Cold Chain
The Use of Mean Kinetic Temperature
(MKT) in the Handling, Storage,
and Distribution of Temperature
Sensitive Pharmaceuticals
Robert H. Seevers, Ph.D., Jeffrey Hofer,
& Paul Harber
Eli Lilly and Company
David A. Ulrich
Abbott Laboratories
Rafik Bishara, Ph.D.
Chair PDA Pharmaceutical
Cold Chain Interest Group
Introduction
S
tability data from both accelerated and long-term studies are used to
establish recommended storage conditions and expiration dating for
drug products [1]. As long as the product remains in its approved
container within the specified temperature range, the quality of the
product is assured until the date of expiration. However, it is likely that
a product will be exposed to temperatures outside of its specified storage
range as it passes through the distribution chain from the manufacturer to
the final customer.
For this reason, it is important to have a means to analyze the
temperature exposures which may occur and to understand their potential
impact on the quality of the drug product. Mean Kinetic Temperature
(MKT) has been proposed as a means of evaluating thermal excursions that
occur during storage and shipment [2]. For example, the United States
Pharmacopeia (USP) has defined Controlled Room Temperature (CRT) as:
A temperature maintained thermostatically that encompasses the
usual and customary working environment of 20° to 25°C (68° to
77° F); that results in a mean kinetic temperature calculated to be not
more than 25°C ; and that allows for excursions between 15° and
30°C (59° and 86°F) that are experienced in pharmacies, hospitals,
and warehouses. Provided the mean kinetic temperature remains
in the allowed range, transient spikes up to 40 are permitted as
long as they do not exceed 24 hours. Spikes above 40°C may be
permitted if the manufacturer so instructs. Articles may be labeled
for storage at “controlled room temperature” or at “up to 25°C ”, or
other wording based on the same mean kinetic temperature. The
mean kinetic temperature is a calculated value that may be used as
an isothermal storage temperature that simulates the non-isothermal
effects of storage temperature variations. [3]
and Controlled Cold Temperature (CCT) as:
This temperature is defined as the temperature maintained
thermostatically between 2° and 8°C (36° and 46°F), that allows for
excursions in temperature between 0° and 15°C (32° and 59°F) that may
be experienced during storage, shipping, and distribution such that the
allowable calculated MKT is not more than 8°C (46°F). Transient spikes
up to 25°C (77° F) may be permitted if the manufacturer so instructs and
provided that such spikes do not exceed 24 hours unless supported by
stability data or the manufacturer instructs otherwise [3].
These definitions each use the principles underlying MKT to provide
a single temperature reflective of the exposure of a product to heat
over the course of time. Thus, understanding MKT and its use is key to
understanding the risks to quality experienced by a drug product exposed
to temperatures outside its recommended storage conditions as it passes
through the distribution system.
This paper will examine the use of MKT as a tool to evaluate typical
thermal excursions that occur during storage and shipment and attempt to
clarify the proper role for MKT in the distribution process.
Definition of MKT
Mean Kinetic Temperature (MKT) is defined in the International
Conference on Harmonization (ICH) Q1A document as [1]:
“A single derived temperature that, if maintained over a defined
period of time, affords the same thermal challenge to a drug substance or
drug product as would be experienced over a range of both higher and
lower temperatures for an equivalent defined period. The mean kinetic
temperature is higher than the arithmetic mean temperature and takes into
account the Arrhenius equation.
When establishing the mean kinetic temperature for a defined
period, the formula of J. D. Haynes (J. Pharm. Sci., 60:927-929, 1971)
can be used.”
The use of MKT to represent the expected impact of temperature variations
on the quality of a drug product was described by Wolfgang Grimm [2].
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The MKT may be calculated as follows [4]:
where:
∆H = the heat of activation for the degradation reaction; assumed to
be 83.144 kJ per mol (see discussion below) unless more accurate
information is available from experimental studies.
R = 8.3144 × 10-3 kJ per degree per mol (the universal gas constant)
T1 = the average temperature, in degrees Kelvin, during the first
time period
T2 = the average temperature, in degrees Kelvin, during the second
time period
Tn = the average temperature, in degrees Kelvin during the
nth time period
n = the total number of temperatures recorded. Note that the interval
between temperature measurements is assumed to be identical.
