Temperature Mapping

Documentation and Training

Q&A - Controlled Temperature Chambers:
Qualification, mapping & monitoring

Nathan Roman
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Documentation and Training for
Healthcare and Life Sciences

Providing Guidance, Support, and Best Practices

For Compliant Mapping and Qualification
December 2022

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CTC Validation Webinar Q&A

Controlled temperature chambers: Qualification, mapping & monitoring

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Question: If modern measurement devices are stable then why is there a need to perform post-calibration?

Answer: (Paul Daniel) Modern measurement devices are stable, but they aren’t perfect. 20 years ago, I was mapping with
thermocouples. To get these properly positioned in the chamber, they would be pulled, bent, and wrapped into position. This physical
wear and tear would affect the thermocouple and cause it to drift. By comparison, a modern data logger using a RTD, or a thermistor
doesn’t need to go through all that abuse. They are generally protected by a plastic housing and simply get set in place, rather than
ties or bent. And of course, modern data loggers have more robust sensors that are much more stable, and quite often more accurate.
They are also a lot more expensive. Pre-cal was a way to prove to myself that my equipment was ready for the study, and post-cal
was a way to prove that the sensors didn’t get damaged in the study in a way that would cause them to drift too much.

Both steps were expected by QA as proof that my study data was valid. Now, I rely on the calibration certificate as proof of pre-cal
because I have faith in the device. But I know I am taking a chance. The data logger could be out of calibration, but I won't know until
I do the post-cal at the end of the study. I am willing to take this chance because I am familiar with the product, and because a pre-cal
is typically a multi-point calibration which takes time and effort. But after the study, I need to do the post-cal. This is an easier process,
usually only a single point verification, so it isn’t much effort. This provides a bookend to our data, to prove that the sensor was within
specs during the study. Without the post-cal, you have no way to prove that your data is good. You can skip the pre-cal, but you are
taking a chance that the devices might not pass post-cal. However, you can’t skip the post-cal. At least, I would never skip it.

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Question: What are the acceptable acceptance criteria for power outage test?

Answer: (Nathan Roman) From my perspective, temperature mapping is a way to validate and document that a temperature-controlled
space is suitable for its intended purpose, right? And so, it is my experience that power outage testing or power failure testing is
performed to determine the time it takes for the temperature to exceed temperature specifications in case the power is lost. If power
is lost, would you like to know how long the temperature in your CTC remains within limits? To provide this information, we must close
the doors and switch off the power and temperature map. The purpose of this test is to find out how long the materials are safe inside
the space once power fails. This study in the IOQ is typically for information only there is no real requirement to include it into your
Mapping Qualification. However, the test data can be used to evaluate the potential impact of temperature excursions occurring during
routine use. It can also help you to write an SOP (Standard Operating Protocol) for the actions to be taken in case of a power failure.

As for acceptable criteria, the equipment should power down successfully and when power is restored the equipment recovers from
the power loss and returns within process range (required operating parameters). In addition, verify that the operating set point and
alarm set points remain as programmed when power is restored to the system.

Answer: (Paul Daniel) This is why I don’t like power outage tests, and I don’t consider them to be validation. Acceptance criteria need
to come from somewhere. We can’t just make them up. And if you don’t have acceptance criteria, it isn’t validation. So where would
be get this acceptance criteria? The vendor of the CTC isn’t going to give it to us. Usually, these studies just say to perform the test
and see how long the temps stay in specification, and then this data is kept on file to evaluate future situations where the power is lost.
There may be situations where a validation department has put in a policy that they want to see temps stay good for 15 minutes with
the power off. This is really the only place I can think of where you will get an acceptance criterion for a power failure test. That’s
because these tests are about gathering information, not about meeting acceptance criteria. That’s why I don’t like calling them
validation.

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Question: What's your opinion on alarm delay settings for monitoring loggers?

Answer: (Paul Daniel) I love alarm delays on monitoring loggers. In Vaisala’s viewLinc system, we have two kinds of delays. The first
is an alarm delay where the alarm is not generated until the temperature has been out of specification for a set period, say 5 minutes.
We also have notification delay. In this case, the alarm would be generated and recorded by the system immediately, but it would not
notify anyone until the delay period had elapsed. Again, this could be five minutes. In the first case, with the alarm delay, an alarm
condition of under 5 minutes would not be registered by the system, even though the data was saved, and the out-of-specification
condition could be seen in the data. However, you wouldn’t see an alarm on the alarm report. In the second case, with the notification
delay, an alarm would be recorded in the system, but if the conditions returned to normal within 5 minutes, no one would be notified.
So, you would see the alarm on the alarm report. My opinion on this practice is positive.

I like alarm delays. But they should be used with caution, and only on a system that is well understood. I would not use alarm delays
immediately after implementing a new monitoring system. I would take time to see how the system responds to normal use and door
opening. Then I would use them as a tool to reduce nuisance alarms, as I became aware of them. If you start using delays before you
understand how the system works, especially with a new monitoring system, you may miss important alarm conditions. And of course,
adding any alarm delays is a serious matter that should be documented as change to the system. And as system data is reviewed, if
we see evidence that alarm delays have been hiding important out-of-specification events, we should be prepared to remove our
delays. And, have special care if you are using alarm delays and physical temperature buffers. They are not the same, but can have
similar effects, and using both strategies at the same time may hide alarm conditions from your notice.

Question: During warehouse mapping, in winter and summer, do we relocate the min max monitoring positions
each season? What if more than one logger records max or min readings? where do we place the monitoring logger
then?

Answer: (Paul Daniel) Hopefully, you are using more than one monitoring logger in a warehouse! You should have enough
monitoring loggers in use that you can place a data logger at every hot and cold spot found during winter and summer mapping.
You can also evaluate your mapping data to learn more about your hot and cold spots. Let’s say you have two hot spots in summer.
If they are both the same temperature at the same time (or close), and you know why they are hot, you can probably monitor just one
of the hot spots and be fine. But do not get distracted by the hot and cold spots. You have an entire warehouse to monitor. Make
sure you place your monitoring sensors evenly distributed through your warehouse, and then add a few extra for your hot and cold
spots.

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Question: What is a good risk-based model for calculation of temperature mapping frequency for warehouses
and/or chambers?

Answer: (Nathan Roman) Great Question! As for temperature mapping frequency periods - I've seen the same as Paul has presented.
However, there are no hard fast regulations applicable for this. New guidance suggests that controlled temperature chambers should
be periodically assessed to determine the need for revalidation or remapping. The control systems, equipment, monitoring, and
procedures for the units should be a part of the periodic review to ensure the unit still operates in a qualified manner. Also, the frequency
of the requalification or remapping is suggested now to be determined on the results of a risk assessment or when significant
modifications are made to the unit. As for the item to consider during risk assessment: what is your level of risk of failure to maintain
uniform temperature or the storage of high value/critical products or temp sensitive products may warrant more frequent requalification.
Industry practice varies but should always be performed in alignment with your risk assessment and rationale for your determined
frequency documented.

Answer: (Paul Daniel) I use a simple model of remapping every 1 to 5 years, with a default of 3 years. If the chamber or warehouse
holds critical products, or operates at extreme temperatures, I would remap every 1 year. An example of this would be a stability
chamber. If the chamber holds low value low risk products, say laboratory reagents, I would map every 5 years. That’s my simple
model. There is a different approach detailed in the latest revision of the ISPE GPG guide on CTC’s. Rather than assigning a
frequency, they recommend evaluation of each unit, based on its risk, it’s repair and maintenance history, its alarm and monitoring
history, to determine if remapping is necessary, and if so, when to do it.

