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The Rules Governing Medicinal Products in the European Union Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use

 

歐盟藥品管理法規第4卷《人用和獸用藥品良好生產規范指南》

 

Annex 1

 

附錄1

 

Manufacture of Sterile Medicinal Products

 

無菌藥品生產

 

Deadline for coming into operation:

 

生效時間：

 

25 August 2023 : one year from the date of publication in Eudralex Volume 4

 

2023 年 8 月 25 日：發布之日起一年后生效（除8.123節外）

 

25 August 2024 : two years from the date of publication in Eudralex Volume 4 for point 8.123

 

2024 年 8 月 25 日：發布之日起兩年后第 8.123 節生效

 

Document map               

 

文件目錄

 

Section  Number 章節	General  overview 概述
1. Scope 范圍	Includes additional areas (other than  sterile products) where the general principles of the annex can be  applied. 包括可適用本附錄一般原則的其他領域（其他非無菌產品外）。
2. Principle 原則	General principles as applied to the  manufacture of sterile products. 適用于無菌產品生產的一般原則。
3. Pharmaceutical Quality System  (PQS) 藥品質量體系（PQS）	Highlights the specific requirements of  the PQS when applied to sterile products. 重點介紹 PQS 在應用于無菌產品時的具體要求。
4. Premises 廠房	General guidance regarding the specific  needs for premises design and also guidance on the qualification of   premises including the use of Barrier Technology. 關于廠房設計的具體要求，以及關于廠房確認的指導，包括使用屏障技術。
5. Equipment 設備	General guidance on the design and  operation of equipment. 關于設備設計和操作的一般指導。
6. Utilities 公用系統	Guidance regarding the special  requirements of utilities such as water, gas and vacuum. 有關水，氣和真空等公用系統特定要求的指南。
7. Personnel 人員	Guidance on the requirements for specific  training, knowledge and skills. Also gives guidance regarding the   qualification of personnel. 關于特定培訓，知識和技能要求的指導。還就人員確認提供了指導。
8. Production and specific technologies 生產和特定技術	Guidance on the approaches to be taken  regarding aseptic and terminal sterilization processes. Guidance on the   approaches to sterilization of products, equipment and   packaging components. Also guidance on different   technologies such as lyophilization and  Form-Fill-Seal where  specific requirements apply. 關于無菌和最終滅菌工藝應采取的方法的指南。關于產品、設備和包裝部件滅菌方法的指南。還就不同技術，如凍干和成型-灌裝-密封，的特定要求提供指導。
9. Environmental and process monitoring 環境和過程監測	This section differs from guidance given  in section 4 in that the guidance here applies to ongoing routine  monitoring  regarding the design of systems and setting of action   limits alert levels and reviewing trend  data. The section  also gives guidance on the  requirements of Aseptic Process  Simulations  (APS). 本節與第 4 節中給出的指導不同，因為此處的指南適用于有關持續日常監測的系統設計和行動限/警戒限設置以及趨勢數據回顧。 本節還就無菌工藝模擬（APS）的要求提供了指導。
10. Quality control (QC) 質量控制（QC）	Guidance on some of the specific Quality  Control requirements relating to sterile products. 關于無菌產品的一些具體質量控制要求的指南。
11. Glossary 術語	Explanation of specific terminology. 具體術語的解釋。

 

1 Scope

 

范圍

 

The manufacture of sterile products covers a wide range of sterile product types (active substance, excipient, primary packaging material and finished dosage form), packed sizes (single unit to multiple units), processes (from highly automated systems to manual processes) and technologies (e.g. biotechnology, classical small molecule manufacturing systems and closed systems). This Annex provides general guidance that should be used in the design and control of facilities, equipment, systems and procedures used for the manufacture of all sterile products applying the principles of Quality Risk Management (QRM), to ensure that microbial, particulate and endotoxin/pyrogen contamination is prevented in the final product.

 

無菌產品的制造涵蓋廣泛的無菌產品類型（活性物質，輔料，內包裝材料和成品制劑），包裝規格（單劑量到多劑量），工藝（從高度自動化系統到手動工藝）和技術（例如生物技術，經典小分子制造系統和密閉系統）。本附錄提供了使用質量風險管理（QRM）原則應用于各類無菌產品的設施，設備，系統和程序的設計和控制的通用指導，以確保最終產品免受微生物，顆粒和內毒素/熱原污染。

 

QRM applies to this document in its entirety and will not, normally, be referred to in specific paragraphs. Where specific limits or frequencies or ranges are specified, these should be considered as a minimum requirement. They are stated due to historical regulatory experience of issues that have been identified and have impacted the safety of patients.

 

QRM適用于本文件的全部內容，通常不會在具體段落中提及。在規定具體限值、頻率或范圍的情況下，應將這些限制或范圍視為最低要求。基于已經確定并影響患者安全的問題的歷史監管經驗對它們進行聲明。

 

The intent of the Annex is to provide guidance for the manufacture of sterile products. However, some of the principles and guidance, such as contamination control strategy, design of premises, cleanroom classification, qualification, validation, monitoring and personnel gowning, may be used to support the manufacture of other products that are not intended to be sterile such as certain liquids, creams, ointments and low bioburden biological intermediates, but where the control and reduction of microbial, particulate and endotoxin/pyrogen contamination is considered important. Where a manufacturer elects to apply guidance herein to non-sterile products, the manufacturer should clearly document which principles have been applied and acknowledge that compliance with those principles should be demonstrated.

 

本附錄的目的是為無菌產品的制造提供指導。然而，一些原則和指導，如污染控制策略，廠房設計，潔凈室分類，確認，驗證，監測和人員更衣，也可用于支持制造其他不需要無菌但有必要控制和減少微生物，顆粒物和內毒素/熱原污染的產品，如某些液體，乳膏，軟膏和低生物負荷生物中間體。如果制造商選擇將此指南應用于非無菌產品，制造商應清楚地記錄已應用的原則，并應認可證明符合這些原則。

 

2 Principle

 

原則

 

2.1 The manufacture of sterile products is subject to special requirements in order to minimize risks of microbial, particulate and endotoxin/pyrogen contamination. The following key areas should be considered:

 

無菌產品的制造須遵守特定要求，以盡量減少微生物、微粒和內毒素/熱原污染的風險。應考慮以下關鍵領域：

 

i.             Facility, equipment and process should be appropriately designed, qualified and/or validated and where applicable, subjected to ongoing verification according to the relevant sections of the Good Manufacturing Practices (GMP) guidelines. The use of appropriate technologies (e.g. Restricted Access Barriers Systems (RABS), isolators, robotic systems, rapid/alternative methods and continuous monitoring systems) should be considered to increase the protection of the product from potential extraneous sources of endotoxin/pyrogen, particulate and microbial contamination such as personnel, materials and the surrounding environment, and assist in the rapid detection of potential contaminants in the environment and the product.

 

設施、設備和工藝應按照良好生產規范（GMP）指南的相關章節進行適當的設計、確認和/或驗證，并在適用的情況下，進行持續確認。應考慮使用適當的技術（例如限制進入屏障系統（RABS）、隔離器、機器人系統、快速/替代方法和連續監測系統），以加強對產品的保護，使其免受潛在的外來內毒素/熱原、顆粒物和微生物來源（如人員、物料和周圍環境）污染的影響，并支持快速檢測環境和產品中的潛在污染物。

 

ii.             Personnel should have adequate qualifications and experience, training and behaviour with a specific focus on the principles involved in the protection of sterile product during the manufacturing, packaging and distribution processes.

 

人員應具有足夠的資質和經驗、培訓和行為規范，并特別關注在制造、包裝和運輸過程中無菌產品保護的原則。

 

iii.             Processes and monitoring systems for sterile product manufacture should be designed, commissioned, qualified, monitored and regularly reviewed by personnel with appropriate process, engineering and microbiological knowledge.

 

無菌產品制造的工藝和監測系統應由具有適當工藝、工程和微生物知識的人員進行設計、調試、確認、監測和定期回顧。

 

iv.             Raw materials and packaging materials should be adequately controlled and tested to ensure that level of bioburden and endotoxin/pyrogen are suitable for use.

 

應充分控制和測試原輔料和包裝材料，以確保生物負荷和內毒素/熱原水平滿足使用要求。

 

2.2 Processes, equipment, facilities and manufacturing activities should be managed in accordance with QRM principles to provide a proactive means of identifying, scientifically evaluating and controlling potential risks to quality. Where alternative approaches are used, these should be supported by appropriate rationale, risk assessment and mitigation, and should meet the intent of this Annex.

 

工藝、設備、設施和制造活動應按照QRM原則進行管理，以提供一種前瞻性手段來識別、科學地評估和控制潛在的質量風險。在使用替代方法時，應有適當的論證、風險評估和緩解措施的支持，并應符合本附錄的目的。

 

In the first instance, QRM priorities should include appropriate design of the facility, equipment and processes, followed by the implementation of well-designed procedures, and finally application of monitoring systems as the element that demonstrates that the design and procedures have been correctly implemented and continue to perform in line with expectations. Monitoring or testing alone does not give assurance of sterility.

 

QRM的優先考慮，首先應是設施、設備和工藝的適當設計，其次是實施設計良好的程序，最后使用監測系統作為表明設計和程序已正確實施并持續如預期執行的要素。僅監測或檢測并不能保證無菌。

 

2.3 A Contamination Control Strategy (CCS) should be implemented across the facility in order to define all critical control points and assess the effectiveness of all the controls (design, procedural, technical and organisational) and monitoring measures employed to manage risks to medicinal product quality and safety. The combined strategy of the CCS should establish robust assurance of contamination prevention. The CCS should be actively reviewed and, where appropriate, updated and should drive continual improvement of the manufacturing and control methods. Its effectiveness should form part of the periodic management review. Where existing control systems are in place and are appropriately managed, these may not require replacement but should be referenced in the CCS and the associated interactions between systems should be understood.

 

應在整個設施中實施污染控制策略（CCS），以定義所有關鍵控制點，并評估用于管理藥品質量和安全風險的所有控制措施（設計，程序，技術和組織）和監測措施的有效性。CCS的組合策略應建立強有力的污染預防保證。CCS應動態審查，并在適當情況下進行更新，并應推動制造和控制方法的持續改進。其有效性應成為定期管理審查的一部分。如果現有的控制系統并得到適當管理，則這些系統可能不需要更換，但應在CCS中引用，并應了解系統之間的相關相互作用。

 

2.4 Contamination control and steps taken to minimize the risk of contamination from microbial, endotoxin/pyrogen and particle sources includes a series of interrelated events and measures. These are typically assessed, controlled and monitored individually but their collective effectiveness should be considered together.

 

污染控制和為最大限度減少微生物、內毒素/熱原和顆粒源污染風險而采取的步驟包括一系列相互關聯的事件和措施。它們通常單獨評估，控制和監測，但應一起考慮其集體有效性。

 

2.5 The development of the CCS requires detailed technical and process knowledge. Potential sources of contamination are attributable to microbial and cellular debris (e.g. pyrogen, endotoxin) as well as particulate (e.g. glass and other visible and sub-visible particles).

 

CCS的制訂需要詳細的技術和工藝知識。潛在的污染源可歸因于微生物和細胞碎片（例如熱原，內毒素）以及顆粒物（例如玻璃和其他可見和亞可見顆粒（不溶性微粒））。

 

Elements to be considered within a CCS should include (but are not limited to):

 

CCS中需要考慮的要素應包括（但不限于）：

 

i.             Design of both the plant and processes including the associated documentation.

 

工廠和工藝的設計，包括相關文件。

 

ii.             Premises and equipment.

 

廠房和設備

 

iii.             Personnel.

 

人員

 

iv.             Utilities.

 

公用系統

 

v.             Raw material controls – including in-process controls.

 

原輔料控制-包括過程控制

 

vi.             Product containers and closures.

 

產品容器和密封部件

 

vii.             Vendor approval – such as key component suppliers, sterilisation of components and single use systems (SUS), and critical service providers.

