EP 通论 1468 发酵产品（中英文）---翻译人：Julia

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EP 通论 1468 发酵产品（中英文） 2013-08-09 16:47:07| 分类： EP |举报|字号 订阅 01/2008:1468 PRODUCTS OF FERMENTATION 发酵产品 This monograph applies to indirect gene products obtained by fermentation. It is not applicable to: 本通论适用于经过发酵获得的间接基因产品。不适用于： — Monographs in the Pharmacopoeia concerning vaccines for human or veterinary use; — 药典中关于人用和兽用疫苗的各论 — Products derived from continuous cell lines of human or animal origin; — 由人或动物源连续细胞线产生的产品 — Direct gene products that result from the transcription and translation from nucleic acid to protein, whether or not subject to post-translational modification; — 采用核酸转录和翻译为蛋白的直接基因产品，不论在转移后是否修饰 — Products obtained by semi-synthesis from a product of fermentation and those obtained by biocatalytic transformation; — 由发酵产品半合成所得的产品，由生物催化转化所得的产品 — Whole broth concentrates or raw fermentation products. — 发酵液浓缩物或原始发酵产品 This monograph provides general requirements for the development and manufacture of products of fermentation. These requirements are not necessarily comprehensive in a given case and requirements complementary or additional to those prescribed in this monograph may be imposed in an individual monograph or by the competent authority. 本通论对发酵产品的研发和生产提供一般要求。这些要求在特定的案例中并不一定要包括，在各论中或官方可能会提出本通论以外的补充或附加要求，要求生产商实施。 DEFINITION 定义 For the purpose of this monograph, products of fermentation are active or inactive pharmaceutical substances produced by controlled fermentation as indirect gene products. They are primary or secondary metabolites of micro-organisms such as bacteria, yeasts, fungi and micro-algae, whether or not modified by traditional procedures or recombinant DNA (rdna) technology. Such metabolites include vitamins, amino acids, antibiotics, alkaloids and polysaccharide. 本通论中，发酵产品指通过受控的发酵工艺产生的活性或非活性药用物质，为间接基因产品。这些产品为微生物的初级或高级代谢产物，如细菌、酵母菌、霉菌和微型藻类，经过或不经过传统工艺或DNA（RDNA）重组技术获得。这种代谢产物包括维生素、氨基酸、抗生素、生物碱类和多聚糖类。 They may be obtained by batch or continuous fermentation processes followed by procedures such as extraction, concentration, purification and isolation. 发酵产品可以由按批或连续的发酵工艺，经过后续处理如萃取、浓缩、纯化和分离获得。 PRODUCTION 生产 Production is based on a process that has been validated and shown to be suitable. The extent of validation depends on the critical nature of the respective process step. 生产应基于经过验证证明适当的工艺。验证的深度取决于相关的工艺步骤的关键程度。 CHARACTERISATION OF THE PRODUCER MICRO-ORGANISM 产生的微生物的特性 The history of the micro-organism used for production is documented. The micro-organism is adequately characterized. This may include determination of the phenotype of the micro-organism, macroscopic and microscopic methods and biochemical tests and, if appropriate, determination of the genotype of the micro-organism and molecular genetic tests. 用于生产的微生物的历史应该记录。微生物应进行充分鉴定，鉴定可以包括微生物种属的确认，宏观和微观的方法和生物化学测试，和（适当时）微生物种属鉴别和分子基因检测。 PROCESSES USING A SEED-LOT SYSTEM 采用种子批系统的工艺 The master cell bank is a homogeneous suspension or lyophilisate of the original cells distributed into individual containers for storage. The viability and productivity of the cells under the selected storage conditions and their suitability for initiating a satisfactory production process after storage must be demonstrated. 主细胞库是原始细胞混合均匀的混悬液或冻干粉，分装于单个容器中进行存贮。细胞在所选择的存贮条件下的活性和再生性，及其在存贮后用于初始工艺的适用性需要进行证明。 Propagation of the master cell bank may take place through a seed-lot system that uses a working cell bank. 主细胞库的传代应采用种子批号系统，使用工作细胞库。 The working cell bank is a homogeneous suspension or lyophilisate of the cell material derived from the master cell bank, distributed in equal volumes into individual containers for storage (for example, in liquid nitrogen). 工作细胞库是一个从主细胞库中产生出的细胞原料混合均匀的混悬液或冻干粉，分装在同样体积的容器中进行存贮（例如装在液氮中） Production may take place by batch or continuous culture and may be terminated under defined conditions. 生产可以按批次进行，也可以持续培养，在界定的条件下结束。 All containers in a cell bank are stored under identical conditions. Once removed from storage, the individual ampoules, vials or culture straws are not returned to the cell bank. 所有细胞库中的容器均应在均一条件下存贮。一旦从存贮条件移出，则该安瓿、小瓶或菌种管不能再返回细胞库。 PROCESSES USING STAGED GROWTH IN CULTURES 采用菌种分段生长的工艺 The contents of a container of the working cell bank are used, if necessary after resuspension, to prepare an inoculum in a suitable medium. After a suitable period of growth, the cultures are used to initiate the fermentation process, if necessary following preculture in a prefermentor. The conditions to be used at each stage of the process are defined and must be met with each production run. 