Question: If a min or max position was identified during mapping, but is not safe for a long-term monitoring sensor,
is it OK to locate the monitoring sensor as close as possible while keeping logger safe?

Answer: (Paul Daniel) Yes. I think I have said this before, but I don’t believe that it is necessary to place a monitoring sensor at the
hot spots and cold spots found during monitoring. This is an idea that showed up during the explosion of GDP guidance in 2011 to
2015, and I think it is wrong. In mapping we have always looked for the hot and cold spots, but this is an artifact of doing statistics. It
is simply the easiest way to analyze the data. You find the hot spot and the cold spot, and if they are both within spec, then your
chamber passes the mapping. The hot spot and cold spot actually aren’t important. If you really read the guidance, you won’t find
many places that say - place a monitoring sensor at the hot spot. And if you look at what is done in practice, especially in smaller
chambers, there is always only one monitoring sensor.

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And since there is only one sensor, it can’t be at BOTH the hot and the cold spot. NO, there is just one sensor because that is all that
is needed, and it is placed on the side of the chamber, out of the way, usually near the door to detect a door open condition.

Let’s present an alternative case. Imagine you had a refrigerator that was supposed to keep temperatures between 2 and 8°C. You
identify a consistent cold spot in one corner at 1.6°C (rounds up to 2°C so it passes) and a consistent hot spot at 8.4°C in another
corner (rounds down to 8°C so it passes). What do you do? Do you place two monitoring sensors in the unit? No. You decide that
the CTC has too much variability to pass the validation. You get preventive maintenance performed, you have facilities tune the
controller, then you remap and see if you get better data. Now your cold spot is 2.4°C and your hot spot is 7.6°C. Awesome. Now
you have proven that the entire unit can achieve the necessary temperatures. If the unit is regularly maintained, and no-one changes
the setpoint, you can reasonably expect that the unit will operate correctly. So, then we add a single monitoring sensor, out of the way,
not to monitor the hot and cold spots, but to serve as a way to detect emergency conditions, such as the door being left open, or the
compressor failing. Monitoring is not about double checking your hot and cold spots. That’s what validation is for. Monitoring is for
surveillance and notification of alarm conditions.

Question: Do you have any suggestions if we want to perform qualification in ambient temperature, as we know
the ambient temperature is various in every region. Also, how to define the acceptance criteria?

Answer: (Paul Daniel) Yes. But never use the word “ambient” as a specification. Always define your specifications numerically, such
as 10 to 25°C. And your actual source of the specifications is the product you are storing. If the product says, “store at ambient
temperatures” then you need to get a hold of the manufacturer and get some actual numbers from them. Ambient is not a specification.

Answer:(Nathan Roman) Agree with Paul. The term ambient is not harmonized among the guidelines due to the significant variance
of climatic conditions. It basically means "room temperature" or normal storage conditions but again depends on where you are located.
To perform qualification of “ambient” CTC’s - be sure to specify the required operating range for the material being stored. That
operating range is your acceptance criteria. All sensors must remain within specified range during temperature mapping study.

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Question: Does the ambient temperature delivery need validation?

Answer: (Paul Daniel) Yes. Again - ambient is not a specification. Whatever product you are delivering, you need to check the label
or contact the manufacturer and determine what they mean when they say “ambient”. Typically, this will be something like 10°C to
25°C. But you must determine the acceptable temperatures, then prove that your delivery system can keep the product within those
temperatures.

Question: Why is an OQ required if the temperature is continuously monitored? I thought that if the output is
100% verified then validation wasn't required. The IQ would just need to be executed to ensure the equipment is
installed appropriately with calibration and preventative maintenance requirements established - is that correct?

Answer: (Paul Daniel) Quick answer to your question… Temperature monitoring doesn’t provide 100% verification. It provides
information from a single or a few spots that give us confidence that the system is operating correctly – no HVAC failures, no doors left
open, no power failures. It doesn’t prove to us that the system can maintain the required temperatures in all possible storage locations.
You need mapping to do that, as part of the OQ, to get that 100% verification of the capability of the warehouse, refrigerator, freezer,
or whatever unit, to prove that the system is capable of the required performance. Then you monitor to ensure that nothing happens
to destabilize that system or change its ability to perform as expected.

Answer: (Nathan Roman) I agree with Paul when he states that monitoring doesn’t provide 100% verification. When you perform
temperature mapping, one of the goals is to verify temperature uniformity. Temperature uniformity refers to the variation in temperature
between different points in the chamber. A temperature measurement at one point may give a slightly different reading to one at another
point. The data collected during mapping or even re-mapping can help to identify temperature fluctuations that could be caused by
events such as opening and closing doors, bad seals, airflow problems, or heat generated by equipment. Over time, these fluctuations
and temperature variations can affect the overall efficacy and quality of the product or material being stored.

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Question: Where does the requirement for requalification of a CTC come from? For example, is there a requirement
for an ultra-low freezer to be periodically re-validated/re-mapped if the freezer is continuously monitored? I mean
not in response to a change, just based on a time frame.

Answer: (Paul Daniel) Mechanical systems change over time; parts wear out, insulation degrades, refrigerants become less effective,
hoses leak, etc. There is an expectation, historically that mechanical systems, including refrigerators freezers, etc., will be revalidated
(in this case remapped) on a schedule. As an alternative, you may have a process in place to evaluate system performance changes
over time to determine if revalidation might add value. For CTCs, like refrigerators and freezer, or even temperature-controlled
warehouse, I typically recommend a revalidation, or at least a remapping, every 3 years, but you might want to do it more often for a
critical unit like a stability chamber. The latest recommendation from the ISPE in their recent revision of their CTC Mapping and
Monitoring Guide, does away with the simple but reliable 3-year rule. Instead, they recommend that you monitor the unit, and make
your remapping decisions based on any changes in performance, repair or maintenance history, or other factors. Whatever your
process and rationale, it should be documented.

Answer: (Nathan Roman) I agree with Paul, the requirement comes from the fact we are maintaining mechanical equipment. The
regulations require you to prove your equipment/systems are of appropriate design, capacity and fit for intended use. Your equipment
is required to be adequately maintained, calibrated, and tested. Not once and done but proving your equipment (through the
qualification process) will consistently produce a result meeting its pre-determined specifications and quality attributes.

Question: For mapping a large space, say a warehouse, for %RH would you use the same number of sensors as
you would for temperature?

Answer: (Paul Daniel) Mapping humidity is more or less like mapping for temperature. The easiest way is to simply use combination
Temp/RH data loggers, so every mapping location has a measurement for temp and RH. You may find it challenging to do post-cal or
pre-cal for RH, so the bests solution there is to buy your RH data loggers from a reputable manufacturer known to provide instruments
with high stability… Maybe Vaisala would be a good choice? Sometimes people want to save some money by using fewer RH data
loggers. This is a possibility if you understand RH and can do the math.