Of particular note is the fact that Grimm [2] selected the rate constant
in the equation example for two reasons. First, the value of 83.144 kJ per
mol lies within the range of rate constants conceivable for the reactions
that lead to loss of drug quality [5]. Secondly, the value simplifies the MKT
equation because the rate constant of 83.133 kJ per mol divided by the gas
constant becomes simply 10,000.
The assumptions relied on to permit MKT to substitute for and
simplify the temperature history of a product are:
1.
2.
The activation energy for the degradation reaction is
approximated by 83.144 kJ per mol
The temperature/rate equation (Arrhenius) is linear through the
temperature range of interest. The range of interest can be stated
as “typical” supply chain temperatures, which are 0-40C. If the
compound/product of interest does not follow the Arrhenius
equation through this whole range, putting upper and lower
temperature control limits would still allow the use of MKT.
The first assumption is justified by noting that this is an average
value of activation energy for breaking most covalent bonds. The use
of activation energies either somewhat higher or lower will not result in
significant changes to the calculated value of MKT. However, it is not
always covalent bond breaking that leads to degradation; changes to
the tertiary or quaternary structure of proteins, for example may result
from hydrogen bond breaking [6,7]. The effect of much lower activation
energies, such as might be seen for hydrogen bond breaking, on the
resulting MKT is addressed below. Regarding proteins/biologics, stability
profiles must be understood since there can be heat-activated or metalactivated enzymes that can dramatically change the degradation rate at
specific temperatures.
The second assumption of a linear model for the reaction rate versus
temperature, in the absence of product-specific kinetic data, may be
justified as follows. The temperature range of concern in the distribution
system is generally from 0°C to 40°C. For temperatures below 0°C, the
risk for solution proteins is agglomeration, and thus prolonged exposure to
these temperatures should be avoided during shipping or storage of such
products, unless data supports otherwise. Since most proteins are active
at a body temperature of 37°C, having the upper control at 30°C (or if data
supports higher) is acceptable. For freeze-dried products, exposures to
temperatures as low as -20°C have been shown not to have a deleterious
effect on the product in the development of the lyophilization cycle, so
extended exposures to temperatures below 0°C would not be expected
to have a quality impact. For solid oral drug products, in the absence of
appropriate specific data, exposure to temperatures below 0°C is to be
avoided. For sterile products, it is possible that exposure to temperatures
below 0°C may impact contain/closure integrity, so testing, such as dye
ingress, at these temperatures is recommended.
However, the issue with low temperatures is not degradation, but
potential physical damage. If moisture (Loss on Drying) or Solvent
(Residue on Ignition) are low, potential physical degradation is probably
not an issue. Similarly, exposures to temperatures above 40°C, unless
supported by specific stability data, are to be avoided. There are certainly
drug products that are not stable even at 30°C, but this will be known
from standard stability studies performed during development, filed in the
marketing authorization (e.g., NDA/BLA) [1].
The assumption of linearity may be viewed another way. Most
degradation reactions are either zero or first order, that is either independent
of the concentration of reactant or dependent on the concentration of only
one reactant (e.g., water) [5]. Thus, the logarithmic plot of the reaction
rate versus 1/T, the Arrhenius plot, will be linear until most of the reactants
have been used up, a condition which seldom applies to drug products
in the distribution environment based off of typical distribution/supply
chain temperatures.
Thus, for most drugs, in the temperature range of interest (0° to
40°C), the assumption that underlies the use of MKT in this range is that
the relationship between reaction rate and temperature is either linear or
pseudolinear. The shorter the timeframe under consideration the greater
the likelihood that the relationship is linear or nearly so in this range.
Methods
In order to explore the use of MKT in evaluating temperature exposures
outside storage conditions during the distribution process, it was decided
to create two model pharmaceuticals, one intended for storage under
refrigerated conditions and the other for Controlled Room Temperature
(CRT). For each pharmaceutical a model temperature exposure history
was developed which tracked the temperature experienced by the drug
product every 20 minutes as it passed through the distribution process
over the course of approximately one year.
