Download Regulatory requirement related to Stability Testing

Regulatory requirement related to Stability
Testing
STABILITY: “The capacity of a drug product to remain within specifications established to
ensure its identity, strength, quality and purity”.
PURPOSE OF STABILITY STUDY:
 To provide evidence of how the quality of drug substances or products varies with time
under the influence of environmental factors. (temperature, humidity and light)
 To establish a re-test period for the drug substances or the shelf-life for the drug
products and recommended storage conditions.
 To ensure that drug products retain their full efficacy until the end of their expiration
date.
Most important guidelines are
 Food and Drug Administration (FDA)
 International Conference on Harmonization (ICH)
 European Union Guidelines (EU)
 Japanese Guidelines (MHW)
 World Health Organization (WHO) Guidelines
Currently ICH guidelines are most commonly accepted which provides information on
stability testing within the areas of European Union (EU), Japan, and United States.
Overview of ICH guideline for stability testing…
Stability Testing in New Drugs and Products
Q1A (R2)
(Revised guideline)
Q1B
Photo-Stability Testing
Stability
Analytical validation
Impurities
Q1C
Stability testing: New Dosage Forms
Q1D
Bracketing and Matrixing Designs for Stability
Testing of Drug Substances and Drug Products
Q1E
Evaluation of Stability Data
Q1F
Stability Data Package for Registration in Climatic
Zones III and IV
Q2A
Q2B
Definitions and Terminology
Methodology
Q3A
Impurity Testing in New Drug Substances
Q3B
Impurities in Dosage Forms: Addendum to the
Guideline on Impurities in New Drug Substances
Q3C
Impurities: Residual Solvents
Pharmacopeias
Q4
Pharmacopeial harmonization
Biotechnology
Quality
Q5A
Viral Safety Evaluation
Q5B
Genetic Stability
Q5C
Stability of Biotechnology Products
Q5D
Cell Substrates
Q6A
Specifications, Test Procedures, and
Acceptance Criteria for New Drug
Substances and Products
Q6B
Biotechnological substance
GMP
Q7A
GMP for active pharmaceutical ingredients
Development
Q8
Pharmaceutical development
Management
Q9
Quality Risk Management
Specification
STABILITY GUIDELINE
S1(A)
S1(B)
S1(C)
S2A
S2B
S(3A)
S(3B)
S4
S5
S6
S7
S8
E1
EFFICACY GUIDELINES
E2(A)
E2(B)
E2C
Guidelines on The Need For Carcinogenicity
studies of pharmaceuticals
Testing for carcinogenicity of pharmaceuticals
Dose selection for carcinogecity studies of
pharmaceuticals
Guidance on specific aspect of regulatory
genotoxicity test for pharmaceuticals
Standard for genotoxicity testing for
pharmaceuticals
Note for guidance on Toxicokinetics
Pharmacokinetic:- Guidance for repeated dose
tissue distribution studies
Duration of Chronic Toxicity testing in Animals
Detection of Toxicity To Reproduction for
Medicinal product and toxicity to male fertility
Preclinical Safety Evaluation Of Biotechnology
derived Pharmaceuticals
Safety Pharmacology studies for Human
Pharmaceuticals
Immunotoxicity studies for Human
Pharmaceuticals
The Extent of Population Exposure to Assess
clinical Safety
Clinical safety Data management
Implementation working group
Clinical safety Data management :- periodic safety
E2(D)
E2(E)
E2(F)
E3
E4
E5
E6
E7
E8
E9
E10
E11
E12
E13
MULTIDISCIPLINEGUIDELINES
M1
M2
M3
update reports & marketed drugs
Post aproval safety data manegemant :Definations and Standards for expedited reporting
Pharmacovigillance Planning
Development safety update report
Structure and content of clinical study reports
Dose response Information to support drug
regisitration
Ethnic factors in the acceptability of foreign
clinical data
Guideline for Good Clinical Practice
Studies in support of Specific Population
General Consideration For Clinical Trials
Stastical Principles For Clinical Trials