Absolute humidity will be more or less the same across an entire warehouse because it is a measurement of the concentration of
gaseous H2O. Gases quickly equilibrate across a closed space, so most of the warehouse will have the same absolute humidity.
Absolute humidity is not the same as relative humidity. But you can calculate relative humidity if you have the absolute humidity and

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the temperature. So basically, you can map a warehouse with 25 temperature data loggers and 5 relative humidity data loggers. Then
you can do the math to determine the relative humidity at the other locations. But you need to be comfortable with doing the
calculations, and comfortable with showing your calculations to any auditors.

Answer: (Nathan Roman) This question of how many humidity sensors vs. temperature sensors comes up from time to time. ISPE
Good Practice Guide: Cold Chain Management and the Good Practice Guide on Controlled Temperature Chambers, Commissioning
and Qualification, Mapping and Monitoring provides guidance on placing fewer RH sensors than Temperature sensors. Generally, the
humidity quickly equalizes across the entire space, and shows uniformity. For the humidity monitoring, the number of humidity loggers
to be placed is typically fewer than number of temperature loggers (as few as one for every six temperature sensors). These loggers
are placed in areas of highest risk (i.e., areas with poor circulation). You’ll need to place sensors in a uniform pattern in all three
dimensions of the space – top to bottom, left to right, and front to back. Add additional sensors where you suspect cool or warm areas
exist, as well as near the control sensors and monitoring sensors.

However, the guidance also states that if there are significant sources of moisture, then the humidity could vary significantly within the
conditioned space, and a greater number of humidity mapping sensors will be required – the number and location can be developed
using similar concepts to those used for the temperature mapping. If you’re concerned about relative humidity, a more defensible
mapping strategy is to track temperature and humidity at all locations with data loggers that record both measurements. It’s important
to use high-quality data loggers that are stable and regularly calibrated.

Question: Can you give recommendations on mapping a freeze dryer? Do we use the same approach that we use
for chambers?

Answer: (Paul Daniel) No. You should not use the same approach as you would for a chamber. A chamber, as far as we have been
discussing them, is being used for a static process of storage. All we are doing in the chamber is maintaining the payload at a stable
temperature for an undefined amount of time. Freeze drying is very different. Freeze drying is a process by which you are cooling a
product, under a vacuum, with the goal of removing moisture by freezing and sublimation. You have completely different acceptance
criteria for successful drying than for successful storage. I consider mapping a freeze dryer or lyophilizer to be much more like mapping
a sterilizer or autoclave. Freeze drying is a dynamic batch process with defined success criteria at the end. CTC storage is a static
process with no end. Some of the techniques might overlap - mapping, pre-cal, post-cal, etc - but the processes are completely
different.

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Answer: (Nathan Roman) I agree with Paul. A freeze dryer will not have the same qualification tests as a CTC. The freeze dryer
operation will go through different phases and temperature changes and pulling vacuum. Freeze dryers are validated or qualified to
ensure proper functionality according to ISO 13408-3. A few example tests in a freezer dryer validation would be mapping the freeze
dryer shelf temperature with no load and with a load, SIP (if applicable) and a vacuum test.

Question: Do you do find companies complete annual temp/rh mapping studies in chambers to verify the
performance following annual maintenance/calibration of the equipment. Are the these completed with standard
24-hour study with the in-situ load?

Answer: (Nathan Roman) Good question. PM and Calibration activities are typically on a 6- or 12-month interval, but Mapping is not
typically performed at the same frequency. However, I have seen yearly temperature mapping performed in a GLP laboratory, but it
was determined based on their level of risk, and they did couple the activity with the calibration interval. 24-hour mapping was
completed, and the chambers were mapped in situ. Unless of course the PM required a defrost, in which the unit would need to be
emptied. Typical industry re-mapping frequency is 3-5 years for CTC’s. However, there are no hard fast regulations applicable for this.
New guidance suggests that controlled temperature chambers should be periodically assessed to determine the need for revalidation
or remapping.

The control systems, equipment, calibration, monitoring, and procedures for the units should be a part of the periodic review to ensure
the unit still operates in a qualified manner. Also, the frequency of the requalification or remapping is suggested now to be determined
on the results of a risk assessment or when significant modifications are made to the unit. As for the item to consider during risk
assessment - ask what your level of risk of failure is to maintain uniform temperature or the storage of high value/critical products or
temperature sensitive products may warrant more frequent requalification. Industry practice varies but should always be performed in
alignment with your risk assessment and rationale for your determined frequency documented.

Question: Is temperature mapping always part of OQ for a storage warehouse for pharmaceutical products? For
example, for the storage of medications that require a "cool dry place". If yes, then how do you handle the fact that
mapping should be done in summer and in winter?

Answer: (Paul Daniel) Yes, temperature mapping should be part of the OQ of any storage location for pharmaceuticals. You will need
to find a numerical definition of “cool dry place”. If you wish, you can reference the USP, which defines “Cool” as between 8°C and
15°C. The USP defines dry as not exceeding 40%RH at 20C, or equivalent water vapor pressure at other temperatures. The need to

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store something at any defined temperature, “Cool and dry” or otherwise, doesn’t change the fact that you must map in winter and
summer in a warehouse. In the summer, you will be challenging your cooling system, and in the winter, you will be challenging your
heating system. The fact that two different systems are in use is WHY we need to map at both times of the year.

Question: I am a validation consultant and my last client asked me to use the ISO 14644-1 guide which states the
particle count sampling locations and use it as the sensor location for temperature and humidity mapping of a bulk
product storage area. Is that justified? Is it a new industry standard?

Answer: (Paul Daniel) As far as I know, there is no overlap or relationship between best practice particle monitoring locations and best
practice temperature mapping locations. There certainly is no rule that says you can’t place mapping sensors at these particle locations
as well as the locations you would normally map at. However, if the customer is asking you to map ONLY at the particle measuring
locations, and nowhere else, I would not do it. Regardless of the best locations for particle monitoring, you must place your
temperature/humidity mapping sensors in locations that represent the entire area that needs to be temperature and humidity controlled.

Answer: (Nathan Roman) There is no new industry standard that specifies this scenario. Please refer to the ISPE Good Practice
Guide: Cold Chain Management or the ISPE Good Practice Guide on Controlled Temperature Chambers, Commissioning and
Qualification, Mapping and Monitoring as it provides guidance on placing Temperature & RH sensors. You’ll need to place sensors in
a uniform pattern in all three dimensions of the space. You’ll need to also consider the potential storage locations, distance between
probes, vulnerable areas that may be in direct path of air or a heat source and add additional sensors where you suspect cool or warm
areas exist, as well as near the control sensors and monitoring sensors.

Question: I’m interested your thoughts on the application of measurement uncertainty for both mapping and
monitoring. Also interested on any methods for monitoring probe positioning.

Answer: (Paul Daniel) My advice is to ignore measurement uncertainty for mapping and monitoring. Uncertainty is a value that can
only be calculated under well-controlled situations, such as a calibration laboratory. You will not be able to accurately calculate
measurement uncertainty in a mapping or monitoring situation. For the sake of giving a complete answer, I will also make the guess
that you are using the term “uncertainty” to refer to what is often called the accuracy of the sensor. For instance, a Vaisala RFL100
data logger has a claimed accuracy of +/- 0.25°C. My advice here as well is to ignore this and take a simpler path. IF the sensor is
calibrated and has a calibration certificate, then accept it as calibrated, and treat the measurements from the sensor as true. If your

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mapping data is so borderline, that the uncertainty or accuracy of the sensor will make the difference between a passing or a failing
study, then it would be much better to fail the study and focus on improving the performance of the chamber.

