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
employed, in any type of operation other than filling a clinical batch or very small number of units. Significant regulatory situations have resulted when some manufacturers have hand-stoppered vials. Again, the concern is the immediate avenue of contamination offered by the operator. It is well recognized that people are the major source of contamination in an aseptic processing filling operation. The longer a person works in an aseptic operation, the more microorganisms will be shed and the greater the probability of contamination.
有代表性的是，被冻干的瓶子由机器进行半加塞。然而一些灌装线表明使用操作工用手安装每个胶塞。这种状况，生产商证明用手操作是正当的是很困难的，即使是使用无菌镊子，除非是灌装临床批次或非常小的批产量。当生产商采用手工加塞时，导致了重大的调整状况。进而关系到污染物直接有操作人员产生。这是一个很好的认识：人是无菌灌装操作过程中的主要污染物。人员在无菌操作工作的时间约长，就会有更多的污染物散发出来，加大污染的可能性。
Once filled and partially stoppered, vials are transported and loaded into the lyophilizer. The transfer and handling, such as loading of the lyophilizer, should take place under primary barriers, such as the laminar flow hoods under which the vials were filled. Validation of this handling should also include the use media fills. 一旦灌装和半加塞，瓶子将被摆放到冻干机。传递和操作（如摆放到冻干机）应处于主要的屏障保护下，例如灌装后的瓶子处于层流罩的保护下。使用培养基灌装验证这种操作。
Regarding the filling of sterile media, there are some manufacturers who carry out a partial lyophilization cycle and freeze the media. While this could seem to greater mimic the process, the freezing of media could reduce microbial levels of some contaminants. Since the purpose of the media fill is to evaluate and justify the aseptic capabilities of the process, the people and the system, the possible reduction of microbiological levels after aseptic manipulation by freezing would not be warranted. The purpose of a media fill is not to determine the lethality of freezing and its effect on any microbial contaminants that might be present.
关于无菌培养基灌装，一些生产商进行部分冻干和冷冻培养基，这样看起来好像更好的模拟了过程，冷冻培养基的过程可以减少微生物的污染水平。培养基灌装是评价和证明过程、人员、系统的无菌能力，这种通过冷冻培养基可能减少微生物污染水平的行为是不能被接收的。培养基灌装的目的不是确定冷冻的毁坏性，它可能会影响本该表现出来的微生物污染水平。
In an effort to identify the particular sections of filling and aseptic manipulation that might introduce contamination, several manufacturers have resorted to expanded media fills. That is, they have filled approximately 9000 vials during a media fill and segmented the fill into three stages. One stage has included filling of 3000 vials and
stoppering on line; another stage included filling 3000 vials, transportation to the lyophilizer and then stoppering; a third stage included the filling of 3000 vials, loading in the lyophilizer, and exposure to a portion of the nitrogen flush and then stoppering. Since lyophilizer sterilization and sterilization of the nitrogen system used to backfill require separate validation, media fills should primarily validate the filling, transportation and loading aseptic operations.
为了努力确定灌装和无菌操作的单元操作可能带入的污染，一些生产商采取增加培养基灌装量。他们在培养基灌装中大约灌装9000瓶，把灌装过程分割为3个阶段。第一部分是灌装3000瓶并且加塞，第二部分是灌装3000瓶，传递到冻干机中再全加塞，第三部分是灌装3000瓶，排放到冻干机内，暴露在氮气流下冻干机的灭菌和用于回填的无菌氮气系统分别进行验证，培养基灌装主要验证灌装、传递和摆放的无菌操作。
The question of the number of units needed for media fills when the capacity of the process is less than 3000 units is frequently asked, particularly for clinical products. Again, the purpose of the media fill is to assure that product can be aseptically processed without contamination under operating conditions. It would seem, therefore, that the maximum number of units of media filled be equivalent to the maximum batch size if it is less than 3000 units.
有个问题经常被问到，就是当生产能力小于3000瓶时的培养基灌装数量，特别是在进行临床样品制备时。培养基灌装的目的是保证在操作条件下的无菌过程不被污染物污染。因此当最大的批产量小于3000瓶时，培养基灌装的数量应等同于最大的批产量。
After filling, dosage units are transported to the lyophilizer by metal trays. Usually, the bottom of the trays are removed after the dosage units are loaded into the lyophilizer. Thus, the dosage units lie directly on the lyophilizer shelf. There have been some situations in which manufacturers have loaded the dosage units on metal trays which were not removed. Unfortunately, at one manufacturer, the trays warped which caused a moisture problem in some dosage units in a batch.
灌装后药物通过金属托盘传递到冻干机里。通常当药物摆放到冻干机里后，托盘底部要被抽走。从而药物直接摆放在冻干机的板层上。有些情况是，生产商摆放药物时不抽走托盘底部。不幸的是托盘的不平会导致一批内的一些产品潮湿问题。
In the transport of vials to the lyophilizer, since they are not sealed, there is concern for the potential for contamination. During inspections and in the review of new facilities, the failure to provide laminar flow coverage or a primary barrier for the transport and loading areas of a lyophilizer has been regarded as an objectionable condition. One manufacturer as a means of correction developed a laminar flow cart
to transport the vials from the filling line to the lyophilizer. Other manufacturers building new facilities have located the filling line close to the lyophilizer and have provided a primary barrier extending from the filling line to the lyophilizer.
