PDA 无菌药品在隔离器中进行无菌处理的注意事项

白牙狮子

上周下属工厂的同事问到VHP传递窗的消毒效果确认装载问题，因此翻了一下PDA相关资料，以下是与工艺开发和验证的第一个问题，后续8个问题也将陆续贴出。

Topic 7: Cleaning, Disinfection, Decontamination: Cycle Development andValidation

话题7：清洁，消毒[1]，消毒[2]: 工艺开发和验证

Q7-1: What are the special considerations for cleaningand disinfecting isolator interiors (non-product contact surfaces) prior todecontamination?

问题1：在消毒[2]之前，对隔离器内部(非产品接触表面)进行清洁和消毒[1]有哪些特别注意事项?

Recommendation推荐

The qualification orvalidation of the cleaning and disinfecting of non-product contact surfacesshould be based on risk assessment. The cleanliness of non-product contactsurfaces should be visually verified, at the least.

非产品接触表面清洁和消毒[1]应基于风险评估进行确认或验证。非产品接触表面的清洁至少应进行目视确认。

Cleaning 清洁

The decontaminationprocess does not remove product or foreign material. The interior of the isola­torshould be cleaned to remove product residue and foreign material prior to thedecontamination process.

消毒[2]过程不会去除产品或异物。在消毒[2]之前，应清洗隔离器内部以去除产品残留物和异物。

The cleaning processshould be documented in a procedure. The cleaning process should be reliableand adequate to remove levels of product residue and foreign material that canpose a risk to the quality of the next product or the performance of thedecontamination process.

清洁工艺应有书面化程序。清洁工艺应可靠且足以去除可能对下一个产品的质量或消毒工艺性能产生风险的产品残留物和异物。

The cleaning processshould be developed based on process and product requirements, the design ofthe isolator interior, and the surfaces to be cleaned. Potential considerationsinclude:

清洁工艺应根据工艺和产品要求、隔离器内部的设计以及要清洁的表面来制定。可能的考虑因素包括：

Ø  Dedicated verses shared or multiproductisolators

专用与共用或多产品隔离器

Ø  Complexity or variability of the cleaningprocess

清洁工艺的复杂性和多变性

Ø  Location of surfaces to be cleaned within theisolator

隔离器中待清洁表面位置

Ø  Activities performed at given locationswithin the isolator

隔离器中给定位置的活动

Ø  Exposure of product to potentiallycontaminated environment or surfaces

产品暴露于可能被污染的环境或表面

Ø  Toxicity and potency of previous product

先前产品的毒性和效力

Ø  Sensitivity of next product to presence ofprevious product

下一产品对前一产品存在的敏感性

Ø  Difficulty in removing product residue orforeign materials from isolator surfaces

从隔离器表面去除产品残留或异物的困难程度

Ø  Ability to visually or analytically detectpresence of product residue or foreign material

目测或分析检测产品残留或异物的能力

Ø  Diversity of products handled or filled inthe isolator

隔离器中处理或灌装产品的多样性

Ø  Effect of cleaning material residue onproduct or isolator interior

清洁剂残留对产品和隔离器内表面的影响

Ø  Material surface quality and cleanability

材料（隔离器内表面）质量和可清洁程度

Ø  Effect of product or foreign material residue(including cleaning material residue) on decontamination process

产品或异物残留（包括清洁剂残留）对消毒2工艺的影响

Ø  Other controls in place to address the riskof contamination of product with previous product residue and foreign material

其他控制措施，以解决产品被先前产品残留和异物污染的风险

Disinfection 消毒[1]

Since theeffectiveness of the decontamination process may depend on the level ofbioburden pres­ent, a disinfection process may establish a baseline prior tothe decontamination of the isolator interior.

由于消毒[2]工艺的有效性取决于微生物负荷水平，消毒[1]工艺应在隔离器内部消毒[2]之前建立一个基准。

The disinfectionprocess should be validated and documented in a procedure. The disinfectionprocess should include limits on hold time prior to disinfection (time afterend of isolator cleaning to initiation of disinfection process) and hold timeafter disinfection (time after completion of disinfec­tion process toinitiation of decontamination process).

