FDA警告信：实验室OOS和数据完整性缺陷

近日，FDA发布了对美国Akorn Inc.的警告信，该警告信包含了OOS和偏差调查、实验室数据完整性、无菌操作和培养基模拟灌装相关的缺陷，内容十分精彩！包括如下：

• 检查发现大量OOS和偏差长时间未关闭（6个月），有些甚至进行了一年多仍未调查完成。

• OOS和偏差调查不充分，包括：

  1、稳定性OOS调查

  2、投诉调查

  3、生产线上发现铝屑的调查，未对铝屑与疑似来源进行比对确认。

  4、实验室过去有关“试验性”进针的调查不充分，未包括所有类型的“试验性”进针

  5、杂质OOS调查不充分，直到得到OOS结果19个月后调查仍未完结

  6、稳定性试验检验时间点超计划2个多月

  7、未指定一项调查可以允许的延期次数

  
  

• 部分实验室仪器数据可以删除，如傅立叶变换红外光谱仪 (FTIR)、总有机碳和粒度分析仪

• 所有单机版实验室仪器没有备份

• 实验室记录未签名，包括色谱打印图纸的复核

• 分析人员有仪器工作站电脑上Windows 文件夹具有全部管理员权限，允许复制、重命名和删除数据

• 无菌操作缺陷

• 培养基模拟灌装缺陷，未包含生产设备（部件）更换

• 质量人员没有评估设备使用日志中的干预活动

• 收率低发起了OOS调查，但是调查未包括检查过程中发现的产品泄漏事件

翻译如下：

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).

贵公司未能彻底调查批次或其任何组分的任何无法解释的偏差或偏离其质量标准，无论该批次是否已放行(21 CFR 211.192)。

Your investigations into out-of-specification (OOS) laboratory results and manufacturing deviations are inadequate and incomplete, do not include scientifically-supported conclusions, and lack prompt corrective action and preventive actions (CAPA). We reviewed numerous investigations that were open for more than six months; some were open for more than a year.

你们对超标 (OOS) 实验室结果和生产偏差的调查不充分且不完整，未能包括科学支持的结论，并且缺乏及时的纠正措施和预防措施 (CAPA)。我们审查发现许多调查进行了六个多月，一些进行了一年多。

Manufacturing Investigations

生产调查

A. You obtained an OOS osmolality result during the 18-month stability test of ketorolac tromethamine ophthalmic solution, 0.5%, lot 6C95A, performed in October 2017. Additional product defects including low volume, product leakage, and residue under the neckband were observed in the same lot in both the 18 and 24 month stability samples. You opened a manufacturing investigation and first concluded that defects in bottles received from the supplier led to the OOS osmolality result.

在2017年10月进行的批号为6C95A的 0.5% 酮罗乳三甲胺眼药水18个月稳定性研究中，你们得到了渗透压OOS结果。在 18 个月和 24 个月稳定性样品中，在同一批次中观察到其他产品缺陷，包括装量不足、产品泄漏和瓶颈有残留物。你们发起了一项生产调查，并首先得出结论，供应商处收到的瓶子缺陷导致了 渗透压OOS 结果。

This investigation was inadequate. You concluded the event was an isolated incident with no complaints received for the product. However, we identified several complaints you received for empty or leaking drug products for lots packaged in the implicated bottles.

此调查是不充分的。你们断定该事件是一个孤立的事件，没有收到有关该产品的投诉。然而，我们发现你们收到的几起投诉，这些投诉涉及包装在涉案瓶子中的大量药品是空瓶或泄漏的。

We note that your bottle supplier informed you in August 2018 that the bottle damage was most likely occurring during tip insertion on your filling line. Your investigation did not include a meaningful evaluation of this or other potential processing line root causes.

我们注意到，你们的瓶子供应商在 2018 年 8 月通知你们，瓶子破损最有可能发生在你们的灌装线上的针头插入过程中。你们的调查不包括对此或处理流程上其他潜在根本原因的实质性评估。

At the time of our inspection, your investigation remained open, and no CAPAs were identified or implemented. Additionally, you had not yet completed a risk assessment of distributed lots and you continued to release drug products manufactured on this filling line.

在我们检查期间，你们的调查仍未关闭，也未确定或实施 CAPA。此外，您并未完成对已放行批次的风险评估，并且仍继续放行在此生产线上生产的药品。

Non-integral containers pose a significant risk of non-sterility and can also impact chemical attributes of drug products.

