美国FDA于2026年7月对美国ABS Corporation出具一封警告信，该警告信为FDA在2026年01月12日至16日对该公司审计后出具。信中指出该公司生产兽药时多项违反CGMP的情况，包括偏差调查不彻底、未对物料进行鉴别、验证不足等方面。缺陷情况汇总如下：

1、该公司未能彻底调查任何无法解释的差异或批次或其任何组分不符合其任何标准的情况，无论该批次是否已分销。具体表现在：a、该公司生产的兽药，未执行经批准的MPR明确要求的纠正措施的情况下，放行了多批经确认OOS结果的药品，且这些OOS也未通过科学合理的调查来判定OOS结果无效。b、在某片剂的验证期间，人员手动更改批记录中的含量上限标准，但是未记录或提供此标准变更的理由。

2、该公司未能对每种组分的样品进行鉴别检验，并确认其符合所有适当的纯度、规格和质量的书面标准。此外，在质量控制部门完成取样、检验、检查并予以放行之前，该公司未能暂停使用这些组分。具体表现在该公司未能对每批进厂的高污染风险组分进行充分的鉴别检测。此外，在收到检测结果之前，将过期的原料用于药品生产，并在该物料复测不合格后，随后放行了这些批次进行分销。

3、该公司未能建立充分的书面生产和工艺控制程序，以确保生产的药品具有其声称或标示所具有的鉴别、规格、质量和纯度。该公司的质量经理向调查员确认，该公司不编写验证方案，并表示"所有设备、步骤和可接受标准均列于批记录中"，且工艺验证后也不编写最终验证报告。FDA检查人员在验证批批记录的审核发现了多项缺陷。这些文件证明产品不能满足质量属性的中控标准、中控监测数据不完整且存在无法解释的空白，以及关键生产设备的工艺参数缺失。关键质量属性的显著变异性既未被调查也未评估，当结果超出既定标准限度时，该公司在验证期间更改了标准以适应不合格的结果，而非调查和纠正根本的工艺缺陷。尽管存在这些缺陷，该公司仍放行了所引用的验证批次，并随后分销。

The United States Food and Drug Administration (FDA) inspected your drug manufacturing facility, ABS Corporation, located at 7031 N 16th St. Omaha, Nebraska, from January 12th to 16th 2026.

美国食品药品监督管理局（FDA）于2026年1月12日至16日检查了你们的药品生产工厂，ABS Corporation，地址位于内布拉斯加州奥马哈市北16街7031号。

This warning letter summarizes significant violations of FDA's 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).

本警告信概述了FDA对成品药品现行药品生产质量管理规范（CGMP）的重大违规行为。参见《美国联邦法规》第21篇（CFR）第210和211部分（21 CFR 第210和211部分）。

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products 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).

由于你们用于生产、加工、包装或保存的方法、设施或控制不符合CGMP，根据《联邦食品、药品和化妆品法案》（FD&C Act）第501(a)(2)(B)条，21 U.S.C. § 351(a)(2)(B)，你们的药品被视为掺假药品。

Current Good Manufacturing Practice Violations

现行药品生产质量管理规范违规行为

We reviewed your January 30, 2026, response to our Form FDA 483 in detail. We have not received any other correspondence from you regarding this inspection.

我们已详细审阅了你们于2026年1月30日对我们的FDA 483表格所作的回复。我们未收到你们关于此次检查的任何其他信函。

1、Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).

你们公司未能彻底调查任何无法解释的差异或批次或其任何组分不符合其任何标准的情况，无论该批次是否已分销（21 CFR 211.192）。

Your firm manufactures animal drugs for (b)(4) and (b)(4) use. Your firm released drug products with confirmed out of specification (OOS) results without performing corrective actions explicitly required by your approved Master Production Records (MPR).

