Topic:– Stability Studies (1)- an Introduction

 

Definition:

“…… to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity & light, & enables recommended storage conditions, re-test periods & shelf lives to be established.”

 

ICH stability guidelines – 1

Q1A(R2)-Stability Testing of New Drug Substances & Products

Q1B- Stability Testing : Photostability Testing of New Drug Substances & Products

Q1C- Stability Testing for New Dosage Forms

Q1D- Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products

Q1E- Evaluation of Stability Data

Note that these have been adopted in the European Union, the United States, and Japan

-Accelerated testing

-Studies designed to increase the rate of chemical degradation or physical change by means of exaggerated storage conditions

-Intermediate testing

-Studies at 30°C/65%RH, intended for extrapolation to long term storage at

25°C [provided that 25°C is appropriate for the market in question]

-Stress testing

-API: Studies which elucidate intrinsic stability of API. Normally during development.

Normally more stressful than ‘accelerated’ testing.

-Finished product: Studies of effect of ‘severe’ conditions. Eg freeze/thaw cycling for suspensions & emulsions, low humidity for aqueous liquids in moisture- permeable containers.

 

• Climatic zones:

–Partition of the world into three temperature classes based on kinetic averaging of monthly temperatures, & subdivision of the hottest class into predominantly wet or predominantly dry

–Zones (Futscher & Schumacher 1972):

• I Temperate (21^oC/45%RH)

• II Subtropical (25^oC/60%RH with possibly high RH)

• III Hot & dry (30^oC/35%RH)

• IV Hot & wet (30^oC/70%RH)

–The temperatures above are kinetic averages

 

“The Secretariat reminded the Committee that the WHO guidelines had been revised in the light of harmonization efforts in collaboration with ICH. Subsequently focus had been placed within regional harmonization initiatives on the recommendations for hot and humid conditions (referred to as Zone IV). After extensive discussion the Committee reached consensus that the WHO stability guidelines be amended to reflect conditions for Zone IV as follows:

• Zone IVa (30 degrees Celsius and 65% RH); and

• Zone IVb (30 degrees Celsius and 75% RH).

It was agreed that each individual Member State within the former Zone IV would need to indicate whether its territory should be classified as Zone IVa or IVb.”

 

• Countries:-

• I – USA, Canada, Northern Europe, Russia.

• II- USA, Southern Europe, Australia, China, Korea, japan, Mexico, South Africa, Turkey.

• III- Iraq, Jordan, Morocco, Sudan, Lybia, Egypt, India.

• IV- Sudan, Taiwan.

• IVa- Bangladesh, Bahrain, Congo, Ethopia, Hong kong, Kuwait, Qatar, Saudi Arabia, Somalia, Sri Lanka, UAE.

• IVb- India, Columbia, Cuba, Ghana, Malaysia, Nigeria, Philippines, Singapore, Thailand.

 

 

 

Each nation within zone IV must now

decide whether to adopt a stability test condition of 30^oC & 65%RH, or 30^oC & 75%RH

ASEAN nations & Brazil have adopted 30^oC & 75%RH

 

 

Reduced study Designs:

-Bracketing :-

-A design in which only the extremes are tested at all time points, eg strength, pack size, container fill etc.

-Matrixing –

-Designs in which a selected subset of samples is tested, eg different strengths, container/closure systems, batches

General case

Study	Storage condition	Minimum time period covered by data at submission
Long term	25oC ±2oC/60%RH ±5%RH or 30oC ±2oC/65%RH ±5%RH	12 months
Intermediate	30oC ±2oC/65%RH ±5%RH	6 months
Accelerated	40oC ±2oC/75%RH ±5%RH	6 months

 

ICH:    “It is up to the applicant to decide whether long term stability studies are performed at 25^oC ±2^oC/60%RH ±5%RH or 30^oC ±2^oC/65%RH ±5%RH.”

 

PQP:   “Unless otherwise justified, 30^oC ±2^oC/65%RH ±5%RH is the real-time condition for the prequalification project.”

And: The minimum time period for intermediate storage is 12 months.

 

“the frequency of testing in the long term storage condition should normally be every 3 months over the first year, every 6 months over the second year, & annually thereafter throughout the proposed shelf life.

Stability studies should include testing of those attributes of the FPP that are susceptible to change during storage and are likely to influence quality, safety and/or efficacy. For instance, in case of tablets:

• appearance          ♦         hardness

• friability                ♦         moisture content

• dissolution time ♦         degradants

• assay                     ♦         microbial purity

 

Significant Change;-

• A 5% change in assay from its initial value.

• Any degradation product exceeding its acceptance criterion.

• Failure to meet the acceptance criteria for appearance, physical attributes, and functionality test (e.g., color, phase separation, hardness).

• As appropriate for the dosage form, g., failure to meet the acceptance criteria for dissolution for 12 dosage units.

Commitment:-

For confirmation of provisional (tentative) shelf-life, real-time data are required;

* First 3 production batches on stability.

* Follow up stability testing (FUST) – one batch per year Variations affecting one or more steps of the same route of synthesis of an API.

* Change in the route of synthesis of an API Change in composition of the FPP.

* Change in immediate packaging of the FPP.

 

Evaluation:-

1. Tabulate and plot stability data on all attributes at all storage conditions and evaluate each attribute separately.

2. No significant change at accelerated conditions within six (6) months.

3. Long-term data show little or no variability and little or no change over time.

4. Accelerated data show little or no variability and little or no change over time.

5. Statistical analysis is normally.

6. Proposed retest period or shelf life = double of period covered by long-tem data (X) but NMT X + 12 months.

7. A retest period or shelf life granted on the basis of extrapolation should always be verified by additional long- term stability data.

 

 

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Disclaimer:-This presentation is solely prepared for training, sharing knowledge and information purpose only  collected from various guidelines and literature. The information presented here is only for reference purpose.

 

 

 

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