Global Long Term Stability Testing Conditions: Position of

Global Long Term Stability Testing Conditions: Position of INDIA Saranjit Singh, Ph.D. National Institute of Pharmaceutical Education and Research (NI...

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Global Long Term Stability Testing Conditions: Position of INDIA Saranjit Singh, Ph.D. National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar

The towering importance of Long-term Stability Test Conditions

According to latest guidelines

Expiry date is determined from Long-Term Stability Test Data Accelerated data considered only supportive

Expiry Date Calculations from Long-term Data based on 95% Confidence Limits

Expiry date

From where did this concept arise?

US FDA Guidance of 1987

Historical Perspective of the Development of Global Storage Conditions

The Development of Concept of Zones Major contribution: Dr Wolfgang Grimm

The zone concept

Region

Zone I and II countries

Zone III and IV countries

Europe

All countries

------

America

Argentina, Bolivia, Chile, Canada, Mexico, Peru, Uruguay, USA

Barbados, Belize, Brazil, Costa Rica, Dominican Republic, Ecuador, El Salvador, Guatemala, Guyana, Haita, Honduras, Jamaica, Columbia, Cuba, Nicaragua, Dutch Antilles, Panama, Paraguay, Puerto Rico, Venezuela. All of these countries are assigned to CZ IV.

Asia

Afghanistan, Armenia, Azerbaijan, China, Georgia, Iran, Israel, Japan, Kazakstan, Kirghizia, Korea, Lebanon, Nepal, Syria, Tadzhikistan, Turkey, Turkmenia, Uzbekistan

Bahrain, Bangladesh, Hong Kong, India, Indonesia, Iraq (III), Jordan (III), Kampuchea, Qatar, Kuwait, Laos, Malaysia, Maldive Islands, Myanmar, Oman, Pakistan, Philippines, Saudi Arabia, Singapore, Sri Lanka, Taiwan, Thailand, United Arab Emirates, Vietnam, Yemen

Africa

Egypt, Algeria, Tunesia, Libya, Morocco, Namibia, Ruanda, South Africa, Tunesia, Zambia, Zimbabwe.

Angola, Ethiopia, Benin, Botswana (III), Burkino Faso, Burundi, Djibouti, Ivory Coast, Gabon, Gambia, Ghana, Guinea, Cameroon, Kenya, Longo, Liberia, Madagascar, Malawi, Mali, Mauritania, Mozambique, Niger, Nigeria, Senegal, Sierra Leone, Somalia, Sudan, Tanzania, Togo, Chad (III), Uganda, Zaire, Central African Republic.

Australian/ oceanic

Australia, New Zealand.

Figi. Society Islands, Marshall Islands, New Caledonia, Papua-New Guinea, Samoa, Tonga.

Advent of Zone Concept in International Guidelines

ICH guideline Q1A (1993) focused on ICH Zones I and II WHO guideline of 1996 covered non-ICH Zones III and IV, in addition to Zones I and II

Stability Storage Conditions in ICH and WHO guidelines ICH Q1A (Zones I and II) Long Term Intermediate Accelerated

25 ± 20C/60 ± 5% RH 30 ± 20C/60 ± 5% RH 40 ± 20C/75 ± 5% RH

WHO (Zones III and IV) Long Term Accelerated

30 ± 20C/35 ± 5% RH (Zone III) 30 ± 20C/70 ± 5% RH (Zone IV) 40 ± 20C/75 ± 5% RH

The Start of Politics on Long-term Stability Storage Conditions

The problem for Industry in ICH regions ICH Q1A (Zones I and II) Long Term Intermediate Accelerated

25 ± 20C/60 ± 5% RH 30 ± 20C/60 ± 5% RH 40 ± 20C/75 ± 5% RH

WHO (Zones III and IV) Long Term Accelerated

30 ± 20C/35 ± 5% RH (Zone III) 30 ± 20C/70 ± 5% RH (Zone IV) 40 ± 20C/75 ± 5% RH

Paper by Dr Nick Turner, Rapporteur, ICH EWG Q1 Stability

Copy of paper

His plea Intermediate storage condition in ICH guideline of 30 °C/60% RH for Zones I and II was equally stressful to long-term condition of 30 °C/70% RH for Zone IV in the WHO guideline