你们公司生产用于(b)(4)和(b)(4)用途的兽药。你们公司在未执行经批准的主生产记录（MPR）明确要求的纠正措施的情况下，放行了具有经确认超标（OOS）结果的药品。

For example, during the manufacture of (b)(4), your firm repeatedly failed to perform required (b)(4) adjustments and released batches with confirmed OOS (b)(4) results. For Lot (b)(4), finished product testing yielded an OOS (b)(4) result of 4.03 (specification: (b)(4)). During your corrective and preventative action (CAPA) investigation, internal retesting of three individual bottles produced (b)(4) results of 4.49, 4.51, and 4.40 — the third result of 4.40 also failed to meet the established specification. Rather than invalidating the OOS result through a scientifically justified investigation, your firm (b)(4) the three results ((b)(4)), (b)(4) to (b)(4), and released the batch for distribution on July 21, 2025. Your investigation identified that the root cause was an in-process OOS result for (b)(4) and that the required corrective (b)(4) adjustment using (b)(4), as specified in your approved MPR, had not been performed.

例如，在(b)(4)的生产过程中，你们公司多次未能执行所需的(b)(4)调整，并放行了具有经确认OOS(b)(4)结果的批次。对于批号(b)(4)，成品检测得出OOS(b)(4)结果为4.03（标准：(b)(4)）。在你们公司的纠正和预防措施（CAPA）调查期间，对三个独立瓶子的内部复测得出(b)(4)结果为4.49、4.51和4.40——第三个结果4.40也未能符合既定标准。你们公司未通过科学合理的调查来判定OOS结果无效，而是(b)(4)了这三个结果((b)(4))，(b)(4)至(b)(4)，并于2025年7月21日将该批次放行分销。你们的调查确定根本原因是(b)(4)的中控OOS结果，且未执行经批准的MPR中规定的使用(b)(4)的所需纠正性(b)(4)调整。

Similarly, for Lot (b)(4), your firm obtained an in-process (b)(4) result of 4.0 (specification: (b)(4)). Again, production personnel failed to perform the corrective (b)(4) adjustment using (b)(4) as specified in your approved MPR. Your contract laboratory subsequently confirmed the finished product (b)(4) OOS at 4.06. Despite this confirmed OOS result, your firm released the batch for distribution on October 9, 2025.

类似地，对于批号(b)(4)，你们公司获得的中控(b)(4)结果为4.0（标准：(b)(4)）。生产人员再次未能执行经批准的MPR中规定的使用(b)(4)的纠正性(b)(4)调整。你们的合同检测实验室随后确认成品(b)(4) OOS为4.06。尽管存在这一经确认的OOS结果，你们公司仍于2025年10月9日将该批次放行分销。

Additionally, during (b)(4) validation of (b)(4) Tablets - (b)(4), Lot (b)(4), 17 out of (b)(4) in-process samples yielded assay results above the product USP specification of (b)(4) mg/tablet (b)(4) ((b)(4) mg/tablet) listed on your batch record. You manually changed the assay upper specification limit in the batch record from (b)(4) mg/tablet to (b)(4) mg/tablet by crossing out "(b)(4)" and handwriting "(b)(4)" with the initials of the person making the change and date (3/27/24). You did not document or provide a justification for this specification change.

此外，在(b)(4)片剂(b)(4)的(b)(4)验证期间，批号(b)(4)的(b)(4)个中控样品中有17个的含量检测结果高于批记录中列出的产品USP标准(b)(4) mg/片(b)(4)（(b)(4) mg/片）。你们通过划掉"(b)(4)"并手写"(b)(4)"并附上更改人姓名首字母和日期（3/27/24），手动将批记录中的含量上限标准从(b)(4) mg/片更改为(b)(4) mg/片。你们未记录或提供此标准变更的理由。

Furthermore, you failed to investigate an in-process sample assay result of 346.90 mg/tablet, which exceeded the revised assay upper specification limit of (b)(4) mg/tablet. Despite exceedances of both the original USP specification and the revised upper specification limit, during in-process testing, (b)(4) Tablets - (b)(4), Lot (b)(4) was sold in March 2024. The Certificate of Analysis for the finished product Lot reported an assay (b)(4) of 333.09 mg/tablet.