消毒[1]工艺应经过验证并有书面化程序。消毒[1]工艺应包括消毒[1]前的保持时间(隔离器清洗结束后到开始消毒[1]的时间)和消毒[1]后的保持时间(消毒[1]结束后到开始消毒[2]的时间)限制。

A risk assessmentshould be used to determine the maximum level of bioburden allowable to assureeffectiveness of the decontamination process and the method for disinfection.Risk-based consider­ation may include the follow factors:

应使用风险评估来确定允许的最大生物负荷水平，以确保消毒[2]工艺和消毒[1]方法的有效性。基于风险的考虑可能包括以下因素：

Ø  Complexity, variability, and effectiveness ofthe disinfection process

消毒[1]工艺的复杂性，可变性和有效性

Ø  Complexity, variability, and effectiveness ofthe decontamination process

消毒[2]工艺的复杂性，可变性和有效性  

Ø  Location of surfaces to be disinfected withinthe isolator

隔离器中待消毒表面的位置

Ø  Bioburden levels assessed through periodicsurface monitoring of the opened isolator

通过对打开的隔离器进行定期的表面监测来评估微生物负荷水平

Ø  Routine environmental monitoring program ofthe isolator

隔离器的日常环境监测计划

Ø  Environmental monitoring of environmentsurrounding the isolator

隔离器周围环境的环境监测

Ø  Ability to remove disinfectant from isolatorinterior and sensitivity of product to levels of disinfectant

从隔离器内部清除消毒剂的能力和产品对消毒剂水平的敏感性

Ø  Occurrence of any occluded surfaces frommoving parts that will be exposed during manufacturing operations, e.g.,conveyor belts

在生产操作过程中暴露的运动部件(如传送带)表面（原先被遮盖）

If the bioburden ofthe isolator interior is higher than the spore log reduction of the validateddecon­tamination cycle, an additional disinfection step may be required afterthe cleaning process.

如果隔离器内部的微生物负荷高于经过验证的消毒[2]工艺的孢子对数减少量，则在清洁后可能需要额外的消毒[1]步骤。

The design of theisolator interior should be adequate for the cleaning and disinfection process.De­sign considerations may include the following factors:

隔离器内部的设计应适合清洁和消毒[1]工艺。设计考虑可能包括以下因素:

Ø  Materials of construction of the isolatorinterior should be cleanable and resistant to cleaning and disinfectantchemicals, treatment, and process

隔离器内部的建筑材料应可清洁，并耐受清洁和消毒剂、处理和工艺

Ø  Surfaces should be smooth and nonporous

表面应光滑无孔

Ø  Surfaces should drain properly and not poolor accumulate liquids

表面能排水，不得积聚液体

Ø  Surfaces close to exposed product or productcontact surfaces should not have excessive or deep seams that can harborproduct residue or foreign material

靠近暴露产品的表面或产品接触表面不应有过多或很深的接缝，以免藏有产品残留物或异物

Ø  Critical spaces (areas, surfaces, orenvironments that, if microbiologically or chemically contaminated, pose a riskof contamination to product or product contact surfaces) should be accessibleto the cleaning procedure

关键空间(如果受到微生物或化学污染，会对产品或产品接触面构成污染风险的区域、表面或环境)应易于清洁

Ø  Areas within the isolator that expose productor generate or harbor foreign material should be limited

隔离器内暴露产品或产生或藏匿异物的区域应受到限制

OtherConsiderations 其他考虑

Precautions should betaken to avoid excessive exposure to foreign material and microbiologicalcontamination when opening the isolator and exposing the interior to thesurrounding environment. To reduce the risk of particulates and microbial load,in addition to Grade C garments, wearing an additional hood, sterile goggles orglasses, and gloves should be considered.

