【Q&A】｜瑞士藥品監管機關針對 EU GMP 附錄 1 的問答（下篇）

9 9 月, 2026

【Q&A】｜瑞士藥品監管機關針對 EU GMP 附錄 1 的問答（下篇）

瑞士藥品監管機關針對 EU GMP Annex 1 的解讀問答，主要涵蓋其中 7 個章節，包括適用範圍 Scope、廠房 Premises、公用設施 Utilities、人員／訓練 Personnel/Training、生產與特定技術 Production and Specific Technologies、環境與製程監測 Environmental & Process Monitoring，以及品質管制 Quality Control（QC）。上篇已說明前四項內容，本篇將針對後三項進行說明，內容如下：

Interpretation: Questions and Answers

解讀:問題與解答

4.5 Production and Specific Technologies (Annex 1, Chapter 8)

生產與特定技術（附錄 1，第 8 章）

Q14：Sterilisation: what are the required loading patterns for initial and periodic autoclave (re-) validations?

滅菌：高壓滅菌器初始確效和定期（再）確效所需的裝載模式是什麼？

A: Initially each loading pattern must be validated. Re-validation of each loading pattern must be done annually. If a suitable worst-case load (the same material, same loading pattern, same cycle) for re-validation (backed up with data) can be identified, not every load of this material needs to be re-validated. A theoretical reference load is not acceptable, as 8.36 states that “each type of load” needs to be validated.

答：初始時必須確效每一種裝載模式，之後每年對各裝載模式進行再確效。若能以資料證明某一適當的最差情況裝載可代表再確效條件（相同物料、相同裝載模式及相同週期），則不必對該物料的每一種裝載逐一再確效。理論上的參考裝載不可接受，因為第 8.36 節規定每一種裝載類型都必須經過確效。

Q15: Moist heat sterilisation: is it expected that routine re-validation includes a temperature mapping for systems where steam in place is used for sterilization?

濕熱滅菌：常規再確效是否包括對使用蒸汽滅菌的系統進行溫度分佈。

A: Yes, routine (or periodic) validation should include tests providing evidence that the positions used for temperature monitoring throughout the sterilization process are still representative of and correspond to the slowest to heat locations during sterilisation.

答：是，常規（或定期）確效應包括測試，證明整個滅菌過程中用於溫度監測的位置仍具有代表性，並與滅菌過程中加熱最慢的位置相對應。

Q16：Is the sterility of the product-contacting surface of a closed system ensured if the system is opened in a cabinet with laminar airflow (LAF)?

如果在單向氣流（LAF）櫃中打開密閉系統，是否能確保密閉系統的產品接觸面的無菌性？

A: Opening a sterile, closed system should be avoided whenever possible. In general, a closed system that needs to be opened should be returned to the sterile state by carrying out a validated sterilization process (if required, preceded by cleaning).

應盡可能避免打開無菌、密閉的系統。一般來說，需要打開的密閉系統應通過經確效的滅菌過程（如果需要，先進行清潔）恢復到無菌狀態。

If a sterilisation of the system after opening is not possible, the system’s opening could be performed in a decontaminated isolator (provided that the introduction of the closed system to be opened or relevant parts of it into the isolator does not compromise the isolator’s decontamination status and can be considered covered by successful APS).

如果無法在打開後對系統進行滅菌，則系統的打開可以在淨化隔離器中進行（前提是將要打開的密閉系統或其相關部件引入隔離器不會影響隔離器的淨化狀態，並可被視為涵蓋在成功的 APS 之中）。

Opening the system in an LAF with classification A and background B could possibly be an alter-native to the isolator but rather to be envisaged in exceptional cases only as the risks of introducing contamination from the environment are higher and require appropriate consideration and risk mitigating measures.

在 B 級背景環境中的 A 級單向氣流區開啟系統，可能作為隔離器的替代方案，但僅應於例外情況下採用。由於此作法從環境引入污染的風險較高，必須審慎評估並採取適當的風險降低措施。

Q17: Are non-aseptic connections allowed to be carried out for coupling closed systems if a sterilization cycle (SIP) occurs prior to use?

如果在使用前進行滅菌 (SIP)，是否允許對接型密閉系統進行非無菌連接？

A : Yes, such an approach is possible, provided that the SIP process used is appropriately validated.

答：是的，只要所使用的 SIP 流程經過適當確效，這種方法是可行的。

Q18: Is the use of sterile aseptic connectors purchased from qualified suppliers permitted as suitable strategy to connect sterile equipment to each other and may the end-user rely on the sterility documentation (sterilisation validation) provided by the respective supplier?

是否允許使用向合格供應商採購的無菌連接器，作為連接無菌設備的適當策略？最終使用者是否可以採用相關供應商提供的無菌證明文件（滅菌確效）？

A : Provided the supplier of the aseptic connector in question was covered by comprehensive qualification activities and the validation package/data provided by the supplier for the connector (e.g., validation of the gamma irradiation process, data on microbial challenge tests, etc.) have been checked and found to be sound, the end-user can rely on such data, but must cover this equipment and its handling during his manufacturing process APS activities. See also paragraph 4.6.4 on single-use systems.

如果有關無菌連接器的供應商已通過全面的資質驗證，而且供應商為連接器提供的確效包/資料（如伽馬輻照過程的確效、微生物挑戰測試資料等）已經過檢查並被認定是可靠的，則最終使用者可以信賴這些資料，但必須在其製造過程的 APS 活動中涵蓋該設備及其處理。另請參見 4.6.4 關於一次性使用系統的內容。

If single-use connectors that are sterilised by the end-user (e.g., by autoclaving) are used for coupling sterile systems, this sterilisation process must be validated. It must also be ensured that single-use connectors are suitable for sterilisation and that the latter does not impact their functionality or integrity (e.g., by causing the material of construction to become more porous).

