返工程序及稳定性试验不符合cGMP，FDA发出警告信。
WARNING LETTER
Bioiberica, SAU
MARCS-CMS 629115 — JUNE 30, 2022
June 30, 2022
Dear Mr. Blasco:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Bioiberica, SAU, FEI 1000418405, at Carrer Antic Cami de Tordera 109-119, Palafolls, Barcelona, from January 31 to February 4, 2022.
美国食品和药物管理局(FDA)于2022年1月31日至2月4日检查了贵司药品生产工厂 Bioiberica，位于巴塞罗那Palafolls Carrer Antic Cami de Tordera 109-119, SAU, FEI 1000418405。
This warning letter summarizes significant deviations from current good manufacturing practice (CGMP) for active pharmaceutical ingredients (API).
本警告信总结了对原料药(API)现行良好生产规范(CGMP)的重大偏差。
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).
由于你们生产、加工、包装或贮存方法、设施或控制不符合CGMP，贵司的原料药根据《联邦食品、药物和化妆品法案》(FD&C法案)第501(a)(2)(B)条21 U.S.C. 351(a)(2)(B)被判定为掺假。
We reviewed your February 18, 2022, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.
我们详细审查了贵司2022年2月18日对我们FDA 483表格的回复，并确认收到了随后的回信。
During our inspection, our investigator observed specific deviations including, but not limited to, the following.
在我们的检查中，我们的调查人员观察到具体的偏差，包括但不限于以下情况。
1. Failure to establish written procedures to monitor the progress and control the performance of processing steps that may cause variability in the quality characteristics of your intermediates and API.
1. 未能建立书面程序来监控过程和控制工艺步骤的性能，这可能会导致中间体和原料药的质量属性发生变化。
You failed to establish appropriate monitoring and controls for reworking batches of (b)(4) USP, API. In 2020 and 2021, approximately 23 batches of (b)(4) USP, API were reworked in your industrial (b)(4) because of microbiological out-of-specification or non-conforming high (b)(4), a class 3 residual solvent, content results. The use of the industrial (b)(4) was not part of the established process validation for (b)(4) USP, API. The investigator documented this (b)(4) was used to rework multiple batches from (b)(4) to as many as (b)(4) times until acceptable results were obtained. No studies had been performed to establish the effectiveness of this rework step. Additionally, your industrial (b)(4) was not equipped with real time (b)(4) monitoring or a (b)(4) summary to monitor the performance of the (b)(4).
未能建立对xx USP，原料药返工批次的适当监控和控制。在2020年和2021年，由于微生物不符合规范或不符合高xx(3类残留溶剂)含量结果，大约有23批xx USP和API进行了返工。工业xx的使用不是xx USP，原料药的既定工艺验证的一部分。研究者记录了该xx被用于从xx到xx多批次的返工，直到获得可接受的结果。没有进行任何研究来确定这个返工步骤的有效性。另外，贵司的xx工业没有配备xx实时监控或xx总结来监控xx的性能。
An ongoing program for monitoring process controls to ensure your rework operations can maintain consistent drug quality is essential. The (b)(4) USP, API you manufactured is used to produce drug products to treat (b)(4). Because of the narrow therapeutic range of these products, proper blending, and manufacture of your product, appropriately evaluated through process validation, is essential to prevent patients from receiving insufficient or excessive doses.
一个持续监控工艺控制的程序以确保返工操作能够保持一致的药品质量是至关重要的。贵司生产的xx USP, API是用于生产治疗xx的药品。由于这些产品的治疗范围较窄，通过工艺验证进行适当评估的混合和生产，对于防止患者接受的剂量不足或过量是至关重要的。
In your response, you agreed that there was inadequate control and monitoring of (b)(4) processes. Additionally, you committed to validating your microbiological contamination reduction process.
回复中，贵司承认对xx流程的控制和监控不充分。此外，承诺确认降低微生物污染的方法。
Your response is inadequate. Your response repeatedly described the additional (b)(4) that was performed as reprocessing. However, the use of equipment that is not part of the validated manufacturing process is considered rework. In addition, you failed to provide interim measures to ensure your manufacturing process can adequately reduce microbiological contamination and (b)(4) content until validation can be conducted. You also failed to provide a corrective action to address the lack of process controls for the industrial (b)(4) used during rework.