The shelf life of most drugs is in the range of 24-36 months, however
distribution to prescription/dispensing is usually within 12 months. Of
that time, a typical drug is likely to spend a month, at most, in various
states of transport [8]. The remainder of the shelf life is spent in storage,
first at the manufacturer, then at storage facilities in the distribution system,
followed by time in storage at locations which may include pharmacies,
doctor’s offices, hospitals, or the patient’s home. This is illustrated in
Figures 1 and 2 which shows the temperature life history of the model
drug products in 20-minute increments over the course of a year from the
time of manufacture to the time the patient takes the drug. The size of
the time increment can be an important consideration in evaluating the
temperature history of a drug as it goes through the distribution process.
In general, the increment selected should take into consideration both
the duration of the segment of the distribution path being tracked (i.e.,
a shipping segment will take hours to days, while a storage segment
is likely to be weeks or months) and the probability of a temperature
excursion being experienced (more likely during shipping than storage
in general). For the model presented here, 20-minute increments were
selected so as to use the same increments for both shipping and storage
portions of the temperature history. In practice, longer increments may
be more appropriate for monitoring storage temperatures, given both the
greater duration expected for storage and the decreased likelihood of
temperature excursion. Tables 1 and 2 show the details of the temperature
life history of our model drugs. Random numbers were used to generate
the temperatures in each segment using the MKT and a standard deviation
of 0.1 degrees.
It can be seen from Figures 1 and 2 that a typical drug spends most of its
lifetime in some type of temperature-controlled storage, whether at the original
manufacturer, wholesaler, or pharmacy. This is true for both refrigerated and
CRT drugs. Due to the relatively effective temperature control typical for such
locations, excursions in this environment are also likely to be of fairly short
duration, i.e., hours to days. Once again, in this time frame the reaction
kinetics of product degradation are likely to be linear or nearly so.
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Table 1. Model Refrigerated Drug Lifetime
Table 2. Model CRT Drug Lifetime
Excursions
Nevertheless, excursions do occur and so the models were modified
to include excursions such as might be expected. Temperature excursions
were inserted into each model to determine their impact on the MKT. The
first excursion was inserted during the time that the drug product is stored
in its commercial container at the manufacturer and the second was placed
during transit from wholesaler to pharmacy. The two excursions added to
each model were the same: each ramped up for 6 hours, reached a high of
20ºC above baseline, stayed at the peak for 36 hours, and ramped down
for 6 hours, for a total excursion time of 48 hours. For the refrigerated
product, the peak temperature was 25ºC and for the CRT product 45ºC.
The models with excursions are shown in Figures 3 and 4.
Figure 3. Refrigerated Product Temperature History with Excursions
Figure 1. Refrigerated Drug Product Temperature History
Figure 4. Controlled Room Temperature Product
Temperature History with Excursions
Figure 2. Controlled Room Temperature Product Temperature History
Results
With the models in place we can test the assumption that the choice
of the activation energy has little impact on the resulting calculated MKT
value. Table 3 shows the result in terms of the calculated MKT for the
entire temperature history shown in Figure 2 for different values of the
activation energy.
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As can been seen in Table 3, the calculated value of MKT is not very
sensitive to the choice of activation energy. Changing from 83.144 kJ/
mol to 4 kJ/mol, from a value that approximates breaking weaker covalent
bonds to one that represents hydrogen bond breaking only decreases
the resulting value by 0.2ºC for both the refrigerated and CRT products.
Similarly, using a value of 125 kJ/mol, an activation energy more in line
with covalent bond breaking, leaves the values unchanged from those
calculated using 83.144 kJ/mol. Finally, using a value of 250 kJ/mol, raises
the MKT by 0.3 ºC for the refrigerated product and 0.2 ºC for the CRT
product. Clearly, knowledge of the actual value of the activation energy of
degradation reactions will permit a more accurate determination of MKT,
but this is challenging in practice. It may not be possible to determine
a single activation energy when more than one degradation reaction is
occurring simultaneously. Furthermore, the kinetic experiments required
to do so are not always performed during the development of a drug
product; however, standard “accelerated stability” studies are performed
(as part of ICH 1A). The value of 83.144 kJ/mol is a reasonable one to use
in the absence of more specific kinetic information.
