ISPE 除热原隧道的验证alidation of a Depyrogenation Tunnel-2025（中英文）

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除热原隧道的验证-2025.11

ISPE

Validation of a Depyrogenation Tunnel

除热原隧道的验证

Introduction 介绍

Dry-heat depyrogenation is the primary method for the inactivation of bacterial endotoxin through thermal

destruction,and it is commonly used with heat-resistant materials,such as glassware.The critical process

parameters in a dry-heat depyrogenation process are time and temperature.

干热除热原法是利用热来破坏灭活细菌内毒素的主要方法，通常用于耐热材料，如：玻璃器皿。干热除热原工艺

的关键工艺参数是时间和温度。

The production of parenteral products requires products to be sterile as well as to be free of pyrogens.Endotoxin

is the most significant pyrogen in the health care industry.These are high-molecular weight complexes

associated with the outer membrane of gram negative bacteria.A depyrogenation tunnel is typically used for

the inactivation of pyrogens prior to asepticfilling of glass containers,and comes after the washing step.This

type of tunnel provides an automated continuous depyrogenation process and usually consists of three zones:

a pre-heating zone to pre-warm the glass containers;a hot zone,where the containers are exposed to the

required temperature the sufficient time to achieve the depyrogentation effect expected;and a cooling zone,

where the containers are returned to room temperature prior to leaving the tunnel and entering the filling

environment.The exposure time of the load inside the tunnel is a function of the length of the tunnel,temperature

and the speed of the conveyor belt.The qualification of a depyrogenation process in a tunnel involves the

equipment qualification (installation qualification,or IQ,and the operational qualification,or OQ)and the

depyrogenation process qualification(PQ).

注射剂的生产要求产品无菌且不含热原。内毒素是医疗保健行业中最主要的热原。内毒素是与革兰氏阴性菌外膜

相关的高分子量复合物。除热原隧道通常用于在无菌灌装玻璃容器之前灭活热原，该隧道位于清洗步骤之后。这

种隧道提供自动化的连续除热原工艺，通常由三个区域组成：预热段，用于预热玻璃容器；高温段，容器在此暴

露于所需温度并保持足够时间，以达到预期的除热原效果；及冷却段，容器在此恢复至室温，然后离开隧道进入

灌装环境。容器在隧道内的暴露时间取决于隧道的长度、温度和网带的速度。隧道除热原工艺的确认包括：设备

确认(安装确认，或IQ, 和运行确认，或OQ) 及除热原工艺确认 (PQ)。

A validation lifecycle approach is recommended to develop a thorough understanding of the equipment and

process by investing more time on the process design phase,prior to validation,and then by the continued

monitoring of the process after validation to ensure that the process is delivering the expected quality while

confirming the state of control of the process.This paper utilizes the lifecycle approach and focuses on the first

two stages:Process Design and Process Qualification to provide recommendations for a standardized and

science-based approach for the qualification of a depyrogenation tunnel.

建议采用验证生命周期方法，通过在验证前的工艺设计阶段投入更多时间，并在验证后持续监测工艺，从而深入

了解设备和工艺，确保工艺达到预期的质量，并确认工艺的控制状态。本文采用生命周期方法，重点关注前两个

阶段：工艺设计和工艺确认，旨在为除热原隧道的确认提供标准化和科学的方法建议。

Lifecycle Approach to a Depyrogentation Process Validation for a Depyrogenation Tunnel

除热原隧道除热原工艺验证的生命周期方法

The lifecycle approach to validation is recommended in the 2011 US Food and Drug Administration guidance

document,titled “Process Validation:General Principles and Practices,"where it states that “the lifecycle

concept links product and process development,qualification of the commercial manufacturing process,and

maintenance of the process ina state of control during routine commercial production."According to the lifecycle

approach,the validation can be divided into three stages:

FDA 于2011年发布的题为《工艺验证：一般原则和实践》的指导文件，推荐采用生命周期验证方法，其中指出

“生命周期概念将产品和工艺开发、商业化生产工艺的确认，以及在日常商业生产过程中保持工艺受控状态联系

起来。”根据生命周期方法，验证可分为三个阶段：

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除热原隧道的验证-2025.11

Stage One:Process design

第1阶段：工艺设计

Stage Two:Process qualification

第2阶段：工艺验证

Stage Three:Continued process verification

第3阶段：持续工艺确证

Some of the main deliverables of Stage One include the development of the user requirement specification

(URS),the definition of the critical quality attributes(CQAs)and critical process parameters(CPPs),the

development of the depyrogenation process and the creation of the standard operating procedure (SOP).

