Mean Kinetic Humidity? Answers & Advice from our MKT Webinar

Mean Kinetic temperature for GxP
Life Science
 

These are a selection of questions that were answered in our recent webinar on Mean Kinetic Temperature. These questions are a sample, to hear all the questions and answers, view the recorded webinar and get the slides here.
But since Vaisala is the world-leader in humidity measurement, folks often ask us questions based on our favorite parameter, so we include it here prior to the webinar Q&A.
 
M wrote:
Moisture extremes impact in-process product quality. Quality sometimes defines parameters that are not well defined. Similarly, from alarming strategy, what impact does duration and/or the magnitude of an excursion have on product quality?
 
Also, requirements are often stated at less than 50%RH at 20°C; since relative humidity is "relative" to temperature, can dew point or vapor pressure control be used as an equivalent parameter? Is there a difference in product impact moisture requirements that use RH versus dew point temperature?
 
Paul Daniel, Vaisala Senior Regulatory expert answers:
1) Moisture extremes impact on in-process product quality.
When in-process, the product is not protected by final packaging.  However, processing usually takes place in well-controlled manufacturing suites, so we often have an opportunity to control moisture and humidity in ways that are not possible downstream, for example in storage and distribution.
 
2) Quality sometimes defines parameters that are not well defined.
Agreed:  In my experience, the only times I have seen this lack of definition overcome is when there is good communication between quality and manufacturing.  Ideally, this is a by-product of a holistic QMS, but it doesn’t always happen.  Quality may seem more concerned with passing audits and can miss the practical concerns we see on the manufacturing floor.
 
3) Regarding the impact that duration and/or magnitude of excursion has on product quality…
This depends entirely on the product, the process, and the manufacturing environment.  For temperature, because of the phenomenon described by Arrhenius in his equation, we can generally state with confidence that the higher the temperature and the longer the duration, the larger impact on product quality. 
 
With humidity, it is harder to say.  Because higher humidity increases the concentration of one of the reactants (gaseous H2O), the reaction kinetics can be quite different.  And often, high humidity effects can be reversible, say for example, in product clumping in powdered product, which can often be fixed by some extra agitation or mixing.  But low humidity effects, as you know, can be a lot harder to reverse, especially if something has completely dried out.  In short, the humidity effects must be decided on a case-by-case basis. Humidity lacks the huge body of empirical data that we have for temperature and its effect on reaction rates.
 
4) Regarding requirements often stated at less than 50%RH at 20°C and your question: “Can we use dew point or vapor pressure control as an equivalent parameter?”
 
You are absolutely correct that relative humidity is exactly that… relative to the temperature.  But it would be a mistake to think that the temperature affects the amount of water vapor (gaseous H2O) in the air sample – it does not.  Increasing the temperature, or lowering it (as long as we don’t lower it past the dew point) will not impact the amount of gaseous water in the gas sample, it only affects the reported RH% value. 
 
For example….  20°C and 50%RH is a vapor pressure of 11.7 mbar and a dew point of 9.2°C.   While 22°C and 44%RH is a vapor pressure of 11.7 mbar and a dew point of 9.2°C.
 
As you can see, while temperature affected the reported %RH value, it didn’t have any effect on the actual amount of moisture in the sample.
 
5) Finally the difference in product impact moisture requirements that use RH versus dew point temperature…
There are two general reasons why we might choose to report our measurements in one parameter over another.
The first reason is linked to what we are trying to achieve. If we are interested in promoting or preventing drying processes, then we want %RH, because drying processes are entirely dependent on the ability of a gas sample to accept more gaseous H2O.  But if our process goal is to prevent condensation in a process, we might be better served with a dew point measurement. 
 
The second reason is accuracy. Percentage of relative humidity measurements are not as reliable when things get really dry (<10%RH), really humid (>90%RH), or in extreme temperatures and extreme pressures.  In these instances, we are better served with dew point or mixing ratio as our reported parameters because we’ll get better resolution and more accuracy.
 

With ambient temperatures and humidity between 10% and 90%RH, relative humidity is probably your best measurement when dealing with pharmaceutical products.  The relative nature of relative humidity is not a variability in the amount of moisture in the air, but a temperature-dependent variability in the maximum amount of gaseous H2O that can be present in a gas sample.

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More Q&A from the MKT webinar

Can you calculate MKT for humidity? Like a Mean Kinetic Humidity?

Yes, sometimes folks try to calculate this value.  Even though it seems like a value that might be useful, I think the idea is flawed, and would require some serious research and support.  MKT is based on Nobel Prize-winning research that produced the Arrhenius equation. The equation showed definitively that in simple reactions, the reaction rates increase with temperature. 
 
To pursue mean kinetic humidity, we would need some similar research to illustrate and prove the relationship between chemical change and humidity. If not for all products, then certainly for a product we are interested in.  I don’t see that depth of research happening for a single compound – it would cost more than just doing a better job controlling your humidity. 
 
Also consider that most products in final packaging are protected from short-term spikes in humidity, because final packaging is usually airtight.  Most of the interest in MKT is from the distribution sector, which often means that the products are in final packaging, where humidity spikes just aren’t as great a concern thanks to packaging.
 
Still, theoretically, you could do it…

Do you know of any regulatory guidance for significant digits?

There are no regulatory requirements that I know of that specifically govern reporting of MKT.  We could go into a deep discussion of rounding rules and significant digits, but the easiest thing is simply to present the same number of digits in your MKT result as you had in your raw data.  You can ignore the significant digits in the Activation energy and Universal Gas Constant because they cancel out. 

How often should we measure temperature to ensure adequate data for MKT?

As often as you can.  Truly, the more data you can feed into this calculation, the better. This is especially true if you are using an automated calculation tool.  Data taken every minute is not too often.  Just ensure data are gathered at regular intervals.  Data gathered at random times will distort the results and make them unreliable.

Is there guidance for manual calculations of MKT?

I would never do this manually, not for any GMP decision making.  There is too high a chance of an error happening in data entry, or in the calculation itself.  Additionally, you can only do manual calculations with a small data set.  If your data set is small enough to make manual calculations feasible, then you probably aren’t using enough data.  This will be quickly obvious to anyone who audits your records.  Your best investment at this point, is an automated system for data collection and MKT calculation.

Can you use Excel for calculating MKT? Can Excel sheets be validated?

I can’t recommend Excel for any GMP calculations. It certainly has its place in your toolkit, but I think its best use is ad hoc data analysis.  Actually, I do think Excel can be validated, but given that it the name Excel now conjures up questions for regulators, I think it's best to use a tool, like viewLinc software, that can calculate MKT directly from your monitoring data.  A big part of successful audits is perception. A validated, purpose-built software application will perceived as a safer choice than a validated Excel spreadsheet.

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