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嘉峪檢測網(wǎng) 2025-08-11 17:35
近日，歐盟委員會發(fā)布了3份新版 EU GMP的新草案——EU GMP 指南附錄 11“計算機化系統(tǒng)”、附錄 22“人工智能”和第4 章“文件記錄”。這些文件由 EMA GMP/GDP 檢查員工作組與PIC/S 共同起草，將于 2026 年作為最終版本發(fā)布，解讀如下：
附錄22《人工智能》
The new annex on AI (Annex 22) sets the stage for EMA’s views on the technology. From the opening paragraphs it is very clear the annex applies only to static models of AI to be used in GMP systems that could impact the safety, efficacy, and quality of the end product. That is, it applies to systems employing AI that do not change after construction and learning, in the development stage of the application, we might use machine learning to create the system’s functionality, but after it is complete it does not continue to learn. These, the annex states, can be used in GMP critical applications. Of course, the beauty of AI is that it is possible to develop a system that continues to learn and adjust to new data it experiences. The EMA is clear on these adaptable systems: they “are not covered by this document and should not be used in critical GMP applications.” Further, “the document does not apply to generative AI and large language models (LLM), and such models should not be used in critical applications.”
這份關(guān)于人工智能的新附錄（附錄 22）為EMA闡述對該技術(shù)的觀點奠定了基礎(chǔ)。從開篇段落即可清晰看出，本附錄僅適用于在GMP系統(tǒng)中使用、且可能影響最終產(chǎn)品安全性、有效性和質(zhì)量的人工智能靜態(tài)模型。也就是說，它適用于這類人工智能系統(tǒng)：在應(yīng)用開發(fā)階段，我們或許會用機器學習構(gòu)建系統(tǒng)功能，但系統(tǒng)建成后不會繼續(xù)學習，即構(gòu)建和學習完成后不再改變。附錄表明，這類系統(tǒng)可用于 GMP 關(guān)鍵應(yīng)用。當然，人工智能的優(yōu)勢在于，能夠開發(fā)出持續(xù)學習并根據(jù)遇到的新數(shù)據(jù)自我調(diào)整的系統(tǒng)。EMA 對這類自適應(yīng)系統(tǒng)態(tài)度明確：“本文件未涵蓋此類系統(tǒng)，且不應(yīng)將其用于關(guān)鍵 GMP 應(yīng)用”。此外，“本文件不適用于生成式人工智能（generative AI）和大語言模型（LLM），此類模型也不得用于關(guān)鍵應(yīng)用”。
That said, the regulator continues to state that if those latter systems are used, they should only be used in noncritical GMP applications that do not have direct impact on patient safety, product quality, and data integrity. If they are used under these circumstances, the systems should be qualified and under the control of qualified personnel who have the final say on output. The annex uses the phrase human in the loop (HITL) for this requirement. The principles applicable to the static systems should be considered and incorporated as appropriate. I predict that after enough experience is gained in the application of Annex 22 principles, the more dynamic systems will be incorporated in the future, because we are still learning.
話雖如此，監(jiān)管機構(gòu)仍強調(diào)：若使用上述（自適應(yīng)、生成式 AI 等）系統(tǒng)，它們只能用于非關(guān)鍵 GMP 應(yīng)用（即不會對患者安全、產(chǎn)品質(zhì)量和數(shù)據(jù)完整性產(chǎn)生直接影響的應(yīng)用）。若在這類場景中使用，系統(tǒng)應(yīng)經(jīng)過確認，且由具備資質(zhì)、對輸出結(jié)果擁有最終決策權(quán)的人員管控。附錄用 “人工參與環(huán)節(jié)（HITL）” 描述這一要求。適用于靜態(tài)系統(tǒng)的原則應(yīng)酌情參考并納入動態(tài)系統(tǒng)管理。在附錄 22 原則的應(yīng)用中積累足夠經(jīng)驗后，未來會納入更動態(tài)的系統(tǒng) —— 畢竟我們?nèi)栽诔掷m(xù)探索學習。
The structure of this annex takes on a predictable form focusing on the underpinning of the security and predictability of the system. People should be skilled in understanding potential ramifications, documentation should be complete, and quality risk management techniques should be used. The central principle in this annex is very similar to the techniques we use to implement computer-based systems. There is a heavy emphasis on unit requirements and establishing that the system meets these requirements. This can be accomplished by subdividing functions and tasks that can be individually assessed and then assessed as a whole. Where we have HITL, the responsibilities of these humans should be defined so their decisions are clear and defensible.
