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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(guī)第4卷《人用和獸用藥品良好生產(chǎn)規(guī)范指南》
Annex 1
附錄1
Manufacture of Sterile Medicinal Products
無菌藥品生產(chǎn)
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(fā)布之日起一年后生效（除8.123節(jié)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(fā)布之日起兩年后第 8.123 節(jié)生效
Document map
文件目錄
|
Section Number
章節(jié) |
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(lǐng)域（其他非無菌產(chǎn)品外）。 |
|
2. Principle
原則 |
General principles as applied to the manufacture of sterile products.
適用于無菌產(chǎn)品生產(chǎn)的一般原則。 |
|
3. Pharmaceutical Quality System (PQS)
藥品質(zhì)量體系（PQS） |
Highlights the specific requirements of the PQS when applied to sterile products.
重點介紹 PQS 在應(yīng)用于無菌產(chǎn)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(guān)于廠房設(shè)計的具體要求，以及關(guān)于廠房確認(rèn)的指導(dǎo)，包括使用屏障技術(shù)。 |
|
5. Equipment
設(shè)備 |
General guidance on the design and operation of equipment.
關(guān)于設(shè)備設(shè)計和操作的一般指導(dǎo)。 |
|
6. Utilities
公用系統(tǒng) |
Guidance regarding the special requirements of utilities such as water, gas and vacuum.
有關(guān)水，氣和真空等公用系統(tǒng)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(guān)于特定培訓(xùn)，知識和技能要求的指導(dǎo)。還就人員確認(rèn)提供了指導(dǎo)。 |
|
8. Production and specific technologies
生產(chǎn)和特定技術(shù) |
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(guān)于無菌和最終滅菌工藝應(yīng)采取的方法的指南。關(guān)于產(chǎn)品、設(shè)備和包裝部件滅菌方法的指南。還就不同技術(shù)，如凍干和成型-灌裝-密封，的特定要求提供指導(dǎo)。 |
|
9. Environmental and process monitoring
環(huán)境和過程監(jiān)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(jié)與第 4 節(jié)中給出的指導(dǎo)不同，因為此處的指南適用于有關(guān)持續(xù)日常監(jiān)測的系統(tǒng)設(shè)計和行動限/警戒限設(shè)置以及趨勢數(shù)據(jù)回顧。 本節(jié)還就無菌工藝模擬（APS）的要求提供了指導(dǎo)。 |
|
10. Quality control (QC)
質(zhì)量控制（QC） |
Guidance on some of the specific Quality Control requirements relating to sterile products.
關(guān)于無菌產(chǎn)品的一些具體質(zhì)量控制要求的指南。 |
|
11. Glossary
術(shù)語 |
Explanation of specific terminology. 具體術(shù)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(chǎn)品的制造涵蓋廣泛的無菌產(chǎn)品類型（活性物質(zhì)，輔料，內(nèi)包裝材料和成品制劑），包裝規(guī)格（單劑量到多劑量），工藝（從高度自動化系統(tǒng)到手動工藝）和技術(shù)（例如生物技術(shù)，經(jīng)典小分子制造系統(tǒng)和密閉系統(tǒng)）。本附錄提供了使用質(zhì)量風(fēng)險管理（QRM）原則應(yīng)用于各類無菌產(chǎn)品的設(shè)施，設(shè)備，系統(tǒng)和程序的設(shè)計和控制的通用指導(dǎo)，以確保最終產(chǎn)品免受微生物，顆粒和內(nèi)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(nèi)容，通常不會在具體段落中提及。在規(guī)定具體限值、頻率或范圍的情況下，應(yīng)將這些限制或范圍視為最低要求?；谝呀?jīng)確定并影響患者安全的問題的歷史監(jiān)管經(jīng)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(chǎn)品的制造提供指導(dǎo)。然而，一些原則和指導(dǎo)，如污染控制策略，廠房設(shè)計，潔凈室分類，確認(rèn)，驗證，監(jiān)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(nèi)毒素/熱原污染的產(chǎn)品，如某些液體，乳膏，軟膏和低生物負(fù)荷生物中間體。如果制造商選擇將此指南應(yīng)用于非無菌產(chǎn)品，制造商應(yīng)清楚地記錄已應(yīng)用的原則，并應(yīng)認(rèn)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(chǎn)品的制造須遵守特定要求，以盡量減少微生物、微粒和內(nèi)毒素/熱原污染的風(fēng)險。應(yīng)考慮以下關(guān)鍵領(lǐng)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(shè)施、設(shè)備和工藝應(yīng)按照良好生產(chǎn)規(guī)范（GMP）指南的相關(guān)章節(jié)進行適當(dāng)?shù)脑O(shè)計、確認(rèn)和/或驗證，并在適用的情況下，進行持續(xù)確認(rèn)。應(yīng)考慮使用適當(dāng)?shù)募夹g(shù)（例如限制進入屏障系統(tǒng)（RABS）、隔離器、機器人系統(tǒng)、快速/替代方法和連續(xù)監(jiān)測系統(tǒng)），以加強對產(chǎn)品的保護，使其免受潛在的外來內(nèi)毒素/熱原、顆粒物和微生物來源（如人員、物料和周圍環(huán)境）污染的影響，并支持快速檢測環(huán)境和產(chǎn)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(yīng)具有足夠的資質(zhì)和經(jīng)驗、培訓(xùn)和行為規(guī)范，并特別關(guān)注在制造、包裝和運輸過程中無菌產(chǎn)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(chǎn)品制造的工藝和監(jiān)測系統(tǒng)應(yīng)由具有適當(dāng)工藝、工程和微生物知識的人員進行設(shè)計、調(diào)試、確認(rèn)、監(jiān)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(yīng)充分控制和測試原輔料和包裝材料，以確保生物負(fù)荷和內(nèi)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(shè)備、設(shè)施和制造活動應(yīng)按照QRM原則進行管理，以提供一種前瞻性手段來識別、科學(xué)地評估和控制潛在的質(zhì)量風(fēng)險。在使用替代方法時，應(yīng)有適當(dāng)?shù)恼撟C、風(fēng)險評估和緩解措施的支持，并應(yīng)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(yōu)先考慮，首先應(yīng)是設(shè)施、設(shè)備和工藝的適當(dāng)設(shè)計，其次是實施設(shè)計良好的程序，最后使用監(jiān)測系統(tǒng)作為表明設(shè)計和程序已正確實施并持續(xù)如預(yù)期執(zhí)行的要素。僅監(jiān)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(yīng)在整個設(shè)施中實施污染控制策略（CCS），以定義所有關(guān)鍵控制點，并評估用于管理藥品質(zhì)量和安全風(fēng)險的所有控制措施（設(shè)計，程序，技術(shù)和組織）和監(jiān)測措施的有效性。CCS的組合策略應(yīng)建立強有力的污染預(yù)防保證。CCS應(yīng)動態(tài)審查，并在適當(dāng)情況下進行更新，并應(yīng)推動制造和控制方法的持續(xù)改進。其有效性應(yīng)成為定期管理審查的一部分。如果現(xiàn)有的控制系統(tǒng)并得到適當(dāng)管理，則這些系統(tǒng)可能不需要更換，但應(yīng)在CCS中引用，并應(yīng)了解系統(tǒng)之間的相關(guān)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(nèi)毒素/熱原和顆粒源污染風(fēng)險而采取的步驟包括一系列相互關(guān)聯(lián)的事件和措施。它們通常單獨評估，控制和監(jiān)測，但應(yīng)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(shù)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(nèi)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(yīng)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(shè)計，包括相關(guān)文件。
ii. Premises and equipment.
