校准风险评估：您从哪里开始？

最近，我们收到了一位博客读者的问题，以回应博客文章on instrument calibration...

亲爱的保罗，
I have a question about Risk Assessment analyses for product impact from sensing instruments that have gone out of calibration, specifically in GxP-compliant applications. Do you have any recommendations on books, training courses, or other resources for managing this?
Thanks!/I

Dear I,
这是一个大问题！首先，让我们想象一下情况：所讨论的乐器是6个月前进行的最后一次校准。校准现在到期，您发现该仪器不超出规格。假设它是一个温度计，应为±0.5°C，但我们发现它的含量为 +1.5°C。因此我们有 +1.0°C的偏差。实际上，我们没有数据可以准确地告诉我们什么时候it went out of calibration. It’s easy to think it was a slow change and it just slid towards +1.0°C. But, the truth is that we actually don’t知道this, it could have been out by +3.0°C a week ago.
The first thing we need to do is quarantine the instrument, then we investigate the situation. The instrument should不是调整或重新服务，直到我们知道出了什么问题。我们可能想打开一个CAPAso that we can determine, if possible, why the instrument has gone out of specification. This knowledge may help prevent the problem from reoccurring. Additionally, it can guide the other part of our investigation – determining if there was any impact on product quality.

Hopefully, we get lucky and we figure out what went wrong, then maybe we can place the failure at a specific point in time, such as during a cleaning or preventive maintenance event. Likely, we won’t know this. But the nature of the instrument going out of spec, combined with information from the instrument vendor, can help understand the failure enough that we can make some good guesses as to whether the failure was gradual or instantaneous, constant or fluctuating, or if it was constantly one-directional or flipping in both directions. This information will guide further investigation.

Determining impact on product quality is a lot harder. You really need to understand your manufacturing process, the properties of your product, and how a change in the variable under investigation (in this case +1.0°C) will affect the product at that point in its manufacturing lifecycle. Some of the time we get lucky (again) and see that there was no impact (such is the case if we know that the deviation was in only one direction and was not variable). For instance, if the specs for the process are 2-8°C and a review of the temperature history shows that the (failed) device gave us values of 4 to 7°C, then we can assume that although the device was reading high, the actual values would have been 3 to 6°C, and therefore within specification.

However, we may need a much deeper investigation. In this case, background information can help so that we can draw on similar investigations and other information such as stability data to determine the impact. We may need to pull retained samples from past lots (during a time when the device could have been out of calibration) and test them to see if there was any quality impact. We may actually need to do a recall if we discover a meaningful quality issue.

Finally, we need to accept that we might not find the answer. If, however, we find enough information to determine whether or not there was negative product impact, we can protect the health of our customers.

执行此类分析的能力取决于一些重要的专业知识：
1)Good diagnostics, perhaps with vendor support, to determine the cause, nature, and timing of the failure.
2）您产品的可靠过程知识指导您的调查以确定是否存在质量影响。通过有据可查的产品历史记录的良好质量系统，这要容易得多。

Thanks for reading our blog and thanks for sending your question! Let me know if you have any further questions...
你的，
Paul

BONUS Post:

我们的连续监视系统产品经理Jon Aldous也在这个问题上加重了这个问题：
乔恩写道："If process parameters are being continuously monitored and alarmed correctly, there are a few things that can indicate an out-of-spec instrument. You may see multiple nuisance alarms or a linear change in value trends that is noticeably different from the trends seen immediately after the last calibration. Typically you need to go back to the last calibration and determine the latest monitored values and then compare trends over time."

PLUS: Our Calibration Development Manager Michael Boeztkes has written about this problem ("my instrument's out of spec... now what?") forPharmAmanufacturing.com。