附录 1：无菌隔离装置

Aseptic processing using isolation systems separates the external cleanroom environment from the aseptic processing line and minimizes its exposure to personnel. A well-designed positive pressure isolator, supported by adequate procedures for its maintenance, monitoring, and control, offers tangible advantages over traditional aseptic processing, including fewer opportunities for microbial contamination during processing. However, users should remain vigilant to potential sources of operational risk. Manufacturers should also be aware of the need to establish new procedures addressing issues unique to isolators.

无菌加工使用的隔离系统将洁净室外部环境与无菌加工线分开，最小化人员对产品的影 响。一个设计良好的正压隔离系统，在有足够的维护、监测和控制程序支持的情况下，提供超越传统无菌加工工艺的实际优势，包括在加工期间减少微生物污染机会。然而，使用者还应当警惕操作带来的潜在风险。药品生产商还应当知道建立解决无菌隔离装置独有问题的专门程序的必要性。

A.Maintenance

维护

1.General

概论

Maintenance of isolator systems differs in some significant respects from the traditional, non- isolated aseptic processing operations. Although no isolator forms an absolute seal, very high integrity can be achieved in a well-designed unit. However, a leak in certain components of the system can constitute a significant breach of integrity. The integrity of gloves, half-suits, and seams should receive daily attention and be addressed by a comprehensive preventative maintenance program. Replacement frequencies should be established in written procedures that ensure parts will be changed before they breakdown or degrade. Transfer systems, gaskets, and seals are among the other parts that should be covered by the maintenance program.

在一些重要方面，隔离系统的维护与传统的非隔离无菌加工系统有所不同。虽然没有隔离系统是完全密封的，但在一个良好设计的单元里，可以达到非常高的密封性。然而，系统中某些部件的泄露可能对完整性造成显著破坏。应当每天检查手套、半截袖和接缝的完整性，并且建立全面的预防性维护程序。应当用书面程序来规定更换频率，保证在这些部分开裂或变质前得到更换。传递系统、垫圈和密封也应当包括在维护程序内。

2.Glove Integrity

手套的完整性

A faulty glove or sleeve (gauntlet) assembly represents a route of contamination and a critical breach of isolator integrity. A preventative maintenance program should be established. The choice of durable glove materials, coupled with a well-justified replacement frequency, are key aspects of good manufacturing practice to be addressed. With every use, gloves should be visually evaluated for any macroscopic physical defect. Physical integrity tests should also be performedroutinely.    A breach in glove integrity can be ofseriousconsequence.    The monitoring and maintenance program should identify and eliminate any glove lacking integrityand minimize the possibility of placing a sterile product at risk.

一个有问题的手套或袖套（护手）构成一条污染的途径，对隔离装置的完整性造成严重破坏。应当建立预防性维护程序。持久耐用的手套材料以及适当的更换频率是遵从  GMP的关键方面。每次使用前，应当目测检查手套的任何肉眼可见缺陷。还应当常规进行手套的

完整性测试。手套完整性被破坏可能造成严重后果。监控和维护程序应当发现、消除任何缺乏完整性的手套，尽量减少对无菌产品造成风险的可能性。

Due to the potential for microbial migration through microscopic holes in gloves and the lack of a highly sensitive glove integrity test, we recommend affording attention to the sanitary quality of the inner surface of the installed glove and to integrating the use of a second pair of thin gloves.

由于微生物可能通过手套上肉眼可见的洞进入手套，而且由于缺乏高灵敏度的手套完整性测试，我们建议要注意隔离罩的手套内表面的卫生质量，并且操作时再戴上一双薄手套。

B.Design设计

1.Airflow气流

There are two types of aseptic processingisolatorso:penandclosed.    Closed isolators employ connections with auxiliary equipment formaterialtransfer.    Open isolators have openings to the surrounding environment that are carefully engineered to segregate the inner isolator environment from the surrounding room viaoverpressure.

有两种无菌加工隔离系统：开放式的和封闭式的。封闭式隔离系统使用与辅助设备的连接来转移材料。开放式隔离系统有通往周围环境的开口，这些开口经过仔细设计，通过正压使内部隔离环境与周围房间隔离开来。

Turbulent flow can be acceptable within closed isolators, which are normally compact in size and do not house processing lines. Other aseptic processing isolators employ unidirectional airflow that sweeps over and away from exposed sterile materials, avoiding any turbulence or stagnant airflow in the area of exposed sterilized materials, product, andcontainerclosures.    In most sound designs, air showers over the critical area once and then is systematically exhausted from the enclosure. The air handling system should be capable of maintaining the requisite environmental conditions within the isolator.

