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近日，歐盟EudraGMDP數(shù)據(jù)庫(kù)更新了一則GMP檢查不符合報(bào)告，其中提及HPLC 系統(tǒng)上的操作系統(tǒng)（Windows XP、Windows 7）過(guò)時(shí)的缺陷，此外還指出其未能實(shí)施歐盟 GMP 新版附錄 1“無(wú)菌藥品生產(chǎn)”的核心原則，包括場(chǎng)地設(shè)計(jì)、物料管理、無(wú)菌區(qū)域的人員行為、暴露表面的質(zhì)量、人員培訓(xùn)等：

檢查機(jī)構(gòu)：西班牙藥監(jiān)局

被檢查企業(yè)：Nectar Life Sciences Limited

最近一次檢查：2025 年 2 月 11日

檢查結(jié)論：不符合

During inspection, 28 deficiencies were identified, 4 of them has been classified as critical and 3 as major. The critical deficiencies are related to Quality Assurance management, aseptic operations in relation to compliance with Annex I of the GMP, maintenance and cleaning of equipment and facilities, and computerised systems. And the major deficiencies were observed in the areas to validation of analytical methods, staff training and batch release.

在檢查過(guò)程中，發(fā)現(xiàn)了 28 項(xiàng)缺陷，其中 4 項(xiàng)被歸類為嚴(yán)重缺陷，3 項(xiàng)被歸類為主要缺陷。嚴(yán)重缺陷與質(zhì)量保證管理、與 GMP 附錄1 相關(guān)的無(wú)菌操作、設(shè)備和設(shè)施的維護(hù)和清潔以及計(jì)算機(jī)化系統(tǒng)有關(guān)。在分析方法驗(yàn)證、員工培訓(xùn)和批放行方面觀察到了主要缺陷。

Since the deficiencies found transversally affect both the manufacturing of non-sterile APIs (some of whose manufacturing facilities were also inspected) as well as sterile API facilities, it has been decided to issue an statement of Non-compliance with GMP that affects both types of products.

由于發(fā)現(xiàn)的缺陷同時(shí)影響了非無(wú)菌 API 的生產(chǎn)（其中一些生產(chǎn)設(shè)施也接受了檢查）和無(wú)菌API 設(shè)施，因此決定發(fā)布影響這兩種類型的產(chǎn)品的不符合 GMP 聲明。

The most relevant or critical deficiencies observed during the inspection are described below :

在檢查期間觀察到的缺陷描述如下：

- A number of severe violations of EU GMP Part II, EU GMP Annex 1 and Annex 11, potentially posing a risk to the quality of manufactured products and therefore to public health, demonstrated a lack of Quality Assurance oversight and understanding of core requirements.

-嚴(yán)重違反歐盟 GMP 第II 部分、歐盟 GMP 附錄 1 和附錄 11，可能對(duì)產(chǎn)品的質(zhì)量構(gòu)成風(fēng)險(xiǎn)，從而對(duì)公眾健康構(gòu)成風(fēng)險(xiǎn)，表明缺乏質(zhì)量保證監(jiān)督和對(duì)核心要求的理解。

- The company failed to implement core principles of EU GMP Annex 1 “Manufacture of Sterile Medicinal Products”. Consequently, the sterility of the Active Pharmaceutical Ingredients (API) manufactured in Block SE, Nectar Life Science Unit II, cannot be guaranteed, posing a risk to human and/or veterinary health. Abundant and important shortcomings were found among the site related to but not limited to site design, materials management, personnel behavior in aseptic areas, quality of exposed surfaces and failure to identify applicable requirements, risks and risk mitigation measures regarding revised Annex and general GMP requirements.

