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10 月 23 日，PDA 正式發(fā)布2025版《TR22 培養(yǎng)基模擬灌裝指南》，內(nèi)容包含無菌工藝模擬的原則、概述、無菌工藝模擬的文件、環(huán)境監(jiān)測、人員確認、可接受標準、調(diào)查的考量、無菌工藝模擬在持續(xù)工藝評估中的應用、培養(yǎng)基和安慰劑考量、無菌工藝模擬執(zhí)行流程、無菌工藝中應用風險評估的實際案例等內(nèi)容：
文件修訂了無菌工藝模擬的可接受標準，過去無菌工藝模擬（APS）中依賴批量大小的污染數(shù)量不再被接受。
文件進一步詳細闡述了針對不同無菌產(chǎn)品類型（如液體產(chǎn)品、混懸劑、凍干產(chǎn)品和粉針劑）開展APS的最佳實踐，并將新技術應用納入每個部分。
文件還區(qū)分了針對隔離器和RABS的不同APS方法。
文件針對階段性生產(chǎn)，指南表示隨著階段性生產(chǎn)周期變長，對整個階段性生產(chǎn)周期進行培養(yǎng)基灌裝的傳統(tǒng)方法變得不切實際，提出生產(chǎn)結(jié)束或階段性生產(chǎn)APS。
新版指南納入了一種更結(jié)構化、更詳細的方法，將風險評估融入無菌加工，并提供了實際案例，說明如何將風險評估原則應用于無菌工藝設計和模擬研究。
新版技術報告包含了多個針對不同產(chǎn)品類型和制造技術討論的新模擬場景。
文件還討論了多產(chǎn)品生產(chǎn)線情況下的分組方法
Table of Contents
目錄
1.0 Introduction
1.0 引言
2.0 Glossary
2.0 術語表
3.0 Aseptic Process Simulation Concepts and Principles
3.0 無菌工藝模擬概念與原則
4.0 Overview of Aseptic Process Simulation for Aseptically Processed Products
4.0 無菌生產(chǎn)產(chǎn)品的無菌工藝模擬概述
5.0 Aseptic Process Simulation Documentation
5.0 無菌工藝模擬文件
6.0 Environmental Monitoring
6.0 環(huán)境監(jiān)測
7.0 Elements of Aseptic Process Simulations
7.0 無菌工藝模擬的要素
8.0 Personnel Qualifications
8.0 人員資質(zhì)
9.0 Aseptic Processing Simulation Acceptance Criteria
9.0 無菌工藝模擬可接受標準
10.0 Considerations for Investigation
10.0 調(diào)查考量
11.0 The Use of Aseptic Process Simulation in Ongoing Process Evaluation
11.0 無菌工藝模擬在持續(xù)工藝評估中的應用
12.0 References
12.0 參考文獻
13.0 Appendix 1: Media and Placebo Considerations
13.0 附錄1：培養(yǎng)基和安慰劑考量
14.0 Appendix 2: Aseptic Process Simulation Performance Sequence
14.0 附錄2：無菌工藝模擬執(zhí)行流程
15.0 Appendix 3: Practical Examples of Using Risk Assessment in Aseptic Process
15.0 附錄3：無菌工藝中應用風險評估的實際案例
16.0 Appendices References
16.0 附錄參考文獻
17.0 Relevant Vendor and Supplier Resources
17.0 相關供應商資源
What is the purpose of this revision?
此次修訂的目的是什么？
While EU GMP Annex 1: Manufacture of Sterile Medicinal Products was certainly one of the driving forces for the revision, it has been more than 10 years since the initial TR-22 was published, and during that time, both the regulations and the technology within our industry have changed significantly. Thus, it was no surprise that many aspects of the technical report required updates and additional context to remain current to today's practices and needs. One example is the aseptic process simulation acceptance criteria.
盡管歐盟GMP附錄1《無菌藥品生產(chǎn)》無疑是此次修訂的推動力之一，但自最初的TR-22發(fā)布以來已超過10年，在此期間，我們行業(yè)內(nèi)的法規(guī)和技術都發(fā)生了顯著變化。因此，該技術報告的許多方面需要更新和補充背景信息，以符合當今的實踐和需求，這并不奇怪。無菌工藝模擬的可接受標準就是一個例子。
A batch size-dependent number of contaminations in aseptic process simulations (APS) is no longer acceptable. Significant improvements have been made in the industry’s best practices for aseptic processing. By virtue of a globally diversified team of experts, we ensured such regulatory changes and best practices are appropriately captured in this document. The revised report aims to reflect changes in therapeutics, technology, regulatory expectations and the industry as a whole. While the revised Annex 1 has had a significant impact, the revised technical report also reflects many other influences.
