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