WHO accepts plea on majority recommendations by experts

Objection by African region 30 °C/60 ± 5% RH 30 °C/55% RH - 30 °C/65% RH Very dry for Coastal Africa

Re-consideration by ICH and WHO

A grand hand-shake between ICH and WHO ICH Intermediate

30 °C/65% RH WHO Zone IV Long-term

30 °C/65% RH Again a win-win situation for industry in ICH regions

Introduction of ICH Q1F guidance

Guideline Q1F for Zones III and IV Parent drug stability guideline considered applicable to Zones III and IV, except conditions for long-term testing Long-term : 30 °C/65% RH for 12 months (also an intermediate condition for Zones I and II) Accelerated: 40 °C/75% RH for 6 months Additional conditions to cover special storage requirements or shipment: 45-50 °C and 25 °C/80% RH

Summary of changes in storage conditions till this point Q1A Stability Storage Condition Long Term

25 ± 20C / 60 ± 5% RH

Q1A(R) 25 ± 20C / 60 ± 5% RH

Q1A(R2)/Q1F 25 ± 20C/ 60 ± 5% RH or 30 ± 20C/65 ± 5% RH (Decision is left to the applicant)

CHANGE

Intermediate

30 ± 20C / 60 ± 5% RH

30 ± 20C / 60 ± 5% RH

30 ± 20C / 65 ± 5% RH

CHANGE

Accelerated

WHO Long-term

40 ± 20C / 75 ± 5% RH

40 ± 20C / 75 ± 5% RH

30 ± 20C/ 70 ± 5% RH

30 ± 20C/ 60 ± 5% RH CHANGE

40 ± 20C / 75 ± 5% RH 30 ± 20C/ 65 ± 5% RH

The buck doesn’t stop there

ASEAN OBJECTION

WORLD HEALTH ORGANIZATION ORGANISATION MONDIALE DE LA SANTE

STABILITY TESTING FOR HOT AND HUMID CLIMATES AN UPDATE FROM THE ASSOCIATION OF SOUTH EAST ASIAN NATIONS (ASEAN) HARMONIZATION PROCESS We should much appreciate your feedback, i.e. your comments, on whether, in light of the attached text, the current WHO conditions for long-term stability testing (real-time) should be changed from 30°C (±2°C), 65% (±5%) RH to 75% (±5%) RH, or back to 70% (±5%) RH. Please send comments to Dr S. Kopp, Quality Assurance and Safety: Medicines, Essential Drugs and Medicines Policy, World Health Organization, 1211 Geneva 27, Switzerland, fax: (+41 22) 791 4730

WORLD HEALTH ORGANIZATION ORGANISATION MONDIALE DE LA SANTE

STABILITY STUDIES IN A GLOBAL ENVIRONMENT Geneva, 13-14 December 2004 Recommendations agreed by the meeting A Revert to 30°C/70%RH as the long-term stability testing condition for Zone IV as it is likely that considerable data are already available. This might serve as a potential platform for future harmonization between ICH and WHO. B Change to 30°C/75%RH as the long-term stability testing condition for Zone IV in the interest of patient safety worldwide. C Add a new climatic Zone IVb to accommodate hot and very humid areas (30°C/75% RH). The present Zone IV (30°C/65%RH) would become Zone IVa. Feedback is requested by end March 2005 at the latest.

http://www.who.int/medicines/areas/quality_safety/quality_assurance/regulatory_ standards/en/index.html

Modified Storage Conditions Long Term

25 ± 20C/60 ± 5% RH (Zones I and II) 30 ± 20C/65 ± 5% RH (Zones III and IVa) 30 ± 20C/75 ± 5% RH (Zone IVb)

Intermediate 30 ± 20C/65 ± 5% RH (Zones I and II) Accelerated

40 ± 20C/75 ± 5% RH (All zones)

Rise in Regional Expectations

Regional guidelines ASEAN EMR

South America

BRAZIL

MEXICO

Central America and the Caribbean

COSTA RICA

PANAMA CENTRAL AMERICA

CHINA

Chinese Pharmacopoeia

Withdrawal of Q1F Stability Data Package for Registration Applications in Climatic Zones III and IV

SUMMARY

The on-going revision of WHO guideline

WHO-EMR Guideline February 2006

The Position of India

Presenting data for long-term storage conditions of India at AAPS workshop at Bethesda, USA on 11 September 2007

INDIA Located in Asia, sandwiched between Africa and Indonesia

North of equator between 8º 4’ and 37º 6’ north latitude and 68º 7’ and 97º 25’ east longitude

INDIA PHYSICAL AND CLIMATIC CONDITIONS

Most of the India's northern states are situated in the Himalayan Mountain Range. The central and eastern India consists of the fertile Indo-Gangetic plain. In the west is the Thar Desert. The southern Indian Peninsula is almost entirely composed of the Deccan plateau, which has two hilly coastal ranges, the Western Ghats and Eastern Ghats.