此外，你们未能调查含量为346.90 mg/片的中控样品结果，该结果超出了修订后的含量上限标准(b)(4) mg/片。尽管超出了原始USP标准和修订后的上限标准，在2024年3月中控检测期间，(b)(4)片剂(b)(4)批号(b)(4)已售出。该成品批号的分析证书报告的含量(b)(4)为333.09 mg/片。

Adequate corrective actions and thorough investigations into a batch failure to meet established specifications are fundamental to ensure your products meet the established quality standards. Your specifications exist to ensure product safety, efficacy, and quality. Deviating from these specifications without scientific justification places animals receiving these products at risk.

充分的纠正措施和对批次未能符合既定标准的彻底调查，是确保你们的产品符合既定质量标准的基础。你们的标准是为了确保产品的安全性、有效性和质量而存在的。在没有科学依据的情况下偏离这些标准，会使接受这些产品的动物面临风险。

Your response acknowledges the inappropriate use of (b)(4) analytical results to override individual OOS findings and the failure to perform corrective (b)(4) adjustments as required by your Master Production Record. You indicated that immediate corrections were implemented during the FDA inspection, including discontinuing the acceptance of averaged analytical results across all drug products and formally closing corrective and preventive action records which addressed (b)(4) OOS events. You committed to revising OOS and deviation investigation procedures to explicitly prohibit (b)(4), or (b)(4) of analytical results for batch disposition decisions, require documented scientific justification and predefined acceptance criteria for any retesting, and mandate Quality Assurance approval for all batch disposition decisions involving OOS results.

你们的回复承认了不当使用(b)(4)分析结果来否定个别OOS发现，以及未能按主生产记录要求执行纠正性(b)(4)调整。你们表示在FDA检查期间已实施了即时纠正措施，包括停止接受所有药品的平均分析结果，并正式关闭了处理(b)(4) OOS事件的纠正和预防措施记录。你们承诺修订OOS和偏差调查程序，以明确禁止(b)(4)或将分析结果(b)(4)用于批次处置决定，要求任何复测均有文件化的科学依据和预定的可接受标准，并规定所有涉及OOS结果的批次处置决定均需质量保证部门批准。

For the validation batch you acknowledged the failure to initiate an OOS investigation for an individual out-of-specification assay result and committed to revising validation procedures to require evaluation of individual assay results, define acceptance criteria for intra-batch and inter-batch variability, and use statistical tools to assess process variability.

对于验证批次，你们承认未对单个超标含量结果启动OOS调查，并承诺修订验证程序，要求评估单个含量结果、定义批内和批间变异性的可接受标准，并使用统计工具评估工艺变异性。

Your response is inadequate because it fails to address the safety and disposition of distributed products. Specifically, the response provides no scientific justification or data to support the claim that OOS does not impact product quality and stability and fails to address the product distributed after a validation that included an OOS assay result and unjustified specification change.

你们的回复是不充分的，因为它未能解决已分销产品的安全性和处置问题。具体而言，该回复未提供科学依据或数据来支持OOS不影响产品质量和稳定性的说法，也未能解决在一次包含OOS含量结果和不合理标准变更的验证之后分销的产品问题。

The response also lacks commitment to retrospective safety assessment of distributed products and provides no specific timelines for procedure revisions or implementation.

该回复也缺乏对已分销产品进行回顾性安全评估的承诺，并未提供程序修订或实施的具体时间表。

In response to this letter, provide:

在回复本信时，请提供：

• A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, OOS results, and failures. Provide a detailed action plan to remediate this system. Your action plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, CAPA effectiveness, quality unit (QU) oversight, and written procedures. Address how your firm will ensure that all phases of investigations are appropriately conducted.