不完整的容器将导致无菌性破坏的重大风险，还可能影响药品的化学特性。

B. On May 3 and 4, 2018, your personnel observed metal shavings on aseptic filling equipment during filling of lidocaine hydrochloride 2% jelly, USP Sterile, lots 8E47B and 8E47C. Your investigation concluded the root cause was non-conforming aluminum tubes.

2018 年 5 月 3 日和 4 日，你们的人员在灌装8E47B 批和8E47C批 2%盐酸利多卡凝胶（USP 无菌）时，在无菌灌装设备上发现了金属屑。你们的调查得出结论，根本原因是铝管不合格。

Your investigation was inadequate because it only identified two of (b)(4) batches filled in the campaign as impacted. You did not perform identification tests to verify that the metal shavings came from the aluminum tubes. Your investigation lacked a review of other drug products packaged and distributed in the same type of aluminum tubes.

你们的调查是不充分的，因为它只确定了在该阶段中生产的2批 (b)(4) 作为受影响批次。你们没有进行鉴别测试来确认金属屑是否来自铝管。你们的调查缺乏对使用同一种铝管分装并放行的其他药品的审查。

At the time of our inspection, your investigation remained open, and no CAPAs were identified.

在我们检查时，你们的调查仍在进行中，没有确定任何 CAPA。

Laboratory Investigations

实验室调查

C. Your investigation into the practice of “trial” injections in your laboratory since June 30, 2011, was inadequate. The protocol we reviewed during the inspection included a retrospective evaluation of injections and sequences containing the words “test,” “trial,” and “dummy,” as well as unnamed injections. However, our inspection identified single injections with additional names including, but not limited to, “Trail” [sic], “sample,” and “Sample-Assay-1.” These single injections would not be identified within the scope of your protocol to assess the extent of “trial” injections in your testing laboratory.

你们对实验室自 2011 年 6 月 30 日以来的"试验性"进针的调查不够充分。我们在检查期间审查的方案，包括对进针和序列的回顾性评估，其中包含"测试"、"试验"[原文：trail]和"挂名"以及未命名的进样。然而，我们的检查发现还有其他名字的单次进样，包括但不限于"试验"[原文：Trail],"样品"和"样品-含量-1"。你们的方案未包括这些单次进样，以评估实验室中试验性进样范围。

Our inspection found unjustified invalidation of OOS results obtained during both “trial injections” and official recorded testing of hydroxyamphetamine hydrobromide API.

我们的检查发现在"试验进样"和正式记录的羟基苯甲酸氢溴API检测期间得到的未经论证的无效OOS结果。

During our 2015 inspection, FDA raised concerns regarding your practice of trial injections. The inspection found that your procedures permitted “Trial injection(s) of sample solutions.” Our current inspection found your (b)(4) standard operating procedure (SOP) had not been revised to remove these instructions.

在 2015 年检查期间，FDA 对你们的试验性进样的做法提出了关注。检查发现，您的规程允许"样品溶液试验性进样"。我们当前的检查发现，你们的 (b)(4) 标准操作规程 (SOP) 尚未修订以删除这些说明。

D. You initiated numerous investigations into OOS azelastine hydrochloride ophthalmic solution, 0.05%, impurity results obtained during multiple stability time points beginning in January 2017. You first determined the root cause to be a laboratory procedure deficiency in March 2017. Later investigations noted the failures could be drug product-related. Your July 2017 Technical Assessment identified an error in the impurity calculation.

你们对0.05%盐酸氮卓斯汀眼液自2017年1月开始的多个稳定性试验时间点的杂质检验OOS结果进行了多次调查。你们于 2017 年 3 月首选确定根本原因为实验室程序缺陷。后来的调查指出,这些失败可能与药品有关。你们于2017 年 7 月的技术评估中，在杂质计算有错误。

At the time of our inspection, approximately 19 months after the initial impurity OOS results were obtained, your investigations remained open, you continued to recalculate test results to accurately report stability test data, and you had not yet determined a root cause for the OOS results. Recalculated impurity results were still OOS for both the nine- and 18-month stability time points.