廠房和設(shè)備
iii. Personnel.
人員
iv. Utilities.
公用系統(tǒng)
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(chǎn)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(yīng)商審批 – 例如關(guān)鍵組分供應(yīng)商、組件和一次性系統(tǒng)（SUS）的滅菌以及關(guān)鍵服務(wù)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(guān)鍵信息的可獲得性/傳遞，例如合同滅菌服務(wù)。
ix. Process risk management.
工藝風(fēng)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(yù)防性維護 – 以確保沒有額外的污染風(fēng)險的標(biāo)準(zhǔn)對設(shè)備、公用系統(tǒng)和廠房進行維護（計劃內(nèi)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(jiān)測系統(tǒng)—包括評估采用科學(xué)合理的替代方法以優(yōu)化環(huán)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(yù)防機制 – 趨勢分析、詳細調(diào)查、根本原因分析、糾正和預(yù)防措施（CAPA）以及綜合調(diào)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(xù)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(yīng)考慮污染控制的各個方面，并進行持續(xù)和定期的審查，從而在藥品質(zhì)量體系內(nèi)酌情更新。對現(xiàn)有系統(tǒng)的變更應(yīng)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(yīng)采取一切必要的步驟和預(yù)防措施，以確保在其設(shè)施內(nèi)制造的產(chǎn)品的無菌性。對無菌性或其他質(zhì)量方面，不應(yīng)僅依賴任何終端過程或成品測試。
3 Pharmaceutical Quality System (PQS)
藥品質(zhì)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(chǎn)品的制造是一項復(fù)雜的活動，需要特定的控制和措施來確保所制造產(chǎn)品的質(zhì)量。因此，制造商的PQS應(yīng)涵蓋并解決無菌產(chǎn)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(chǎn)品中微生物，顆粒物和內(nèi)毒素/熱原污染的風(fēng)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(chǎn)品制造的PQS還應(yīng)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(fēng)險管理體系整合到產(chǎn)品生命周期的所有領(lǐng)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(chǎn)品的質(zhì)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(chǎn)品以及采用的影響產(chǎn)品質(zhì)量的設(shè)備，工程和制造方法方面有足夠的知識和專業(yè)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(shè)備故障的根本原因分析以正確識別和理解產(chǎn)品風(fēng)險的方式進行，以便實施適當(dāng)?shù)募m正和預(yù)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(fēng)險管理應(yīng)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(fēng)險。風(fēng)險管理應(yīng)記錄在案，并應(yīng)包括就降低風(fēng)險和接受剩余風(fēng)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(yīng)有效監(jiān)督整個設(shè)施和產(chǎn)品生命周期的受控狀態(tài)。在變更期間，在出現(xiàn)重大問題時，以及在定期產(chǎn)品質(zhì)量回顧期間，風(fēng)險管理結(jié)果應(yīng)作為持續(xù)質(zhì)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(chǎn)品的最終處理、儲存和運輸相關(guān)的過程不應(yīng)損害無菌產(chǎn)品。應(yīng)考慮的方面包括：容器完整性，污染風(fēng)險以及通過確保產(chǎn)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(fù)責(zé)無菌產(chǎn)品認(rèn)證/放行的人員可適當(dāng)獲取生產(chǎn)和質(zhì)量信息，并在無菌產(chǎn)品的生產(chǎn)和相關(guān)的關(guān)鍵質(zhì)量屬性方面擁有足夠的知識和經(jīng)驗。以使這些人員能夠確定無菌產(chǎn)品是否按照注冊標(biāo)準(zhǔn)和批準(zhǔn)的工藝生產(chǎn)，并具有所需的質(zhì)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(rèn)證/放行之前，應(yīng)充分調(diào)查所有不符合項，例如無菌測試失敗，環(huán)境監(jiān)測超標(biāo)或不符合既定程序的偏差。調(diào)查應(yīng)確定對工藝和產(chǎn)品質(zhì)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(chǎn)品或批次納入調(diào)查或排除在外的原因應(yīng)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(chǎn)品的制造應(yīng)在適當(dāng)?shù)臐崈羰疫M行，（人員、設(shè)備、物品等）應(yīng)通過change rooms進入，這些change rooms充當(dāng)人員、設(shè)備和物料的氣閘。潔凈室和change rooms應(yīng)保持適當(dāng)?shù)臐崈舳葮?biāo)準(zhǔn)，并提供通過適當(dāng)效率過濾器的空氣。控制和監(jiān)測應(yīng)科學(xué)論證，并應(yīng)有效評估潔凈室、氣閘和傳遞窗的環(huán)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(chǎn)品配制和灌裝的各種操作應(yīng)在潔凈室或設(shè)施內(nèi)采取適當(dāng)?shù)募夹g(shù)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(tǒng)（RABS）或隔離器有助于確保所需條件并最大限度地減少與關(guān)鍵區(qū)域直接人為干預(yù)相關(guān)的微生物污染。在CCS中應(yīng)考慮它們的使用。任何替代RABS或隔離器的方法都應(yīng)進行論證。
