Mean Kinetic Temperature - Vaisala · The mean kinetic temperature is higher than the arithmetic...

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Mean KineticTemperatureHistory, Math, and Applications

Paul Daniel Sr. Regulatory Compliance [email protected]

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Practical Webinar Stuff

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Speaker:

Paul DanielSr. Regulatory Compliance Expert

Chat Operator:

Janice LivingstonMarketing Manager

Vaisala Team

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We serve customers in weather and controlled environment markets

80 years of experience in providing a comprehensive range of innovative observation and measurement products and services

Vaisala in Brief

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Our Goal is to help customers• Reduce risk of lost or

adulterated product

• Reduce their risk of failing to meet GxP regulations and/or guidelines

Our OfferingProvides measurement instrumentation, continuous monitoring systems and validation systems for regulated or highly controlled life science environments.

Vaisala in Life Science

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Mean KineticTemperatureHistory, Math, and Applications


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HISTORY - Where did MKT come from?

MATH – How do we calculate MKT?

APPLICATION – What can we do with MKT?

Goals

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http://images.knowledge.vaisala.com/Web/Vaisala/{ddcc6ffa‐3507‐419f‐92bd‐938aab9cf4c8}_CEN‐G‐Mean‐Kinetic‐Temperature‐Application‐Note‐B211534EN‐A‐FINAL.pdf

MKT Application Note

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Other kinds of MKT

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Mean kinetic temperature: 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...

From ICH Q1A(R2) Stability Testing of New Drug Substances and Products

MKT from ICH

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MKT: Like a weighted average…

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Swedish Physicist -1903 Nobel Prize – Chemistry

Why we care… The “Arrhenius Equation”

Describes the relationship between Temperature and Reaction Rate

– For simple reactions

Svante Arrhenius (1859-1927)

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Boiling EggsCooking at Altitude

–Colorado: Water Boils at 92C– Egg cooks in 4½ minutes

–Sea Level: Water Boils at 100C– Egg cooks in 3 minutes

Snowy Tree CricketChirp rate varies with temperature

– 13C – 15 chirps every 13 seconds– 32C – 49 chirps every 13 seconds

Reaction Rate Examples

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Svante Arrhenius Arrhenius

Equation

Accelerated Aging

Arrhenius equation can be used to estimate accelerated aging!

Accelerated Aging Increasing environmental conditions to speed up aging process!

Paper at 100C for 72 hours = 18 to 25 years of normal aging.

On the MKT Wiki Trail

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“Virtual Temperature” – J.D. Haynes, 1971 Identified temperatures to use for product expiry testing

– To simulate uncontrolled ambient storage– Warehouses and Pharmacies

“Virtual Temperature” is “Mean Kinetic Temperature” By 1985 - Accepted to use climate data to determine MKT

– W. Grimm – Climatic Zones I, II, III, and IV

ICH (1993) – Includes Haynes’ equation and Grimm’s Zones

Regulatory History

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MKT of Climate – Simulate POTENTIAL Storage

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2001 – John Taylor U.K. Medicines Control Agency (predecessor to MHRA)– “Recommendations on Control and Monitoring of Storage and Transportation

Temperatures of Medicinal Products”

Taylor suggests a new idea!! Use MKT to evaluate exposure by measuring storage environment.– MKT as a tool to evaluate temperature excursions!

More Regulatory History

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MKT of Storage – Evaluate ACTUAL Storage

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“Original” Use of MKT Source Data: Expected Climate–Goal: Predict Stability Temperatures

“New” Use of MKT Source Data: Storage History–Goal: Estimate Product Degradation

Past and Future

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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...

From ICH Q1A(R2) Stability Testing of New Drug Substances and Products

MKT from ICH

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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.

Single temperature

Deconstructing MKT - Temperature

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Single temperatureCalculated

Deconstructing MKT - Calculated

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Single temperatureCalculated from a range of temperatures

Deconstructing MKT - Range

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Single temperatureCalculated from a range of temperaturesRepresenting the same thermal challenge

Deconstructing MKT - Challenge

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Single temperatureCalculated from a range of temperaturesRepresenting the same thermal challengeOver the same time period

Deconstructing MKT - Time

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MKT vs Average

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Now lets do the math…∆

ln ∆

∆

⋯ ∆

TK = MKT (in Kelvin)

T1 to Tn = sample temperatures.