贵司的答复不充分。回复中反复描述了作为再处理的附加xx。然而，如果使用的设备不是经过验证的生产工艺的一部分，则被认为是返工。此外，未能提供临时措施以确保生产工艺在进行验证之前能够充分减少微生物污染和xx含量。也没有提供纠正措施来解决返工过程中使用的工业xx缺乏过程控制的问题。
In response to this letter, provide the following:
针对本函，请提供以下内容：
An assessment of the (b)(4) USP, API manufacturing process, including rework activities performed, to ensure that there is a data-driven and scientifically sound program that identifies and controls all sources of variability, such that your production processes will consistently meet appropriate specifications and manufacturing standards. This includes, but is not limited to, evaluating suitability of equipment for its intended use, sufficiency of detectability in your monitoring and testing systems, quality of input materials, reliability of each manufacturing process step and control, and the need to revalidate your manufacturing process.
对USP、原料药生产工艺，包括所执行的返工活动进行评估，以确保有数据支持的科学合理的程序来识别和控制所有可变性来源，这样生产工艺将始终符合适当的规范和生产标准。这包括但不限于评估设备的预期用途的适用性、监控和测试系统的可检测性的充分性、原材料的质量、每个生产工艺步骤和控制的可靠性，以及再验证生产工艺的需要。
Timelines for completing process performance qualification studies on remediated processes for marketed drug products for which a state of control has not been adequately/fully established.
未充分/完全建立控制状态的上市药品的整改程序，及完成工艺性能确认研究的时间表。
A comprehensive, independent assessment of the design and control of your firm’s manufacturing operations, with a detailed and thorough review of all microbiological hazards.
对贵公司生产操作的设计和控制进行综合独立的评估，并详细、彻底地审查所有微生物危害。
2. Failure to ensure that reworked batches have been subjected to appropriate evaluation and stability testing to show that the reworked material is of equivalent quality to that produced by the original process.
2. 未能确保返工批次经过适当的评估和稳定性测试，以表明返工批次与原工艺生产的批次具有同等质量。
Reworked (b)(4) USP, API batches were not placed on stability. In 2020 and 2021, approximately 23 batches of (b)(4) USP, API batches, were subjected to rework in an industrial (b)(4) that was not a part of your validated manufacturing process. These batches were reworked because of microbiological out-of-specification or non-conforming high (b)(4) results. None of the reworked batches were placed on stability to ensure they were of quality equivalent to that produced by the validated process.
返工的xx USP、原料药批次未进行稳定性试验。在2020年和2021年，大约有23批xx USP和原料药批次在不属于验证生产工艺的工业xx中进行了返工。这些批次是由于微生物不符合规范或不符合高(b)(4)结果而返工。返工的批次没有进行稳定性试验，以确保它们的质量等同于经过验证的工艺生产的产品。
In your response, you committed to develop impurity profile parameters and stability-indicating analytical methods.
回复中，贵司承诺确认杂质分析和稳定性试验分析方法。
However, you failed to provide interim measures until your proposed actions are complete. Additionally, the stability of reworked batches currently on the market have not been evaluated.
但是，在拟议的行动完成之前，贵司未能采取临时措施。此外，目前市场上返工批次的稳定性尚未得到评估。
In response to this letter, provide the following:
针对本函，请提供以下内容：
Interim measures implemented until corrective and preventive actions are completed.