The other part of your question was about placing monitoring probes. The prevailing advice is to place the sensor in a location that is
representative of the hot/cold spot. But in a small chamber, this will almost always be a spot on the side of the unit, on the same side
as the door handle, maybe 10 cm in from the edge. This keeps the sensor out of the area needed for storage and keeps it near the
number one threat to any chamber - someone leaving the door open. In a larger space like a warehouse, you will have multiple probes,
and if you like, you can place sensors at the actual hot and cold spot locations.

Question: I have a scientific 2-5°C storage chamber that has two cold spots by 3C. I have contacted the
manufacturer and attempted to adjust the settings. Are there techniques I can use during mapping to get this
chamber qualified?

Answer: (Paul Daniel) So, to make sure I understand the question, you have a chamber with two cold spots that are out of spec by
3°C. It sounds like you have already adjusted the setpoint based on the manufacturer’s input. SO, that is a good first step. I wonder,
did the manufacturer have anything else to say about the performance? If it is a new chamber, that might be enough to justify a
warranty replacement. But let’s assume you need to work with what you have. My next step would be to get facilities to help.

Have them perform preventive maintenance to clean the compressor and any filters. And have them tune the controller, this may
improve the response and help balance the temperatures in the unit. If that doesn’t work, you have three options. First option- buy a
better chamber. Second option - Buffer your mapping probes and use procedural controls to make sure no small items are stored in
this chamber. Third option - Install a fence to block these cold areas from use, so nothing can be stored in them. Repeat your
mapping with sensors arranged in the remaining usable space.

Answer: (Nathan Roman) I am sorry to hear your difficulties with this storage chamber. But I would like to first mention the definition
of the term qualification. I don’t want to get to far lost and not remember that Qualification is the act of testing and proving that a
specific piece of equipment is installed correctly, works correctly and consistently produces the expected result and fit for intended
use. We don’t want to get into the situation where we are doing whatever we can to get the chamber to pass testing when it may not
actually be fit for use. Paul mentions above all the steps one can try when temperature range inside the unit is off. Walk through
those steps, and after having tuned the controller be sure to have the unit recalibrated (maybe a three-point calibration vs. the typical

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one point). Perhaps running an engineering study for a shorter period of time to confirm the changes you’ve made have indeed
improved the control and temperature range inside the chamber.

Question: When qualifying a new CTC for use over a range of temp/hum. what would you suggest as a good
strategy? How many studies and how many set points should be performed?

Answer: (Paul Daniel) I would have your customer group define for you exactly what ranges at which they intend to use the CTC.
Then I would do a single study for each use case. If there are ten different temperature/humidity combinations, I would do ten different
studies. It might seem like a lot of work, but it will be simpler in the long run, and easier to explain to auditors.

Answer: (Nathan Roman) If you are planning to use an individual CTC with different set points, then yes, I would suggest performing
a single mapping study at each one on the setpoints, as Paul explained. One key point I would like to recommend is that you calibrate
your CTC to cover the entire range. A multi-point calibration that covers the planned or potential use intended.

Question: Temperature mapping always shows the air temperature. How is the effect of changing air temperature
to the stored product assessed and validated? E.g., storage at room temperature - duration of cooling down and
influence on stored product with low/cool temperature?

Answer: (Paul Daniel) If you are talking about cooling down a product, then this is not a STORAGE process. What you are talking
about is a COOLING process. This is much different. For a COOLING process, you need to measure air AND product temperature.
For COOLING you want to be able to prove that the product reaches X temperature in Y time with Z temperature, and to do this you
need to measure air and product temperatures. The latest rev of the ISPE CTC guidance is only about storage, not about dynamic
processes like cooling.

Question: What about "recommended requirement" to do mapping in summer (hot outside) and winter (cold
outside) in walk-in freezers with outside walls?

Answer: (Paul Daniel) For any CTC or storage area, including cold-rooms and warehouses, if the performance of the CTC is affected
by seasonal changes, then you should do seasonal mapping. For an outside cold-room, I would definitely do seasonal mapping.

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Question: Do you consider the self-heating effect when using thermistors?

Answer: (Paul Daniel) As the end customer, using a calibrated data logger that is equipped with a thermistor-based sensor, you should
not need to worry about any self-heating effects. Any self-heating effects are accounted for during the calibration of the sensor.

Question: When doing an open-door test, how should the opening be defined? I assume there might be some
difference in temp rising times between a fully open door and a door that is only slightly open, which I guess would
be a typical case when someone doesn't fully close the door in a hurry but leaves just a small opening.

Answer: (Paul Daniel) You get to define “opening” in your validation protocol. If the protocol does not specify the amount of opening,
ask your colleagues what amount of opening is typically used at that facility. Whatever you choose document it in your protocol, so
reviewers and approvers know how you defined “open”. I agree with you that the most typical case you be a door open a little bit, so
that it appears closed but is not. To be truly circumspect, you could do the test twice - once at 1” open, and the other at full open.

Answer: (Nathan Roman) From my experience the test script in the protocol should specify how far the door is opened, whether 1”
opened or fully open CTC door. This specification of test is fully defined by you as Paul mentions.

Question: Can you outline how to carry out pre and post calibration checks for data loggers with no external
sensors?

Answer: (Paul Daniel) Talk to the data logger manufacturer to find out where the sensor is located. On Vaisala data loggers with
internal sensors, the sensor is in a corner, with vents cut into the plastic housing to allow air flow and quicker response times for the
sensor. Once you know the location of the internal sensor, you can arrange your data loggers such that the internal sensor is as close
as possible to your temperature reference.

Question: A thermistor (NTC) is cheaper than the PTC like PT100 as its losing its accuracy with time (decaying)
even it has more accuracy is that right?

Answer: (Paul Daniel) Thermistors are available in both NTC (negative temperature coefficient) and PTC (positive temperature
coefficient) forms. RTD’s are always PTC. There can be many reasons for cost differences between sensors, but I have not heard
what the cost difference was based on…

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Question: Can we use several thermocouple data loggers up to 36 sensors to validate autoclaves? And does the
software cover F0 calculations?

Answer: (Paul Daniel) The webinar focused on mapping and monitoring of CTCs for storage. Mapping autoclaves and sterilizers is a
very different process. None of the monitoring software or mapping systems offered by Vaisala offer lethality (F0) calculations. You
would need to export your data to Excel or some other spreadsheet to perform the lethality calculations.

Question: Do the viewLinc software reports comply with DKD R 5-7?

Answer: (Paul Daniel) Please forgive me, I am not familiar with the specification DKD R 5-7. I found it on the internet, and it seems to
be concerned with the calibration of climatic chambers and meant to serve as an adjunct to ISO 17025. From a quick review, I can
say that our Vaisala mapping and monitoring software do not produce reports that address the variables described in the specification
(e.g., spatial inhomogeneity, temporal instability, radiation effect, loading effect, etc.).

Question: If we do not calibrate loggers pre and post what if data logger located in magnetic field near a transformer
failed during use, even in the end of the year if it shows drift in yearly cal what can we do regarding the completed
jobs?

