Transcript Document

MKT
Mean Kinetic Temperature
PLF 7 - Verona
May 2005
Shirley Ann Feld / Christa Baenziger
1
Summary





Background
Arrhenius
MKT
How to apply to storage
How to apply to transport
2
Background

The ICH stability testing guidelines defines
mean kinetic temperature (MKT) as “a single
derived temperature which, if maintained
over a defined period, would afford the
same
thermal
challenge
to
a
pharmaceutical product as would have been
experienced over a range of both higher
and lower temperatures for an equivalent
defined period”
3
Arrhenius
The degradation rate of a product
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

Depends on the storage temperature to
which it is exposed
Is not a linear function of the
temperature (in °K)
Is determined by the Arrhenius equation
4
Arrhenius (cont’d)
The Arrhenius equation calculates the
degradation rate (=reaction rate) as a
function of

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Arrhenius constant (product specific)
Activation energy (product specific)
Universal gas constant
Temperature (°K)
k= A*exp(-ΔHa/R*T)
5
Arrhenius (cont’d)

If stability test results at two (or
more) temperatures are available
the product specific attributes of
the Arrhenius equation can be
calculated:
Arrhenius constant
 Activation energy

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Arrhenius (cont’d)
Example
Assay vs Storage Time
100
1.170 % / month
0.125% / month
98
96
%
94
0.400 % / month
92
90
0
3
6
9
12
15
18
21
24
months
5°C
15°C
25°C
Activation energy : 77 kJ/mol
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Arrhenius (cont’d)
Example – degradation of product to various temperatures
Duration
(months)
Temperature
(°C)
1
5
1
15
1
25
Total after 3 months
Degradation
(%)
0.125
0.400
1. 170
1. 695
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Arrhenius (cont’d)
Summary


The Arrhenius equation allows the calculation
of the degradation of a product as a function
of the temperature
Stability data at two or more temperatures
permit the determination of the product
specific attributes of the Arrhenius equation
9
MKT Concept

The MKT of a product which is exposed
to varying temperatures during a given
period can be determined by calculating
the incremental degradations at the
different temperatures (applying the
Arrhenius equation).
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MKT Equation
T is the MKT,
ΔH is the activation energy, with its value being given in the
USP as 83.144 kJ/mol. (Note: this value is specified as an alternative to an
experimentally derived estimate)
R is the universal gas constant
T is the temperature in degrees Kelvin,
n is the total number of periods of the same storage duration at different
temperatures and
e is the natural log base.
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MKT Concept
Example using stability data of previous example
(see before)
Activation energy
77 kJ/mol
Exposure
1 month at 5°C
1 month at 15°C
1 month at 25°C
Degradation
1st month
2nd month
3rd month
total
0.125%
0.400%
1. 170%
1.695%
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MKT Concept
Question
Which constant temperature results in the same
degradation after 3 months ?
Answer: 18.17°C ( with MKT Calculation)
Remark:
 the MKT is higher than the arithmetic mean
temperature of 15°C
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MKT Application
Activation Energy (AT)
T°C
77
=A8+273.1 =-C2/0.00
83144
T°C
5.0
5.0
5.0
5.0
5.0
5.0
5.0
15.0
15.0
15.0
15.0
15.0
15.0
15.0
25.0
25.0
25.0
25.0
25.0
25.0
25.0
T°K
278.1
278.1
278.1
278.1
278.1
278.1
278.1
288.1
288.1
288.1
288.1
288.1
288.1
288.1
298.1
298.1
298.1
298.1
298.1
298.1
298.1
-AT/R
-9261.041
-9261.041
-9261.041
-9261.041
-9261.041
-9261.041
-9261.041
-9261.041
-9261.041
-9261.041
-9261.041
-9261.041
-9261.041
-9261.041
-9261.041
-9261.041
-9261.041
-9261.041
-9261.041
-9261.041
-9261.041
(kJ/mol)
=+C8/B8
-AT/RT
-33.3011
-33.3011
-33.3011
-33.3011
-33.3011
-33.3011
-33.3011
-32.1452
-32.1452
-32.1452
-32.1452
-32.1452
-32.1452
-32.1452
-31.0669
-31.0669
-31.0669
-31.0669
-31.0669
-31.0669
-31.0669
=EXP(D8)
exp
3.44753E-15
3.44753E-15
3.44753E-15
3.44753E-15
3.44753E-15
3.44753E-15
3.44753E-15
1.09523E-14
1.09523E-14
1.09523E-14
1.09523E-14
1.09523E-14
1.09523E-14
1.09523E-14
3.21973E-14
3.21973E-14
3.21973E-14
3.21973E-14
3.21973E-14
3.21973E-14
3.21973E-14
=SUM(E8:E28)
/J8
Somme exp
1.55324E-14
=LN(F8)
ln somme
-31.7958508
=+C8/G8
Tk (°K)
291.27
=H8-273.1 =COUNT
(A5:A133)
Tk (°C)
18.17
n
21
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MKT Application
Activation Energy (AT)
T°C
83
=A8+273.1 =-C2/0.00
83144
T°C
5.0
5.0
5.0
5.0
5.0
5.0
5.0
15.0
15.0
15.0
15.0
15.0
15.0
15.0
25.0
25.0
25.0
25.0
25.0
25.0
25.0
T°K
278.1
278.1
278.1
278.1
278.1
278.1
278.1
288.1
288.1
288.1
288.1
288.1
288.1
288.1
298.1
298.1
298.1
298.1
298.1
298.1
298.1
-AT/R
-9982.681
-9982.681
-9982.681
-9982.681
-9982.681
-9982.681
-9982.681
-9982.681
-9982.681
-9982.681
-9982.681
-9982.681
-9982.681
-9982.681
-9982.681
-9982.681
-9982.681
-9982.681
-9982.681
-9982.681
-9982.681
(kJ/mol)
=+C8/B8
-AT/RT
-35.8960
-35.8960
-35.8960
-35.8960
-35.8960
-35.8960
-35.8960
-34.6501
-34.6501
-34.6501
-34.6501
-34.6501
-34.6501
-34.6501
-33.4877
-33.4877
-33.4877
-33.4877
-33.4877
-33.4877
-33.4877
=EXP(D8)
exp
2.57372E-16
2.57372E-16
2.57372E-16
2.57372E-16
2.57372E-16
2.57372E-16
2.57372E-16
8.9469E-16
8.9469E-16
8.9469E-16
8.9469E-16
8.9469E-16
8.9469E-16
8.9469E-16
2.86075E-15
2.86075E-15
2.86075E-15
2.86075E-15
2.86075E-15
2.86075E-15
2.86075E-15
=SUM(E8:E28)
/J8
Somme exp
1.33761E-15
=LN(F8)
ln somme
-34.2478953
=+C8/G8
Tk (°K)
291.48
=H8-273.1 =COUNT
(A5:A133)
Tk (°C)
18.38
n
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MKT Application
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Activation energy 77 kJ/mol
Activation energy 83* kJ/mol
Activation energy 100 kJ/mol
MKT
18.17
18.38
18.95
* USP default value if data not available
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MKT – Application
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MKT Application
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MKT – How to apply to storage