 

供應商審批 – 例如關鍵組分供應商、組件和一次性系統（SUS）的滅菌以及關鍵服務提供商。

 

viii.             Management of outsourced activities and availability/transfer of critical information between parties, e.g. contract sterilisation services.

 

外包活動管理以及各方之間關鍵信息的可獲得性/傳遞，例如合同滅菌服務。

 

ix.             Process risk management.

 

工藝風險管理

 

x.             Process validation.

 

工藝驗證

 

xi.             Validation of sterilisation processes.

 

滅菌工藝驗證

 

xii.             Preventative maintenance – maintaining equipment, utilities and premises (planned and unplanned maintenance) to a standard that will ensure there is no additional risk of contamination.

 

預防性維護 – 以確保沒有額外的污染風險的標準對設備、公用系統和廠房進行維護（計劃內和計劃外維護）。

 

xiii.             Cleaning and disinfection.

 

清潔和消毒

 

xiv.             Monitoring systems - including an assessment of the feasibility of the introduction of scientifically sound, alternative methods that optimize the detection of environmental contamination.

 

監測系統—包括評估采用科學合理的替代方法以優化環境污染檢測的可行性。

 

xv.             Prevention mechanisms – trend analysis, detailed investigation, root cause determination, corrective and preventive actions (CAPA) and the need for comprehensive investigational tools.

 

預防機制 – 趨勢分析、詳細調查、根本原因分析、糾正和預防措施（CAPA）以及綜合調查工具的需要。

 

xvi.             Continuous improvement based on information derived from the above.

 

基于上述信息的持續改進。

 

2.6 The CCS should consider all aspects of contamination control with ongoing and periodic review resulting in updates within the pharmaceutical quality system as appropriate. Changes to the systems in place should be assessed for any impact on the CCS before and after implementation.

 

CCS應考慮污染控制的各個方面，并進行持續和定期的審查，從而在藥品質量體系內酌情更新。對現有系統的變更應在實施前后評估其對CCS的影響。

 

2.7 The manufacturer should take all steps and precautions necessary to assure the sterility of the products manufactured within its facilities. Sole reliance for sterility or other quality aspects should not be placed on any terminal process or finished product test.

 

制造商應采取一切必要的步驟和預防措施，以確保在其設施內制造的產品的無菌性。對無菌性或其他質量方面，不應僅依賴任何終端過程或成品測試。

 

3 Pharmaceutical Quality System (PQS)

 

藥品質量體系（PQS）

 

3.1 The manufacture of sterile products is a complex activity that requires specific controls and measures to ensure the quality of products manufactured. Accordingly, the manufacturer’s PQS should encompass and address the specific requirements of sterile product manufacture and ensure that all activities are effectively controlled so that the risk of microbial, particulate and endotoxin/pyrogen contamination is minimized in sterile products. In addition to the PQS requirements detailed in Chapter 1 of the GMP guidelines (Part I - Basic Requirements for Medicinal Products), the PQS for sterile product manufacture should also ensure that:

 

無菌產品的制造是一項復雜的活動，需要特定的控制和措施來確保所制造產品的質量。因此，制造商的PQS應涵蓋并解決無菌產品制造的特定要求，并確保有效控制所有活動，以最大限度減少無菌產品中微生物，顆粒物和內毒素/熱原污染的風險。除了GMP指南（第一部分 - 藥品基本要求）第1章中詳述的PQS要求外，無菌產品制造的PQS還應確保：

 

i.             An effective risk management system is integrated into all areas of the product life cycle with the aim to minimize microbial contamination and to ensure the quality of sterile products manufactured.

 

將有效的風險管理體系整合到產品生命周期的所有領域，旨在最大限度地減少微生物污染，并確保所制造的無菌產品的質量。

 

ii.             The manufacturer has sufficient knowledge and expertise in relation to the products manufactured and the equipment, engineering and manufacturing methods employed that have an impact on product quality.

 

制造商在所制造的產品以及采用的影響產品質量的設備，工程和制造方法方面有足夠的知識和專業技能。

 

iii.             Root cause analysis of procedural, process or equipment failure is performed in such a way that the risk to product is correctly identified and understood so that suitable corrective and preventive actions (CAPA) are implemented.

 

對程序、工藝或設備故障的根本原因分析以正確識別和理解產品風險的方式進行，以便實施適當的糾正和預防措施（CAPA）。

 

iv.             Risk management is applied in the development and maintenance of the CCS, to identify, assess, reduce/eliminate (where applicable) and control contamination risks. Risk management should be documented and should include the rationale for decisions taken in relation to risk reduction and acceptance of residual risk.

 

將風險管理應用于CCS的制訂和維護，以識別，評估，減少/消除（如適用）和控制污染風險。風險管理應記錄在案，并應包括就降低風險和接受剩余風險作出決定的理由。

 

v.             Senior management should effectively oversee the state of control throughout the facility and product lifecycle. Risk management outcome should be reviewed regularly as part of the on- going quality management, during change, in the event of a significant emerging problem, and during the periodic product quality review.

 

高級管理層應有效監督整個設施和產品生命周期的受控狀態。在變更期間，在出現重大問題時，以及在定期產品質量回顧期間，風險管理結果應作為持續質量管理的一部分定期審查。

 

vi.             Processes associated with the finishing, storage and transport of sterile products should not compromise the sterile product. Aspects that should be considered include: container integrity, risks of contamination and avoidance of degradation by ensuring that products are stored and maintained in accordance with the registered storage conditions.

 

與無菌產品的最終處理、儲存和運輸相關的過程不應損害無菌產品。應考慮的方面包括：容器完整性，污染風險以及通過確保產品按照注冊存儲條件進行儲存和維護來避免降解。

 

vii.             Persons responsible for the certification/release of sterile products have appropriate access to manufacturing and quality information and possess adequate knowledge and experience in the manufacture of sterile products and the associated critical quality attributes. This is in order to allow such persons to determine if the sterile products have been manufactured in accordance with the registered specifications and approved process and are of the required quality.

 

負責無菌產品認證/放行的人員可適當獲取生產和質量信息，并在無菌產品的生產和相關的關鍵質量屬性方面擁有足夠的知識和經驗。以使這些人員能夠確定無菌產品是否按照注冊標準和批準的工藝生產，并具有所需的質量。

 

3.2 All non-conformities, such as sterility test failures, environmental monitoring excursions or deviations from established procedures should be adequately investigated before certification/release of the batch. The investigation should determine the potential impact upon process and product quality and whether any other processes or batches are potentially impacted. The reason for including or excluding a product or batch from the scope of the investigation should be clearly justified and recorded.

 

在批認證/放行之前，應充分調查所有不符合項，例如無菌測試失敗，環境監測超標或不符合既定程序的偏差。調查應確定對工藝和產品質量的潛在影響，以及任何其他工藝或批次是否受到潛在影響。將某一產品或批次納入調查或排除在外的原因應明確說明理由并記錄在案。

 

4 Premises

 

廠房

 

4.1 The manufacture of sterile products should be carried out in appropriate cleanrooms, entry to which should be through change rooms that act as airlocks for personnel and airlocks for equipment and materials. Cleanrooms and change rooms should be maintained to an appropriate cleanliness standard and supplied with air that has passed through filters of an appropriate efficiency. Controls and monitoring should be scientifically justified and should effectively evaluate the state of environmental conditions of cleanrooms, airlocks and pass-through hatches.

 

無菌產品的制造應在適當的潔凈室進行，（人員、設備、物品等）應通過change rooms進入，這些change rooms充當人員、設備和物料的氣閘。潔凈室和change rooms應保持適當的潔凈度標準，并提供通過適當效率過濾器的空氣。控制和監測應科學論證，并應有效評估潔凈室、氣閘和傳遞窗的環境條件的狀況。

 

4.2 The various operations of component preparation, product preparation and filling should be carried out with appropriate technical and operational separation measures within the cleanroom or facility to prevent mix up and contamination.

 

組分制備，產品配制和灌裝的各種操作應在潔凈室或設施內采取適當的技術性和操作性隔離措施，以防止混淆和污染。

 

4.3 Restricted Access Barrier Systems (RABS) or isolators are beneficial in assuring required conditions and minimizing microbial contamination associated with direct human interventions in the critical zone. Their use should be considered in the CCS. Any alternative approaches to the use of RABS or isolators should be justified.

 

限制進入屏障系統（RABS）或隔離器有助于確保所需條件并最大限度地減少與關鍵區域直接人為干預相關的微生物污染。在CCS中應考慮它們的使用。任何替代RABS或隔離器的方法都應進行論證。

 

4.4 For the manufacture of sterile products, there are four grades of cleanroom/zone.

 

對于無菌產品的制造，有四個等級的潔凈室/區域。

 

l  Grade A: The critical zone for high-risk operations (e.g. aseptic processing line, filling zone, stopper bowl, open primary packaging or for making aseptic connections under the protection of first air). Normally, such conditions are provided by a localised airflow protection, such as unidirectional airflow workstations within RABS or isolators. The maintenance of unidirectional airflow should be demonstrated and qualified across the whole of the grade A area. Direct intervention (e.g. without the protection of barrier and glove port technology) into the grade A area by operators should be minimized by premises, equipment, process and procedural design.

 

l  A級：高風險操作的關鍵區域（例如無菌加工線，灌裝區，膠塞斗，未密閉的內包裝材料或在第一空氣的保護下進行無菌連接）。通常，這些條件由局部氣流保護提供，例如RABS或隔離器中的單向流工作站。應證實和確認整個A級區域內單向流的維持。應通過廠房、設備、工藝和程序設計最大限度減少操作人員對A級區域的直接干預（例如，在沒有屏障和手套箱技術的保護下）。

 

l  Grade B: For aseptic preparation and filling, this is the background cleanroom for grade A (where it is not an isolator). Air pressure differences should be continuously monitored. Cleanrooms of lower grade than grade B can be considered where isolator technology is used (see paragraph 4.20 ).

 

l  B級：對于無菌配制和灌裝，B級為A級（隔離器除外）的背景區域。應持續監測壓差。在使用隔離器技術的情況下，可以考慮低于B級的潔凈室（見4.20）。

 

l  Grade C and D: These are cleanrooms used for carrying out less critical stages in the manufacture of aseptically filled sterile products or as a background for isolators. They can also be used for the preparation/filling of terminally sterilised products. (See section 8 for the specific details on terminal sterilisation activities).

 

l  C級和D級：用于在無菌灌裝無菌產品的制造中執行不太關鍵的階段，或作為隔離器的背景。還可用于最終滅菌產品的配制/灌裝。（有關最終滅菌活動的具體細節，請參閱第8節）。

 

4.5 In cleanrooms and critical zones, all exposed surfaces should be smooth, impervious and unbroken in order to minimize the shedding or accumulation of particles or micro-organisms.

 

在潔凈室和關鍵區域，所有暴露的表面應光滑、無滲漏、不破損，以最大限度減少顆粒或微生物的脫落或積聚。

 

4.6 To reduce accumulation of dust and to facilitate cleaning there should be no recesses that are difficult to clean effectively, therefore projecting ledges, shelves, cupboards and equipment should be kept to a minimum. Doors should be designed to avoid recesses that cannot be cleaned. Sliding doors may be undesirable for this reason.

 

為了減少灰塵的積聚并便于清潔，不應有難以有效清潔的凹槽，因此應最大限度減少突出的窗臺，架子，柜子和設備。門的設計應避免無法清潔的凹槽。由于這個原因，滑動門可能是不可取的。

 

4.7 Materials used in cleanrooms, both in the construction of the room and for items used within the room, should be selected to minimize generation of particles and to permit the repeated application of cleaning, disinfectant and sporicidal agents where used.