在我们进行检查时，在得到初始 OOS 杂质结果大约 19 个月后，你们的调查仍然完结，继续重新计算测试结果以准确报告稳定性测试数据，并且尚未确定根导致 OOS 结果的原因。对于 9 个月和 18 个月的稳定时间点，重新计算的杂质结果仍为 OOS。

E. You obtained an OOS impurity result during the 18-month stability test of ciprofloxacin ophthalmic solution, 0.3%, lot 6D68A, performed on November 29, 2017. Testing was conducted at 20 months: two months after the drug product had expired. Previous stability results for the nine- and 12-month time points were at the upper specification limit (not more than (b)(4)%). You did not appropriately evaluate signals of potential quality problems. Your investigation determined the OOS impurity result would have occurred at 14 months. At the time of our inspection, approximately nine months after the initial OOS, your investigation remained open, and you had not yet determined a root cause for the impurity failure.

在2017年11月29日进行的批号为6D68A 的0.3%环丙沙星眼科溶液18个月稳定性测试中，你们得到了OOS杂质结果。测试是在20个月的时候进行的，此时已超期两个月。先前9 个月和 12 个月时间点的稳定性结果则处于标准上限(不超过 (b)(4)%) 。你们没有适当地评估潜在质量问题的信号。你们的调查确定 OOS 杂质结果可能发生在 14 个月。在我们检查时，在最初的 OOS 大约九个月后，你们的调查仍处于开放状态，你们尚未确定杂质问题的根本原因。

Many of your investigations, including those initiated for stability failures, remained open for long periods of time, up to 19 months, without adequate justification. Unresolved drug product quality problems may pose a risk to patients.

你们的许多调查，包括那些因稳定性失败而发起的调查，长期处于开放状态，长达19个月，而没有充分的论证。未解决的药品质量问题可能对患者造成风险。

Your response is inadequate. The details provided in your response did not clearly define management responsibilities relating to timeliness and the number of extensions that may be granted to an ongoing investigation. We acknowledge that you have initiated efforts to remediate your investigation programs; however, your response did not provide enough detail of your remediation or adequately specify how you will improve root cause determinations.

你们的回复是不充分的。回复中提供的细节没有明确界定与及时性有关的管理责任，以及一项调查的可能给予的延期次数。我们知道，你们已开始整改你们的调查程序；但是，你们的回复没有提供足够的整改细节，也没有充分说明你们讲如何改进根本原因确定程序。

We acknowledge that you halted distribution of azelastine hydrochloride ophthalmic solution, 0.05%, on May 2, 2017, and recalled all batches of the product during the inspection on August 6, 2018. We also acknowledge that you recalled 21 lots of ciprofloxacin ophthalmic solution, 0.3%, on September 20, 2018.

我们知道你们于2017年5月2日停止销售0.05%盐酸氮卓斯汀眼液，并在2018年8月6日检查期间召回所有批次的产品。我们还知道，你们在 2018 年 9 月 20 日召回了 21 批0.3%环丙沙星眼科溶液。

2. Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records (21 CFR 211.68(b)). Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to ensure compliance with established specifications and standards (21 CFR 211.194(a)).

贵公司未能对计算机或相关系统实施适当的控制，以确保只有经授权的人员才能更改主生产和控制记录或其他记录(21 CFR 211.68(b))。贵公司未能确保实验室记录包含从所有必要的测试中获得的完整数据，以确保符合既定质量标准 (21 CFR 211.194(a)。)。

Our inspection found that data could be deleted and altered from laboratory instruments, such as the Fourier transform infrared spectrometer (FTIR), total organic carbon, and (b)(4) particle size analyzer instruments. Also, standalone laboratory instruments were not backed up.

我们的检查发现，数据可以从实验室仪器中删除和更改，例如傅立叶变换红外光谱仪 (FTIR)、总有机碳和 (b)(4) 粒度分析仪。此外，单机版实验室仪器没有备份。

At the end of the inspection, you told our investigators that you discovered that the database, usage logs, and audit trails had been deleted from your high accuracy particle counter (b)(4) instrument on August 24, 2018.

在检查结束时，你们告诉我们的检查人员，你们发现高精度粒子计数器 (b)(4) 也已于 2018 年 8 月 24 日删除了数据库、使用日志和审计追踪。

Laboratory records failed to include signatures. From January 2017 to August 2018, 294 sample injection sequences did not contain signatures denoting electronic data was reviewed, as required by your procedure. Your procedure requires review of chromatographic data to ensure completeness, accuracy, and compliance of laboratory data. More than 730 additional injection sequences, including standard and suitability injections, method validation, and calibration injections, did not contain the required signatures. Your response noted that additional injection sequences without the required signatures were identified after our inspection.

