关键⼯艺参数的定义指南（中英对照）
Guidance in defining critical process parameters
关键参数的定义指南
The criticality of a process parameter is an asssment of the probability that it can be consistently and reproducibly controlled within the proven acceptable range (PAR) during routine manufacturing.
⼯艺参数的关键性是指在⽣产中对可接受范围的持续重复控制的可能性的评估，
This probability depends on
可能性主要取决于：
t he robustness of the process parameter (the width of the PAR)
⼯艺参数的稳定性（可接受范围的宽度）
t he ability to technically control the parameter (technical limitations)
参数控制的技术能⼒（技术限制）
t he uncertainty of the measurement of the parameter (reflected by the standard deviation σ)
参数测量的不确定性（⽤标准偏差来反映）
The robustness of a process parameter is reflected by the width of the proven acceptable range. The wider the range within which a parameter could be varied during process qualification without impacting product quality, the more robust it is.
可接受的参数范围反映⼯艺参数的稳定性。在参数确认中不影响产品质量的可改变的参数的范围越宽，⼯艺越稳定。
The ability to technically control a parameter is a function of a combination of process properties and equipment capabilities. For example, a highly exothermic reaction might be well controlled in a small stainless steel vesl, but could prove impossible to control in a larger glass-lined vesl.
参数的技术控制能⼒是⼯艺特性和设备能⼒的综合功能。例如，⼀个⾼放热的反应可能在⼀个⼩的不锈钢反应釜内能够很好的被控制，但是在⼀个⼤的塘玻璃反应釜内证明是不可能控制的。
The uncertainty of a measurement (σ) is the combined uncertainty of the calibration of the probe, the variance of the probe itlf, and the variance of the signal transmission from the probe to the distribu
ted control system (DCS). If the measurement is normally distributed, 3.4 out of a million data points will be outside a range of +/- 4.5 standard deviations. This is the basis of the ‘six sigma’ theory. The difference of 1.5 between 4.5 and 6 is an empirical value chon bad on the obrvation that the mean of real process tends to drift by this value over time. Bad on the ‘6σ’-concept we define a parameter as ‘critical’when the proven acceptable range is narrower than ± six standard deviations.
测量的不确定性是探头或检测器的校验，监测器本⾝的变化和从探头到DCS的信号传输的变化的不确定因素的综合。如果测量结果是正态分布的，3.4PPM（百万分之⼀）将在+/-4.5标准偏差的范围之外。这是六西格玛理论的基础。4.5和6之间1.5的差异是⼀个经验值基于观察实际⼯艺趋势相对时间数值的漂移。基于六西格玛概念当⼀个参数的可接受的范围⽐+/-六个标准偏差窄时，我们定义这个参数为关键参数。
figure 1: critical parameter figure 2: non-critical parameter
t point t point
lower/upper edge of failure
Whereas a proven acceptable range depends only on the process, the variance of a control system is equipment-specific.
The variance of a control system for the same process parameter might be different in another operational environment, which could result in a different criticality asssment (e.g. a critical process parameter in one plant may be judged to be non-critical in another plant which has a control system with a lower variance).
如果⼀个可接受的参数范围仅仅依赖于⼯艺，控制系统的变异是设备属性。对同样的⼯艺参数的控制系统的变异可能在另⼀个操作环境下不同，这个可能导致⼀个不同的关键性评估（⽐如在⼀个⼯⼚的⼀个关键参数在另⼀个有较低变异的控制系统的⼯⼚就可能被判定为不关键）
The following table can be ud for guidance to asss the criticality of a process parameter
以下列表在指南中⽤于评定⼀个⼯艺参数的关键性
1) The pH is typically much more difficult to be controlled than to be measured. Unless a system is in place which significantly reduces the control uncertainties (local pH, re-adjustment, etc.) a PAR of +/-1.0 pH units is recommended.
pH是典型的控制⽐检测要难得多。如果⼀个适当的系统能够显著的降低控制的不确定性（在线pH，重新校正等）推荐使⽤+/-
1.0pH的可接受的范围。
2) Taking into account the difficulties of controlling a pressure under changing process conditions as obrved drying, distillation operation and reactions under pressure, a PAR of +/-20% is recommended.
考虑到在⼲燥、蒸馏操作和压⼒下反应中观察到的⼯艺条件改变时压⼒控制的难度。推荐使⽤+/-20%的可接受的参数范围
Examples:
例⼦：
1）A reaction temperature is likely to be not critical if the proven acceptable range (PAR) for a t point of 50°C is determined as 42°- 58°C for a calibrated temperature range of 200°C (e.g. -20°C to +180°C).
如果⼀个可接受参数范围是温度范围是42~58°C，设定点是50°C，⽽校验过的温度为200°C（⽐如-20°C~180°C），那么⼀个反应温度或许就是不关键的。
2）A pH has to be adjusted to 5.0 (PAR: 4.4 –5.6) by charging acid. The final pH is relevant; an overcharge of acid can be corrected by charging ba. This parameter is well controlled and not critical.
⼀个pH必须通过加酸调节⾄5.0（范围：4.4~5.6），最终pH是相应的。加过量的酸可以通过加碱来校正。那么这个参数可以被很好的控制并不关键。
3）During a reaction an acid is relead and the pH has to be controlled between 6.4 and 7.6 by charging ba. This parameter is likely to be critical as the local pH might differ significantly from the value measured and as the charge of ba has to be controlled.
在⼀个反应中酸已经加了，pH必须通过加碱控制在6.4~7.6，因为现场的pH与检测的值可能有显著不同，碱的加⼊必须控制，所以这个参数可能是关键的。
4）A distillation is to be carried out under a pressure of <10KPa. The t-point should be defined as 8KPa, the parameter likely to be not critical.
⼀个蒸馏在压⼒⼩于10KPa的条件下进⾏。这个设定点应该定义为8KPa。这个参数可能就是不关键的。
5）A hydrogenation has to be carried out at 0.8 Mpa, it can be run between 0.6 and 1 MPa; below 0.6MPa the reaction stops and more than 1MPa could not be tested. This parameter is very likely to be not critical. ⼀个氢化反应必须在0.8Mpa下进⾏。它可能在在0.6~1MPa下进⾏。低于0.6MPa反应停⽌，⼤于1MPa没有测试过。那么这个参数⾮常可能就是不关键的。
6）A reaction has to be carried out at a pressure of 5 bar; at 4 bar and at 6 bar different side products form. The edge of failure has to be determined and the parameter is to be regarded as critical.
⼀个反应必须在0.5MPa下进⾏，0.4MPa和0.6MPa是不同的两边产品形式。失败的边缘必须被定义，这个参数考虑是关键的。