 

潔凈室使用的材料，無論是在房間的建造中還是在房間內使用的物品，都應選擇以盡量減少顆粒的產生，并允許重復使用清潔、消毒劑和殺孢子劑。

 

4.8 Ceilings should be designed and sealed to prevent contamination from the space above them.

 

天花板的設計和密封應防止來自上方空間的污染。

 

4.9 Sinks and drains should be prohibited in the grade A and grade B areas. In other cleanrooms, air breaks should be fitted between the machine or sink and the drains. Floor drains in lower grade cleanrooms should be fitted with traps or water seals designed to prevent back flow and should be regularly cleaned, disinfected and maintained.

 

應禁止在A級和B級區域使用水槽和排水管。在其他潔凈室中，應在設備或水槽與排水管之間安裝空氣隔斷。低級別潔凈室的地漏應安裝存水彎或水封，以防止回流，并應定期清潔，消毒和維護。

 

4.10 The transfer of equipment and materials into and out of the cleanrooms and critical zones is one of the greatest potential sources of contamination. Any activities with the potential to compromise the cleanliness of cleanrooms or the critical zone should be assessed and if they cannot be eliminated, appropriate controls should be implemented.

 

設備和物料進出潔凈室和關鍵區域是最大的潛在污染源之一。任何可能損害潔凈室或關鍵區域潔凈度的活動都應進行評估，如果無法消除，則應實施適當的控制措施。

 

4.11 The transfer of materials, equipment, and components into the grade A or B areas should be carried out via a unidirectional process. Where possible, items should be sterilised and passed into these areas through double-ended sterilisers (e.g. through a double-door autoclave or depyrogenation oven/tunnel) sealed into the wall. Where sterilisation upon transfer of the items is not possible, a procedure which achieves the same objective of not introducing contamination should be validated and implemented, (e.g. using an effective transfer disinfection process, rapid transfer systems for isolators or, for gaseous or liquid materials, a bacteria-retentive filter). The removal of items from the grade A and B areas (e.g. materials, waste, environmental samples) should be carried out via a separate unidirectional process. If this is not possible, time-based separation of movement (incoming/exiting material) by procedure should be considered and controls applied to avoid potential contamination of incoming items.

 

物料、設備和組件向A級或B級區域的轉移應通過單向過程進行。在可能的情況下，應對物品進行滅菌，并通過密封在墻上的雙開口滅菌器（例如通過雙扉門高壓滅菌器或去熱原烘箱/隧道）進入這些區域。如果無法在轉移物品時進行滅菌，則應驗證和實施實現不引入污染的相同目標的程序（例如，使用有效的轉移消毒程序，隔離器的快速轉移系統，或對于氣體或液體物料，使用除菌級過濾器）。從A級和B級區域傳出物品（例如物料，廢棄物，環境樣品）應通過單獨的單向過程進行。如果無法做到這一點，應考慮按程序對這種轉移（傳入/傳出）進行基于時間的分離，并采取控制措施，以避免對傳入物料/物品的潛在污染。

 

4.12 Airlocks should be designed and used to provide physical separation and to minimize microbial and particle contamination of the different areas and should be present for material and personnel moving between different grades. Wherever possible, airlocks used for personnel movement should be separated from those used for material movement. Where this is not practical, time-based separation of movement (personnel/material) by procedure should be considered. Airlocks should be flushed effectively with filtered air to ensure that the grade of the cleanroom is maintained. The final stage of the airlock should, in the “at rest” state, be of the same cleanliness grade (viable and total particle) as the cleanroom into which it leads. The use of separate change rooms for entering and leaving the grade B area is desirable. Where this is not practical, time-based separation of activities (ingress/egress) by procedure should be considered. Where the CCS indicates that the risk of contamination is high, separate change rooms for entering and leaving production areas should be used. Airlocks should be designed as follows:

 

氣閘的設計和使用應提供物理分隔，并最大限度地減少不同區域的微生物和顆粒污染，并且應用于在不同等級之間移動的物料和人員。在可能的情況下，用于人員流動的氣閘應與用于物料流動的氣閘分開。如無法實現，應考慮按時間將移動（人員/物料）分開的程序。氣閘應使用經過濾的空氣有效沖洗，以確保保持該潔凈室的等級。在氣閘的最后階段，在“靜態”下，應與其進入的潔凈室具有相同的潔凈度等級（活性粒子和總粒子）。使用單獨的更衣室進出B級區域是可取的。如無法做到，應考慮按程序對活動（進/出）進行基于時間的分離。如果CCS表明污染風險很高，則應使用單獨的更衣室進出生產區域。氣閘應設計如下：

 

i.             Personnel airlocks: Areas of increasing cleanliness used for entry of personnel (e.g. from the grade D area to the grade C area to the grade B area). In general hand washing facilities should be provided only in the first stage of the changing room and not be present in changing rooms directly accessing the grade B area.

 

人員氣閘：用于人員進入的潔凈度越來越高的區域（例如，從D級區域到C級區域再到B級區域）。一般來說，洗手設施應僅在更衣室的第一階段提供，而不應出現在直接進入B級區域的更衣室中。

 

ii.             Material airlocks: used for materials and equipment transfer.

 

物料氣閘：用于物料和設備的轉移。

 

l  Only materials and equipment that have been included on an approved list and assessed during validation of the transfer process should be transferred into the grade A or grade B areas via an airlock or pass-through hatches. Equipment and materials (intended for use in the grade A area) should be protected when transiting through the grade B area. Any unapproved items that require transfer should be pre-approved as an exception. Appropriate risk assessment and mitigation measures should be applied and recorded as per the manufacturer's CCS and should include a specific disinfection and monitoring programme approved by quality assurance.

 

l  只有已列入批準清單并在轉移驗證期間進行評估的物料和設備才能通過氣閘或傳遞窗轉移到A級或B級區域。在通過B級區域時，應對設備和物料（打算在A級區域使用）進行保護。任何需要轉移的未經批準的物品都應作為例外情況預先獲得批準。應根據制造商的CCS使用和記錄適當的風險評估和緩解措施，并應包括質量保證部門批準的具體消毒和監測計劃。

 

l  Pass-through hatches should be designed to protect the higher-grade environment, for example by effective flushing with an active filtered air supply.

 

l  傳遞窗的設計應保護更高級別的環境，例如通過主動過濾空氣供應進行有效沖洗。

 

l  The movement of material or equipment from lower grade or unclassified area to higher-grade clean areas should be subject to cleaning and disinfection commensurate with the risk and in line with the CCS.

 

l  將物料或設備從較低等級或未分類區域移動到較高等級的潔凈區域時，應進行與風險相稱并符合CCS的清潔和消毒。

 

4.13 For pass-through hatches and airlocks (for material and personnel), the entry and exit doors should not be opened simultaneously. For airlocks leading to the grade A and grade B areas, an interlocking system should be used. For airlocks leading to grade C and D areas, a visual and/or audible warning system should be operated as a minimum. Where required to maintain area segregation, a time delay between the closing and opening of interlocked doors should be established.

 

 對于傳遞窗和氣閘（用于物料和人員），不應同時打開入口和出口的門。對于通向A級和B級區域的氣閘，應使用聯鎖系統。對于通往C級和D級區域的氣閘，應至少使用聲光報警系統。如果需要保持區域隔離，則應在互鎖門的關閉和打開之間建立時間延遲。

 

4.14 Cleanrooms should be supplied with a filtered air supply that maintains a positive pressure and/or an airflow relative to the background environment of a lower grade under all operational conditions and should flush the area effectively. Adjacent rooms of different grades should have an air pressure difference of a minimum of 10 Pascals (guidance value). Particular attention should be paid to the protection of the critical zone. The recommendations regarding air supplies and pressures may need to be modified where it is necessary to contain certain materials (e.g. pathogenic, highly toxic or radioactive products or live viral or bacterial materials). The modification may include positively or negatively pressurized airlocks that prevent the hazardous material from contaminating surrounding areas. Decontamination of facilities (e.g. the cleanrooms and the heating, ventilation, and air-conditioning (HVAC) systems) and the treatment of air leaving a clean area, may be necessary for some operations. Where containment requires air to flow into a critical zone, the source of the air should be from an area of the same or higher grade.

 

潔凈室應配備經過濾的送風，在所有操作條件下保持相對于較低等級的背景環境的正壓和/或氣流，并應有效沖洗該區域。不同等級的相鄰房間的氣壓差應至少為10帕斯卡（指導值）。應特別注意保護關鍵區域。在需要含有某些物料（例如致病性、劇毒或放射性產品或活病毒或細菌物料）的情況下，可能需要修改有關送風和壓力的建議。這種修改可能包括正壓或負壓氣閘，以防止危險物質污染周圍區域。對于某些操作，可能需要對設施（例如潔凈室和HVAC系統）進行凈化以及處理排風。如果密閉要求空氣流入關鍵區域，則空氣源應來自相同或更高等級的區域。

 

4.15 Airflow patterns within cleanrooms and zones should be visualised to demonstrate that there is no ingress from lower grade to higher grade areas and that air does not travel from less clean areas (such as the floor) or over operators or equipment that may transfer contamination to the higher grade areas. Where unidirectional airflow is required, visualisation studies should be performed to determine compliance, (see paragraphs 4.4 & 4.19). When filled, closed products are transferred to an adjacent cleanroom of a lower grade via a small egress point, airflow visualization studies should demonstrate that air does not ingress from the lower grade cleanrooms to the grade B area. Where air movement is shown to be a contamination risk to the clean area or critical zone, corrective actions, such as design improvement, should be implemented. Airflow pattern studies should be performed both at rest and in operation (e.g. simulating operator interventions). Video recordings of the airflow patterns should be retained. The outcome of the air visualisation studies should be documented and considered when establishing the facility's environmental monitoring programme.

 

 應將潔凈室和區域內的氣流流型可視化，以證明沒有從較低等級區域進入到較高等級區域，并且空氣不會從不太干凈的區域（如地板）或通過操作人員或設備將污染物轉移到較高等級區域。需要單向流時，應進行可視化研究以確定符合性（見第4.4和4.19段）。充填后，已密封的產品通過一個小的出口轉移到相鄰的較低等級的潔凈室，氣流可視化研究應證明空氣不會從較低等級的潔凈室進入B級區域。如果氣流對潔凈區域或關鍵區域構成污染風險，則應采取糾正措施，例如設計改進。氣流流型研究應在靜態和動態下（例如，模擬操作員干預）進行。應保留氣流流型的視頻記錄。在制訂環境監測計劃時，應記錄和考慮空氣可視化研究的結果。

 

4.16 Indicators of air pressure differences should be fitted between cleanrooms and/or between isolators and their background. Set points and the criticality of air pressure differences should be considered within the CCS. Air pressure differences identified as critical should be continuously monitored and recorded. A warning system should be in place to instantly indicate and warn operators of any failure in the air supply or reduction of air pressure differences (below set limits for those identified as critical). The warning signal should not be overridden without assessment and a procedure should be available to outline the steps to be taken when a warning signal is given. Where alarm delays are set, these should be assessed and justified within the CCS. Other air pressure differences should be monitored and recorded at regular intervals.

 

應在潔凈室和/或隔離器與其背景之間安裝壓差指示器。在CCS中應考慮設置點和此壓差的關鍵性。應持續監測和記錄被確定為關鍵的壓差。應建立報警系統，以立即向操作人員指示和警告送風的任何故障或壓差的降低（低于確定為關鍵的限值）。警告信號不應在未經評估的情況下被覆蓋，并應提供程序來概述在發出警告信號時應采取的步驟。如果設置了報警延遲，則應在CCS中對其進行評估并證明其合理性。應定期監測和記錄其他壓差。

 

4.17 Facilities should be designed to permit observation of production activities from outside the grade A and B areas (e.g. through the provision of windows or remote cameras with a full view of the area and processes to allow observation and supervision without entry). This requirement should be considered when designing new facilities or during refurbishment of existing facilities.

