GUIDE TO INSPECTIONS OF
LYOPHILIZATION OF PARENTERALS
Note: This document is reference material for investigators and other FDA personnel. The document does not bind FDA, and does no confer any rights, privileges, benefits, or immunities for or on any person(s).
generatedINTRODUCTION
Lyophilization or freeze drying is a process in which water is removed from a product after it is frozen and placed under a vacuum, allowing the ice to change directly from solid to vapor without passing through a liquid phase. The process consists of three separate, unique, and interdependent processes; freezing, primary drying (sublimation), and secondary drying (desorption).
冻干是将产品置于冷冻和真空的状态下，除去水分的过程。在这个过程中冰有固态直接变为水蒸汽，而不经过液态。这个过程由三个独立的分开的又相互影响的过程组成。冷冻、主干燥（生化）和二次干燥（解吸附）。
The advantages of lyophilization include:
冻干的优点：
Ease of processing a liquid, which simplifies aseptic handling
简单的液体过程，无菌处理简单。
Enhanced stability of a dry powder
提高干粉的稳定性。
Removal of water without excessive heating of the product
不需要过多的加热产品就可以除去水分。
Enhanced product stability in a dry state
在干燥的情况下提高产品的稳定性。
Rapid and easy dissolution of reconstituted product
快速简单的产品复溶
Disadvantages of lyophilization include:
冻干的缺点
Increased handling and processing time
增加操作和处理时间
Need for sterile diluent upon reconstitution
还原时需要无菌液体
Cost and complexity of equipment
负责、昂贵的设备
The lyophilization process generally includes the following steps:
冻干过程包括下列步骤：
Dissolving the drug and excipients in a suitable solvent, generally water for injection (WFI).
把产品和赋形剂溶解于适当的溶媒中，通常是注射用水。
Sterilizing the bulk solution by passing it through a 0.22 micron bacteria-retentive filter.
使用0.22微米的除菌滤摸过滤原液，进行灭菌。
Filling into individual sterile containers and partially stoppering the containers under aseptic conditions.
在无菌条件下分倒装单个的无菌容器中，半加塞。
Transporting the partially stoppered containers to the lyophilizer and loading into the chamber under aseptic conditions.
在无菌条件下转移半加塞的容器到冻干机中，放置在前箱中。
Freezing the solution by placing the partially stoppered containers on cooled shelves in a freeze-drying chamber or pre-freezing in another chamber.
在冻干机的前箱板层或其他的预冷冻箱体内将半加塞容器内的液体冷冻。Applying a vacuum to the chamber and heating the shelves in order to evaporate the water from the frozen state.
使用真空泵并加热板层，使水分由冷冻状态下蒸。发
Complete stoppering of the vials usually by hydraulic or screw rod stoppering mechanisms installed in the lyophilizers.
使用安装在冻干机内的液压装置或螺杆全加塞。
There are many new parenteral products, including anti-infectives, biotechnology derived products, and in-vitro diagnostics which are manufactured as lyophilized products. Additionally, inspections have disclosed potency, sterility and stability problems associated with the manufacture and control of lyophilized products. In order to provide guidance and information to investigators, some industry procedures and deficiencies associated with lyophilized products are identified in this Inspection Guide.
一些新的非肠道给药产品，包括抗感染药物、生物技术起源的药物、诊断药物采用冻干的方法生产。在检查中发现，无菌和稳定性问题与冻干产品的制造和控制密切联系。
It is recognized that there is complex technology associated with the manufacture and control of a lyophilized pharmaceutical dosage form. Some of the important aspects of these operations include:
the formulation of solutions; filling of vials and validation of the filling operation; sterilization and engineering aspects of the lyophilizer; scale-up and validation of the lyophilization cycle; and testing of the end product. This discussion will address some of the problems associated with the manufacture and control of a lyophilized dosage form.
现在公认复杂的技术与冻干制剂的制造和控制相互关联。关键的步骤包括：溶液的处方、瓶子灌装和灌装操作的验证、冻干机的灭菌和动力因素、按比例扩大和冻干周期的验证、最终产品的测试。这个讨论是关于与冻干制剂制造和控制相关的问题。
PRODUCT TYPE/FORMULATION
产品类型和处方
Products are manufactured in the lyophilized form due to their instability when in solution. Many of the antibiotics, such as some of the semi-synthetic penicillins,
cephalosporins, and also some of the salts of erythromycin, doxycycline and chloramphenicol are made by the lyophilization process. Because they are antibiotics, low bioburden of these formulations would be expected at the time of batching. However, some of the other dosage forms th
at are lyophilized, such as hydrocortisone sodium succinate, methylprednisolone sodium succinate and many of the biotechnology derived products, have no antibacterial effect when in solution.