• 对你们公司调查偏差、差异、投诉、OOS结果和失败的整体系统进行全面、独立的评估。提供一份详细的行动计划来补救该系统。你们的行动计划应包括但不限于在调查能力、范围确定、根本原因评估、CAPA有效性、质量部门（QU）监督和书面程序方面的重大改进。说明你们公司将如何确保调查的所有阶段都得到适当执行。

• An independent assessment and remediation plan for your CAPA program. Provide a report that evaluates whether the program includes effective root cause analysis, ensures CAPA effectiveness, analyzes investigation trends, improves the CAPA program when needed, implements final QU decisions, and is fully supported by executive management.

• 对你们公司CAPA计划的独立评估和补救计划。提供一份报告，评估该计划是否包括有效的根本原因分析、确保CAPA有效性、分析调查趋势、在需要时改进CAPA计划、执行QU的最终决定，并得到执行管理层的全力支持。

2. Your firm failed to test samples of each component for identity and conformity with all appropriate written specifications for purity, strength, and quality. Additionally, your firm failed to withhold components from use until sampling, testing, examination, and release by the quality control unit (21 CFR 211.84(d) and 21 CFR 211.84(a)).

你们公司未能对每种组分的样品进行鉴别检验，并确认其符合所有适当的纯度、规格和质量的书面标准。此外，在质量控制部门完成取样、检验、检查并予以放行之前，你们公司未能暂停使用这些组分（21 CFR 211.84(d)和21 CFR 211.84(a)）。

You failed to perform adequate identity testing on each shipment and lot of incoming components at high risk of contamination. Additionally, you used expired raw material in the manufacture of drug products before receiving test results and subsequently released those batches for distribution after the material failed retesting. For example:

你们公司未能对每批进厂的高污染风险组分进行充分的鉴别检测。此外，你们公司在收到检测结果之前，将过期的原料用于药品生产，并在该物料复测不合格后，随后放行了这些批次进行分销。例如：

Your firm's raw material examination reports for (b)(4) lots identified by "(b)(4)" (b)(4) and (b)(4) used to manufacture (b)(4), Lot (b)(4), exp. (b)(4), (b)(4), Lot (b)(4), exp. (b)(4) and (b)(4), exp. (b)(4) lacked data for identity, (b)(4), and (b)(4) limits. Further, your firm manufactures (b)(4) products containing (b)(4), including (b)(4) (Lot (b)(4) and others). Your Quality Manager confirmed that your firm has not tested any received (b)(4) for the limit of (b)(4).

你们公司对用于生产(b)(4)（批号(b)(4)，有效期(b)(4)）、(b)(4)（批号(b)(4)，有效期(b)(4)）和(b)(4)（有效期(b)(4)）的、标识为"(b)(4)"的(b)(4)和(b)(4)批次的原料检验报告，缺乏鉴别、(b)(4)和(b)(4)限度的数据。此外，你们公司生产含有(b)(4)的(b)(4)产品，包括(b)(4)（批号(b)(4)等）。你们公司的质量经理确认，你们公司未对任何接收的(b)(4)进行(b)(4)限度检测。

Your firm used (b)(4) (item number (b)(4), (b)(4)) in the manufacture of Lot (b)(4) and Lot (b)(4), expiration date (b)(4), of (b)(4) despite the material having passed its retest date of April 25, 2024. On June 11, 2024, your contract laboratory reported that the material failed retesting. However, your firm released both batches for distribution on the same day you received the failing retest results (June 11, 2024). Your decision was based on a qualitative comparison of the Fourier-transform infrared (FT-IR) spectroscopy scan for OOS raw material and a previous scan spectrum of itself, that determined the material passed specification.