Answer: (Paul Daniel) I don’t know off-hand what levels of magnetic fields our devices can withstand without having negative effects
on their memory, or on their stored calibration offsets. This would probably be a good use case for data loggers with remote probes
where the calibration settings were stored in the data logger body and not in the probe. However, the basic question remains the same
- should you do pre-cal and post-cal, or can you rely on modern data loggers to be accurate through an entire year, and risk failing
studies when you get as-found cal data that is out of spec. The easiest answer is that if you are worried about this situation, then by
all means do a pre-cal and a post-cal. Personally, for a Vaisala data logger, I would accept the factory calibration in place of a pre-cal,
then I would do a single-point (point-of-use) post cal sanity check to protect my study and give me a reference point to know if the data
logger was still good for use in future studies.

But that doesn’t answer your questions - you asked what we can do if we find out we have a data logger that has failed post-cal after
a mapping study is complete. For that I have two solutions. Solution 1 is to include in my protocol an allowance that a certain number
of data loggers can fail post-cal without endangering the study. Then if one fails, well, you are covered. The other solution is to do

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some diagnostics, you maybe can figure out why the data logger failed. If you can prove that the failure had a directional effect on
readings, for example, the data logger failed in a way that made it record temperatures as 1C higher than actual, then you can go back
to your data set and see if there was any effect on your data, such that readings were not out of spec once adjusted for the higher level
of error. You might find that your study is just fine. That said, you may not be able to conclusively determine why the data logger
failed, and to do so may require some forensic study by the data logger manufacturer that could take significant time. Better to do the
post-cal, no?

Question: Do the Vaisala loggers have zero and span for customer calibration or shall it returns to Vaisala for
yearly calibration?

Answer: (Paul Daniel) Customers can calibrate Vaisala data loggers themselves. It’s a little more complicated than zero and span.
You need the appropriate Vaisala calibration utility, and possibly a compatible reference probe (depending on the type of data logger).

Question: Is 1-point calibration acceptable for stability chamber continuous monitoring temperature and humidity
sensors?

Answer: (Paul Daniel) That is a question that only you and your organization can answer, and I would involve QA and metrology in
that discussion. Personally, I would not do a single point calibration for a high-value high-risk CTC like a stability chamber. I do
know some companies that are perfectly happy with single-point field calibrations for their monitoring probes, though of course no
adjustments are ever done in the field - if a probe fails the single point calibration it gets sent to the lab for a full calibration. I also
know other companies that would never consider accepting a single-point calibration for their monitoring probes. Again, this is a
question your company needs to answer, as a matter of risk tolerance vs cost. Personally, in cases like this, I imagine myself sitting
in front of an auditor and explaining my rationale. If I am uncomfortable with the idea, or I am unable to articulate in a convincing
manner why I think it is okay, then I simply don’t do it.

Question: How do you determine number of sensors and how long to map a CTC during a validation?

Answer: (Paul Daniel) Well, that is the number one question that gets asked. For number of sensors and positions, refer to the ISPE
Good Practice Guide on Controlled Temperature Chambers. It will tell you to use 9 sensors for CTCs less than two cubic meters, and
to use 15 sensors for CTCs between 2 and 20 cubic meters. For larger areas, you need to develop a scientific rationale for your sensor
placement. Again, refer to the ISPE guide. Duration of mapping is another animal. There are no recommendations from the guide.

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Personally, I aim for 72-hour mappings for smaller chambers and rooms, and I aim for 1 week for larger rooms and warehouses.
Longer mappings give you more data and more confidence that the CTC can maintain the required uniformity. That is usually enough
to satisfy an auditor.

Answer: (Nathan Roman) For the typical controlled temperature chamber we perform mapping studies on a daily basis, the sensors
would be placed in each of the eight corners, with one in the geometric center of the space. So, that a minimum of 9. And then you
don’t want to forget an additional sensor(s) should be placed adjacent to the display, control, and monitoring probe(s). This would be
a good configuration for most refrigerators, freezers, and incubators. This layout of course is dependent on the size of the unit you are
mapping (e.g., counter height units vs. upright or double door units). For larger units, you could place 5 sensors on the middle shelf or
even lay out an alternate pattern on the middle shelves. As for duration, it is my experience CTCs are temperature mapped at 24 hours
and walk-in cold rooms at 72 hours and warehouses are a minimum of 7 consecutive days.

Question: Regarding the monitoring probes - is having a buffering medium or being exposed to open air overall
better for monitoring? Would it be most efficient to have 2 monitoring probes, one in a buffering medium and one
in open air?

Answer: (Paul Daniel) Love this question. I never thought of doing this. I think you should do this and let us know what you find after
about a year or so. But to answer your question, I don’t think this would be an efficient approach at all. For one, you need two times
as many monitoring sensors. Then you need to realize that they are going to react differently, especially to put-of-spec alarm conditions.
So, you need to decide which one you are going to pay attention to and may even maintain two different set of alarm criteria. While I
love the idea, I don’t think it will make your life any easier. You likely need to pick which strategy makes the most sense for your
application, and deal with the challenges that come with either choice.

Question: Is a loaded mapping test with empty boxes an accurate method of mapping?

Answer: (Paul Daniel) I think this strategy provides the maximum challenge and is also a lot easier to do than filling the boxes with
placebo products. But our goal is not to provide the maximum challenge, it is to provide an appropriate or reasonable challenge. And
since there will likely never be a time that the chamber is filled with empty boxes, this may not be a representative test. I would go
ahead and do this, being careful not to overload the unit, and see what happens. If the study fails, be prepared to repeat it with boxes
that are full of product, as this is a much more likely real scenario, that will be easier to pass, though harder to perform.

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Answer: (Nathan Roman) Loaded chamber testing is conducted to provide verification that the system performs per its intended use
when operated under routine challenged conditions and that the unit meets the pre-approved criteria. For the loaded study I would use
material that best represents the contents of what is expected to be stored. If using empty boxes represents the material of contents
then document this into your protocol, if freezer cold packs best represents the stored material then load the unit with a specified
number of freezer cold packs.

Question: Regarding where to put your sensor for monitoring in a freezer for example, would you put it in the
warmest location, or would you stick to the middle/by wall location that you were mentioning?

Answer: (Paul Daniel) I would stick it on the middle of the wall by the door handle. That is because I believe that the temperature
mapping has proven that the entire unit is capable of meeting our temperature uniformity requirements, so there is no reason to
selectively monitor one spot vs another (such as the hot spot). I think the purpose of monitoring is to detect emergency conditions -
power failures, compressor failures, doors left open… However, not everybody agrees with me. Many think that monitoring is there
to perform long-term surveillance on the hot spot. There is actually a middle line here.

Some companies map but do not qualify their chambers, which is better termed “temperature profiling”. If I only did a temperature
profile, I would want a sensor at the hot spot. But if I did a full qualification including temperature mapping, I would put the sensor at
the side as mentioned. There are also logistical problems with placing sensors at hot spots. Presumably, every unit will have a different
hot spot, so every unit will need to have the sensor placed in a unique location, and procedures in place to make sure that no-one
moves it or damages it. In the US and Europe, in GMP pharma and biotech facilities, freezers tend (over 80% or higher) to always
have a single monitoring sensor in the same location, on the side as mentioned.

Question: What are the recommended intervals for remapping freezers/warehouses?

Answer: (Paul Daniel) Per the new revision of the ISPE CTC guide, this is something that you get to determine yourself, based on the
performance and history and criticality of the chamber. The guide now allows you to not remap in some situations. Personally, I have
always defaulted to a 3-year rule as a starting place. Remap every 3 years. If the chamber is used for expensive stuff or critical
processes, then consider remapping more often. One example here is a stability chamber. If the chamber is used for inexpensive low-
risk items, then I would remap every 5 years. An example here would be a refrigerator holding lab reagents. And for warehouse, if
you do need to remap, I would remap both summer and winter.

