CVM GFI #198 (VICH GL45) Bracketing and Matrixing Designs For Stability Testing of New Veterinary Drug Substances and Medicinal Products

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#198
Guidance for Industry
Bracketing and Matrixing Designs
for Stability Testing of New Veterinary Drug
Substances and Medicinal Products
VICH GL45
Submit comments on this guidance at any time. Submit electronic comments on the guidance
to http://www.regulations.gov. 	Submit written comments to the Division of Dockets
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Room 1061,
Rockville, MD 20852. 	All written comments should be identified with the Docket No. FDA-
2009-D-0309.
For further information regarding this document, contact Mai Huynh, Center for Veterinary
Medicine (HFV-142), Food and Drug Administration, 7500 Standish Place, Rockville, MD
20855, 240-402-0670, email: 	mai.huynh@fda.hhs.gov.
Additional copies of this guidance document may be requested from the Policy and
Regulations Staff (HFV-6), Center for Veterinary Medicine, Food and Drug Administration,
7519 Standish Place, Rockville, MD 20855, and may be viewed on the Internet at either
http://www.fda.gov/AnimalVeterinary/default.htm or http://www.regulations.gov.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Veterinary Medicine
July 2015

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VICH GL 45 (Quality) – Bracketing and Matrixing
April 2010
For implementation at Step 7
Quality: Bracketing and Matrixing
Designs for Stability Testing of
New Veterinary Drug Substances
and Medicinal Products
Adopted at Step 7 of the VICH Process
by the VICH Steering Committee
in April 2010
for implementation by April 2011
This Guidance has been developed by the appropriate VICH Expert W orking Group and is subject to
consultation by the parties, in accordance with the VICH Process. At Step 7 of the Process the final draft is
recommended for adoption to the regulatory bodies of the European Union, Japan and the USA.

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Table of Contents
1. 	INTRODUCTION ......................................................................................................... 4
1.1 Objectives of the Guidance............................................................................................ 4
1.2 Background................................................................................................................. 4
1.3 Scope of the Guidance .................................................................................................. 4
2. 	GUIDANCE ................................................................................................................. 4
2.1 General....................................................................................................................... 4
2.2 Applicability of Reduced Designs ................................................................................... 5
2.3 Bracketing .................................................................................................................. 5
2.3.1 Design Factors....................................................................................................... 5
2.3.2 Design Considerations and Potential Risks ................................................................. 6
2.3.3 Design Example..................................................................................................... 7
2.4 Matrixing .................................................................................................................... 7
2.4.1 Design Factors....................................................................................................... 7
2.4.2 Design Considerations ............................................................................................ 8
2.4.3 Design Examples ................................................................................................... 8
2.4.4 Applicability and Degree of Reduction .....................................................................11
2.4.5 Potential Risk .......................................................................................................11
2.5 Data Evaluation ..........................................................................................................11

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Guidance for Industry
Bracketing and Matrixing Designs for Stability Testing of New Veterinary
Drug Substances and Medicinal Products
1. 	INTRODUCTION
1.1 Objectives of the Guidance
This guidance is intended to address recommendations on the application of bracketing and
matrixing to stability studies conducted in accordance with principles outlined in the
Harmonised Tripartite guidance on Stability Testing of New Veterinary Drug Substances and
Medicinal Products (Revision) VICH GL3(R) (hereafter referred to as the VICH GL3(R)).
FDA’s guidance documents, including this guidance, do not establish legally enforceable
responsibilities. 	Instead, guidances describe the Agency’s current thinking on a topic and
should be viewed only as recommendations, unless specific regulatory or statutory
requirements are cited. The use of the word should in Agency guidances means that
something is suggested or recommended, but not required.
1.2 Background
VICH GL3(R) notes that the use of matrixing and bracketing can be applied, if justified, to
the testing of new veterinary drug substances and medicinal 	products, but provides no
further guidance on the subject.
1.3 Scope of the Guidance
This document provides guidance on bracketing and matrixing study designs. 	Specific
principles are defined in this guidance for situations in which bracketing or matrixing can be
applied. 	Sample designs are provided for illustrative 	purposes, and should not be
considered the only, or the most appropriate, designs in all cases.
2. 	GUIDANCE
2.1 General
A full study design is one in which samples for every combination of all design factors
are tested at all time points. 	A reduced design is one in which samples for every factor
combination are not all tested at all time points. 	A reduced design can be a suitable
alternative to a full design when multiple design factors are involved. 	Any reduced design
should have the ability to adequately predict the retest period or shelf life. 	Before a reduced
design is considered, certain assumptions should be assessed and justified. 	The potential risk
This guidance represents the current thinking of the Food and Drug Administration (FDA or
Agency) on this topic. It does not establish any rights for any person and is not binding on FDA
or the public. You can use an alternative approach if it satisfies the requirements of the
applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff
responsible for this guidance as listed on the title page.

