1. STABILITY TESTING OF ACTIVE PHARMACEUTICAL INGREDIENTS (API) & ASSIGNING RETEST PERIOD OF API’S
January, 2015

2. Brief About the Presentation
This presentation discusses stability testing of API, Evaluation of Stability data and Assigning the re-test period of the API

3. OVERVIEW OVERVIEW: Stability: Fundamentals Global Climatic Zones
Stress Studies
Selection of Batches
Container Closure System
Specifications
Testing Frequency
Stability Conditions
Evaluation of Stability Data
(Storage Statement/Labelling & Assigning Re-test period of API)

4. Stability: Fundamentals
Stability: The ability of a pharmaceutical product to retain its properties within specified limits throughout its shelf life. Aspects of stability that are to be considered include: Physical, Chemical & Microbiological.

5. Stability: Fundamentals
Why Stability:
To provide evidence on how the quality of a drug substance / product varies with the influence of variety of environmental factors such as temperature, humidity & light
To recommend storage conditions
To recommend retest period
To assign shelf life
To review the product quality
To fulfill the regulatory requirement for dossier submission

6. Global Climatic Zones
GLOBAL CLIMATIC ZONES

7. Global Climatic Zones Global Climatic Zones:
The world is divided into 4 climatic zones based on the environmental conditions as below:
Zone–I
Zone–II
Zone–III
Zone–IV
Zone–IV is further divided into Zone–IVA and Zone–IVB.

8. Long-term testing conditions
Global Climatic Zones
Global climatic zones and Long-term testing conditions:
Climatic zone
Definition
Criteria (Mean annual temp measured in open air/ mean annual partial water vapour pressure)
Long-term testing conditions I
Temperate climate
≤15ºC/ ≤11 hPa
21ºC/ 45%RH II
Subtropical and
Mediterranean
climate
>15 to 22ºC/ >11 to 18 hPa
25ºC/ 60%RH
III
Hot and dry climate
>22°C/ ≤15 hPa
30°C/ 35% RH
IVA
Hot and humid
>22°C/ >15 to 27 hPa
30°C/ 65% RH
IVB
Hot and very
humid climate
>22°C/ >27 hPa
30°C/ 75% RH

9. Global Climatic Zones
Distribution of Nations into different climatic zones: 
Region
Zone I & II
Zone III & IV
Europe
All countries -
American
Argentina, United states, Mexico
Canada, Chile, Brazil
Asian
Republic of Korea, Japan
India, Sri lanka, Indonasia
African
Algeria, Malawi, Zambia
South Africa, Uganda

10. Stress Studies
Stress Studies

11. Stress Studies Stress Studies:
Stress testing is an important part of developmental studies, used to:
Establish the degradation pathways and the intrinsic stability of the molecule.
Validate the stability-indicating power of the analytical procedures

12. Stress Studies Stress Studies…
Stress study must be carried on one batch of API. Stress testing should study the effect of
Temperature, in 10oC increments above accelerated (i.e., 50oC, 60oC…)
Humidity (75% or greater)
Oxidation
Hydrolysis (Across wide range of pH)
Photo stability testing

13. Stress Studies
Photo stability testing: Light source: Option 1: Artificial daylight fluorescent lamp combining visible and UV outputs, xenon or metal halide lamp. Or Option 2: A cool white fluorescent lamp & a near UV fluorescent lamp having a spectral emission range from 320 nm to 400 nm

14. Stress Studies
Photo stability testing:…. Level of exposure for stability study: Overall illumination of not less than 1.2 million lux hours and an integrated near UV energy of not less than 200 watt hours/m2. This can be monitored by either actinometry, calibrated radiometers or lux meters. To exclude the thermal effect, a protected control sample (wrapped in aluminum foil) may be exposed side by side.

15. Stress Studies Assessment of Stress Studies:
Degradation to occur to a small extent, typically 10-30% (Some degradation occurs, but not enough to generate secondary products).
If the degradation is observed during Photostability, a storage statement should be included as “Protect from light”.
Confirm the stability-indication of methods where intended (i.e., mass balance, peak homogeneity)

16. Selection of Batches
Selection of Batches

17. Selection of Batches Selection of Batches
3 pilot scale batches* to establish the re-test period of the drug substance at the time of submission.
Three commercial scale batches when available.
One batch every year in all years when manufacturing of the API is undertaken.
*Pilot batches must be of the same synthesis route, and with method of manufacture and procedure which simulates the final process for commercial scale batches.

18. Container Closure System

19. Container Closure System
Container Closure System: The stability studies should be conducted on the drug substance packaged in a container closure system that is the same as or simulates the packaging proposed for storage and distribution, unless justification provided (i.e., container used in studies is equally protective compared to proposed container).