你们公司在生产(b)(4)批号(b)(4)和批号(b)(4)（有效期(b)(4)）时使用了(b)(4)（物料编号(b)(4)，(b)(4)），尽管该物料已于2024年4月25日超过复验期。2024年6月11日，你们公司的合同实验室报告该物料复验不合格。然而，你们公司在收到不合格复验结果的同一天（2024年6月11日）放行了这两个批次进行分销。你们的决定是基于对OOS原料的傅里叶变换红外光谱（FT-IR）扫描与自身先前扫描图谱的定性比较，据此判定该物料符合标准。

Without adequate testing, you do not have scientific evidence that your raw materials conform to the appropriate specifications before their use in the manufacture of your drug products. Your failure to adequately test high-risk components including (b)(4) and (b)(4) before use in drug manufacturing could result in adverse effects and represent considerable safety risk to animals receiving the drug products using these components.

没有充分的检测，你们公司就缺乏科学证据来证明原料在用于药品生产之前符合适当的标准。你们公司未能在药品生产使用前对包括(b)(4)和(b)(4)在内的高风险组分进行充分检测，可能导致不良影响，并对接受使用这些组分的药品的动物构成相当大的安全风险。

As a manufacturer, you are responsible for sampling, testing, and examining drug components before their use in production to ensure adequate quality and to mitigate contamination risks.

作为生产企业，你们公司有责任在生产使用前对药物组分进行取样、检测和检查，以确保足够的质量并降低污染风险。

Your response acknowledged inadequate sampling and testing controls and recognized that (b)(4) and (b)(4) are high-risk components requiring appropriate testing. You indicated that immediate corrections were implemented, including a requirement that each container of (b)(4) received for use in ingested drug products undergo (b)(4) and (b)(4) limit testing prior to release for manufacturing use, and each lot of (b)(4) received for use in drug product manufacturing undergo (b)(4) limit testing prior to release.

你们的回复承认了取样和检测控制不足，并确认(b)(4)和(b)(4)是需要适当检测的高风险组分。你们表示已实施即时纠正措施，包括要求每件收到的用于口服药品生产的(b)(4)容器，在放行用于生产使用前进行(b)(4)和(b)(4)限度检测，以及每批收到的用于药品生产的(b)(4)在放行前进行(b)(4)限度检测。

You committed to revising raw material sampling and testing procedures, updating incoming inspection and quarantine procedures and providing targeted training to Quality Control and Quality Assurance personnel on the revised procedures. Further, you committed to verify compliance with the new established procedures through routine receiving and batch record review, and trending of high-risk component testing to confirm compliance.

你们承诺修订原料取样和检测程序，更新进厂检验和隔离程序，并对质量控制和质量保证人员就修订后的程序进行有针对性的培训。此外，你们承诺通过常规的接收和批记录审核以及高风险组分检测的趋势分析来验证对新建立程序的合规性。

Regarding the use of components beyond its re-test date and releasing drug products that were manufactured using out of specification components, your response did not specifically address this deviation.

关于使用超过复验期的组分以及放行使用不合格组分生产的药品，你们的回复未具体解决这一偏差。

Your response is inadequate. While you committed to implement proper testing going forward, you failed to address the already distributed products that were manufactured with inadequately tested components. The response does not address the testing status or disposition of (b)(4) and (b)(4) containers currently in inventory that were received prior to implementation of the new testing requirements and provides no commitment to test retained samples from distributed product batches. You provided no risk assessment evaluating the probability of contamination in untested material and failed to commit or conduct a comprehensive retrospective review identifying all batches manufactured with inadequately tested material. Additionally, your response lacks specific timelines for procedure revisions, training completion, and full implementation of testing requirements.

你们的回复是不充分的。虽然你们承诺未来实施适当的检测，但你们未能解决已分销的、使用未经充分检测组分生产的药品问题。该回复未涉及在新检测要求实施之前接收的、目前库存中的(b)(4)和(b)(4)容器的检测状态或处置问题，也未承诺对已分销批次的留样进行检测。你们未提供评估未经检测物料污染可能性的风险评估，也未承诺或进行全面回顾性审核以识别所有使用未经充分检测物料生产的批次。此外，你们的回复缺乏程序修订、培训完成和检测要求全面实施的具体时间表。

In response to this letter, provide:

