MEAN KINETIC TEMPERATURE IN GXP ENVIRONMENTS - VAISALA
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
Application Note
www.vaisala.com
Mean Kinetic Temperature Mean Kinetic Temperature:
in GxP Environments
“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.”
From ICH Q1A (R2) “Stability
Testing of New Drug
Mean kinetic temperature (MKT) was first developed for and applied Substances & Products”
to controlled room temperature (CRT) storage in warehouses.
Regulatory bodies and Regulatory Bodies in a given region. The equation
stakeholder organizations in he developed for “Virtual
and Definitions
drug and device manufacturing Temperature” is the same equation
and distribution have long been The document most cited in that is used today to calculate
working toward creating standards GxP-regulated industries for MKT. It is based on the Arrhenius
for temperature monitoring that the definition of mean kinetic equation, which describes the
ensure the shelf life, quality, and temperature is the International temperature dependence of simple
safety of products. In the last 15 Conference on Harmonization chemical reaction rates at ambient
years of these ongoing efforts, (ICH) guideline: “Stability Testing temperatures where the rate of
mean kinetic temperature (MKT) of New Drug Substances and reaction generally doubles with
has been identified as one of Products Q1A(R2).” The definition every 10 degrees Celsius increase
the potential tools available from this guideline is shown in temperature.
for evaluating the impact of above. The original purpose of
temperature on product quality. the 1971 Haynes paper was to When establishing the
address the fact that climate- temperatures for long-term
MKT can be a difficult tool to based temperature variation in stability testing of products to be
understand and apply properly. uncontrolled pharmaceutical stored at room temperature (RT)
MKT was first proposed to storage made it difficult to or controlled room temperature
guide stability studies and is select a single temperature for (CRT), the mean kinetic
now considered as a tool for use in product expiry testing. temperature in any part of the
evaluating temperature excursions Simply put, changes in storage world can be derived from climatic
in the dynamic arena of Good temperatures can affect the data. The WHO divides the world
Distribution Practices. The math is rate at which products degrade. into four climatic zones: temperate,
difficult for most laypersons, and Haynes sought to address this subtropical, hot/dry, and
there is not a consensus on how variation by calculating a “Virtual hot/humid, based on drug stability
MKT should be applied. Temperature” for use in expiry research. Rules described in ICH
testing that would consider the Q1A(R2) are meant for climatic
expected temperature variability zones I-II (USA, EU, and Japan).
The description for stability testing In short, MKT is a weighted non- was presented. Taylor argued
conditions in countries located in linear average that shows the that MKT could be applied to
Climatic Zones III (hot and dry) effects of temperature variations evaluate temperature excursions
and IV (hot and humid) can be over time. in product storage. This was a
found in ICH Q1F explanatory note landmark change in the application
and in the WHO technical report Mean kinetic temperature is the of MKT, providing industry with
“Annex 2: Stability testing of active value used when planning long- a tool to evaluate the impact of
pharmaceutical ingredients and term stability study temperatures. temperature excursions.
finished pharmaceutical products.” The value includes the annual
variations, e.g., lower and higher Taylor’s new MKT application was
In practice, products stored at temperatures during winter and widely accepted. It was a timely
controlled room temperature are summer seasons. Thus, storage concept, especially in the light of
often tested for long-term stability at a continuous temperature of the regulatory challenges in Good
in simulated laboratory conditions 25°C during a real-time stability Distribution Practices. It should be
of 25 or even 30 degrees (at 25°C study includes the actual noted that Taylor recommended
± 2°C/60% RH ± 5% RH or 30°C ± temperature exposure likely to caution in the application of MKT to
2°C/65% RH ±5% RH) for dating be encountered under ambient evaluate temperature excursions.