 

設施的設計應允許從A級和B級區域之外觀察生產活動（例如，通過提供窗口或遠程攝像機，可以全面查看該區域和過程，以便在不進入的情況下進行觀察和監督）。在設計新設施或翻新現有設施時，應考慮這一要求。

 

Barrier Technologies

 

屏障技術

 

4.18 Isolators or RABS, which are different technologies, and the associated processes, should be designed to provide protection through separation of the grade A environment from the environment of the surrounding room. The hazards introduced from entry or removal of items during processing should be minimized and supported by high capability transfer technologies or validated systems that robustly prevent contamination and are appropriate for the respective technology.

 

隔離器或RABS是不同的技術和工藝，應設計為通過將A級環境與周圍房間的環境分開來提供保護。在加工過程中，應盡量減少因進入或移除物品而造成的危害，并得到高能力轉移技術或經驗證可有效防止污染的系統的支持，并適用于相應的技術。

 

4.19 The design of the technology and processes used should ensure appropriate conditions are maintained in the critical zone to protect the exposed product during operations.

 

所用技術和工藝的設計應確保在關鍵區域保持適當的條件，以便在操作過程中保護暴露的產品。

 

i.             Isolators:

 

隔離器

 

a)        The design of open isolators should ensure grade A conditions with first air protection in the critical zone and unidirectional airflow that sweeps over and away from exposed products during processing.

 

開放式隔離器的設計應確保A級條件，在關鍵區域有第一空氣保護，在加工過程中單向氣流掃過暴露的產品，然后遠離。

 

b)        The design of closed isolators should ensure grade A conditions with adequate protection for exposed products during processing. Airflow may not be fully unidirectional in closed isolators where simple operations are conducted. However, any turbulent airflow should not increase risk of contamination of the exposed product. Where processing lines are included in closed isolators, grade A conditions should be ensured with first air protection in the critical zone and unidirectional airflow that sweeps over and away from exposed products during processing

 

密閉式隔離器的設計應確保在加工過程中對暴露的產品提供足夠保護的A級條件。在進行簡單操作的封閉隔離器中，氣流可能不是完全單向的。但是，任何湍流氣流都不應增加暴露產品污染的風險。如果工藝流程中包含在密閉式隔離器中，則應確保A級條件，在關鍵區域提供第一空氣保護，并在加工過程中單向氣流掃過暴露的產品，然后遠離

 

c)        Negative pressure isolators should only be used when containment of the product is considered essential (e.g. radiopharmaceutical products) and specialized risk control measures should be applied to ensure the critical zone is not compromised.

 

只有當產品隔離（例如放射性藥物產品）被認為必要時，才應使用負壓隔離器，并應采取專門的風險控制措施以確保關鍵區域不受損害。

 

ii.             RABS:

 

RABS：

 

The design of RABS should ensure grade A conditions with unidirectional airflow and first air protection in the critical zone. A positive airflow from the critical zone to the supporting background environment should be maintained.

 

RABS的設計應確保具有單向氣流的A級條件和在關鍵區域的第一空氣保護。應保持從關鍵區域到支持背景環境的正向氣流。

 

4.20 The background environment for isolators or RABS should ensure the risk of transfer of contamination is minimized.

 

隔離器或RABS的背景環境應確保將污染轉移的風險降至最低。

 

i.             Isolators:

 

隔離器

 

a)        The background environment for open isolators should generally correspond to a minimum of grade C. The background for closed isolators should correspond to a minimum of grade D. The decision on the background classification should be based on risk assessment and justified in the CCS.

 

開放式隔離器的背景環境通常應符合C級的最低要求。密閉式隔離器的背景應與最低 D 級相對應。關于背景級別的決定應以風險評估為基礎，并在CCS中說明理由。

 

b)        Key considerations when performing the risk assessment for the CCS of an isolator should include (but are not limited to); the bio-decontamination programme, the extent of automation, the impact of glove manipulations that may potentially compromise ‘first air’ protection of critical process points, the impact of potential loss of barrier/glove integrity, transfer mechanisms used and activities such as set-up or maintenance that may require the doors to be opened prior to the final bio-decontamination of the isolator. Where additional process risks are identified, a higher grade of background should be considered unless appropriately justified in the CCS.

 

對隔離器CCS進行風險評估時的關鍵考慮因素應包括（但不限于）：生物凈化程序，自動化程度，手套操作可能對關鍵工藝點的“第一空氣”保護造成潛在損害的影響、屏障/手套完整性的潛在損失的影響、所使用的可能需要在隔離器最終生物凈化之前開門的傳遞機制以及裝機或維護等活動。當發現其他工藝風險，應考慮更高級別的背景，除非CCS中已適當證明其合理性。

 

c)        Airflow pattern studies should be performed at the interfaces of open isolators to demonstrate the absence of air ingress.

 

開放式隔離器的接口應進行氣流流型研究，以證明沒有空氣進入。

 

ii.             RABS:

 

RABS：

 

The background environment for RABS used for aseptic processing should correspond to a minimum of grade B and airflow pattern studies should be performed to demonstrate the absence of air ingress during interventions, including door openings if applicable.

 

用于無菌處理的RABS的背景環境應最低與B級相對應，并應進行氣流流型研究，以證明干預期間沒有空氣進入，包括開門（如適用）。

 

4.21 The materials used for glove systems (for both isolators and RABS), should be demonstrated to have appropriate mechanical and chemical resistance. The frequency of glove replacement should be defined within the CCS.

 

用于手套系統（隔離器和RABS）的材料應證明具有適當的機械和耐化學性。手套的更換頻率應在CCS內定義。

 

i.             Isolators:

 

隔離器

 

a)        For isolators, leak testing of the glove system should be performed using a methodology demonstrated to be suitable for the task and criticality. The testing should be performed at defined intervals. Generally glove integrity testing should be performed at a minimum frequency of the beginning and end of each batch or campaign. Additional glove integrity testing may be necessary depending on the validated campaign length.

 

對于隔離器，應使用一種被證明適合該任務和關鍵性的方法進行手套系統的泄漏測試。測試應以規定的時間間隔進行。一般來說，手套完整性測試應至少在每批或每個生產周期的開始和結束進行。根據已驗證的生產周期長度，可能需要額外的手套完整性測試。

 

b)        Glove integrity monitoring should include a visual inspection associated with each use and following any manipulation that may affect the integrity of the system.

 

手套完整性監測應包括在每次使用和任何可能影響系統完整性的操作后進行目視檢查。

 

c)        For manual aseptic processing activities where single unit or small batch sizes are produced, the frequency of integrity verification may be based on other criteria, such as the beginning and end of each manufacturing session.

 

對于生產單件或小批量的人工無菌工藝活動，完整性確認的頻率可能基于其他標準，如每個生產環節的開始和結束。

 

d)        Integrity / leak testing of isolator systems should be performed at defined intervals.

 

隔離器系統的完整性/泄漏測試應以規定的時間間隔進行。

 

ii.             RABS:

 

RABS：

 

For RABS, gloves used in the grade A area should be sterilised before installation and sterilised or effectively bio-decontaminated by a validated method prior to each manufacturing campaign. If exposed to the background environment during operation, disinfection using an approved methodology following each exposure should be completed. Gloves should be visually examined with each use, and integrity testing should be performed at periodic intervals.

 

對于RABS，在A級區域使用的手套應在安裝前進行滅菌，并在每次制造活動之前通過經驗證的方法進行滅菌或有效消毒。如果在操作過程中暴露于背景環境，則應在每次暴露后使用批準的方法進行消毒。每次使用時應目視檢查手套，并應定期進行完整性測試。

 

4.22 Decontamination methods (cleaning and bio-decontamination, and where applicable inactivation for biological materials) should be appropriately defined and controlled. The cleaning process prior to the bio-decontamination step is essential; any residues that remain may inhibit the effectiveness of the decontamination process. Evidence should also be available to demonstrate that the cleaning and bio-decontamination agents used do not have adverse impact on the product produced within the RABS or isolator.

 

應適當界定和控制去污方法（清潔和生物凈化，以及在適用的情況下對生物材料進行滅活）。生物凈化步驟之前的清潔過程至關重要;殘留的任何殘留物都可能抑制去污過程的有效性。還應提供證據證明所使用的清潔劑和生物凈化劑不會對RABS或隔離器內生產的產品產生不利影響。

 

i.             For isolators

 

對于隔離器

 

The bio-decontamination process of the interior should be automated, validated and controlled within defined cycle parameters and should include a sporicidal agent in a suitable form (e.g. gaseous or vaporized form). Gloves should be appropriately extended with fingers separated to ensure contact with the agent. Methods used (cleaning and sporicidal bio-decontamination) should render the interior surfaces and critical zone of the isolator free from viable microorganisms.

 

隔離器內部的生物凈化過程應在既定的循環參數內自動化，驗證和控制，并應包括合適形式（例如氣態或汽態）的殺孢劑。手套應適當伸展，手指分開，以確保與殺孢子劑接觸。使用的方法（清潔和殺孢生物凈化）應使隔離器的內表面和關鍵區域沒有活的微生物。

 

ii.             For RABS

 

對于RABS

 

The sporicidal disinfection should include the routine application of a sporicidal agent using a method that has been validated and demonstrated to robustly include all areas of the interior surfaces and ensure a suitable environment for aseptic processing.

 

殺孢子消毒應包括殺孢劑的日常使用，使用經驗證和證明的方法，以有效地包含內表面的所有區域，并確保無菌處理的合適環境。

 

Cleanroom and clean air equipment qualification

 

潔凈室和潔凈空氣設備確認

 

4.23 Cleanrooms and clean air equipment such as unidirectional airflow units (UDAFs), RABS and isolators, used for the manufacture of sterile products, should be qualified according to the required characteristics of the environment. Each manufacturing operation requires an appropriate environmental cleanliness level in the operational state in order to minimize the risk of contamination of the product or materials being handled. Appropriate cleanliness levels in the “at rest” and “operational” states should be maintained.

 

用于制造無菌產品的潔凈室和潔凈空氣設備，如單向氣流單元（UDF）、RABS和隔離器，應按照所需的環境特性進行確認。每個生產操作都需要在動態條件下具有適當的環境潔凈度水平，以最大限度地降低所處理的產品或物料受到污染的風險。應保持在“靜態”和“動態”狀態的適當潔凈度水平。

 

4.24 Cleanrooms and clean air equipment should be qualified using methodology in accordance with the requirements of Annex 15. Cleanroom qualification (including classification) should be clearly differentiated from operational environmental monitoring.

 

潔凈室和潔凈空氣設備應使用符合附錄15要求的方法進行確認。潔凈室確認（包括分級）應與生產環境監測明確區分開來。

 

4.25 Cleanroom and clean air equipment qualification is the overall process of assessing the level of compliance of a classified cleanroom or clean air equipment with its intended use. As part of the qualification requirements of Annex 15, the qualification of cleanrooms and clean air equipment should include (where relevant to the design/operation of the installation):

 

潔凈室和潔凈空氣設備確認是評估已分級潔凈室或潔凈空氣設備適合其預期用途的總體過程。作為附錄15確認要求的一部分，潔凈室和潔凈空氣設備的確認應包括（在設計/運行有關）：

 

i.             Installed filter system leakage and integrity testing.

 

已安裝過濾系統泄漏和完整性測試。

 

ii.             Airflow tests - volume and velocity.

 

氣流測試-風量和風速

 

iii.             Air pressure difference test.

 

壓差測試

 

iv.             Airflow direction test and visualisation.

 

氣流方向測試和可視化

 

v.             Microbial airborne and surface contamination.

 

空氣微生物和表面微生物

 

vi.             Temperature measurement test.

 

溫度測試

 

vii.             Relative humidity test.

 

相對濕度測試

 

viii.             Recovery test.

 

恢復測試

 

ix.             Containment leak test.

 

隔離泄漏測試

 

Reference for the qualification of the cleanrooms and clean air equipment can be found in the ISO 14644 series of standards.