During Stage Two,the equipment qualification is completed with the performance of the IQ and OQ and the

depyrogenation process is qualified during the performance qualification(PQ)according to the approved

protocols.During Stage Three,the process is continuously monitored to confirm the expected results and the

state of control of the process.

第 1 阶段的主要交付成果包括：制定用户需求规范(URS) 、定义关键质量属性(CQA) 和关键工艺参数(CPP) 、开

发除热原工艺、及制定标准操作规程(SOP) 。第2阶段，通过执行安装确认(IQ)和运行确认(OQ) 完成设备确认，

并根据已批准的方案，在性能确认(PQ) 过程中验证除热原工艺。第3阶段，持续监控该工艺，以确认预期结果和

工艺的控制状态。

This concept paper will concentrate on the main points of the Process Design phase and the Process

Qualification phase.

本概念文件将重点介绍工艺设计阶段和工艺确认阶段的要点。

Depyrogenation Process Design 除热原工艺的设计

During the Process Design phase,the specifications of the depyrogenation tunnel are defined in the URS .

Operational specifications include the capacity of the unnel in containers/hour according to production

requirements,specific load size(e.g.,volume and dimensions of glassware containers),temperature range and

conveyor belt speed.

在工艺设计阶段，用户需求规范( URS) 中会定义除热原隧道的具体规范。运行规范包括：根据生产需求确定的

隧道每小时处理容器数量、特定负载尺寸(例如：玻璃器皿容器的体积和尺寸)、温度范围及网带速度。

As for the critical process parameters(CPPs),these are time and temperature for a dry-heat depyrogenation

process.The vials are driven by a conveyor belt through each of the three zones.In the hot zone,dry air is

heated to the specified temperatures through heat exchangers in order to heat the containers.The exposure

time of the load inside the tunnel is a function of the length of the tunnel,the temperature and the speed of the

conveyor belt.

对于干热除热原工艺而言，关键工艺参数 (CPP) 为时间和温度。样品瓶由网带驱动，依次通过三个区域。在高

温段，干燥空气通过热交换器加热至指定温度，从而加热样品瓶。样品瓶在隧道内的停留时间取决于隧道长度、

温度和网带速度。

The process operational parameters of a depyrogenation tunnel should be designed to achieve at least a three-

log reduction of bacterial endotoxin.The temperature of the hot zone in depyrogenation tunnels is usually set

between 220℃and 350℃.It is important that all the different vials which are going to be depyrogenated are

exposed to at least the defined temperature and for not less than the time determined in the design phase.The

European Pharmacopeia Chapter 2.6.8.establishes dry heat at a minimum of 250℃for at least 30 minutes for

the depyrogenation of materials such as glassware.For higher temperatures the depyrogenation time required

might be only a few minutes.

除热原隧道的运行参数应设计为至少实现细菌内毒素3个对数单位的下降。除热原隧道高温段的温度通常设定

在220℃ 至 350℃ 之间。重要的是，所有待除热原的样品瓶都必须暴露在至少规定的温度下，且持续时间不得

少于设计阶段确定的时间。欧洲药典第2.6.8章规定，对于玻璃器皿等材料，除热原时，干热温度至少应为250℃,

持续时间至少为30分钟。对于更高的温度，所需的除热原时间可能仅需几分钟。

Similar to the F0 value for steam sterilization,Fh is a measure of heat input and is used to calculate the time in

minutes equivalent to a lethality or endotoxin destruction effect delivered by dry heat at 250℃.For

depyrogenation the minimum z-value is set at 46,5℃.Although there is no minimum Fh value required for

ISPE

除热原隧道的验证-2025.11

depyrogenation,the determination of the Fh value for each probe may be helpful to ensure consistency and

reproducibility of the depyrogenation process.