Clinical Investigation of medicinal products In The
Pediatric population
Principles Of Clinical Evaluation of New Antihypertensive drugs
The Clinical Evaluation of proarrythmic potential
for Non-Antiarrythmic drugs
Definations of genomic biomarkers,
pharmacoecononomics, pharmacogenetics,
Genomic DATA & sample coding categories
Maintenance of The ICH Guideline on non-clinical
safety studies for the conduct of human clinical
trials for pharmaceuticals
Electronic Transmission of Individual Case Safety
Reports Message Specification
Organisation of the Common Technical Document
for the Registration of Pharmaceuticals for Human
Use
INTERNATIONAL CLIMATIC ZONES AND CLIMATIC CONDITIONS
Climatic
Condition
Zone I
Temperate
Zone II
Mediterranean
(sub-tropical)
Zone III
Zone IV
Hot/dry or
Very
Hot/moderate hot/humid
RH
Mean Annual < 20°C
Temperature
20.5-24°C
>24°C
>24°C
Kinetic Mean 21°C
Temperature
(Virtual
temperature)
26°C
31°C
31°C
Mean Annual 45%
Relative
Humidity
60%
40%
70%
REQUIREMENT OF TEMPERATURE DEPENDED ON TYPE OF TESTING
TYPE OF STUDY
Long term
Intermediate
Accelerated
TEMPERATURE
25°C ± 2°C
30°C± 2°C
40°C± 2°C/
RELATIVE
HUMIDITY
/60% RH ± 5% RH
/65% RH ± 5% RH
75% RH ± 5% RH
TIME DURATION
12 months
6 months
6 months
DIFFERENT TEMPERATURE REQUIREMENT DEPEND UPON TYPE OF DOSAGE
FORMS
FOR DISTINCT
PRODUCTS
Solid oral DF, solids for
reconstitution, dry
&lyophilized powders in
glass vials
Liquids in glass bottles
,vials, sealed glass
ampoules which provide an
impermeable barrier to
water loss
Drug products in
semipermeable containers
TYPE OF STUDY
AST
40°C ± 2°C
75 % ± 5%RH
40°C ± 2°C
Ambient
Humidity
40°C ± 2°C
NMT 25 %
RH
IST
40°C±2°C
75 % ± 5% RH
30°C±2°C
Ambient
humidity
30°C±2°C
65 % ± 5%
RH
LST
40°C±2°C
75 % ± 5% RH
25°C±2°C
Ambient
Humidity
25°C±2°C
40 % ± 5% RH
Or 30°C±2°C
35 % ± 5% RH
SUPAC GUIDELINES
1) Stability Testing for New Drug Applications(NDA)
A. Drug Substance
B. Drug Product
2) Stability Testing for Abbreviated New Drug Applications(ANDA)
A. Drug Substance Stability Data Submission
 Supporting information may be provided directly to the drug product ANDA or by
reference to an appropriately referenced drug master file (DMF).
 For ANDA bulk drug substances- on a minimum of one pilot-scale batch.
 ANDA bulk drug substances produced by fermentation- on three production batches,
at least two of which should be generated from different starter cultures.
B. Drug Substance Testing
 A program for stability assessment may include storage at accelerated, long-term,
and, if applicable, intermediate stability study storage conditions (refer to IV.G. of
the ICH Q1A Guidance and Section II.A. of this guidance).
C. Drug Product
 As per ICH Q1 A [Section II.B.]
D. ANDA Data Package Recommendations
 Accelerated stability data at 0, 1, 2, and 3 months. A tentative expiration dating
period of upto 24 months will be granted based on satisfactory accelerated stability
data unless not supported by the available long-term stability data.
 Long-term stability data
 Additional stability studies
 accelerated stability study.
E. Stability Study Acceptance
3) Stability Testing For Investigational New Drug Applications
 The amount of information needed to achieve that assurance will vary with
o The phase of the investigation,
o The proposed duration of the investigation,
o The dosage form.
A. General
 Supportive stability data for changes to an approved drug application (i.e. post
approval changes) required .
 If change does not alter the stability of the drug product, the previously approved
expiration dating period can be used.
 But now SUPAC-IR, MR , SS guidance are followed for stability studies .
 Provides 5 stability data package types .
B. Change in Manufacturing Process of the Drug Substance
 Carried out at approved manufacturing site .