如果由最終用戶滅菌（例如通過高壓滅菌）的一次性連接器用於連接無菌系統，則必須確效該滅菌過程。還必須確保一次性連接器適合滅菌，並且滅菌不會影響其功能或完整性（例如，導致結構材料變得更加多孔）。

Q19: Is it considered acceptable to introduce small amounts of product or cells into a sterile closed system with a syringe fitted with a needle through a septum? Can the system be considered closed after piercing of the septum?

使用裝有針頭的注射器穿過隔膜將少量產品或細胞引入無菌密閉系統是否可以接受？刺穿隔膜後，系統是否可視為密閉系統？

A :Such a practice should be avoided for aseptic steps, as piercing a septum with a needle is to be regarded as a breach of the sterile barrier. In aseptic processes where the above approach is used, measures must be taken to re-design and optimise the procedure accordingly.

答：在無菌步驟中應避免這種做法，因為用針刺穿隔膜會被視為破壞無菌屏障。在使用上述方法的無菌製程中，必須採取措施重新設計和優化相應的程式。

If the process concerned cannot be improved and adapted immediately, consideration should be given, as a temporary measure, to minimise the risk of contamination, as to whether the syringe should be left with the needle inserted in the septum after completion of the material addition and appropriately secured in this position. In addition, it should be considered that the top of the septum (prior to piercing) be protected by a sterile film, which is removed just prior to insertion of the syringe needle to reduce the risk of contaminants on the septum surface entering the process and avoiding treating the septum with a disinfectant, which may also pose a risk of contamination of the product (by disinfectant residues).

如果不能立即改進和調整有關製程，應考慮採取臨時措施，將污染風險降至最低，考慮是否應在物料添加完成後將針頭留在隔膜中。此外，應考慮在隔膜頂部（穿刺前）貼上一層無菌薄膜，在插入注射器針頭前移除，以減少隔膜表面的污染物進入加工過程的風險，並避免用消毒劑處理隔膜，因為消毒劑殘留也可能造成產品污染的風險。

Q20: Is tubing welding considered a suitable strategy for aseptically connecting equipment parts maintaining the closed status of a system?

管道焊接是否被認為是無菌連接設備部件以維持系統密閉狀態的合適策略？

A:Welding equipment and processes must be qualified/validated. If such processes are used in sterile or aseptic filling processes, they must be covered also by APS.

答：焊接設備和製程必須經過驗證/確效。如果在無菌灌裝過程中使用此類製程，則也必須納入 APS 的範圍。

However, as tubing welding processes are both less monitorable and entail risks of undetected integrity deficiencies, such practices should be avoided and more reliable systems should be used, which should be taken into account when-ever possible already during facility and process design.

然而，由於管道焊接製程的監測性較差，並且存在未檢測到完整性缺陷的風險，因此應避免這種做法，並應使用更可靠的系統，在設施和製程設計期間應盡可能考慮到這一點。

Q21: Closed systems: in case of using single-use systems, can system integrity tests performed by the respective suppliers be leveraged without having to carry out own tests?

密閉系統：在使用一次性系統的情況下，是否可以利用相關供應商進行的系統完整性測試，而無需自己進行測試？

A :Whenever possible, the integrity of critical single-use systems should be tested by the end-user on site (i.e., before use in production). It is acknowledged that such an integrity test, e.g., by means of a pressure hold test using an inert gas, is difficult to establish for small single-use bags/containers and is also only reliable to a limited extent. However, the decision in this respect must be justified by well-founded measures and considerations, be verified by risk assessments and must be included in the CCS.

答：如果可能的話，最終用戶應在現場（即在用於生產之前）對關鍵一次性使用系統的完整性進行測試。眾所周知，對於小型一次性使用袋/容器來說，很難進行這種完整性測試，例如使用惰性氣體進行保壓測試，而且這種測試的可靠性也很有限。但是，這方面的決定必須有充分依據的措施和考慮，並通過風險評估進行驗證，並且必須包含在 CCS 中。

The possibility of relying for single-use materials (such as bags) on integrity test results provided by the respective suppliers requires a detailed assessment of the situation, taking into account, among other things, the criticality of possible integrity deficiencies on the manufacturing processes/product quality and their detection probability during the process.

一次性使用材料（例如袋子）依賴于各自供應商提供的完整性測試結果的可能性需要對實際情況進行詳細評估，除其他事項外，考慮生產製程/產品質量中可能存在的完整性缺陷的嚴重性以及在生產過程中發現這些缺陷的可能性。

The adoption of integrity results from the vendor requires an in-depth qualification of the supplier and must also take into account the risks of sub-sequent damage to the single-use material during its delivery and installation in production.

採用供應商提供的完整性結果需要對供應商進行深入的資質審查，還必須考慮到一次性使用材料在生產中的交付和安裝過程中後續損壞的風險。

Q22: Single-use systems: what are the expectations placed on the assessment of such suppliers and what must it comprise?

一次性使用系統：對這類供應商的評估有什麼期望？評估必須包括哪些內容？

A: The supplier assessment should be understood as a comprehensive qualification of the single-use systems (SUS) supplier. This assessment/qualification should cover not only the supplier delivering the SUS but in particular the SUS manufacturer (or each relevant manufacturing site, if the SUS in question is produced at several sites) as well as any sub-contractors involved in critical services or processes (e.g., sterilisation of the SUS). The supplier assessment/qualification should be carried out in parallel with the evaluation of the SUS material and should play a crucial role in the SUS selection decision.