在回复本信时，请提供：

• A comprehensive, independent review of your material system, including but not limited to:

• 对你们公司物料系统的全面独立审核，包括但不限于：

• evaluating all suppliers of materials (components, containers, and closures) to determine if they are reliable and appropriately qualified;

• 评估所有物料（组分、容器和密闭器）的供应商，以确定其是否可靠且经过适当确认；

• an assessment of all materials to determine whether they are consistently of acceptable quality;

• 对所有物料进行评估，以确定其是否持续具有可接受的质量；

• a review to ensure assigned expiration or retest dates are appropriate (supported by data);

• 审核以确保指定的有效期或复验期是适当的（有数据支持）；

• adequacy of the supplier qualification program, and its selection, qualification, and disqualification provisions.

• 供应商确认计划的充分性，及其选择、确认和取消确认的规定。

• Based on a thorough review, provide a summary of your systems corrective action and preventive action (CAPA) to remediate the supplier qualification program and prevent use of unsuitable components, containers and closures.

• 基于全面审核，提供你们公司系统性纠正和预防措施（CAPA）的摘要，以补救供应商确认计划并防止使用不合适的组分、容器和密闭器。

• The chemical and microbiological quality control specifications you use to test and release each incoming lot of components for use in manufacturing.

• 你们公司用于检测和放行每批进厂组分以用于生产的化学和微生物质量控制标准。

• A description of how you will test each component lot for conformity with all appropriate specifications for identity, strength, quality, and purity. If you intend to accept any results from your suppliers' COAs instead of testing each component lot for strength, quality, and purity, specify how you will robustly establish the reliability of your supplier's results through initial validation as well as periodic re-validation. In addition, include a commitment to always conduct at least one specific identity test for each incoming component lot.

• 对你们公司将如何检测每个组分批次以确保其符合所有适当的鉴别、规格、质量和纯度标准的描述。如果你们公司打算接受供应商COA的部分结果，而不对每个组分批次进行规格、质量和纯度检测，请具体说明你们公司将如何通过初始验证和定期再验证来确认供应商结果持续的可靠性。此外，请承诺始终对每个进厂组分批次至少进行一项专属鉴别检测。

• A summary of results obtained from testing all components to evaluate the reliability of the COA from each component manufacturer. Include your SOP that describes this COA validation program.

• 通过检测所有组分以评估每个组分生产商COA可靠性所获得的结果摘要。请附上描述此COA验证程序的你们公司SOP。

• A summary of your program for qualifying and overseeing contract facilities that test the drug products you manufacture.

• 你们公司对检测所生产药品的合同设施进行确认和监督的计划的摘要。

• The firm name, address, and supplier qualification report, for your third-party laboratory or laboratories conducting your raw material testing.

• 进行你们公司原料检测的第三方实验室的公司名称、地址和供应商确认报告。

3. Your firm failed to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a)).

你们公司未能建立充分的书面生产和工艺控制程序，以确保你们公司生产的药品具有其声称或标示所具有的鉴别、规格、质量和纯度（21 CFR 211.100(a)）。

Your Quality Manager confirmed with the investigator that your firm does not write validation protocols, stating that "all equipment, steps, and acceptance criteria are listed within the batch record." The quality manager further confirmed to the investigator that your firm does not write final validation reports after process validation.

你们公司的质量经理向调查员确认，你们公司不编写验证方案，并表示"所有设备、步骤和可接受标准均列于批记录中"。该质量经理进一步向调查员确认，你们公司在工艺验证后不编写最终验证报告。

Our review of your (b)(4) Tablets - (b)(4) validation lot (b)(4) batch record found multiple deficiencies. The document evidenced product failure to meet quality attributes in-process specifications, incomplete in-process monitoring data with unexplained gaps and missing process parameters for key manufacturing equipment. Together, these deficiencies prevent an adequate assessment of process consistency and control and provide no evidence to establish validated operating ranges or to ensure process reproducibility.