 

有關潔凈室和潔凈空氣設備確認的參考，請參見 ISO 14644 系列標準。

 

4.26 Cleanroom classification is part of the cleanroom qualification and is a method of assessing the level of air cleanliness against a specification for a cleanroom or clean air equipment by measuring the total particle concentration. Classification activities should be scheduled and performed in order to avoid any impact on process or product quality. For example, initial classification should be performed during simulated operations and reclassification performed during simulated operations or during aseptic process simulation (APS).

 

潔凈室級別確認是潔凈室確認的一部分，是通過測量總粒子濃度來根據潔凈室或潔凈空氣設備的規范評估空氣潔凈度水平的方法。應安排和執行級別確認活動，以避免對工藝或產品質量產生任何影響。例如，初始級別確認應在模擬操作期間執行，級別再確認可在模擬操作或無菌工藝模擬（APS）期間進行。

 

4.27 For cleanroom classification, the total of particles equal to or greater than 0.5 and 5 µm should be measured. This measurement should be performed both at rest and in simulated operations in accordance with the limits specified in Table 1.

 

對于潔凈室級別確認，應測量等于或大于0.5和5μm的粒子總數。該測量應根據表1中規定的限值在靜態和模擬動態中進行。

 

Table 1: Maximum permitted total particle concentration for classification

 

表1:用于分級的最大允許總粒子濃度

 

Grade 級別	Maximum  limits for total particle 總粒子最大限度		Maximum  limits for total particle 總粒子最大限度
	≥  0.5 µm/m3		≥  5 µm/m3
	at  rest 靜態	in  operation 動態	at  rest 靜態	in  operation 動態
A	3  520	3  520	Not  specified (a) 不作規定	Not  specified (a) 不作規定
B	3  520	352  000	Not  specified (a) 不作規定	2  930
C	352  000	3  520 000	2  930	29  300
D	3  520 000	Not predetermined  (b) 未設定	29  300	Not predetermined  (b) 未設定

 

a)        Classification including 5µm particles may be considered where indicated by the CCS or historical trends.

 

根據CCS或歷史趨勢，可考慮5 μ m粒子的級別。

 

b)        For grade D, in operation limits are not predetermined. The manufacturer should establish in operation limits based on a risk assessment and routine data where applicable.

 

對于D級，（本文件）未預先確定動態標準。制造商應根據風險評估和日常數據(如適用)建立動態標準。

 

4.28 For classification of the cleanroom, the minimum number of sampling locations and their positioning can be found in ISO 14644 Part 1. For the aseptic processing area and the background environment (the grade A and grade B areas, respectively), additional sample locations should be considered and all critical processing areas such as the point of fill and container closure feeder bowls should be evaluated. Critical processing locations should be determined by documented risk assessment and knowledge of the process and operations to be performed in the area.

 

對于潔凈室的級別確認，可以在ISO 14644第1部分中找到采樣點的最小數量及其位置。對于無菌加工區域和背景環境（分別為A級和B級區域），應考慮額外的取樣位置，并應評估所有關鍵處理區域，例如灌裝點和容器密封部件給料斗。關鍵處理位置應通過書面的風險評估和對該區域所執行的工藝和操作的了解來確定。

 

4.29 Cleanroom classification should be carried out in the “at rest” and “in operation” states.

 

4.29 潔凈室級別確認應在“靜態”和“動態”狀態下進行。

 

i.             The definition of “at rest” state is the condition whereby the installation of all the utilities is complete including any functioning HVAC, with the main manufacturing equipment installed as specified but not operating and without personnel present in the room.

 

“靜態”狀態的定義是所有公用設施的安裝已完成，包括任何正常運行的HVAC，主要生產設備按既定安裝但不運行并且沒有人員在房間內的條件。

 

ii.             The definition of “in operation” state is the condition where the installation of the cleanroom is complete, the HVAC system fully operational, equipment installed and functioning in the manufacturer’s defined operating mode with the maximum number of personnel present performing or simulating routine operational work.

 

“動態”狀態的定義是潔凈室的安裝完成，HVAC系統完全運行，設備在制造商定義的操作模式下安裝和運行，并且具有執行或模擬日常操作工作的最大人員數量的條件。

 

iii.             The total particle limits given in Table 1 above for the “at rest” state should be achieved after a “clean up” period on completion of operations and line clearance/cleaning activities. The "clean up" period (guidance value of less than 20 minutes) should be determined during the qualification of the rooms, documented and adhered to in procedures to reinstate a qualified state of cleanliness if disrupted during operation.

 

上文表1中給出的“靜態”條件的總粒子限度應在完成操作和生產線清除/清場活動后的“自凈”期后達到。“自凈”期（指導值小于20分鐘）應在房間的確認期間確定，并在操作期間中斷時記錄并遵守程序，以恢復已確認的潔凈狀態。

 

4.30 The speed of air supplied by unidirectional airflow systems should be clearly justified in the qualification protocol including the location for air speed measurement. Air speed should be designed, measured and maintained to ensure that appropriate unidirectional air movement provides protection of the product and open components at the working position (e.g. where high-risk operations occur and where product and/or components are exposed). Unidirectional airflow systems should provide a homogeneous air speed in a range of 0.36 – 0.54 m/s (guidance value) at the working position, unless otherwise scientifically justified in the CCS. Airflow visualization studies should correlate with the air speed measurement.

 

單向流系統提供的氣流速度應在確認方案中明確證明，包括風速測量的位置。應設計、測量和維護氣流速度，以確在工作位置（例如，發生高風險操作以及產品和/或組件暴露的位置）有足夠的單向氣流為產品和暴露的組件提供保護。單向流系統應在工作位置提供 0.36 – 0.54 m/s（指導值）范圍內的均勻氣流速度，除非 CCS 中另有科學論證。氣流可視化研究應與風速相關聯。

 

4.31 The microbial contamination level of the cleanrooms should be determined as part of the cleanroom qualification. The number of sampling locations should be based on a documented risk assessment and the results obtained from room classification, air visualization studies and knowledge of the process and operations to be performed in the area. The maximum limits for microbial contamination during qualification for each grade are given in Table 2. Qualification should include both “at rest” and “in operation” states.

 

潔凈室的微生物污染水平應作為潔凈室確認的一部分來確定。采樣點的數量應基于書面的風險評估和從房間級別確認，氣流可視化研究以及有關在該區域執行的工藝和操作的知識中獲得的結果。每個級別的確認過程中微生物污染的最大限值見表2。確認應包括“靜態”和“動態”狀態。

 

Table 2: Maximum permitted microbial contamination level during qualification

 

表2：確認期間最大允許微生物污染水平

 

Grade 級別	Air  sample CFU/m3 浮游菌 CFU/立方	Settle  plates (diameter  90 mm) CFU/4  hours (a) 沉降菌（直徑90mm） CFU/4小時	Contact  plates (diameter  55 mm) CFU/plate 接觸皿（直徑55mm） CFU/皿
A	No  growth 無生長
B	10	5	5
C	100	50	25
D	200	100	50

 

a)        Settle plates should be exposed for the duration of operations and changed as required after a maximum of 4 hours. Exposure time should be based on recovery studies and should not allow desiccation of the media used.

 

沉降皿應在操作期間進行暴露，并在最多4小時后根據需要更換。暴露時間應基于回收率研究，并且不應使所用的培養基干燥。

 

Note 1: All methods indicated for a specific grade in the table should be used for qualifying the area of that specific grade. If one of the methods tabulated is not used, or alternative methods are used, the approach taken should be appropriately justified.

 

注1：表中為各潔凈級別所指定的所有方法應應用于確認該級別的領域。如未使用表中的任一方法，或者使用了替代方法，則應適當證明所采用的方法的合理性。

 

Note 2: Limits are applied using CFU throughout the document. If different or new technologies are used that present results in a manner different from CFU, the manufacturer should scientifically justify the limits applied and where possible correlate them to CFU.

 

注 2：在整個文件中使用了單位為CFU 的限度。如果使用其他的或新的技術，以不同于CFU的方式呈現結果，制造商應科學證明所使用的限度的合理性，并在可能的情況下將其與CFU相關聯。

 

Note 3: For the qualification of personnel gowning, the limits given for contact plates and glove prints in Table 6 should apply.

 

注3：對于人員更衣的確認，應使用表6中給出的接觸皿和手套的限度。

 

Note 4: Sampling methods should not pose a risk of contamination to the manufacturing operations.

 

注4：取樣方法不應對生產操作造成污染風險。

 

4.32 The requalification of cleanrooms and clean air equipment should be carried out periodically following defined procedures. The requalification should include at a minimum the following:

 

潔凈室和潔凈空氣設備應按照規定的程序定期進行再確認。再確認至少應包括以下內容：

 

l  Cleanroom classification (total particle concentration).

 

l  潔凈室級別確認（總粒子濃度）

 

l  Integrity test of final filters.

 

l  終端過濾器完整性測試

 

l  Airflow volume measurement.

 

l  風量測試

 

l  Verification of air pressure difference between rooms.

 

l  不同房間之間的壓差確認

 

l  Air velocity test (Note: For grade B, C and D the air velocity test should be performed according to a risk assessment documented as part of the CCS. However, it is required for filling zones supplied with unidirectional airflow (e.g. when filling terminally sterilised products or background to grade A and RABS). For grades with non-unidirectional airflow, a measurement of recovery testing should replace velocity testing).

 

l  風速測試（注：對于B級，C級和D級，應根據CCS中記錄的風險評估進行風速測試。但是，對于提供單向流的灌裝區域（例如，最終滅菌產品的灌裝或A級和RABS背景）是必須的。對于非單向流的潔凈區域，可用恢復測試取代風速測試）。

 

The maximum time interval for requalification of grade A & B areas, is 6 months.

 

A級和B級區域再確認的最大時間間隔為6個月。

 

The maximum time interval for requalification of grade C & D areas, is 12 months.

 

C&D級區域再確認的最大時間間隔為12個月。

 

Appropriate requalification consisting of at least the above tests should also be carried out following completion of remedial action implemented to rectify an out of compliance equipment or facility condition or after changes to equipment, facility or processes as appropriate. The significance of a change should be determined through the change management process. Examples of changes to be considered include but are not limited to the following:

 

在為糾正設備或設施不合規狀況而采取的補救措施完成后，或在適當的設備、設施或工藝變更之后，也應進行適當的再確認，至少包括上述測試。變更的重要性應通過變更管理流程來確定。需要考慮的變更示例包括但不限于以下：

 

l  Interruption of air movement which affects the operation of the installation.

 

l  影響設備操作的空氣流動中斷。

 

l  Change in the design of the cleanroom or of the operational setting parameters of the HVAC system.

 

l  改變潔凈室的設計或HVAC系統的運行設置參數。

 

l  Special maintenance which affects the operation of the installation (e.g. change of final filters).

 

l  影響設備操作的特殊維護（例如更換終端過濾器）。

 

Disinfection

 

消毒

 

4.33 The disinfection of cleanrooms is particularly important. They should be cleaned and disinfected thoroughly in accordance with a written programme. For disinfection to be effective, prior cleaning to remove surface contamination should be performed. Cleaning programmes should effectively remove disinfectant residues. More than one type of disinfecting agent should be employed to ensure that where they have different modes of action, their combined usage is effective against bacteria and fungi. Disinfection should include the periodic use of a sporicidal agent. Monitoring should be undertaken regularly in order to assess the effectiveness of the disinfection programme and to detect changes in types of microbial flora (e.g. organisms resistant to the disinfection regime currently in use).

 

潔凈室的消毒尤為重要。應按照書面程序徹底清潔和消毒。為了使消毒有效，應在此之前進行清潔以去除表面污染。清潔程序應有效去除消毒劑殘留。應使用一種以上的消毒劑，以確保在它們具有不同作用機理且它們的組合使用對細菌和真菌有效。消毒應包括定期使用殺孢子劑。應定期進行監測以評估消毒程序的有效性，并監測微生物菌群類型的變化（例如，對當前使用的消毒模式耐受的生物體）。

 

4.34 The disinfection process should be validated. Validation studies should demonstrate the suitability and effectiveness of disinfectants in the specific manner in which they are used and on the type of surface material, or representative material if justified, and should support the in-use expiry periods of prepared solutions.