答：應將供應商評估理解為對一次性使用系統（SUS）供應商的全面資質驗證。這種評估/資質驗證不僅應包括提供一次性使用系統的供應商，還應特別包括一次性使用系統的製造商（或每個相關的生產場地，如果有關一次性使用系統是在多個場地生產的話），以及參與關鍵服務或製程（如一次性使用系統的滅菌）的任何分包商。供應商評估/資質驗證應與一次性使用材料評估同時進行，並應在 SUS 選擇決策中發揮關鍵作用。

For all SUS that the end-user intends to use in his manufacturing process and that will have direct contact with the product, intermediates, process solutions or starting materials/raw materials, a Quality Agreement should be concluded with the respective supplier. This Quality Agreement should cover the SUS specifications as well as quality relevant service conditions (e.g., requirement to manufacture SUS in cleanrooms) and regulate, among other things, the terms relevant for the notification of planned changes and their approval by customers, the procedures in the event of major/critical deviations impacting delivered SUS, the terms in case of customer complaints and the oversight responsibility for sub-contractors.

對於最終使用者打算在其製造過程中使用並將與產品、中間體、製程溶液或起始物料/原料直接接觸的所有 SUS，應與相應的供應商簽訂質量協議。本質量協議應涵蓋 SUS 規格以及與質量相關的服務條件（例如，在潔淨室中製造 SUS 的要求），並規定與計劃變更通知及其客戶批准相關的條款、影響交付 SUS 的重大/關鍵偏差事件、客戶投訴條款以及分包商的監督責任等。

Supplier qualifications must include an assessment of the supplier’s quality systems, a comprehensive review of all relevant technical documentation received (incl. for example drawings, documentation of components used such as filters, aseptic connectors, tubings etc., certificates and validation/study packages), and audits. It is expected that audits cover all systems, relevant processes and control strategies (e.g., sterilisation process and its validation, subcontractor qualification, etc.) considered critical for the respective SUS and these contents must be comprehensibly documented in the respective audit report.

供應商資格認可必須包括評估供應商的品質系統、全面審查所收到的相關技術文件（包括圖面，以及所用元件如濾器、無菌連接器、管路等的文件、證書與確效／研究資料套件），並執行稽核。稽核預期應涵蓋對相關 SUS 至關重要的所有系統、相關製程及管制策略（例如滅菌製程及其確效、分包商資格認可等），且這些內容必須完整記錄於相關稽核報告中。

Q23: What aspects should be taken into account by the end-user when determining the acceptance criteria of the respective SUS and in which form should they be specified?

在確定相應 SUS 的可接受標準時，最終用戶應考慮哪些方面以及應以何種形式規定這些標準？

A: Acceptance criteria should be defined taking into account the intended use of the particular SUS in the manufacturing process, the criticality of its use/impacted process, existing process knowledge, as well as available SUS experience. Acceptance criteria should encompass quality aspects (e.g., sterility, biocompatibility, visible particles testing by compendial method, integrity tests, certificates, etc.), functionality (e.g., inserts and components required, temperature resistance in operating range, autoclaving or freezing resistance, chemical compatibility, substainable pressure, packaging requirements, etc.) as well as validation/qualification requirements to be fulfilled by the SUS and its supplier. According to Annex 1, paragraph 8.132, the use of SUS and the associated risks should be also assessed as part of the Contamination Control Strategy, taking into account the fragile nature and potential complexity of the SUS in question, possible interactions of the SUS surfaces with the product, risks associated with manual operations/connections and risks of holes or particle contaminations. The resulting conclusions from these assessments and any risk mitigating measures should be taken into account, if appropriate, when establishing the SUS acceptance criteria and the expectations placed on the SUS suppliers. To comply with the requirements of paragraph 8.138, according to which the conformity of the SUS with the approved specification has to be checked upon good receipt, the quality requirements should be defined in a written specification (including or referencing a technical drawing of the material). The other expectations regarding the functionality of the SUS or the expected validation / qualification/study package to be made available by the supplier and to be agreed with the supplier, can be defined in another document, such as a SUS user requirement document, an annex to the Quality Agreement, or similar.

答：可接受標準的確定應考慮特定 SUS 在製造過程中的預期用途、其使用/受影響製程的關鍵性、現有製程知識以及可用的 SUS 經驗。可接受標準應涵蓋質量方面（例如，無菌性、生物相容性、通過藥典方法進行的可見微粒測試、完整性測試、證書等）、功能方面（例如，所需的插入件和組件、工作範圍內的耐熱性、耐高壓滅菌或耐冷凍性、化學相容性、可承受壓力、包裝要求等）以及 SUS 及其供應商要滿足的確效/驗證要求。根據附錄 1 的8.132 ，SUS 的使用及其相關風險也應作為污染控制策略的一部分進行評估，同時考慮到所討論的 SUS 的脆弱性和潛在的複雜性、SUS 表面與產品可能發生的相互作用、與手動操作/連接相關的風險以及孔洞或顆粒污染的風險。在制定 SUS 可接受標準和對 SUS 供應商的期望時，應酌情考慮這些評估得出的結論和任何降低風險的措施。為了符合8.138 的要求，根據該要求，必須在收貨時檢查 SUS 是否符合批准的質量標準，質量要求應在書面規程中定義（包括或參考材料的技術圖紙）。關於 SUS 功能的其他期望或由供應商提供並與供應商達成一致的預期確效/驗證/研究包，可以在另一個檔中定義，例如 SUS 用戶需求檔、質量協議附錄或類似檔。

Q24: What should the incoming goods inspection at the end-user include to comply with paragraph 8.138 & 8.134?