在打开隔离器。将内部暴露于周围环境时，应采取预防措施，避免过度暴露于外源物质和微生物污染。为了降低微粒和微生物负荷的风险，除了C级洁净服外，还应考虑佩戴额外的兜帽、无菌护目镜或眼镜和手套。

A quality riskdocument for the complete process within the isolator must define criticalareas where product could be open and process operations are critical. Thehigher the risk to the product, the more detailed the cleaning and disinfectionprocedure needed. For the most critical areas, dedicated cleaning equipment andutensils should be used by appropriately trained operators.

隔离器内整个工艺的质量风险文件必须明确产品暴露和工艺操作的关键区域。产品的风险越高，需要的清洁和消毒[1]程序就越详细。对于最关键的区域，应由经过适当培训的操作人员使用专用的清洁设备和用具。

Rationale 理由

The objective of theisolator cleaning and disinfection procedure is to remove residues, foreign mat­ter,and bioburden prior to decontamination of the isolator interior to ensure theeffectiveness of the decontamination cycle and, thus, the sterility of product.Cleaning should further reduce the levels and risk of particulate,cross-contamination, chemical contamination, and toxic substances in prod­uctfilled or processed in the isolator.

隔离器清洗和消毒[1]程序的目标是在隔离器内部消毒[2]之前去除残留物、异物和微生物负荷，以确保消毒[2]工艺的有效性，从而确保产品的无菌性。清洁应进一步降低在隔离器中灌装或加工的产品中的粒子、交叉污染、化学污染和有毒物质的水平和风险。

The objective of thedecontamination process is to render isolator surfaces and items in theisolator incapable of contaminating sterile product, materials, or surfaces.Effective decontamination of the isolator interior, including gloves, transferports, STUs, equipment, materials, and items within the isolator, is essentialto the control of sterile product contamination and the sterility of theproduct.

消毒[2]工艺的目的是使无菌产品、材料或表面不被隔离器表面和隔离器内的物品不能污染。隔离器内部的有效消毒[2]，包括手套、传输端口、传递舱、设备、材料和隔离器内的物品，对于控制无菌产品污染和产品的无菌是至关重要的。

A risk-based approachto designing the cleaning, disinfection, and decontamination processes willhelp identify the conditions and variables that must be controlled. Thisapproach will also help establish the procedures, parameters, and acceptancecriteria needed to ensure that the isolator is in a condition that allows foran effective decontamination and manufacturing process.

基于风险的方法来设计清洁、消毒[1]和消毒[2]工艺将有助于确定必须控制的条件和变量。这种方法还将有助于建立所需的程序、参数和接受标准，以确保隔离器处于有效的消毒和生产工艺条件下。

References 参考

Denk, R, et al. Isolator Surfacesand Contamination Risks to Personnel | GMP Cleaning Requirements for Non-productContact Surfaces. PDA Letter 2017, Nov/Dec, 36-40.

Parenteral Drug Association. TechnicalReport No. 51: Biological Indicators for Gas and Vapor-Phase Decontami­nationProcesses: Specification, Manufacture, Control and Use; PDA: Bethesda, Md.,2010. www.pda.org/book­store (accessed Oct 11 2018).

PI 014-3 PIC/SGuide: Isolators Used for Aseptic Processing and Sterility Testingharmaceutical Inspection Convention (Scheme): 2007. http://www.picscheme.org/pdf/29_pi-014-3-recommendation-on-isolators.pdf(accessed November19, 2019).

注：中文中将Disinfection和Decontamination都翻译成消毒，实际上他们是有区别的，以下是定义。

Decontamination 消毒

An action taken torender the surface of an item, environment, material, or component in the isola­torincapable of microbiologically contaminating sterile product, product contactsurfaces, or mate­rials (also referred to as bio-decontamination).

使隔离器中的物品、环境、材料或部件表面不受微生物污染，或使无菌产品、产品接触表面或材料不受微生物污染(也称为生物消毒)。

Disinfection 消毒

Process by whichsurface bioburden is reduced to a safe level or eliminated. Some disinfectionagents are effective only against vegetative mi­crobes, while others possessadditional capability to effectively kill bacterial and fungal spores (1).

