ICH Q1A R2 Stability testing Guideline is 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, and light, and to establish a re-test period for the drug substance or a shelf life for the drug product and recommended storage conditions.
Introduction
The ICH Q1A R2 guideline addresses the stability data to be submitted in registration applications for new molecular entities and associated drug products within the three regions of the EC, Japan, and the United States.
This guideline does not currently seek to cover the information to be submitted for abbreviated (ANDA) or abridged applications, variations, clinical trial applications, etc.
The mean kinetic temperature in any part of the world can be derived from climatic data, and the world can be divided into four climatic zones, I-IV. This guideline addresses climatic zones I and II.
ICH Q1A R2 Stability testing Guideline for Drug Substance (API)
Selection of Batches
Stability studies as per ICH Q1A R2 Stability testing Guideline should be provided on at least three primary batches of the drug substance. The batches should be manufactured to a minimum of pilot scale by the same synthetic route as to be used for production batches.
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.
Specification
The testing should cover, as appropriate, the physical, chemical, biological, and microbiological attributes. Validated stability-indicating analytical procedures should be applied as per ICH Q1A R2 Stability testing Guideline.
Stress Testing
Stress testing of the drug substance can help identify the likely degradation products, which can in turn help establish the degradation pathways and the intrinsic stability of the molecule and validate the stability indicating power of the analytical procedures used.
Stress testing is to be carried out on a single batch. It should include the effect of temperatures (in 10°C increments (e.g., 50°C, 60°C, etc.) above that for accelerated testing), humidity (e.g., 75% RH or greater) where appropriate, oxidation, photolysis, hydrolysis on the drug substance.
Testing Frequency as per ICH Q1A R2 Stability testing Guideline
The frequency of testing at the long term storage condition should be at 0, 3, 6, 12, 18, 24 and annually thereafter through the proposed re-test period.
At the accelerated storage condition, a minimum of three time points 0, 3, and 6 months study is recommended.
When testing at the intermediate storage condition, a minimum of four time points, 0, 6, 9, 12 months study is recommended.
Storage Conditions
The long term testing should cover a minimum of 12 months duration on at least three primary batches at the time of submission and should be continued for a period of time sufficient to cover the proposed re-test period. Data from the accelerated storage condition and intermediate storage condition can be used to evaluate.
Storage conditions for stability testing of Drug substances
| Study | Storage condition | Minimum time period covered by data at submission |
| Long term | 25 ± 2°C and 60 ± 5% RH or 30 ± 2°C and 65 ± 5% RH | 12 months |
| Intermediate | 30 ± 2°C and 65 ± 5% RH | 6 months |
| Accelerated | 40 ± 2°C and 75 ± 5% RH | 6 months |
Storage conditions for Drug substances intended for storage in a refrigerator
| Study | Storage condition | Minimum time period covered by data at submission |
| Long term | 5 ± 3°C | 12 months |
| Accelerated | 25 ± 2°C and 60 ± 5% RH | 6 months |
Storage conditions for Drug substances intended for storage in a freezer
| Study | Storage condition | Minimum time period covered by data at submission |
| Long term | – 20 ± 5°C | 12 months |
Storage conditions for Drug substances intended for storage below -20°C
Drug substances intended for storage below -20°C should be treated on a case-by-case basis.
Evaluation
The purpose of the stability study is to evaluating the stability information (physical, chemical, biological, and microbiological tests) and a re-test period applicable to all future batches.
Evaluation of the stability study should cover the assay and the levels of degradation products and other appropriate attributes.
Labeling
A storage statement should be established for the labeling in accordance with relevant national/regional requirements and should be based on the stability evaluation. re-test date should be displayed on the container label if appropriate.
Also Read : ICH Q1B Guideline for photostability testing of pharmaceutical products
ICH Q1A (R2) Stability testing Guideline
ICH Q1D Guidelines for stability testing of pharmaceutical products
Stability testing Guideline for Drug Product (Tablet, Capsule etc.)
Selection of Batches
Stability studies should be provided on at least three primary batches using different AR Number of the API of the drug product. The primary batches should be of the same formulation and packaged in the same container closure system as proposed for marketing. Two of the three batches should be at least pilot scale batches and the third one can be smaller, if justified.
Stability studies should be performed on each individual strength and container size of the drug product unless bracketing or matrixing is applied.
Container Closure System
Stability testing should be conducted on the dosage form packaged in the container closure system proposed for marketing (including, as appropriate, any secondary packaging and container label).
Specification
The testing should cover, as appropriate, the physical, chemical, biological, and microbiological attributes, preservative content (e.g., antioxidant, antimicrobial preservative), functionality tests (e.g., for a dose delivery system) and shelf life acceptance criteria. Analytical procedures should be fully validated and stability indicating.
Testing Frequency as per ICH Q1A R2 Stability testing Guideline
The frequency of testing at the long term storage condition should be at 0, 3, 6, 12, 18, 24 and annually thereafter through the proposed re-test period.
At the accelerated storage condition, a minimum of three time points 0, 3, and 6 months study is recommended.
When testing at the intermediate storage condition, a minimum of four time points, 0, 6, 9, 12 months study is recommended.