20. Specifications
Specifications

21. Specifications Specifications:
Specifications should include testing of those attributes that are susceptible to change during storage.
Testing should cover, physical, chemical, biological and microbiological attributes. (Ex: Appearance, LOD or MC, Purity, Assay, Polymorphism and others susceptible to change).
Analytical methods should be stability indicating

22. Testing Frequency
Testing Frequency

23. Testing Frequency Testing Frequency:
* Testing at intermediate storage condition is carried out as a result of significant change at the accelerated storage condition.
“significant change” is failure to meet the specification for any parameter
Type of Stability
Testing Frequency
Remarks
Long-term
1st Year: Every 3 Months
2nd Year: Every 6 Months
Subsequent Years: Annually
Ex: 0, 3, 6, 9, 12, 18, 24, 36, 48….
Accelerated
Minimum 3 time points including 0 and final
Ex: 0, 3 and 6
Intermediate*
Minimum of 4 time points including initial and final time points
Ex: 0, 3, 6, 9 and 12

24. Stability Conditions
Stability Conditions

25. Stability Conditions API intended for storage at Room temperature:
Storage condition of long-term stability studies are determined by the climatic condition under which the API is intended to be stored. Testing at a more severe long-term condition can be an alternative storage condition.
If 30°C±2°C/65% RH or 30°C±2°C/75% RH is the long-term condition there is no intermediate condition.
Study
Storage Condition
Long-term*
25°C ± 2°C/60% RH ± 5% RH or
30°C ± 2°C/65% RH ± 5% RH or
30°C ± 2°C/75% RH ± 5% RH
Accelerated
40°C ± 2°C/75% RH ± 5% RH
Intermediate*
30°C ± 2°C/65% RH ± 5% RH

26. Stability Conditions API intended for storage in a Refrigerator:
Whether accelerated stability studies are performed at 25±2°C/ 60% RH or 30°C±2°C/65% RH or 30°C±2°C/75% RH is based on a risk-based evaluation. Testing at a more severe long-term condition can be an alternative to storage testing at 25°C/60%RH or 30 °C/65%RH.
Study
Storage Condition
Long-term*
5°C ± 3°C
Accelerated
25°C ± 2°C/60% RH ± 5% RH or
30°C ± 2°C/65% RH ± 5% RH or
30°C ± 2°C/75% RH ± 5% RH

27. Stability Conditions API intended for storage in a Freezer:
Testing on a single batch at an elevated temperature (e.g. 5 °C ± 3 °C or 25 °C ± 2 °C or 30 °C ± 2 °C) for an appropriate time period should be conducted to address the effect of short-term excursions outside the proposed label storage condition, e.g. during shipping or handling.
Study
Storage Condition
Long-term*
-20 °C ± 5 °C

28. Evaluation of Stability Data

29. Evaluation of Stability Data
Storage Statement/Labelling

30. Storage Statement/Labelling
A storage statement should be established for the labelling in accordance with relevant national/regional requirements.
Where applicable specific instructions should be provided, particularly for APIs that cannot tolerate freezing or excursions in temperature.
Terms such as “ambient conditions” or “room temperature” should be avoided.

31. Storage Statement/Labelling
Recommended labelling statements of APIs for WHO.
* “Protect from moisture” should be added as applicable.
Testing condition under which the stability of the API has been demonstrated
Recommended labelling
statement
25 °C/60% RH (LT); 40 °C/75% RH (ACC)
“Do not store above 25 °C”
25 °C/60% RH (LT);
30 °C/65% RH (intermediate, failure of ACC)
“Do not store above 25 °C”*
30 °C/65% RH (LT); 40 °C/75% RH (ACC)
“Do not store above 30 °C”*
30 °C/75% RH (LT); 40 °C/75% RH (ACC)
“Do not store above 30 °C”
5 °C ± 3 °C
”Store in a refrigerator
(2 °C to 8 °C)”
-20 °C ± 5 °C
“Store in freezer”

32. Storage Statement/Labelling
Recommended labelling statements of APIs for EU
Testing condition under which the stability of the API has been demonstrated
Recommended labelling
statement
25 °C/60% RH (LT), 40°C/75% RH (ACC)
This medicinal product does not require any special storage conditions.
30 °C/65% RH (LT); 40 °C/75% RH (ACC)
25°C/60%RH (LT); 30°C/65%RH (intermediate or LT)
Do not store above 30°C or Store below 30°C
25°C/60%RH (LT)
Do not store above 25°C or Store below 25°C
5°C ± 3°C
Store in a refrigerator or Store and transport refrigerated*
-20°C ± 5°C
Store in a freezer or Store and transport frozen

33. Storage Statement/Labelling
Recommended labelling statements of APIs for EU…
*The stability data generated at 25°C/60%RH (acc) should be taken into account when deciding whether or not transport under refrigeration is necessary. The statement should only be used in exceptional cases.