 

應驗證消毒過程。驗證研究應以具體使用方式和表面材料類型或代表性材料（如經論證）證明消毒劑的適用性和有效性，并應支持所制備溶液的使用有效期。

 

4.35 Disinfectants and detergents used in grade A and grade B areas should be sterile prior to use. Disinfectants used in grade C and D may also be required to be sterile where determined in the CCS. Where the disinfectants and detergents are diluted / prepared by the sterile product manufacturer, this should be done in a manner to prevent contamination and they should be monitored for microbial contamination. Dilutions should be kept in previously cleaned containers (and sterilized where applicable) and should only be stored for the defined period. If the disinfectants and detergents are supplied “ready-made” then results from certificates of analysis or conformance can be accepted subject to successful completion of the appropriate vendor qualification.

 

在A級和B級區域使用的消毒劑和清潔劑在使用前應無菌。在C級和D級中使用的消毒劑也可能在CCS中要求是無菌的。如消毒劑和清潔劑由無菌產品制造商稀釋/制備，則應以防止污染的方式進行，并應監測微生物污染。（消毒液）稀釋液應保存在預先清潔的容器中（并在適當時進行滅菌），并且只應儲存在規定的期限內。如使用“市售現成”消毒劑和清潔劑，那么在成功完成適當的供應商確認后，分析或合格證書的結果可以接受。

 

4.36 Where fumigation or vapour disinfection (e.g. Vapour-phase Hydrogen Peroxide) of cleanrooms and associated surfaces are used, the effectiveness of any fumigation agent and dispersion system should be understood and validated.

 

在對潔凈室和相關表面進行熏蒸或蒸汽消毒(例如，汽化過氧化氫)時，應了解和驗證任何熏蒸劑和分散系統的有效性。

 

5 Equipment

 

設備

 

5.1 A written, detailed description of the equipment design should be available (including process and instrumentation diagrams as appropriate). This should form part of the initial qualification package and be kept up to date.

 

應提供設備設計的書面詳細描述（包括適當的過程和儀表圖）。這應作為初始確認的一部分，并保持最新狀態。

 

5.2 Equipment monitoring requirements should be defined in “user requirements specifications” during early stages of development, and confirmed during qualification. Process and equipment alarm events should be acknowledged and evaluated for trends. The frequency at which alarms are assessed should be based on their criticality (with critical alarms reviewed immediately).

 

設備監測需求應在開發的早期階段在“用戶需求規范”中定義，并在驗證期間確認。應確認過程和設備報警事件并評估其趨勢。評估警報的頻率應基于其嚴重性（嚴重警報立即審查）。

 

5.3 As far as practicable, equipment, fittings and services should be designed and installed so that operations, maintenance, and repairs can be performed outside the cleanroom. If maintenance has to be performed in the cleanroom, and the required standards of cleanliness and/or asepsis cannot be maintained, then precautions such as restricting access to the work area to specified personnel, generation of clearly defined work protocols and maintenance procedures should be considered. Additional cleaning, disinfection and environmental monitoring should also be considered. If sterilisation of equipment is required, it should be carried out, wherever possible, after complete reassembly.

 

如可行，設備，配件和服務應設計和安裝以在潔凈室外進行操作，維護和維修。如果必須在潔凈室內進行維護，并且無法保持所需的潔凈度和/或無菌標準，則應考慮采取預防措施，例如限制特定人員進入工作區域，制定明確定義的工作規程和維護程序。還應考慮額外的清潔、消毒和環境監測。如果需要對設備進行滅菌，則應在完全重新組裝后盡可能進行滅菌。

 

5.4 The cleaning process should be validated to be able to:

 

清潔過程應驗證能夠：

 

i.             Remove any residue or debris that would detrimentally impact the effectiveness of the disinfecting agent used.

 

清除任何會對所用消毒劑的有效性產生不利影響的殘留或雜物。

 

ii.             Minimize chemical, microbial and particulate contamination of the product during the process and prior to disinfection.

 

在清潔過程中和消毒之前，最大限度地減少產品的化學、微生物和顆粒污染。

 

5.5 For aseptic processes, direct and indirect product contact parts should be sterilised. Direct product contact parts are those that the product passes through, such as filling needles or pumps. Indirect product contact parts are equipment parts that do not contact the product, but may come into contact with other sterilised surfaces, the sterility of which is critical to the overall product sterility (e.g. sterilised items such as stopper bowls and guides, and sterilised components).

 

對于無菌工藝，應對產品直接和間接接觸的部件進行滅菌。直接接觸產品的部件是產品通過的部件，例如灌裝針頭或泵。間接產品接觸部件是指不接觸產品但可能與其他滅菌表面接觸的設備部件，其無菌性對產品的整體無菌至關重要（例如，滅菌物品，如膠塞斗和導軌，以及已滅菌組件）。

 

5.6 All equipment such as sterilisers, air handling systems (including air filtration) and water systems should be subject to qualification, monitoring and planned maintenance. Upon completion of maintenance, their return to use should be approved.

 

所有設備，如滅菌器、空氣處理系統（包括空氣過濾）和水系統，都應進行確認、監測和計劃性維護。維護完成后，其恢復使用應經批準。

 

5.7 Where unplanned maintenance of equipment critical to the sterility of the product is to be carried out, an assessment of the potential impact to the sterility of the product should be performed and recorded.

 

如果要對產品無菌性至關重要的設備進行計劃外維護，則應評估對產品無菌性的潛在影響。

 

5.8 A conveyor belt should not pass through a partition between a grade A or B area and a processing area of lower air cleanliness, unless the belt itself is continually sterilised (e.g. in a sterilising tunnel).

 

傳送帶不應穿過 A 級或 B 級區域與空氣潔凈度較低的加工區域之間的隔板，除非傳送帶本身連續滅菌（例如在滅菌隧道中）。

 

5.9 Particle counters, including sampling tubing, should be qualified. The manufacturer’s recommended specifications should be considered for tube diameter and bend radii. Tube length should typically be no longer than 1m unless justified and the number of bends should be minimized. Portable particle counters with a short length of sample tubing should be used for classification purposes. Isokinetic sampling heads should be used in unidirectional airflow systems. They should be oriented appropriately and positioned as close as possible to the critical location to ensure that samples are representative.

 

粒子計數器，包括采樣管，應經確認。應考慮制造商對管徑和彎曲半徑的建議標準。采樣長度通常不應超過1m（否則應進行論證）且應最大限度減少彎曲次數。應使用采樣管長度較短的便攜式粒子計數器進行級別確認。應使用等動力采樣頭應用于單向流系統。它們應有適當的方向并盡可能靠近關鍵位置，以確保樣品具有代表性。

 

6 Utilities

 

公用系統

 

6.1 The nature and extent of controls applied to utility systems should be commensurate with the risk to product quality associated with the utility. The impact should be determined via a risk assessment and documented as part of the CCS.

 

適用于公用系統的控制的性質和程度應與公用系統相關的產品質量風險相稱。應通過風險評估確定影響，并作為CCS的一部分進行記錄。

 

6.2 In general, higher risk utilities are those that:

 

一般而言，高風險公用系統是指：

 

i.             Directly contact product e.g. water for washing and rinsing, gases and steam for sterilisation.

 

直接接觸產品，例如用于清洗和漂洗的水，用于滅菌的氣體和蒸汽。

 

ii.             Contact materials that will ultimately become part of the product.

 

接觸物料，最終將成為產品的一部分。

 

iii.             Contact surfaces that come into contact with the product.

 

與產品接觸的表面。

 

iv.             Otherwise directly impact the product.

 

其他直接影響產品的系統。

 

6.3 Utilities should be designed, installed, qualified, operated, maintained and monitored in a manner to ensure that the utility system functions as expected.

 

公用系統的設計、安裝、確認、運行、維護和監測應確保公用系統如預期運行。

 

6.4 Results for critical parameters and critical quality attributes of high risk utilities should be subject to regular trend analysis to ensure that system capabilities remain appropriate.

 

高風險公用系統的關鍵參數和關鍵質量屬性的結果應定期進行趨勢分析，以確保系統保持適當的能力。

 

6.5 Records of utility system installation should be maintained throughout the system’s life-cycle. Such records should include current drawings and schematic diagrams, construction material lists and system specifications. Typically, important information includes attributes such as:

 

應在系統的整個生命周期內保存公用系統安裝記錄。此類記錄應包括當前圖紙和原理圖、建筑材料清單和系統規范。通常，重要信息包括以下屬性：

 

i.             Pipeline flow direction, slopes, diameter and length.

 

管道流向、坡度、直徑和長度。

 

ii.             Tank and vessel details.

 

罐和容器詳細信息

 

iii.             Valves, filters, drains, sampling and user points.

 

閥門、過濾器、排水管、取樣點和使用點。

 

6.6 Pipes, ducts and other utilities should not be present in cleanrooms. If unavoidable, then they should be installed so that they do not create recesses, unsealed openings and surfaces which are difficult to clean. Installation should allow cleaning and disinfection of outer surface of the pipes.

 

管道和其他公用設施不應存在于潔凈室中。如果不可避免，則應安裝以免產生凹槽，未密封的開口和難以清潔的表面。安裝應允許清潔和消毒管道的外表面。

 

Water systems

 

水系統

 

6.7 Water treatment plant and distribution systems should be designed, constructed, installed, commissioned, qualified, monitored and maintained to prevent microbiological contamination and to ensure a reliable source of water of an appropriate quality. Measures should be taken to minimize the risk of presence of particulates, microbial contamination/proliferation and endotoxin/pyrogen (e.g. sloping of piping to provide complete drainage and the avoidance of dead legs). Where filters are included in the system, special attention should be given to their monitoring and maintenance. Water produced should comply with the current monograph of the relevant Pharmacopeia.

 

應設計、建造、安裝、調試、確認、監測和維護水處理和分配系統以防止微生物污染，并確保適當質量的可靠水源。應采取措施盡量減少顆粒物、微生物污染/增殖和內毒素/熱原存在的風險（例如，傾斜管道以完全排水和避免死角）。如果系統中包含過濾器，則應特別注意其監控和維護。產生的水應符合相關藥典的現行標準。

 

6.8 Water systems should be qualified and validated to maintain the appropriate levels of physical, chemical and microbial control, taking the effect of seasonal variation into account.

 

水系統應經確認和驗證，以保持適當的物理、化學和微生物控制水平，同時考慮到季節變化的影響。

 

6.9 Water flow should remain turbulent through the pipes in water distribution systems to minimize the risk of microbial adhesion, and subsequent biofilm formation. The flow rate should be established during qualification and be routinely monitored.

 

水流通過配水系統中的管道應保持湍流，以盡量減少微生物粘附和隨后生物膜形成的風險。應在確認期間確定流速，并進行日常監測。

 

6.10 Water for injections (WFI) should be produced from water meeting specifications that have been defined during the qualification process, stored and distributed in a manner which minimizes the risk of microbial growth (e.g. by constant circulation at a temperature above 70°C). WFI should be produced by distillation or by a purification process that is equivalent to distillation. This may include reverse osmosis coupled with other appropriate techniques such as electrodeionization (EDI), ultrafiltration or nanofiltration.

 

注射用水（WFI）應由符合既定確認標準的水生產，并以盡量減少微生物生長風險的方式儲存和分配（例如，通過在高于70°C的溫度下恒溫循環）。WFI應通過蒸餾或相當于蒸餾的純化過程產生。這可以包括反滲透聯合其它適當的技術，例如電去離子（EDI），超濾或納濾。

 

6.11 Where WFI storage tanks are equipped with hydrophobic bacteria retentive vent filters, the filters should not be a source of contamination and the integrity of the filter tested before installation and after use. Controls should be in place to prevent condensation formation on the filter (e.g. by heating).