4.4 For the manufacture of sterile products, there are four grades of cleanroom/zone.
對于無菌產(chǎn)品的制造，有四個等級的潔凈室/區(qū)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(fēng)險操作的關(guān)鍵區(qū)域（例如無菌加工線，灌裝區(qū)，膠塞斗，未密閉的內(nèi)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(yīng)證實和確認(rèn)整個A級區(qū)域內(nèi)單向流的維持。應(yīng)通過廠房、設(shè)備、工藝和程序設(shè)計最大限度減少操作人員對A級區(qū)域的直接干預(yù)（例如，在沒有屏障和手套箱技術(shù)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(qū)域。應(yīng)持續(xù)監(jiān)測壓差。在使用隔離器技術(shù)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(chǎn)品的制造中執(zhí)行不太關(guān)鍵的階段，或作為隔離器的背景。還可用于最終滅菌產(chǎn)品的配制/灌裝。（有關(guān)最終滅菌活動的具體細節(jié)，請參閱第8節(jié)）。
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(guān)鍵區(qū)域，所有暴露的表面應(yīng)光滑、無滲漏、不破損，以最大限度減少顆?；蛭⑸锏拿撀浠蚍e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(yīng)有難以有效清潔的凹槽，因此應(yīng)最大限度減少突出的窗臺，架子，柜子和設(shè)備。門的設(shè)計應(yīng)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(nèi)使用的物品，都應(yīng)選擇以盡量減少顆粒的產(chǎn)生，并允許重復(fù)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(shè)計和密封應(yīng)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(yīng)禁止在A級和B級區(qū)域使用水槽和排水管。在其他潔凈室中，應(yīng)在設(shè)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(yīng)安裝存水彎或水封，以防止回流，并應(yīng)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(shè)備和物料進出潔凈室和關(guān)鍵區(qū)域是最大的潛在污染源之一。任何可能損害潔凈室或關(guān)鍵區(qū)域潔凈度的活動都應(yīng)進行評估，如果無法消除，則應(yīng)實施適當(dāng)?shù)目刂拼胧?/span>
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(shè)備和組件向A級或B級區(qū)域的轉(zhuǎn)移應(yīng)通過單向過程進行。在可能的情況下，應(yīng)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(qū)域。如果無法在轉(zhuǎn)移物品時進行滅菌，則應(yīng)驗證和實施實現(xiàn)不引入污染的相同目標(biāo)的程序（例如，使用有效的轉(zhuǎn)移消毒程序，隔離器的快速轉(zhuǎn)移系統(tǒng)，或?qū)τ跉怏w或液體物料，使用除菌級過濾器）。從A級和B級區(qū)域傳出物品（例如物料，廢棄物，環(huán)境樣品）應(yīng)通過單獨的單向過程進行。如果無法做到這一點，應(yīng)考慮按程序?qū)@種轉(zhuǎn)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(shè)計和使用應(yīng)提供物理分隔，并最大限度地減少不同區(qū)域的微生物和顆粒污染，并且應(yīng)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(yīng)與用于物料流動的氣閘分開。如無法實現(xiàn)，應(yīng)考慮按時間將移動（人員/物料）分開的程序。氣閘應(yīng)使用經(jīng)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(tài)”下，應(yīng)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(qū)域是可取的。如無法做到，應(yīng)考慮按程序?qū)顒樱ㄟM/出）進行基于時間的分離。如果CCS表明污染風(fēng)險很高，則應(yīng)使用單獨的更衣室進出生產(chǎn)區(qū)域。氣閘應(yīng)設(shè)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(qū)域（例如，從D級區(qū)域到C級區(qū)域再到B級區(qū)域）。一般來說，洗手設(shè)施應(yīng)僅在更衣室的第一階段提供，而不應(yīng)出現(xiàn)在直接進入B級區(qū)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(shè)備的轉(zhuǎn)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(zhǔn)清單并在轉(zhuǎn)移驗證期間進行評估的物料和設(shè)備才能通過氣閘或傳遞窗轉(zhuǎn)移到A級或B級區(qū)域。在通過B級區(qū)域時，應(yīng)對設(shè)備和物料（打算在A級區(qū)域使用）進行保護。任何需要轉(zhuǎn)移的未經(jīng)批準(zhǔn)的物品都應(yīng)作為例外情況預(yù)先獲得批準(zhǔn)。應(yīng)根據(jù)制造商的CCS使用和記錄適當(dāng)?shù)娘L(fēng)險評估和緩解措施，并應(yīng)包括質(zhì)量保證部門批準(zhǔn)的具體消毒和監(jiān)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(shè)計應(yīng)保護更高級別的環(huán)境，例如通過主動過濾空氣供應(yīng)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(shè)備從較低等級或未分類區(qū)域移動到較高等級的潔凈區(qū)域時，應(yīng)進行與風(fēng)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(yīng)同時打開入口和出口的門。對于通向A級和B級區(qū)域的氣閘，應(yīng)使用聯(lián)鎖系統(tǒng)。對于通往C級和D級區(qū)域的氣閘，應(yīng)至少使用聲光報警系統(tǒng)。如果需要保持區(qū)域隔離，則應(yīng)在互鎖門的關(guān)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(yīng)配備經(jīng)過濾的送風(fēng)，在所有操作條件下保持相對于較低等級的背景環(huán)境的正壓和/或氣流，并應(yīng)有效沖洗該區(qū)域。不同等級的相鄰房間的氣壓差應(yīng)至少為10帕斯卡（指導(dǎo)值）。應(yīng)特別注意保護關(guān)鍵區(qū)域。在需要含有某些物料（例如致病性、劇毒或放射性產(chǎn)品或活病毒或細菌物料）的情況下，可能需要修改有關(guān)送風(fēng)和壓力的建議。這種修改可能包括正壓或負(fù)壓氣閘，以防止危險物質(zhì)污染周圍區(qū)域。對于某些操作，可能需要對設(shè)施（例如潔凈室和HVAC系統(tǒng)）進行凈化以及處理排風(fēng)。如果密閉要求空氣流入關(guān)鍵區(qū)域，則空氣源應(yīng)來自相同或更高等級的區(qū)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(yīng)將潔凈室和區(qū)域內(nèi)的氣流流型可視化，以證明沒有從較低等級區(qū)域進入到較高等級區(qū)域，并且空氣不會從不太干凈的區(qū)域（如地板）或通過操作人員或設(shè)備將污染物轉(zhuǎn)移到較高等級區(qū)域。需要單向流時，應(yīng)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(chǎn)品通過一個小的出口轉(zhuǎn)移到相鄰的較低等級的潔凈室，氣流可視化研究應(yīng)證明空氣不會從較低等級的潔凈室進入B級區(qū)域。如果氣流對潔凈區(qū)域或關(guān)鍵區(qū)域構(gòu)成污染風(fēng)險，則應(yīng)采取糾正措施，例如設(shè)計改進。氣流流型研究應(yīng)在靜態(tài)和動態(tài)下（例如，模擬操作員干預(yù)）進行。應(yīng)保留氣流流型的視頻記錄。在制訂環(huán)境監(jiān)測計劃時，應(yīng)記錄和考慮空氣可視化研究的結(jié)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(yīng)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(yīng)考慮設(shè)置點和此壓差的關(guān)鍵性。應(yīng)持續(xù)監(jiān)測和記錄被確定為關(guān)鍵的壓差。應(yīng)建立報警系統(tǒng)，以立即向操作人員指示和警告送風(fēng)的任何故障或壓差的降低（低于確定為關(guān)鍵的限值）。警告信號不應(yīng)在未經(jīng)評估的情況下被覆蓋，并應(yīng)提供程序來概述在發(fā)出警告信號時應(yīng)采取的步驟。如果設(shè)置了報警延遲，則應(yīng)在CCS中對其進行評估并證明其合理性。應(yīng)定期監(jiān)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(shè)施的設(shè)計應(yīng)允許從A級和B級區(qū)域之外觀察生產(chǎn)活動（例如，通過提供窗口或遠程攝像機，可以全面查看該區(qū)域和過程，以便在不進入的情況下進行觀察和監(jiān)督）。在設(shè)計新設(shè)施或翻新現(xiàn)有設(shè)施時，應(yīng)考慮這一要求。