# of samples

Gas Constant: 0.008314472 kJ/mol/°K

Activation Energy: ∆ = 83.14472 kJ/mol

Aspirin: 122.2

Acetaminophen: 68.13

Vitamin C: 32.8

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10000

ln ⋯

∆

ln ∆

∆

⋯ ∆

°K∆ = 83.14472 kJ/mol

R = 0.008314472 kJ/mol/°K

Math Step 1:

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10000

ln ⋯

10000

ln . . . . 4

T1 20°C 293.15°KT2 27°C 300.15°KT3 21°C 294.15°KT4 28°C 301.15°K

0°C 273.15°K

Math Step 2: Temperatures

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10000

ln . . . . 4

10000

ln . . . . 4

Math Step 3: Division

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Math Step 4: Solve each

10000

ln 1.53196 10 3.39431 10 1.72033 10 3.79139 104

10000

ln . . . . 4

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10000ln 2.60950 10

10000

ln 1.53196 10 3.39431 10 1.72033 10 3.79139 104

Math Step 5: Addition / Division

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1000033.5796

297.799°K

10000ln 2.60950 10

0°C 273.15°K

Math Steps 6, 7, & 8

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Intended Purpose (Decreasing Duration)

Measurement Technology (Increasing # of Data Points)

Calculation Technology (Increasing Ease of Calculation)

Historical Context

Min/Max Thermometer → Chart Recorder → Logger → CMS

Stability Studies → Controlled Storage → Distribution

Pencil → Calculator → Custom SW → Spreadsheet → CMS

1971 2018

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Keep Intended Purpose/Duration in Mind Stability Studies Controlled Storage Distribution

Use all the data you have. More data = more accurate calculation.

Use software to do automated calculation. Make sure it is validated.

Calculation Recommendations

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The MKT calculation is difficult. viewLinc automates the MKT calculation.

Calculation uses all historical samples, not averages. More accurate calculation.

Easy inclusion into reports. Part of report statistics.

Any ∆ may be used. Defaults to standard ∆ = 83.14472 kJ/mol

How does viewLinc help with MKT?

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Calculation Recommendations

Environmental Stability Requirements for MKT

Temperatures suitable for MKT analysis

Processes Suitable for MKT analysis

What does Guidance say about MKT?

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Guidance says use MKT…

Only in well-controlled environments–Do not use MKT to compensate for control issues.

Only where excursions are not common– Frequent excursions will not be captured in min/max readings.

Only where excursions are below 30C.–Reaction kinetics may change at higher temperatures.–Reactions speed up so MKT is no longer reliable estimate.

Stability Requirements for MKT

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Guidance says use MKT…

Only for ambient environments.–Cool or Room Temperature only.

What about Frozen?– Slow reaction rates at low temperatures.–High Temp damage (freeze/thaw) does not follow Arrhenius.

What about Refrigerated?– Low Temp damage (freeze/thaw) hidden from MKT.–High Temp damage from spoilage may not follow Arrhenius.

Temperatures suitable for MKT

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Guidance does not have consensus…

All guidance supports MKT in storage.

Only some guidance supports MKT in transport.– Supports: USP and MHRA

– The support is “cautious”.–Does Not Support: German ZLG

Safest choice…–Use for storage only.

Processes suitable for MKT

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GDP Guidance and Regulation is changing quickly. No consensus on MKT analysis for Transportation.

Challenges in GDP Controlling the environment. Monitoring the environment.

MKT looks like a perfect solution. Prove mathematically that drug is still good.

MKT and GDP (Part I)

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Challenges

Is it the right calculation?

Collecting and managing monitoring data.

Lifetime MKT Budget

Sufficient stability data to support conclusions.

MKT and GDP (Part 2)

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1. Don’t use MKT to compensate for temperature excursions.

2. Use as many samples (time/ temperature) as you can.

3. Don’t use MKT where temperature is not well controlled.

4. Only use MKT if storage specification is 25˚C or less.

5. Don’t use MKT for controlled low temperature.

6. MKT aside, investigate all temperature excursions.

6 MKT Rules (from our Application Note)

http://images.knowledge.vaisala.com/Web/Vaisala/{ddcc6ffa‐3507‐419f‐92bd‐938aab9cf4c8}_CEN‐G‐Mean‐Kinetic‐Temperature‐Application‐Note‐B211534EN‐A‐FINAL.pdf

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HISTORY - Where did MKT come from?

MATH – How do we calculate MKT?

APPLICATION – What can we do with MKT?

Review

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Questions on GxP – email [email protected] on applications – email [email protected] ensure you can receive Vaisala emails –set your email preferences at: http://knowledge.vaisala.com/email-preferences

Contacts:

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European Medicines Agency, Committee for Human Medicinal Products (CHMP), “Guideline on Declaration of Storage Conditions: A) In the product information of Medicinal Products B) For Active Substances”, CPMP/ QWP/609/96/Rev 2, 2007.

European Compliance Academy (ECA), GMP News 07.05.2014: “GDP Question: When to use Mean Kinetic Temperature Calculation (MKT)?”

European Compliance Academy (ECA), GMP News 22.04.2015: “GDP: Is temperature control required for each Transport? ”

FDA, Draft Guidance, Stability Testing of Drug Substances and Drug Products, 1998. ICH Harmonized Tripartite Guideline, Stability Testing of New Drug Substances and Products Q1A(R2), 2003. ICH Q1F, Explanatory Note on the 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, Chapter <1160>, Pharmaceutical Calculations in Prescription Compounding. 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” Drugs made in Germany, by Dietz,

R., Feilner, K., Gerst, F., Grimm, W. USP 35 Chapter <1150>, Pharmaceutical Stability USP 36 Chapter <1079>, Good Storage and Distribution Practices for Drug Products

References and Sources

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