 Should be supported by the submission of sufficient data to show that such change
does not compromise the quality , purity , or stability of the drug substance and the
resulting drug product
 Special concerns are there for biological products.
C. Change in Manufacturing Site
Site changes consists of change in location site of :
 Manufacture
 Packaging operations
 Analytical testing laboratory both of company owned and contract
manufacturing.
 Sufficient data to show that such a change does not alter the characteristics or
compromise the quality, purity, or stability of the drug substance or drug product
may be necessary.
 The data should include a side-by-side comparison of all attributes to demonstrate
comparability and equivalency of the drug substance or drug product manufactured
at the two facilities.
 New manufacturing locations should have a satisfactory cGMP inspection.
D. Change in Formulation of the Drug Product
 Historically, all changes in drug product formulation were grouped together and
required extensive stability documentation, usually submitted as a prior-approval
supplement.
 An exception was the detection of a color from a product that could be reported in
an annual report without supporting stability data
E. Addition of a New Strength for the Drug Product
 The addition of a new strength for an approved drug product will generally
require the submission of a prior-approval supplement.
 Demonstration of equivalent stability between the approved drug product and the
new strength will allow extension of the approved drug product expiration dating to
the new strength.
 New strengths intermediate to those of an approved drug product may be supported
by bracketing/Matrixing studies (See Section VII.G. and VII.H.).
F. Change in Manufacturing Process and/or Equipment for the Drug Product
 Can be supported by the submission of sufficient data to show that such a change
does not alter the characteristics or compromise the stability of the drug product.
 The standard stability commitment to conduct and/or complete the stability studies
on the first three production batches produced by the revised manufacturing
process in accordance with the approved stability protocol is necessary.
 If the data are found acceptable, the approved expiration dating period may be
retained.
G. Change in Batch Size of the Drug Product
 A key question : whether the change involves a change in equipment or its mode of
operation, or other manufacturing parameters described for the approved batch
size.
 Table 19 presents the recommended stability data packages for a variety of batch
size situations not involving equipment or mode of operation changes.
 If an equipment change is part of the batch size change, please refer to Change in
Manufacturing Process of the Drug Product (Section IX.F.).
H. Reprocessing of a Drug Product
 Stability data submitted should take into account the nature of the reprocessing
procedure and any specific impact that might have upon the existing stability profile
of the drug.
 The expiration dating period for a reprocessed batch should not exceed that of the
parent batch, and the expiration date should be calculated from the original date of
manufacture of the oldest batch.
 Reprocessing range from repackaging to regrinding and recompressing tablets.
 Any batch of the drug product that is reprocessed should be placed on accelerated
and long-term stability studies using the approved protocol to generate a Type 2
stability data package.
I. Change in Container and Closure of the Drug Product
 The first factor used in determining the stability data package recommendation is
whether or not the protective properties of the container/closure system are
affected by the proposed change.
 Protective properties of the container/closure system include,
Moisture permeability,
Oxygen permeability,
Light transmission.
 Changes that may affect these properties should be supported by a greater amount
of data to support the change.
 The second factor is the nature of the dosage form itself. A solid dosage form will
generally be less affected by a container change than a liquid dosage form
PHOTOSTABILITY TESTING OF NEW DRUG SUBSTANCES AND
PRODUCTS
1.
GENERAL
 The ICH Harmonized Tripartite Guideline covering the Stability Testing of New Drug
Substances and Products notes that light testing should be an integral part of stress
testing.
A. Preamble
 The intrinsic photostability characteristics of new drug substances and products should
be evaluated to demonstrate that, as appropriate, light exposure does not result in
unacceptable change.
 Normally, photostability testing is carried out on a single batch of material.
 Under some circumstances these studies should be repeated if certain variations and
changes are made to the product (e.g., formulation, packaging).
 The guideline primarily addresses the generation of photostability information for
submission in Registration Applications for new molecular entities and associated drug
products. The guideline does not cover the photostability of drugs after administration
(i.e. under conditions of use).
 A systematic approach to photostability testing is recommended covering, as
appropriate, studies such as:
i) Tests on the drug substance;
ii) Tests on the exposed drug product outside of the immediate pack;
And if necessary;
iii) Tests on the drug product in the immediate pack;
And if necessary;
iv) Tests on the drug product in the marketing pack.