将表面微生物负荷降低到安全水平或去除微生物负荷的过程。一些消毒剂仅对营养体微生物有效，而其他消毒剂具有有效杀死细菌和真菌孢子的额外能力(1)。

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白牙狮子

前一段时间比较忙下，今天贴出工艺开发和验证的第二个问题：
Q7-2: What are the current options for isolator interior decontamination?
问题2：现在隔离器内部消毒的选择是什么？

Recommendation 推荐
The predominant decontamination agents currently being used for isolator interior decontamination are VHP and peracetic acid. Alternative agents and technologies could become available that may be considered for decontamination. A careful risk assessment should be performed to evaluate, select, develop, qualify, and validate agents, technologies, methods, and cycles based on equipment condi¬tion, process performance, product quality and sterility, and personnel safety.
目前用于隔离器内部消毒的主要消毒剂是VHP和过氧乙酸。用于消毒的替代试剂和技术可能会出现。应根据设备条件、工艺性能、产品质量和无菌性以及人员安全，进行仔细的风险评估，以评估、选择、开发、确认和验证消毒剂、技术、方法和工艺。
The selection of the decontamination process, agent, and dispersion technology or procedure should take into consideration the:
在选择消毒工艺、消毒剂和分散技术或程序时应考虑：
        Effectiveness of the decontamination process as applied to the condition, design, and use of the isolator
在隔离器的条件、设计和使用中应用的消毒工艺的有效性
        Production requirements
产品要求
        Potential impact of the agent and procedure on the isolator, product, process, and personnel
消毒剂和程序对隔离器、产品、工艺和人员的潜在影响
        Corrosive or reactive properties of the agent and its impact on the equipment and materials present in the isolator
消毒剂的腐蚀性或反应性及其对隔离器中设备和材料的影响
        Potential impact of the agent on personnel and the external environment
消毒剂对人员和外部环境的潜在影响
        History or familiarity with an agent or technology
消毒剂或技术的历史或熟悉程度
        Preference for an agent or technology at the user’s site or location
用户工厂或地点对消毒剂或技术的偏好
        Availability of alternative agents or technologies
替代消毒剂或技术的可得性
Decontamination agents are typically dispersed in two basic states: gaseous and vapor phase. VHP in the vapor phase may be used to decontaminate pharmaceutical isolators. VHP decontamination is an extremely potent, complex process due to its biphasic nature [both liquid and vapor (gas) phases are typically present in the chamber]. The phase equilibrium is extremely sensitive to minor differences in temperature, VHP, and water concentration, making it virtually impossible to know the exact pro¬cess physical parameters at any given time and location. Consequently, no industrial standard exists that defines the required process parameters of either the mechanical design of vapor generation or the distribution systems. As a result, there are a vast variety of commercial systems used throughout the industry with different designs and process descriptions.
消毒剂通常以两种基本状态分散：气态和汽态。汽态的VHP可用于消毒药品生产隔离器。VHP消毒，由于其双相性质[腔体中通常同时存在液相和汽(气)相]，是非常有效且复杂的工艺。相平衡对温度、VHP和水份的微小差异极其敏感，因此在任何给定的时间和位置几乎不可能知道确切的物理参数。因此，没有工业标准来定义蒸汽产生或分配系统的机械设计所需的工艺参数。结果导致整个行业中使用的商业化系统种类繁多，具有不同的设计和工艺。
No matter what system is being used, the process fundamentals remain the same. VHP is distributed in the decontaminated chamber until enough VHP has been deposited (i.e., adsorbed/condensed) on the decontaminated surfaces to yield the targeted decontamination effect. The generally accepted understanding is that increasing the saturation of the VHP atmosphere increases the efficacy, because a large amount of liquid VHP is deposited on the surfaces.
无论使用什么系统，工艺的基本原理都是相同的。VHP在消毒腔体中分布，直到有足够的VHP凝结(即吸附/冷凝)在被消毒表面，以产生有针对性的消毒效果。普遍接受的理解是，增加VHP的饱和度可以提高效率，因为大量的液态VHP凝结在表面上。
Too much deposited VHP, however, can lead to long aeration and increasing material compatibil¬ity and VHP ingress concerns. Depending on the VHP and water concentration, air pressure, and temperature, systems operating below or above saturation (i.e., surface temperature below or above VHP-water mixture vapor dew point) can be used. Two main approaches for VHP vapor generation used in the industry are hot plate vaporization and fogging.
然而，凝结过多的VHP会导致长时间的通风，增加材料的兼容性和VHP侵入问题。根据VHP和水的浓度、气压和温度，可以使用低于或高于饱和浓度(即表面温度低于或高于VHP-水混合物蒸汽露点)的系统。工业上使用的VHP蒸汽产生的两种主要方法是加热板蒸发和雾化。
