Due to numerous and serious GMP violations in the aseptic area, the FDA issued a Warning Letter to an Indian sterile manufacturer in October.The violations concern media fills, employee behaviour in the aseptic area, cleanroom and equipment design, environmental monitoring and CAPA.

由于无菌区多次严重违反GMP，FDA于10月向一家印度无菌制造商发出警告信。违规行为涉及培养基灌装、无菌区员工行为、洁净室和设备设计、环境监测和CAPA。

Media Fill

培养基灌装

According to the FDA, employees carry out lengthy, highly manual aseptic work steps.Therefore, the duration of the process simulation should be very similar to the actual manufacturing process. The FDA criticizes the fact that the processes during the media fill do not sufficiently simulate the real processes during aseptic filling. For example, the quantities used manually differ from the real quantities, such as the quantity of sterile API added manually to the compounding tank. In addition, bags used in commercial production may have been opened and resealed beforehand, which was not simulated in the media fill.

根据FDA的说法，员工需要执行冗长、高度手动的无菌操作步骤。因此，工艺模拟的持续时间应该与实际制造过程非常相似。FDA指出培养基灌装过程没有充分模拟无菌灌装过程中的实际过程这一事实。例如，手动操作的数量与实际数量不同，如手动加到配制罐中的无菌API的数量。此外，商业化生产中使用的袋子可能已经打开并重新密封，这在培养基灌装中没有模拟。

Poor aseptic behaviour

薄弱的无菌行为

According to the FDA, media fills and smoke studies show inadequate aseptic behaviour among employees, e.g. when adding sterile API to the preparation container. Among other things

根据FDA的说法，培养基灌装和发烟测试表明员工的无菌行为不足，例如，在制剂容器中添加无菌API时。除此之外，还发现其它日常问题：

·An operator touched the product contact surface of the stopper.

·操作员触摸塞子的产品接触面。

·The operator's movements in the critical areas were not always slow and deliberate.

·操作员在关键区域的动作并不总是缓慢而小心翼翼的。

·An operator blocked the laminar air flow during various activities, including by reaching over the open, sterile container several times.

·一名操作员在各种活动中阻断了层流气流，包括多次越过未封口的无菌容器。

The FDA also writes that there was a serious failure with media fill in November 2021 that revealed serious deficiencies and risks in operation. However, the manufacturer did not conduct a timely risk assessment to determine whether the quality and sterility of the medicinal products distributed were affected by these defects. A recall was not initiated until five months later. The failure to proactively identify deficiencies and implement timely and sustained corrective and preventive actions (CAPA) is unacceptable according to the FDA.

FDA还写道，2021年11月，培养基灌装出现严重故障，暴露出严重缺陷和操作风险。然而，制造商没有及时进行风险评估，以确定所发运的药品质量和无菌性是否受到这些缺陷的影响。直到五个月后才开始召回。FDA表示，未能主动发现缺陷并及时持续实施纠正和预防措施（CAPA）是不可接受的。

Cleanroom design

洁净室设计

The FDA writes that the ISO-5 cleanroom areas used for the aseptic manufacturing and filling of drugs are inadequately designed and do not provide adequate protection.For example, the ISO-5 area lacked physical barriers to prevent potential contamination of sterile components, including the sterile API, during manual operations. Personnel's bodies and hands were in close proximity to the sterile API during preparation and syringe loading in the filling station. Operators also hand-filled sterile components into a compounding tank through a large funnel with a wide opening. The smoke studies showed an undirected, recirculating airflow on and around the funnel. According to the FDA, fundamental design flaws and manual labour-intensive interventions undermine the maintenance of aseptic performance.

FDA写道，用于无菌生产和灌装药物的ISO-5洁净室区域设计不充分，无法提供足够的保护。例如，ISO-5区域缺乏物理屏障，以防止手动操作期间无菌成分（包括无菌API）的潜在污染。在灌装站进行制备和注射器装载过程中，人员的身体和手都非常接近无菌API。操作员还通过一个开口较宽的大漏斗将无菌部件手动灌装到配制罐中。发烟测试研究表明，漏斗上和周围存在乱流。据FDA称，基本设计缺陷和人工劳动密集型干预措施破坏了无菌性能的维持。

Environmental monitoring

环境监测

According to the FDA, the manufacturer failed to establish an adequate system to monitor environmental conditions. For example, there is no functional environmental monitoring of surfaces and air in the immediate vicinity of aseptic dispensing operations. There is also no monitoring at the point where sterile API is manually added to the compounding tank. However, the manufacturer has not designated this point as a "high-risk" sampling point for environmental monitoring. Furthermore, the data on personnel monitoring was not adequately recorded. Especially for highly manual aseptic operations, the FDA expects a sound environmental and personnel monitoring program.

FDA写道，制造商未能建立足够的系统来监测环境条件。例如，无菌配药操作附近的表面和空气没有功能性环境监测。在手动将无菌API添加到配制罐的位置也没有监测。然而，制造商尚未将该点指定为环境监测的“高风险”采样点。此外，人员监测数据没有得到充分记录。特别是对于高度手动无菌操作，FDA期望有一个健全的环境和人员监测计划。

Equipment design

设备设计

The FDAalso found GMP deficiencies in the production equipment used. For example, the manufacturer used unsuitable equipment for filling vials, which led to significant contamination of injection solution vials with foreign substances. The manufacturer was aware that the design of the filling equipment, in combination with the viscous nature of the drug, generated friction. This friction causes an abrasion effect, resulting in fine metal particles entering the vials during filling. The manufacturer had stated that the affected parts had been withdrawn from circulation. However, the FDA found manufacturing records proving that these parts were still in use two years after the cause of the black particles was discovered.

FDA还发现所使用的生产设备存在GMP缺陷。例如，制造商使用了不合适的设备来灌装小瓶，这导致注射溶液小瓶被异物严重污染。制造商意识到灌装设备的设计，加上药物的粘性，产生了摩擦。这种摩擦会产生磨损效应，导致细小的金属颗粒在灌装过程中进入小瓶。制造商表示，受影响的零件已不再使用。然而，FDA发现制造记录证明，在发现黑色颗粒的原因两年后，这些部件仍在使用。

Deviations and CAPA

偏差和CAPA

The FDA also criticized the handling of deviations.For example, there was a water leak in a cleanroom that was insufficiently investigated. Appropriate CAPA measures were not initiated and the investigation was not extended to other potentially affected batches. In this case, water had entered ISO cleanroom 5 through a leak in the HVAC system in the service area through the cleanroom ceiling. The water had previously collected above the cleanroom ceiling before entering the aseptic filling room. Although the manufacturer had sealed the gaps in the ceiling, they did not adequately inspect the intermediate area, LAF ceiling and HVAC ducts for mold growth and water damage after the repairs. Also, no risk assessment was performed for the sterile product manufactured in this cleanroom since the last preventive maintenance, approximately two months before the leak was discovered.

FDA还批评了偏差的处理。例如，一间洁净室发生漏水，但调查不充分。没有启动适当的CAPA措施，调查也没有扩展到其他可能受影响的批次。在这种情况下，水通过洁净室天花板通过HVAC系统的泄漏进入ISO-5洁净室。在进入无菌灌装室之前，水已经聚集在洁净室天花板上方。虽然制造商已经密封了天花板上的缝隙，但他们没有在维修后充分检查中间区域、LAF天花板和HVAC管道的霉菌生长和水损坏情况。此外，自上次预防性维护以来，大约在发现泄漏前两个月，没有对该洁净室生产的无菌产品进行风险评估。