Global Long Term Stability Testing Conditions: Position of INDIASaranjit 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 coverednon-ICH Zones III and IV, in addition to Zones I and II

ICH Q1A (Zones I and II)25 ± 20C/60 ± 5% RHLong Term30 ± 20C/60 ± 5% RHIntermediate40 ± 20C/75 ± 5% RHAccelerated

Stability StorageConditions in ICH and WHO guidelines

WHO (Zones III and IV)30 ± 20C/35 ± 5% RH (Zone III)Long Term

40 ± 20C/75 ± 5% RHAccelerated30 ± 20C/70 ± 5% RH (Zone IV)

The Start of Politics on Long-term Stability Storage

Conditions

ICH Q1A (Zones I and II)25 ± 20C/60 ± 5% RHLong Term30 ± 20C/60 ± 5% RHIntermediate40 ± 20C/75 ± 5% RHAccelerated

The problem for Industry in ICH regions

WHO (Zones III and IV)30 ± 20C/35 ± 5% RH (Zone III)Long Term

40 ± 20C/75 ± 5% RHAccelerated30 ± 20C/70 ± 5% RH (Zone IV)

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 Very dry for Coastal AfricaCoastal Africa

Re-consideration by ICH and WHO

A grand hand-shakebetween ICH and WHO

ICH Intermediate30 °C/65% RH

WHO Zone IV Long-term30 °C/65% RH

Again a win-win situation for industry in ICH regions

Introduction of ICH Q1F guidance

Guideline Q1F for Zones III and IVParent drug stability guideline considered applicable to Zones III and IV, except conditions for long-term testingLong-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

Q1A Q1A(R) Q1A(R2)/Q1F

25 ± 20C / 60 ± 5% RH

25 ± 20C / 60 ± 5% RH

25 ± 20C/ 60 ± 5% RHor 30 ± 20C/65 ± 5% RH

(Decision is left to the applicant)

Stability StorageCondition

Long Term

30 ± 20C / 60 ± 5% RH

30 ± 20C / 60 ± 5% RH

30 ± 20C / 65 ± 5% RHIntermediate

40 ± 20C / 75 ± 5% RH

40 ± 20C / 75 ± 5% RH

40 ± 20C / 75 ± 5% RHAccelerated

CHANGE

CHANGE

Summary of changes in storage conditions till this point

30 ± 20C/65 ± 5% RH

30 ± 20C/60 ± 5% RH

30 ± 20C/70 ± 5% RH

WHO Long-term

CHANGE

The buck doesn’t stop there

ASEAN OBJECTION

STABILITY TESTING FOR HOT AND HUMID CLIMATESAN UPDATE FROM THE ASSOCIATION OF SOUTH EAST ASIAN

NATIONS (ASEAN) HARMONIZATION PROCESSWe 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 ENVIRONMENTGeneva, 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.

WORLD HEALTH ORGANIZATION

ORGANISATION MONDIALE DE LA SANTE

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

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)

Long Term

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

40 ± 20C/75 ± 5% RH (All zones)Accelerated

Modified Storage Conditions

Rise in Regional Expectations

Regional guidelinesASEAN

EMR

BRAZIL

MEXICO

South America

PANAMA

CENTRAL AMERICA

COSTA RICA

Central America and the Caribbean

Chinese Pharmacopoeia

CHINA

Withdrawal of Q1FStability 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 Located in Asia, sandwiched between

Africa and IndonesiaAfrica and Indonesia

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

INDIAPHYSICAL 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 Utaranchal Himachal

Gujarat coast

Maharashtra Lakshwadeep

Rajasthan Madhya Pradesh

Andhra PradeshKerala

Source: Wikimedia Commons

‘’’&(

INDIACALCULATION OF LONG-TERM

STABILITY TEST CONDITIONS BY ZAHN’S RISK-BASED APPROACH

Calculation MethodologyCalculations for Margins of SafetyCalculations for Margins of Safety

YT = [(TSYT = [(TS--T)/T]*100, YPD = [(PST)/T]*100, YPD = [(PS--P)/P]*100P)/P]*100YT = 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

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

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

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

YT and/or YPD <0 means probability of failure

Mean Kinetic Temperature calculationMean Kinetic Temperature calculation(Haynes equation)

Ea/REa/R--lnln [(e[(e--Ea/R*T1Ea/R*T1+ e+ e--Ea/R*T2Ea/R*T2++……)/n])/n]