Hot plate vaporizers use heat to transform injected liquid aqueous VHP solution into hot vapor, which is then distributed within the chamber to be decontaminated. Hot plate vaporizers should be operated to ensure flash vaporization of injected VHP. An operating temperature too low or liquid dosing too high may result in VHP boiling that will affect the efficacy and may even lead to explo¬sion! Hot vapor entering the chamber should be well distributed to prevent local hot spots or posi¬tions with too much VHP condensation. When using remote vapor generators, premature cooling and condensation of generated VHP vapor inside the piping needs to be prevented before reaching the target destination.
加热板蒸发器利用热量将注入的液态VHP水溶液转化为热蒸汽，然后将其分布在腔体内进行消毒。操作加热板蒸发器时，应确保注入的VHP快速汽化。操作温度过低或液体剂量过高可能导致VHP沸腾，影响消毒效果，甚至可能导致爆炸！进入腔体内的VHP应分布均匀，防止局部热点或VHP冷凝过多的位置。在使用远程蒸发器时，需要防止管道内产生的VHP蒸汽在到达目标地点前过早冷却和冷凝。
Fogging processes are based on the generation of micron-sized droplets with enormous surface area, which facilitates natural vaporization without the need of additional heat. The vaporization of drop¬lets continues until the maximum vapor saturation is reached and the fog is created. Depending on the generated droplet size, fog is termed “dry” or “wet” by the industry. In this context, “wet” fog is considered aerosol with droplet sizes larger than approximately 15–20 μm. Such particles settle and attach more easily to surfaces compared to smaller droplets. Consequently, decontamination using “wet” fog is a combination of vapor- and liquid-deposited VHP. Sprays with a droplet size below 15 μm are typically considered “dry.” Small droplets experience minimal sedimentation and tend to bounce off surfaces without leaving liquid deposits. Adsorption of vapor phase VHP on surfaces is the main mechanism of action. Dry fogging provides fast surface decontamination and reduces the aeration time due to short contact time of the VHP on the surfaces. Nozzles or nebulizers should be operated to allow enough space for the spray to develop and spread throughout the chamber; objects too close to the nozzle may receive an excessive deposit of VHP “wetting.” The initial temperature and humidity should be considered for fogging processes as these determine how much VHP vapor can be generated by atomization.
雾化过程是产生具有巨大表面积的微米级液滴，这可由自然蒸发产生，而不需要额外的热量。液滴的蒸发一直持续到达到最大饱和度，形成雾。根据产生的液滴大小，雾被业界分为“干”或“湿”两种。在这种情况下，“湿”雾被认为是液滴尺寸大于约15-20 μm的气溶胶。与较小的液滴相比，这种颗粒更容易沉降并附着在表面。因此，使用“湿”雾消毒是气相和液相凝结的VHP的组合。液滴尺寸低于15 μm的喷雾通常被认为是“干的”。小凝结的小液滴，往往从表面反弹而不留下液体凝结物。气相VHP在表面的吸附是其主要作用机理。由于干雾法的VHP和表面接触时间短，可进行快速的表面消毒和减少通风时间。应采用喷嘴或雾化器，以使喷雾有足够的空间喷洒并扩散到整个腔室；太靠近喷嘴的物体可能会收到过多的VHP“润湿”凝结。雾化过程应考虑初始温度和湿度，因为这决定了雾化能产生多少VHP蒸汽。
Rationale 理由
This recommendation primarily focuses on VHP because it is the predominate agent and technology used. Factors and limitations are presented that should be understood and considered when using this method. Other means to decontaminate the isolator interior are under development and are being evaluated. This section is not intended to be all-inclusive or to dissuade firms from exploring, considering, or using alternative methods.
本建议主要集中于VHP，因为它是主要使用的消毒剂和技术。提出了使用该方法时应了解和考虑的因素和局限性。其他清除隔离器内部污染的方法正在开发和评估中。本节的目的不是包罗一切，也不是劝阻公司探索、考虑或使用替代方法。
Regardless of the method selected, due to the design and use of the isolator, having an effective method for decontamination of the environment and surfaces is essential to the proper performance of the isolator and the aseptic process. The toxic nature of the decontamination agent emphasizes the equal importance of the effects of the decontamination procedure on equipment and personnel safety.
无论选择何种方法，由于隔离器的设计和使用，采用一种有效的环境和表面消毒方法对于隔离器的正确性能和无菌工艺至关重要。消毒剂的毒性决定了消毒程序对设备和人员安全的影响同等重要。
Due to the complexity of the entire decontamination process, diversity of isolator designs, aseptic processes, products, components, and materials exposed in the isolator, a risk-based approach is rec¬ommended for such a selection. It is essential to carefully evaluate, qualify, and validate the method and the equipment used to disperse and monitor the process.
由于整个消毒工艺的复杂性、隔离器设计、无菌工艺、产品、组件和暴露在隔离器中的材料的多样性，建议采用基于风险的方法进行选择。仔细评估、确认和验证用于分散和监测工艺的方法和设备是至关重要的。
References 参考
Parenteral Drug Association. Technical Report No. 51: Biological Indicators for Gas and Vapor-Phase Decontamination Pro¬cesses: Specification, Manufacture, Control and Use; PDA: Bethesda, Md., 2010. www.pda.org/bookstore (accessed Oct 11 2018).
Parenteral Drug Association. PDA Research: 2017 PDA Aseptic Processing Survey; PDA: Bethesda, Md., 2017. www.pda.org/ bookstore (accessed Feb 11, 2019).