為符合 8.138 與 8.134 的規定，最終使用者的進料檢驗應包括哪些內容？

A: Due to the special nature of SUS and their delivery in packaging that serves to protect them from damage but does not allow for a full visual inspection of the materials, the scope of a feasible routine incoming inspection program upon receipt is generally very limited.

答：由於 SUS 的特殊性質及其在包裝中交付的情況，該包裝可保護其免受損壞，但不允許對材料進行全面的目視檢查，因此接收時可行的常規入廠檢驗計劃的範圍通常非常有限。

Immediately upon receipt, in accordance with paragraph 8.138, an initial documented inspection of the shipment should be performed, consisting primarily of a review of the documents provided by the supplier, a visual check of the integrity of the outer packaging, label printing, and a reasonably cursory verification of the contents of the shipment (without complete unpacking of the SUS to avoid the risk of damages). On the basis of a positive result of this first in-coming check, the SUS can be released, allowing its transfer to the production area to be subjected to a more thorough examination. This examination must consist at least of a deep visual inspection of the SUS by qualified employees according to an established procedure, and the results of which must be documented as part of the batch record. The visual inspection should include verification of the compliance of the SUS with approved technical drawings, the presence of gamma irradiation points (if applicable and as evidence of the sterilization), and a visual examination for integrity (e.g., inspection of the welds, connectors, absence of critical scratches, etc.) as well as for the absence of particulates. If technically practicable and indicated, the integrity of the single-use system should be verified by means of a pressure hold test.

根據 8.138 的規定，在收到貨物後，應立即對貨物進行有記錄的初步檢查，主要包括審查供應商提供的單據、目視檢查外包裝的完整性、標籤的印刷情況，以及對貨物內容物進行合理的粗略核查（不完全拆開 SUS 包裝，以避免損壞的風險）。如果第一次入廠檢驗結果良好，則可以放行 SUS，將其轉運到生產區進行更徹底的檢查。這種檢查必須至少包括由有資質員工按照既定程式對 SUS 進行仔細的目視檢查，檢查結果必須作為批次記錄的一部分進行記錄。目視檢查應包括核查 SUS 是否符合經批准的技術圖紙、是否存在伽馬輻照點（如適用，並作為滅菌的證據）、目視檢查是否完整（如檢查焊縫、連接部位、沒有嚴重劃痕等）以及是否存在顆粒。如果技術上可行並有說明，應通過保壓測試來驗證一次性使用系統的完整性。

Q25: Is it considered acceptable that some study or validation data provided by SUS suppliers (e.g., validation packages incl. sterilization or material chemical and biological compatibility data) are incorporated by the end-user into his own assessments without the need to carry full studies/validations on his own?

最終用戶將 SUS 供應商提供的某些研究或確效資料（如包括滅菌或物料化學和生物相容性資料）納入其自己的評估，而無需自行進行完整的研究/確效，是否認為可以接受？

A:When looking at the wording in the paragraphs on single-use systems (SUS), it can be concluded that Annex 1 allows principally the adoption by the end-user of data received from qualified suppliers. However, this requires that the end-user confirms through a detailed review of the respective documentation that its contents meet the user’s standards and that the conditions used by the suppliers when generating the data are representative (or worst-cases) for its own actual production conditions. The extent of the end-user’s own studies/verifications or validations activities depends on the representative-ness of the supplier data, the criticality of the intended SUS use in the process, established control strategies at the end-user which allow detection of possible SUS deficiencies (e.g., pressure hold test, extensive program of micro-biological testing during the process), etc.

答：從有關一次性使用系統（SUS）的章節措辭中可以得出結論，附錄 1 原則上允許最終用戶採用合格供應商提供的資料。但是，這要求最終用戶通過詳細審查相關檔，驗證其內容符合使用者的標準，並驗證供應商在生成資料時所使用的條件對其實際生產條件具有代表性（或最差情況）。最終用戶自身的研究/驗證或確效活動的程度取決於供應商數據的代表性、製程中使用的 SUS 的關鍵性、最終用戶為檢測可能存在的 SUS 缺陷而制定的控制策略（例如，保壓測試、製程過程中的大量微生物測試程式）等。

For example, an end-user operating in the bio-tech area must verify with own studies or assessments whether possible leachables emitted from the films of a single-use bioreactor can negatively affect the growth of cells and it is also the responsibility of the end-user to verify or provide data to prove whether absorption effects of its product on the SUS surface are possible, resulting in an impact on product quality (see para-graph 8.132, «…These risks include but are not limited to: i. the interaction between the product and product contact surface (such as adsorption, or leachables and extractables)»).

例如，在生物技術領域的最終用戶必須通過自己的研究或評估來驗證一次性生物反應器的薄膜中可能排放的浸出物是否會對細胞的生長產生負面影響，這也是最終用戶的責任- 使用者驗證或提供資料以證明其產品在 SUS 表面是否可能產生吸附效應，從而對產品質量產生影響（參見 8.132 ，《……這些風險包括但不限於：i .產品與產品接觸表面之間的相互作用（例如吸附、或浸出物和可提取物）»)。

When SUS are used in the sterile production, it is mandatory that they are covered by APS, as required in paragraph 8.139. For cell culture (or fermentative) processes, the end-user should evaluate the need to perform a process simulation before starting routine production to confirm the suitability, integrity, and handling of the SUS equipment.

在無菌生產中使用 SUS 時，必須按照 8.139 的要求將其納入 APS 的範圍內。對於細胞培養（或發酵）製程，最終使用者應評估是否需要在開始常規生產前進行製程模擬，以驗證 SUS 設備的適用性、完整性和操作。

Q26: Do end-users have to carry out their own extractable studies or can they use the supplier’s data and when is it necessary to execute leachable studies?