我们对你们公司(b)(4)片剂(b)(4)验证批次(b)(4)批记录的审核发现了多项缺陷。该文件证明产品未能满足质量属性的中控标准、中控监测数据不完整且存在无法解释的空白，以及关键生产设备的工艺参数缺失。综上所述，这些缺陷阻碍了对工艺一致性和控制的充分评估，并无法提供任何证据来确立经过验证的操作范围或确保工艺的可重复性。

Further, significant variability in critical quality attributes was neither investigated nor evaluated or changes documented and justified. When results exceeded established specification limits, your firm changed the specifications during validation to accommodate failing results rather than investigating and correcting the underlying process deficiencies.

此外，关键质量属性的显著变异性既未被调查也未评估，或变更未被记录和论证。当结果超出既定标准限度时，你们公司在验证期间更改了标准以适应不合格的结果，而非调查和纠正根本的工艺缺陷。

Despite these deficiencies, you released the referenced validation batch and subsequently distributed multiple batches of (b)(4) Tablets - (b)(4) without adequate evidence that your manufacturing process is validated, controlled, or capable of consistently producing tablets that meet quality standards.

尽管存在这些缺陷，你们公司仍放行了所引用的验证批次，并随后分销了多批(b)(4)片剂(b)(4)，而缺乏充分的证据证明你们的生产工艺经过验证、受控或能够持续生产符合质量标准的片剂。

Process validation evaluates the design integrity and state of control of a manufacturing process throughout its lifecycle. Each significant manufacturing stage must be appropriately designed to ensure the quality of inputs, in-process materials, and finished products. Process qualification studies establish whether an initial state of control has been achieved and must be successfully completed before commercial distribution. Ongoing monitoring of process performance and product quality is then required to maintain a stable manufacturing operation over the product lifecycle.

工艺验证评估生产工艺在其整个生命周期内的设计完整性和受控状态。每个重要的生产阶段都必须经过适当设计，以确保投入物料、中间物料和成品的质量。工艺确认研究确定是否已达到初始受控状态，且必须在商业分销前成功完成。此后，需要对工艺性能和产品质量进行持续监测，以在产品生命周期内维持稳定的生产运营。

Your response acknowledges deficiencies in process validation and change control and commits to revising your Validation Master Plan, updating validation protocol and report templates to include identification of critical quality attributes and critical process parameters with predefined acceptance criteria, and revising change control procedures to require documented assessment of validation impact and training requirements.

你们的回复承认了工艺验证和变更控制方面的缺陷，并承诺修订验证主计划，更新验证方案和报告模板以包含关键质量属性和关键工艺参数的识别并附有预定的可接受标准，并修订变更控制程序以要求对验证影响和培训需求进行文件化评估。

The response is inadequate because it fails to address the validation status and safety of products already distributed to the market. You provide no commitment to revalidating existing processes using scientifically sound protocols with proper evaluation, no assessment of whether your currently marketed products were manufactured by processes in a state of control, and no scientific justification for the specification changes implemented, including toxicological assessment or stability data supporting the increased API concentration.

该回复是不充分的，因为它未能解决已分销至市场产品的验证状态和安全性问题。你们未承诺使用科学合理的方案和适当评估对现有工艺进行再验证，未评估你们当前上市产品是否由处于受控状态的工艺生产，也未对所实施的标准变更提供科学依据，包括支持API浓度增加的毒理学评估或稳定性数据。

Your response also lacks specific timelines for completing procedure revisions, implementing new validation requirements, conducting revalidation studies, and training personnel. You state only that actions are "being revised" or "pending final approval" without providing commitment dates.

你们的回复也缺乏完成程序修订、实施新验证要求、进行再验证研究和培训人员的具体时间表。你们仅声明相关行动"正在修订中"或"待最终批准"，而未提供承诺日期。

In response to this letter, provide:

在回复本信时，请提供：

• A detailed summary of your validation program for ensuring a state of control throughout the product lifecycle, along with associated procedures. Describe your program for process performance qualification and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.