白牙狮子

白牙狮子 发表于 2023-2-28 16:19
前一段时间比较忙下，今天贴出工艺开发和验证的第二个问题：
Q7-2: What are the current options for iso ...

整个topic 7，如有版权问题，请联系本人删除。

Smile1234567813

白牙狮子 发表于 2023-3-1 14:03
整个topic 7，如有版权问题，请联系本人删除。

看文件里面的内容，是摘自各个欧美的法规，然后总结回答。。。是这样子吗···

白牙狮子

Smile1234567813 发表于 2023-3-5 09:29
看文件里面的内容，是摘自各个欧美的法规，然后总结回答。。。是这样子吗···

这个topic是对VHP消毒工艺的开发和验证中的一些问题的回答。

101ximeng

白牙狮子 发表于 2023-2-28 16:19
前一段时间比较忙下，今天贴出工艺开发和验证的第二个问题：
Q7-2: What are the current options for iso ...

老师，是否有完整的 PDA 无菌药品在隔离器中进行无菌处理的注意事项

101ximeng

白牙狮子 发表于 2023-3-1 14:03
整个topic 7，如有版权问题，请联系本人删除。

老师是否有完整版的 PDA 无菌药品在隔离器中进行无菌处理的注意事项？如果有，可否发一份，非常感谢！

xinhuawbo

101ximeng 发表于 2023-7-16 13:58
老师是否有完整版的 PDA 无菌药品在隔离器中进行无菌处理的注意事项？如果有，可否发一份，非常感谢！

同求，这份文件不是很好找