MKT = Mean kinetic temperature (°K)Ea = Activation energy (~83 KJ/mol)R = Universal gas constant (=8.314J/°K mol)T = Absolute temperature (°K)

MKTMKT ==

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

LnLn PS = PS = ΣΣggii TTii--2 2 + g+ g77 lnTlnT

LnLn PD = PD = ΣΣggii TTddii--22 + g+ g77 lnTlnTdd

PS = Saturated vapor pressure over water in pure phase (Pa)

PD = Partial water vapor pressure

T = Temperature (°K)

Td = Dew point temperature (°K)

go = - 2.8365744 x 103

g1 = - 6.028076559 x 103

g2 = 1.954263612 x 101

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.)

66

i = 0i = 0

Relative Humidity calculationRelative Humidity calculation

RH = [PD/PS]*100RH = [PD/PS]*100RH = Relative humidity

PS = Saturated vapor pressure

PD = Partial vapor pressure

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

66

i = 0i = 0

Calculations taking Indian Climatological data

Cities T MKT YT PD RH RH % Testing condition PD [hPa] YPD

[°C] [°C] [%] [hPa] [%] at 30 °C [°C/% RH] at test condition [%]

Mumbai 34.01 34.10 -12.02 26.28 78.08 62.06 30/65 27.61 5.05 30/75 31.85 21.18

Chennai 35.12 35.71 -15.98 27.90 75.17 65.88 30/65 27.61 -1.04 30/75 31.85 14.16

Calcutta 35.04 35.61 -15.76 26.23 75.50 61.95 30/65 27.61 5.25 30/75 31.85 21.41

Trivandrum 32.24 32.29 -7.09 27.90 79.17 65.89 30/65 27.61 -1.04 30/75 31.85 14.16

Bangalore 31.63 31.96 -6.12 19.75 79.00 46.64 30/65 27.61 39.80 30/75 31.85 61.27

Hyderabad 34.93 35.68 -15.91 20.04 68.33 47.33 30/65 27.61 37.76 30/75 31.85 58.92

Nagpur 36.95 38.12 -21.31 17.79 59.58 42.01 30/65 27.61 55.19 30/75 31.85 79.02

Patna 35.66 36.87 -18.64 21.54 66.08 50.87 30/65 27.61 28.17 30/75 31.85 47.85

Stability testing condition for selected cities of India based on

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 [%].

Indian climatological data (1951-1980), calculated according to Zahn

Cities T PD RH % Testing [°C] [hPa] T/PD at 30 °C Conditions CZ

Mumbai 34.01 27.28 > 22°C / > 15-27 hPa 62.06 30°C / 65% RH IVA Chennai 35.12 27.90 > 22°C / > 27 hPa 65.88 30°C / 75% RH IVB Calcutta 35.04 26.23 > 22°C / > 15-27 hPa 61.95 30°C / 65% RH IVA Trivandrum 32.24 27.90 > 22°C / > 27 hPa 65.89 30°C / 75% RH IVB Bangalore 31.63 19.75 > 22°C / > 15-27 hPa 46.64 30°C / 65% RH IVA Hyderabad 34.93 20.04 > 22°C / > 15-27 hPa 47.33 30°C / 65% RH IVA Nagpur 36.95 17.79 > 22°C / > 15-27 hPa 42.01 30°C / 65% RH IVA Patna 35.66 21.54 > 22°C / > 15-27 hPa 50.87 30°C / 65% RH IVA

Assignment of CZ for selected cities of India based on

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 [%].

Indian climatological data (1951-1980) according to current WHO Classification

Calculations taking data supplied by Dr Zahn

Selection of cities1. 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

Cities T MKT YT PD RH RH % Testing condition PD [hPa] YPD

[°C] [°C] [%] [hPa] [%] at 30 °C [°C/% RH] at test

condition [%]