 The formal labeling requirements for photo labile drug substances and drug products
are established by national/regional requirements.
B. Light Sources
 The light sources described below may be used for photo stability testing.
 The applicant should maintain an appropriate control of temperature to minimize the
effect of localized temperature changes.
Option 1
 Any light source that is designed to produce an output similar to the D65/ID65 emission
standard such as an artificial daylight fluorescent lamp combining visible and ultraviolet
(UV) outputs, xenon, or metal halide lamp.
 D65 is the internationally recognized standard for outdoor daylight as defined in ISO
10977 (1993). ID65 is the equivalent indoor indirect daylight standard.
 For a light source emitting significant radiation below 320 nm, an appropriate filter(s)
may be fitted to eliminate such radiation.
Option 2
 For option 2 the same sample should be exposed to both the cool white fluorescent and
near ultraviolet lamp.
1. A cool white fluorescent lamp designed to produce an output similar to that
specified in ISO 10977(1993) ; and
2. A near UV fluorescent lamp having a spectral distribution from 320 nm to 400 nm
with a maximum energy emission between 350 nm and 370 nm; a significant
proportion of UV should be in both bands of 320 to 360 nm and 360 to 400 nm.
C. Procedure
 For confirmatory studies, samples should be exposed to light providing an overall
illumination of not less than 1.2 million lux hours and an integrated near ultraviolet
energy of not less than 200 watt hours/square meter to allow direct comparisons to be
made between the drug substance and drug product.
DECISION FLOW CHART FOR PHOTOSTABILITY TESTING OF DRUG PRODUCTS
2. DRUG SUBSTANCE
 For drug substances, photostability testing should consist of two parts: forced
degradation testing and confirmatory testing.
 The purpose of forced degradation testing studies is to evaluate the overall
photosensitivity of the material for method development purposes and/or degradation
pathway elucidation.
 This testing may involve the drug substance alone and/or in simple
solutions/suspensions to validate the analytical procedures.
 In these studies, the samples should be in chemically inert and transparent containers.
 In these forced degradation studies, a variety of exposure conditions may be used,
depending on the photosensitivity of the drug substance involved and the intensity of
the light sources used.
 For development and validation purposes it is appropriate to limit exposure and end the
studies if extensive decomposition occurs.
 For photo stable materials, studies may be terminated after an appropriate exposure
level has been used.
 Under forcing conditions, decomposition products may be observed that are unlikely to
be formed under the conditions used for confirmatory studies.
 Confirmatory studies should then be undertaken to provide the information necessary
for handling, packaging, and labeling.
 Normally, only one batch of drug substance is tested during the development phase, and
then the photo stability characteristics should be confirmed on a single batch if the drug
is clearly photo stable or photo labile.
 If the results of the confirmatory study are equivocal, testing of up to two additional
batches should be conducted.
 Samples should be selected as described in the Parent Guideline.
A. Presentation of Samples
 Care should be taken to ensure that the physical characteristics of the samples under
test are taken into account and efforts should be made, such as cooling and/or placing
the samples in sealed containers, to ensure that the effects of the changes in physical
states such as sublimation, evaporation or melting are minimized.
 All such precautions should be chosen to provide minimal interference with the
exposure of samples under test. Possible interactions between the samples and any
material used for containers or for general protection of the sample, should also be
considered and eliminated wherever not relevant to the test being carried out.
 As a direct challenge for samples of solid drug substances, an appropriate amount of
sample should be taken and placed in a suitable glass or plastic dish and protected with
a suitable transparent cover if considered necessary.
 Solid drug substances should be spread across the container to give a thickness of
typically not more than 3 millimeters.
 Drug substances that are liquids should be exposed in chemically inert and transparent
containers.
B. Analysis of Samples
 At the end of the exposure period, the samples should be examined for any changes in
physical properties (e.g., appearance, clarity, or color of solution) and for assay and
degradants by a method suitably validated for products likely to arise from
photochemical degradation processes.
 Where solid drug substance samples are involved, sampling should ensure that a
representative portion is used in individual tests. Similar sampling considerations, such
as homogenization of the entire sample, apply to other materials that may not be
homogeneous after exposure.