本附錄的結(jié)構(gòu)符合可預(yù)測的邏輯，聚焦于系統(tǒng)安全性和可預(yù)測性的底層支撐。相關(guān)人員應(yīng)具備理解潛在影響的能力，文件記錄需完整，且應(yīng)運用質(zhì)量風險管理技術(shù)。本附錄的核心原則與我們實施計算機化系統(tǒng)所用的方法高度相似：著重強調(diào)單元需求，并確保系統(tǒng)滿足這些需求?？赏ㄟ^細分可單獨評估的功能與任務(wù)、再從整體層面評估的方式實現(xiàn)這一點。涉及人工參與環(huán)節(jié)（HITL）時，應(yīng)明確這些人員的職責，確保其決策清晰、有理有據(jù)。
Sections on acceptance criteria, test data, and its independency are defined, and key points include the following.
關(guān)于接受標準、測試數(shù)據(jù)及其獨立性的章節(jié)已明確，要點包括以下內(nèi)容：
Assure that the acceptance criteria and test metrics generate a system as good as the system it is replacing.
確保接受標準和測試項目可以使新的系統(tǒng)與被替代系統(tǒng)的質(zhì)量水平相當。
Criteria for ‘accept and reject’ should be clear and defensible.
“接受” 與 “拒收” 的判定標準應(yīng)清晰明確、有理有據(jù)。
Test data should represent the full spectrum of experience, not a subset.
測試數(shù)據(jù)應(yīng)覆蓋完整的經(jīng)驗場景，而非僅選取部分場景（子集）。
Any elements of data ‘manipulation’ (data processing, exclusion, etc.) should be verified to assure no bias.
任何數(shù)據(jù) “處理” 環(huán)節(jié)（如數(shù)據(jù)加工、排除等）均應(yīng)經(jīng)過驗證，確保無偏差。
Data used for the system to learn should be separate and separated from data used to test the system.
用于系統(tǒng) “學習” 的數(shù)據(jù)，應(yīng)與用于測試系統(tǒng)的數(shù)據(jù)相互獨立、明確區(qū)分。
Above all, documentation of what was done should be comprehensive.
最重要的是，對所開展工作的文件記錄應(yīng)全面詳盡。
Sections on test execution, explainability, confidence, and operation assure that the end product is fully justified. As with any validation activity: it is critical to define the plan and control and minimize change in the execution. Test plans should be followed with deviations recorded and justified. The use of modern techniques like SHAP values (SHapley Additive exPlanations), LIME (Local Interpretable Model - agnostic Explanations), and heat maps should be used to describe the interplay of parameters and reliability of the decisions mandating. Of course, good documentation is essential. Confidence in the decisions and, again, modern techniques of confidence scoring and threshold analysis give measure of the validity and robustness of the outputs. During the execution of the scripts and data processing there must be adherence and good change control as well as impact configuration control. Deviations should be documented and investigated thoroughly and their requiring assigned. The system should be monitored to assure it is performing as predicted and that the data is still within the defined parameters, with robust ranges of the defined testing areas as predicted. Any use of the outputs by humans for decisions should be fully documented and defensible.
關(guān)于測試執(zhí)行、可解釋性、置信度和操作的章節(jié)，確保最終產(chǎn)品具備充分的合理性依據(jù)。和任何驗證活動一樣：明確計劃、進行控制并在執(zhí)行中盡量減少變更，這至關(guān)重要。測試計劃應(yīng)嚴格遵循，偏差需記錄并說明理由。應(yīng)運用 SHAP 值（沙普利加法解釋）、LIME（局部可解釋與模型無關(guān)解釋）和熱圖等現(xiàn)代技術(shù)，來描述參數(shù)間的相互作用以及所要求決策的可靠性。當然，完善的文件記錄必不可少。對決策的置信度（同樣，置信度評分和閾值分析等現(xiàn)代技術(shù)）可衡量輸出結(jié)果的有效性和穩(wěn)健性。在腳本執(zhí)行和數(shù)據(jù)處理過程中，必須嚴格遵循規(guī)定，做好變更控制以及影響性配置控制。偏差應(yīng)記錄在案并深入調(diào)查，同時明確整改要求。應(yīng)對系統(tǒng)進行監(jiān)測，確保其按預(yù)期運行，且數(shù)據(jù)仍處于規(guī)定參數(shù)范圍內(nèi)（包括規(guī)定測試區(qū)域的合理波動范圍符合預(yù)期）。人員利用輸出結(jié)果進行決策的任何情況，都應(yīng)完整記錄，且決策依據(jù)充分可查。
附錄 11《計算機化系統(tǒng)》
The pharmaceutical quality management system mentioned in section 3. clarifies not only the usual topics (deviations, changes, self-inspections) but also the responsibility of senior management to regularly review all elements that influence the proper operation of the system.
