EDQM 发酵产品各论(1486)快速实施

蒲公英 2020-10-14 18:02:23

翻译: julia  来源: Julia法规翻译

2018年3月1日 EDQM发布快速实施EP 1486通知,通知全文及EP 1468全文如下。

通知官网链接:https://www.edqm.eu/en/news/rapid-implementation-monograph-products-fermentation-1468

由于快速实施来不及更新印刷版本和下载版本EP,官网提供1486公开下载地址:https://www.edqm.eu/sites/default/files/1468e.pdf

文中红字部分为新增内容


Rapid implementation of the monograph Products of fermentation (1468)

发酵产品各论(1468)快速实施

 Due to the public health risk associated withhistamine contamination, further requirements related to the quality of rawmaterials have been added to the Raw materials section of the monograph onProducts of fermentation (1468).

鉴于与组胺污染有关的公众健康风险,发酵产品各论(1486)的原料部分已增加了原料质量相关的更多要求。

Therevised monograph will be implemented on 1 April 2018. The pdf version of thetext is availablehere. The revised monograph has already been added to the onlineversion of the Ph. Eur., starting with Supplement 9.4. It will be included inthe printed and downloadable versions starting with Supplement 9.6.

修订后的各论将于201841实施。PDF版本可以官网下载。修订后的各论已自9.4增补开始增加到EP在线版本中。印刷版和下载版将自9.6增补版本中增加。

04/2018:1468

PRODUCTSOF FERMENTATION 发酵产品

Productaab fermentatione

This monograph applies toindirect gene products obtained by fermentation. It is not applicable to:

本各论适用于发酵获得的直接基因产品,不适用于:

–      monographs in thePharmacopoeia concerning vaccines for human or veterinary use;

     人用和兽用疫苗相关的药典各论;

–      products derived fromcontinuous cell lines of human or animal origin;

     人体或动物来源连续细胞线生成的产品;

–      direct gene products thatresult from the transcription and translation from nucleic acid to protein,whether or not subject to post-translational modification;

     核苷酸转译成蛋白生成的直接基因产品,无论转译后是否修饰;

–      products obtained bysemi-synthesis from a product of fermentation and those obtained bybiocatalytic transformation;

     从发酵产品半合成获得的产品,以及通过生物催化转化获得的产品;

–      whole broth concentrates orraw fermentation products.

     发酵液整体浓缩或原始发酵产品。

This monograph providesgeneral requirements for the development and manufacture of products offermentation. These requirements are not necessarily comprehensive in a givencase and requirements complementary or additional to those prescribed in thismonograph may be imposed in an individual monograph or by the competentauthority.

本各论为发酵产品的开发和生产提供通用要求。这些要求在特定情形下并不必须全部满足,对本各论中所述内容的补充要求和附加要求可能会以产品各论方式或由药监当局强制执行。

DEFINITION定义

For the purposes of thismonograph, products of fermentation are active or inactive pharmaceutical substancesproduced by controlled fermentation as indirect gene products. They are primaryor secondary metabolites of micro-organisms such as bacteria, yeasts, fungi andmicro-algae, whether or not modified by traditional procedures or recombinantDNA (rDNA) technology. Such metabolites include vitamins, amino acids,antibiotics, alkaloids and polysaccharides.

在本各论中,发酵产品指通过受控发酵生产的作为直接基因产品的活性或非活性药用物质。它们是微生物如细菌、酵母菌、霉菌和微藻的一级或二级代谢物,可能经过或未经过传统的工艺或重组DNArDNA)技术修饰。此类代谢物包括维生素、氨基酸、抗生素、生物碱和多糖。

They may be obtained by batchor continuous fermentation processes followed by procedures such as extraction,concentration, purification and isolation.

可以通过间歇或连续发酵工艺,加上萃取、浓缩、精制和分离等程序获得此类产品。

PRODUCTION生产

Production is based on aprocess that has been validated and shown to be suitable. The extent ofvalidation depends on the critical nature of the respective process step.