無菌工藝模擬（APS）中依賴批量大小的污染數(shù)量不再被接受。行業(yè)在無菌加工的最佳實踐方面已取得重大改進。憑借一支全球多元化的專家團隊，我們確保此類法規(guī)變化和最佳實踐在本文件中得到適當體現(xiàn)。修訂后的指南旨在反映治療學、技術、法規(guī)期望以及整個行業(yè)的變化。雖然修訂后的附錄1產(chǎn)生了重大影響，但修訂后的技術報告也反映了許多其他影響因素。
What are the new technology applications addressed in the revised TR-22?
新版TR-22涉及哪些新的技術應用？
One of the key updates of the revised TR-22 is the detailed elaboration on best practices for conducting APS across different sterile product types, such as solutions, suspensions, lyophilized products and dry powders, and incorporating new technology applications into each section. This section offers practical, up-to-date guidance that aligns with current regulatory standards, expectations and industry best practices in aseptic processing. As regulators increasingly encourage the adoption of advanced technologies, such as isolators, robotics and single-use systems (SUS), we recognized a growing need in the industry for clear, actionable guidance on conducting APS with these technologies.
新版TR-22的關鍵更新之一是詳細闡述了針對不同無菌產(chǎn)品類型（如液體產(chǎn)品、混懸劑、凍干產(chǎn)品和粉針劑）開展APS的最佳實踐，并將新技術應用納入每個部分。本部分提供了實用且最新的指南，與無菌加工領域當前的法規(guī)標準、期望和行業(yè)最佳實踐保持一致。隨著監(jiān)管機構越來越鼓勵采用隔離器、機器人技術和一次性系統(tǒng)（SUS）等先進技術，我們認識到行業(yè)對使用這些技術開展APS的清晰、可操作指南的需求日益增長。
The updated TR-22 addresses common questions like, “What different approach in APS applies to isolators or restricted access barrier systems (RABS) compared to conventional aseptic lines?” This and other such questions are answered comprehensively, supported by the scientific rationale that covers several critical areas like barrier systems (including isolators, RABS and blow-fill-seal technology), closed systems, pre-use post-sterilization integrity testing (PUPIT) assembly, manual aseptic operations (with a specific focus on advanced therapy medicinal products [ATMP]) and SUS.
更新后的TR-22解答了一些常見問題，例如“與傳統(tǒng)無菌生產(chǎn)線相比，針對隔離器或RABS的APS方法有何不同？”該問題以及其他類似問題都得到了全面解答，并以涵蓋多個關鍵領域的科學依據(jù)作為支撐，這些領域包括屏障系統(tǒng)（包括隔離器、RABS和吹灌封技術）、封閉系統(tǒng)、使用前滅菌后完整性測試（PUPIT）組件、手動無菌操作（特別關注先進治療醫(yī)藥產(chǎn)品[ATMP]）和一次性系統(tǒng)（SUS）。
These updates reflect the industry’s growing focus on risk management, contamination control and the use of cutting-edge technologies. By exploring these advancements, the revised TR-22 provides valuable knowledge for manufacturers looking to enhance their APS to meet the current industry benchmark and regulatory expectations.
這些更新反映了行業(yè)對風險管理、污染控制和前沿技術應用的關注度日益提升。通過探討這些進展，修訂后的TR-22為制造商提供了寶貴的知識，助力他們改進APS，以滿足當前的行業(yè)基準和法規(guī)期望。
Does this new revision address the “end of production or campaign APS”?
此次新修訂是否涉及“生產(chǎn)結(jié)束或階段性生產(chǎn)APS”？
End-of-production (or “piggyback”) APS gained traction across the industry as isolators became more widespread. As confidence in using isolators grew, manufacturers started to feel more comfortable, increasing the number of product lots managed within a single campaign and the overall campaign length. With longer campaigns, the traditional approach of media fills for the entire campaign duration became impractical.
隨著隔離器的應用愈發(fā)廣泛，生產(chǎn)結(jié)束時（或“附帶式”）的APS在行業(yè)內(nèi)逐漸受到關注。隨著對隔離器使用的信心增強，制造商開始更放心地在一個階段性生產(chǎn)內(nèi)增加產(chǎn)品批次數(shù)量，并延長整體階段性生產(chǎn)時長。由于階段性生產(chǎn)時長變長，對整個階段性生產(chǎn)周期進行培養(yǎng)基灌裝的傳統(tǒng)方法變得不切實際。
To address this, the concept emerged of revalidating a campaign by processing several batches and substituting the final product batch with an APS, thus introducing the piggyback APS. However–spoiler alert–while a piggyback APS plays an important role in the overall APS strategy, it is insufficient to fully validate or revalidate a line. This is primarily because a piggyback APS fails to adequately capture the critical operations required to set up the production line, install critical equipment and perform aseptic interventions.