一般在生产中会采用工作细胞库容器中的菌种（必要时此前进行混悬培养），接种在适当的培养基上。经过一段时间的生长，将菌种用于初步的发酵工艺，必要时其后在发酵罐中进行预发酵。每个阶段所采用的条件需要进行界定，每一个生产批次均需要符合这些条件。 CHANGE CONTROL 变更控制 If the production process is altered in a way that causes a significant change in the impurity profile of the product, the critical steps associated with this change in impurity profile are revalidated. 如果生产工艺变更引起产品杂质概况的显著变更，与此变更相关的引起杂质概况变更的关键步骤需要进行再验证。 If a significant change has taken place in the micro-organism used for production that causes a significant change in the impurity profile of the product, the critical steps of the production process associated with this change, particularly the procedure for purification and isolation, are revalidated. 如果对用于生产的微生物的重大变更，引起产品杂质概况的显著变化，则与此变更相应的关键生产步骤，尤其是纯化和分离步骤需要进行再验证。 Revalidation includes demonstration that new impurities present in the product as a result of the change are adequately controlled by the test procedures. If necessary, additional or alternative tests must be introduced with appropriate limits. If the change in the process or in the micro-organism results in an increase in the level of an impurity already present, the acceptability of such an increase is addressed. 再验证包括证明产品中由于变更引起的新杂质可以由检验方法进行充分地控制。必要时，应增加附加测试或替代测试，并制订适当的限度。如果工艺变更或微生物变更引起已有杂质水平升高，则需要说明该增加的可接受标准。 When a master cell bank is replaced, the critical steps of the production process must be revalidated to the extent necessary to demonstrate that no adverse change has occurred in the quality and safety of the product. Particular attention must be given to possible changes in the impurity profile of the product if a modified or new micro-organism is introduced into the process. 如果主细胞库被替换，生产工艺的关键步骤必须进行重新验证，以证明对产品的质量和安全性没有负面影响。如果采用了修饰的或新的微生物用于生产，尤其要注意产品杂质概况的可能变化。 RAW MATERIALS 原料 The raw materials employed in the fermentation and/or down-stream processing are of suitable quality for the intended purpose. They are tested to ensure that they comply with written specifications. 用于发酵和/或后续处理的原料的质量应满足其所需用途，需要对其进行检测以保证其符合书面质量标准。 Levels of bioburden in media or in the inlet air for aeration are reduced to an adequately low level to ensure that if microbiological contamination occurs, it does not adversely affect the quality, purity and safety of the product. Addition of components such as nutrients, precursors, and substrates during fermentation takes place aseptically. 培养基或进气的生物负载水平应降低至一定的低水平，以保证如果发生微生物污染，不会对产品质量、纯度和安全性造成负面影响。在发酵期间加入相关成份，如营养剂、前体和基质的操作应为无菌操作。 IN-PROCESS CONTROLS 中间控制 In-process controls are in place to ensure the consistency of the conditions during fermentation and down-stream processing and of the quality of the isolated product. Particular attention must be paid to ensure that any microbial contamination that adversely affects the quality, purity and safety of the product is detected by the controls applied. 中控是为了保证发酵期间生产条件、后期处理条件和分离出的产品质量的一致性，需要特别注意的要保证会对产品质量、纯度和安全性造成负面影响的微生物污染能被这些控制所检出。 Production conditions may be monitored, as appropriate, by suitable procedures for example to control and check: 生产条件需要采用合适的方法进行适当监控，监控项目举例如下 — temperature, — 温度 — pH, — pH值 — rate of aeration, — 进气速度 — rate of agitation, — 搅拌速度 — pressure, — 压力 and to monitor the concentration of the required product. 并监控所需产品的浓度。 DOWN-STREAM PROCESSING 后续处理 At the end of fermentation, the producer micro-organism is inactivated or removed. Further processing is designed to reduce residues originating from the culture medium to an acceptable level and to ensure that the desired product is recovered with consistent quality. 在发酵结束后，产生的微生物被灭活或清除。后期处理用于降低菌种培养基产生的残留至可接受水平，保证获得品质一致的产品。 Various purification processes may be used, for example, charcoal treatment, ultrafiltration and solvent extraction. It must be demonstrated that the process or processes chosen reduce to a minimum or remove: 可以采用不同的提纯工艺，例如，活性炭处理，超滤和溶剂萃取。必须证明所选用的这些工艺可以最大程度降低或移除以下杂质 — residues from the producer micro-organism, culture media, substrate and precursors, — 微生物、培养基和前体中的残留 — unwanted transformation products of substrates and precursors. — 预期之外的基质和前体转化产品 If necessary, suitable tests are performed either as in-process controls or on the isolated product of fermentation. 必要时，应在中控或发酵物分离时进行适当的检测。 IDENTIFICATION, TESTS AND ASSAY 鉴别、检查和含量 The requirements with which the product must comply throughout its period of validity, as well as specific test methods, are stated in the individual monographs. 各产品在其有效期内所应符合的要求，和其特定的检验方法均在各产品的各论中说明。

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