purposes in climatic zones I-II, conditions throughout Europe,
without using the exact calculated North American, and Japan, The MKT value is supposed to
MKT value for a particular including real-time excursions encompass the total amount
location. These temperatures are from 25°C. However, MKT is of product deterioration for
recommended by WHO in climatic different than other weighted a period that is equivalent to
zones I-II and (compared to the average calculations because it the incremental deterioration
Haynes article) are probably high. accounts for the non-linear effect that would occur in separate
They are an example of the worst- of temperature excursions. excursions. However, the
case scenario ideology often seen calculation is never to be used
in the pharmaceutical and biotech The FDA and European as a substitution for control and
industries. (For recommended long- Commission regard the calculation understanding of a controlled
term testing conditions all over as a tool to help determine storage environment. Any temperature
the world, see the WHO Technical conditions, especially for shipping excursions must be rigorously
Report Series No. 953, 2009, Annex and storage in specific climatic investigated. An MKT value
2, Appendix 1 “Long-term stability zones. (See also the European does not negate investigative
testing conditions as identified by Medicines Agency document responsibility because a short-
WHO Member States.”) from the Committee for Human term spike can indicate a larger
Medicinal Products (CHMP) problem, or a problem that may
For another regulatory source “Guideline on Declaration of worsen. Root causes, as well as
that defines mean kinetic Storage Conditions” 2007.) precise time and temperature
temperature, refer also to the data, must be documented
FDA’s draft document: “Guidance Mean kinetic temperature may and preventive actions then
for Industry, Stability Testing have uses beyond stability testing. incorporated into a CAPA
of Drug Substances and Drug In 2001, in a paper by J. Taylor of (corrective actions, preventive
Products.” This draft gives a much the Medicine Controls Agency, actions) management plan.
briefer definition: “Mean Kinetic a different application for MKT
Temperature (MKT) is defined as
the isothermal temperature that
corresponds to the kinetic effects
of a time-temperature distribution.”
The U. S. Pharmacopeia (USP 43
Chapter , “Pharmaceutical
Calculations in Pharmacy
Practice”) definition: “MKT is a
single calculated temperature
at which the total amount of
degradation over a particular
period is equal to the sum of the
individual degradations that would
occur at various temperatures.”
When & Where to Use advice to the wholesale Ways to Calculate MKT
authorization holder. This clearly
Mean Kinetic Temperature
indicates that the MHRA supports In its draft article for manufacturers,
Because Vaisala’s Continuous the use of MKT in transportation. re-packagers, and warehouses,
Monitoring System software viewLinc the FDA recommends inserting all
calculates MKT, we are often asked In addition, USP Chapter 1079, data points into the MKT equation
how to apply the calculation. MKT includes MKT among the tools directly. A minimum of weekly high
was first developed and applied available to address short-term and low readings is recommended,
to ambient storage in warehouses, temperature deviations during and more rigorous approximations
and our recommendations are transportation. using daily highs and lows, or even
consistent with this application. We more frequent temperature readings,
recommend using it for relatively In contrast, the German ZLG are also described. When calculating
stable, controlled room temperature (Zentralstelle der Lander fur a yearly MKT, a minimum of 104
environments during storage Gesundheitsschutz bei Arzneimitteln weekly high and low readings would
applications. MKT can be used for und Medizinprodukten/Central be used. The yearly MKT should be
refrigerated applications if the typical Authority of the German Federal calculated from the monthly MKT
degradation pathway is a chemical Lander for Health Protection calculations. The FDA recognizes
breakdown, rather than the result Regarding Medicinal Products that, when the yearly MKT of a
of spoilage. We do not recommend and Medical Devices) states that facility begins to exceed 25˚C, it
the MKT calculation for incubators the mean kinetic temperature may not necessarily have an impact
and stability chambers, which are is not appropriate for use in a on products that have been stored
well controlled environments and transportation risk assessment. for less than one year at the time.
not used for the storage of finished Again, this is because the value does Rather, this value should be taken as
products. We do not recommend not account for effects that may a warning that the facility may not be
MKT for cold storage applications, as lead to irreversible quality defects, under adequate control.
the degradation resulting from phase even when certain temperature
changes are not well described by The USP provides some additional
limits established during stability
the Arrhenius equation. guidance in Chapter 1079 for
studies are exceeded only for a short
calculating MKT for temperature
time. The MKT value also does not
Nor is MKT ideal for long-term excursions. For a CRT environment,
account for finer points such as the
storage for the obvious reason that in a 30-day period is recommended,
possible formation of fissures in glass
any average over time, an increase in or the average time that a product
ampoules and injection bottles at
data points will eliminate spikes, such is in the holder’s possession. For
temperatures near freezing point.