Barrier Technologies
屏障技術(shù)
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(shù)和工藝，應(yīng)設(shè)計為通過將A級環(huán)境與周圍房間的環(huán)境分開來提供保護。在加工過程中，應(yīng)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(zhuǎn)移技術(shù)或經(jīng)驗證可有效防止污染的系統(tǒng)的支持，并適用于相應(yīng)的技術(shù)。
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(shù)和工藝的設(shè)計應(yīng)確保在關(guān)鍵區(qū)域保持適當(dāng)?shù)臈l件，以便在操作過程中保護暴露的產(chǎn)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(shè)計應(yīng)確保A級條件，在關(guān)鍵區(qū)域有第一空氣保護，在加工過程中單向氣流掃過暴露的產(chǎn)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(shè)計應(yīng)確保在加工過程中對暴露的產(chǎn)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(yīng)增加暴露產(chǎn)品污染的風(fēng)險。如果工藝流程中包含在密閉式隔離器中，則應(yīng)確保A級條件，在關(guān)鍵區(qū)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(chǎn)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(dāng)產(chǎn)品隔離（例如放射性藥物產(chǎn)品）被認(rèn)為必要時，才應(yīng)使用負(fù)壓隔離器，并應(yīng)采取專門的風(fēng)險控制措施以確保關(guān)鍵區(qū)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(shè)計應(yīng)確保具有單向氣流的A級條件和在關(guān)鍵區(qū)域的第一空氣保護。應(yīng)保持從關(guān)鍵區(qū)域到支持背景環(huán)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(huán)境應(yīng)確保將污染轉(zhuǎn)移的風(fēng)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(huán)境通常應(yīng)符合C級的最低要求。密閉式隔離器的背景應(yīng)與最低 D 級相對應(yīng)。關(guān)于背景級別的決定應(yīng)以風(fēng)險評估為基礎(chǔ)，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(fēng)險評估時的關(guān)鍵考慮因素應(yīng)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(guān)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(dāng)發(fā)現(xiàn)其他工藝風(fēng)險，應(yīng)考慮更高級別的背景，除非CCS中已適當(dāng)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(yīng)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(huán)境應(yīng)最低與B級相對應(yīng)，并應(yīng)進行氣流流型研究，以證明干預(yù)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(tǒng)（隔離器和RABS）的材料應(yīng)證明具有適當(dāng)?shù)臋C械和耐化學(xué)性。手套的更換頻率應(yīng)在CCS內(nèi)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(yīng)使用一種被證明適合該任務(wù)和關(guān)鍵性的方法進行手套系統(tǒng)的泄漏測試。測試應(yīng)以規(guī)定的時間間隔進行。一般來說，手套完整性測試應(yīng)至少在每批或每個生產(chǎn)周期的開始和結(jié)束進行。根據(jù)已驗證的生產(chǎn)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(jiān)測應(yīng)包括在每次使用和任何可能影響系統(tǒng)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(chǎn)單件或小批量的人工無菌工藝活動，完整性確認(rèn)的頻率可能基于其他標(biāo)準(zhǔn)，如每個生產(chǎn)環(huán)節(jié)的開始和結(jié)束。
d) Integrity / leak testing of isolator systems should be performed at defined intervals.
隔離器系統(tǒng)的完整性/泄漏測試應(yīng)以規(guī)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(qū)域使用的手套應(yīng)在安裝前進行滅菌，并在每次制造活動之前通過經(jīng)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(huán)境，則應(yīng)在每次暴露后使用批準(zhǔn)的方法進行消毒。每次使用時應(yīng)目視檢查手套，并應(yīng)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(yīng)適當(dāng)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(guān)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(yīng)提供證據(jù)證明所使用的清潔劑和生物凈化劑不會對RABS或隔離器內(nèi)生產(chǎn)的產(chǎn)品產(chǎn)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(nèi)部的生物凈化過程應(yīng)在既定的循環(huán)參數(shù)內(nèi)自動化，驗證和控制，并應(yīng)包括合適形式（例如氣態(tài)或汽態(tài)）的殺孢劑。手套應(yīng)適當(dāng)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(yīng)使隔離器的內(nèi)表面和關(guān)鍵區(qū)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(yīng)包括殺孢劑的日常使用，使用經(jīng)驗證和證明的方法，以有效地包含內(nèi)表面的所有區(qū)域，并確保無菌處理的合適環(huán)境。
Cleanroom and clean air equipment qualification
潔凈室和潔凈空氣設(shè)備確認(rèn)
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(chǎn)品的潔凈室和潔凈空氣設(shè)備，如單向氣流單元（UDF）、RABS和隔離器，應(yīng)按照所需的環(huán)境特性進行確認(rèn)。每個生產(chǎn)操作都需要在動態(tài)條件下具有適當(dāng)?shù)沫h(huán)境潔凈度水平，以最大限度地降低所處理的產(chǎn)品或物料受到污染的風(fēng)險。應(yīng)保持在“靜態(tài)”和“動態(tài)”狀態(tài)的適當(dāng)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(shè)備應(yīng)使用符合附錄15要求的方法進行確認(rèn)。潔凈室確認(rèn)（包括分級）應(yīng)與生產(chǎn)環(huán)境監(jiān)測明確區(qū)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(shè)備確認(rèn)是評估已分級潔凈室或潔凈空氣設(shè)備適合其預(yù)期用途的總體過程。作為附錄15確認(rèn)要求的一部分，潔凈室和潔凈空氣設(shè)備的確認(rèn)應(yīng)包括（在設(shè)計/運行有關(guān)）：
i. Installed filter system leakage and integrity testing.
已安裝過濾系統(tǒng)泄漏和完整性測試。
ii. Airflow tests - volume and velocity.