Table 3. MKT Values for Model Temperature History for
Different Activation Energies
The impact of excursions on the calculated MKT values was
determined and the results are shown in Table 4. MKT was calculated
for Scenario 1 (without excursions) and Scenario 2 (with excursions) for
the storage segment at the Manufacturer, for transit to the Pharmacy, and
for the full year of the product’s life. The results shed light on the impact
of excursions on MKT and, thus, on the value of MKT in evaluating the
impact of such excursions.
Table 4. Calculated MKT Values for the Segments of the
Model Drug Lifetime
It can be seen that the impact of adding two excursions, each with a
temperature rise of 20ºC, each lasting 48 hours, on the calculated mean
kinetic temperature for the entire lifetime of both the refrigerated and CRT
drug, is to raise the MKT 1.6ºC and 0.6ºC, respectively. In neither case
would the resulting small increase in MKT be likely to cause any concern
in regard to quality.
The impact of the excursions on their individual segments was also
examined and is shown in Table 4. Although the excursions are identical,
the change in MKT that results is not. The addition of the excursion raised
the MKT of the Manufacturer Storage segment by 1.9ºC for the refrigerated
drug and 1.6ºC for the CRT drug. The impact of the excursion on the
Transit to Pharmacy segment was more significant: a rise of 9.8ºC for
the refrigerated product and 19.2ºC for the CRT one. The resulting MKT
values are 14.8ºC and 34.2ºC, respectively, making it likely that concern
would be raised about the impact of the excursion on product quality.
But no such alarm would be raised about the identical excursion in the
manufacturer storage segment, if MKT is the only result relied upon. The
difference is clearly due to the difference in the length of the segments.
The transit segment is only 7 days while the storage segment is 2 months.
It is also possible to calculate the MKT for the time period of the
excursion alone. For the refrigerated drug product the two excursions each
have a calculated MKT value of 23.5ºC. For the CRT drug product, both
excursions have calculated a MKT value of 43.5ºC. Clearly, these are values
that would result in an investigation and careful determination of the likely
impact of the excursion on product quality, if these values were considered,
rather than ones dominated by the long baseline of a storage segment.
Conclusions
It is clear from the models presented above that the calculated mean
kinetic temperature is not sensitive to the impact of excursions that may
occur if the baseline is a long period of time such as a storage segment
or the entire lifetime of the drug product. For shorter baseline periods
of time, such as transport segments, an excursion can have a significant
impact on the resulting MKT for that segment; however, this would not
necessarily have a significant impact on product quality.
For most refrigerated drugs, spending 48 hours at 23.5ºC would
probably raise minimal concern, since accelerated stability data at 25ºC
would routinely be available to the manufacturer to help interpret the
likely impact of such an excursion. In the case of room temperature drugs
spending 48 hours at 43.5 ºC, this would cause concern, since it would
exceed readily available accelerated stability data for the product at 40ºC
for six months. The key here is that it is better to compare the length of
the actual excursion approximating its magnitude with a calculated MKT
against product stability data than it is to calculate an MKT for an entire
segment because the length of each segment compared to the length of
the typical excursion masks the impact when the MKT covers the entire
segment. The value of MKT for evaluating long-term storage segments of
a drug’s lifetime is then limited because, first, the length of temperature
excursions will naturally tend to be limited to a small fraction of the storage
time (hours or days vs. months), and second, because storage facilities are
not subject to the external causes of temperature excursions that affect
transport vehicles (e.g., traffic and customs). This calls into question the
USP recommendation for making the standard calculation of a warehouse
MKT over 12 months [4]. Over the period of a year, only a temperature
excursion that covered several weeks would have a significant impact on
the resulting MKT.
Further, this illustrates the importance of setting upper and lower
bounds on the use of MKT based on available stability data. In the CRT
case above, unless the manufacturer had obtained stability data above
40ºC, something that may not routinely be done, it would be hard to
estimate the impact of the excursions that went up to 45ºC and had
calculated MKTs of 43.5ºC [9].
Therefore, it is appropriate to use the calculated Mean Kinetic
Temperature for a drug product to approximate the effects of temperature
variation that may occur during product transport in the absence of productspecific kinetic data. This is because, in the range of temperatures of interest
for most drug products, the MKT equation is a valid approximation, given
the magnitude of the activation energy expected and the anticipated linear
or nearly linear nature of any degradation reaction that may occur. The use
of long temperature histories is likely to mask the impact of a temperature
excursion that lasts only hours or days unless the MKT is calculated just
for the period of the excursion. Further, it is incumbent on manufacturers
to perform the necessary stability studies so that the MKT of a temperature
excursion can be compared against available stability data to enable an
informed conclusion regarding the impact on product quality [9].