实验室记录未包含签名。从 2017 年 1 月到 2018 年 8 月，294 个样品进样序列未包含表示电子数据已按照你们的规程要求进行审核的签名。你们的规程要求审核色谱数据以确保实验室数据的完整性、准确性和合规性。超过 730 个其他进样序列(包括对照品和适宜性进样、方法验证和校准进样)未包含所要求的签名。你们的答复指出，在我们的检查后，还发现了其他未包含所要求签名的进样序列。

We also found inadequate controls over your computerized systems. Chemists at your firm had full administrator access to the Windows folder on the FTIR computer, allowing data to be copied, renamed, and deleted. Similar user settings were observed on other laboratory instruments.

我们还发现对计算机化系统的控制不足。贵公司的化学分析师有对 FTIR 计算机上的 Windows 文件夹具有全部管理员权限，允许复制、重命名和删除数据。在其他实验室仪器上也发现了类似的用户设置。

Without complete and accurate records, you cannot make appropriate batch release decisions, stability decisions, and other decisions that are fundamental to ongoing assurance of quality.

没有完整和准确的记录，你们无法做出足以持续保证质量的适当的批放行决策、稳定性决策和其他决策。

Your response is inadequate.

你们的回复是不充分的。

You stated the “reviewer” of each laboratory test is responsible for confirming there are no signs of data deletion or modification as part of the audit trail review. You did not provide documentation of this activity.

你们说，作为审计追踪审核的一部分，每个实验室测试的“审核人”有责任确认没有数据删除或修改的迹象。你们没有提供此活动的文档。

You committed to investigate and review all outstanding electronic data for anomalies or other issues, to identify potential root causes, and to assess product impact. You stated laboratory data “reviewers" evaluated laboratory notebooks and source data during their chromatographic data review. You did not provide supporting evidence.

你们承诺调查和审查所有未完成的电子数据，以发现异常或其他问题，找出潜在的根本原因，并评估产品影响。你们陈述了实验室数据“审阅人”在其审核色谱数据时评估了实验室记录和源数据。你们没能提供支持证据。

The extent of the data integrity violations throughout your facility remains unknown. We acknowledge that FDA initiated our inspection after Akorn notified FDA of (b)(4) and (b)(4). We also acknowledge that you commissioned a new laboratory space and purchased new laboratory equipment.

数据完整性问题在整个工厂的违规程度仍不得而知。我们知道，FDA是在Akorn通知FDA (b)(4)和(b)(4)事件后启动检查的。我们还知道你们建造了一个新的实验室并购买了新的实验室设备。

3. Your firm failed to follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)).

贵公司未能遵循用以防止无菌药品的微生物污染的适当的书面规程，包括对所有无菌和灭菌过程的验证(21 CFR 211.113(b))。

Poor Aseptic Behavior

不良无菌操作

Operators repeatedly displayed multiple poor aseptic practices during set-up and filling operations of lidocaine hydrochloride 2% jelly, USP Sterile, lot 8G37A.

在装机和批号为8G37A的2%盐酸利多卡因凝胶的分装过程中，操作人员反复进行了多个不良无菌操作。

A. Without sanitizing their hands, an operator performed an aseptic connection after moving the (b)(4). Another operator crouched to wipe the bottom of their foot with plastic wrap. Without sanitizing their hands, the same operator connected a new tank to the fill line.

在不对其双手进行消毒的情况下，操作员在移动 (b)(4) 后进行无菌连接。另一名操作员蹲下用塑料袋擦拭脚底。在不消毒双手的情况下，该操作员将一个新的容器连接到灌装线上。

B. Sterile lidocaine hydrochloride 2% jelly leaked onto the floor during set-up and filling operations. Filling continued as operators attempted to clean up the spilled product by placing wipes and other materials over the area with their feet. Aseptic connections were made directly above the spilled product.

在装机和灌装操作期间，2%无菌盐酸利多卡因凝胶泄漏到地板上。当操作人员试图通过用脚将湿巾和其他物料放在该区域上来清理漏出的产品时，灌装仍在继续。无菌连接位于漏出产品的正上方。

Leaks of sterilized product and unsecure connections increase the risk of product contamination. No additional sterilization activities take place once the product is brought into the fill room where final aseptic filling operations occur.

