Ich Guidelines

ICH Guidelines: Climatic Zones The world has been divided into four climate zones with countries being assigned to the relevant zones. This is largely the work of W.Grimm (Grimm, 1985) who used the mean kinetic temperature (MRT) as the basis. The four zones are described in figure. Classified according to four climatic zones Designation I II III IV

Climatic Condition Moderate Subtropical Hot (dry) Tropical

Temp. 210C 250C 300C 300C

Relative Humidity 45% 60% 55% 70%

mbar 11.2 19.0 15.0 30.0

The values are derived from measurement obtained in the various zones during one-year period. The countries have been assigned to climatic zones as follows (examples). •

Climatic zone-I

•

Climatic zone-II - USA, Japan, Southern Europe (mediterranean region)

•

Climatic zone-III - Iran, Iraq, Sudan

•

Climatic zone-IV - Brazil, Ghana, Indonesia, Nicaragua, Philippines

- Great Britain, Northern Europe, Canada, Russia.

As this classification demonstrates, approximately 90% of the global pharmaceutical market lies in the moderate or subtropical climate zones. This has been used as the basis for deriving standard storage conditions for climate zones I and II in ICH guideline Q1A :

Standard storage condition in accordance with ICH Q1A (R2) and ICH Q1F for climate zone I & II Long-term studies Intermediate conditions Accelerated studies for climate zones III & IV Long-term studies Accelerated studies

Temperature 250C ± 20C 300C ± 20C 400C ± 20C

Relative humidity 60% ± 5% 65% ± 5% 75% ± 5%

300C ± 20C 400C ± 20C

65% ± 5% 75% ± 5%

1. Introduction

1.3 General Principles • Purpose of stability testing is to provide evidence how quality varies with time under influence as - temperature - humidity - light, • establish re-test period for drug substances • establish shelf life for drug products • recommend storage conditions • Test conditions based on analysis of effects of climatic conditions in the three regions of the EC, Japan, USA • mean kinetic temperature can be derived from climatic data • world can thereby divided into four climatic zone I-IV • This guideline addresses climatic zones I and II • Stability information generated in one of the three regions is mutually acceptable to the other two provided: - information is consistent with this guideline, - labelling is in accord with national/ regional requirements.

The four Climatic Zones Climatic Zone Definition Climatic Zone Definition

1 2

Temperate climate Subtropical and

Storage conditions

21°C/ 45% r.h 25°C/60%r.h.

Mediterranean climate 3

Hot, dry climate

30°C/35%r.h

4

Hot, humid climate

30°C/70%r.h.

ICH Q1AR2 C 19

Countries of climatic zones I and II Europe: EU, Belarus, Bulgaria, Estonia, Hungary, Latvia, Lithuania, Norway, Rumania, Russia, Switzerland, Ukraine America: USA, Argentina, Bolivia, Chile, Canada, Mexico, Peru, Uruguay Africa: Egypt, Algeria, Canary Islands, Libya, Morocco, Namibia, Rwanda, South Africa, Tunisia, Zambia, Zimbabwe Asia: Japan, Afghanistan, Armenia, Azerbaijan, China, Georgia, Iran, Israel, Kazakhstan, Kirghizia, Korea, Lebanon, Nepal, Syria, Tadzhikistan, Turkey, Turkmen, Uzbekistan, Australia, New Zealand.

2.2.6 Testing Frequency Long term studies • first year every three months. 0, 3, 6, 9, 12 • second year every six months: 12, 18, 24 • third year and longer annually: 24, 36, 48, 60 Accelerated studies • general minimum three time points: 0,3,6 months • expectation of significant change increases testing adding samples at final time point or forth time point: 0, 3, 2x6 or 0, 1, 3, 6 months Intermediate storage condition studies Minimum four time points, including initial and final e.g.: 0,6,9,12 months, at time of submission 0,6 months Reduced design Matrixing or bracketing for reduction of testing frequency if justified

Study Long term*

Storage condition

Minimum time

period at submission 25°C ± 2°C/60% ± 5% 12 months or 30°C ± 2°C/65% ± 5%

Intermediate**

30°C ± 2°C/65% ± 5%

6 mon

Accelerated

40°C ± 2°C/75% ± 5%

6 mon.