使用冻干方法进行制造产品是由于它在溶液中不稳定。一些抗生素如半合成的青霉素、一些含盐的红霉素、强力霉素、氯霉素使用冻干方法制造。因为它们是抗生素，所以在定量的时候处方里有较低的微生物污染水平。然而有些其他的剂形采用冻干方法，如一些激素类的产品和生物技术来源的产品，当它们是溶液时没有抗菌能力。
For these types of products, bioburden should be minimal and the bioburden should be determined prior to sterilization of these bulk solutions prior to filling. Obviously, the batching or compounding of these bulk solutions should be controlled in order to prevent any potential increase in microbiological levels that may occur up to the time that the bulk solutions are filtered (sterilized). The concern with any microbiological level is the possible increase in endotoxins that may develop. Good practice for the compounding of lyophilized products would also include batching in a controlled environment and in sealed tanks, particularly if the solution is to be held for any length of time prior to sterilization.
这些产品，微生物污染水平应被控制在最小的水平上，微生物的污染决定了，原液在进行灌装前必须经过灭菌。显然，为了避免在原液除菌过滤时，任何潜在的微生物污染水平的升高，所以在定量和混
合这些原液时必须严格控制。这关系到微生物污染水平可能引起内毒素的升高。好的方法是在混合冻干产品时，定量操作在一个受控的环境进行，在灭菌前的时间里溶液应在一个密闭的罐中。
In some cases, manufacturers have performed bioburden testing on bulk solutions after prefiltration and prior to final filtration. While the testing of such solutions may be meaningful in determining the bioburden for sterilization, it does not provide any information regarding the potential formation or presence of endotoxins. While the testing of 0.1 ml samples by LAL methods of bulk solution for endotoxins is of value, testing of at least 100 ml size samples prior to prefiltration, particularly for the presence of gram negative organisms, would be of greater value in evaluating the process. For example, the presence of Pseudomonas sp. in the bioburden of a bulk solution has been identified as an objectionable condition.
在一些案例中，生产厂商，在原液进行预滤后，在进行最终过滤前取样进行微生物污染水平测试。这个测试表示着进行灭菌时的微生物污染水平。它不能提供任何信息关于潜在的形式和内毒素的存在。这时取样0.1ml原液样品，用LAL法
测定内毒素是有价值的。如果在预滤前取样100ml，克级的生物阴性结果，对于评价这个过程更有价值。例如在原液中使用假单孢菌模拟一个最差条件。FILLING
灌装
The filling of vials that are to be lyophilized has some problems that are somewhat unique. The stopper is placed on top of the vial and is ultimately seated in the lyophilizer. As a result the contents of the vial are subject to contamination until they are actually sealed.
灌装冻干产品的瓶子有些独特的问题。胶塞加载在瓶子的顶部，最终在冻干机内定位。瓶子在被完全密闭前都会被污染。
V alidation of filling operations should include media fills and the sampling of critical surfaces and air during active filling (dynamic conditions).
灌装操作的验证必须包括培养基灌装和灌装过程中的表面微生物取样评价和空气取样评价（动态条件）。
Because of the active involvement of people in filling and aseptic manipulations, an environmental program should also include an evaluation of microbiological levels on people working in aseptic processing areas. One method of evaluation of the training of operators working in aseptic processing facilities includes the surface monitoring of gloves and/or gowns on a daily basis. Manufa
cturers are actively sampling the surfaces of personnel working in aseptic processing areas. A reference which provides for this type of monitoring is the USP XXII discussion of the Interpretation of Sterility Test Results. It states under the heading of "Interpretation of Quality Control Tests" that review consideration should be paid to environmental control data, icrobial monitoring, records of operators, gowns, gloves, and garbing practices. In those situations in which manufacturers have failed to perform some type of personnel monitoring, or monitoring has shown unacceptable levels of contamination, regulatory situations have resulted.
因为这些活动包括人员在灌装和无菌操作的活动，所以当人员在无菌处理区域工作时环境监控程序必须包括微生物污染水平的评价。评价在无菌处理车间中工作人员的培训，可以监控每日手套和工作服的表面微生物污染水平。在USP XXII 中讨论了解释无菌测试结果，可以作为这类监控类型的参考。它在“解释质量控制测试”项目下被描述，回顾必须基于环境控制数据，包括微生物监控、操作记录、工作服、手套和更衣活动。在这些情况下，生产商有一些失败的人员监控，或者是监控表明了一些不可接收的污染水平，必须要调整这些情况。Typically, vials to be lyophilized are partially stoppered by machine. However, some filling lines have been noted which utilize an operator to place each stopper on top of the vial by hand. At this time, it would seem that it would be difficult for a manufacturer to justify a hand-stoppering operation, even if sterile forceps are
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. V alidation 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

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