Köppen system India hosts several major climatic subtypes: Alpine tundra and glaciers in the north, Arid desert in the west, Humid tropical regions supporting rainforests in the southwest and the island territories. Many regions have starkly different microclimates. The nation has four seasons: Winter (January and February), Summer (March to May), Monsoon (rainy) season (June to September), Post-monsoon period (October to December).

Leh and Ladakh

Rajasthan

Kerala

Utaranchal

Himachal

Madhya Pradesh

Gujarat coast

Maharashtra Andhra Pradesh

Lakshwadeep

Source: Wikimedia

Commons

‘’’&(

INDIA CALCULATION OF LONG-TERM STABILITY TEST CONDITIONS BY ZAHN’S RISK-BASED APPROACH

Calculation Methodology Calculation for Vapor Pressures (Revised Wexler’s Equation)

6

Ln PS = Σgi Ti-2 + g7 lnT i=0 6

Ln PD = Σgi Tdi-2 + g7 lnTd i=0

PS = Saturated vapor pressure over water in pure phase (Pa) PD = Partial water vapor pressure T = Temperature (°K)

Calculations for Margins of Safety YT = [(TS-T)/T]*100, YPD = [(PS-P)/P]*100 YT = Margin of Safety for Temperature [%] TS = Stability testing storage temperature T = Temperature measured in the environment or calculated as MKT YPD = Margin of Safety for Partial Water Vapor Pressure [%] TS = Partial water vapor pressure at stability testing storage RH

Td = Dew point temperature (°K)

T = partial water vapor pressure at pressure measured in the environment or calculated as MKT

go = - 2.8365744 x 103

YT >0 if TS >T and YT =0 if TS =T

g1 = - 6.028076559 x 103

YPD >0 if PS >P and YPD =0 if PS =P

g2 = 1.954263612 x 101

YT and/or YPD <0 means probability of failure

g3 = - 2.737830188 x 10-2 g4 = - 1.6261698 x 10-5 g5 = 7.0229056 x 10-10 g6 = 1.8680009 x 10-13 g7 = 2.7150305 (Wexler, A., Vapor Pressure Formulation for Water in Range 0 to 100°C. A Revision Journal of Research of the National Bureau of Standards – A. Physics and Chemistry September – December 1976, Vol. 80A, Nos. 5 and 6, 775-7.)

Mean Kinetic Temperature calculation (Haynes equation)

Relative Humidity calculation RH = [PD/PS]*100 RH = Relative humidity PS = Saturated vapor pressure PD = Partial vapor pressure

Ea/R

MKT = -ln [(e-Ea/R*T1+ e-Ea/R*T2+…)/n] MKT = Mean kinetic temperature (°K) Ea = Activation energy (~83 KJ/mol) R = Universal gas constant (=8.314J/°K mol) T = Absolute temperature (°K)

‰ MKT and PD are calculated on the basis of mean metrological values (temperature and dew point) obtained after the assessment of climate data of the particular place (city here). ‰ Hottest and the most humid place amongst the cities taken for calculation will determine the long term testing conditions applicable to the entire country

Calculations taking Indian Climatological data

Stability testing condition for selected cities of India based on Indian climatological data (1951-1980), calculated according to Zahn

Cities

T

MKT

YT

PD

RH

[°C]

[°C]

[%]

[hPa]

[%]

RH %

Testing condition

at 30 °C [°C/% RH]

Mumbai

34.01 34.10 -12.02 26.28

78.08

62.06

Chennai

35.12 35.71 -15.98 27.90

75.17

65.88

Calcutta

35.04 35.61 -15.76 26.23

75.50

61.95

Trivandrum 32.24 32.29

-7.09

27.90

79.17

65.89

Bangalore 31.63 31.96

-6.12

19.75

79.00

46.64

Hyderabad 34.93 35.68 -15.91 20.04

68.33

47.33

Nagpur

36.95 38.12 -21.31 17.79

59.58

42.01

Patna

35.66 36.87 -18.64 21.54

66.08

50.87

30/65 30/75 30/65 30/75 30/65 30/75 30/65 30/75 30/65 30/75 30/65 30/75 30/65 30/75 30/65 30/75