Srinagar 2.78 6.30 376.17 5.52 73.71 13.03 30/65 27.61 400.45 30/75 31.85 477.31

Jodhpur 25.74 28.36 5.76 13.70 41.35 32.35 30/65 27.61 101.56 30/75 31.85 132.51

Ahmedabad 26.87 28.07 6.88 19.38 74.59 45.76 30/65 27.61 42.46 30/75 31.85 64.34

Mumbai 26.24 27.12 10.63 22.03 64.55 52.01 30/65 27.61 25.36 30/75 31.85 44.61

Goa 25.58 26.33 13.94 21.86 66.62 51.62 30/65 27.61 26.29 30/75 31.85 45.68

Trivandrum 27.31 27.48 9.17 29.14 80.20 68.80 30/65 27.61 -5.24 30/75 31.85 9.31

Chennai 28.25 29.09 3.11 25.93 67.56 61.22 30/65 27.61 6.49 30/75 31.85 22.85

Puri 26.69 27.37 9.62 26.16 74.69 61.78 30/65 27.61 5.54 30/75 31.85 21.74

Kolkata 25.71 26.94 11.36 24.15 73.25 57.04 30/65 27.61 14.31 30/75 31.85 31.86

Mizoram 22.40 23.35 28.51 20.11 74.41 47.49 30/65 27.61 37.27 30/75 31.85 58.35

Cherapunji 22.42 23.50 27.67 21.56 79.71 50.92 30/65 27.61 28.05 30/75 31.85 47.71

Patna 25.16 26.96 11.27 20.33 63.70 48.01 30/65 27.61 35.80 30/75 31.85 35.80

Delhi 24.53 27.40 9.48 17.09 55.62 40.36 30/65 27.61 61.54 30/75 31.85 86.35

Bhopal 25.71 27.78 7.98 15.76 47.80 37.22 30/65 27.61 75.16 30/75 31.85 75.16

Nagpur 26.74 28.49 5.32 19.21 54.81 45.35 30/65 27.61 43.75 30/75 31.85 65.83

Hyderabad 27.27 28.40 5.63 20.88 57.74 49.29 30/65 27.61 32.26 30/75 31.85 52.57

Bangalore 24.99 25.71 16.68 20.99 66.46 49.56 30/65 27.61 31.55 30/75 31.85 51.76

Amritsar 21.49 24.49 22.52 15.64 61.18 36.93 30/65 27.61 76.56 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 [%].

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

Cities T PD RH % Testing [°C] [hPa]

T/ PD at 30 °C Conditions

CZ

Srinagar 2.78 5.52 ≤ 15°C / ≤ 11 hPa 13.03 21°C / 45% RH I Jodhpur 25.74 13.70 > 22°C / ≤ 15 hPa 32.35 30°C / 35% RH III Ahmedabad 26.87 19.38 > 22°C / > 15-27 hPa 45.76 30°C / 65% RH IVA Mumbai 26.24 22.03 > 22°C / > 15-27 hPa 52.01 30°C / 65% RH IVA Goa 25.58 21.86 > 22°C / > 15-27 hPa 51.62 30°C / 65% RH IVA Trivandrum 27.31 29.14 > 22°C / > 27 hPa 68.80 30°C / 75% RH IVB Chennai 28.25 25.93 > 22°C / > 15-27 hPa 61.22 30°C / 65% RH IVA Puri 26.69 26.16 > 22°C / > 15-27 hPa 61.78 30°C / 65% RH IVA Kolkata 25.71 24.15 > 22°C / > 15-27 hPa 57.04 30°C / 65% RH IVA Mizoram 22.40 20.11 > 22°C / > 15-27 hPa 47.49 30°C / 65% RH IVA Cherapunji 22.42 21.56 > 22°C / > 15-27 hPa 50.92 30°C / 65% RH IVA Patna 25.16 20.33 > 22°C / > 15-27 hPa 48.01 30°C / 65% RH IVA Delhi 24.53 17.09 > 22°C / > 15-27 hPa 40.36 30°C / 65% RH IVA Bhopal 25.71 15.76 > 22°C / > 15-27 hPa 37.22 30°C / 65% RH IVA Nagpur 26.74 19.21 > 22°C / > 15-27 hPa 45.35 30°C / 65% RH IVA Hyderabad 27.27 20.88 > 22°C / > 15-27 hPa 49.29 30°C / 65% RH IVA Banglore 24.99 20.99 > 22°C / > 15-27 hPa 49.56 30°C / 65% RH IVA Amritsar 21.49 15.64 > 22°C / > 15-27 hPa 36.93 30°C / 65% RH IVA

Assignment of CZ for selected cities of India according tocurrent WHO classification criteria

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 [%].

