在我们的检查中，你公司提供了题为“GMP和培训”和“员工培训”的培训程序，这两个程序都是在我们预先宣布的检查开始前大约一周创建的。你们的回复是不充分的，因为你们公司在制定你们的程序之前就开始了 CGMP 测试，并且你们未能对以前的实验室人员进行回顾性评估，以证明他们具有支持向你们客户提供的测试结果的专业知识或培训。
In response to this letter, provide the following:
在回复本函时请提交以下资料：
• 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.
• 对你们实验室规范、程序、方法、设备、文件和分析人员能力进行全面、独立的评估。在此审查的基础上，提供一个详细的计划来修复和评估您的实验室系统的有效性。
• 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.
• 对以前的实验室人员进行回顾性评估，以证明他们具备正确执行 CGMP 检测的专业知识。该评估的时间框架应确保包括对所有有效期内的药物进行 CGMP 检测。
CGMP Consultant Recommended CGMP顾问建议
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.
根据我们在贵公司发现的缺陷的性质，我们强烈建议聘请有资格评估你公司操作的顾问，以协助贵公司满足 CGMP 要求。你们使用顾问并不能免除你公司遵守 CGMP 的义务。你公司的执行管理层仍负责解决所有缺陷和系统缺陷，确保持续遵守 CGMP。
API Testing Ceased/Suspended 停止/暂停API检测
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.
我们了解到你们承诺停止在该设施进行痕量金属分析并暂停XX对 API 的检测操作。 在回复这封信时，请说明你们是否打算将来在该场所恢复检测任何药物。
If you plan to resume any CGMP testing, notify this office before resuming your operations.
如果您计划恢复任何 CGMP 测试，请在恢复运营之前通知该办公室。

Conclusion 结论
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.
此函中所引用的违规并不是全部。你们有责任对这些缺陷进行调查，确定原因，防止其再次发生，防止你们设施内其它缺陷的发生。
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.
请及时纠正所有缺陷。未能及时和充分解决这些问题可能会导致监管或法律行动，恕不另行通知，其中包括但不限于扣押和禁令。缺陷未得到改下也可能无法与其他联邦机构签订合同。
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.
未能纠正这些偏差可能还会导致FDA停止签发出口证明。在所有缺陷得到全面补救并且由FDA确认你公司符合CGMP要求之前，FDA可能会搁置对你公司作为药品生产的新申报资料或增补申报资料的批准。我们可能会重新检查你公司，核查你们是否已完成所有纠正措施，改正所有缺陷。
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.
本函用于通知您我们的调查结果，并为你公司提供解决上述缺陷的机会。收到本函后，请在 15 个工作日内以书面形式回复本办公室。说明你公司为解决所有缺陷并防止其再次发生所做的工作。在回复这封信时，你公司可以提供更多信息供我们考虑，因为我们将继续评估你公司活动和做法。如果您无法在 15 个工作日内完成纠正措施，请说明延迟的原因和完成时间表。
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