PD [hPa] at test condition 27.61 31.85 27.61 31.85 27.61 31.85 27.61 31.85 27.61 31.85 27.61 31.85 27.61 31.85 27.61 31.85

YPD [%] 5.05 21.18 -1.04 14.16 5.25 21.41 -1.04 14.16 39.80 61.27 37.76 58.92 55.19 79.02 28.17 47.85

T = Temperature, MKT = Mean Kinetic Temperature, YT = Margin of Safety for Temperature [%], PD = Partial Water Vapor Pressure, RH = Relative Humidity [%], YPD = Margin of Safety for Partial Water Vapor Pressure [%].

Assignment of CZ for selected cities of India based on Indian climatological data (1951-1980) according to current WHO Classification

Cities

T [°C] Mumbai 34.01 Chennai 35.12 Calcutta 35.04 Trivandrum 32.24 Bangalore 31.63 Hyderabad 34.93 Nagpur 36.95 Patna 35.66

PD [hPa] 27.28 27.90 26.23 27.90 19.75 20.04 17.79 21.54

T/PD > 22°C / > 15-27 hPa > 22°C / > 27 hPa > 22°C / > 15-27 hPa > 22°C / > 27 hPa > 22°C / > 15-27 hPa > 22°C / > 15-27 hPa > 22°C / > 15-27 hPa > 22°C / > 15-27 hPa

RH % at 30 °C 62.06 65.88 61.95 65.89 46.64 47.33 42.01 50.87

Testing Conditions 30°C / 65% RH 30°C / 75% RH 30°C / 65% RH 30°C / 75% RH 30°C / 65% RH 30°C / 65% RH 30°C / 65% RH 30°C / 65% RH

CZ IVA IVB IVA IVB IVA IVA IVA IVA

T = Temperature, MKT = Mean Kinetic Temperature, YT = Margin of Safety for Temperature [%], PD = Partial Water Vapor Pressure, RH = Relative Humidity [%], YPD = Margin of Safety for Partial Water Vapor Pressure [%].

Calculations taking data supplied by Dr Zahn

Selection of cities 1. Srinagar 2. Amritsar 3. Jodhpur 4. Ahmedabad 5. Mumbai 6. Goa 7. Trivandrum 8. Chennai 9. Puri 10. Kolkata 11. Mizoram 12. Cherapunji 13. Patna 14. Delhi 15. Bhopal 16. Nagpur 17. Hyderabad 18. Bangalore

Stability testing condition for selected cities of India (Data received from Dr Zahn) Zahn) Cities

T

MKT

YT

PD

RH

RH %

[°C]

[°C]

[%]

[hPa]

Srinagar

2.78

6.30 376.17

Jodhpur

25.74 28.36

5.76

13.70 41.35

32.35

Ahmedabad

26.87 28.07

6.88

19.38 74.59

45.76

Mumbai

26.24 27.12 10.63

22.03 64.55

52.01

Goa

25.58 26.33 13.94

21.86 66.62

51.62

Trivandrum

27.31 27.48

9.17

29.14 80.20

68.80

Chennai

28.25 29.09

3.11

25.93 67.56

61.22

Puri

26.69 27.37

9.62

26.16 74.69

61.78

Kolkata

25.71 26.94 11.36

24.15 73.25

57.04

Mizoram

22.40 23.35 28.51

20.11 74.41

47.49

Cherapunji

22.42 23.50 27.67

21.56 79.71

50.92

Patna

25.16 26.96 11.27

20.33 63.70

48.01

Delhi

24.53 27.40

9.48

17.09 55.62

40.36

Bhopal

25.71 27.78

7.98

15.76 47.80

37.22

Nagpur

26.74 28.49

5.32

19.21 54.81

45.35

Hyderabad

27.27 28.40

5.63

20.88 57.74

49.29

Bangalore

24.99 25.71 16.68

20.99 66.46

49.56

Amritsar

21.49 24.49 22.52

15.64 61.18

36.93

at 30 °C 5.52 73.71 13.03 [%]