• 关于你们公司为确保整个产品生命周期内处于受控状态的验证计划及相关程序的详细摘要。请描述你们公司的工艺性能确认计划以及对批内和批间变异性进行持续监测以确保持续受控状态的计划。

• A timeline for performing process performance qualification for each of your marketed drug products.

• 为你们公司每种已上市药品进行工艺性能确认的时间表。

• Process performance protocol(s), and written procedures for qualification of equipment and facilities.

• 工艺性能方案以及设备和设施确认的书面程序。

• A detailed program for designing, validating, maintaining, controlling and monitoring each of your manufacturing processes that includes vigilant monitoring of intra-batch and inter-batch variation to ensure an ongoing state of control. Also, include your program for qualification of your equipment and facility.

• 一份用于设计、验证、维护、控制和监测每种生产工艺的详细计划，包括对批内和批间变异性进行警惕性监测，以确保持续的受控状态。同时，请包括你们的设备和设施确认计划。

CGMP Consultant Recommended

建议聘请CGMP顾问

Based upon the nature of the violations we identified at your firm, you should engage a consultant qualified as set forth in 21 CFR 211.34 to evaluate your operations and to assist your firm in meeting CGMP requirements. The qualified consultant should also perform a comprehensive six-system audit of your entire operation for CGMP compliance and evaluate the completion and efficacy of your corrective actions and preventive actions before you pursue resolution of your firm's compliance status with FDA.

基于我们在你们公司发现的违规行为的性质，你们公司应聘请一名符合21 CFR 211.34规定资格的顾问来评估你们公司的运营，并协助你们公司满足CGMP要求。在你们公司寻求与FDA解决合规状态之前，该合格顾问还应对你们公司的整个运营进行全面的六大体系CGMP合规性审计，并评估你们公司纠正和预防措施的完成情况和有效性。

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.

你们公司聘请顾问并不免除你们公司遵守CGMP的义务。你们公司的执行管理层仍负责解决所有缺陷和系统性漏洞，以确保持续的CGMP合规性。

Conclusion

结论

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.

本信引用的违规行为并非旨在成为你们工厂存在的所有违规行为的详尽清单。你们公司有责任调查并确定任何违规行为的原因，并防止其再次发生或出现其他违规行为。

You must correct any violations 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 violations may also prevent other Federal agencies from awarding contracts.

你们必须及时纠正任何违规行为。未能及时和充分地处理此事可能导致在不另行通知的情况下采取监管或法律行动，包括但不限于查封和禁令。未解决的违规行为也可能阻止其他联邦机构授予合同。

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.

FDA可能会暂缓批准将你们公司列为药品生产商的新申请或补充申请，直至所有违规行为得到完全解决并且我们确认你们符合CGMP。我们可能会重新检查，以核实你们已完成对任何违规行为的纠正措施。

This letter notifies you of our findings and provides you with 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 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.

本信函告知你们我们的发现，并为你们提供解决上述缺陷的机会。收到此信后，请在15个工作日内以书面形式回复本办公室。请说明你们为解决任何违规行为并防止其再次发生所做的工作。在回复本信时，你们可以提供额外信息供我们在继续评估你们的活动和实践时考虑。如果你们无法在15个工作日内完成纠正措施，请说明你们的延迟原因和完成时间表。

Send your electronic reply to CVM-483-Responses@fda.hhs.gov. Refer to the CMS Case number 732115 FEI 1950042 and ATTN: Dayna I. Martinez when replying.

请将你们的电子回复发送至 CVM-483-Responses@fda.hhs.gov。回复时请注明CMS案件编号732115、FEI 1950042和收件人：Dayna I. Martinez

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* 声明：

文章英文原文来源于FDA官网，中文译文由科威利华团队机翻并初校后发布，供大家参考使用，如有疑问请参考原文，同时欢迎大家留言指正。整理不易，转载请注明出处。