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1、GUIDE TO INSPECTIONS OF STERILE DRUG SUBSTANCE MANUFACTURERSFDA无菌原料药检查指南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). 注：本文件是FDA现场检查官和其他FD
2、A人员的参考资料。本文件并不束缚FDA，也不赋予任何人任何权利、特权、利益或豁免权。One of the more difficult processes to inspect and one which has presented considerable problems over the years is that of the manufacture of sterile bulk drug substances. Within the past several years, there have been a number of batches of sterile bulk dru
3、g substances from different manufacturers which exhibited microbiological contamination. One manufacturer had approximately 100 batches contaminated in a 6 month time period. Another had approximately 25 batches contaminated in a similar period. Other manufacturers have had recalls due to the lack o
4、f assurance of sterility. Although the Inspection Guide for Bulk Drug Substances provides some direction for the inspection of the sterile bulk drug substance, it does not provide the detailed direction needed.多年来现场检查最难的、也是出现问题最多的领域就是无菌原料药的生产。在过去几年中，有数批来自不同制造商的无菌原料药出现了微生物污染。一个制造商在6个月中有100批产品有污染。另一个在
5、相同的时间内出现了25批污染。其它一些生产商由于缺少无菌保证而召回了产品。虽然大宗原料药的现场检查指南在对无菌原料药的检查上提供了一些指导，但它未能提供所需要的详细指导。I. INTRODUCTION简介In the manufacture of the sterile bulk powders, it is important to recognize that there is no further processing of the finished sterile bulk powder to remove contaminants or impurities such as part
6、iculates, endotoxins and degradants.在大宗无菌粉的制造中，认识到下面一点很重要，即最终无菌粉生产出来之后，再也没有别的处理来去除微粒、内毒素和降解物。As with other inspections, any rejected batches, along with the various reasons for rejection, should be identified early in the inspection to provide direction for the investigator. For example, lists of ba
7、tches rejected and/or retested over a period of time should be obtained from the manufacturer to provide direction for coverage to be given to specific processes or systems. Because some of the actual sterile bulk operations may not be seen, and because of the complexity of the process, it is partic
8、ularly important to review reports and summaries, such as validation studies, reject lists, Environmental Monitoring Summary Reports, QA Investigation Logs, etc. These systems and others are discussed in the Basic Inspection Guide. This is particularly important for the foreign sterile bulk drug sub
9、stance manufacturer where time is limited. In the preparation for a sterile bulk drug substance inspection, a flow chart with the major processing steps should be obtained. Generally, the manufacture of a sterile bulk substance usually includes the following steps: 与其它检查一样，在检查的早期，应向检查官提供拒绝使用的批（不合格批）
10、及拒绝的各种理由，以使检查官把握方向。例如，应从制造商处获得一段时间内拒绝的批（不合格批）清单，为检查具体的工艺或系统提供方向。由于某些实际无菌操作可能看不见，同时加上工艺的复杂性，审阅一些报告和总结，如验证研究、拒绝（不合格批）清单、环境监控总结报告、质量保证调查记录等就变得非常重要。这些系统和相关部分在基本现场检查指南中有论述。这对海外无菌原料药制造商尤其重要，因为受时间所限。在准备无菌原料药现场检查时，应获得包含主要工艺步骤的流程图。通常，无菌原料药的生产包含如下步骤：1. Conversion of the non-sterile drug substance to the steri
11、le form by dissolving in a solvent, sterilization of the solution by filtration and collection in a sterilized reactor (crystallizer). 1. 通过在溶媒中溶解，将非无菌原料药转换为无菌原料药。溶液通过过滤除菌后收集在一个无菌反应罐中（即结晶罐）。2. Aseptic precipitation or crystallization of the sterile drug substance in the sterile reactor.2. 在无菌反应罐中进行无
12、菌沉淀或结晶。3. Aseptic isolation of the sterile substance by centrifugation or filtration.3. 通过离心或过滤实现无菌分离。4. Aseptic drying, milling and blending of the sterile substance.4.无菌干燥、磨粉和混合。5. Aseptic sampling and packaging the drug substance.5.无菌抽样和包装。These operations should be performed in closed systems, w
13、ith minimal operator handling. Any aseptic operations performed by an operator(s) other than in a closed system should be identified and carefully reviewed.这些操作应在密闭系统进行，尽可能少的人工参与。如果操作员在密闭系统之外进行无菌操作，应当标示出来并仔细审查。II. COMPONENTS组成部分In addition to the impurity concerns for the manufacture of bulk drug su
14、bstances, there is a concern with endotoxins in the manufacture of the sterile bulk drug substances. The validation report, which demonstrates the removal, if present, of endotoxins to acceptable levels, should be reviewed. Some manufacturers have commented that since an organic solvent is typically
15、 used for the conversion of the non-sterile bulk drug substance to the sterile bulk drug substance, that endotoxins will be reduced at this stage. As with any operation, this may or may not be correct. For example, in an inspection of a manufacturer who conducted extensive studies of the conversion (crystallization) of the non-sterile substance to the sterile drug substance, they found no cha