最終使用者是否必須自行進行可萃取物研究，或可採用供應商提供的資料？何時需要執行可浸出物研究？

A: Most SUS suppliers provide comprehensive extractable studies packages to end-users. In recent years, efforts have been undertaken by international industry working groups to harmonize and standardize the conditions for extractions and analysis of extractables. Additionally, many suppliers also provide certificates covering the product contact films, e.g., Biological Reactivity Test in Vivo per USP <88>, Class VI.

答：大多數 SUS 供應商向最終用戶提供全面的可提取物研究包。近年來，國際行業工作組一直在努力協調和標準化可提取物的提取和分析條件。此外，許多供應商還提供涵蓋產品接觸膜的證書，例如，根據USP <88>, VI 類進行的體內生物反應性測試。

It is expected that based on the package of extractables data obtained, the end-users evaluate the adequacy of the data provided, potentially “add together” data from different SUS components, and define the need for additional extractables studies to simulate process-specific worst-case conditions and perform health safety assessments, as appropriate.

預計最終使用者將根據獲得的可提取物資料包評估所提供資料的充分性，可能將來自不同 SUS 組件的資料“加在一起”，並確定是否需要進行額外的可提取物研究以模擬特定製程的最差情況-視情況進行健康安全評估。

The decision to carry out leachable studies with the respective product is usually based on a comprehensive evaluation of the possible risks of administering leachables in doses that may be of concern when using the respective drug product. In addition to the results of the extractable data and any resulting safety assessments, the decision regarding the need for a leachable study should take into account the route of administration of the respective drug (e.g., oral, parenteral, subcutaneous), the dosing frequency to a patient, the use of the respective SUS in the process (e.g., use in early or late manufacturing step) and the contact time of the process solution/product with SUS surface.

對相應產品進行可浸出物研究的決定通常基於對使用相應藥品時可能關注的可浸出物劑量的可能風險的綜合評估。除了可提取物資料的結果和任何由此產生的安全性評估之外，關於是否需要進行可浸出物研究的決定還應考慮相應藥物的給藥途徑（例如口服、注射、皮下給藥）、患者的給藥頻率、在此過程中使用相應的SUS（例如，在早期或後期生產步驟中使用）以及製程溶液/產品與 SUS 表面的接觸時間。

Based on an assessment of such aspects, the company may justify that no leachable studies are performed for products that are still in the clinical phase and/or are only administered infrequently (e.g., vaccines). Since extractable/leachable studies are part of the filing dossier for marketing authorization, it is necessary to align the strategy with the requirements of the marketing authorization or, if necessary, with the respective regulatory authority.

基於對這些方面的評估，公司可能會證明不對仍處於臨床階段和/或僅不頻繁給藥的產品（例如疫苗）進行可浸出物研究。由於可提取/可浸出物研究是上市許可備案檔案的一部分，因此有必要使策略與上市許可的要求保持一致，或者在必要時與相應的監管機構要求保持一致。

Q27: Is it expected that there are two redundant sterilizing filtration steps in the process before aseptic filling?

是否期望在無菌灌裝之前的製程中有兩個冗餘除菌過濾步驟？

A: Annex 1 encourages an additional filtration through a sterile sterilising grade filter, as close to the point of fill as possible. The installation of such a redundant sterile filter significantly reduces the risk of a product quality impact in the event of a failed filter integrity test, which is why this risk-minimising measure is to be considered state of the art process and should be used especially for new processes.

答：附錄 1 鼓勵在盡可能接近充填點的位置，再以一個無菌的除菌級濾器進行過濾。安裝此類備援除菌濾器，可大幅降低濾器完整性測試失敗時對產品品質造成影響的風險。因此，這項降低風險的措施可視為目前先進的製程設計，尤其應用於新製程。

The risks and impacts of filter integrity failures of pre-fill point sterile filters should be assessed as part of the CCS evaluations and the decision not to install a redundant sterilising filter be justified in the CCS.

應將灌裝點前的除菌篩檢程式的篩檢程式完整性故障的風險和影響作為 CCS 評估的一部分進行評估，並在 CCS 中證明不安裝冗餘除菌篩檢程式的決定是合理的。

Even in the case of using two sterilising filters, any filter integrity failure that may have occurred should be investigated.

即使在使用兩臺除菌篩檢程式的情況下，也應對任何可能發生的篩檢程式完整性故障進行調查。

Q28: Paragraph 8.83 makes reference to the relevant Pharmacopeia requirements in relation to the validation of sterile filtration of fluids. Which paragraph of the Pharmacopeia should be considered for this purpose?

8.83 提到藥典中關於液體除菌過濾確效的相關要求。為此應考慮藥典中的哪一段？

A: Relevant guidance can be found in Ph. Eur. 5.1.1, paragraph “Membrane filtration/Filtration effectiveness” and in guideline EMA/CHMP/CVMP/QWP/850374/2015. Useful details and expected data/methods can also be found in PDA TR26 “Sterilizing filtration of liquids”.

答：相關指南參見歐洲藥典 5.1.1，”膜過濾/過濾有效性 “和 EMA/CHMP/CVMP/QWP/850374/2015 指南。PDA TR26 “液體除菌過濾 “中也提供了有用的詳細資訊和預期資料/方法。

Q29: Is a pre-use / post-sterilisation integrity testing (“PUPSIT”) of sterilising grade filters used in aseptically processes mandatory?

無菌製程中使用的除菌篩檢程式是否必須進行使用前/滅菌後完整性測試（“PUPSIT”）？

A: The expectation is that PUPSIT be applied to verify the integrity of the sterilized filter assembly.