生产应基于一个经过验证并证明稳定的工艺。验证的程度取决于相应工艺步骤的关键程度。

CHARACTERISATIONOF THE PRODUCER MICRO-ORGANISM 生产商微生物鉴定

The history of themicro-organism used for production is documented. The micro-organism isadequately characterised.

应记录用于生产的微生物历史。微生物应充分鉴定。

This may include determinationof the phenotype of the micro-organism, macroscopic and microscopic methods andbiochemical tests and, if appropriate, determination of the genotype of themicro-organism and molecular genetic tests.

鉴定可能包括确定微生物的显形、目视和显微方法以及生化测试和,适当时,确定微生物的基因类型以及进行分子基因测试。

PROCESSESUSING A SEED-LOT SYSTEM 使用种子批系统的工艺

The master cell bank is ahomogeneous suspension or lyophilisate of the original cells distributed intoindividual containers for storage. The viability and productivity of the cellsunder the selected storage conditions and their suitability for initiating asatisfactory production process after storage must be demonstrated. Propagationof the master cell bank may take place through a seed-lot system that uses aworking cell bank.

工作细胞库应为细胞原料的均匀的混悬液或冻干粉,分装于各容器中存贮。必须证明在所选择的存贮条件下细胞的活性和生长力,以及存贮后其适合用于启动成功的生产工艺。母细胞库可以通过工作细胞库的种子批系统传代。

The working cell bank is ahomogeneous suspension or lyophilisate of the cell material derived from themaster cell bank, distributed in equal volumes into individual containers forstorage (for example, in liquid nitrogen).

工作细胞库应为从母细胞库制得的细胞原料的均匀的混悬液或冻干粉,以相等体积分装于各容器中存贮(例如,存贮在液氮中)。

Production may take place bybatch or continuous culture and may be terminated under defined conditions.

生产可采用间歇式或连续式培养,可以在指定条件下停止。

All containers in a cell bankare stored under identical conditions. Once removed from storage, theindividual ampoules, vials or culture straws are not returned to the cell bank.

细胞库中所有容器均应存贮在相同的条件下。一旦从存贮处取出,该支安瓿、小瓶或培养管即不可再退回细胞库中。

PROCESSESUSING STAGED GROWTH IN CULTURES 培养中使用分段生长的工艺

The contents of a container ofthe working cell bank are used, if necessary after resuspension, to prepare aninoculum in a suitable medium. After a suitable period of growth, the culturesare used to initiate the fermentation process, if necessary followingpreculture in a prefermentor. The conditions to be used at each stage of theprocess are defined and must be met with each production run.

应使用工作细胞库容器中的内容物(必要时制作混悬液)在适当的培养基中制备菌液。在生长适当时长后,使用培养物开始发酵工艺,必要时在预培养罐中先进行预培养。应指定工艺每个步骤所用条件,并且每个生产周期均应符合这些条件。

CHANGECONTROL 变更控制

If the production process isaltered in a way that causes a significant change in the impurity profile ofthe product, the critical steps associated with this change in impurity profileare revalidated.

如果生产工艺的变更会导致产品杂质概况的重大变化,则应重新验证与杂质概况变化有关的关键工艺。

If a significant change hastaken place in the micro-organism used for production that causes a significantchange in the impurity profile of the product, the critical steps of the productionprocess associated with this change, particularly the procedure forpurification and isolation, are revalidated.

如果用于生产的微生物发生重大变更,导致产品杂质概况发生重大变化,则与此变更有关的生产工艺的关键步骤,尤其是精制和分离程序,应进行再验证。

Revalidation includesdemonstration that new impurities present in the product as a result of the changeare adequately controlled by the test procedures. If necessary, additional or alternativetests must be introduced with appropriate limits. If the change in the processor in the micro-organism results in an increase in the level of an impurityalready present, the acceptability of such an increase is addressed.

