USP发布《干热去热原》新标准

娟子66

USP发布《干热去热原》新标准

娟子66

USP发布《干热去热原》新标准：不再要求内毒素下降3个log

原创： 翻译组  制药经理人  3天前
USP 发布了新的通论1228.1《Dry Heat Depyrogenation干热去热原》，该章节对干热去热原不再要求250℃*30min的去热原参数，也不再要求内毒素下降3个log。该章节对干热去热原定义了新的标准：认为关注待处理物料（如玻璃瓶）的内毒素负荷，和处理后物料的内毒素残留水平（当内毒素下降到NMT 0.1 EU时，该工艺被认为可以接受。），比单纯的关注内毒素下降度更有意义。解读如下：
定义干热灭菌F值，即FD值，而不是FH值。
在首验证、验证维护和变更控制期间计算FD值。
取z=50 ℃作为标准 z 值。也接受使用其他45℃–55℃的值
定义用于累计FD值的参考温度为250℃，不是170℃。FD = 1 即在250°加热1分钟内达到的去热原效果。
应定期监测FD值的变化趋势，以确认随着时间的推移的一致性。
应在验证前, 充分了解待处理物料的内毒素负荷, 以及用以确保患者安全所需的下降水平。
对于去热原隧道, 只规定了在满载条件下的温度研究，空载温度分布的实际价值有限。
玻璃瓶通常以湿的状态进入去热原过程 (无论是隧道还是烘箱) , 应进行评估, 以适当确定对整体热输入的影响。
去热原隧道温度研究过程中，网带上同一直线上放置的温度探头应不少于5个。
在验证研究之前, 应评估待处理的材料/玻璃物质的内毒素含量。这包括验收入库和清洗结束后的玻璃瓶。
在烘箱去热原验证的温度探头数量为不少于10个
去热原工艺的标准：如果处理后每个样品的内毒素量≤0.1EU, 则该工艺被认为是可以接受的。

翻译如下：

DEPYROGENATION PROCESS CONTROL
去热原工艺控制

The dosimetric measurementfor dry heat depyrogenation processes is the FD unit. An FD = 1 is definedas the depyrogenation effect achieved by 1 min of heating at 250°.
干热去热原工艺的测定指标是FD。FD = 1 即在250°加热1分钟内达到的去热原效果。FD值可对整个过程持续期间 (时间) 内的温度进行积分。

The z-value for dry heat depyrogenation hasbeen shown to be in the range of 45°–55°. For the purposes of this chapter, 50°is used as a standard z-value. Othervalues may be used. (1,2)
干热去热原的 z 值经证实在45℃–55℃的范围内。本章节使用 50 ℃作为标准 z 值。可以使用其他值。(1, 2)

The FD approach isused as a means to compare dry heat depyrogenation effects produced byprocesses that operate at vary-ing temperatures. Basic mathematics can be usedto calculate the depyrogenation effect produced at temperatures other than 250°to determine equivalence to that provided at 250°.
FD方法被用来比较在不同温度下工作的过程所产生的干热去热原效果。可以使用基本数学来计算在250°以外的温度下产生的去热原效果，以确定与250°条件下的等效性。

Using a reference temperature of 250° and anassumed z-value of 50°, the FD calculation can be determined:
使用250℃作为参考温度，设定z=50℃，FD计算如下：

FD= accumulated destruction
Fd=累积杀灭时间
t1= process start time
t1=过程开始时间
t2= process endtime
t2=过程结束时间
T = temperature at each time increment
T=每段时间的温度
Dt =time interval between temperature measurements
温度测试时间间隔

The FD calculation isused during initial validation, validation maintenance, and change control.
在首验证、验证维护和变更控制期间使用FD计算。

FD values areused to confirm process consistency over time as correlation to endotoxindestruction is rarely possible.
由于很难监测到与内毒素破坏相关的指标，FD值用于确认工艺随着时间的推移的一致性。