It must always be kept in mind, however, that a calculated MKT
represents an approximation of the impact of temperature variation on the
drug. For this reason, the use of MKT in the distribution environment should
be limited to temperatures for which there are stability data to support it.
At higher temperatures than evaluated in accelerated or other stability
studies, the kinetics of product degradation may change or other routes of
degradation may become possible. At temperatures at or below 0ºC, phase
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change may occur (tablets with moistures below 1% would be likely to have
no observable effect). This may or may not be detrimental to the product,
but this will not be known unless freeze-thaw studies have been done [9].
There are drugs which show significantly different rates of
degradation at higher temperatures [10]. This is why it is so important that
the use of MKT for a drug is supported by kinetic and stability data which
verify the temperature range for which a linear temperature-degradation
relationship can be expected to hold. Thus, implementing upper and
lower temperature control limits that are either justified or based off of
data allows MKT to be used consistently and effectively throughout the
supply chain. Such studies are typically performed by the manufacturer
of a drug, who will, therefore, have the necessary data to analyze the
impact of temperature excursions on the drug. Others in the distribution
chain will only have access to what is provided in the drug’s labeling,
typically storage statements (e.g., Store at Controlled Room Temperature;
excursions permitted 15-30ºC, or Do Not Freeze).
Therefore, proper temperature maintenance during the storage of
a drug product has the potential to have a greater positive impact on
drug quality than a short-term excursion such as might happen during
transportation has to damage it. Furthermore, if any excursion, whether
during storage or transportation, reaches a temperature for which no
stability data are available to permit understanding of the effect, then
calculating MKT does not help; the product may be at significant risk.
At the present time, the distribution of drugs is set up in a manner
where temperature data may not be collected over the entire supply chain
or may not be shared from one leg to another [8]. MKT calculations
for each portion of the distribution process may be used to estimate the
impact of temperature excursions on the quality of the drug product. The
effectiveness of this process is limited, however, because 1) temperature
data may not be collected, 2) if temperature data is collected, it is critically
dependent on monitor placement; the temperature exposure observed by
the monitor may not be representative of drug product that is at some
distance, 3) temperature data may not be shared from one distribution
leg to another, 4) only the manufacturer has all the stability and kinetic
data to fully interpret the calculated MKT, and 5) the calculated MKT for a
longer segment such as storage may minimize the impact of a temperature
excursion due to the long baseline as demonstrated above.
For these reasons MKT cannot be used as the “whole” answer to
the impact of temperature excursion to drug quality. It is essential for
manufacturers to set upper and lower temperature limits outside of which
MKT is and is not appropriate. Manufacturers, wholesalers and mailorder
pharmacies need to know (by monitoring if necessary) the temperatures to
which they expose products in the distribution process.
Based on the data presented here, the authors have the following
recommendations:
•
•
•
•
For brief segments such as transport, the MKT for the segment
is best used together with proper adherence to upper and lower
temperature control limits based on available stability data.
For longer segments like storage, calculating the MKT of only
the excursion may be preferable.
Within these limitations, MKT and the Controlled Room
Temperature and Cold Temperature as defined by USP are
useful in understanding the impact of temperature excursions
on product quality over the lifetime of a drug.
Each successive owner of the material (manufacturer, wholesaler,
pharmacy, and patient) can, at best, be responsible for only his or her
particular segment, including the storage and transport temperatures
and the interpretation of the resulting partial MKT values.
ɶɶ Manufacturers should establish upper and lower
control temperatures based on available stability data
outside of which MKT should not be used.
ɶɶ It may be useful for manufacturers to publish MKT
data in the package insert.
Finally, the manufacturer of a drug product has a unique responsibility
since it is the manufacturer who performs the stability studies to determine
the expiration dating of the drug. It is those stability studies, plus any
additional ones that the manufacturer may choose to do such as freezethaw and temperature cycle studies beyond the standard ICH data
package, that enable informed decisions to be made about the use of MKT
to evaluate the impact of typical temperature excursions on the product.