為解決這一問題，通過加工多個批次并將最終產(chǎn)品批次替換為APS來驗證階段性生產(chǎn)的概念應運而生，由此引入了附帶式APS。然而——盡管附帶式APS在整體APS策略中發(fā)揮著重要作用，但它不足以完全驗證或重新驗證一條生產(chǎn)線。這主要是因為附帶式APS無法充分涵蓋生產(chǎn)線裝配、關鍵設備安裝和無菌干預所需的關鍵操作。
Does this version provide any input with respect to the application of the concepts with real-world examples?
本版本是否通過實際案例對這些概念的應用提供了相關說明？
Several of the real-world examples that have been added are aimed at helping the reader see the application of the concepts laid out in TR-22 in a very practical format. They are there to help the reader put the applications of those concepts into practice, thus establishing to facilitate the application in their specific scenario. The revised technical report outlines a valuable approach for establishing a risk-based model in ATMP manufacturing. It involves a recent adaptation of the Intervention Risk Evaluation and Management (IREM) framework. This model specifically breaks down interventions and assesses their associated risk, with particular consideration given to the manual processes involved in ATMP manufacture.
新增的幾個實際案例旨在幫助讀者以非常實用的形式了解TR-22中闡述的概念的應用。這些案例有助于讀者將這些概念的應用付諸實踐，從而便于在其具體場景中應用。新版技術報告概述了在先進治療醫(yī)藥產(chǎn)品（ATMP）生產(chǎn)中建立基于風險的模型的寶貴方法。它采用了最新調(diào)整的干預風險評估與管理（IREM）框架。該模型專門對干預措施進行分解并評估其相關風險，特別考慮了ATMP生產(chǎn)中涉及的手動流程。
With the increased emphasis on risk assessment in the recent regulatory guidelines, is there anything new about risk assessment in the TR-22 revision?
鑒于近期法規(guī)指南對風險評估的重視程度不斷提高，TR-22修訂版在風險評估方面有何新意？
The revised TR-22 significantly emphasizes risk assessment in alignment with recent regulatory guidelines, reflecting the growing industry focus on quality risk management (QRM). The new version incorporates a more structured and detailed approach to integrating risk assessment into aseptic processing. One of the key additions is the introduction of an appendix that provides real-life examples of how risk assessment principles can be applied to aseptic process design and simulation studies. This would help organizations better understand the practical implementation of QRM in their processes.
新版TR-22顯著強化了與近期法規(guī)指南一致的風險評估內(nèi)容，反映了行業(yè)對質(zhì)量風險管理（QRM）日益增長的關注。新版本納入了一種更結(jié)構化、更詳細的方法，將風險評估融入無菌加工。其中一個關鍵新增內(nèi)容是引入了一個附錄，該附錄提供了實際案例，說明如何將風險評估原則應用于無菌工藝設計和模擬研究。這將幫助各機構更好地理解QRM在其流程中的實際實施。
The report encourages a proactive approach, focusing on identifying and mitigating potential risks early through robust process design and controls rather than relying solely on reactive measures. Not only is there a section dedicated to risk management, but the concepts of risk management are also visible throughout nearly every section of the document.
該報告鼓勵采用主動式方法，重點通過穩(wěn)健的工藝設計和控制盡早識別并減輕潛在風險，而非單純依賴被動應對措施。不僅有一個章節(jié)專門論述風險管理，而且風險管理的概念在文檔的幾乎每個章節(jié)中都有所體現(xiàn)。
How does this new document address the role of APS in contamination control strategy of an organization?
這份新文件如何闡述APS在機構污染控制策略中的作用？
The APS is an integral component of a successful contamination control strategy (CCS), supporting both the validation of aseptic processes and the continuous monitoring and improvement needed to maintain product sterility and regulatory compliance. Annex 1 emphasizes that APS should not be viewed in isolation, thus ensuring that all aspects of aseptic production, including human interventions and equipment performance, are optimized to minimize contamination risks.
APS是成功的污染控制策略（CCS）的一個不可或缺的組成部分，既支持無菌工藝的驗證，又支持為維持產(chǎn)品無菌性和法規(guī)合規(guī)性所需的持續(xù)監(jiān)測和改進。附錄1強調(diào)，不應孤立地看待APS，從而確保無菌生產(chǎn)的所有方面，包括人為干預和設備性能，都得到優(yōu)化，以最大限度地降低污染風險。
This revised technical report will provide considerations not only on how to appropriately integrate your APS into your CCS but also on leveraging the specifics of your CCS to develop the most appropriate APS for your facility. This is the fundamental expectation for companies to evolve and maintain ongoing improvements to these critical programs.