第 3 節(jié)中提到的藥品質(zhì)量管理體系。不僅闡明了通常的主題（偏差、變更、自查），而且還闡明了高級管理層定期審查影響系統(tǒng)正常運行的所有要素的責任。
The elements of risk management referred to in section 4. reference ICH Q9; there is also an initial reference to the IT security requirements mentioned later in the document.
第 4 節(jié)中提到的風險管理要素。參考 ICH Q9；該文件還初步提到了IT 安全要求。
Almost one page is reserved for requirements specifications (section 6. User Requirements), which are often neglected in practice, and there - as in many other places in the document - reference is made to the possibility of using modern electronic tools to compile them.
第 6 節(jié) 用戶需求：幾乎有一頁內(nèi)容提到需求規(guī)范（URS），他們在實踐中經(jīng)常被忽視，文件還提到了使用現(xiàn)代電子工具編寫它們的可能性。
Section 7. deals in detail with the services of external IT companies that are widely employed today and the various requirements for their control (audit, contract, documentation), where the expected contractual regulations are mentioned with nine subsections.
第 7 節(jié)：詳細處理了當今廣泛使用的外部 IT 公司的服務(wù)及其控制（審計、合同、文件）的各種要求，其中通過九個小節(jié)提到了預(yù)期的合同法規(guī)。
A new topic is the very detailed specification under 8. for the requirements for alarms and their verification with associated documentation, for example in the batch record. A non-erasable/deactivatable record (log) with a corresponding annotation, similar to an audit trail, is expected here.
第 8 節(jié)是一個非常詳細的新的主題——報警及其確認的要求，使用相關(guān)記錄，例如在批記錄中。這要求具有相應(yīng)注釋的不可擦除/不可停用的記錄（日志），類似于審計追蹤。
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8. Alarms8. 報警 |
Qualification and validation of the computerized system (Section 9.) correspond to the regulations in the old Annex 11, but reference is made to the possibility of using an application in a limited scope even if validation has not been fully completed, provided that this is explicitly stated in the validation report.
計算機化系統(tǒng)的確認和驗證（第9節(jié)）與舊版附錄11中的規(guī)定相對應(yīng)，但提到即使驗證尚未完全完成，也可以在有限范圍內(nèi)使用該系統(tǒng)，但必須在驗證報告中明確說明。
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9.8.Completion prior to use. Qualification and validation activities should be successfully completed and reported prior to approval and taking a system into use. Conditional approval to proceed to taking a system into use may be granted where certain acceptance criteria have not been met, or deviations have not been fully addressed. A condition for this is, that there is a documented assessment, that any deficiencies in the affected system functionality or Page 8 of 19 GMP processes, will not impact product quality, patient safety or data integrity. Where a conditional approval is issued, it should be explicitly stated in the validation report and there should be close follow-up on approval of outstanding actions according to plan.9.8. 使用前完成：確認和驗證活動應(yīng)在批準并啟用系統(tǒng)之前成功完成并報告。在某些接受標準未滿足或偏差未完全解決的情況下，可有條件批準啟用系統(tǒng)。前提是應(yīng)有書面的評估，證明受影響的系統(tǒng)功能或藥品GMP流程中的任何缺陷不會影響產(chǎn)品質(zhì)量、患者安全或數(shù)據(jù)完整性。若有條件批準，應(yīng)在驗證報告中明確說明，且應(yīng)根據(jù)計劃密切跟進未完成行動的批準情況 。 |
The risk of manual data entry instead of electronic interfaces between systems is pointed out in section 10. This section also contains an initial reference to the encryption of critical data.