as a slowly climbing temperatures refrigerated environments, this time
that may indicate an equipment drops to only 24 hours. If MKT is used
Furthermore, calculation of MKT
breakdown. A weighted, but non- to evaluate temperature excursions,
requires that the temperature
linear average over time is best used it should only be for isolated short-
profiles of all previous transports are
when short excursions are less likely term events that are not recurring.
known, but usually these data are
to cause serious harm (as in CRT) A storage or transportation system
not available.
and over less time. The calculation that has repeated excursions should
makes sense in storage and be considered out of control.
distribution applications, especially
The British Medicines Authority It may be worth noting that
where there can be fluctuations –
MHRA gives the following many companies are moving
either because of the climatic zone, instructions: “MKT should not away from using the term CRT in
or the season. be used to compensate for their operating procedures and
poor temperature control of documents. Many instead use a
It is not internationally agreed as storage facilities. It may be
specific temperature range.
to whether MKT is suitable for use applied in situations where
in evaluating excursions during control is relatively good, but We recommend that control
transportation and shipping. For where occasional excursions
specifications be unambiguous
may be encountered.”
instance, the MHRA states that and not subject to interpretation.
if the wholesale authorization J. Taylor. It may be that CRT will fall into
holder can provide the marketing “Recommendations on the Control disuse in quality documents and
authorization holder with details of and Monitoring of Storage and standard operating procedures soon.
MKT, including the times and extent Transportation Temperatures of
EMEA guidelines support the same
Medicinal Products,”
of any temperature deviations, this The Pharmaceutical Journal ideology. The use of terms such as
information may assist the marketing (vol 267) July 2001 `room temperature´ or `ambient
authorization holder in formulating conditions´ is unacceptable.
oup Statistics
Threshold
w Name Zone Units Value Max Avg Min MKT STD Sample
Lines
Temp viewLinc/Va... Temp 23.6 °C 25 22.8 22 23.3 1.8 7
Humidity viewLinc/Va... Humidity 32.5 %RH 35 31.8 29 N/A 3.7 7
Figure 1: MKT is often calculated in
continuous monitoring software.
The MHRA has stated: “It is not possible to obtain a meaningful MKT value from daily readings of simple max / min
thermometers as temperature fluctuation is not a linear function. It is noted that some data loggers and building
management systems are capable of recording multiple temperature readings over a time period and some
offer the function of calculating the MKT over a given time period.” The MHRA is clearly stating that continuous
monitoring data can provide a more meaningful MKT value.
Regulations evolve with technology and like many monitoring systems, Vaisala’s software viewLinc automatically
calculates MKT, using every historical data sample. Simply select the timespan you are interested in and the MKT
values will appear in the software window automatically. (Figure 1). Please note that mean kinetic temperature
values alone should not be used in decision-making when temperature excursions have occurred. It is repeatedly
mentioned throughout regulatory documents that information about the excursion duration and extent is required,
as well as an evaluation of potential effects of the temperature excursion on product quality.
The MKT Calculation Equation Key
The easiest and the most meaningful way to get an MKT value is by letting ▪ ∆H = the heat of activation,
the data loggers and software do the work for you. It is possible to do the which equals 83.144 kJ per
calculation yourself, but remember that you need an extensive amount of mol (default value; unless more
data and a calculation tool (e.g., Excel sheets). Otherwise, the calculation accurate information is available
can easily be overwhelming. Furthermore, any tool used for calculating MKT from experimental studies)
for use in GMP decision making requires validation. ▪ R = universal gas constant,
which equals 8.3144 x 10-3 kJ
– ∆H per degree per mol
The equation is:
R
TK =
ln (
– ∆H / RT1
+e
– ∆H / RT2 – ∆H / RTn
+... + e
)
,
▪ T1 = the (average) temperature,
n in degrees Kelvin, during the
first time point
The values used in the MKT formula are shown at right in the Equation Key.