封闭式隔离系统内的湍流是可以接受的，封闭式隔离系统通常空间较小，没有安装生产线。其它无菌加工隔离系统使用单向气流  ，这些气流吹过暴露的无菌材料，  应避免在暴露无菌材料、产品和容器密封区域的湍流或气流停滞。在更合理的设计中，空气通过关键区域一次，然后就从密封系统中依次排出。空调系统应当能维持隔离系统内必要的环境质量。

2.Materials ofConstruction

建筑材料

As in any aseptic processing design, suitable materials should be chosen based on durability,as well as ease of cleaning and decontamination.  For example, rigid wall construction incorporating stainless steel and glass materials is widelyused.

正如在任何无菌加工设计中一样，应当根据耐用性以及是否容易清洁和去除污染来选择合适材料。例如，在坚硬的墙结构中广泛使用不锈钢和玻璃材料。

3.PressureDifferential

压差

Isolators that include an open portal should be designed to ensure complete physicalseparation from the external environment. A positive air pressure differential adequate to achieve this separation should be employed and supported byqualificationstudies.    Positive air pressure differentials from the isolator to the surrounding environment have largely ranged from approximately 17.5 to 50 Pascals2.2The appropriate minimum pressure differential established by a firm will depend on the system    ’s design and, when applicable, its exit port. Air balance between the isolator and other direct interfaces (e.g., dry heat tunnel) should also be qualified.

隔离系统包括开放式的隔离系统在物理设计上应当能与外部环境完全隔离。应当使用能足够实现这种隔离的空气正压差，并由验证资料支持。从隔离系统到周围环境的空气正压差可以在大约 17.5 到 50 Pa之间。[22]公司所规定的恰当最小压差应当取决于系统设计，在合适的情况下还应考虑出口。应当限定隔离系统和其它直接接口   (如：干热通道 )的空气平衡。

The positive pressure differential should be coupled with an appropriately designed openingto the external environment to prevent potential ingress of surrounding room air by induction.

Induction can result from local turbulent flow causing air swirls or pressure waves that might push extraneous particles into the isolator. Local Class 100 (ISO 5) protection at an opening is an example of a design provision that can provide a further barrier to the externalenvironment.

正压差应当配合一个设计合理的到外部环境的开口，这样可以防止周围房间空气在诱导下的可能进入。局部湍流造成空气旋涡或压力波可能导致将外源颗粒推到隔离系统中。在开口处的局部 100 级(ISO 5)是一个设计实例，能够提供对外部环境的更进一步屏障。

4.Clean AreaClassifications

洁净区域分级

The interior of the isolator should meet Class 100 (ISO5)standards.    The classification of the environment surrounding the isolator should be based on the design of its interfaces (e.g., transfer ports), as well as the number of transfers into and out of the isolator. A Class 100,000 (ISO 8) background is commonly used based on consideration of isolator design and manufacturing situations.    An aseptic processing isolator should not be located in anunclassified room.

隔离装置的内部应当符合  100级(ISO 5)标准。隔离装置周围环境的分级应当基于其接口(如：传递口)的设计，以及进出隔离装置的传递次数。  基于隔离系统设计和生产情况的考虑，通常使用100,000级(ISO8)背景。无菌加工隔离装置不应当位于一个无级别的房间。

C.Transfer ofMaterials/Supplies

材料/供应的传递

The ability to maintain integrity of a decontaminated isolator can be affected impacted by the design of transfer ports. Various adaptations, of differing capabilities, allow for the transfer of supplies into and out of the isolator.

传递口的设计可能影响已消毒隔离系统保持完整性的能力。不同容量的传递口适应不同量的应用物料进出隔离装置。

Multiple material transfers are generally made during the processing of a batch. Frequently, transfers are performed via direct interface with manufacturing equipment. Properly maintained and operated rapid transfer ports (RTPs) are an effective transfer mechanism for aseptic transfer of materials into and out of isolators. Some transfer ports might have significant limitations, including marginal decontaminating capability (e.g., ultraviolet) or a design that has the potential to compromise isolation by allowing ingress of air from thesurroundingroom.    In the latter case, localized HEPA-filtered unidirectional airflow cover in the area of such a port should be implemented. Isolators often include amouseholeor other exit port through which product is discharged, opening the isolator to the outside environment. Sufficient overpressure should be supplied and monitored on a continuous basis at this location to ensure that isolation is maintained.