与蒸汽灭菌的 Fo 值类似，Fn 是衡量热输入的指标，用于计算在250℃干热条件下达到致死或内毒素破坏效果所

需的时间(以分钟为单位)。对于除热原，最小z值设定为46.5℃。虽然除热原没有最低Fn 值要求，但测定每个

探头的 Fh值有助于确保除热原工艺的一致性和可重复性。

Particle count in the depyrogenation tunnel should be appropriate to the exiting environment classification.

Operational qualification should verify that the HEPA-filtered aseptic environment is maintained within the

specifications for an ISO 5/Grade A environment.Unidirectional air flow is required to ensure that clean air is

always supplied for the heating of the containers.Pressure difference between the zones of the tunnel is needed

to avoid air moving from dirty to clean.The minimum differential pressure depends on the design of the tunnel

and therefore the specification should be checked with the manufacturer.

除热原隧道内的颗粒计数，应与出口环境等级相符。运行确认应确证经HEPA 过滤的无菌环境是否符合 ISO 5/A

级环境的规范。需要单向气流以确保始终为容器加热提供洁净空气。隧道各区域之间需要存在压差，以避免空气

从脏空气流向洁净空气。最小压差取决于隧道的设计，因此应向制造商确认具体的规范。

Figure 1:Scheme of the pressure cascade in a depyrogenation tunnel.

图1: 除热原隧道内压力级联示意图。

The image iscourtesyofSyntegon.

图片由 Syntegon 公司提供。

装载区域<预热段预热段灭菌段冷却段洁净室

Loading Zone

<Pre-Heating

Zone

Pre-Heating

Zone

+10 Pa

Sterilizing

Zone

>+11 Pa

Cooling

Zone

+10 Pa

Clean-

room

+25 Pa

Empty and loaded chamber temperature studies can be performed as part of the factory acceptance test(FAT)

and then repeated after equipment installation and commissioning at the manufacturing facility,as part of the

site acceptance test (SAT)and/or as part of the IQ/OQ.Empty chamber temperature distribution studies are

necessary to confirm that the air balance and heated air supply willprovide even heating.For these studies

thermocouples are placed inside the tunnel equally distributed.The variability in the temperature in the different

areas of the tunnel depends on the design and expected variability may therefore be derived from

manufacturer's specifications.Loaded chamber heat distribution studies are also performed to assess the

impact of the load in the heat distribution uniformity of the hot zone in the tunnel.3

空腔和负载腔室的温度研究，可作为工厂验收测试(FAT)的一部分进行，并在设备安装调试完毕后，作为现场验

收测试(SAT )和/或安装确认/运行确认(IQ/OQ) 的一部分重复进行。空腔温度分布研究对于确认空气平衡和热风供

应能够提供均匀加热至关重要。在这些研究中，热电偶均匀的分布在隧道内。隧道不同区域的温度差异取决于设

计，因此预期差异可从制造商的规范中得出。负载腔室热分布研究，也用于评估负载对隧道高温段热分布均匀性

的影响。

Heat distribution inside the load can vary depending on the load mass,configuration and other parameters.For

this reason,heat penetration studies are done to help determine “worst-case”conditions in the load and cold

spots.Heat penetration studies confirm the temperature of the load under operating conditions reaches and

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@Clear1/7除热原隧道的验证-2025.11ISPEValidationofaDepyrogenationTunnel除热原隧道的验证Introduction介绍Dry-heatdepyrogenationistheprimarymethodfortheinactivationofbacterialendotoxinthroughthermaldestruction,anditiscommonlyusedwithheat-resistantmaterials,suchasglassware.Thecriticalprocessparametersinadry-heatdepyrogena...

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