氣流測試-風(fēng)量和風(fēng)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(fù)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(guān)潔凈室和潔凈空氣設(shè)備確認(rèn)的參考，請參見 ISO 14644 系列標(biāo)準(zhǔn)。
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(rèn)是潔凈室確認(rèn)的一部分，是通過測量總粒子濃度來根據(jù)潔凈室或潔凈空氣設(shè)備的規(guī)范評估空氣潔凈度水平的方法。應(yīng)安排和執(zhí)行級別確認(rèn)活動，以避免對工藝或產(chǎn)品質(zhì)量產(chǎn)生任何影響。例如，初始級別確認(rèn)應(yīng)在模擬操作期間執(zhí)行，級別再確認(rèn)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(rèn)，應(yīng)測量等于或大于0.5和5μm的粒子總數(shù)。該測量應(yīng)根據(jù)表1中規(guī)定的限值在靜態(tài)和模擬動態(tài)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(tài) |
in operation
動態(tài) |
at rest
靜態(tài) |
in operation
動態(tài) |
|
|
A |
3 520 |
3 520 |
Not specified (a)
不作規(guī)定 |
Not specified (a)
不作規(guī)定 |
|
B |
3 520 |
352 000 |
Not specified (a)
不作規(guī)定 |
2 930 |
|
C |
352 000 |
3 520 000 |
2 930 |
29 300 |
|
D |
3 520 000 |
Not
predetermined (b)
未設(shè)定 |
29 300 |
Not
predetermined (b) 未設(shè)定 |
a) Classification including 5µm particles may be considered where indicated by the CCS or historical trends.
根據(jù)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(yù)先確定動態(tài)標(biāo)準(zhǔn)。制造商應(yīng)根據(jù)風(fēng)險評估和日常數(shù)據(jù)(如適用)建立動態(tài)標(biāo)準(zhǔn)。
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(rèn)，可以在ISO 14644第1部分中找到采樣點的最小數(shù)量及其位置。對于無菌加工區(qū)域和背景環(huán)境（分別為A級和B級區(qū)域），應(yīng)考慮額外的取樣位置，并應(yīng)評估所有關(guān)鍵處理區(qū)域，例如灌裝點和容器密封部件給料斗。關(guān)鍵處理位置應(yīng)通過書面的風(fēng)險評估和對該區(qū)域所執(zhí)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(rèn)應(yīng)在“靜態(tài)”和“動態(tài)”狀態(tài)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(tài)”狀態(tài)的定義是所有公用設(shè)施的安裝已完成，包括任何正常運行的HVAC，主要生產(chǎn)設(shè)備按既定安裝但不運行并且沒有人員在房間內(nèi)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(tài)”狀態(tài)的定義是潔凈室的安裝完成，HVAC系統(tǒng)完全運行，設(shè)備在制造商定義的操作模式下安裝和運行，并且具有執(zhí)行或模擬日常操作工作的最大人員數(shù)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(tài)”條件的總粒子限度應(yīng)在完成操作和生產(chǎn)線清除/清場活動后的“自凈”期后達到。“自凈”期（指導(dǎo)值小于20分鐘）應(yīng)在房間的確認(rèn)期間確定，并在操作期間中斷時記錄并遵守程序，以恢復(fù)已確認(rèn)的潔凈狀態(tài)。
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(tǒng)提供的氣流速度應(yīng)在確認(rèn)方案中明確證明，包括風(fēng)速測量的位置。應(yīng)設(shè)計、測量和維護氣流速度，以確在工作位置（例如，發(fā)生高風(fēng)險操作以及產(chǎn)品和/或組件暴露的位置）有足夠的單向氣流為產(chǎn)品和暴露的組件提供保護。單向流系統(tǒng)應(yīng)在工作位置提供 0.36 – 0.54 m/s（指導(dǎo)值）范圍內(nèi)的均勻氣流速度，除非 CCS 中另有科學(xué)論證。氣流可視化研究應(yīng)與風(fēng)速相關(guān)聯(lián)。
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(yīng)作為潔凈室確認(rèn)的一部分來確定。采樣點的數(shù)量應(yīng)基于書面的風(fēng)險評估和從房間級別確認(rèn)，氣流可視化研究以及有關(guān)在該區(qū)域執(zhí)行的工藝和操作的知識中獲得的結(jié)果。每個級別的確認(rèn)過程中微生物污染的最大限值見表2。確認(rèn)應(yīng)包括“靜態(tài)”和“動態(tài)”狀態(tài)。
Table 2: Maximum permitted microbial contamination level during qualification
表2：確認(rèn)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(yīng)在操作期間進行暴露，并在最多4小時后根據(jù)需要更換。暴露時間應(yīng)基于回收率研究，并且不應(yīng)使所用的培養(yǎng)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(yīng)應(yīng)用于確認(rèn)該級別的領(lǐng)域。如未使用表中的任一方法，或者使用了替代方法，則應(yīng)適當(dāng)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(shù)，以不同于CFU的方式呈現(xiàn)結(jié)果，制造商應(yīng)科學(xué)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(guān)聯(lián)。
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(rèn)，應(yīng)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(yīng)對生產(chǎn)操作造成污染風(fēng)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(shè)備應(yīng)按照規(guī)定的程序定期進行再確認(rèn)。再確認(rèn)至少應(yīng)包括以下內(nèi)容：
l Cleanroom classification (total particle concentration).
l 潔凈室級別確認(rèn)（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(fēng)量測試
l Verification of air pressure difference between rooms.
l 不同房間之間的壓差確認(rèn)
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(fēng)速測試（注：對于B級，C級和D級，應(yīng)根據(jù)CCS中記錄的風(fēng)險評估進行風(fēng)速測試。但是，對于提供單向流的灌裝區(qū)域（例如，最終滅菌產(chǎn)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(qū)域，可用恢復(fù)測試取代風(fēng)速測試）。
The maximum time interval for requalification of grade A & B areas, is 6 months.