Cities T MKT YT PD RH RH % Testing condition PD [hPa] YPD [°C] [°C] [%] [hPa] [%] at 30 °C [°C/% RH] at test condition [%]

Mumbai 34.01 34.10 -12.02 26.28 78.08 62.06 30/65 27.61 5.05 30/70 29.73 13.11 30/75 31.85 21.18

Chennai 35.12 35.71 -15.98 27.90 75.17 65.88 30/65 27.61 -1.04 30/70 29.73 6.56 30/75 31.85 14.16

Calcutta 35.04 35.61 -15.76 26.23 75.50 61.95 30/65 27.61 5.25 30/70 29.73 13.33 30/75 31.85 21.41

Trivandrum 32.24 32.29 -7.09 27.90 79.17 65.89 30/65 27.61 -1.04 30/70 29.73 6.56 30/75 31.85 14.16

Bangalore 31.63 31.96 -6.12 19.75 79.00 46.64 30/65 27.61 39.80 30/70 29.73 50.53 30/75 31.85 61.27

Hyderabad 34.93 35.68 -15.91 20.04 68.33 47.33 30/65 27.61 37.76 30/70 29.73 48.34 30/75 31.85 58.92

Nagpur 36.95 38.12 -21.31 17.79 59.58 42.01 30/65 27.61 55.19 30/70 29.73 67.10 30/75 31.85 79.02

Patna 35.66 36.87 -18.64 21.54 66.08 50.87 30/65 27.61 28.17 30/70 29.73 38.01 30/75 31.85 47.85

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

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 [%].

Cities T MKT YT PD RH RH % Testing condition

PD [hPa] YPD

[°C] [°C] [%] [hPa] [%] at 30 °C

[°C/% RH] at test condition

[%]

Mizoram 22.40 23.35 28.51 20.11 74.41 47.49 30/65 27.61 37.27

30/70 29.73 47.81

30/75 31.85 58.35

Cherapunji 22.42 23.50 27.67 21.56 79.71 50.92 30/65 27.61 28.05

30/70 29.73 37.88

30/75 31.85 47.71

Patna 25.16 26.96 11.27 20.33 63.70 48.01 30/65 27.61 35.80

30/70 29.73 46.23

30/75 31.85 35.80

Delhi 24.53 27.40 9.48 17.09 55.62 40.36 30/65 27.61 61.54

30/70 29.73 73.94

30/75 31.85 86.35

Bhopal 25.71 27.78 7.98 15.76 47.80 37.22 30/65 27.61 75.16

30/70 29.73 88.61

30/75 31.85 75.16

Nagpur 26.74 28.49 5.32 19.21 54.81 45.35 30/65 27.61 43.75

30/70 29.73 54.79

30/75 31.85 65.83

Hyderabad 27.27 28.40 5.63 20.88 57.74 49.29 30/65 27.61 32.26

30/70 29.73 42.42

30/75 31.85 52.57

Banglore 24.99 25.71 16.68 20.99 66.46 49.56 30/65 27.61 31.55

30/70 29.73 41.66

30/75 31.85 51.76

Amritsar 21.49 24.49 22.52 15.64 61.18 36.93 30/65 27.61 76.56

30/70 29.73 90.11

30/75 31.85 103.67

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

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 [%].

Cities T MKT YT PD RH RH % Testing

condition PD [hPa] YPD

[°C] [°C] [%] [hPa] [%] at 30

°C [°C/% RH] at test

condition [%]

Srinagar 2.78 6.30 376.2 5.52 73.71 13.03 30/65 27.61 400.45 30/70 29.73 438.88 30/75 31.85 477.31

Jodhpur 25.74 28.36 5.76 13.70 41.35 32.35 30/65 27.61 101.56 30/70 29.73 117.04 30/75 31.85 132.51

Ahmedabad 26.87 28.07 6.88 19.38 74.59 45.76 30/65 27.61 42.46 30/70 29.73 53.40 30/75 31.85 64.34

Mumbai 26.24 27.12 10.63 22.03 64.55 52.01 30/65 27.61 25.36 30/70 29.73 34.98 30/75 31.85 44.61

Goa 25.58 26.33 13.94 21.86 66.62 51.62 30/65 27.61 26.29 30/70 29.73 35.99 30/75 31.85 45.68

Trivandrum 27.31 27.48 9.17 29.14 80.20 68.80 30/65 27.61 -5.24 30/70 29.73 2.04 30/75 31.85 9.31

Chennai 28.25 29.09 3.11 25.93 67.56 61.22 30/65 27.61 6.49 30/70 29.73 14.67 30/75 31.85 22.85

Puri 26.69 27.37 9.62 26.16 74.69 61.78 30/65 27.61 5.54 30/70 29.73 13.64 30/75 31.85 21.74

Kolkata 25.71 26.94 11.36 24.15 73.25 57.04 30/65 27.61 14.31 30/70 29.73 23.08 30/75 31.85 31.86

So what is the real long-term stability test condition for INDIA?