VALIDATION
验证

Because dryheat depyrogenation is appropriate only for heat stable materials, a highmargin for safety is always attainable. Times and temperatures used for thepurpose of destroying challenge materials can result in extreme challenges tomaterial integrity and stability. Attention to depyrogenation processes,including an understanding of the resident endotoxin load on incoming materialsand reduction to levels needed to assure patient safety, should take placeduring drug product development, prior to validation.
因为干热去热原只适用于热稳定的材料, 可以达到高度安全的保证。用于降低挑战材料的时间和温度可能会对材料的完整性和稳定性带来极大的挑战。在药物产品开发过程中, 应在验证前, 充分了解待处理物料的内毒素负荷, 以及用以确保患者安全所需的下降水平。

Empty Chamber Temperature Distribution for Ovens
烘箱空载温度分布

The oven shouldbe evaluated for empty chamber temperature distribution. This is assessed bymeasurement of temperature at each corner of oven, near the controllingprobe(s) and other locations as justified. Differences in the cycle dwellperiod can be discounted in this evaluation, as only the shortest dwell periodneed be evaluated. The evaluation is best performed over the last few minutesof the dwell period once the system has fully stabilized. The acceptancecriteria for this test vary with the oven's design and operating conditions;however, temperature distribution is typically substantially less uniform thanobserved in autoclaves and may be ±15° or more. Depyrogenation ovens that arelocated at floor level may have even greater ranges in temperature. Thetemperature distribution measurement may be of value in the evaluation ofchanges to the oven.
烘箱应评估空载温度分布。这通过测量烘箱每个角落，控制探头附近和其他合理的位置的温度进行评估。在此评估中，可以忽略温度保持时间的差异, 因为只需要评估最短的保持时间。一旦系统完全稳定, 评估最好在保持时间的最后几分钟内进行。此测试的验收标准随烘箱的设计和操作条件而异；然而，温度分布通常比在高压灭菌器中观察到的均匀程度要低得多, 可能为±15℃或更多。低水准的去热原烘箱的温度范围可能更大。温度分布测量在评估烘箱变更时可能很有价值。

Empty Temperature Distributionin Tunnels
隧道空载温度分布

While these studies are oftendone, they are actually of limited value. Unloaded depyrogenation tunnels willalways produce far more variability in temperature distribution than will afully loaded tunnel. Therefore, for depyrogenation tunnels, tempera-turestudies under fully loaded conditions only are indicated. Important to theproper operation of the dry heat tunnel is the establishment of the requiredair flow balance between the tunnel and the adjoining areas. Improper air flowcan cause un-even heating across the load being processed. The temperaturedistribution measurement may be of value in the evaluation of changes to thetunnel.
虽然这些研究往往是做的, 但实际上价值有限。去热原隧道的空载温度分布变化总是远远大于隧道满载时。因此, 对于去热原隧道, 只规定了在满载条件下的温度研究。对干热隧道的正常运行很重要的是在隧道和毗邻地区之间建立所需的气流平衡。不适当的气流会导致在正在处理的负载中不均匀加热。温度分布测试在评价隧道变更方面可能很有价值。

Component Mapping
部件热穿透

The ability of dry heat topenetrate load items and to bring them to the required temperature should bedetermined.
应确定干热穿透负载物品并将其提高到所需温度的能力。

Load items that are complex,of significant mass, with enclosed volumes and product contact surfaces thatmust be depyrogenated, should be subjected to component mapping to determineinternal cold spots. All load items should be prepared, wrapped (if that is thepractice), and oriented in a manner consistent with how they will be processed.Glass typically enters the depyrogenation process (whether tunnel or oven) wetand must be evaluated wet to properly determine the effect on overall thermalinput. Mapping of glass components to be processed in tunnels is not necessary;all monitoring of temperature in tunnels is accomplished with probes in contactwith the bottom of the container.
如装载复杂、质量大、带有封闭容积和产品接触面的物品, 应进行组件温度分布, 以确定内部冷点。应准备所有的装载，包装 (如适用), 并以与处理方式一致的方式进行。玻璃通常以湿的状态进入去热原过程 (无论是隧道还是烘箱) , 应进行评估, 以适当确定对整体热输入的影响。没有必要对隧道处理玻璃物品进行温度分布；隧道内的所有温度测试都是通过与容器底部接触的探头完成的。