However, paragraph 8.87 allows some flexibility in justified cases supported by risk analysis and covered in the CCS.

答：期望應用 PUPSIT 來驗證滅菌篩檢程式組件的完整性。

然而，8.87允許在有風險分析支援的合理情況下有一定的靈活性，並包括在CCS中。

4.6 Environmental & Process Monitoring (Annex 1, Chapter 9)
環境與製程監測（附錄 1，第 9 章）

Q30: What is deemed regularly (“These risk assessments should be reviewed regularly”)? How often does the risk assessment need to be reviewed?

什麼是定期（”應定期審查這些風險評估”）？多長時間需要審查一次風險評估？

A: It is not possible to give definitive guidance here, because, as ICH Q9 (R1) states, the frequency of Risk Review should be based on the level of risk. The frequency or timing of a Risk Review exercise may be based on the type and number of risks identified during an earlier Risk Assessment exercise, and on the extent of risk control that was required to mitigate risks. It may also depend on the level of uncertainty (i.e. lack of knowledge) that was present during an earlier risk assessment. The higher the level of uncertainty in relation to risk estimates and the related risk-based decisions, the greater the need to review those estimates and decisions at an early timepoint once such uncertainties have been reduced.

答：此處不可能給出明確的指導，因為正如 ICH Q9 (R1) 所述，風險審查的頻率應基於風險水準。風險審查活動的頻率或時間安排可能取決於早期風險評估活動中確定的風險類型和數量，以及為降低風險所需的風險控制程度。它還可能取決於早期風險評估期間存在的不確定性水準（即缺乏知識）。與風險評估和基於風險的相關決定有關的不確定程度越高，就越有必要在不確定程度降低後儘早審查這些評估和決定。

An environmental monitoring trend report will be compiled every year and depending on the results, the risk assessment might be reviewed. It should be assessed annually if the review of the risk assessment is required. Swissmedic recommends to review the risk assessment regularly, e.g. for a new plant it is recommended to reassess the RA after one year when more experience and knowledge have been gained.

每年將編制環境監測趨勢報告，並根據結果對風險評估進行審查。如果需要審查風險評估，則應每年進行一次評估。Swissmedic 建議定期審查風險評估，例如對於新工廠，建議一年後獲得更多經驗和知識後重新評估 RA。

Q31: When do we expect more stringent action limits?

我們預計什麼時候會採取更嚴格的行動限？

A:More stringent action limits might be necessary if the trend data shows very low levels of detection of total particles and viable particles with no action limit excursions over a longer time period (e.g. one year).

答：如果趨勢資料顯示總顆粒和微生物的檢測水準非常低，且在較長時間內（如一年）未出現行動限超標，則可能需要更嚴格的行動限。

Q32: What statistics do we expect for establishing alert levels?

我們期望哪些統計資料來建立警戒限？

A:For a new process where limited data and experience for environmental monitoring data is available, it is acceptable e.g., to calculate the alert level limit based as 50% of the action level limit. When more data becomes available the alert level limits should be statistically from the environmental monitoring data to ensure that the alert setting takes into account its own recent historical behaviour.

答：對於可獲得的環境監測資料和經驗有限的新製程，可以接受，例如，根據行動限的50%計算警戒限。當獲得更多資料時，應根據環境監測資料統計警戒限，以確保警報設考慮到其自身近期的歷史行為。

Traditionally the “2 or 3 standard deviation rule” (alert level = Average value + 2 x SD) which assumes the data is normally distributed, has been applied.

傳統上會採用「2 或 3 個標準差法則」（警戒限＝平均值＋2 × 標準差），此法假設資料呈常態分布。

As environmental monitoring data are usually not normally distributed, other statistical approaches such as a nonparametric approach based on 99.9Th or 99.99th percentiles, a non-parametric tolerance limit approach, or a cut-off Value approach (e.g., at 59th or 99th percentiles) should be used.

由於環境監測資料通常不呈常態分佈，因此應採用其他統計方法，如基於第 99.9 個百分位數或第 99.99 個百分位數的非參數方法、非參數容差限值方法或截止值方法（如第 59 個百分位數或第 99 個百分位數）。

Alert level limits should be reviewed regularly by the company and be adapted, if necessary, based on the actual performance. Performance based alert levels that are well below the action limits should be considered as a confirmation of solid microbial control of the environment.

公司應定期審查警戒限，必要時根據實際情況進行調整。基於性能的警戒限如果遠低於行動限，則應視為對環境固體微生物控制的驗證。

Q33: Is it possible to fully replace microbiological monitoring using e.g. settle plates and volumetric air sampling systems, by other integrated sampling and testing systems (e.g. Rapid Microbiological Methods, RMM)?

是否可使用其他整合式採樣與檢測系統（例如快速微生物方法，RMM），完全取代以沉降培養皿及主動式空氣採樣系統等方式執行的微生物監測？

A: Paragraph 9.22 requires a microbial monitoring using a combination of methods such as settle plates, volumetric air sampling, glove, gown and surface sampling. New technologies are available as continuous active air sampling and rapid microbial testing system, e.g., based on digital imaging technology to detect and count growing microbes.

答：9.22要求綜合使用沉降培養皿、主動式空氣取樣、手套、防護服和表面取樣等方法進行微生物監測。新技術包括連續主動空氣取樣和快速微生物檢測系統，如基於數位成像技術的檢測和計數生長微生物系統。

Equivalence of methods should be demonstrated and the effectiveness of the chosen method should be proven, including for in-house germs. Validation data of these new methods should include recovery studies of the sampling method. The exposure time should not have any negative effect on the suitability of the media used.

