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发表于 2015-7-1 08:00:33
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Lyophilization Operation - The methods employed for lyophilization process simulation are generally
similar to those used for solution fills with the addition of the transport, loading, simulation of
freeze-drying, stoppering, unloading, and closing steps. Presented below are several possible means for
evaluation of these activities. Other approaches are possible.
冻干操作－这个冻干工艺模拟试验一般和液体灌装类似， 增加了转移， 装载，冻干模拟，加塞， 出
箱以及关闭的步骤。。下面介绍一些评价这些活动的可能的方法，其他的方法也是可以采用的。
4.3.1 Simulated Load/Unload with Shortened Hold Time
模拟进箱、出箱停留的时间
Containers are filled with medium, and stoppers are partially inserted. The containers are loaded into the
lyophilizer at ambient temperature. A partial vacuum, insufficient to cause boiling of the medium, is drawn
on the chamber and this level is held for a pie-determined time. The chamber is then vented and the
stoppers are seated within the chamber. The stoppered units are removed from the aseptic processing area
and sealed.
培养基灌装到容器中，在瓶颈上进行半加塞。将容器放置到冻干机内部。加载部分真空，保持一个
预先确定的时间周期。然后箱体破真空，在箱体内进行全加塞。加塞了的瓶子从无菌区域转移，并
且密封。
Advantage(s)
优点
The medium is not frozen. Therefore, there are fewer concerns with regard to microbial survival in a
freezing process or the ability of the medium to support growth.
培养基不冷冻。所以不存在冷冻过程对微生物的影响和对培养基促生长的影响。
Focuses on loading and sealing activities, which are presumed to be the greatest source of potential
contamination.
假定进箱和全加塞是过程中最大的潜在污染源。
4.3.2 Simulated lyophilization
模拟冻干
Containers are filled with (full strength) medium, and stoppers are partially inserted in the necks. The
containers are transported and loaded into the lyophilizer. A partial vacuum, insufficient to cause boiling of
the medium, is drawn on the chamber at ambient temperature, and maintained for the duration of a normal
lyophilization process. The stoppered units are removed from the lyophilizer and sealed.
培养基灌装到容器中，在瓶颈上进行半加塞。容器转移并安放到冻干机内。在冻干机的
箱体内全部或部分的抽真空，维持一个正常的冻干过程时间。然后箱体破空，在箱体内
进行全加塞。加塞了的瓶子从无菌区域转移，并且密封。
Advantage(s)
优点
The medium is not frozen. Therefore, there are fewer concerns about microbial survival in a freezing
process or the ability of the medium to support growth.
培养基不冷冻。所以不存在冷冻过程对微生物的影响和对培养基促生长的影响。
Simulates duration of the lyophilization process.
模拟整个冻干工艺。
Disadvantage(s)
缺点
Time-consuming to perform, extending the simulation through the entire lyophilization cycle.
耗时较长，要完成全部的冻干循环。
4.3.3 Special Considerations unique to the Production of lyophilized Products
对于冻干产品的特殊考虑
4.3.3.1 Freezing of Media
培养基的冷冻
In order to maximize microbial recovery, freezing of media is not recommended.
为了使微生物的回收最大化，不建议冷冻培养基。
4.3.3.2 Vacuum Levels and Duration
真空水平和维持时间
In the simulation of a lyophilization process, the depth of vacuum drawn on the chamber and the period of
time for which this vacuum is held are important considerations. The vacuum must not be so low as to
permit the medium in the container to boil out, thereby invalidating the simulation.
在进行冻干工艺模拟时，施加在冻干机的真空程度和真空时间时需要重点观注的。真空度需要保持
在一个低水平上，避免由于容器内的培养基沸腾，因而造成模拟失败。
4.3.3.3 Anaerobic Conditions
厌氧条件
In the production of lyophilized products it is common practice to use sterile inert gases to break the
vacuum on the chamber. These gases can remain in the product containers after sealing. Where
Soybean-Casein Digest Medium is used for the conduct of the process simulation, air should be used rather
than an inert gas to assure aerobic conditions for the process simulation. The introduction of air and the
elimination of the inert gas introduction should not enhance the aseptic process or represent a
'better-than-production' process condition. (See Section 7.3.) The use of an inert gas and anaerobic
medium (e.g. Alternate Fluid Thioglycollate Medium) would be appropriate where the persistent presence
of strict anaerobic organisms has been confirmed in either environmental monitoring or, more likely,
during end product sterility testing. Where anaerobes have not been detected in the environmental
monitoring or sterility testing, lyophilizer process simulations should utilize Soybean-Casein Digest
Medium and air.
对于冻干产品常见的是用无菌的惰性气体对箱体进行破空，并且在密封后仍然存在在容器中。在使
用大豆胰蛋白消化肉汤培养基进行工艺模拟实验时，使用空气要优于使用惰性气体，以保证一个有
氧的条件。 采用空气和消除惰性气体并不能提高无菌工艺或表示better-than-production的工艺条件。
（见7.3章。） 如果在日常的环境监测中确定发现了厌氧菌，甚至在最终产品的无菌监测中发现了厌
氧菌，则应该使用惰性气体和厌氧培养基（ Fluid Thioglycollate Medium）。如果在日常的环境监测和
产品的无菌监测中没有确定发现厌氧菌，冻干工艺模拟实验应该使用大豆胰蛋白胨消化肉汤培养基
和空气。 |
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