 The analysis of the exposed sample should be performed concomitantly with that of any
protected samples used as dark controls if these are used in the test.
C. Judgement of Results
 The forced degradation studies should be designed to provide suitable information to
develop and validate test methods for the confirmatory studies.
 These test methods should be capable of resolving and detecting photolytic degradants
that appear during the confirmatory studies.
 When evaluating the results of these studies, it is important to recognize that they form
part of the stress testing and are not therefore designed to establish qualitative or
quantitative limits for change.
 The confirmatory studies should identify precautionary measures needed in
manufacturing or in formulation of the drug product, and if light resistant packaging is
needed.
 When evaluating the results of confirmatory studies to determine whether change due
to exposure to light is acceptable, it is important to consider the results from other
formal stability studies in order to assure that the drug will be within justified limits at
time of use (see the relevant ICH Stability and Impurity Guidelines).
3. DRUG PRODUCT
(It is same as that described in drug substances)
4.
ANNEX
A. Quinine Chemical Actinometry
 The following provides details of an actinometric procedure for monitoring exposure to
a near UV fluorescent lamp (based on FDA/National Institute of Standards and
Technology study).
 For other light sources/actinometric systems, the same approach may be used, but each
actinometric system should be calibrated for the light source used.
 Prepare a sufficient quantity of a 2 per cent weight/volume aqueous solution of quinine
monohydrochloride dihydrate (if necessary, dissolve by heating).
Option 1: Use 20 ml colourless ampoules (seal hermetically).
Shape and Dimensions for ampoule specifications.
Option 2: Use 1 cm quartz cell.
 For both the options, prepare sample and control wrap in aluminum foil to protect
completely from light, and measure their absorbance At and Ao respectively at 400nm
using 1cm path length. Measure the change in absorbance.
 The length of exposure should be sufficient to ensure a change in absorbance of at least
0.9.
BRACKETING AND MATRIXING DESIGNS FOR STABILITY
TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS
1.
GUIDELINES
1.1 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.
 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.
1.2 Applicability of Reduced Designs
 Reduced designs can be applied to the formal stability study of most types of drug
products, although additional justification should be provided for certain complex drug
delivery systems where there are a large number of potential drug-device interactions.
 Whether bracketing or matrixing can be applied depends on the circumstances.
 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.
1.3 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.
1.3.1
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.
1.3.1.1 Strength
 Bracketing can be applied to studies with multiple strengths of identical or closely
related formulations.
 Examples
(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).
 In cases where different excipients are used among strengths, bracketing generally
should not be applied.
1.3.1.2 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.
 The characteristics such as 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 should be compared to select the
extremes which may affect the product stability.
 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.
1.3.2
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.
 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).
1.3.3 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 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
Batch
Container size
15 ml
75 mg
1
2
3
T
T
T
T
1
2
100 mg
3
1
2
3
T
T
T
T
T
T
T
T
100 ml
500 ml
Key: T = Sample tested
1.4 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. 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.
 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.
1.4.1 Design Factors
 Matrixing designs can be applied to strengths with identical or closely related
formulations. Examples (same as bracketing).
 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.
1.4.2 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, 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.
1.4.3 Design Examples
Examples of matrixing designs on time points for a 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.
Table 2: Examples of Matrixing Designs on Time Points for a Product withTwo Strengths
“One-Half Reduction”
Time point (months)
S
t
r
e
S1
0
3
Batch 1
T
Batch 2
T
Batch 3
T
6
9
12
T
T
T
T
T
T
T
T
T
T
T
T
18
24
36
T
T
n
g
t
h
S2
Batch 1
T
Batch 2
T
Batch 3
T
T
T
T
T
T
T
T
T
T
T
T
T
T
24
36
T
T
Key: T = Sample tested
“One-Third Reduction”
Time point (months)
0
3
S1
Batch 1
T
T
Batch 2
T
T
Batch 3
T
T
Batch 1
T
T
Batch 2
T
T
Batch 3
T
T
S
t
r
e
n
g
t
h
S2
6
9
12
T
T
T
18
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
T
Key: T = Sample tested
Additional examples of matrixing designs for a 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.
