发布时间 : 星期六 文章冻干检查指南（中英文对照）更新完毕开始阅读
投诉，表明一些预先被封闭的瓶子没有经过冻干的步骤，造成了产品处于液体状态或没有冻干。不幸的是，这些公司100%的瓶子检查没有将有缺陷的瓶子鉴别出来。
Typically, the product is frozen at a temperature well below the eutectic point. 产品的冷冻温度应低于它的共晶点。
The scale-up and change of lyophilization cycles, including the freezing procedures, have presented some problems. Studies have shown the rate and manner of freezing may affect the quality of the lyophilized product. For example, slow freezing leads to the formation of larger ice crystals. This results in relatively large voids, which aid in the escape of water vapor during sublimation. On the other hand, slow freezing can increase concentration shifts of components. Also, the rate and manner of freezing has been shown to have an affect on the physical form (polymorph) of the drug substance. 放大的和变更的冻干循环，包括冷冻程序，表现出一些问题。研究表明冷冻的速度和方式影响冻干产品的质量。例如，缓慢冷冻造成较大的冰晶排列，造成冰晶升华时有较大的逃逸通道。另一方面缓慢冷冻会造成产品组分的浓度上升。冷冻的速度和方式会影响药物组分的物理形态（同质异构）。
It is desirable after freezing and during primary drying to hold the drying temperature (in the product) at least 4-5o below the eutectic point. Obviously, the manufacturer should know the eutectic point and have the necessary instrumentation to assure the uniformity of product temperatures. The lyophilizer should also have the necessary instrumentation to control and record the key process parameters. These include: shelf temperature, product temperature, condenser temperature, chamber pressure and condenser pressure. The manufacturing directions should provide for time, temperature and pressure limits necessary for a lyophilization cycle for a product. The monitoring of product temperature is particularly important for those cycles for which there are atypical operating procedures, such as power failures or equipment breakdown.
冷冻以后，在主干燥阶段，控制产品的干燥温度低于共晶点4-5℃。显然生产商需要知道产品的共晶点，而且需要使用仪器保证产品的温度是均一的。冻干机要有必须的仪器控制和记录关键的过程参数。包括：板层温度、产品温度、冷凝器温度、前箱压力、冷凝器压力。生产说明中应注明冻干循环中的时间压力和温度限制。在一些非典型的操作程序中（例如断电或设备故障）监测产品的温度是十分重要的。
Electromechanical control of a lyophilization cycle has utilized cam-type recorder-controllers. However, newer units provide for microcomputer control of the freeze drying process. A very basic requirement for a computer controlled process is a flow chart or logic. Typically, operator involvement in a computer controlled lyophilization cycle primarily occurs at the beginning. It consists of loading the
chamber, inserting temperature probes in product vials, and entering cycle parameters such as shelf temperature for freezing, product freeze temperature, freezing soak time, primary drying shelf temperature and cabinet pressure, product temperature for establishment of fill vacuum, secondary drying shelf temperature, and secondary drying time.
电子控制冻干循环一般使用多通道记录仪。一些新的设备配备了电脑，用于控制冻干过程。对电脑控制过程的最基本的要求是流程图和逻辑控制。包括前箱的摆放、向产品瓶中插入温度探头，输入循环参数，例如：板层冷冻温度、产品冷冻温度、追加冷冻时间、主干燥时的板层温度和前箱压力、开始抽真空时的产品温度、第二次干燥时的板层温度、第二次干燥的时间。
In some cases, manufacturers have had to continuously make adjustments in cycles as they were being run. In these situations, the lyophilization process was found to be non-validated.
在一些案例中，生产商在循环开始前不断的调整参数。在这种情况下，冻干过程被认为是没有被经过验证的。
Validation of the software program of a lyophilizer follows the same criteria as that for other processes. Basic concerns include software development, modifications and security. The Guide to Inspection of Computerized Systems in Drug Processing contains a discussion on potential problem areas relating to computer systems. A Guide to the Inspection of Software Development Activities is a reference that provides a more detailed review of software requirements.
冻干机的软件系统验证和其他过程的验证相同。包括软件的变革、修改和安全。《Guide to Inspection of Computerized Systems in Drug Processing》讨论了相关的问题。《Guide to the Inspection of Software Development Activities》提供了逐条的软件需求。
Leakage into a lyophilizer may originate from various sources. As in any vacuum chamber, leakage can occur from the atmosphere into the vessel itself. Other sources are media employed within the system to perform the lyophilizing task. These would be the thermal fluid circulated through the shelves for product heating and cooling, the refrigerant employed inside the vapor condenser cooling surface and oil vapors that may migrate back from the vacuum pumping system.
冻干机的泄漏有不同的来源。象一些真空箱，泄漏使空气进入容器内部。其他来源是冻干过程使用的一些媒介。包括为产品加热和制冷的热传递液体；冷凝蒸发器内制冷剂；真空泵油的回流。
Any one, or a combination of all, can contribute to the leakage of gases and vapors into the system. It is necessary to monitor the leak rate periodically to maintain the integrity of the system. It is also necessary, should the leak rate exceed specified
limits, to determine the actual leak site for purposes of repair.