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Answer: (Nathan Roman) Typical industry re-mapping frequency is 3-5 years for CTC’s. However, there are no hard fast regulations
applicable for this. New guidance suggests that controlled temperature chambers should be periodically assessed to determine the
need for revalidation or remapping. The control systems, equipment, monitoring, and procedures for the units should be a part of the
periodic review to ensure the unit still operates in a qualified manner. Also, the frequency of the requalification or remapping is
suggested now to be determined on the results of a risk assessment or when significant modifications are made to the unit. As for the
item to consider during risk assessment: what is your level of risk of failure to maintain uniform temperature or the storage of high
value/critical products or temp sensitive products may warrant more frequent requalification. Industry practice varies but should always
be performed in alignment with your risk assessment and rationale for your determined frequency documented.

As for the warehouse mapping seasons - here in US it is typical for the 2 seasons (winter and summer). But besides basing it just on
season alone, you'll want to also consider or anticipate for a change in storage conditions of the warehouse, repairs to the HVAC, any
modification to the environment will require additional mapping. Your validation plan should provide enough flexibility to capture weather
extremes, including the changes/modifications just mentioned. For example, depending on the climate in your area, your plan might
call for mapping when summer temperatures exceed 30°C and winter temperatures fall below 0°C. Seasonal changes and extreme
weather may justify mapping the warehouse with greater frequency or rescheduling a test for a more “seasonable” temperature.

Question: What percentage of the shelf space should be occupied for full load scenario in an incubator or
refrigerator and what type of material should be used for loading?

Answer: (Paul Daniel) The best source for full load limits is the chamber manufacturer. We can infer some information from the ISPE
CTC guide. The sensors at the sides and corner are not placed in the absolute corner, but rather at the edge of what is called the
“working area”. In the French Norm that the ISPE placements are based on, this distance is defined as 10% of the unit’s dimensions.
So, a CTC of exactly 1 cubic meter of volume, and a perfect square 1 meter on a side, would only have a “working area” of 80cm x
80cm x 80cm. If you do the math, that is about 51% of the total volume if we allow space on the sides for air flow. You may be able
to get this information from the owner of the incubator/refrigerator - sometimes they will include load limits in their SOPs. And of course,
depending on the type of unit, air flow might not matter at all. For Instance, an ultralow freezer relies on conduction, not convection
(airflow) to keep a space cool, so you can usually pack these units full. The challenge with these units is not to pack them so full that
you can’t find what you are looking for. But for a rule of thumb, on a typical refrigerator or incubator, I would not go over 50% for a full
load.

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Question: What is the recommended max period for a temp excursion before investigation is required in an
incubator used for microbiological media?

Answer: (Paul Daniel) There is no single value for this. It is entirely dependent on what you are storing and at what temperatures.
You can talk to the manufacturer of the media, or you can talk to your customer about their own storage specifications. No doubt the
customer will already know what they consider to be an acceptable time (and temperature values) for a temperature excursion.

Question: How many sensors should we use for cold room & stability chamber? Please share with us the regulatory
guidelines for this.

Answer: (Paul Daniel) You won’t find a regulatory guideline for the number of sensors for either application. Regulators do not give
this information on purpose. You need to look at guidance from non-regulatory agencies, such as the USP, WHO, and the ISPE. The
latest rev of the ISPE CTC Guide will tell you to use 9 sensors to map any space that is less than 2 cubic meters in volume, and to use
15 for spaces up to 20 meters in volume. For larger spaces, like your cold room, you can look at the WHO guidelines for some
information. Personally, I think the WHO recommends too many sensors, but that is something you will need to decide for yourself,
based on your equipment, application, and risk tolerance.

Answer: (Nathan Roman) As Paul mentions above there is no official regulatory guideline that deciphers the question so many people
have related to ‘How Many Sensors’ However, guidance that is accepted by the regulatory bodies is available.

Here are a few that you can research.

1. World Health Organization (2015). Technical Supplement 8 to WHO Technical Report Series, No. 961, 2011. Temperature
Mapping of Storage Areas.
2. USP (2018). USP41-NF36 <1079>. Good Storage and Distribution Practices for Drug Products
3. ISPE (2021) Good Practice Guide: Controlled Temperature Chambers 2nd Edition

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Question: When advanced to re-certifications after determination of WCL in initial PQ, what should be taken into
account to determine if WCL has changed?

Answer: (Paul Daniel) I am going to assume WCL means Worst Case Load. I will assume this means the maximum load you would
put into a CTC. If you have WCL specs for your chambers, and your company decides that it wants to increase the WCL for a chamber,
then that sounds like a change that would trigger a change control. And as part of the evaluation of that change, you would need to
decide if remapping was necessary. It seems a little backwards to me if the requalification process is used to determine if the WCL
has changed, rather than a change to the WCL triggering a requalification.

Question: Can you share the name of the sensors and the software you're using?

Answer: (Paul Daniel) There are a lot of options out there. In the past, the good old days, we used several products from Kaye, such
as Digistrips or the Validator 2000. But all of our latest mapping efforts have been done using data loggers from Vaisala. The
associated software is either vLog or viewLinc.

Answer: (Nathan Roman) Vaisala Dataloggers VL-1416-44V. Each logger consists of four external channels for temperature mapping.
The associated software is either vLog or viewLinc.

Question: Is there a guideline which can tell me how long a mapping should be? It was a question raised by an
auditor questing why we were doing 24-hr mapping instead of 72hr mapping. Is there a guideline for duration of
mapping during qualification?

Answer: (Paul Daniel) Sorry, I haven’t found a good recommendation for this. There is nothing in the ISPE guide. I have seen some
guidance from the WHO that says 24 to 72 hours for chambers, and 7 to 10 days for warehouses. On this one, I prefer to give the
process some thought. We are mapping to prove that the chamber system has the capability to maintain temperature uniformity, at
whatever temperature is specified. Is 24 hours long enough to do that? What is happening in the chamber during a normal day?
Doors get opened and closed, sometimes for a long time, and sometimes for a short time. Product gets moved in, and product gets
moved out. Some days, such as a weekend, there may be no activity at all. In your mapping, you want to capture a representative
sample of the conditions experienced by the chamber.

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Personally, I don’t think 24 hours can do that. Therefore, I recommend 72 hours for a chamber, and at least 1 week for a warehouse,
so we can capture all the general activities that are happening in the space and prove that temperature uniformity is maintained during
these activities. Another approach is to do a 72-hour test mapping, and really look at the data. You will probably find that one of the
days will have a higher max temp or a lower min temp. And you probably won’t have a way to explain why. So better to do 72 hours
and have the margin of safety.

Answer: (Nathan Roman) There is no regulatory guideline or formal limit for how long your mapping study should be other than the
guidance mentioned previously, but typically for CTC’s not affected by seasonal temperatures the mapping study should be between
24 and 72 hours. It is my experience for freezers, refrigerators and incubators to run a 24 hour undisturbed temperature study. Meaning
no one goes in or out of the unit until temperature study has completed.

Question: Is there any requirement/limit for door open recovery test and power fail test?