Load Mapping in Ovens
烘箱负载温度分布

Fixed loading patterns arenecessary in oven depyrogenation because of the limited heat capacity of theair; fully packed conditions because of their greater mass ordinarily result inthe best process temperature uniformity. Load mapping assures that items placedthroughout the load attain the desired depyrogenation conditions. Identificationof cold zones within the oven should be established during depyrogenation cycledevelopment. Information from the load mapping is used to adjust cycle timingto assure appropriate efficacy across the entire load. It may be possible tovalidate maximum and minimum loads (as determined by either the number of itemsor their mass).
由于空气的热容量有限, 在烘箱去热原过程中需要固定的装载模式，满载条件, 因为它们的质量更大, 通常会产生最佳的工艺温度均匀性。负载温度分布可确保放置在整个负载中的物品达到所需的去热原条件。在去热原程序的开发过程中, 应确定烘箱内的冷区。负载温度分布的信息用于确定程序时间, 以确保在整个负载均具有适当的效果。可以验证最大和最小装载 (通过物品数量或其质量决定)。

FD is calculated from thetemperature data at all monitored locations within the load pattern.
FD是根据负载模式中所有被测试位置的温度数据计算得出的。

Load Mapping in Tunnels
隧道负载温度分布

Load mapping can be assessedusing sets of calibrated sensors (i.e., trailing or wireless temperaturesensors) positioned with-in the glass pack as it moves through the tunnel.Temperature sensors should be placed into direct contact with the glass item atthe bottom of the container. Temperature measurements should be made on theleading edge, the middle (highest densi-ty), and the trailing edge of the glasspack across the width of the conveyor belt. There should be NLT 5 temperature sensorspositioned across the belt in each section of the load. FD iscalculated from the temperature data at all monitored locations. Studies shouldbe performed using all container sizes to determine the lowest FD locations.The FD results can be used to sup-port the selection of containers/conditionsto be evaluated in the confirmation studies (see below). There is norequirement to perform temperature heat distribution measurements during thesestudies.
负载温度分布的评估可以使用玻璃瓶中放置一组经过校准的传感器 (即有线或无线温度传感器)并通过隧道来进行。温度传感器应与容器底部的玻璃物品直接接触。温度测量应在玻璃瓶堆的前缘、中间 (最高密度) 和后缘上覆盖整个隧道宽度。在负载的每个部分, 网带上应放置不少于 5温度传感器。FD是根据所有被测试位置的温度数据计算的。应使用所有尺寸的容器进行研究, 以确定最低的FD位置。FD结果可用于支持在确认研究中评估的容器/条件的选择 (见下文)。在这些研究中, 不需要进行温度分布测试。

