发布时间 : 星期三 文章冻干检查指南（中英文对照）更新完毕开始阅读
大概有自己的循环参数。一个生产商使用一个循环为同一个产品的不同浓度，说明它们没有开发循环，而且没有充分的验证它们的过程。调查人应回顾报告和数据去支持文件化的大概循环。
LYOPHILIZER STERILIZATION/DESIGN 冻干机的灭菌和设计
The sterilization of the lyophilizer is one of the more frequently encountered problems noted during inspections. Some of the older lyophilizers cannot tolerate steam under pressure, and sterilization is marginal at best. These lyophilizers can only have their inside surfaces wiped with a chemical agent that may be a sterilant but usually has been found to be a sanitizing agent. Unfortunately, piping such as that for the administration of inert gas (usually nitrogen) and sterile air for backfill or vacuum break is often inaccessible to such surface \very difficult for a manufacturer to be able to demonstrate satisfactory validation of sterilization of a lyophilizer by chemical \
在检查过程中，冻干机的灭菌是被提问到的最多的问题。一些老的冻干机不能忍受灭菌的压力。灭菌最多也是最低限度的。这些冻干机只能使用化学溶液利用抹布对冻干机内表面进行处理，这些溶液可能是杀菌剂，但大部分是消毒剂。但是一些管路系统，例如进气管路（氮气），用于回填的无菌空气，或者是真空管路，难以达到表面灭菌的状态。生产商很难证明使用化学处理的方法进行灭菌的验证是令人满意的。
Another method of sterilization that has been practiced is the use of gaseous ethylene oxide. As with any ethylene oxide treatment, humidification is necessary. Providing a method for introducing the sterile moisture with uniformity has been found to be difficult.
另一种灭菌方法是使用环氧乙烷。在使用环氧乙烷灭菌时需要控制湿度。很难找到无菌而且潮湿的方法。
A manufacturer has been observed employing Water For Injection as a final wash or rinse of the lyophilizer. While the chamber was wet, it was then ethylene oxide gas sterilized. As discussed above, this may be satisfactory for the chamber but inadequate for associated plumbing.
一个生产商说冻干机的最终淋洗水是WFI，所以箱体是湿的，可以进行环氧乙烷灭菌。这对箱体来说是可以的，但是相关的管路是不行的。
Another problem associated with ethylene oxide is the residue. One manufacturer had a common ethylene oxide/nitrogen supply line to a number of lyophilizers connected in parallel to the system. Thus, there could be some ethylene oxide in the nitrogen supply line during the backfilling step. Obviously, this type of system is objectionable.
有关环氧乙烷灭菌的另一个问题是残留。一个生产商环氧乙烷的进口公用氮气的进口。很明显管路中残留的环氧乙烷会在进行氮气回填的时候进入箱体，这时不可接受的。
A generally recognized acceptable method of sterilizing the lyophilizer is through the use of moist steam under pressure. Sterilization procedures should parallel that of an autoclave, and a typical system should include two independent temperature sensing systems. One would be used to control and record temperatures of the cycle as with sterilizers, and the other would be in the cold spot of the chamber. As with autoclaves, lyophilizers should have drains with atmospheric breaks to prevent back siphonage. 一个可以接受的冻干机灭菌方法是使用湿润的蒸汽在一定的压力下进行灭菌。灭菌过程与蒸汽灭菌柜相同。典型的相同包括两个独立的温度探头。一个用于控制和记录灭菌过程的温度，另一个安放在箱体的冷点。与蒸汽灭菌柜一样，冻干机的下水应有液封，防止大气回流。
As discussed, there should also be provisions for sterilizing the inert gas or air and the supply lines. Some manufacturers have chosen to locate the sterilizing filters in a port of the chamber. The port is steam sterilized when the chamber is sterilized, and then the sterilizing filter, previously sterilized, is aseptically connected to the chamber. Some manufacturers have chosen to sterilize the filter and downstream piping to the chamber in place. Typical sterilization-in-place of filters may require steaming of both to obtain sufficient temperatures. In this type of system, there should be provisions for removing and/or draining condensate. The failure to sterilize nitrogen and air filters and the piping downstream leading into the chamber has been identified as a problem on a number of inspections.
作为一个讨论，必须规定进入气体或空气和供应管路需要灭菌。一些生产商使用安放在箱体上的除菌滤器。Port是随箱体进行蒸汽灭菌的。除菌滤器是预先灭菌的。然后在无菌条件下进行连接。一些生产商选择在线对除菌滤器和下游管路进行灭菌。典型的过滤器SIP需要双向通蒸汽，以达到灭菌温度。在这种方式下需要排除冷凝水。失败的氮气和空气过滤器及下游管路的灭菌被许多检查员认为是个问题。
Since these filters are used to sterilize inert gas and/or air, there should be some assurance of their integrity. Some inspections have disclosed a lack of integrity testing of the inert gas and/or air filter. The question is frequently asked how often should the vent filter be tested for integrity? As with many decisions made by manufacturers, there is a level of risk associated with the operation, process or system, which only the manufacturer can decide. If the sterilizing filter is found to pass the integrity test after several uses or batches, then one could claim its integrity for the previous batches. However, if it is only tested after several batches have been processed and if found to fail the integrity test, then one could question the sterility of all of the previous
batches processed. In an effort to minimize this risk, some manufacturers have resorted to redundant filtration.