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should be considered of establishing a shorter retest period or shelf life than could be derived
from a full design due to the reduced amount of data collected.
During the course of a reduced design study, a change to full testing or to a less reduced
design can be considered if a justification is provided and the principles of full designs and
reduced designs are followed. 	However, proper adjustments should be made to the statistical
analysis, where applicable, to account for the increase in sample size as a result of the change.
Once the design is changed, full testing or less reduced testing should be carried out through
the remaining time points of the stability study.
2.2 Applicability of Reduced Designs
Reduced designs can be applied to the formal stability study of most types of new veterinary
medicinal products, although additional justification should be provided for certain complex
drug delivery systems where there are a large number of potential drug-device interactions.
For the study of new veterinary drug substances, matrixing is of limited utility and
bracketing is generally not applicable.
Whether bracketing or matrixing can be applied depends on the circumstances, as discussed
in detail below. 	The use of any reduced design should be justified. In certain cases, the
conditions described in this guidance are sufficient justification for use, while in other cases,
additional justification should be provided. 	The type and level of justification in each of
these cases will depend on the available supporting data. 	Data variability and product
stability, 	as shown by supporting data, should be considered when a matrixing design is
applied.
Bracketing and matrixing are reduced designs based on different principles. 	Therefore,
careful consideration and scientific justification should precede the use of bracketing and
matrixing together in one design.
2.3 Bracketing
As defined in the glossary to VICH GL3(R), 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.
2.3.1 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.

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2.3.1.1 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., colorants, flavorings).
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.
2.3.1.2 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, and water vapor 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.
2.3.2 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).

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2.3.3 Design Example
An example of a bracketing design is given in Table 1. 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 milliliter (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.
Table 1: Example of a Bracketing Design
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
Key: T = Sample tested
2.4 Matrixing
As defined in the glossary of the VICH GL3(R), 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 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 medicinal 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.
When a secondary packaging system contributes to the stability of the veterinary
medicinal 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.
2.4.1 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., colorants or flavorings).

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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
vapor transmission rates or similar 	protection against light. 	Alternatively, 	supporting data
could be supplied to show that the medicinal product is not affected by oxygen, moisture, or
light.
2.4.2 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.
2.4.3 Design Examples
Examples of matrixing designs on time points for a medicinal product in two strengths (S1
and S2) are shown in Table 2. 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 Table 2,
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 discussed in section 2.4.2. 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.

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Table 2: Examples of Matrixing Designs on Time Points for a Medicinal Product
with Two Strengths
One-Half Reduction
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
Key: T = Sample tested
One-Third Reduction
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
Key: T = Sample tested
Additional 	examples of matrixing 	designs for a medicinal product with three strengths
and three container sizes are given in Tables 3a and 3b. Table 3a shows a design with
matrixing on time points only and Table 3b depicts a design with matrixing on time points
and factors. In Table 3a, all combinations of batch, strength, and container size are tested,
while in Table 3b, certain combinations of batch, strength and container size are not tested.

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Tables 3a and 3b: Examples of Matrixing Designs for a Medicinal Product with Three
Strengths and Three Container Sizes
3a Matrixing on Time Points
Strength 	S1 	S2 	S3
Container size 	A 	B 	C 	A 	B 	C 	A 	B 	C
Batch 1 	T1 	T2 	T3 	T2 	T3 	T1 	T3 	T1 	T2
Batch 2 	T2 	T3 	T1 	T3 	T1 	T2 	T1 	T2 	T3
Batch 3 	T3 	T1 	T2 	T1 	T2 	T3 	T2 	T3 	T1
3b Matrixing on Time Points and Factors
Strength 	S1 	S2 	S3
Container size 	A 	B 	C 	A 	B 	C 	A 	B 	C
Batch 1 	T1 	T2 	T2 	T1 	T1 	T2
Batch 2 	T3 	T1 	T3 	T1 	T1 	T3
Batch 3 	T3 	T2 	T2 	T3 	T2 	T3
Key:
Time-point
(months)
0 	3 	6 	9 	12 	18 	24 	36
T 1 	T 	T 	T 	T 	T 	T 	T
T 2 	T 	T 	T 	T 	T 	T
T 3 	T 	T 	T 	T 	T 	T
S 1, S2, and S3 are different strengths. A, B, and C are different container sizes.
T = Sample tested

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2.4.4 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 medicinal product
• 	availability of supporting data
• 	stability differences in the medicinal product within a factor or among
factors and/or
• 	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 supporting 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.
2.4.5 Potential Risk
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 cannot 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.
2.5 Data Evaluation
Stability data from studies in a reduced design should be treated in the same manner as data
from full design studies.