再验证包括证明由于变更而出现在产品中的新杂质已由检验方法进行充分的控制。必要时,必须引入具有适当限度的附加方法或替代方法。如果工艺变更或微生物变更导致现有杂质水平增加,则应说明此类增加的可接受程度。

When a master cell bank isreplaced, the critical steps of the production process must be revalidated tothe extent necessary to demonstrate that no adverse change has occurred in the qualityand safety of the product. Particular attention must be given to possible changesin the impurity profile of the product if a modified or new micro-organism isintroduced into the process.

如果更换母细胞库,则必须对生产工艺的关键步骤进行再验证,验证程度应证明产品质量和安全未产生不良变化。如果引入修饰后或新的微生物至该工艺,则必须特别注意产品杂质概况的可能变化。

RAWMATERIALS 原料

The raw materials employed inthe fermentation and/or down-stream processing are of suitable quality for the intendedpurpose. They are tested to ensure that they comply with writtenspecifications. Special attention must be paid to the levels of free histidine in fish peptones as the presence of free histidine may lead to histamine formation in certain conditions.

发酵和/或下游工艺所用原料应具备其既定用途所需的适当质量。应对其进行检测以确保其符合书面质量标准。必须特别注意鱼蛋白胨中自由组胺酸的水平,因为自游离组胺酸可能在特定条件下会导致组胺形成。

Levels of bioburden in mediaor in the inlet air for aeration are reduced to an adequately low level toensure that if microbial contamination occurs, it does not adversely affect thequality, purity and safety of the product. Addition of components such asnutrients, precursors, and substrates during fermentation takes placeaseptically.

培养基和供氧进气中生物负载的水平应降低至足够低的水平以确保如果发生微生物污染,其不会对产品的质量、纯度和安全性产生不良影响。发酵期间加入组份如营养成分、前体和基质等应无菌添加。

IN-PROCESSCONTROLS 中控

In-process controls are inplace to ensure the consistency of the conditions during fermentation anddown-stream processing and of the quality of the isolated product. Particularattention must be paid to ensure that any microbial contamination that adverselyaffects the quality, purity and safety of the product is detected by thecontrols applied.

应有中控确保发酵期间和下游加工期间条件的一致性,以及所分离产品质量的一致性。必须特别注意确保所有对产品质量、纯度和安全性产生不良影响的微生物污染均能被所执行的控制检出。

Production conditions may bemonitored, as appropriate, by suitable procedures for example to control andcheck:

适当时,可采用适当的程序对生产条件进行监测,如控制和检查:

      temperature, 温度

–      pH,

      rate of aeration, 补气速度

      rate of agitation, 搅拌速度

      pressure, 压力

and to monitor theconcentration of the required product.

以及监测所需产品的浓度。

DOWN-STREAMPROCESSING 下游加工

At the end of fermentation,the producer micro-organism is inactivated or removed. Further processing isdesigned to reduce residues originating from the culture medium to an acceptablelevel and to ensure that the desired product is recovered with consistentquality.

在发酵结束时,生产用微生物应灭活或清除。应设计进一步加工工艺养活培养基中的残留物至可接受水平,并确保所回收的有用产品具备一致的质量。

Various purification processesmay be used, for example, charcoal treatment, ultrafiltration and solventextraction. It must be demonstrated that the process or processes chosen reduceto a minimum or remove:

可采用不同纯化工艺,例如,活性炭处理、超滤和溶剂萃取。必须证明所选择的工艺可将以下清除或降至最低:

–      residues from the producermicro-organism, culture media, substrates and precursors,

     生产用微生物、培养基、基质和前体中的残留;

–      unwanted transformationproducts of substrates and precursors.

     基质和前体的非所需转化物;

If necessary, suitable testsare performed either as in-process controls or on the isolated product offermentation.

必要时应实施适当的检测作为中控或对分离出的发酵产品进行适当检测。

IDENTIFICATION,TESTS AND ASSAY 鉴别、检查和含量

The requirements with which theproduct must comply throughout its period of validity, as well as specific testmethods, are stated in the individual monographs.

产品在其有效其内必须符合的要求,以及具体的检测方法在产品各论中列出。