Storage Conditions
The long term testing should cover a minimum of 12 months duration on at least three primary batches at the time of submission and should be continued for a period of time sufficient to cover the proposed shelf life. Data from the accelerated storage condition and intermediate storage condition can be used to evaluate.
Storage conditions for stability testing of Drug products
| Study | Storage condition | Minimum time period covered by data at submission |
| Long term | 25 ± 2°C and 60 ± 5% RH or 30 ± 2°C and 65 ± 5% RH | 12 months |
| Intermediate | 30 ± 2°C and 65 ± 5% RH | 6 months |
| Accelerated | 40 ± 2°C and 75 ± 5% RH | 6 months |
Storage conditions for Drug products packaged in impermeable containers
Stability studies for products stored in impermeable containers can be conducted under any controlled or ambient humidity condition.
Storage conditions for Drug products packaged in semi-permeable containers
| Study | Storage condition | Minimum time period covered by data at submission |
| Long term | 25 ± 2°C and 40 ± 5% RH or 30 ± 2°C and 35 ± 5% RH | 12 months |
| Intermediate | 30 ± 2°C and 65 ± 5% RH | 6 months |
| Accelerated | 40 ± 2°C and NMT 25% RH | 6 months |
Storage conditions for Drug products intended for storage in a refrigerator
| Study | Storage condition | Minimum time period covered by data at submission |
| Long term | 5 ± 3°C | 12 months |
| Accelerated | 25 ± 2°C and 60 ± 5% RH | 6 months |
Storage conditions for Drug products intended for storage in a freezer
| Study | Storage condition | Minimum time period covered by data at submission |
| Long term | – 20 ± 5°C | 12 months |
Storage conditions for Drug products intended for storage below -20°C
Drug products intended for storage below -20°C should be treated on a case-by-case basis.
Evaluation
A systematic approach should be adopted in the presentation and evaluation of the stability information, which should include, as appropriate, results from the physical, chemical, biological, and microbiological tests, including particular attributes of the dosage form (for example, dissolution rate for solid oral dosage forms).
The purpose of the stability study is to establish, based on testing a minimum of three batches of the drug product, a shelf life and label storage instructions applicable to all future batches of the drug product manufactured and packaged under similar circumstances.
Labeling
A storage statement should be established for the labeling in accordance with relevant national/regional requirements and based on the stability evaluation. An expiration date should be displayed on the container label [ ICH Q1A R2 Stability testing Guideline].
Also Read : ICH Q1B Guideline for photostability testing of pharmaceutical products
ICH Q1A (R2) Stability testing Guideline
ICH Q1D Guidelines for stability testing of pharmaceutical products
ICH Q1E
ICH Q1A R2 Stability testing Guideline – FAQ
What is Significant change ?
In general, “significant change” for a drug product is defined as:
1. A 5% change in assay from its initial value; or failure to meet the acceptance criteria for potency when using biological or immunological procedures;
2. Any degradation product’s exceeding its acceptance criterion; Failure to meet the acceptance criteria for appearance, physical attributes, and functionality test (e.g., color, phase separation, re-suspendibility, caking, hardness, dose delivery per actuation);
3.Failure to meet the acceptance criterion for pH.
4.Failure to meet the acceptance criteria for dissolution for 12 dosage units.
What is Accelerated testing?
Studies designed to increase the rate of chemical degradation or physical change of a drug substance or drug product by using exaggerated storage conditions as part of the formal stability studies. Data from these studies, in addition to long term stability studies, can be used to assess longer term chemical effects at non-accelerated conditions and to evaluate the effect of short term excursions outside the label storage conditions such as might occur during shipping. Results from accelerated testing studies are not always predictive of physical changes.
What is Bracketing?
The design of a stability schedule such that only samples on the extremes of certain design factors, e.g., strength, package size, are tested at all time points as in a full design. The design assumes that the stability of any intermediate levels is represented by the stability of the extremes tested. Where a range of strengths is to be tested, bracketing is applicable if the strengths are identical or very closely related in composition (e.g., for a tablet range made with different compression weights of a similar basic granulation, or a capsule range made by filling different plug fill weights of the same basic composition into different size capsule shells). Bracketing can be applied to different container sizes or different fills in the same container closure system.
What is Matrixing ?
The design of a stability schedule such that a selected subset of the total number of possible samples for all factor combinations is tested at a specified time point. At a subsequent time point, another subset of samples for all factor combinations is tested. The design assumes that the stability of each subset of samples tested represents the stability of all samples at a given time point. The differences in the samples for the same drug product should be identified as, for example, covering different batches, different strengths, different sizes of the same container closure system, and, possibly in some cases, different container closure systems.
What is Expiration date?
The date placed on the container label of a drug product designating the time prior to which a batch of the product is expected to remain within the approved shelf life specification if stored under defined conditions, and after which it must not be used.
What is Shelf life?
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.
What are the 5 different ICH stability zones?
1. Temperate
2. Mediterranean & subtropical
3. Hot dry
4. Hot humid & tropical
5. Hot & higher humidity zones
What are the 4 climate zones?
1. Equatorial
2. Tropical
3. Temperate
4. Polar
Which are the four ICH guidelines?
1. Quality Guidelines
2. Safety Guidelines
3. Efficacy Guidelines
4. Multidisciplinary Guidelines