A級和B級區(qū)域再確認(rèn)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(qū)域再確認(rèn)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(shè)備或設(shè)施不合規(guī)狀況而采取的補救措施完成后，或在適當(dāng)?shù)脑O(shè)備、設(shè)施或工藝變更之后，也應(yīng)進行適當(dāng)?shù)脑俅_認(rèn)，至少包括上述測試。變更的重要性應(yīng)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(shè)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(shè)計或HVAC系統(tǒng)的運行設(shè)置參數(shù)。
l Special maintenance which affects the operation of the installation (e.g. change of final filters).
l 影響設(shè)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(yīng)按照書面程序徹底清潔和消毒。為了使消毒有效，應(yīng)在此之前進行清潔以去除表面污染。清潔程序應(yīng)有效去除消毒劑殘留。應(yīng)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(yīng)包括定期使用殺孢子劑。應(yīng)定期進行監(jiān)測以評估消毒程序的有效性，并監(jiān)測微生物菌群類型的變化（例如，對當(dāng)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(yīng)驗證消毒過程。驗證研究應(yīng)以具體使用方式和表面材料類型或代表性材料（如經(jīng)論證）證明消毒劑的適用性和有效性，并應(yīng)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(qū)域使用的消毒劑和清潔劑在使用前應(yīng)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(chǎn)品制造商稀釋/制備，則應(yīng)以防止污染的方式進行，并應(yīng)監(jiān)測微生物污染。（消毒液）稀釋液應(yīng)保存在預(yù)先清潔的容器中（并在適當(dāng)時進行滅菌），并且只應(yīng)儲存在規(guī)定的期限內(nèi)。如使用“市售現(xiàn)成”消毒劑和清潔劑，那么在成功完成適當(dāng)?shù)墓?yīng)商確認(rèn)后，分析或合格證書的結(jié)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(guān)表面進行熏蒸或蒸汽消毒(例如，汽化過氧化氫)時，應(yīng)了解和驗證任何熏蒸劑和分散系統(tǒng)的有效性。
5 Equipment
設(shè)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(yīng)提供設(shè)備設(shè)計的書面詳細描述（包括適當(dāng)?shù)倪^程和儀表圖）。這應(yīng)作為初始確認(rèn)的一部分，并保持最新狀態(tài)。
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(shè)備監(jiān)測需求應(yīng)在開發(fā)的早期階段在“用戶需求規(guī)范”中定義，并在驗證期間確認(rèn)。應(yīng)確認(rèn)過程和設(shè)備報警事件并評估其趨勢。評估警報的頻率應(yīng)基于其嚴(yán)重性（嚴(yán)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(shè)備，配件和服務(wù)應(yīng)設(shè)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(nèi)進行維護，并且無法保持所需的潔凈度和/或無菌標(biāo)準(zhǔn)，則應(yīng)考慮采取預(yù)防措施，例如限制特定人員進入工作區(qū)域，制定明確定義的工作規(guī)程和維護程序。還應(yīng)考慮額外的清潔、消毒和環(huán)境監(jiān)測。如果需要對設(shè)備進行滅菌，則應(yīng)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(yīng)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(chǎn)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(chǎn)品的化學(xué)、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(yīng)對產(chǎn)品直接和間接接觸的部件進行滅菌。直接接觸產(chǎn)品的部件是產(chǎn)品通過的部件，例如灌裝針頭或泵。間接產(chǎn)品接觸部件是指不接觸產(chǎn)品但可能與其他滅菌表面接觸的設(shè)備部件，其無菌性對產(chǎn)品的整體無菌至關(guān)重要（例如，滅菌物品，如膠塞斗和導(dǎo)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(shè)備，如滅菌器、空氣處理系統(tǒng)（包括空氣過濾）和水系統(tǒng)，都應(yīng)進行確認(rèn)、監(jiān)測和計劃性維護。維護完成后，其恢復(fù)使用應(yīng)經(jīng)批準(zhǔn)。
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(chǎn)品無菌性至關(guān)重要的設(shè)備進行計劃外維護，則應(yīng)評估對產(chǎn)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(yīng)穿過 A 級或 B 級區(qū)域與空氣潔凈度較低的加工區(qū)域之間的隔板，除非傳送帶本身連續(xù)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(shù)器，包括采樣管，應(yīng)經(jīng)確認(rèn)。應(yīng)考慮制造商對管徑和彎曲半徑的建議標(biāo)準(zhǔn)。采樣長度通常不應(yīng)超過1m（否則應(yīng)進行論證）且應(yīng)最大限度減少彎曲次數(shù)。應(yīng)使用采樣管長度較短的便攜式粒子計數(shù)器進行級別確認(rèn)。應(yīng)使用等動力采樣頭應(yīng)用于單向流系統(tǒng)。它們應(yīng)有適當(dāng)?shù)姆较虿⒈M可能靠近關(guān)鍵位置，以確保樣品具有代表性。
6 Utilities
公用系統(tǒng)
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(tǒng)的控制的性質(zhì)和程度應(yīng)與公用系統(tǒng)相關(guān)的產(chǎn)品質(zhì)量風(fēng)險相稱。應(yīng)通過風(fēng)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(fēng)險公用系統(tǒng)是指：
i. Directly contact product e.g. water for washing and rinsing, gases and steam for sterilisation.
直接接觸產(chǎn)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(chǎn)品的一部分。
iii. Contact surfaces that come into contact with the product.
與產(chǎn)品接觸的表面。
iv. Otherwise directly impact the product.
其他直接影響產(chǎn)品的系統(tǒng)。
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(tǒng)的設(shè)計、安裝、確認(rèn)、運行、維護和監(jiān)測應(yīng)確保公用系統(tǒng)如預(yù)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(fēng)險公用系統(tǒng)的關(guān)鍵參數(shù)和關(guān)鍵質(zhì)量屬性的結(jié)果應(yīng)定期進行趨勢分析，以確保系統(tǒng)保持適當(dāng)?shù)哪芰Α?/span>
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(yīng)在系統(tǒng)的整個生命周期內(nèi)保存公用系統(tǒng)安裝記錄。此類記錄應(yīng)包括當(dāng)前圖紙和原理圖、建筑材料清單和系統(tǒng)規(guī)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(shè)施不應(yīng)存在于潔凈室中。如果不可避免，則應(yīng)安裝以免產(chǎn)生凹槽，未密封的開口和難以清潔的表面。安裝應(yīng)允許清潔和消毒管道的外表面。
Water systems
水系統(tǒng)
