ICH Q1D Guidelines for stability testing of pharmaceutical products is intended to address recommendations on the application of bracketing and matrixing to stability studies conducted in accordance with the ICH Q1A guideline on Stability Testing of New Drug Substances and Products.
Scope of the ICH Q1D guidelines
This document will help you understand how to use bracketing and matrixing study designs. It gives you guidance on when to use these approaches and explains the basic principles involved. The document also includes some example designs to give you a better idea, but remember that these are just for illustration and may not always be the best choice for every situation. [ICH Q1D Guidelines for stability testing of pharmaceutical products].
Introduction of ICH Q1D Guidelines for stability testing of pharmaceutical products
A full study design means testing samples for all combinations of factors at all time points. A reduced design, on the other hand, means not testing all factor combinations at all time points. A reduced design can be a good alternative when dealing with multiple factors. However, before using a reduced design, certain assumptions need to be assessed and justified.
There is a potential risk in using a reduced design because it may lead to establishing a shorter retest period or shelf life due to having less data. Therefore, careful consideration is needed.
During a reduced design study, it is possible to switch to full testing or a less reduced design if there is a valid reason and the principles of both designs are followed. However, when making this change, it is important to adjust the statistical analysis to account for the increased sample size resulting from the change.
ICH Q1D Guidelines for stability testing of pharmaceutical products describe how to use reduced design study for stability testing. [ICH Q1D Guidelines for stability testing of pharmaceutical products].
Applicability of Reduced Designs
Reduced designs can be used for most drug products in formal stability studies, but for complex drug delivery systems with many potential drug-device interactions, additional justification is needed. When studying drug substances, matrixing is not very useful and bracketing is generally not applicable. Whether bracketing or matrixing can be used depends on the specific circumstances, as explained in more detail below.
The use of a reduced design should always be justified. In some cases, the conditions described in this guideline are enough justification, while in other cases, additional justification should be provided. The type and amount of justification needed depend on the supporting data available. When applying a matrixing design, it’s important to consider data variability and product stability as demonstrated by the supporting data.
Bracketing and matrixing are two different types of reduced designs based on different principles. Therefore, before using both bracketing and matrixing together in one design, careful consideration and scientific justification are necessary. [ICH Q1D Guidelines for stability testing of pharmaceutical products].
Bracketing
bracketing is the design of a stability schedule such that only samples on the extremes of certain design factors (e.g., strength, container size and/or fill) 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.
The use of a bracketing design would not be considered appropriate if it cannot be demonstrated that the strengths or container sizes and/or fills selected for testing are indeed the extremes. [ICH Q1D Guidelines for stability testing of pharmaceutical products].
Design Factors
Design factors are variables (e.g., strength, container size and/or fill) to be evaluated in a study design for their effect on product stability
Strength
Bracketing can be applied to studies with multiple strengths of identical or closely related formulations. Examples include but are not limited to (1) capsules of different strengths made with different fill plug sizes from the same powder blend, (2) tablets of different strengths manufactured by compressing varying amounts of the same granulation, and (3) oral solutions of different strengths with formulations that differ only in minor excipients (e.g., colourants, flavourings).
With justification, bracketing can be applied to studies with multiple strengths where the relative amounts of drug substance and excipients change in a formulation. Such justification can include a demonstration of comparable stability profiles among the different strengths of clinical or development batches.
In cases where different excipients are used among strengths, bracketing generally should not be applied. [ICH Q1D Guidelines for stability testing of pharmaceutical products].
Container Closure Sizes and/or Fills
Bracketing can be applied to studies of the same container closure system where either container size or fill varies while the other remains constant. However, if a bracketing design is considered where both container size and fill vary, it should not be assumed that the largest and smallest containers represent the extremes of all packaging configurations. Care should be taken to select the extremes by comparing the various characteristics of the container closure system that may affect product stability. These characteristics include container wall thickness, closure geometry, surface area to volume ratio, headspace to volume ratio, water vapour permeation rate or oxygen permeation rate per dosage unit or unit fill volume, as appropriate.
With justification, bracketing can be applied to studies for the same container when the closure varies. Justification could include a discussion of the relative permeation rates of the bracketed container closure systems. [ICH Q1D Guidelines for stability testing of pharmaceutical products].
Design Considerations and Potential Risks
If, after starting the studies, one of the extremes is no longer expected to be marketed, the study design can be maintained to support the bracketed intermediates. A commitment should be provided to carry out stability studies on the marketed extremes post-approval.