无菌产品泄漏和不安全连接的会增加产品污染的风险。在产品进入进行最终无菌灌装操作的灌装间时，没有额外的灭菌操作。

C. Your aseptic filling equipment design, room space, protection of the area and filling equipment where connections are made, and the number of personnel present during filling operations are deficient. Basic design deficiencies and manually intensive interventions in your operation undermine the ability to maintain asepsis.

你们的无菌灌装设备的设计、房间空间、进行无菌连接的区域和灌装设备的保护，以及灌装期间的人员数量是不充分的。基本设计缺陷和无菌操作过程的人员过度干预削弱了你们的无菌保持能力。

Inadequate Media Fills

培养基灌装缺陷

Interventions are not appropriately simulated in media fills. You replaced or fixed the (b)(4) cutting apparatus during aseptic production operations approximately 15 times between February 16, 2018, and August 13, 2018. However, your media fill program only evaluates the adjustment and wipe down of the cutting apparatus and not its replacement. Replacement can take approximately (b)(4)

在培养基灌装中未能充分模拟干预。在 2018 年 2 月 16 日和 2018 年 8 月 13 日的无菌生产操作期间，你们更换或安装了 (b)(4) 切割装置约 15 次。但是，你们的培养基灌装程序仅评估切割装置的调整和擦拭，而不是更换。更换可能进行大约 (b)(4)

Your firm’s response was inadequate. We acknowledge that, before the inspection, you engaged a third party to assist in efforts to strengthen aseptic operations and to enhance the media fill program. You also stated that you plan to improve procedures and revalidate the filling lines by completing (b)(4) media fill runs per line. In addition, we acknowledge your decision to reject lidocaine hydrochloride 2% jelly, USP Sterile, lot 8G37A, following the inspection.

贵公司的回复是不充分的。我们知道，在检查之前，你们聘请了第三方顾问以加强无菌操作，并改善培养基灌装程序。你们还表示，你们计划改善程序并每条线完成 (b)(4) 次培养基灌装测试再验证。此外，我们知道你们决定在检查后拒绝批号为8G37A的2%无菌盐酸利多卡因凝胶。

However, you did not provide a sufficient evaluation of all batches that were produced with inadequate aseptic technique or under atypical operational conditions. You did not commit to evaluate the impact of lengthy maintenance operations during processing on product quality.

但是，你们没有对所有在不良无菌操作或异常操作条件下生产的批次进行充分的评估。你们没有承诺在工艺过程中评估长时间维修操作对产品质量的影响。

4. Your firm failed to prepare batch production and control records with complete information relating to the production and control of each batch of drug product produced (21 CFR 211.188).

贵公司未能准备包含与所生产每批药品相关的生产和控制(21 CFR 211.188)有关的完整信息的批生产和控制记录。

You failed to document in your batch record the lidocaine hydrochloride 2% jelly, USP Sterile, lot 8G37A leak during aseptic filling operations on July 7, 2018. Further, your investigation into a low OOS yield for this batch did not discuss the leak observed during filling.

在 2018 年 7 月 7 日的无菌灌装操作中，你们未能在批记录中记录8G37A 批次2%无菌盐酸利多卡因凝胶的泄漏。此外，你们对该批收率低的 OOS调查没有讨论所观察到的灌装过程中的泄漏。

You also failed to document significant filling machine interventions in the batch record. Quality personnel did not evaluate interventions recorded in the Mechanical Support (b)(4) Use Logbook. We acknowledge the commitments you made to review impact on product quality related to the lidocaine hydrochloride 2% jelly, USP Sterile leak. We also acknowledge your commitment to ensure all interventions, including mechanical interventions, will be documented in the batch record.

你们也未能在批记录中记录重要的灌装机干预。质量人员没有评估设备使用日志中记录的干预活动。我们知道你们承诺审查与2%无菌盐酸利多卡因凝胶泄漏相关的产品质量影响。我们还知道你们承诺保证所有干预措施(包括设备干预)将记录在批记录中。

Your response is inadequate because you did not sufficiently address the failure to document the leak and other mechanical interventions in your batch records. You did not provide your retrospective evaluation and risk assessment of mechanical interventions that may have warranted an investigation.

你们的回复是不充分的，因为你们没有充分解决在批记录中记录泄漏和其他机械干预的失败。你们没有提供设备干预的回顾性评估和风险评估，这可能需要一个调查。

       文章来源：GMP办公室

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