Testing condition [°C/% RH] 30/65 30/75 30/65 30/75 30/65 30/75 30/65 30/75 30/65 30/75 30/65 30/75 30/65 30/75 30/65 30/75 30/65 30/75 30/65 30/75 30/65 30/75 30/65 30/75 30/65 30/75 30/65 30/75 30/65 30/75 30/65 30/75 30/65 30/75 30/65 30/75

PD [hPa] at test condition 27.61 31.85 27.61 31.85 27.61 31.85 27.61 31.85 27.61 31.85 27.61 31.85 27.61 31.85 27.61 31.85 27.61 31.85 27.61 31.85 27.61 31.85 27.61 31.85 27.61 31.85 27.61 31.85 27.61 31.85 27.61 31.85 27.61 31.85 27.61 31.85

YPD [%] 400.45 477.31 101.56 132.51 42.46 64.34 25.36 44.61 26.29 45.68 -5.24 9.31 6.49 22.85 5.54 21.74 14.31 31.86 37.27 58.35 28.05 47.71 35.80 35.80 61.54 86.35 75.16 75.16 43.75 65.83 32.26 52.57 31.55 51.76 76.56 103.67

T = Temperature, MKT = Mean Kinetic Temperature, YT = Margin of Safety for Temperature [%], PD = Partial Water Vapor Pressure, RH = Relative Humidity [%], YPD = Margin of Safety for Partial Water Vapor Pressure [%].

Assignment of CZ for selected cities of India according to current WHO classification criteria Cities

T [°C]

PD [hPa]

T/ PD

RH % at 30 °C

Testing Conditions

CZ

Srinagar

2.78

5.52

≤ 15°C / ≤ 11 hPa

13.03

21°C / 45% RH

I

25.74 26.87 26.24 25.58 27.31 28.25 26.69 25.71 22.40 22.42 25.16 24.53 25.71 26.74 27.27 24.99 21.49

13.70 19.38 22.03 21.86 29.14 25.93 26.16 24.15 20.11 21.56 20.33 17.09 15.76 19.21 20.88 20.99 15.64

> 22°C / ≤ 15 hPa > 22°C / > 15-27 hPa > 22°C / > 15-27 hPa > 22°C / > 15-27 hPa > 22°C / > 27 hPa > 22°C / > 15-27 hPa > 22°C / > 15-27 hPa > 22°C / > 15-27 hPa > 22°C / > 15-27 hPa > 22°C / > 15-27 hPa > 22°C / > 15-27 hPa > 22°C / > 15-27 hPa > 22°C / > 15-27 hPa > 22°C / > 15-27 hPa > 22°C / > 15-27 hPa > 22°C / > 15-27 hPa > 22°C / > 15-27 hPa

32.35 45.76 52.01 51.62 68.80 61.22 61.78 57.04 47.49 50.92 48.01 40.36 37.22 45.35 49.29 49.56 36.93

30°C / 35% RH 30°C / 65% RH 30°C / 65% RH 30°C / 65% RH 30°C / 75% RH 30°C / 65% RH 30°C / 65% RH 30°C / 65% RH 30°C / 65% RH 30°C / 65% RH 30°C / 65% RH 30°C / 65% RH 30°C / 65% RH 30°C / 65% RH 30°C / 65% RH 30°C / 65% RH 30°C / 65% RH

III IVA IVA IVA IVB IVA IVA IVA IVA IVA IVA IVA IVA IVA IVA IVA IVA

Jodhpur Ahmedabad Mumbai Goa Trivandrum Chennai Puri Kolkata Mizoram Cherapunji Patna Delhi Bhopal Nagpur Hyderabad Banglore Amritsar

T = Temperature, MKT = Mean Kinetic Temperature, YT = Margin of Safety for Temperature [%], PD = Partial Water Vapor Pressure, RH = Relative Humidity [%], YPD = Margin of Safety for Partial Water Vapor Pressure [%].