34. Storage Statement/Labelling
Recommended labelling statements of APIs for US
The storage statements must be followed as per USP monograph.
If the storage condition is not specified in the USP monograph or the product is not listed in USP, storage statements must be followed based on the stability study conducted.
If the stability of the API differs from USP storage condition, storage statements must be followed based on the stability study conducted.
Protect from Light and moisture must be included where ever applicable.

35. Storage Statement/Labelling
Recommended labelling statements of APIs for US…
Testing condition under which the stability of the API has been demonstrated
Recommended labelling
statement
25 °C/60% RH (LT);
40 °C/75% RH (ACC)
“Store at Controlled room temperature or Store at 20-25°C (Excursions between 15°C and 30°C)”
30 °C/65% RH (LT)
25°C/60%RH (LT)
30°C/65%RH (intermediate or LT)
25°C/60%RH (long term)
5 °C ± 3 °C
“Store at Controlled cold temperature or Store at 2 to 8°C”**
-20 °C ± 5 °C
Store in freezer or Store between -25°C and -10°C.

36. Assigning Re-test Period of API

37. Assigning Re-test Period of API
Re-test period of the API:
The period of time during which the drug substance is expected to remain within its specification and, therefore, can be used in the manufacture of a given drug product, provided that the drug substance has been stored under the defined conditions. After this period, a batch of drug substance destined for use in the manufacture of a drug product should be re-tested for compliance with the specification and then used immediately.
Shelf life (also referred to as expiration dating period)
The time period during which a drug product is expected to remain within the approved shelf life specification, provided that it is stored under the conditions defined on the container label.

38. Assigning Re-test Period of API
(If accelerated stability data for 6 months is OK)
For drug substances intended for storage in a freezer, the re-test period should be based on the real time data obtained at the long term storage condition. X
Y (If the API is to be stored at room temperature)
Y (If the API is to be stored at Refrigerator)
Long Term
(9 months OK)
Y = 2X {Shelf life / re-test date is 18 months}
Y = 1.5X {Shelf life / re-test date is 13.5 months}
(12 months OK)
Y = 2X {Shelf life / re-test date is 24 months}
Y = X + 6 {Shelf life / re-test date is 18 months}
(18 months OK)
Y = X + 12 {Shelf life / re-test date is 30 months}
Y = X + 6 {Shelf life / re-test date is 24 months}
(24 months OK)
Y = X + 12 {Shelf life / re-test date is 36 months}
Y = X + 6 {Shelf life / re-test date is 30 months}

39. Assigning Re-test Period of API
Assigning the Re-test period of API……
Note :
The above table is applicable only when the “Accelerated data show: little or no change over time and little or no variability?”
If the accelerated stability data show change over time then “Long-term data is amenable to statistical analysis” and if backed by statistical analysis and relevant supporting data, then the above table shall be applicable.
 If the accelerated stability data show change over time and statistical analysis is not performed. If backed by relevant supporting data: Y = up to 1.5X, but not exceeding X + 6 months; or if refrigerated, Y = up to X + 3 months

40. Assigning Re-test Period of API
Assigning the Re-test period of API
If accelerated stability data for 6 months is not OK X Y
Intermediate & Long term 12 months OK (Long- term data amenable to statistical analysis and statistical analysis performed)
If backed by statistical analysis and relevant supporting data:
Y = up to 1.5X, but not exceeding X + 6 months
Intermediate & Long term 12 months OK (Statistical analysis not performed)
Y = X + 3 months
Shelf life / re-test date is 15 months
Significant change at intermediate condition?
No extrapolation; shorter retest period or shelf life can be called for statistical analysis if long-term data show variability
Significant change at accelerated condition within 3 months for the products intended to stored at refrigerated condition
No extrapolation; shorter retest period or shelf life and data covering excursions can be called for; statistical analysis if long-term data show variability.

41. References References:
ICH Q1A(R2): Stability testing of new drug substances and products.
ICH Q1B: Stability testing: Photostability testing of new drug substances and products.
Q1E: Evaluation for stability data.
WHO TRS – 953: Annex 2- Stability testing of API and finished pharmaceutical products.
EMEA Guideline: Guideline on declaration of storage conditions.
General Notices of USP 37 – NF 32.

42. Questions?

43. Thank You