Mean Kinetic Temperature

Transcription

1 Mean Kinetic Temperature History, Math, and Applications Paul Daniel Sr. Regulatory Compliance Expert

2 Practical Webinar Stuff Challenges with your audio connection? Try calling toll-free: Other technical challenges? Try logging in to webinar again. Participate by: Answering poll questions. Ask questions using Chat function. You will receive a link to the presentation in .

3 Vaisala Team Speaker: Paul Daniel Sr. Regulatory Compliance Expert Chat Operator: Janice Livingston Marketing Manager

4 Vaisala in Brief 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

5 Vaisala in Life Science Our Offering Provides measurement instrumentation, continuous monitoring systems and validation systems for regulated or highly controlled life science environments. 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

6 Mean Kinetic Temperature History, Math, and Applications Paul Daniel Sr. Regulatory Compliance Expert

7 Goals HISTORY - Where did MKT come from? MATH How do we calculate MKT? APPLICATION What can we do with MKT?

8 MKT Application Note f 92bd 938aab9cf4c8}_CEN G Mean Kinetic Temperature Application Note B211534EN A FINAL.pdf

9 Other kinds of MKT

10 MKT from ICH 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

11 MKT: Like a weighted average

12 Svante Arrhenius ( ) Swedish Physicist Nobel Prize Chemistry Why we care The Arrhenius Equation Describes the relationship between Temperature and Reaction Rate For simple reactions

13 Reaction Rate Examples Boiling Eggs Cooking 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 Cricket Chirp rate varies with temperature 13C 15 chirps every 13 seconds 32C 49 chirps every 13 seconds

14 On the MKT Wiki Trail 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.

15 Regulatory History 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 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

16 MKT of Climate Simulate POTENTIAL Storage

17 More Regulatory History 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!

18 MKT of Storage Evaluate ACTUAL Storage

19 Past and Future Original Use of MKT Source Data: Expected Climate Goal: Predict Stability Temperatures New Use of MKT Source Data: Storage History Goal: Estimate Product Degradation

20 MKT from ICH 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

21 Deconstructing MKT - Temperature 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 and takes into account the Arrhenius equation. Single temperature

22 Deconstructing MKT - Calculated 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 and takes into account the Arrhenius equation. Single temperature Calculated

23 Deconstructing MKT - Range 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 and takes into account the Arrhenius equation. Single temperature Calculated from a range of temperatures

24 Deconstructing MKT - Challenge 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 and takes into account the Arrhenius equation. Single temperature Calculated from a range of temperatures Representing the same thermal challenge

25 Deconstructing MKT - Time 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 and takes into account the Arrhenius equation. Single temperature Calculated from a range of temperatures Representing the same thermal challenge Over the same time period

26 MKT vs Average

27 Now lets do the math ln T K = MKT (in Kelvin) T 1 to T n = sample temperatures. # of samples Gas Constant: kj/mol/ K Activation Energy: = kj/mol Aspirin: Acetaminophen: Vitamin C: 32.8

28 Math Step 1: ln = kj/mol R = kj/mol/ K K ln

29 Math Step 2: Temperatures ln T 1 20 C K T 2 27 C K T 3 21 C K T 4 28 C K 0 C K ln.... 4

30 Math Step 3: Division ln ln.... 4

31 Math Step 4: Solve each ln ln

32 Math Step 5: Addition / Division ln ln

33 Math Steps 6, 7, & ln K 0 C K

34 MKT vs Average = kj/mol = kj/mol = kj/mol

35 Historical Context Intended Purpose (Decreasing Duration) Stability Studies Controlled Storage Distribution Measurement Technology (Increasing # of Data Points) Min/Max Thermometer Chart Recorder Logger CMS Calculation Technology (Increasing Ease of Calculation) Pencil Calculator Custom SW Spreadsheet CMS

36 Calculation Recommendations 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.

37 How does viewlinc help with MKT? 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 = kj/mol

38 What does Guidance say about MKT? Calculation Recommendations Environmental Stability Requirements for MKT Temperatures suitable for MKT analysis Processes Suitable for MKT analysis

39 Stability Requirements for MKT 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.

40 Temperatures suitable for MKT 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.

41 Processes suitable for MKT 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.

42 MKT and GDP (Part I) 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.

43 MKT and GDP (Part 2) Challenges Is it the right calculation? Collecting and managing monitoring data. Lifetime MKT Budget Sufficient stability data to support conclusions.

44 6 MKT Rules (from our Application Note) 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 f 92bd 938aab9cf4c8}_CEN G Mean Kinetic Temperature Application Note B211534EN A FINAL.pdf

45 Review HISTORY - Where did MKT come from? MATH How do we calculate MKT? APPLICATION What can we do with MKT?

46 Contacts: Questions on GxP Questions on applications To ensure you can receive Vaisala s set your preferences at:

47 Thank you for your time! For more information. viewlinc.vaisala.com Paul Daniel Sr. Regulatory Compliance Expert 47

48 References and Sources 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, European Compliance Academy (ECA), GMP News : GDP Question: When to use Mean Kinetic Temperature Calculation (MKT)? European Compliance Academy (ECA), GMP News : GDP: Is temperature control required for each Transport? FDA, Draft Guidance, Stability Testing of Drug Substances and Drug Products, ICH Harmonized Tripartite Guideline, Stability Testing of New Drug Substances and Products Q1A(R2), ICH Q1F, Explanatory Note on the Withdrawal of ICH Q1F on the ICH Website. J. Pharm. Sci., 60: , John D. Haynes. Worldwide Virtual Temperatures for Product Stability Testing. The Pharmaceutical Journal (vol 267), July 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