該公司未能實(shí)施歐盟 GMP 附錄 1“無(wú)菌藥品生產(chǎn)”的核心原則。因此，無(wú)法保證所生產(chǎn)的活性藥物成分（API）的無(wú)菌性，導(dǎo)致對(duì)健康構(gòu)成風(fēng)險(xiǎn)。在現(xiàn)場(chǎng)發(fā)現(xiàn)了大量重要的缺陷，包括但不限于場(chǎng)地設(shè)計(jì)、物料管理、無(wú)菌區(qū)域的人員行為、暴露表面的質(zhì)量，以及未能確定與新修訂GMP附錄和一般 GMP 要求相關(guān)的要求、風(fēng)險(xiǎn)和風(fēng)險(xiǎn)緩解措施。

-There is a significant risk of contamination/cross contamination of non-sterile APIs/intermediates manufactured based on the cleaning and/or maintenance status of the facility and the equipment used. Several observations made during the inspection of Oral Block F conclude that the manufacturing facilities and equipment for active ingredients have not been adequately maintained over the years, resulting in a significant deterioration of their condition and therefore posing a risk to the quality of APIs and ultimately to the patient. These observations include lack of maintenance, cleaning, presence of corrosion, concrete cracks, signs of liquid leakages, lack of hand-washing facilities, and other significant signs of poor maintenance, management and hygiene.

根據(jù)設(shè)施和所用設(shè)備的清潔和/或維護(hù)狀態(tài)進(jìn)行生產(chǎn)的非無(wú)菌 API/中間體存在污染/交叉污染的重大風(fēng)險(xiǎn)。在檢查期間進(jìn)行的幾次觀察得出結(jié)論，活性成分的生產(chǎn)設(shè)施和設(shè)備多年來(lái)沒(méi)有得到充分維護(hù)，導(dǎo)致其狀況惡化，因此對(duì)API 的質(zhì)量構(gòu)成風(fēng)險(xiǎn)，并最終對(duì)患者構(gòu)成風(fēng)險(xiǎn)。這些觀察結(jié)果包括缺乏維護(hù)、清潔、腐蝕、混凝土裂縫、液體泄漏跡象、缺乏洗手設(shè)施以及其他維護(hù)、管理和衛(wèi)生不良。

- Several potential breaches on data integrity were found. Main aspects related to computerised systems were not addressed. The firm failed to implement basic requirements with regard to computerised systems as outlined in EU GMP Annex 11 and EU GMP Part II section 5.4ff. The flaws detected could potentially lead to failures in analytical testing and/or breaches in data integrity. The following shortcomings, among others, were observed: outdated operating systems on HPLC systems (Windows XP, Windows 7), no traceability (e.g. audit trail) or approval of the change of some HPLC sequences, problems with operators’ privileges and lack of computerised systems validation.

發(fā)現(xiàn)了幾個(gè)潛在的數(shù)據(jù)完整性漏洞。與計(jì)算機(jī)化系統(tǒng)相關(guān)的主要方面沒(méi)有得到解決。該公司未能實(shí)施歐盟 GMP 附錄 11 和歐盟 GMP 第II 部分第 5.4ff 節(jié)中概述的有關(guān)計(jì)算機(jī)化系統(tǒng)的基本要求。檢測(cè)到的缺陷可能會(huì)導(dǎo)致分析測(cè)試失敗和/或數(shù)據(jù)完整性違規(guī)。除其他外，觀察到以下缺陷：HPLC 系統(tǒng)上的操作系統(tǒng)（Windows XP、Windows 7）過(guò)時(shí)，某些 HPLC 序列的更改沒(méi)有可追溯性（例如審計(jì)追蹤）或得到批準(zhǔn)，操作人員權(quán)限問(wèn)題以及缺乏計(jì)算機(jī)化系統(tǒng)驗(yàn)證。

- The Company also disregards pivotal aspects of GMP rules such as training (for instance, on the reviewed Annex I or failure to fulfill training requirements of the personnel), analytical method validation (not even planned to be done), or batch release verifications.

公司還無(wú)視 GMP 規(guī)則的關(guān)鍵方面，例如培訓(xùn)（例如，關(guān)于新版附錄1 的培訓(xùn)或未能滿足人員的培訓(xùn)要求）、分析方法驗(yàn)證（甚至沒(méi)有計(jì)劃進(jìn)行）或批放行確認(rèn)。