It should be noted that ∆H, the activation energy, describes the reaction
▪ T2 = the (average) temperature,
in degrees Kelvin, during the
rate for the degradation of the active ingredients in a drug. A default value second time point
of 83.144 kJ/mol is typically used as it is a good approximation for most
pharmaceutical compounds. The default value simplifies the math because
▪ Tn = the (average) temperature,
in degrees Kelvin, during the
it is numerically similar to the universal gas constant. Please note that it nth measured time point;
is possible to use a different ∆H value that is specific to a given product if n being the amount of the
that information is available. measured time points
If you want to see some simplified examples how to calculate the MKT,
▪ TK = result in degrees Kelvin.
You’ll receive the final result MKT
please check USP 43 Chapter “Pharmaceutical Calculations in (in degree Celsius) by subtraction
Pharmacy Practice.” Bear in mind that MHRA doesn’t support these (TK – 273.15°K)
simplified calculations, nor does the FDA.Conclusion References
To summarize, we can make six basic recommendations for using • European Medicines Agency, committee
for human medicinal products (CHMP),
mean kinetic temperature:
“Guideline on Declaration of Storage
1. MKT should not be used to compensate for temperature excursions Conditions:
A) In the product information of
in any application.
Medicinal Products
2. When using MKT, ensure you have an adequate number of samples B) For Active Substances”
(time/temperature). The more samples included in the equation, the • European Compliance Academy (ECA),
better the MKT calculation. GMP News 07.05.2014: “GDP Question:
When to use Mean Kinetic Temperature
3. MKT should not be used in areas where temperature is not well Calculation (MKT)?”
controlled.
• European Compliance Academy
4. Use MKT only if the storage temperature specified on the label of (ECA), GMP News 22.04.2015: “GDP: Is
the product does not exceed 25˚C. temperature control required for each
Transport?”
5. MKT should not be used for products that require temperatures
below freezing. • FDA: Guidance for Industry Q1A(R2)
Stability Testing of New Drug
6. Regardless of whether you use the MKT calculation or not, all Substances and Products
temperature excursions should be investigated.
• ICH Harmonized Tripartite Guideline,
Stability Testing of New Drug
We hope that this exploration of the history and application of MKT is Substances and Products Q1A(R2)
useful. This topic, and its applications in distribution, will likely continue
• ICH Q1F, Explanatory Note on the
to evolve as guidance, regulations, and technologies progress.
Withdrawal of ICH Q1F on the ICH
Website
• J. Pharm. Sci., 60:927-929, 1971. John D.
Haynes. “Worldwide Virtual Temperatures
for Product Stability Testing”
• The Pharmaceutical Journal (vol 267),
July 2001. J. Taylor. “Recommendations
on the Control and Monitoring
of Storage and Transportation
Temperatures of Medicinal Products”
• USP 43 Chapter Pharmaceutical
calculations in Pharmacy Practice
• USP 43 Chapter Risks and
Mitigation Strategies for the Storage
and Transportation of Finished Drug
Products
• WHO Technical Report Series No. 953,
2009, Annex 2, Appendix 1 “Long-term
stability testing conditions as identified
by WHO Member States”
• WHO Technical Report Series, No. 953,
2009, Annex 2, Stability testing of active
pharmaceutical ingredients and finished
pharmaceutical products
• “Drug Stability Testing – Classification
of countries according to climatic zone”
published in Drugs made in Germany, by
Dietz, R., Feilner, K., Gerst, F., Grimm, W.
Please contact us at Ref. B211534EN-B ©Vaisala 2021
This material is subject to copyright protection, with all copyrights
www.vaisala.com/contactus retained by Vaisala and its individual partners. All rights reserved.
Any logos and/or product names are trademarks of Vaisala or its
individual partners. The reproduction, transfer, distribution or
storage of information contained in this brochure in any form
without the prior written consent of Vaisala is strictly prohibited.
www.vaisala.com Scan the code for
more information
All specifications — technical included — are subject to change
without notice.You can also read