For this reason, when questions arise during the distribution process about
such temperature excursions, they are best raised with the manufacturer
who can use the stability data to interpret the MKT that results.
Acknowledgements
The authors are grateful to the members of the Pharmaceutical Cold
Chain Interest Group of the PDA for their help and comments in the
development of this paper.
References
1.
International Conference on Harmonization (ICH) Q1A(R2):
Stability Testing of New Drug Substances and Products (Second
Revision).
2. Grimm, W., Storage conditions for stability testing in the EC, Japan
and USA; the most important market for drug products. Drug Dev
Ind Pharm 1993;19:2795– 830.
3. United States Pharmacopeia (USP) General Notices.
4. USP General Chapter <1160> Pharmaceutical Calculations In
Prescription Compounding.
5. Carstensen J.T. Solution Kinetics in Carstensen J.T. and Rhodes C.T.
eds., Drug Stability Principles and Practices, 3rd Edition, Marcel
Dekker, Inc, New York, 2000, pp 19-55.
6. Dibiase, M.D., and Kottke, M., Stability of Polypeptides and
Proteins in Carstensen J.T. and Rhodes C.T. eds., Drug Stability
Principles and Practices, 3rd Edition, Marcel Dekker, Inc, New
York, 2000, pp 553-578.
7. Kommanaboyina, B. and Rhodes, C. T., Effects of Temperature
Excursions on Mean Kinetic Temperature and Shelf Life’, Drug
Development and Industrial Pharmacy,25:12,1301 — 1306, 1999.
8. USP General Chapter <1079> Good Storage and Shipping Practices.
9. Seevers, R.H., Bishara, R.H., Harber, P.J. and Lucas, T.I.,“Designing
Stability Studies for Time/Temperature Exposure”, American
Pharmaceutical Outsourcing, September 2005, pp. 18-23 and 55.
10. Kishore, A K. Nagwekar, J B., Influence of temperature and
hydrophobic group-associated icebergs on the activation energy of
drug decomposition and its implication in drug shelf-life prediction,
Pharm Res. 7(7):730-5, 1990 Jul.
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Robert H. Seevers, Ph.D. is a Principal
Regulatory Scientist, Global Regulatory
Affairs (CMC) with Eli Lilly and
Company in Indianapolis, Indiana (Lilly
Research Laboratories, Lilly Corporate
Center, Indianapolis, IN 46285).
Cold Chain
Rafik H. Bishara, Ph.D. is retired from
his position as Director, Quality
Knowledge Management and Technical
Support with Eli Lilly and Company in
Indianapolis, Indiana. He is Chair of the
Pharmaceutical Cold Chain Interest
Group, of the Parenteral Drug Association.
Paul Harber — (AgEn, BS, MS, Purdue
Univ., 1981) is an Associate
Engineering Consultant at Eli Lilly and
Company. Paul has 28 years experience
with Lilly, the past 14 years in
Packaging Development. He has been
active in the Pharmaceutical Cold Chain Discussion
Group for the past 10 years. He has co-authored
numerous articles relating to various aspects of cold
chain subjects. Currently, his work is primarily devoted
to supporting the shipment of early phase compounds,
Active Pharmaceutical Ingredients, Clinical Trial
Materials, as well as launch support for new products.
Dave Ulrich is the QA Director for
Distribution and Logistics for
Abbott’s Global Pharmaceutical
Operations (GPO) division. He has
been in his current role for 4 years
and his responsibilities include
standardization & optimization of quality systems
(cGDPs), cold chain management, supply chain system
optimization, ePedigree/Track-n-Trace and import export
compliance activities (FDA, USDA and EPA).
He has been at Abbott 21 years, with the majority
of time spent in bulk (API) manufacturing operations,
manufacturing QA and plant maintenance, validation &
engineering.
Jeffrey Hofer — (MS, Iowa State
University, 1990) is a Research Advisor
at Eli Lilly and Company. Jeff has 19
years experience with Lilly, the past 16
years
in
Product
Development.
Currently, his work is primarily devoted
to supporting the analytical and pharmaceutical scientists
during the development of the process understanding
and design space exploration for new products. Jeff is
also very active externally and has been an active
member of the PhRMA CMC Statistics Expert Team for
the past 14 years and chaired the committee for several
years during that time.
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