Calculations by including 30 ºC/70% RH Stability testing condition for selected cities of India based on Indian climatological data (1951-1980) Cities Mumbai

T MKT YT PD [°C] [°C] [%] [hPa] 34.01 34.10 -12.02 26.28

RH [%] 78.08

Chennai

35.12 35.71 -15.98 27.90

75.17

Calcutta

35.04 35.61 -15.76 26.23

75.50

Trivandrum 32.24 32.29

-7.09

27.90

79.17

Bangalore 31.63 31.96

-6.12

19.75

79.00

Hyderabad 34.93 35.68 -15.91 20.04

68.33

Nagpur

36.95 38.12 -21.31 17.79

59.58

Patna

35.66 36.87 -18.64 21.54

66.08

RH % Testing condition PD [hPa] at 30 °C [°C/% RH] at test condition 30/65 62.06 27.61 30/70 29.73 30/75 31.85 65.88 30/65 27.61 30/70 29.73 30/75 31.85 30/65 61.95 27.61 30/70 29.73 30/75 31.85 65.89 30/65 27.61 30/70 29.73 30/75 31.85 30/65 46.64 27.61 30/70 29.73 30/75 31.85 30/65 47.33 27.61 30/70 29.73 30/75 31.85 30/65 42.01 27.61 30/70 29.73 30/75 31.85 30/65 50.87 27.61 30/70 29.73 30/75 31.85

YPD [%] 5.05 13.11 21.18 -1.04 6.56 14.16 5.25 13.33 21.41 -1.04 6.56 14.16 39.80 50.53 61.27 37.76 48.34 58.92 55.19 67.10 79.02 28.17 38.01 47.85

T = Temperature, MKT = Mean Kinetic Temperature, YT = Margin of Safety for Temperature [%], PD = Partial Water Vapor Pressure, RH = Relative Humidity [%], YPD = Margin of Safety for Partial Water Vapor Pressure [%].

Calculations by including 30 ºC/70% RH Stability testing condition for selected cities of India for data received from Dr Zahn Cities

Srinagar

Jodhpur

T

MKT

YT

PD

[°C]

[°C]

[%]

[hPa]

2.78

6.30

376.2

5.52

25.74 28.36

Ahmedabad 26.87 28.07

Mumbai

Goa

Puri

Kolkata

6.88

26.24 27.12 10.63

25.58 26.33 13.94

Trivandrum 27.31 27.48

Chennai

5.76

28.25 29.09

26.69 27.37

9.17

3.11

9.62

25.71 26.94 11.36

13.70

19.38

22.03

21.86

29.14

25.93

26.16

24.15

RH

RH %

Testing condition

PD [hPa]

YPD

at 30 at test [%] [°C/% RH] °C condition 73.71 13.03 30/65 27.61 400.45 30/70 29.73 438.88 30/75 31.85 477.31 41.35 32.35 30/65 27.61 101.56 30/70 29.73 117.04 30/75 31.85 132.51 74.59 45.76 30/65 27.61 42.46 30/70 29.73 53.40 30/75 31.85 64.34 64.55 52.01 30/65 27.61 25.36 30/70 29.73 34.98 30/75 31.85 44.61 66.62 51.62 30/65 27.61 26.29 30/70 29.73 35.99 30/75 31.85 45.68 80.20 68.80 30/65 27.61 -5.24 30/70 29.73 2.04 30/75 31.85 9.31 67.56 61.22 30/65 27.61 6.49 30/70 29.73 14.67 30/75 31.85 22.85 74.69 61.78 30/65 27.61 5.54 30/70 29.73 13.64 30/75 31.85 21.74 73.25 57.04 30/65 27.61 14.31 30/70 29.73 23.08 30/75 31.85 31.86

Cities

T

MKT

YT

PD

RH

RH %

Testing condition

PD [hPa]

YPD

at 30 at test [°C/% RH] [%] °C condition 22.40 23.35 28.51 20.11 74.41 47.49 30/65 27.61 37.27 [°C] [°C] [%] [hPa] [%]

[%]

