2018年3月1日 EDQM發布快速實施EP 1486通知，通知全文及EP 1486全文如下。

通知官網鏈接：https://www.edqm.eu/en/news/rapid-implementation-monograph-products-fermentation-1468

由於快速實施來不及更新印刷版本和下載版本EP，官網提供1486公開下載地址：https://www.edqm.eu/sites/default/files/1468e.pdf

文中紅字部分為新增內容

Rapid implementation of the monograph Products of fermentation (1468)

發酵產品各論（1486）快速實施

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).

鑒於與組胺污染有關的公眾健康風險，發酵產品各論（1486）的原料部分已增加了原料質量相關的更多要求。

Therevised monograph will be implemented on1 April 2018. The pdf version of thetextis 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.

修訂後的各論將於2018年4月1日實施。PDF版本可以官網下載。修訂後的各論已自9.4增補開始增加到EP在線版本中。印刷版和下載版將自9.6增補版本中增加。

04/2018:1468

PRODUCTSOF FERMENTATION發酵產品

Productaab fermentatione

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

本各論適用於發酵獲得的直接基因產品，不適用於：

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

–人用和獸用疫苗相關的藥典各論；

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

–人體或動物來源連續細胞線生成的產品；

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

–核苷酸轉譯成蛋白生成的直接基因產品，無論轉譯後是否修飾；

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

–從發酵產品半合成獲得的產品，以及通過生物催化轉化獲得的產品；

–whole broth concentrates orraw fermentation products.

–發酵液整體濃縮或原始發酵產品。

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.

本各論為發酵產品的開發和生產提供通用要求。這些要求在特定情形下並不必須全部滿足，對本各論中所述內容的補充要求和附加要求可能會以產品各論方式或由葯監當局強制執行。

DEFINITION定義

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.

在本各論中，發酵產品指通過受控發酵生產的作為直接基因產品的活性或非活性藥用物質。它們是微生物如細菌、酵母菌、黴菌和微藻的一級或二級代謝物，可能經過或未經過傳統的工藝或重組DNA（rDNA）技術修飾。此類代謝物包括維生素、氨基酸、抗生素、生物鹼和多糖。

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

可以通過間歇或連續發酵工藝，加上萃取、濃縮、精製和分離等程序獲得此類產品。

PRODUCTION生產

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.

生產應基於一個經過驗證並證明穩定的工藝。驗證的程度取決於相應工藝步驟的關鍵程度。

CHARACTERISATIONOF THE PRODUCER MICRO-ORGANISM生產商微生物鑒定

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

應記錄用於生產的微生物歷史。微生物應充分鑒定。

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.

鑒定可能包括確定微生物的顯形、目視和顯微方法以及生化測試和，適當時，確定微生物的基因類型以及進行分子基因測試。

PROCESSESUSING A SEED-LOT SYSTEM使用種子批系統的工藝

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.

工作細胞庫應為細胞原料的均勻的混懸液或凍乾粉，分裝於各容器中存貯。必須證明在所選擇的存貯條件下細胞的活性和生長力，以及存貯後其適合用於啟動成功的生產工藝。母細胞庫可以通過工作細胞庫的種子批系統傳代。

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).

工作細胞庫應為從母細胞庫製得的細胞原料的均勻的混懸液或凍乾粉，以相等體積分裝於各容器中存貯（例如，存貯在液氮中）。

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

生產可採用間歇式或連續式培養，可以在指定條件下停止。

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.

細胞庫中所有容器均應存貯在相同的條件下。一旦從存貯處取出，該支安瓿、小瓶或培養管即不可再退回細胞庫中。

PROCESSESUSING STAGED GROWTH IN CULTURES培養中使用分段生長的工藝

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.

應使用工作細胞庫容器中的內容物（必要時製作混懸液）在適當的培養基中製備菌液。在生長適當時長後，使用培養物開始發酵工藝，必要時在預培養罐中先進行預培養。應指定工藝每個步驟所用條件，並且每個生產周期均應符合這些條件。

CHANGECONTROL變更控制

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.

如果生產工藝的變更會導致產品雜質概況的重大變化，則應重新驗證與雜質概況變化有關的關鍵工藝。

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.

如果用於生產的微生物發生重大變更，導致產品雜質概況發生重大變化，則與此變更有關的生產工藝的關鍵步驟，尤其是精製和分離程序，應進行再驗證。

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.

再驗證包括證明由於變更而出現在產品中的新雜質已由檢驗方法進行充分的控制。必要時，必須引入具有適當限度的附加方法或替代方法。如果工藝變更或微生物變更導致現有雜質水平增加，則應說明此類增加的可接受程度。

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.

如果更換母細胞庫，則必須對生產工藝的關鍵步驟進行再驗證，驗證程度應證明產品質量和安全未產生不良變化。如果引入修飾後或新的微生物至該工藝，則必須特別注意產品雜質概況的可能變化。

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.

發酵和/或下游工藝所用原料應具備其既定用途所需的適當質量。應對其進行檢測以確保其符合書面質量標準。必須特別注意魚蛋白腖中自由組胺酸的水平，因為自遊離組胺酸可能在特定條件下會導致組胺形成。

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.

培養基和供氧進氣中生物負載的水平應降低至足夠低的水平以確保如果發生微生物污染，其不會對產品的質量、純度和安全性產生不良影響。發酵期間加入組份如營養成分、前體和基質等應無菌添加。

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.

應有中控確保發酵期間和下游加工期間條件的一致性，以及所分離產品質量的一致性。必須特別注意確保所有對產品質量、純度和安全性產生不良影響的微生物污染均能被所執行的控制檢出。

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

適當時，可採用適當的程序對生產條件進行監測，如控制和檢查：

–temperature,溫度

–pH,

–rate of aeration,補氣速度

–rate of agitation,攪拌速度

–pressure,壓力

and to monitor theconcentration of the required product.

以及監測所需產品的濃度。

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.

在發酵結束時，生產用微生物應滅活或清除。應設計進一步加工工藝養活培養基中的殘留物至可接受水平，並確保所回收的有用產品具備一致的質量。

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:

可採用不同純化工藝，例如，活性炭處理、超濾和溶劑萃取。必須證明所選擇的工藝可將以下清除或降至最低：

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

–生產用微生物、培養基、基質和前體中的殘留；

–unwanted transformationproducts of substrates and precursors.

–基質和前體的非所需轉化物；

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

必要時應實施適當的檢測作為中控或對分離出的發酵產品進行適當檢測。

IDENTIFICATION,TESTS AND ASSAY鑒別、檢查和含量

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

產品在其有效其內必須符合的要求，以及具體的檢測方法在產品各論中列出。

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