Answer: (Paul Daniel) I don’t know of any requirements for these tests from regulatory agencies. The only time I have seen them
required is when an individual company has included them in tier validation SOPs as a requirement. That doesn’t mean you won’t
have an auditor ask why you didn’t do it. It also doesn’t mean that an auditor won’t ask why you did it.

Answer: (Nathan Roman) There is no regulatory requirement for these tests, however there is guidance from non-regulatory agencies,
such as the USP and WHO that speaks of performance testing such as scenarios including door open, door closed, and simulated
equipment failure. So, to answer your question, there is no requirement or limit for the open door or power fail testing. Should you
decide that these are tests you want to perform, I can help you develop test scripts for such testing.

Question: Didn't USP guidelines require mapping prior to 2010?

Answer: (Paul Daniel) The USP did mention mapping prior to 2010. But that was in chapter <1079>, and all the USP chapters with
numbers over 1000 are considered to be guidance only, and not enforceable by the FDA. So, by my interpretation, the USP did not
REQUIRE it. They just recommended it. I may have misstated my purpose in the webinar so I will restate it here. 2011 was the first
year that a national regulatory agency (in this case it was Health Canada) put in an actual regulation (not a guidance) that temperature
mapping was expected.

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Question: Do you need a calibration certificate for each of your temperature monitoring sensors or is it acceptable
to use a resistance key for verification?

Answer: (Paul Daniel) I will admit that you are stretching my personal knowledge here of potential calibration techniques for monitoring
sensors. All the monitoring sensors I am familiar with and have seen in use are closed devices and complete instruments that require
an individual calibration, and therefore an individual calibration certificate for each sensor/data logger. I am going to hazard a guess
that you are discussing a calibration technique for a large multi-input data logger, say with multiple thermocouples, and you wish to
calibrate just the data logger itself with the resistance key, rather than calibrate the sensors as a loop while they are attached to the
data logger. I don’t feel like I know enough about a process like that to give an opinion. I would consult with a metrologist who is
familiar with the equipment you are using.

Question: What are the requirements and frequency for the re-qualification of CTCs?

Answer: (Nathan Roman) Per the new revision of the ISPE CTC guide, this is something that you get to determine yourself, based on
the performance and history and criticality of the chamber. The guide now allows you to not remap in some situations. Personally, I
have always defaulted to a 3-year rule as a starting place. Remap every 3 years. If the chamber is used for expensive stuff or critical
processes, then consider remapping more often. One example here is a stability chamber. If the chamber is used for inexpensive low-
risk items, then I would remap every 5 years. An example here would be a refrigerator holding lab reagents. And for warehouse, if
you do need to remap, I would remap both summer and winter.

Question: Would you consider the VL-1000-21N as semi buffered during temperature mapping as the thermistor is
hidden inside the logger and not fully exposed to the air?

Answer: (Paul Daniel) While I appreciate the distinction you are trying to make, but I would not consider this to be buffered. The VL-
1000-21N has an internal sensor, but it is not hidden deep inside. The sensor element is right at the edge of the PCB next to generous
vents cut in the side of the plastic housing, allowing it to measure air temperature. Granted, this will have a slower response time than
a fully exposed sensor, but it is not much difference, maybe 15 seconds. Most sensors are protected in some way so they can have a
long life safe from abuse. Your average RTD appears to be a metal cylinder, but that is just a housing covering the sensing element.
So, if we applied the same rationale, we would have to call a normal RTD semi-buffered. When dealing with protected sensors, it is
probably better just to think of reaction times. And recognize that there is a clear distinction between a protected sensor with a short
reaction time, and a buffered sensor located in media that has a large thermal mass relative to the sensor itself.

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Question: Is it acceptable to use empty boxes during a loaded chamber mapping to challenge air-flow, or is it better
to use containers filled with simulated product (placebo)?

Answer: (Repeat from earlier questions) I think this strategy provides the maximum challenge and is also a lot easier to do than filling
the boxes with placebo products. But our goal is not to provide the maximum challenge, it is to provide an appropriate or reasonable
challenge. And since there will likely never be a time that the chamber is filled with empty boxes, this may not be a representative test.
I would go ahead and do this, being careful not to overload the unit, and see what happens. If the study fails, be prepared to repeat it
with boxes that are full of product, as this is a much more likely real scenario, that will be easier to pass, though harder to perform.

Question: I am from the Slovak academy of science. I have a question regarding instrument of Vaisala GMP252, is
there any manual or protocol of how to use it in a close chamber? Thank you!

Answer: (Paul Daniel) We will have to refer you to a product specialist to better answer your question – Please send this question
here: https://www.vaisala.com/en/lp/contact-form

Question: When temperature mapping our cold storage units (-20 Freezers and 4°C refrigerators), what level of
precision should we expect, at any given time point, during temperature mapping? ISPE Good Practice Guide:
Controlled Temperature Chambers page 15, describes peak variation as -7°C to +4°C, is this standard? Fridges, as
well?
Answer: (Paul Daniel) Precision isn’t really the right word here. Uniformity is probably a better choice. You should have no
expectations of temperature uniformity for any CTC, other than perhaps what might be provided by the manufacturer. Generally, higher
quality units, such as industrial-grade or commercial-grade chambers will have greater uniformity. The reason we map is to verify
uniformity of the CTC is within our specifications. I would use the ISPE guide Page 15 info for freezers simply as an example of the
ranges you might experience. For example, a freezer set at -20°C might show temperature variation inside during mapping from -27°C
to -16°C.
But this is not a standard, just an example. Your company should have published somewhere in your policies and procedures what
temperature range is acceptable for a -20C freezer; probably -20°C +/- 10°C or something like that, and it should be based on what
they intend to store in the chamber. That is your uniformity target. Nothing else matters, especially not that bit of info on Page 15.

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And of course, there is no standard uniformity for fridges. These will all vary by chamber quality and by mapping method (type of
sensors, where they are placed, buffered or not).

Question: For units with auto-defrost function pose a considerable hurdle during temperature mapping as the
defrost cycle will often exceed the acceptable temperature range unless placed in a buffer. How can you mitigate
high defrost temperatures or ensure your temperature map is not rejected?
Answer: (Paul Daniel) Defrost cycles have long been a problem for mapping. Instead of mapping your defrost cycle and trying to
make it acceptable and squeak within the specs, I would turn this one around. Tell your quality department that defrost cycles are a
fact of life, especially if your company buys units with auto-defrost. Ask them to edit their specs to define allowable excursions for
defrost cycles. Then you will have a specification you can work with. One way to force the issue is to hand them your failed study data
with the defrost cycle well defined (i.e., Temps go 5C over spec for 30 minutes during defrost at locations 1 through 4). This will give
them some of the information they need to determine an acceptable defrost cycle excursion. It might also make them push back and
require the company to acquire units without auto-defrost, but those create their own complications.
The other option, of course, is what you have alluded to with temperature buffering, which takes us through some old and reliable tools.
You can buffer the temp sensors to minimize the effect of the defrost cycle on your sensors. Be sure to that your buffers are smaller
than the product stored in the freezer, and you institute procedural controls (like signage) to make sure smaller items aren’t stored in
the fridge. Or you can declare certain areas of limits for storage because of the defrost cycle, again with procedural controls like
signage, SOP changes, and physical barriers.