Confirmation of Depyrogenation
去热原的确认

The materials/glass componentsto be depyrogenated should be assessed for their incoming endotoxin contentprior to the validation study. This would include glass as received andimmediately after washing. All tested materials should be handled and preparedusing defined procedures. Materials and glass prepared in the same manner are usedin the depyrogenation validation studies. The addition of challenge material tothe load items, including a requirement to demonstrate a 3-log reduction, maynot be required if time and temperature studies consistently indicate thatdepyrogenation conditions are met. Tempera-ture monitoring as described abovemust be done simultaneously with the depyrogenation confirmation studies. Theconfir-mation studies should be performed at reduced time-temperatureconditions from those utilized in routine processing and deliverlower FD results when compared to those determined in the mapping studies andare considered “worst case” confirmation of depyrogenation process efficacy.There is no requirement to perform temperature heat distribution measurementsdur-ing these studies.
在验证研究之前, 应评估待处理的材料/玻璃物质的内毒素含量。这包括验收入库和清洗结束后的玻璃瓶。所有挑战的材料都应使用规定的程序进行处理和准备。以同样的方式制备的材料和玻璃被用于去热原验证研究。如果时间和温度研究表明持续达到去热原条件, 则可能不需要在负载物品中添加挑战材料, 包括要求证明减少 3-log。上述温度测试必须与去热原确认研究同时进行。确认研究应在低于日常处理的时间温度条件下进行，并给出比温度分布研究更低的FD值，被认为去热原过程效果确认的"最坏情况"。在这些研究中不需要进行温度分布测试。

OVENS
烘箱

A minimum of five (5) samplesshould be taken in proximity at NLT 10 temperature-monitored locations(including those determined to be the coldest from the oven load mapping study)in the oven and tested for endotoxin content post-process-ing. The process isconsidered acceptable if the amount of endotoxin per sample is NMT 0.1 EU.
在烘箱中的不少于10个温度测试点 (包括从烘箱负载温度分布研究中确定的最冷点) 附近至少应采集5个样品, 并检验其处理后的内毒素含量。如果每个样品的内毒素量≤0.1EU, 则该工艺被认为是可以接受的。

TUNNELS
隧道

A minimum of five (5) samplesshould be taken in proximity to each monitored position within the tunnel load(including those determined to be the coldest from the tunnel load mappingstudy) and tested for endotoxin content post-processing. The process isconsidered acceptable if the amount of endotoxin per sample is NMT 0.1 EU.
应在隧道负载内每个测试点附近至少采集5个样本(包括隧道负载温度分布研究中确定的最冷点)，并检验其处理后的内毒素含量。如果每个样品的内毒素量≤0.1EU, 则该工艺被认为是可以接受的。

麦田.守望

更注重实际内毒素负荷了，在监测进厂和清洗后负荷的基础上，可以不做3LOG研究。

dajiahao557

学习了，谢谢！

syhorchid

学习一下

往事随风12

谢谢分享，学习一下。

往事随风12

谢谢分享，学习一下。

jixia

谢谢分享

lhd000000

不错，谢谢

大师兄

学习了

zhaosc8326

学习一下，谢谢

老鸟

谢谢分享
在验证研究之前, 应评估待处理的材料/玻璃物质的内毒素含量。这包括验收入库和清洗结束后的玻璃瓶。所有挑战的材料都应使用规定的程序进行处理和准备。以同样的方式制备的材料和玻璃被用于去热原验证研究。如果时间和温度研究表明持续达到去热原条件, 则可能不需要在负载物品中添加挑战材料, 包括要求证明减少 3-log。上述温度测试必须与去热原确认研究同时进行。确认研究应在低于日常处理的时间温度条件下进行，并给出比温度分布研究更低的FD值，被认为去热原过程效果确认的"最坏情况"。在这些研究中不需要进行温度分布测试。
确认研究应在低于日常处理的时间温度条件下进行，并给出比温度分布研究更低的FD值，被认为去热原过程效果确认的"最坏情况"。

这个低于日常处理的时间温度条件，有没有建议值啊，随便定一个？

陈三

谢谢分享

往事随风12

谢谢分享，学习一下。

墨石

增加了工作难度吗？

王先生

学习一下   

韶光换

那么验证时内毒素的初始负载是多少没有要求吗？

a881407

真厉害！

这个社会谁懂

去热原工艺的标准：如果处理后每个样品的内毒素量≤0.1EU, 则该工艺被认为是可以接受的。
怎么做？检测西林瓶内毒素，在证明能降低3个log的效果。

哈尔滨-HR

学习学习

zpzjm2010

谢谢分享。