Tables 3a and 3b: Examples of Matrixing Designs for a 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
Batch 3
T2
T3
T3
T1
T1
T2
T3
T1
T1
T2
T2
T3
T1
T2
T2
T3
T3
T1
B
C
T1
T2
3b Matrixing on Time Points and Factors
S1
S2
Strength
Container size
A
B
Batch 1
T1
T2
Batch 2
Batch 3
T3
T3
C
A
B
T2
T1
T2
T3
C
S3
A
T1
T1
T2
T1
T3
T2
T3
T3
Time-point
(months)
T1
0
T2
T3
T
T
3
T
T
T
6
9
12
18
24
36
T
T
T
T
T
T
T
T
T
T
T
T
T
T
S1, S2, and S3 are different strengths. A, B, and C are different container sizes.
1.4.4
Applicability and Degree of Reduction
 The following 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 and also 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.
1.4.5 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.
IMPURITY PROFILE
ICH guidelines:
Impurities
Q3A
Impurity Testing in New Drug Substances
Q3B
Impurities in Dosage Forms: Addendum to
the Guideline on Impurities in New Drug
Substances
Q3C
Impurities: Residual Solvents
IMPURITIES IN NEW DRUG SUBSTANCES
1. PREAMBLE
This document is intended to provide guidance for registration applications on the
content and qualification of impurities in new drug substances produced by chemical
syntheses and not previously registered in a region or member state. It is not intended
to apply to new drug substances used during the clinical research stage of development.
The following types of drug substances are not covered in this guideline:
 biological/biotechnological
 peptide,
 oligonucleotide,
 radiopharmaceutical,
 fermentation product and semi-synthetic products derived there from,
 herbal products, and crude products of animal or plant origin.


Impurities in new drug substances are addressed from two perspectives:
Chemistry Aspects include classification and identification of impurities, report
generation, listing of impurities in specifications, and a brief discussion of analytical
procedures; and
Safety Aspects include specific guidance for qualifying those impurities that were not
present, or were present at substantially lower levels, in batches of a new drug
substance used in safety and clinical studies.
2. CLASSIFICATION OF IMPURITIES
Impurities can be classified into the following categories:

Organic impurities (process- and drug-related)

Inorganic impurities

Residual solvents
Organic impurities can arise during the manufacturing process and/or storage of the
new drug substance. They can be identified or unidentified, volatile or non-volatile,
and include:

Starting materials

By-products

Intermediates






Degradation products
Reagents, ligands and catalysts
Inorganic impurities can result from the manufacturing process. They are normally
known and identified and include:
Reagents, ligands and catalysts
Heavy metals or other residual metals
Inorganic salts
Other materials (e.g., filter aids, charcoal)
Solvents are inorganic or organic liquids used as vehicles for the preparation of
solutions or suspensions in the synthesis of a new drug substance. Since these are
generally of known toxicity, the selection of appropriate controls is easily
accomplished.
IMPURITIES IN NEW DRUG PRODUCTS
INTRODUCTION
1.1
Objective of the guideline
 This document provides guidance for registration applications on the content and
qualification of impurities in new drug products produced from chemically synthesised
new drug substances not previously registered in a region or member state.
1.2 Scope of the guideline
 This guideline addresses only those impurities in new drug products classified as
degradation products of the drug substance or reaction products of the drug substance
with an excipient and/or immediate container closure system.
 Impurities arising from excipients present in the new drug product or extracted or
leached from the container closure system are not covered by this guideline.
 This guideline also does not apply to new drug products used during the clinical research
stages of development.
 The following types of products are not covered in this guideline:
biological/biotechnological products
 Peptides
 Oligonucleotides
 Radiopharmaceuticals
 fermentation products and semi-synthetic products derived therefrom
 herbal products, and crude products of animal or plant origin.
2. RATIONALE FOR THE REPORTING AND CONTROL OF DEGRADATION PRODUCTS
 The applicant should summarise the degradation products observed during manufacture
and/or stability studies of the new drug product.
 This summary should be based on impurities arising from the interaction with excipients
and/or the immediate container closure system.
 In addition, the applicant should summarise any laboratory studies conducted to detect
degradation products in the new drug product.
3. ANALYTICAL PROCEDURES
 The registration application should include documented evidence that the analytical
procedures have been validated and are suitable for the detection and quantitation of
degradation products.
