冻干检查指南（中英文对照）.docx

本文格式为Word版，下载可任意编辑冻干检查指南（中英文对照） 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). INTRODUCTION 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、主枯燥（生化）和二次枯燥（解吸附） The advantages of lyophilization include: 冻干的优点： Ease of processing a liquid, which simplifies aseptic handling 简朴的液体过程，无菌处理简朴 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 在枯燥的处境下提高产品的稳定性 Rapid and easy dissolution of reconstituted product 快速简朴的产品复溶 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 恢复时需要无菌液体 Cost and complexity of equipment 负责、昂贵的设备 The lyophilization process generally includes the following steps: 冻干过程包括以下步骤： 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，举行灭菌 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。

在检查中察觉，无菌和稳定性问题与冻干产品的制造和操纵紧密联系 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. 现在公认繁杂的技术与冻干制剂的制造和操纵相互关联。

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议论是关于与冻干制剂制造和操纵相关的问题 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 that are lyophilized, such as hydrocortisone sodium succinate, methylprednisolone sodium succinate and many of the biotechnology derived products, have no antibacterial effect when in solution. 使用冻干方法举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由于它们是抗生素，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才能 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 th。