第10節(jié)指出了系統(tǒng)之間手動輸入數(shù)據(jù)而不是電子接口的風險。本節(jié)還包含對關(guān)鍵數(shù)據(jù)加密的初始引用。
The correct management of access to computerized systems (Section 11.) is discussed in detail in a number of subsections. In 11.3 it is outlined that system access by means of a smart card, which could be used by another person, for example, is not adequate. Requirements for secure passwords can be found in 11.5; the working group limits this to the general requirements, but does not specify a minimum length or a maximum validity period for passwords, nor for the regular verification of user accounts (11.11). The need to separate administrator rights from user rights (Segregation of Duties, SoD) is briefly discussed in 11.10.
對計算機化系統(tǒng)的訪問的正確管理（第 11 節(jié)）在一些小節(jié)中進行了詳細討論。11.3 中概述了通過智能卡（例如，門禁卡）進行系統(tǒng)訪問是不夠的，例如，智能卡（例如，門禁卡）可以被另一個人使用。安全密碼的要求可以在 11.5 中找到;工作組將此限制在一般要求范圍內(nèi)，但沒有規(guī)定密碼的最短長度或最長有效期，也沒有規(guī)定用戶帳戶的定期驗證（11.11）。11.10 簡要討論了將管理員權(quán)限與用戶權(quán)限（職責分離，SoD）分開的必要性。
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11.3.Certain identification. The method of authentication should identify users with a high degree of certainty and provide an effective protection against unauthorised access. Typically, it may involve a unique username and a password, although other methods providing at least the same level of security may be employed (e.g. biometrics). Authentication only by means of a token or a smart card is not sufficient, if this could be used by another user.11.3. 可靠識別：身份驗證方法應(yīng)能高度可靠地識別用戶，并有效防止未經(jīng)授權(quán)的訪問。通常，這可能涉及唯一用戶名和密碼，不過也可采用其他至少具備同等安全級別的方法（如生物識別 ）。僅通過令牌或智能卡進行身份驗證是不夠的，如他們可以被其他用戶使用。 |
The fact that there was no details on the management of audit trails in the old Annex 11 has been taken into account in section 12: the requirements for the technical setup and an on-time review are clarified in ten neatly structured subsections.
第12節(jié)考慮到了舊版附錄11中沒有關(guān)于審計追蹤管理的細節(jié)這一事實：結(jié)構(gòu)整齊的十個小節(jié)澄清了技術(shù)設(shè)置和及時審查的要求。
Electronic signatures are addressed in Section 13, which also uses some of the definitions listed in 21 CFR Part 11 (e.g. Open Systems) and also discusses hybrid solutions.
第 13 節(jié)涉及電子簽名，該節(jié)還使用了 21 CFR 第 11 部分中列出的一些定義（例如開放系統(tǒng)），并討論了混合解決方案。
The periodic reviews of the systems (Section 14), which were not included in the old Annex 11, take up a lot of space. The expectations of the periodic review are listed in twelve subsections.
對舊版附錄11中未包括的系統(tǒng)的定期審查（第14節(jié)）占用了大量篇幅。定期審查的要求列在十二個小節(jié)中。
It is positive that the current topic of IT security (Section 15.) is treated in detail, with clearly defined requirements for the IT infrastructure (firewalls, disaster recovery - RTO/RPO, patches, virus protection, etc.). In this context, the necessity of regular penetration tests for critical systems is also emphasized, which will unfortunately have a considerable impact on costs.
積極的是，當前的 IT 安全主題（第 15 節(jié)）得到了詳細處理，并明確定義了對 IT 基礎(chǔ)設(shè)施的要求（防火墻、災(zāi)難恢復(fù) - RTO/RPO、補丁、病毒防護等）。在此背景下，還強調(diào)了對關(guān)鍵系統(tǒng)進行定期滲透測試的必要性，不幸的是，這將對成本產(chǎn)生相當大的影響。
The topic of back-up can be found in section 16 with a definition of the requirements for physical and logical separation as well as regular restore tests.
備份主題可以在第 16 節(jié)中找到，其中定義了物理和邏輯分離以及定期恢復(fù)測試的要求。
It is most welcome that - as in the OECD GLP guidelines - the new Annex 11 addresses the archiving of data (Section 17.), as this was previously handled very briefly in the GMP regulations.
與OECD GLP 指南一樣，新的附錄 11 涉及數(shù)據(jù)歸檔（第 17 節(jié)），這是非常受歡迎的，因為此前在 GMP 法規(guī)中對此僅進行了非常簡短的處理。
At the end of the document there is a glossary where a large number of technical terms are explained.