在药品批加工时通常要进行多次物料传递。通常，物料转移是通过与生产设备的直接接口来进行。适当维护和操作的快速传递口 (RTP)是无菌传递材料进出隔离系统的有效转移机制。有些传递口可能会有明显限制，包括最低限度的消毒能力   (如：紫外线 )，或者有影响隔离能力的设计，允许周围房间空气的进入。对于后者，应当用局部 HEPA 滤器过滤的单向气流保护这个开口区域。隔离系统通常包括卸料的一个小洞或其它出口，使隔离装置与外部环境相通。应当连续提供和监控足够的正压，以确保维持隔离。

D.Decontamination消毒

1.Surface Exposure

表面暴露

Decontamination procedures should ensure full exposure of all isolator surfaces to the chemical agent. The capability of a decontaminant to penetrate obstructed or covered surfaces is limited. For example, to facilitate contact with the decontaminant, the glove apparatus should be fully extended with glove fingers separated during thedecontaminationcycle.    It is also important to clean the interior of the isolator per appropriate procedures to allow for a robustdecontamination process.

消毒程序应当确保所有隔离装置表面全部暴露于化学试剂。消毒剂渗透阻塞的或覆盖表面的能力有限。如：为了便利与消毒剂的接触，手套装置应当全部伸展，并将手套手指分 开。重要的是用合适程序清洁隔离装置内部，保证有效的消毒过程。

2.Efficacy

功效

The decontamination method should render the inner surfaces of the isolator free of viable microorganisms.    Multiple available vaporized agents are suitable for achieving decontamination. Process development and validation studies should include a thorough determination of cyclecapability. The characteristics of these agents generally preclude the reliable use of statistical methods (e.g., fraction negative) to determine processlethality(Ref.    13). An appropriate, quantified Biological Indicator (BI) challenge should be placed on various material2s3and in many locations throughout the isolator, including difficult to reach areas. Cycles should be developed with an appropriate margin of extra kill to provide confidence in robustness of the decontamination processes. Normally, a four-to

six-log reduction can be justified depending on the application. The specific BI spore titer used and the

selection of BI placement sites should be justified. For example, demonstration of a four-log reduction should be sufficient for controlled, very low bioburden materials introduced into a transfer isolator, including wrapped sterile supplies that are briefly exposed to the surrounding cleanroom environment.

消毒方法应当使隔离系统的内部表面没有活的微生物。多种可用的蒸汽灭菌剂适合于消  毒。工艺开发和验证研究应当包括对蒸汽循环能力的确认。这些试剂通常要通过统计学方法(如fractionnegative)的应用来确定消毒过程的致死率  (参考文献13)。另一个适当的方法，应当在各种材料上[23]和隔离装置的许多位置，包括难以接近的区域，放置定量的生物指示剂(BI)。消毒过程应当有足够的杀菌能力，保证消毒工艺的有效性。通常根据应

用，应当有4到6个log值的降低。应当证明所使用的具体  BI孢子滴度和BI放置位置的选择是合适的。如：对于要引入隔离装置物品的是受控制的、生物负荷很低的材料，  4

log 的降低应当足够，包括暂时暴露于周围洁净室环境的包装好的无菌材料。

The uniform distribution of a defined concentration of decontaminating agent should alsobe evaluated as part of these studies (Ref. 14). Chemical indicators may also be useful as a qualitative tool to show that the decontaminating agent reached a given location.

 If the various isolator materials are thoroughly evaluated during cycle development, a firm might consider placing more focus on material texture and porosity during validation of the decontamination process.

如果在循环发展期间彻底评价不同的隔离装置材料，制药厂在消毒工艺验证过程中可能考虑将重点更多放

在材料的质地和孔率上。作为这些研究的一部分，还应当评估确定消毒剂浓度的均一分布  (参考文献14)。化学指示剂也可用于显示消毒剂达到给定位置的定性工具。

3.Frequency

频率

The design of the interior and content of an isolator should provide for its frequent decontamination. When an isolator is used for multiple days between decontamination cycles, the frequency adopted should be justified. This frequency, established during validation studies, should be reevaluated and increased if production data indicate deterioration of the microbiological quality of the isolator environment.