應證明方法的等效性，並證明所選方法的有效性，包括對內部菌的有效性。這些新方法的確效資料應包括取樣方法的回收率研究。暴露時間不應對所用介質的適用性產生任何負面影響。

For the use of real-time viable particle counting and given the non-equivalency AFUs versus CFUs and current GMP/Pharmacopeial limits are in CFU, the company need to collect data on their process for the real-time viable particle counting to compare it to the standard environmental monitoring data.

對於實時微生物計數的使用，考慮到 AFU 與 CFU 的非等效性以及現行 GMP/藥典限值以 CFU 為單位元，公司需要收集有關實時微生物計數過程的資料，以便與標準環境監測資料進行比較。

A full understanding of what triggers signals and what is a normal AFU signal in the process and the development of appropriate alert and action limits based on this data, together with appropriate procedures that should define the actions to be taken in response to alarms including the consideration of additional microbial monitoring must be established. A scientific justification for the limits applied is required. Data must be available for at least 12 months.

充分瞭解在製程過程中是什麼觸發了信號，什麼是正常的 AFU 信號，並根據這些資料制定適當的警戒限和行動限，同時制定適當的程式，確定回應警報時應採取的行動，包括考慮進行額外的微生物監測。應用的限度必須有科學依據。必須提供至少 12 個月的資料。

Required elements the company needs to have:

公司需要具備的必要元素：

Primary Validation Package of the vendor for the system
系統供應商的主要確效包
User specific Validation Package / Data for Verification of Validation
使用者特定的確效包/確效資料
Parallel phase grade A (RRM/traditional active air sampling method) in operation to gain experience with new technology under grade A
A 級並行階段（RRM/傳統主動空氣取樣法）的運行，以獲得 A 級下新技術的經驗
Test for interferences to be addressed, e.g., by disinfectants, materials or product
測試要解決的幹擾，例如消毒劑、物料或產品
Operational Approach: Implementation / Alarm Handling Concept
操作方法：實施/警報處理概念
Supportive data: Collection and evaluation of data in a production area grade C and D
支援資料：C級和D級生產區資料的收集和評估

Identification of microorganisms must be performed as it is essential to determine the (possible) root cause of a contamination and evaluate the risk of the contamination for the drug product. If an action limit exceedance occurs, the agar plate from the system must be incubated in order to isolate associated CFUs and to allow identification of species for further investigation and impact assessment of product quality.

必須執行微生物鑑別，因為這對於判定污染的可能根本原因，以及評估該污染對藥品造成的風險至關重要。若發生超出行動限值的情況，必須培養系統中的培養基平板，以分離相關 CFU 並鑑別菌種，供後續調查及產品品質影響評估使用。

Q34: What means “frequency” here? Absolute number of interventions or how often they occur during a certain time interval?

這裡的「頻率」是指什麼？是介入操作的絕對次數，還是在特定時間區間內的發生頻率？

A:Frequency means that the absolute number of interventions that occur during the routine aseptic process should be included in the APS.

答：頻率是指在常規無菌製程過程中發生的介入的絕對數量應包括在APS中。

Q35: What interventions should be included in the APS for the annual operator’s requalification?

在進行操作人員年度資質再驗證時，APS中應包含哪些介入措施？

A: Each operator should perform each intervention. The worst case must be covered, which means that the interventions are independent of the lot size and the duration of the production. See in more detail in the Chapter above about Personnel (Annex 1, paragraph 7.4).

答：每位操作人員都應執行每一項介入操作。必須涵蓋最差情況，也就是介入操作不因批量大小或生產持續時間而異。詳見前述人員章節（附錄 1，第 7.4 節）。

Q36: What does “same container/closure configuration” mean?

“相同的容器/密封件設定”是什麼意思？

A: “Same container/closure configuration” refers to the dimensions, (e.g. diameter of opening) shape and material of the container and closure, like e.g. vial/stopper. E.g. has a stopper for lyophilisation a different form than a stopper for liquid products, this is therefore considered a different container/closure system.

答：“相同的容器/密閉設定”是指容器和密封件的尺寸（如開口直徑）、形狀和材料，如小瓶/塞子。例如，冷凍乾燥用塞子與液體產品用塞子的形式不同，因此被視為不同的容器/密閉系統。

Q37: There is a filling line with subsequent lyophilisation. Can the liquid filling with subsequent lyophilization be considered as worst case, so that APS of liquid filling with lyophilization would cover as well liquid filling process without lyophilization?

灌裝後進行冷凍乾燥的灌裝線，是否可以將隨後冷凍乾燥的液體灌裝視為最差情況，以便冷凍乾燥液體灌裝的APS涵蓋沒有冷凍乾燥的液體灌裝過程？

A: No, liquid filling and lyophilisation are different processes on the same line, with different paths.

答：否，液體灌裝和凍乾是同一條生產線上的不同工序，有不同的路徑。

Q38: When can a bracketing or matrix approach be applied?

什麼時候可以採用分組法或矩陣法？

A: If equivalence can be shown between e.g. glassware and stoppers a bracketing approach can be applied for the APS. New materials must be validated and an APS is part of the validation.

答：如果可以證明如玻璃器皿和瓶塞之間的等效性，則可以對 APS 採用分組法。新材料必須經過確效，而 APS 是確效的一部分。

Q39: Does the APS of campaign manufacturing require the simulation of the maximal number of batches and duration of a campaign?

階段性生產的APS是否需要類比階段性生產的最大批次數和持續時間？

A: This is a complex question and the scenario depends on many factors. Consideration should be given to designing and performing the process simulation so that it simulates the risks associated with both the beginning and the end of the campaign and demonstrating the campaign duration does not pose any risk. The start-of-campaign (including aseptic assemblies if the case) AND end-of-campaign studies should be conducted in any case.