 In particular, analytical procedures should be validated to demonstrate specificity for
the specified and unspecified degradation products.
 As appropriate, this validation should include samples stored under relevant stress
conditions: light, heat, humidity, acid/base hydrolysis, and oxidation.
 The quantitation limit for the analytical procedure should be not more than () the
reporting threshold.
 Degradation product levels can be measured by a variety of techniques, including those
that compare an analytical response for a degradation product to that of an appropriate
reference standard or to the response of the new drug substance itself.
 Reference standards used in the analytical procedures for control of degradation
products should be evaluated and characterised according to their intended uses. The
drug substance can be used to estimate the levels of degradation products.
4. REPORTING DEGRADATION PRODUCTS CONTENT OF BATCHES
 Analytical results should be provided in the registration application for all relevant
batches of the new drug product used for clinical, safety, and stability testing, as well as
batches that are representative of the proposed commercial process.
 Quantitative results should be presented numerically.
 For each batch of the new drug product described in the registration application, the
documentation should include:
 Batch identity, strength, and size
 Date of manufacture
 Site of manufacture
 Manufacturing process
 Immediate container closure
 Degradation product content, individual and total
 Use of batch (e.g., clinical studies, stability studies)
 Reference to analytical procedure used
 Batch number of the drug substance used in the new drug product
 Storage conditions for stability studies
5. LISTING OF DEGRADATION PRODUCTS IN SPECIFICATIONS
 The specification for a new drug product should include a list of degradation products
expected to occur during manufacture of the commercial product and under
recommended storage conditions.
 Stability studies, knowledge of degradation pathways, product development studies,
and laboratory studies should be used to characterize the degradation profile.
 The selection of degradation products in the new drug product specification should be
based on the degradation products found in batches manufactured by the proposed
commercial process.
 Those individual degradation products with specific acceptance criteria included in the
specification for the new drug product are referred to as "specified degradation
products" in this guideline.
 Specified degradation products can be identified or unidentified.
 A rationale for the inclusion or exclusion of degradation products in the specification
should be presented.
 This rationale should include a discussion of the degradation profiles observed in the
safety and clinical development batches and in stability studies, together with a
consideration of the degradation profile of batches manufactured by the proposed
commercial process.
 In summary, the new drug product specification should include, where applicable, the
following list of degradation products:
 Each specified identified degradation product
 Each specified unidentified degradation product
 Any unspecified degradation product with an acceptance criterion of not more than ()
the identification threshold
 Total degradation products.
6. QUALIFICATION OF DEGRADATION PRODUCTS
 Qualification is the process of acquiring and evaluating data that establishes the
biological safety of an individual degradation product or a given degradation profile at
the level(s) specified.
 The level of any degradation product present in a new drug product that has been
adequately tested in safety and/or clinical studies would be considered qualified.
 Therefore, it is useful to include any available information on the actual content of
degradation products in the relevant batches at the time of use in safety and/or clinical
studies.
 Degradation products that are also significant metabolites present in animal and/or
human studies are generally considered qualified.
 Degradation products could be considered qualified at levels higher than those
administered in safety studies based on a comparison between actual doses given in the
safety studies and the intended dose of the new drug product.
 Justification of such higher levels should include consideration of factors such as: (1) the
amount of degradation product administered in previous safety and/or clinical studies
and found to be safe; (2) the increase in the amount of the degradation product; and (3)
other safety factors, as appropriate.
REFERENCE:
1. ICH HARMONISED TRIPARTITIE GUIDELINES
www.ich.org
2. Drug Stability: Principles and Practices, 3rd Edition, edited by Jens T. Carstensen and C.
T. Rhodes; chapter-13 & 17.
3. Remington, The Science and Practice of Pharmacy; 21st Edition, volume-1, chapter4. Stability of drugs and dosage forms by Sumie yoshika & valentio stella; chapter- 6; page
no- 205
5. 17. Food and Drug Administration for immediate release consumer media: 888-InfoFDA. May 6, 1998.
6. Chemical Works of Gedeon Richter Ltd., P.O.B. 27, H-1475 Budapest, Hungary(Talanta 44
(1997) 1517-1526)