使用过滤器对氮气和空气进行灭菌，必须保证过滤器的完整性。一些检查发现，没有对过滤器进行完整性测试。“多长时间进行通风过滤器的完整性监测”经常被问到。生产商必须判定是否存在一定的风险水平，关系到操作、过程和系统。如果在使用几次或几批后发现过滤器通过完整性监测，有人杂批开始前进行完整性检查。然而，在生产结束后进行检查，如果发现完整性检查失败，就会置疑之前生产的批次。为了最小化风险，一些生产商安装多余的过滤器。
For most cycles, stoppering occurs within the lyophilizer. Typically, the lyophilizer has some type of rod or rods (ram) which enter the immediate chamber at the time of stoppering. Once the rod enters the chamber, there is the potential for contamination of the chamber. However, since the vials are stoppered, there is no avenue for contamination of the vials in the chamber which are now stoppered. Generally, lyophilizers should be sterilized after each cycle because of the potential for contamination of the shelf support rods. Additionally, the physical act of removing vials and cleaning the chamber can increase levels of contamination.
很多循环中全加塞在冻干机里完成，冻干机里有一些螺杆，在全加塞时使用。一旦使用这些螺杆，就会对箱体内造成潜在的污染。然而一旦全加塞完成，污染物就没有通道进入瓶子中。通常冻干机每个循环结束后都需要灭菌，因为板层的制成螺杆存在潜在的污染。另外移走瓶子和箱体清洁会增加污染水平。
In some of the larger units, the shelves are collapsed after sterilization to facilitate loading. Obviously, the portions of the ram entering the chamber to collapse the shelves enters from a non-sterile area. Attempts to minimize contamination have included wiping the ram with a sanitizing agent prior to loading. Control aspects have included testing the ram for microbiological contamination, testing it for residues of hydraulic fluid, and testing the fluid for its bacteriostatic effectiveness. One lyophilizer fabricator has proposed developing a flexible \
In addition to microbiological concerns with hydraulic fluid, there is also the concern with product contamination.
During steam sterilization of the chamber, there should be space between shelves that permit passage of free flowing steam. Some manufacturers have placed \between shelves to prevent their total collapse. Others have resorted to a two phase sterilization of the chamber. The initial phase provides for sterilization of the shelves when they are separated. The second phase provides for sterilization of the chamber and piston with the shelves collapsed.
灭菌过程中，板层应该流出一定的空间，让流通蒸汽通过。一些生产商在板层之间使用“spaces”防止它们全部叠在一起。另外有人使用两阶段箱体灭菌。第一阶段是板层分离时灭菌，第二阶段是对箱体灭菌、活塞灭菌（板层叠在一起）。
Typically, biological indicators are used in lyophilizers to validate the steam sterilization cycle. One manufacturer of a Biopharmaceutical product was found to have a positive biological indicator after sterilization at 121oC for 45 minutes. During the chamber sterilization, trays used to transport vials from the filling line to the chamber were also sterilized. The trays were sterilized in an inverted position on shelves in the chamber. It is believed that the positive biological indicator is the result of poor steam penetration under these trays.
在冻干机蒸汽灭菌验证中会使用生物指示剂。应该生产商风险在经过121℃45分钟灭菌后生物指示剂为阳性。在灭菌过程中，托盘被倒扣在板层上，蒸汽无法穿透托盘，造成生物指示剂为阳性。
The sterilization of condensers is also a major issue that warrants discussion. Most of the newer units provide for the capability of sterilization of the condenser along with the chamber, even if the condenser is external to the chamber. This provides a greater assurance of sterility, particularly in those situations in which there is some equipment malfunction and the vacuum in the chamber is deeper than in the condenser. 冷凝器的灭菌是一直被讨论的。一些新的系统能够使冷凝器与前箱一同灭菌，即使冷凝器是在前箱以外的。这提供了更高的无菌保证，当设备故障时，前箱的真空度要比冷凝器高。
Malfunctions that can occur, which would indicate that sterilization of the condenser is warranted, include vacuum pump breakdown, refrigeration system failures and the potential for contamination by the large valve between the condenser and chamber. This is particularly true for those units that have separate vacuum pumps for both the condenser and chamber. When there are problems with the systems in the lyophilizer, contamination could migrate from the condenser back to the chamber. It is recognized that the condenser is not able to be sterilized in many of the older units, and this represents a major problem, particularly in those cycles in which there is some equipment and/or operator failure.
当发生故障时，更证明冷凝器灭菌是有正当理由的。包括真空泵崩溃、冷冻系统失败、前箱与冷凝器之间的主阀存在的潜在的污染。一些系统上，前箱和冷凝器有分离的真空泵，当冻干机故障时，污染物会从冷凝器回流到前箱。在一些老的系统上冷凝器是无法灭菌的。在这些系统上的循环和操作是失败的。
As referenced above, leakage during a lyophilization cycle can occur, and the door seal or gasket presents an avenue of entry for contaminants. For example, in an inspection, it was noted that during steam sterilization of a lyophilizer, steam was leaking from the unit. If steam could leak from a unit during sterilization, air could possibly enter the chamber during lyophilization.
在冻干过程中有可能发生泄漏，门上的密封圈或垫圈有可能是污染物的通道。有人检查时发现，冻干机灭菌时有蒸汽泄漏出来，蒸汽可以泄漏，也说明了在冻干