在文件的末尾有一個詞匯表，其中解釋了大量技術(shù)術(shù)語。
EU GMP 正文 第四章 文件記錄
With issuance of Annex 22 and revision of Annex 11, Chapter 4 of GMP is in need of revision to reflect the use of electronic systems for documentation. As with Annex 11, new sections are added, as well as revisions made to other sections. However, many sections are unchanged.
隨著附錄 22 的發(fā)布以及附錄 11 的修訂，GMP的第四章需要進行修訂，以體現(xiàn)文件記錄中電子系統(tǒng)的應(yīng)用情況。與附錄 11 類似，本章新增了部分內(nèi)容，同時也對其他章節(jié)進行了修訂。不過，許多章節(jié)仍保持不變。
Two new sections on data governance and risk management are included. With data integrity being a significant focus for the industry, data governance describes the interplay of these systems. The principles of ICH Q9² are captured in the risk management section. The section on general requirements for documentation has been expanded to include data integrity principles and AI.
新增了兩個關(guān)于數(shù)據(jù)治理和風險管理的章節(jié)。鑒于數(shù)據(jù)完整性是行業(yè)重點關(guān)注內(nèi)容，數(shù)據(jù)治理章節(jié)闡述了這些系統(tǒng)之間的相互作用。ICH Q9 的原則在風險管理章節(jié)中有所體現(xiàn)。關(guān)于文件記錄一般要求的章節(jié)已擴充，納入了數(shù)據(jù)完整性原則和人工智能相關(guān)內(nèi)容。
The ALCOA++ principle is also included in this document. ALCOA was first proposed in the FDA's "Guidance for Industry : Part 11, Electronic Records; Electronic Signatures - Scope and Application" in 1999. In 2011, the FDA's "Guidance for Industry : Questions and Answers on Data Integrity and Compliance for Drug CGMP" added the ALCOA+ principle. In 2016, an international data integrity working group proposed the ALCOA++ principle, and the resulting document was titled "Good Data Management Practices for GMP Regulated Laboratories" and published in the scientific journal Analytical Chemistry. The EMA adopted the ALCOA++ principle in its "Guideline on Information Systems and Data Integrity in Clinical Trials" in March 2023. Now, the European Commission has also added the ALCOA++ principle to the revised draft of Chapter 4 of the new EU GMP.
ALCOA++原則也寫入該文件。ALCOA原則首次在1999年FDA《行業(yè)指南: Part 11，電子記錄;電子簽名-范圍和應(yīng)用》中提出。2011 年，F(xiàn)DA發(fā)布的《行業(yè)指南：藥品 CGMP 數(shù)據(jù)完整性與合規(guī)問答》中增加了 ALCOA+ 原則。 2016 年，一個國際數(shù)據(jù)完整性工作組提出ALCOA++ 原則，由此產(chǎn)生的文件名為《GMP 監(jiān)管實驗室的良好數(shù)據(jù)管理規(guī)范》，并發(fā)表在《分析化學》科學期刊上。EMA在2023年3月在其《臨床試驗中信息系統(tǒng)和數(shù)據(jù)完整性指南》采納了ALCOA++原則。現(xiàn)在，歐盟委員會在新版EU GMP章節(jié)4的修訂稿中也增加了ALCOA++原則。
Within good documentation principles, some new sections include data integrity as a major focus. A comprehensive separate section dedicated to data integrity is also included. The definition of signatures includes wet as well as electronic. The use of hybrid systems is included. These are all compatible with the well - established guidance on data integrity issued by EMA in 2016.?
在良好文件記錄原則框架內(nèi)，部分新增章節(jié)將數(shù)據(jù)完整性作為主要關(guān)注點。還包含一個專門針對數(shù)據(jù)完整性的完整獨立章節(jié)。簽名的定義既涵蓋手寫簽名，也包括電子簽名。同時納入了混合系統(tǒng)的使用情況。這些內(nèi)容均與EMA 2016 年發(fā)布的成熟數(shù)據(jù)完整性指南相兼容。
All other sections are either the same or the revisions are minor and do not change the philosophy or breadth.
其他所有章節(jié)要么保持不變，要么修訂內(nèi)容輕微，并未改變其理念或范圍。
來源：GMP辦公室
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