 

如果WFI儲罐配有疏水性細菌截留通風過濾器（呼吸過濾器），則過濾器不應成為污染源，并且在安裝前和使用后測試過濾器的完整性。應采取適當的控制措施（例如通過加熱），以防止在過濾器上形成冷凝。

 

6.12 To minimize the risk of biofilm formation, sterilisation, disinfection or regeneration of water systems should be carried out according to a predetermined schedule and as a remedial action following out-of-limit or specification results. Disinfection of a water system with chemicals should be followed by a validated rinsing/flushing procedure. Water should be tested after disinfection/regeneration. Chemical testing results should be approved before the water system is returned to use and microbiological/endotoxin results verified to be within specification and approved before batches manufactured using water from the system are considered for certification/release.

 

為最大限度地降低生物膜形成的風險，應按照預定的時間計劃進行水系統的滅菌，消毒或再生，并在超限或超標結果后作為補救措施。使用化學品對水系統進行消毒后，應遵循經驗證的沖洗/沖洗程序。消毒/再生后應測試水質。水系統恢復使用前，化學檢測結果得到批準，微生物/內毒素結果則應在使用該水系統所生產的批次被放行前確認符合標準并得到批準。

 

6.13 Regular ongoing chemical and microbial monitoring of water systems should be performed to ensure that the water continues to meet compendial expectations. Alert levels should be based on the initial qualification data and thereafter periodically reassessed on data obtained during subsequent re-qualifications, routine monitoring, and investigations. Review of ongoing monitoring data should be carried out to identify any adverse trend in system performance. Sampling programmes should reflect the requirements of the CCS and should include all outlets and points of use, at a specified interval, to ensure that representative water samples are obtained for analysis on a regular basis. Sample plans should be based on the qualification data, should consider the potential worst case sampling locations and should ensure that at least one representative sample is included every day of the water that is used for manufacturing processes.

 

 應定期對水系統進行化學和微生物監測，以確保水持續符合藥典標準。警戒限應基于初始確認數據，然后根據在隨后的再確認、日常監測和調查期間獲得的數據定期重新評估。應審查持續監測數據以發現系統性能的任何不良趨勢。取樣方案應反映CCS的要求，并應在規定的時間間隔內包括所有出口和使用點，以確保定期獲得具有代表性的水樣進行分析。取樣計劃應基于確認數據，應考慮潛在的最差情況取樣位置，并應確保每天至少包括一個用于制造過程的水的代表性樣品。

 

6.14 Alert level excursions should be documented and reviewed, and include an investigation to determine whether the excursion is a single (isolated) event or if results are indicative of an adverse trend or system deterioration. Each action limit excursion should be investigated to determine the probable root causes and any potential impact on the quality of products and manufacturing processes as a result of the use of the water.

 

應記錄和審查警戒級別的偏移，并包括調查以確定偏移是個別（孤立的）事件，還是表面不良趨勢或系統惡化。應調查每個行動限偏移，以確定可能的根本原因以及由于使用（超行動限的）水而對產品質量和制造過程的任何潛在影響。

 

6.15 WFI systems should include continuous monitoring systems such as Total Organic Carbon (TOC) and conductivity, as these may give a better indication of overall system performance than discrete sampling. Sensor locations should be based on risk.

 

WFI系統應包括連續監測系統，如總有機碳（TOC）和電導率，因為這些系統可能比離線取樣更好地表面整體系統性能。傳感器位置應基于風險。

 

Steam used as a direct sterilising agent

 

用作直接滅菌劑的蒸汽

 

6.16 Feed water to a pure steam (clean steam) generator should be appropriately purified. Pure steam generators should be designed, qualified and operated in a manner to ensure that the quality of steam produced meets defined chemical and endotoxin levels.

 

純蒸汽（潔凈蒸汽）發生器的給水應適當凈化。純蒸汽發生器的設計、確認和運行方式應確保產生的蒸汽質量符合規定的化學和內毒素水平。

 

6.17 Steam used as a direct sterilising agent should be of suitable quality and should not contain additives at a level that could cause contamination of product or equipment. For a generator supplying pure steam used for the direct sterilisation of materials or product-contact surfaces (e.g. porous hard-good autoclave loads), steam condensate should meet the current monograph for WFI of the relevant Pharmacopeia (microbial testing is not mandatory for steam condensate). A suitable sampling schedule should be in place to ensure that representative pure steam is obtained for analysis on a regular basis. Other aspects of the quality of pure steam used for sterilisation should be assessed periodically against validated parameters. These parameters should include the following (unless otherwise justified): non-condensable gases, dryness value (dryness fraction) and superheat.

 

用作直接滅菌劑的蒸汽應具有合適的質量，并且不應含有可能導致產品或設備污染的添加劑。對于供應用于物料或產品接觸表面（例如，多孔堅硬高壓滅菌器負載）直接滅菌的純蒸汽發生器，蒸汽冷凝水應符合相關藥典WFI的現行標準（蒸汽冷凝水的微生物測試不是強制的）。應制定適當的取樣計劃，以確保定期獲得具有代表性的純蒸汽進行分析。用于滅菌的純蒸汽質量的其他方面應根據經驗證的參數定期進行評估。這些參數應包括以下內容（除非另有說明）：不凝性氣體，干燥度值（干燥度分數）和過熱度。

 

Gases and vacuum systems

 

氣體和真空系統

 

6.18 Gases that come in direct contact with the product/primary container surfaces should be of appropriate chemical, particulate and microbial quality. All relevant parameters, including oil and water content, should be specified, taking into account the use and type of the gas, the design of the gas generation system and, where applicable, comply with the current monograph of the relevant Pharmacopeia or the product quality requirement.

 

與產品/內包裝容器表面直接接觸的氣體應具有適當的化學、顆粒和微生物質量。應指定所有相關參數，包括油分和水分，同時考慮到氣體的用途和類型，氣體制備系統的設計，并在適用的情況下，符合相關藥典的現行標準或產品質量要求。

 

6.19 Gases used in aseptic processes should be filtered through a sterilising grade filter (with a nominal pore size of a maximum of 0.22 µm) at the point of use. Where the filter is used on a batch basis (e.g. for filtration of gas used for overlay of aseptically filled products) or as product vessel vent filter, then the filter should be integrity tested and the results reviewed as part of the batch certification/release process. Any transfer pipework or tubing that is located after the final sterilising grade filter should be sterilised. When gases are used in the process, microbial monitoring of the gas should be performed periodically at the point of use.

 

無菌工藝中使用的氣體應在使用點通過除菌級過濾器（標稱孔徑最大為0.22μm）進行過濾。如果過濾器按批使用（例如，用于無菌灌裝產品覆蓋層氣體的過濾器）或作為產品容器通風過濾器，則應對過濾器進行完整性測試并審查結果作為批放行過程的一部分。在終端除菌級過濾器之后的任何管道都應進行滅菌。當在工藝中使用氣體時，應在使用點定期對氣體進行微生物監測。

 

6.20 Where backflow from vacuum or pressure systems poses a potential risk to the product, there should be mechanism(s) to prevent backflow when the vacuum or pressure system is shut off.

 

如果來自真空或壓力系統的回流對產品構成潛在風險，則應有機制在真空或壓力系統關閉時防止回流。

 

Heating and cooling and hydraulic systems

 

加熱，冷卻和液壓系統

 

6.21 Major items of equipment associated with hydraulic, heating and cooling systems should, where possible, be located outside the filling room. There should be appropriate controls to contain any spillage and/or cross contamination associated with the system fluids.

 

與液壓、加熱和冷卻系統有關的主要設備應盡可能位于灌裝室外。應有適當的控制措施，以控制與系統流體相關的任何溢出和/或交叉污染。

 

6.22 Any leaks from these systems that would present a risk to the product should be detectable (e.g. an indication system for leakage).

 

這些系統對產品構成風險的任何泄漏都應可檢測（例如，泄漏指示系統）。

 

7 Personnel

 

人員

 

7.1 The manufacturer should ensure that there are sufficient appropriate personnel, suitably qualified, trained and experienced in the manufacture and testing of sterile products, and any of the specific manufacturing technologies used in the site’s manufacturing operations, to ensure compliance with GMP applicable to the manufacture and handling of sterile products.

 

制造商應確保有足夠的適當人員，在無菌產品的生產和檢驗以及現場生產操作中使用的任何特定生產技術方面經適當的確認、培訓并有經驗，以確保符合適用于無菌產品生產和加工的GMP。

 

7.2 Only the minimum number of personnel required should be present in cleanrooms. The maximum number of operators in cleanrooms should be determined, documented and considered during activities such as initial qualification and APS, so as not to compromise sterility assurance.

 

潔凈室中應盡量配備最少數量的人員。在初始確認和APS等活動中，應確定，記錄和考慮潔凈室中的最大操作人員數量，以避免對無菌保證的損害。

 

7.3 All personnel including those performing cleaning, maintenance, monitoring and those that access cleanrooms should receive regular training, gowning qualification and assessment in disciplines relevant to the correct manufacture of sterile products. This training should include the basic elements of microbiology and hygiene, with a specific focus on cleanroom practices, contamination control, aseptic techniques and the protection of sterile products (for those operators entering the grade B cleanrooms and/or intervening into grade A) and the potential safety implications to the patient if the product is not sterile. The level of training should be based on the criticality of the function and area in which the personnel are working.

 

所有人員，包括進行清潔、維護、監測的人員和其他進入潔凈室的人員，都應接受與正確生產無菌產品相關的學科的定期培訓、更衣確認和評估。培訓應包括微生物學和衛生的基本要素，特別關注潔凈室實踐，污染控制，無菌技術和無菌產品的保護（適用于進入B級潔凈室和/或對A級進行干擾的操作人員）以及如果產品長菌，對患者的潛在安全影響。培訓的水平應基于人員工作的職能和領域的重要性。

 

7.4 The personnel accessing grade A and B areas should be trained for aseptic gowning and aseptic behaviours. Compliance with aseptic gowning procedures should be confirmed by assessment and periodic reassessment at least annually, and should involve both visual and microbial assessment (using monitoring locations such as gloved fingers, forearms, chest and hood (facemask / forehead). See paragraph 9.30 for the expected limits). The unsupervised access to the grade A and grade B areas where aseptic operations are or will be conducted should be restricted to appropriately qualified personnel, who have passed the gowning assessment and have participated in a successful APS.

 

進入A級和B級區域的人員應接受無菌更衣和無菌行為培訓。應至少每年通過評估和定期重新評估來確認無菌更衣程序的合規性，并且應包括視覺和微生物評估（使用監測位置，例如手套手指，前臂，胸部和頭罩（面罩/前額）。預期標準見第9.30段）。在無人監督的情況下進入正在或將要進行無菌操作的A級和B級區域時，應只允許已通過更衣評估并已成功參與APS的經適當確認的人員。

 

7.5 Unqualified personnel should not enter grade B cleanrooms or grade A in operation. If needed in exceptional cases, manufacturers should establish written procedures outlining the process by which unqualified personnel are brought into the grade B and A areas. An authorized person from the manufacturer should supervise the unqualified personnel during their activities and should assess the impact of these activities on the cleanliness of the area. Access by these persons should be assessed and recorded in accordance with the PQS.

 

未經確認的人員不得進入正在操作中的B級潔凈室或A級潔凈室。在特殊情況下，如果需要，制造商應制定書面程序，概述將未經確認人員帶入B級和A級區域的流程。制造商的授權人員應在活動期間監督未經確認的人員，并應評估這些活動對該區域潔凈度的影響。這些人員的進入應根據PQS進行評估和記錄。

 

7.6 There should be systems in place for the disqualification of personnel from working in or given unsupervised entry into cleanrooms that is based on aspects including ongoing assessment and/or identification of an adverse trend from the personnel monitoring programme and/or after being implicated in a failed APS. Once disqualified, retraining and requalification should be completed before permitting the operator to have any further involvement in aseptic practices. For operators entering grade B cleanrooms or performing intervention into grade A, this requalification should include consideration of participation in a successful APS.