不论是哪种方式，都会造成气体或蒸汽进入系统。需要定期的监控泄漏率，以维护系统的完整性。确定泄漏率符合限度，确定真实的泄漏率以判断是否需要进行修补。
Thus, it would be beneficial to perform a leak test at some time after sterilization, possibly at the beginning of the cycle or prior to stoppering. The time and frequency for performing the leak test will vary and will depend on the data developed during the cycle validation. The pressure rise found acceptable at validation should be used to determine the acceptable pressure rise during production. A limit and what action is to be taken if excessive leakage is found should be addressed in some type of operating document.
灭菌之后、开始循环之前或全加塞之前进行泄漏测试是有益的进行泄漏测试的时间和频率是多种多样的。是需要在循环验证中积累的数据来确定。在验证中确定的压力升高可接收标准将被用在生产过程中。泄漏限度和发生泄漏后如何处理应写在相关的文件中。
In order to minimize oil vapor migration, some lyophilizers are designed with a tortuous path between the vacuum pump and chamber. For example, one fabricator installed an oil trap in the line between the vacuum pump and chamber in a lyophilizer with an internal condenser. Leakage can also be identified by sampling surfaces in the chamber after lyophilization for contaminants. One could conclude that if contamination is found on a chamber surface after lyophilization, then dosage units in the chamber could also be contaminated. It is a good practice as part of the validation of cleaning of the lyophilization chamber to sample the surfaces both before and after cleaning.
为了最小化油蒸汽的回流，一些冻干机在真空泵和前箱间设计了弯曲的管路。例如有的制造商在真空泵和前箱间安装了有内部冷凝器的捕油器。可以在冻干结束后进行前箱的表面污染物取样，判断是否泄漏。如果判定在冻干结束后前箱的表面被污染，那么也可以判定产品也被污染。在冻干机清洗验证中的好的方法是在清洗的前后进行表面取样。
Because of the lengthy cycle runs and strain on machinery, it is not unusual to see equipment malfunction or fail during a lyophilization cycle. There should be provisions in place for the corrective action to be taken when these atypical situations occur. In addition to documentation of the malfunction, there should be an evaluation of the possible effects on the product (e.g., partial or complete meltback. Refer to subsequent discussion). Merely testing samples after the lyophilization cycle is concluded may be insufficient to justify the release of the remaining units. For example, the leakage of chamber shelf fluid into the chamber or a break in sterility would be cause for rejection of the batch.
因为周期较长和机械疲劳，设备故障和冻干失败是比较常见的现象。当非典型的状况出现时必须规定纠正措施。另外，在故障的文件中应对产品可能存在的潜在影响进行评价。仅仅对冻干后的产品进行检验来判定是否放行是不可接收的。例如板层油泄漏到板层中，会导致拒绝这批产品。
The review of Preventive Maintenance Logs, as well as Quality Assurance Alert Notices, Discrepancy Reports, and Investigation Reports will help to identify problem batches when there are equipment malfunctions or power failures. It is recommended that these records be reviewed early in the inspection.
当设备故障或动力故障发生时，回顾预防性维护记录、QA警告、偏差报告、调查报告是对鉴定问题批次有帮助的。推荐在进行检查前就回顾这些记录。 CYCLE VALIDATION
Many manufacturers file (in applications) their normal lyophilization cycles and validate the lyophilization process based on these cycles. Unfortunately, such data would be of little value to substantiate shorter or abnormal cycles. In some cases, manufacturers are unaware of the eutectic point. It would be difficult for a manufacturer to evaluate partial or abnormal cycles without knowing the eutectic point and the cycle parameters needed to facilitate primary drying.
一些生产商把正常的冻干循环文件化，并且基于这种循环进行冻干过程的验证。不幸的是这些数据对于突发的或不正常的循环没有价值。在一些案例里，生产商不知道产品的共晶点。不知道产品的共晶点，对于不正常的循环的评价是困难的。循环参数需要指导主干燥。
Scale-up for the lyophilized product requires a knowledge of the many variables that may have an effect on the product. Some of the variables would include freezing rate and temperature ramping rate. As with the scale-up of other drug products, there should be a development report that discusses the process and logic for the cycle. Probably more so than any other product, scale-up of the lyophilization cycle is very difficult.
放大生产冻干产品，需要知道更多的变量，这些变量会影响产品。这些变量包括冷冻速率和温度斜率。放大气体的药物产品，需要一个报告，用于讨论循环的过程和逻辑。与其他的产品相比，放大一个冻干循环是十分困难的。
There are some manufacturers that market multiple strengths, vial sizes and have different batch sizes. It is conceivable and probable that each will have its own cycle parameters. A manufacturer that has one cycle for multiple strengths of the same product probably has done a poor job of developing the cycle and probably has not adequately validated their process. Investigators should review the reports and data that support the filed lyophilization cycle.
一些生产商销售不同浓度、不同瓶子尺寸，不同批量大小的产品。可以想像它们