答：這是一個複雜的問題，具體情況取決於很多因素。應考慮設計和執行製程模擬，以便模擬與階段性生產開始和結束相關的風險，並證明階段性生產持續時間不會造成任何風險。在任何情況下都應進行階段性生產開始（包括在此情況下的無菌裝配）和結束研究。

Q40: Can we differentiate between 1 CFU and >1 CFU like in ISO 13408-1 (2015) for 5’000 10’000 and > 10’000 units filled: if 1 CFU is detected, investigation, and consideration of one APS, if > 1 CFU, investigation, corrective measures and repetition of validation with 3 APS runs?

我們是否可以像ISO 13408-1（2015）中一樣，區分1個CFU和>1個CFU，灌裝5,000 -10,000個和>1,0000個單位：如果檢測到1個CFU，則調查並考慮進行一次APS，如果檢測到>1 CFU，則調查、採取糾正措施並進行3次APS重複確效？

A:No. The new Annex 1 is stricter than the ISO 13408-1 (2015). Any contaminated unit with a contamination > 0 CFU results in a failed APS and actions according to chapter 9.46 should be followed.

答：否。新的附錄 1 比 ISO 13408-1 (2015) 更為嚴格。任何污染> 0 CFU 的污染單元都會導致 APS 不合格，應按照 9.46 的規定進行處理。

Q41: With identification of root cause and corrective actions implemented, would it be acceptable to resume production (with batches at risk if a positive) prior to the 14-day reads off test and completion of successful growth promotion? Release of batches could only resume after completion of successful revalidation (3x APS)?

在確定了根本原因並採取了糾正措施後，在14天的讀數測試和成功完成生長促進之前恢復生產（如果陽性，則批次有風險）是否可以接受？只有在成功完成再確效（3x APS）後才能恢復批次放行？

A: No, as it clearly states, that PRODUCTION should resume only after completion of successful revalidation (9.46 vii)

答：否，因為它明確規定，只有在成功完成再確效後才能恢復生產（9.46 vii)

4.7 Quality Control (QC) (Annex 1, Chapter 10)

品質管制（QC）（附錄 1，第 10 章）

Q42: To support the design of manufacturing activities, environmental monitoring regime etc., Annex 1 requires that personnel with appropriate training and experience in microbiology and sterility assurance should be available. What is considered appropriate training and experience?

為支持生產活動和環境監測制度等的設計，附錄 1 要求應配備在微生物學和無菌保證方面接受過適當培訓並具有相關經驗的人員。什麼是適當的培訓和經驗？

A: Microbiological knowledge (incl. sterility assurance) can be acquired by education, training and experience.

答：微生物知識（包括無菌保證）可以通過教育、培訓和經驗獲得。

The best prerequisite for the involvement of a person as an expert, for example in CCS assessments, the definition of resulting measures or in investigations on microbial contaminations, is an education (in particular a university degree or an equivalent diploma e.g. an institution of higher technical education) in the field of micro-biology (or possibly other natural sciences, or medicine).

作為專家參與例如CCS評估、制定相應措施或微生物污染調查等工作的最佳先決條件是擁有微生物學（或其他自然科學或醫學）領域的教育背景（特別是大學學位或同等文憑，如高等技術教育機構）。

However, a good understanding of the manufacturing processes concerned is also required.

然而，還需要對相關生產製程有充分的瞭解。

Q43: What limits do we expect for specifications for raw materials, components and products? What is typical?

我們預期原料、零組件及產品的品質標準應採用哪些限值？一般常用的限值為何？

A:The need for microbiological testing of raw materials and the limits to be defined for such testing should take into account the nature of the raw materials (e.g., if of biological origin and whether they can be considered growth promoting) and their use in the respective process. The relevant chapters and monographs in the Pharmacopeia, the requirements as defined in the marketing authorisation and other regulations should be considered.

答：對原料進行微生物檢測的必要性以及為這種檢測確定的限值應考慮到原料的性質（如是否源於生物，是否可被視為促進生長）及其在相關製程中的用途。應考慮藥典中的相關章節和各論、上市許可中規定的要求及其他法規。

Raw materials, components and products and their handling should be assessed as part of the CCS.

原料、組分和產品及其處理應作為 CCS 的一部分進行評估。

The specifications should be justified.

質量標準應合理。

Q44: Should bioburden be tested on each batch of raw material as incoming control AND on the compounding solution in which it is formulated before sterile filtration?

是否應對每批原料進行微生物負荷測試作為進料控制的一部分？是否應該在除菌過濾前對配製溶液進行微生物負荷測試？

A:Yes

答：是的

Q45: What does “different lyophilization loads” actually mean? First and last? Different lyophilizers? Worst cases? Does that mean each sample from a different lyophilizer or samples from different batches in the same lyophilizer?

“不同的凍乾裝載”到底指的是什麼？第一次和最後一次？不同的凍乾機？最差情況？這是否是指來自不同凍乾機的每個樣品或來自同一凍乾機中不同批次的樣品？

A:Lyophilization load means loads for each lyophilizer for each batch, if e.g. more than one lyophilizer is used.

答：凍乾裝載是指每臺凍乾機的每批次的裝載，例如使用不止一臺凍乾機。

Q46: How should situations for products with short shelf life be handled when data exceeds the established limits (including OOS for sterility, see 10.) only after product batch certification?

對於有效期間較短的產品，若在批次認證後才發現資料超出既定限值（包括無菌試驗 OOS，參見第 10 章），應如何處理？

A: A procedure should be in place in case a post-release OOS should be obtained to inform physicians, patient and health authorities, to assess the risk for the patient and to define remediation steps as needed.