Before a bracketing design is applied, its effect on the retest period or shelf life estimation should be assessed. If the stability of the extremes is shown to be different, the intermediates should be considered no more stable than the least stable extreme (i.e., the shelf life for the intermediates should not exceed that for the least stable extreme).
Design Example
An example of a bracketing design is given in Table. This example is based on a product available in three strengths and three container sizes. In this example, it should be demonstrated that the 15 ml and 500 ml high-density polyethylene container sizes truly represent the extremes. The batches for each selected combination should be tested at each time point as in a full design.
Example of a Bracketing Design (Key: T = Sample tested)
| Strength | 50 mg | 75 mg | 100 mg | |||||||
| Batch | 1 | 2 | 3 | 1 | 2 | 3 | 1 | 2 | 3 | |
| Container size | 15 ml | T | T | T | T | T | T | |||
| 100 ml | ||||||||||
| 500 ml | T | T | T | T | T | T | ||||
[ICH Q1D Guidelines for stability testing of pharmaceutical products].
Also Read : ALL Regulatory guidelines for pharmaceutical industry
Matrixing
Matrixing is the design of a stability schedule such that a selected subset of the total number of possible samples for all factor combinations would be tested at a specified time point. At a subsequent time point, another subset of samples for all factor combinations would be tested.
The design assumes that the stability of each subset of samples tested represents the stability of all samples at a given time point.
When a secondary packaging system contributes to the stability of the drug product, matrixing can be performed across the packaging systems.
Each storage condition should be treated separately under its own matrixing design. Matrixing should not be performed across test attributes. However, alternative matrixing designs for different test attributes can be applied if justified.[ICH Q1D Guidelines for stability testing of pharmaceutical products].
Design Factors
Matrixing designs can be applied to strengths with identical or closely related formulations. Examples include but are not limited to (1) capsules of different strengths made with different fill plug sizes from the same powder blend, (2) tablets of different strengths manufactured by compressing varying amounts of the same granulation, and (3) oral solutions of different strengths with formulations that differ only in minor excipients (e.g., colourants or flavourings).
Other examples of design factors that can be matrixed include batches made by using the same process and equipment, and container sizes and/or fills in the same container closure system.
With justification, matrixing designs can be applied, for example, to different strengths where the relative amounts of drug substance and excipients change or where different excipients are used or to different container closure systems. Justification should generally be based on supporting data. For example, to matrix across two different closures or container closure systems, supporting data could be supplied showing relative moisture vapour transmission rates or similar protection against light. Alternatively, supporting data could be supplied to show that the drug product is not affected by oxygen, moisture, or light. [ICH Q1D Guidelines for stability testing of pharmaceutical products].
Design Considerations
A matrixing design should be balanced as far as possible so that each combination of factors is tested to the same extent over the intended duration of the study and through the last time point prior to submission. However, due to the recommended full testing at certain time points, as discussed below, it may be difficult to achieve a complete balance in a design where time points are matrixed.
In a design where time points are matrixed, all selected factor combinations should be tested at the initial and final time points, while only certain fractions of the designated combinations should be tested at each intermediate time point. If full long-term data for the proposed shelf life will not be available for review before approval, all selected combinations of batch, strength, container size, and fill, among other things, should also be tested at 12 months or at the last time point prior to submission. In addition, data from at least three time points, including initial, should be available for each selected combination through the first 12 months of the study. For matrixing at an accelerated or intermediate storage condition, care should be taken to ensure testing occurs at a minimum of three time points, including initial and final, for each selected combination of factors.
When a matrix on design factors is applied, if one strength or container size and/or fill is no longer intended for marketing, stability testing of that strength or container size and/or fill can be continued to support the other strengths or container sizes and/or fills in the design.[ICH Q1D Guidelines for stability testing of pharmaceutical products].
Design Examples
Examples of matrixing designs on time points for a product in two strengths (S1 and S2) are shown in below table.