Controlled Room Temperature (USP)
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 MKT remains in the allowed range transient
"spikes" up to 40°C are permitted as long as they do not
exceed 24 hours- USP 27 / NF 22
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MKT – How to apply to storage

Controlled Cold Temperature
A temperature maintained thermostatically that
encompasses the usual and customary working environment
of 2° to 8°C; that results in a mean kinetic temperature
calculated to be not more than 8°C; and that allows for
excursions between 0° and 15°C (32° and 59° F) that are
experienced in pharmacies, hospitals, and warehouses.
Transient "spikes" up to 25°C may be permitted if the
manufacturer instructs and as long as they do not exceed 24
hours.
Dr. Claudia Okeke, USP, 25.01.05 Brussels, 01.03.05 Montreal
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MKT – How to apply to transport
USP Claudia Okeke:
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Over 52 weeks
Including transportation
Including temperature ranges for products between
+2°and +8°C, not just +20° to +25°C
Calculate by entering the mean of the highest and
lowest temperatures during the preceding weeks
If the mean over a 52-week period in a year is 8°C, then
calculate MKT as follows:
N = 52; T1 = 8°C = 273.1 + 8 = 281.1°K
R = 0.0083144kj/mol/degree; Tn = 8°C = 281.1°K
ΔH = 83.144 kJ/mol; ΔH/R = -10000
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MKT – How to apply to transport

The USP has performed and published several
studies on temperature conditions during
transport which used MKT:
Temperature and Humidity Conditions During Shipment in
International Commerce by Claudia C. Okeke, Thomas
Medwick, Leonard C. Bailey, and Lee T. Grady
Independent Study of Mail Distribution Temperatures and
Humidity by Claudia C. Okeke, Leonard C. Bailey, Thomas
Medwick, and Lee T. Grady
Medication Storage Temperatures on U.S. Ambulances: A
Prospective Multicenter Observational Study by Lawrence H.
Brown, Leonard C. Bailey, Thomas Medwick, Claudia C. Okeke,
Kurt Krumperman, Calvin D. Tran
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MKT Summary
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The MKT calculation allows the calculation of the impact on
quality of product exposure to varying temperatures.
If stability studies at two or more temperatures are
available for a product, the MKT can be calculated with the
real activation energy.
If stability studies are available at one temperature only,
the activation energy must be estimated based on product
knowledge. Higher activation energies lead to higher
(=conservative) MKT values. USP default value: 83
MKT calculations can only be used when the temperatures
remain within limits that are to be defined based on
product knowledge.
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