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

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

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)

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.

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

Global Climatic Zones GLOBAL CLIMATIC ZONES

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.

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

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

Stress Studies Stress Studies

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

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

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

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.

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)

Selection of Batches Selection of Batches

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.

Container Closure System

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).

Specifications Specifications

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

Testing Frequency Testing Frequency

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

Stability Conditions Stability Conditions

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

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

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

Evaluation of Stability Data

Evaluation of Stability Data Storage Statement/Labelling

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.

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”

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

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.

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.

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.

Assigning Re-test Period of API

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.

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}

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

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.

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.

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