The terms “one-half reduction” and “one-third reduction” refer to the reduction strategy initially applied to the full study design. For example, a “one-half reduction” initially eliminates one in every two time points from the full study design and a “one-third reduction” initially removes one in every three. In the examples shown in below table, the reductions are less than one-half and one-third due to the inclusion of full testing of all factor combinations at some time points as ICH Q1D as discussed. These examples include full testing at the initial, final, and 12-month time points. The ultimate reduction is therefore less than one-half (24/48) or one-third (16/48), and is actually 15/48 or 10/48, respectively.
| Time point (months) | 0 | 3 | 6 | 9 | 12 | 18 | 24 | 36 | ||
| Strength | S1 | Batch 1 | T | T | T | T | T | T | ||
| Batch 2 | T | T | T | T | T | T | ||||
| Batch 3 | T | T | T | T | T | |||||
| S2 | Batch 1 | T | T | T | T | T | ||||
| Batch 2 | T | T | T | T | T | T | ||||
| Batch 3 | T | T | T | T | T | |||||
[ICH Q1D Guidelines for stability testing of pharmaceutical products].
| Time point (months) | 0 | 3 | 6 | 9 | 12 | 18 | 24 | 36 | ||
| Strength | S1 | Batch 1 | T | T | T | T | T | T | ||
| Batch 2 | T | T | T | T | T | T | ||||
| Batch 3 | T | T | T | T | T | T | T | |||
| S2 | Batch 1 | T | T | T | T | T | T | T | ||
| Batch 2 | T | T | T | T | T | T | ||||
| Batch 3 | T | T | T | T | T | T | ||||
[ICH Q1D Guidelines for stability testing of pharmaceutical products].
Applicability and Degree of Reduction
The following, although not an exhaustive list, should be considered when a matrixing design is contemplated:
- Knowledge of data variability
- Expected stability of the product
- Availability of supporting data
- stability differences in the product within a factor or among factors
- Number of factor combinations in the study
In general, a matrixing design is applicable if the supporting data indicate predictable product stability. Matrixing is appropriate when the supporting data exhibit only small variability. However, where the supporting data exhibit moderate variability, a matrixing design should be statistically justified. If the supportive data show large variability, a matrixing design should not be applied.
A statistical justification could be based on an evaluation of the proposed matrixing design with respect to its power to detect differences among factors in the degradation rates or its precision in shelf life estimation.
If a matrixing design is considered applicable, the degree of reduction that can be made from a full design depends on the number of factor combinations being evaluated. The more factors associated with a product and the more levels in each factor, the larger the degree of reduction that can be considered. However, any reduced design should have the ability to adequately predict the product shelf life. [ICH Q1D Guidelines for stability testing of pharmaceutical products].
Potential Risk [ICH Q1D Guidelines for stability testing of pharmaceutical products].
Due to the reduced amount of data collected, a matrixing design on factors other than time points generally has less precision in shelf life estimation and yields a shorter shelf life than the corresponding full design. In addition, such a matrixing design may have insufficient power to detect certain main or interaction effects, thus leading to incorrect pooling of data from different design factors during shelf life estimation. If there is an excessive reduction in the number of factor combinations tested and data from the tested factor combinations can not be pooled to establish a single shelf life, it may be impossible to estimate the shelf lives for the missing factor combinations.
A study design that matrixes on time points only would often have similar ability to that of a full design to detect differences in rates of change among factors and to establish a reliable shelf life. This feature exists because linearity is assumed and because full testing of all factor combinations would still be performed at both the initial time point and the last time point prior to submission. [ ICH Q1D Guidelines for stability testing of pharmaceutical products].
Data Evaluation [ICH Q1D Guidelines for stability testing of pharmaceutical products].
Stability data from studies in a reduced design should be treated in the same manner as data from full design studies [ ICH Q1D Guidelines for stability testing of pharmaceutical products].
Also Read : ICH Q1C Guidelines for stability testing of New formulation.
ICH Q1B Guideline for photostability testing of pharmaceutical products
ICH Q1A (R2) Stability testing Guideline
ICH Q1D Guidelines for stability testing – FAQ
What are the ICH Q1 guidelines?
Following are the ICH Q1 guidelines for Stability testing
Q1A (R2) : Stability testing of new drug substances and products
Q1B : Stability testing: Photostability testing of new drug substances and products
Q1C : Stability testing for new dosage forms
Q1D : Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products
Q1E : Evaluation for Stability Data
Q1F : Stability Data Package for Registration Applications in Climatic Zones III and IV
Which are the four ICH guidelines?
1. Quality Guidelines
2. Safety Guidelines
3. Efficacy Guidelines
4. Multidisciplinary Guidelines
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
What is the ICH limit of solvents?
ICH Q3C guideline is to recommend acceptable amounts for residual solvents in pharmaceuticals for the safety of the patient. For example ICH limit of Methanol is 3000 ppm, while ICH solvent limit for 1,1,1-Trichloroethane is 1500 ppm based on a review of the safety data.