在传递瓶子到冻干机里，由于瓶子不是密闭的，所以存在潜在的污染可能性。在检查和回顾一些新的工厂时，在传递和摆放到冻干机的区域缺乏一个层流罩或主要的屏障被认为是不可接收的。有的生产商的补救措施是使用层流车，在灌装线和冻干机之间传递瓶子。还有的生产商建造新的车间时，将灌装线和冻干机摆放的很近，并且在灌装机和冻干机之间安装主要的屏障。
In order to correct this type of problem, another manufacturer installed a vertical laminar flow hood between the filling line and lyophilizer. Initially, high velocities with inadequate return caused a contamination problem in a media fill. It was speculated that new air currents resulted in rebound contamination off the floor. Fortunately, media fills and smoke studies provided enough meaningful information that the problem could be corrected prior to the manufacture of product. Typically, the lyophilization process includes the stoppering of vials in the chamber.
为了解决这类问题，一些生产商在灌装线和冻干机之间安装层流罩。最初由于周转频率太快，导致了培养基灌装的污染问题。推测可能是气流由地板反弹造成的污染。幸运的是培养基灌装和烟笔试验提供了足够的有用信息，能够在生产产品前纠正问题。冻干过程包括在冻干机前箱内的全加塞。
Another major concern with the filling operation is assurance of fill volumes. Obviously, a low fill would represent a subpotency in the vial. Unlike a powder or liquid fill, a low fill would not be readily apparent after lyophilization particularly for a biopharmaceutical drug product where the active ingredient may be only a milligram. Because of the clinical significance, sub-potency in a vial potentially can be a very serious situation.
另一个主要的问题是灌装过程中保证灌装量。很明显低灌装量会造成药物效力的降低。不象粉末和液体灌装，冻干后的产品不能明显的发现低灌装量。特别是生物药品，它们的活性成分可能仅有几毫克。因为临床的重要性，潜在的药效降低将被严肃对待。
For example, in the inspection of a lyophilization filling operation, it was noted that the firm was having a filling problem. The gate on the filling line was not coordinated with the filling syringes, and splashing and partial filling was occurring. It was also observed that some of the partially filled vials were loaded into the lyophilizer. This resulted in rejection of the batch.
例如，检查一个冻干的灌装操作，显示了这个公司存在灌装操作问题。灌装线上的闸门没有按照灌装注射器进行调整，洒料，不平均的灌装是事故。观察到一些
部分灌装的产品被装载到冻干机。这样的结果是拒绝这批产品。
On occasion, it has been seen that production operators monitoring fill volumes record these fill volumes only after adjustments are made. Therefore, good practice and a good quality assurance program would include the frequent monitoring of the volume of fill, such as every 15 minutes. Good practice would also include provisions for the isolation of particular sections of filling operations when low or high fills are encountered.
观察灌装量只是通过检查操作人的灌装量监控记录，灌装量是通过调整调节器决定的。好的方法和好的质量管理程序是包括装量检查的频率，例如每15分钟检查一次。好的方法是当发现低或高灌装量时应隔离。
There are some atypical filling operations which have not been discussed. For example, there have also been some situations in which lyophilization is performed on trays of solution rather than in vials. Based on the current technology available, it would seem that for a sterile product, it would be difficult to justify this procedure. 一些非典型的灌装操作没有讨论，例如，有些冻干是在托盘上进行的而不是在瓶子里，基于现在的技术条件，把它看成无菌产品，是很难被证明是正当的。 The dual chamber vial also presents additional requirements for aseptic manipulations. Media fills should include the filling of media in both chambers. Also, the diluent in these vials should contain a preservative. (Without a preservative, the filling of diluent would be analogous to the filling of media. In such cases, a 0% level of contamination would be expected.)
双腔体瓶子对无菌操作提出了新的要求。培养基灌装必须包括灌装两个腔体。 LYOPHILIZATION CYCLE AND CONTROLS 冻干周期控制
After sterilization of the lyophilizer and aseptic loading, the initial step is freezing the solution. In some cycles, the shelves are at the temperature needed for freezing, while for other cycles, the product is loaded and then the shelves are taken to the freezing temperature necessary for product freeze. In those cycles in which the shelves are precooled prior to loading, there is concern for any ice formation on shelves prior to loading. Ice on shelves prior to loading can cause partial or complete stoppering of vials prior to lyophilization of the product. A recent field complaint of a product in solution and not lyophilized was attributed to preliminary stoppering of a few vials prior to exposure to the lyophilization cycle. Unfortunately, the firm's 100% vial inspection failed to identify the defective vial.
冻干机灭菌和无菌摆放后的第一个步骤是冷冻溶液。在一些冻干周期里板层已经冷冻到冷冻温度，在另外一些循环中，当产品摆放到冻干机板层后才开始进行冷冻到冷冻温度。在预先冷冻的循环过程中，在板层表面在产品摆放之前会结冰。在摆放产品前板层结冰，会导致冻干开始前瓶子被部分或完全封闭。最近的一些