Mizoram

Cherapunji 22.42 23.50 27.67 21.56 79.71 50.92

Patna

Delhi

Bhopal

Nagpur

25.16 26.96 11.27 20.33 63.70 48.01

24.53 27.40 9.48 17.09 55.62 40.36

25.71 27.78 7.98 15.76 47.80 37.22

26.74 28.49 5.32 19.21 54.81 45.35

Hyderabad 27.27 28.40 5.63 20.88 57.74 49.29

Banglore

Amritsar

24.99 25.71 16.68 20.99 66.46 49.56

21.49 24.49 22.52 15.64 61.18 36.93

30/70

29.73

47.81

30/75

31.85

58.35

30/65

27.61

28.05

30/70

29.73

37.88

30/75

31.85

47.71

30/65

27.61

35.80

30/70

29.73

46.23

30/75

31.85

35.80

30/65

27.61

61.54

30/70

29.73

73.94

30/75

31.85

86.35

30/65

27.61

75.16

30/70

29.73

88.61

30/75

31.85

75.16

30/65

27.61

43.75

30/70

29.73

54.79

30/75

31.85

65.83

30/65

27.61

32.26

30/70

29.73

42.42

30/75

31.85

52.57

30/65

27.61

31.55

30/70

29.73

41.66

30/75

31.85

51.76

30/65

27.61

76.56

30/70

29.73

90.11

30/75

31.85

103.67

T = Temperature, MKT = Mean Kinetic Temperature, YT = Margin of Safety for Temperature [%], PD = Partial Water Vapor Pressure, RH = Relative Humidity [%], YPD = Margin of Safety for Partial Water Vapor Pressure [%].

So what is the real long-term stability test condition for INDIA? 30 ºC/65% RH

Taking country at large

30 ºC/70% RH

Taking value for Trivandrum, based on actual calculation

30 ºC/75% RH

Taking value for Trivandrum, based on current WHO classification

INDIA has a Diverse climate, but it is not truly a Diver’s climate

Brazil 30 ºC/75% RH

INDIA

ASEAN 30 ºC/75% RH

30 ºC/65% RH Taking country at large 30 ºC/70% RH Taking value for Trivandrum, based on actual calculation 30 ºC/75% RH Taking value for Trivandrum, based on current WHO classification

Consideration of Climatological and Population Maps Köppen Map

30 ºC/65% RH

Taking country at large

30 ºC/70% RH Considering tropical wet conditions and dense population in the state of Kerala 30 ºC/75% RH

Taking value for Trivandrum, based on current WHO classification

Revised criteria to classify Climatic Zones and recommended testing conditions CZ

Definition

I

Temperate climate Subtropical and Mediterranean Climate Hot and dry climate Hot and low humid climate Hot and moderately humid climate Hot and very humid climate

II III IVA IVB IVC

Criteria Mean annual temperature measured in the open air / Mean annual partial water vapour pressure ≤ 15°C / ≤ 11 hPa

21°C / 45% RH

> 15 to 22°C / > 11 to 18 hPa

25°C / 60% RH

> 22°C / ≤ 15 hPa

30°C / 35% RH

> 22°C / > 15 to 27 hPa

30°C / 65% RH

> 22°C / 27 to 30 hPa

30°C / 70% RH

> 22°C / > 30 hPa

30°C / 75% RH

Testing conditions

Current criteria to classify Climatic Zones and recommended testing conditions CZ

Definition

I

Temperate climate Subtropical and Mediterranean Climate Hot and dry climate Hot and humid climate Hot and very humid climate

II III IVA IVB

Criteria Mean annual temperature measured in the open air / Mean annual partial water vapour pressure ≤ 15°C / ≤ 11 hPa

21°C / 45% RH

> 15 to 22°C / > 11 to 18 hPa

25°C / 60% RH

> 22°C / ≤ 15 hPa

30°C / 35% RH

> 22°C / > 15 to 27 hPa

30°C / 65% RH

> 22°C / > 27 hPa

30°C / 75% RH

Testing conditions

Current Trends in Stability Testing to Support Global Markets Series: Biotechnology: Pharmaceutical Aspects Huynh-Ba, Kim (Ed.) 2009, Approx. 215 p. 11 illus., 4 in color., Hardcover ISBN: 978-1-4419-0888-9 Due: October 2009 approx. 145,55 €

The more recent development

Suggested revision Regional Office for South-East Asia (SEARO) Bangladesh Bhutan

30°C/65% RH2

Democratic People's Republic of Korea India

30°C/70% RH1/30°C/75% RH1

Indonesia

30°C/75% RH1

Maldives Myanmar

30°C/75% RH1

Nepal

30°C/75% RH2

Sri Lanka Thailand Timor-Leste

30°C/75% RH1

Consequence of 30 °C/70% RH/30 °C/75% RH

N. A. Visalakshi, T. T. Mariappan, Hemant Bhutani, and Saranjit Singh, Pharmaceutical Development and Technology, 10, 489–497 (2005)

What is the meaning of the word ‘TROPICAL’

Southern Europe Swelters in Second Heat Wave The Associated Press 26.07.07

Heat wave scorches Western states of US Triple-digit temperatures forecast to set records www.msn.com 06.07.07

Intense light conditions in Zones III/IV In Zones III/IV >> Light intensity ≅ 50,000 lux on any summer day One week of light in an Asian country ≡ total light in a year in a country in Europe

What is the meaning of the word ‘TROPICAL’ • High Temperature? • High Humidity? • Intense Light? • High Temperature + High Humidity? • High Temperature + High Humidity + Intense Light?