Taking value for Trivandrum, based on actual calculation

30 ºC/70% RH

Taking country at large30 ºC/65% RH

Taking value for Trivandrum, based on current WHO classification

30 ºC/75% RH

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

INDIAASEAN

30 ºC/75% RHBrazil

30 ºC/75% RH

Taking value for Trivandrum, based on actual calculation

30 ºC/70% RH

Taking country at large

30 ºC/65% RH

Taking value for Trivandrum, based on current WHO classification

30 ºC/75% RH

Consideration of Climatological and Population Maps

Köppen Map

Considering tropical wet conditions and dense population in the state of Kerala

30 ºC/70% RH

Taking country at large30 ºC/65% RH

Taking value for Trivandrum, based on current WHO classification

30 ºC/75% RH

Revised criteria to classify Climatic Zones and recommended testing conditions

CZ Definition

Criteria Mean annual temperature measured in the open air / Mean annual partial water vapour

pressure

Testing conditions

I Temperate climate ≤ 15°C / ≤ 11 hPa 21°C / 45% RH

II Subtropical and Mediterranean

Climate > 15 to 22°C / > 11 to 18 hPa 25°C / 60% RH

III Hot and dry climate > 22°C / ≤ 15 hPa 30°C / 35% RH

IVA Hot and low humid climate

> 22°C / > 15 to 27 hPa 30°C / 65% RH

IVB Hot and moderately humid climate

> 22°C / 27 to 30 hPa 30°C / 70% RH

IVC Hot and very humid climate

> 22°C / > 30 hPa 30°C / 75% RH

Current criteria to classify Climatic Zones and recommended testing conditions

CZ Definition

Criteria Mean annual temperature measured in the open air / Mean annual partial water vapour

pressure

Testing conditions

I Temperate climate ≤ 15°C / ≤ 11 hPa 21°C / 45% RH

II Subtropical and Mediterranean

Climate > 15 to 22°C / > 11 to 18 hPa 25°C / 60% RH

III Hot and dry climate > 22°C / ≤ 15 hPa 30°C / 35% RH

IVA Hot and humid climate

> 22°C / > 15 to 27 hPa 30°C / 65% RH

IVB Hot and very humid climate

> 22°C / > 27 hPa 30°C / 75% RH

approx. 145,55 €

Current Trends in Stability Testing to Support Global MarketsSeries: 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

The more recent development

Suggested revision

Timor-Leste30°C/75% RH1Thailand

Sri Lanka30°C/75% RH2Nepal30°C/75% RH1Myanmar

Maldives30°C/75% RH1Indonesia30°C/70% RH1/30°C/75% RH1India

Democratic People's Republic of Korea

30°C/65% RH2BhutanBangladeshRegional Office for South-East Asia (SEARO)

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 WaveThe Associated Press 26.07.07

Heat wave scorches Western states of USTriple-digit temperatures forecast to set records

www.msn.com 06.07.07

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

Intense light conditions in Zones III/IV

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)

Difference in gain of moisture by drugs and excipients in light as compared to dark

0

10

20

30

40

Drugs/Excipients

Max

imum

diff

eren

ce in

wei

ght g

ain,

%

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/Light (5 d)Exp to 40 °C/75% RH (5 d)

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

ControlDark 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)

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

Control

Dark

Light

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% RHwith 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% RHwith a minimum of 1.2

million lux h fluorescent and 200 Wh/m2 UVA light

Any need for extended Accelerated Testing?

RELEVANCE OFSTABILITY 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 sunlightSo suggested conditions very relevant

A change is needed

Poor storage conditions, transportation without refrigeration degrade most pharma productsJanuary 4, 2002Our Bureau, MumbaiPoor 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.

Moisture in solid formulations should be restricted up to 1-2%

Stringent microbial control of excipients or alternatively addition of preservatives even in solid formulations

Use of excipients that do not absorb oradsorb moisture

Protection of products from light

Some other suggestions

Other solutions

Rugged packaging with moisture resistant properties

• Glass bottles

• Cold- formed aluminum foil-foil blisters

• Aluminum flexible foil-strip blisters

• PVC, PVC/PVDC or ACLAR blisters

Qualification of inks and packagingmaterials before use

THANKSTHANKS