隔离装置内部及内容附件的设计应当满足其频繁消毒的需要。当隔离装置在消毒循环之间使用多日时，所使用的消毒频率应有正当理由。如果生产数据表明隔离装置环境的微生物质量变差，应当重新评价并增加在以前验证研究中建立的频率。

A breach of isolator integrity should normally lead to adecontaminationcycle.    Integrity can be affected by power failures, valve failure, inadequate overpressure, holes in gloves and seams,or other leaks.  Breaches of integrity should be investigated.  If it is determined that the environment may have been compromised, any product potentially impacted by the breach should berejected.

在隔离装置完整性招到破坏时应当重新进行消毒循环。电力故障、阀门故障、超压不足、在手套和接缝上的漏洞或其它泄露等等可能影响完整性。应当调查对完整性的破坏。如果确定环境已经被破坏，应当拒绝任何受到该破坏影响的产品。

E.Filling LineSterilization

分装线灭菌

To ensure sterility of product contact surfaces from the start of each operation, the entire pathof the sterile processing stream shouldbesterilized.    In addition, aseptic processing equipment or ancillary supplies to be used within the isolator should be chosen based on their ability to withstand steam sterilization (orequivalentmethod).    It is expected that materials that permit heat sterilization (e.g., SIP) will be rendered sterile bysuchmethods.    Wheredecontamination

methods are used to render certain product contact surfaces free of viable organisms, a minimum of a six-log reduction should be demonstrated using a suitable biological indicator.

为了保证从每次操作开始时产品接触表面的无菌性，应当灭菌无菌工艺线的整个管线。此外，应当根据承受蒸气灭菌  (或相似方法)的能力，选择无菌加工设备或在隔离装置内使用的辅助物料。能允许热消毒  (如：SIP)的材料应当是可以用所述方法消毒的。当使用消毒方法去除某些产品接触表面的活的微生物时，使用合适的生物指示剂应当证明至少  6个log的降低。

F.Environmental Monitoring

环境监测

An environmental monitoring program should be established that routinely ensuresacceptable microbiological quality of air, surfaces, and gloves (or half-suits) as well as particle levels, within the isolator. Nutrient media should be cleaned off of surfaces following a contact plate sample.    Air quality should be monitored periodically duringeachshift.    For example, we recommend monitoring the exit port for particles to detect anyunusualresults.    Media usedfor

environmental monitoring should not be exposed to decontamination cycle residues, as recovery of microorganisms would be inhibited.

应当建立日常环境监测程序，保证隔离装置内空气、表面和手套  (或half-suit)的微生物质量和尘埃粒子水平在合格范围内。接触平板取样后，从表面清洁去除营养培养基。每个班  次定期监测空气质量。例如，我们建议监测出口的尘埃粒子，以检出任何不寻常的结果。  用于环境监测的培养基不应当暴露于残余的消毒剂中，因为这会阻止微生物生长。

G.Personnel

人员

Although cleanroom apparel considerations are generally reduced in an isolator operation, the contamination risk contributed by manual factors can not be overlooked. Isolation processes generally include periodic or even frequent use of one or more gloves for aseptic manipulations and handling of material transfers into and out of the isolator. One should be aware that locations on gloves, sleeves, or half suits can be among the more difficult to reach placesduring decontamination, and glove integrity defects might not be promptly detected. Traditional aseptic processing vigilance remains critical, with an understanding that contaminated isolator gloves can lead to product nonsterility. Accordingly, meticulous aseptic technique standards must be observed (211.113), including appropriate use of sterile tools for manipulations.

虽然在隔离装置内操作时洁净室工作服的考虑一般不多，但可能人工操作引起的污染风险不可忽视。隔离装置操作通常包括定期或频繁使用一双或多双手套，进行无菌操作或处理进出隔离装置的物料转移。应当了解，手套、袖子或半身服上的位置可能是最难消毒的位置，并且手套完整性的缺陷可能不能及时发现。  传统的无菌加工注意事项仍然是关键的，同时理解受污染的隔离装置手套可能导致产品无菌性被破坏。因此，必须认真遵守无菌技术标准 (211.113)，包括合理应用无菌操作工具。

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