這份新版技術報告不僅將提供關于如何恰當?shù)貙⒛腁PS整合到您的CCS中的考量，還將提供關于利用您的CCS的具體情況為您的設施制定最合適的APS的考量。這是企業(yè)發(fā)展并持續(xù)改進這些關鍵項目的基本期望。
Are there any new simulation scenarios discussed in the TR-22 revision?
TR-22修訂版中是否討論了任何新的模擬場景？
The revised technical report contains several new simulation scenarios discussed across various product types and manufacturing technologies. It is never possible to cover every possible permutation. Still, the revision aims to provide the foundational basis to support the user in risk-assessing their own individual applications.
新版技術報告包含了多個針對不同產(chǎn)品類型和制造技術討論的新模擬場景。要涵蓋所有可能的排列組合是不可能的。盡管如此，此次修訂旨在提供基礎依據(jù)，以支持用戶對其自身的具體應用進行風險評估。
Is there a bracketing approach in the case of multiproduct lines discussed in this document?
本文件中是否討論了多產(chǎn)品生產(chǎn)線情況下的分組方法？
The revised TR-22 looks at bracketing approaches across various parameters including, but not limited to, container closure configurations, line speeds and product types. One of the aspects discussed is the case of different product formulations on a single line and speaks to some of the parameters to consider in those cases to create an appropriate bracketing strategy.
新版TR-22研究了涵蓋各種參數(shù)的分組方法，這些參數(shù)包括但不限于容器密封配置、生產(chǎn)線速度和產(chǎn)品類型。所討論的一個方面是單條生產(chǎn)線上不同產(chǎn)品配方的情況，并闡述了在這些情況下創(chuàng)建適當分組策略時需要考慮的一些參數(shù)。
There is no universal answer, as the specifics will vary from line to line, but the guidance provided aims to allow the application of the concepts to create a scientifically sound and justified approach that can be implemented for each case.
不存在通用答案，因為具體情況因生產(chǎn)線而異，但所提供的指南旨在使這些概念得以應用，從而創(chuàng)建一種科學合理且有理有據(jù)的方法，可針對每種情況實施。
Does this document address novel product categories like ATMPs?
本文件是否涉及諸如先進治療醫(yī)藥產(chǎn)品（ATMPs）之類的新型產(chǎn)品類別？
The revised TR-22 provides guidance on APS strategies tailored for ATMPs, recognizing their unique manufacturing challenges, manual dependencies and requirements. It covers areas like manual aseptic operations and the use of advanced technologies, ensuring that the APS for ATMPs aligns with both regulatory expectations and industry best practices.
新版TR-22針對先進治療醫(yī)藥產(chǎn)品（ATMPs）提供了量身定制的APS策略指南，認可其獨特的制造挑戰(zhàn)、手動操作依賴性和要求。它涵蓋了手動無菌操作和先進技術應用等領域，確保針對ATMPs的APS符合法規(guī)期望和行業(yè)最佳實踐。
Are there any changes in the approach discussed in this document related to personnel training and qualification?
本文件中討論的與人員培訓和確認相關的方法是否有變化？
Employee training and qualification are crucial aspects of the CCS of any facility that manufactures sterile drug products. This is an area to which the industry needs to pay closer attention to ensure product and patient safety. The revised report contains an updated section dealing with training, qualification and periodic requalification for personnel who enter classified areas.
員工培訓和確認是任何無菌藥品生產(chǎn)設施的污染控制策略（CCS）的關鍵方面。這是行業(yè)需要更加關注的領域，以確保產(chǎn)品和患者安全。新版報告包含一個更新的章節(jié)，涉及進入分級區(qū)域人員的培訓、確認和定期再確認。
TR-22 aims to provide a holistic roadmap for the appropriate training and qualification of personnel involved in aseptic operations, up to and including their qualification during APS and the maintenance of that qualification over time. It discusses a phased approach, beginning with employee induction, followed by qualification for performing less critical tasks under supervision, advancing through various stages of training and qualification and culminating in the final qualification stage through APS. Additionally, it highlights the requirements for ongoing requalification to ensure sustained proficiency in aseptic operations, thus minimizing the potential risk of contamination.
TR-22旨在為參與無菌操作的人員提供適當培訓和確認的整體路線圖，包括他們在APS期間的確認以及該資質(zhì)的長期維護。它討論了一種分階段方法，從員工入職培訓開始，隨后是在監(jiān)督下執(zhí)行不太關鍵任務的確認，接著經(jīng)歷不同的培訓和確認階段，最終通過APS完成最終確認階段。此外，它還強調(diào)了持續(xù)再確認的要求，以確保無菌操作的持續(xù)熟練程度，從而最大限度地降低潛在污染風險。
來源：GMP辦公室
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