What INTENSE LIGHT can do?

Saranjit Singh, R. Manikandan and Sukhjeet Singh, Pharmaceutical Technology, 24(5), 58-72 (2000)

Saranjit Singh, H. Bhutani, T.T. Mariappan, H. Kaur, M. Bajaj, and S.P. Pakhale, International Journal of Pharmaceutics, 245, 37-44 (2002)

Maximum difference in weight gain, %

40

30

20

10

0 Drugs/Excipients Difference in gain of moisture by drugs and excipients in light as compared to dark

Saranjit Singh, T.T. Mariappan and H. Kaur, Pharmaceutical Technology, 27(12) 52,54, 56 (2003)

Exp to 40 °C/75% RH (5 d)

Exp to 40 °C/75% RH/Light (5 d)

Exp to 40 °C/75% RH (5 d)

Exp to 40 °C/75% RH/Light (5 d)

Saranjit Singh and B. Mohan, The International Journal of Tuberculosis and Lung Disease, 7(3) 298-303 (2003)

Control

Dark

Light

H. Bhutani, T.T. Mariappan and Saranjit Singh, The International Journal of Tuberculosis and Lung Disease, 8 (9) 1073-1080 (2004)

Control

Dark

Light

A. Gaur, H. Bhutani, T.T. Mariappan and Saranjit Singh, Indian Journal Pharmaceutical Sciences, 67(4) 438-443 (2005)

Control

Dark

Light

A. Gaur, H. Bhutani, T.T. Mariappan and Saranjit Singh, Indian Journal Pharmaceutical Sciences, 67(4) 438-443 (2005)

So should the stability chambers be dark from inside?

Stability chambers with temperature, humidity, and light

So the best stability test condition for

INDIA

Long-term Test Condition 30 ºC/70% RH with continuous exposure to average indoor light ?

Why this suggestion? There are several field problems that are practically observed but not revealed through stability studies in dark chambers

Proposed Stress Condition

40 °C/75% RH with a minimum of 1.2 million lux h fluorescent 2 and 200 Wh/m UVA light

Any need for extended Accelerated Testing?

RELEVANCE OF STABILITY TEST CONDITIONS OF

INDIA

EXPORTS FROM INDIA

Stability data generated under suggested INDIAN conditions should be acceptable in large parts of the world

IMPORTS TO INDIA

Stability studies by exporters shall comply to tropical environment of India

MANUFACTURE AND SALE WITHIN INDIA

There is minimum tempering in distribution system Products are sold without secondary packs Shops facing East direction open directly to sunlight So suggested conditions very relevant

A change is needed

Poor storage conditions, transportation without refrigeration degrade most pharma products January 4, 2002 Our Bureau, Mumbai Poor storage conditions in pharmaceutical factory godowns, transportation without refrigeration and absence of air-conditioning in retail chemist shops are all causing steady degradation of a large number of essential and life saving drugs before they reach the ultimate consumer. Informed sources said that in the absence of any study, it is very difficult to assess extend of damage that happens to the pharmaceutical products sold in retail shops. Companies do accelerated degradation studies in factory environs, but the temperatures and the extent of exposure may not always stand by the theoretic calculations. The problem is not serious as the consumer, the poor patient, hardly knows what degradation is when he goes to a shop to pick his drug.

Some other suggestions 9Moisture in solid formulations should be restricted up to 1-2% 9Stringent microbial control of excipients or alternatively addition of preservatives even in solid formulations 9Use of excipients that do not absorb or adsorb moisture 9Protection of products from light

Other solutions 9Rugged packaging with moisture resistant properties • Glass bottles • Cold- formed aluminum foil-foil blisters • Aluminum flexible foil-strip blisters • PVC, PVC/PVDC or ACLAR blisters

9Qualification of inks and packaging materials before use

THANKS