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(yīng)設(shè)計、建造、安裝、調(diào)試、確認(rèn)、監(jiān)測和維護水處理和分配系統(tǒng)以防止微生物污染，并確保適當(dāng)質(zhì)量的可靠水源。應(yīng)采取措施盡量減少顆粒物、微生物污染/增殖和內(nèi)毒素/熱原存在的風(fēng)險（例如，傾斜管道以完全排水和避免死角）。如果系統(tǒng)中包含過濾器，則應(yīng)特別注意其監(jiān)控和維護。產(chǎn)生的水應(yīng)符合相關(guān)藥典的現(xiàn)行標(biāo)準(zhǔn)。
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(tǒng)應(yīng)經(jīng)確認(rèn)和驗證，以保持適當(dāng)?shù)奈锢怼⒒瘜W(xué)和微生物控制水平，同時考慮到季節(jié)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(tǒng)中的管道應(yīng)保持湍流，以盡量減少微生物粘附和隨后生物膜形成的風(fēng)險。應(yīng)在確認(rèn)期間確定流速，并進行日常監(jiān)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(yīng)由符合既定確認(rèn)標(biāo)準(zhǔn)的水生產(chǎn)，并以盡量減少微生物生長風(fēng)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(huán)）。WFI應(yīng)通過蒸餾或相當(dāng)于蒸餾的純化過程產(chǎn)生。這可以包括反滲透聯(lián)合其它適當(dāng)?shù)募夹g(shù)，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(fēng)過濾器（呼吸過濾器），則過濾器不應(yīng)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(yīng)采取適當(dāng)?shù)目刂拼胧ɡ缤ㄟ^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(fēng)險，應(yīng)按照預(yù)定的時間計劃進行水系統(tǒng)的滅菌，消毒或再生，并在超限或超標(biāo)結(jié)果后作為補救措施。使用化學(xué)品對水系統(tǒng)進行消毒后，應(yīng)遵循經(jīng)驗證的沖洗/沖洗程序。消毒/再生后應(yīng)測試水質(zhì)。水系統(tǒng)恢復(fù)使用前，化學(xué)檢測結(jié)果得到批準(zhǔn)，微生物/內(nèi)毒素結(jié)果則應(yīng)在使用該水系統(tǒng)所生產(chǎn)的批次被放行前確認(rèn)符合標(biāo)準(zhǔn)并得到批準(zhǔn)。
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(yīng)定期對水系統(tǒng)進行化學(xué)和微生物監(jiān)測，以確保水持續(xù)符合藥典標(biāo)準(zhǔn)。警戒限應(yīng)基于初始確認(rèn)數(shù)據(jù)，然后根據(jù)在隨后的再確認(rèn)、日常監(jiān)測和調(diào)查期間獲得的數(shù)據(jù)定期重新評估。應(yīng)審查持續(xù)監(jiān)測數(shù)據(jù)以發(fā)現(xiàn)系統(tǒng)性能的任何不良趨勢。取樣方案應(yīng)反映CCS的要求，并應(yīng)在規(guī)定的時間間隔內(nèi)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(yīng)基于確認(rèn)數(shù)據(jù)，應(yīng)考慮潛在的最差情況取樣位置，并應(yīng)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(yīng)記錄和審查警戒級別的偏移，并包括調(diào)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(tǒng)惡化。應(yīng)調(diào)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(chǎn)品質(zhì)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(tǒng)應(yīng)包括連續(xù)監(jiān)測系統(tǒng)，如總有機碳（TOC）和電導(dǎo)率，因為這些系統(tǒng)可能比離線取樣更好地表面整體系統(tǒng)性能。傳感器位置應(yīng)基于風(fēng)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(fā)生器的給水應(yīng)適當(dāng)凈化。純蒸汽發(fā)生器的設(shè)計、確認(rèn)和運行方式應(yīng)確保產(chǎn)生的蒸汽質(zhì)量符合規(guī)定的化學(xué)和內(nèi)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(yīng)具有合適的質(zhì)量，并且不應(yīng)含有可能導(dǎo)致產(chǎn)品或設(shè)備污染的添加劑。對于供應(yīng)用于物料或產(chǎn)品接觸表面（例如，多孔堅硬高壓滅菌器負(fù)載）直接滅菌的純蒸汽發(fā)生器，蒸汽冷凝水應(yīng)符合相關(guān)藥典WFI的現(xiàn)行標(biāo)準(zhǔn)（蒸汽冷凝水的微生物測試不是強制的）。應(yīng)制定適當(dāng)?shù)娜佑媱?，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(zhì)量的其他方面應(yīng)根據(jù)經(jīng)驗證的參數(shù)定期進行評估。這些參數(shù)應(yīng)包括以下內(nèi)容（除非另有說明）：不凝性氣體，干燥度值（干燥度分?jǐn)?shù)）和過熱度。
Gases and vacuum systems
氣體和真空系統(tǒng)
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(chǎn)品/內(nèi)包裝容器表面直接接觸的氣體應(yīng)具有適當(dāng)?shù)幕瘜W(xué)、顆粒和微生物質(zhì)量。應(yīng)指定所有相關(guān)參數(shù)，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(tǒng)的設(shè)計，并在適用的情況下，符合相關(guān)藥典的現(xiàn)行標(biāo)準(zhǔn)或產(chǎn)品質(zhì)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(yīng)在使用點通過除菌級過濾器（標(biāo)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(chǎn)品覆蓋層氣體的過濾器）或作為產(chǎn)品容器通風(fēng)過濾器，則應(yīng)對過濾器進行完整性測試并審查結(jié)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(yīng)進行滅菌。當(dāng)在工藝中使用氣體時，應(yīng)在使用點定期對氣體進行微生物監(jiān)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(tǒng)的回流對產(chǎn)品構(gòu)成潛在風(fēng)險，則應(yīng)有機制在真空或壓力系統(tǒng)關(guān)閉時防止回流。
Heating and cooling and hydraulic systems
加熱，冷卻和液壓系統(tǒng)
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(tǒng)有關(guān)的主要設(shè)備應(yīng)盡可能位于灌裝室外。應(yīng)有適當(dāng)?shù)目刂拼胧?，以控制與系統(tǒng)流體相關(guān)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(tǒng)對產(chǎn)品構(gòu)成風(fēng)險的任何泄漏都應(yīng)可檢測（例如，泄漏指示系統(tǒng)）。
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(yīng)確保有足夠的適當(dāng)人員，在無菌產(chǎn)品的生產(chǎn)和檢驗以及現(xiàn)場生產(chǎn)操作中使用的任何特定生產(chǎn)技術(shù)方面經(jīng)適當(dāng)?shù)拇_認(rèn)、培訓(xùn)并有經(jīng)驗，以確保符合適用于無菌產(chǎn)品生產(chǎn)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(yīng)盡量配備最少數(shù)量的人員。在初始確認(rèn)和APS等活動中，應(yīng)確定，記錄和考慮潔凈室中的最大操作人員數(shù)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(jiān)測的人員和其他進入潔凈室的人員，都應(yīng)接受與正確生產(chǎn)無菌產(chǎn)品相關(guān)的學(xué)科的定期培訓(xùn)、更衣確認(rèn)和評估。培訓(xùn)應(yīng)包括微生物學(xué)和衛(wèi)生的基本要素，特別關(guān)注潔凈室實踐，污染控制，無菌技術(shù)和無菌產(chǎn)品的保護（適用于進入B級潔凈室和/或?qū)級進行干擾的操作人員）以及如果產(chǎn)品長菌，對患者的潛在安全影響。培訓(xùn)的水平應(yīng)基于人員工作的職能和領(lǐng)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(qū)域的人員應(yīng)接受無菌更衣和無菌行為培訓(xùn)。