在纠正和预防措施完成之前实施的临时措施。
A comprehensive, independent assessment and CAPA plan to ensure the adequacy of your stability program. Your remediated program should include, but not be limited to:
一份综合独立的评估和CAPA计划，以确保稳定性计划的充分性。整改计划应包括但不限于:
o Stability studies for (b)(4) USP, API that is reworked in its marketed container-closure system before distribution is permitted
在允许销售前，上市的容器封闭系统中进行返工的USP，原料药的稳定性研究
o An ongoing program in which representative batches of each product are added each year to the program to determine if the shelf-life claim remains valid
o一个持续计划，每年增加每个产品的代表性批次以确定货架期声明是否仍然有效
o Detailed definition of the specific attributes to be tested at each station (timepoint)
o每个点(时间点)需检测的具体属性的详细定义
All procedures that describe these and other elements of your remediated stability program.
描述整改稳定性计划的以上要素和其他要素的所有规程。
Rework procedure that describes how reworked batches will be evaluated to determine their equivalence to the validated process.
返工程序，描述了如何对返工批次进行评估，以确定其与验证工艺的等效性。
Process Controls
过程控制
Your firm does not have an adequate ongoing program for monitoring process control to ensure stable manufacturing operations and consistent drug quality.
贵公司没有足够的持续程序来监控工艺控制以确保稳定的生产操作和一致的药品质量。
See FDA’s guidance document Process Validation: General Principles and Practices for general principles and approaches that FDA considers appropriate elements of process validation at https://www.fda.gov/files/drugs/published/Process-Validation--General-Principles-and-Practices.pdf.
请参阅FDA指南文件《工艺验证:一般原则和实践》，了解FDA认为工艺验证的适当元素的一般原则和方法，网址为https://www.fda.gov/files/drugs/published/Process-Validation--General-Principles-and-Practices.pdf。
CGMP Consultant Recommended
建议聘请CGMP顾问
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.
基于我们在贵公司发现的偏差的性质，我们强烈建议聘请有资质的顾问来评估贵司的操作，以协助贵公司满足CGMP要求。聘请顾问并不能免除贵公司遵守CGMP的义务。公司的执行管理层仍有责任全面解决所有缺陷，以确保持续的CGMP合规。
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.
在这封信中引用的偏差并非包含所有存在于贵工厂的偏差清单。贵公司有责任调查和确定任何偏差的原因，并防止其再次发生或其他偏差的发生。
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.
如果正在考虑一项可能导致贵工厂生产的药品供应中断的行动，FDA要求贵司立即联系CDER的药品短缺工作人员，邮箱为drugshortages@fda.hhs.gov，以便FDA可以与贵司合作，以最有效的方式使企业的操作符合法律。根据21 U.S.C. 356C(b)，联系药品短缺工作人员也允许贵司履行可能需要报告药品生产中断的任何义务。这也允许FDA尽快考虑采取何种行动（如有），以避免短缺和保护依赖贵司产品的患者的健康。
Correct any deviations promptly. 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 any deviations.
请及时纠正任何偏差。在完全解决任何偏差并确认符合CGMP之前，FDA可能会拒绝批准将贵公司列为药品生产商的新申请或补充申请。我们可能会重新检查，以验证贵司是否完成了对任何偏差的纠正措施。
Failure to address any deviations may also result in the FDA refusing admission of articles manufactured at Bioiberica, SAU, FEI 1000418405, at Carrer Antic Cami de Tordera 109-119, Palafolls, Barcelona 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).
根据21 U.S.C. 381(a)(3)《FD&C法案》第801(a)(3)条，未能解决任何偏差也可能导致FDA拒绝将贵公司生产的产品进入美国。根据FD&C法案第501(a)(2)(B)条，21 U.S.C. 351(a)(2)(B)的含义，在本授权下，掺假的物品可能会被扣留或拒绝入境，因为在其生产中使用的方法和控制不符合CGMP。
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.
这封信告知贵司我们的发现，并提供解决上述缺陷的机会。收到此信后，请在15个工作日内书面回复本办公室。说明已经采取措施来解决任何偏差，并防止其再次发生。在回复这封信时，可以提供额外的信息供我们考虑，我们将继续评估贵司的活动和操作。如果不能在15个工作日内完成纠正措施，说明延迟的原因和完成计划。
Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov. Identify your response with FEI 1000418405 and ATTN: Joseph Lambert, Pharm.D.
Sincerely,
/S/
Francis Godwin
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research