Question: Is it necessary to perform two separate load mapping scenarios where airflow is impeded during one
and thermal mass during another? We generally perform both simultaneously but allow the material to reach
temperature before starting the mapping.
Answer: (Paul Daniel) I like where you are going with this, and the fact that you have recognized the difference between each type of
challenge. However, I think of these as opposite sorts of challenges. A chamber loaded with equilibrated thermal mass is not a
challenge (if airflow is not blocked). This is only going to help the chamber appear to perform better and improve its equilibrium and
increase its uniformity. So, I don’t really think of added thermal mass as a challenge. I need to put this in context however, because I
am only speaking of thermal mass that has reached equilibrium temperature.
If you are putting in a thermal mass that is not already equilibrated at the target temperature, you are no longer mapping a storage
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process and requires different techniques than simple temperature mapping. Now on the other scenario with the impeding of airflow,
now I think that is a true challenge, and an even better challenge if there is minimal thermal mass involved, such as empty boxes. Here
there is no thermal mass to make it easier, and blockages to airflow to make it harder to achieve uniformity.
The key here is not to overload the chamber accidentally. The chamber manufacturer should have specs about what is an appropriate
maximum load. And this is also implied by the ISPE CTC guide as well, as the sensors along the walls and corners are expected to
be 10% of the width of the unit away from the walls. So in a chamber that was a perfect 1m cube, we would have 10cm of space all
around the sensors and the load, making the available storage space actually 80cm x 80c, x 80cm (which is about 51% of the possible
1 cubic meter)
But to answer your question, I would only do the loadout that impedes airflow (because it is a challenge) and drop the loadout that
focuses on thermal mass (because it is not a challenge). However, since you will never see a chamber filled with empty boxes, it
probably doesn’t matter if you combine them. It just means that your “challenge scenario” isn’t as challenging as it could be, but
probably is a good representation of the worst-case scenario the chamber will see in actual use.

Question: I am doing a warehouse validation using 26 valprobes one passed pre calibration but failed to read data
I was told that you are allowed 5 -10% of your thermocouples to fail. Is that accurate?
Answer: (Paul Daniel) Sorry to hear about your failed probe. You need to refer to your mapping protocol and see what failure rate of
sensors was allowed. Typically, I write an allowance of 10% into my protocols to deal with cases like this. But if you your protocol
doesn’t include an acceptable failure, you will likely have to treat this as a deviation and see what explanation you can get QA to accept.
Good luck!

Answer: (Nathan Roman) The typical acceptance criteria for all the validation protocols I’ve written and executed, when related to
sensor post-calibration or post verification in the life sciences industry, had a 90% confidence level most often used. If this was not pre-
populated or specified in your protocol, then you will need to treat it as a deviation.

Question: How do you evaluate the location of your temperature monitoring probe of a BAS based on mapping
data? It is something we need to justify in our validation report as described in Canadian GMP guides?
Answer: (Paul Daniel) Personally, I don’t think that the purpose of mapping is to determine where to put your monitoring probes. This
idea didn’t show up until GDP guidance and regulations became commonplace, so I consider this a new idea. In my opinion, the
purpose of mapping is to prove that a chamber or a room is capable of meetings its performance specifications, whatever temperature

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range that happens to be. If the mapping meets the acceptance criteria, then the unit is qualified, and every spot mapped is qualified.
By saying that we need to monitor the hot/cold spots found during the mapping we are saying that we don’t have confidence in our
mapping qualification and that we are worried something will happen at that hot or cold spot. I reject this idea.
Granted, I have the luxury to reject this idea because I am not staring at an auditor who doesn’t agree. But I have to point out that the
guidance doesn’t say “Place your monitoring probe(s) at the hot/cold spots.” Guidance tends to say something similar to: “Select
representative locations for your monitoring probe(s) based on the mapping data”, or “Take your hot/cold spot(s) into consideration
when placing your monitoring probes.” With vague guidance like that, if all points in your mapping study met the acceptance criteria,
it follows that you could look at your data set, find that the hot/cold spots are within the acceptance criteria and state that therefore, the
hot/cold spots don’t require dedicated probes because they were within the acceptance criteria.
I would much rather select my monitoring probe locations by placing them in locations that were most likely to have a temperature
excursion due to a likely failure in the system, such as a door left open. With that sort of risk model in behind your placement choices,
the only reasons to place a sensor at the hot spot are
1) You think it will be hotter in the future due to an unseasonably warm day,
2) You think someone might increase the set point, or
3) You don’t want any chance of criticism under audit.
If #1 or #2 are your reasons, then you likely need to improve the control of your system. If #3 is your reason, well, you are just risk-
averse, and that is okay. And you can always use more than one sensor, especially in large areas like a warehouse, where it might
just be simplest to put a probe or two in the hot/cold spot and not worry about having this conversation with an auditor. But wherever
you do put your monitoring probes, regardless of your reason, it should be supported by a documented rationale (which may just be
another way of saying “justified”). But I admit, I’ve never agreed with this idea anyway.
Answer: (Nathan Roman) As described in Canadian GMP guide GUI-0069 “Monitor the area to demonstrate storage conditions
indicated on the label are being met and keep a record of your findings. Use calibrated monitoring devices to control and monitor
temperatures. Keep temperature monitoring records and notes of any alarms. Monitor the locations in your storage location where
temperatures are most likely to deviate from the required temperature range (i.e., worst-case locations). Identify those areas through
temperature mapping (as Paul mentions above) and ensure you are monitoring at the most appropriate locations.
The guidance does lead one to believe you need a monitoring sensor in the hot or cold spot but in all things monitoring, I will certainly
defer to Paul, as I know it’s his favorite topic. To be honest in all my years of mapping chambers and performing equipment qualifications

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I’ve only really encountered less than a handful of clients placing their monitoring probes at the hot and cold spots inside their storage
space of a controlled temperature chamber.
I believe what we said during the webinar about large spaces such as a warehouse you may have multiple sensors, monitoring sensors,
so you can consider placing monitoring sensors at the hot and cold spots for monitoring but for smaller control temperature chambers
like refrigerators and freezers I only ever see one monitoring sensor and it’s generally always in the same place.
From time to time that sensor may be adjusted or relocated, but I go so far as to say that is because it’s been placed in the same
location as the unit control probe and that control probe has been moved to maintain temperature setpoint within the unit.
I agree with Paul where he mentions the purpose of temperature mapping is to prove that a chamber or room can meet its performance
specifications. Regulatory guidance tells us that adequate control should be established, and it should be demonstrated that the
temperature is maintained in all parts of the relevant storage area and must be within the specified temperature range. And that is
performed through temperature mapping. In a validation protocol the acceptable criteria states that all sensor locations in your storage
space will need to be within your specified temperature range, this would include the minimum (cold) and maximum (hot) temperature
locations.
I recommend that where historical data is available you evaluate your chambers to ensure that all the temperature data is consistent
and in a state of control, while meeting specifications. Using that data to establish alarm limits that are inside process limits. This gives
a buffer between the alarm and the lower or upper acceptable limit. For example, establish alarm points at 2.5° and 7.5°C for a 2° to
8°C refrigerator. In addition, if your storage spaces are found to be off-center or the actual temperature range is slightly higher or lower
than the unit should be examined to determine if there’s an opportunity to change the setpoint or whether the system calibration or
maintenance is needed.

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Get in touch:
Nathan Roman, Validation DirectorGenesis AEC
Contact Genesis for more information

Paul Daniel, Sr. GxP Regulatory ExpertVaisala

Contact Vaisala for more information

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