應(yīng)至少每年通過評估和定期重新評估來確認(rèn)無菌更衣程序的合規(guī)性，并且應(yīng)包括視覺和微生物評估（使用監(jiān)測位置，例如手套手指，前臂，胸部和頭罩（面罩/前額）。預(yù)期標(biāo)準(zhǔn)見第9.30段）。在無人監(jiān)督的情況下進入正在或?qū)⒁M行無菌操作的A級和B級區(qū)域時，應(yīng)只允許已通過更衣評估并已成功參與APS的經(jīng)適當(dāng)確認(rèn)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(jīng)確認(rèn)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(yīng)制定書面程序，概述將未經(jīng)確認(rèn)人員帶入B級和A級區(qū)域的流程。制造商的授權(quán)人員應(yīng)在活動期間監(jiān)督未經(jīng)確認(rèn)的人員，并應(yīng)評估這些活動對該區(qū)域潔凈度的影響。這些人員的進入應(yīng)根據(jù)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(yīng)建立制度，根據(jù)以下方面取消人員在潔凈室工作或在無人監(jiān)督的情況下進入潔凈室的權(quán)限，包括持續(xù)評估和/或從人員監(jiān)測計劃中發(fā)現(xiàn)不良趨勢和/或失敗的APS后。權(quán)限一旦取消，應(yīng)在允許操作人員進一步參與無菌操作之前完成再培訓(xùn)和再確認(rèn)。對于進入B級潔凈室或進行A級干預(yù)的操作人員，這種再確認(rèn)應(yīng)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(biāo)準(zhǔn)的個人衛(wèi)生和清潔對于防止過度脫落或防止增加微生物污染風(fēng)險至關(guān)重要。參與無菌產(chǎn)品生產(chǎn)的人員應(yīng)被指示報告任何可能導(dǎo)致異常數(shù)量或類型污染物脫落并因此應(yīng)避免進入潔凈室的特定健康狀況或疾病。應(yīng)由指定的主管人員提供可能引入不適當(dāng)微生物危害的人員健康狀況和應(yīng)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(yǎng)（除當(dāng)前制造過程中已使用的物料外），或從事任何可能對質(zhì)量產(chǎn)生負(fù)面影響（例如微生物污染）的活動的人員，不應(yīng)進入潔凈區(qū)，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(qū)。潔凈室中使用的電子設(shè)備，例如移動電話和平板電腦，如果制造商提供的電子設(shè)備僅用于潔凈室，如果經(jīng)過適當(dāng)設(shè)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(shè)備的使用和消毒應(yīng)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(yīng)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(qū)域的轉(zhuǎn)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(zhì)量應(yīng)適合工作區(qū)域的工藝和潔凈級別。其穿戴方式應(yīng)能保護產(chǎn)品免受污染。當(dāng)所選的潔凈服類型需要為操作人員提供產(chǎn)品防護時，不應(yīng)損害產(chǎn)品的污染保護。在更衣之前和之后，應(yīng)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(yīng)檢查潔凈服的完整性。對于滅菌的潔凈服和眼罩，應(yīng)特別注意確保其在使用前已經(jīng)過滅菌，并在其規(guī)定的保存期限內(nèi)，并且其包裝經(jīng)過目視檢查以確保其完整?？芍貜?fù)使用的潔凈服（包括眼罩）一旦發(fā)現(xiàn)損壞，應(yīng)進行更換，或以確認(rèn)研究期間確定的設(shè)定頻率進行更換。潔凈服的確認(rèn)應(yīng)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(yīng)選擇以限制因操作人員移動而導(dǎo)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(yù)A級）：在穿戴潔凈服之前，應(yīng)穿戴專用于已滅菌潔凈服下使用的適當(dāng)服裝（見第7.14段）。在穿上已滅菌的衣服時，應(yīng)戴上適當(dāng)滅菌的，無粉橡膠或塑料手套。無菌頭罩應(yīng)將所有毛發(fā)（包括面部毛發(fā)）封閉起來，如果與潔凈服的其余部分分開，則應(yīng)將其塞入無菌套裝的頸部。應(yīng)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(yīng)穿適當(dāng)?shù)囊褱缇男ɡ缪プ樱?。褲腿?yīng)塞在鞋內(nèi)。服裝袖子應(yīng)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(yīng)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(rèn)期間，應(yīng)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(yīng)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?jié)崈舴佑|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(yīng)遮蓋頭發(fā)和胡須。應(yīng)穿連體或分體式褲衫，手腕處收緊，高領(lǐng)，穿經(jīng)適當(dāng)消毒的鞋子或套鞋。它們應(yīng)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(yīng)遮蓋頭發(fā)和胡須。應(yīng)穿通用防護服和適當(dāng)消毒的鞋子或套鞋。應(yīng)采取適當(dāng)措施，避免任何污染物從潔凈區(qū)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(qū)域進行CCS所定義的被認(rèn)為存在污染風(fēng)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(yīng)在適當(dāng)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(nèi)衣除外）在內(nèi)的戶外服裝不應(yīng)帶入直接通往B級和C級區(qū)域的更衣室。在進入B級和C級更衣室之前，應(yīng)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(yīng)對更衣區(qū)域或工序造成污染風(fēng)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(qū)域的操作人員每次進入時，都應(yīng)穿上適當(dāng)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(yīng)作為潔凈服確認(rèn)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(yīng)定期對手套進行消毒。如果衣服和手套損壞并存在任何產(chǎn)品污染的風(fēng)險，應(yīng)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(fù)使用的潔凈區(qū)衣服應(yīng)在與生產(chǎn)操作充分分離的洗衣房中清洗，使用經(jīng)確認(rèn)的工藝，確保衣服在重復(fù)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(shè)施不應(yīng)引入污染或交叉污染的風(fēng)險。衣服的不當(dāng)處理和使用可能會損壞纖維并增加顆粒脫落的風(fēng)險。應(yīng)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(yīng)作為潔凈區(qū)確認(rèn)的一部分進行評估和確定，并應(yīng)包括最大清洗和滅菌次數(shù)。
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(yīng)最大限度減少對生產(chǎn)過程不重要的潔凈區(qū)活動，特別是在無菌操作進行時。人員的移動應(yīng)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(zhí)行無菌操作的操作人員應(yīng)始終堅持使用無菌技術(shù)，以防止氣流變化而導(dǎo)致質(zhì)量較低的空氣進入關(guān)鍵區(qū)域。應(yīng)限制與關(guān)鍵區(qū)域相鄰的運動，并應(yīng)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(yīng)被視為培訓(xùn)計劃的一部分。
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來源：GMP辦公室
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