 

應建立制度，根據以下方面取消人員在潔凈室工作或在無人監督的情況下進入潔凈室的權限，包括持續評估和/或從人員監測計劃中發現不良趨勢和/或失敗的APS后。權限一旦取消，應在允許操作人員進一步參與無菌操作之前完成再培訓和再確認。對于進入B級潔凈室或進行A級干預的操作人員，這種再確認應包括考慮參與成功的APS。

 

7.7 High standards of personal hygiene and cleanliness are essential to prevent excessive shedding or increased risk of introduction of microbial contamination. Personnel involved in the manufacture of sterile products should be instructed to report any specific health conditions or ailments that may cause the shedding of abnormal numbers or types of contaminants and therefore preclude cleanroom access. Health conditions and actions to be taken with regard to personnel who could be introducing an undue microbial hazard should be provided by the designated competent person and described in procedures.

 

高標準的個人衛生和清潔對于防止過度脫落或防止增加微生物污染風險至關重要。參與無菌產品生產的人員應被指示報告任何可能導致異常數量或類型污染物脫落并因此應避免進入潔凈室的特定健康狀況或疾病。應由指定的主管人員提供可能引入不適當微生物危害的人員健康狀況和應采取的行動，并在程序中加以說明。

 

7.8 Personnel who have been engaged in the processing of human or animal tissue materials or of cultures of micro-organisms, other than those used in the current manufacturing process, or any activities that may have a negative impact to quality (e.g. microbial contamination), should not enter clean areas unless clearly defined and effective decontamination and entry procedures have been followed and documented.

 

從事人類或動物組織材料加工或微生物培養（除當前制造過程中已使用的物料外），或從事任何可能對質量產生負面影響（例如微生物污染）的活動的人員，不應進入潔凈區，除非已遵循明確定義和有效的去污染和進入程序并形成文件。

 

7.9 Wristwatches, make-up, jewellery, other personal items such as mobile phones and any other non-essential items should not be allowed in clean areas. Electronic devices used in cleanrooms, e.g. mobile phones and tablets, that are supplied by the manufacturer solely for use in the cleanrooms, may be acceptable if suitably designed to permit cleaning and disinfection commensurate with the grade in which they are used. The use and disinfection of such equipment should be included in the CCS.

 

手表、化妝品、珠寶、其他個人物品（如手機）和任何其他非必需品不得帶入潔凈區。潔凈室中使用的電子設備，例如移動電話和平板電腦，如果制造商提供的電子設備僅用于潔凈室，如果經過適當設計以允許與其使用等級相稱的清潔和消毒，則可以接受。此類設備的使用和消毒應包括在CCS中。

 

7.10 Cleanroom gowning and hand washing should follow a written procedure designed to minimize contamination of cleanroom clothing and/or the transfer of contaminants to the clean areas.

 

潔凈室更衣和洗手應遵循書面程序以最大限度地減少潔凈服的污染和/或污染物向潔凈區域的轉移。

 

7.11 The clothing and its quality should be appropriate for the process and the grade of the working area. It should be worn in such a way as to protect the product from contamination. When the type of clothing chosen needs to provide the operator protection from the product, it should not compromise the protection of the product from contamination. Garments should be visually checked for cleanliness and integrity immediately prior to and after gowning. Gown integrity should also be checked upon exit. For sterilised garments and eye coverings, particular attention should be taken to ensure they have been subject to the sterilisation process, are within their specified hold time and that the packaging is visually inspected to ensure it is integral before use. Reusable garments (including eye coverings) should be replaced if damage is identified, or at a set frequency that is determined during qualification studies. The qualification of garments should consider any necessary garment testing requirements, including damage to garments that may not be identified by visual inspection alone.

 

潔凈服及其質量應適合工作區域的工藝和潔凈級別。其穿戴方式應能保護產品免受污染。當所選的潔凈服類型需要為操作人員提供產品防護時，不應損害產品的污染保護。在更衣之前和之后，應立即對潔凈服進行目視檢查，以確保潔凈度和完整性。退出潔凈室時也應檢查潔凈服的完整性。對于滅菌的潔凈服和眼罩，應特別注意確保其在使用前已經過滅菌，并在其規定的保存期限內，并且其包裝經過目視檢查以確保其完整。可重復使用的潔凈服（包括眼罩）一旦發現損壞，應進行更換，或以確認研究期間確定的設定頻率進行更換。潔凈服的確認應考慮任何必要的潔凈服測試要求，包括僅通過目視檢查可能無法識別的服裝損壞。

 

7.12 Clothing should be chosen to limit shedding due to operators’ movement.

 

潔凈服應選擇以限制因操作人員移動而導致的（顆粒）脫落。

 

7.13 A description of typical clothing required for each cleanliness grade is given below:

 

下面給出了每個潔凈等級所需的典型服裝的描述：

 

i.             Grade B (including access / interventions into grade A): appropriate garments that are dedicated for use under a sterilised suit should be worn before gowning (see paragraph 7.14). Appropriately sterilised, non-powdered, rubber or plastic gloves should be worn while donning the sterilised garments. Sterile headgear should enclose all hair (including facial hair) and where separate from the rest of the gown, it should be tucked into the neck of the sterile suit. A sterile facemask and sterile eye coverings (e.g. goggles) should be worn to cover and enclose all facial skin and prevent the shedding of droplets and particles. Appropriate sterilised footwear (e.g. over-boots) should be worn. Trouser legs should be tucked inside the footwear. Garment sleeves should be tucked into a second pair of sterile gloves worn over the pair worn while donning the gown. The protective clothing should minimize shedding of fibres or particles and retain particles shed by the body. The particle shedding and the particle retention efficiencies of the garments should be assessed during the garment qualification. Garments should be packed and folded in such a way as to allow operators to don the gown without contacting the outer surface of the garment and to prevent the garment from touching the floor.

 

B級（包括進入/干預A級）：在穿戴潔凈服之前，應穿戴專用于已滅菌潔凈服下使用的適當服裝（見第7.14段）。在穿上已滅菌的衣服時，應戴上適當滅菌的，無粉橡膠或塑料手套。無菌頭罩應將所有毛發（包括面部毛發）封閉起來，如果與潔凈服的其余部分分開，則應將其塞入無菌套裝的頸部。應佩戴無菌面罩和無菌眼罩（例如護目鏡）以覆蓋和封閉所有面部皮膚，并防止飛沫和顆粒脫落。應穿適當的已滅菌的鞋（例如靴子）。褲腿應塞在鞋內。服裝袖子應塞進第二副無菌手套中，戴在穿潔凈服時戴的那雙手套之上。潔凈服應盡量減少纖維或顆粒的脫落，并截留自身體脫落的顆粒。在潔凈服確認期間，應評估潔凈服的顆粒脫落和顆粒截留效率。潔凈服的包裝和折疊方式應允許操作人員在不接觸潔凈服外表面的情況下穿上，并防止潔凈服接觸地板。

 

ii.             Grade C: Hair, beards and moustaches should be covered. A single or two-piece trouser suit gathered at the wrists and with high neck and appropriately disinfected shoes or overshoes should be worn. They should minimize the shedding of fibres and particles.

 

C級：應遮蓋頭發和胡須。應穿連體或分體式褲衫，手腕處收緊，高領，穿經適當消毒的鞋子或套鞋。它們應該盡量減少纖維和顆粒的脫落。

 

iii.             Grade D: Hair, beards and moustaches should be covered. A general protective suit and appropriately disinfected shoes or overshoes should be worn. Appropriate measures should be taken to avoid any ingress of contaminants from outside the clean area.

 

D級：應遮蓋頭發和胡須。應穿通用防護服和適當消毒的鞋子或套鞋。應采取適當措施，避免任何污染物從潔凈區以外進入。

 

iv.             Additional gowning including gloves and facemask may be required in grade C and D areas when performing activities considered to be a contamination risk as defined by the CCS.

 

在C級和D級區域進行CCS所定義的被認為存在污染風險的活動時，可能需要額外的潔凈服，包括手套和口罩。

 

7.14 Cleanroom gowning should be performed in change rooms of an appropriate cleanliness grade to ensure gown cleanliness is maintained. Outdoor clothing including socks (other than personal underwear) should not be brought into changing rooms leading directly to grade B and C areas. Single or two-piece facility trouser suits, covering the full length of the arms and the legs, and facility socks covering the feet, should be worn before entry to change rooms for grades B and C. Facility suits and socks should not present a risk of contamination to the gowning area or processes.

 

潔凈室更衣應在適當潔凈等級的更衣室進行，以確保保持潔凈服的潔凈度。包括襪子（個人內衣除外）在內的戶外服裝不應帶入直接通往B級和C級區域的更衣室。在進入B級和C級更衣室之前，應穿覆蓋整個胳膊和腿的分體式或連體式套裝，以及覆蓋腳的潔凈襪。套裝和潔凈襪不應對更衣區域或工序造成污染風險。

 

7.15 Every operator entering grade B or A areas should gown into clean, sterilised protective garments (including eye coverings and masks) of an appropriate size at each entry. The maximum period for which the sterilised gown may be worn before replacement during a shift should be defined as part of the garment qualification.

 

每個進入B級或A級區域的操作人員每次進入時，都應穿上適當尺寸的干凈、已滅菌的潔凈服（包括眼罩和口罩）。無菌潔凈服在一個班次的最長穿戴時間應作為潔凈服確認的一部分進行定義。

 

7.16 Gloves should be regularly disinfected during operations. Garments and gloves should be changed immediately if they become damaged and present any risk of product contamination.

 

操作期間應定期對手套進行消毒。如果衣服和手套損壞并存在任何產品污染的風險，應立即更換。

 

7.17 Reusable clean area clothing should be cleaned in a laundry facility adequately segregated from production operations, using a qualified process ensuring that the clothing is not damaged and/or contaminated by fibres or particles during the repeated laundry process. Laundry facilities used should not introduce risk of contamination or cross-contamination. Inappropriate handling and use of clothing may damage fibres and increase the risk of shedding of particles. After washing and before packing, garments should be visually inspected for damage and visual cleanliness. The garment management processes should be evaluated and determined as part of the garment qualification programme and should include a maximum number of laundry and sterilisation cycles.

 

可重復使用的潔凈區衣服應在與生產操作充分分離的洗衣房中清洗，使用經確認的工藝，確保衣服在重復的清洗過程中不會損壞和/或被纖維或顆粒污染。所使用的洗衣設施不應引入污染或交叉污染的風險。衣服的不當處理和使用可能會損壞纖維并增加顆粒脫落的風險。應在清洗之后和包裝之前目視檢查衣服的損壞和目視清潔度。潔凈服管理過程應作為潔凈區確認的一部分進行評估和確定，并應包括最大清洗和滅菌次數。

 

7.18 Activities in clean areas that are not critical to the production processes should be kept to a minimum, especially when aseptic operations are in progress. Movement of personnel should be slow, controlled and methodical to avoid excessive shedding of particles and organisms due to over-vigorous activity. Operators performing aseptic operations should adhere to aseptic technique at all times to prevent changes in air currents that may introduce air of lower quality into the critical zone. Movement adjacent to the critical zone should be restricted and the obstruction of the path of the unidirectional (first air) airflow should be avoided. A review of airflow visualisation studies should be considered as part of the training programme.

 

應最大限度減少對生產過程不重要的潔凈區活動，特別是在無菌操作進行時。人員的移動應緩慢，可控和有條不紊，以避免由于過度劇烈的活動而過度脫落顆粒和生物體。執行無菌操作的操作人員應始終堅持使用無菌技術，以防止氣流變化而導致質量較低的空氣進入關鍵區域。應限制與關鍵區域相鄰的運動，并應避免阻擋單向流（第一空氣）的路徑。對氣流可視化研究的閱覽應被視為培訓計劃的一部分。

 

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