5.regulatory Req For Stability

SEMINAR on
Regulatory requirement
related to stability testing
PREPARED BY: MANAVADRIYA HIMANSHU
GUIDED BY: Dr R.K PARIKH

M.PHARM: I
ROLL NO: 02
DEPARTMENT OF PHARMACEUTICS AND

PHARMACEUTICAL TECHNOLOGY
L. M. COLLEGE OF PHARMACY, AHMEDABAD- 09

Paper 910101 regulatory requirement related to stability testing
M.Pharm-І-2009-10 HIMANSHU
List of Contents:
Contents
Introduction
Over view of ICH guidelines
Climate zones
SUPAC guidelines
Photo stability testing of new drug

substance & products
Bracketing and metrixing of new drug

substance & products
Impurity profile
References
Department of pharmaceutics and pharmaceutical technology,LMCP

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STABILITY[2,3,4]: “The capacity of a drug product to remain within specifications

established to ensure its identity, strength, quality and purity”.
PURPOSE OF STABILITY STUDY[2,3,4]:

 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[2,3,4]

 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 Q1A Stability Testing in New Drugs and
(R2) Products (Revised guideline)
Q1B Photo-Stability Testing
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
Analytical Q2A Definitions and Terminology
validation Q2B Methodology
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
Pharmacopeias Q4 Pharmacopeial harmonization

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Biotechnology Q5A Viral Safety Evaluation

Quality
Q5B Genetic Stability
Q5C Stability of Biotechnology Products
Q5D Cell Substrates
Specification 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
STABILITY S1(A) Guidelines on The Need For

GUIDELINE Carcinogenicity studies of
pharmaceuticals
S1(B) Testing for carcinogenicity of
pharmaceuticals
S1(C) Dose selection for carcinogecity
studies of pharmaceuticals
S2A Guidance on specific aspect of
regulatory genotoxicity test for
pharmaceuticals
S2B Standard for genotoxicity testing for
pharmaceuticals
S(3A) Note for guidance on
Toxicokinetics
S(3B) Pharmacokinetic:- Guidance for
repeated dose tissue distribution
studies
S4 Duration of Chronic Toxicity
testing in Animals
S5 Detection of Toxicity To
Reproduction for Medicinal product
and toxicity to male fertility
S6 Preclinical Safety Evaluation Of
Biotechnology derived

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Pharmaceuticals
S7 Safety Pharmacology studies for
Human Pharmaceuticals
S8 Immunotoxicity studies for Human
Pharmaceuticals
EFFICACY E1 The Extent of Population Exposure

GUIDELINES to Assess clinical Safety
E2(A) Clinical safety Data management
E2(B) Implementation working group
E2C Clinical safety Data management :-
periodic safety update reports &
marketed drugs
E2(D) Post aproval safety data
manegemant :- Definations and
Standards for expedited reporting
E2(E) Pharmacovigillance Planning
E2(F) Development safety update report
E3 Structure and content of clinical
study reports
E4 Dose response Information to
support drug regisitration
E5 Ethnic factors in the acceptability of
foreign clinical data
E6 Guideline for Good Clinical
Practice
E7 Studies in support of Specific
Population
E8 General Consideration For Clinical
Trials
E9 Stastical Principles For Clinical
Trials
E10 Clinical Investigation of medicinal
products In The Pediatric
population
E11 Principles Of Clinical Evaluation of
New Anti-hypertensive drugs
E12 The Clinical Evaluation of
proarrythmic potential for Non-
Antiarrythmic drugs

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E13 Definations of genomic biomarkers,

pharmacoecononomics,
pharmacogenetics, Genomic DATA
& sample coding categories
MULTIDISCIP M1 Maintenance of The ICH Guideline
LINE- on non-clinical safety studies for the
GUIDELINES conduct of human clinical trials for
pharmaceuticals
M2 Electronic Transmission of
Individual Case Safety Reports
Message Specification
M3 Organisation of the Common
Technical Document for the
Registration of Pharmaceuticals for
Human Use
INTERNATIONAL CLIMATIC ZONES AND CLIMATIC

CONDITIONS[1,2,3,4]
Climatic Zone I Zone II Zone III Zone IV

Condition Temperate Mediterranean Hot/dry or Very
(sub-tropical) Hot/moderate hot/humid
RH
Mean < 20°C 20.5-24°C >24°C >24°C
Annual
Temperature
Kinetic 21°C 26°C 31°C 31°C
Mean
Temperature
(Virtual
temperature)
Mean 45% 60% 40% 70%
Annual
Relative
Humidity

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REQUIREMENT OF TEMPERATURE DEPENDED ON TYPE OF

TESTING
TYPE OF TEMPERATURE RELATIVE TIME

STUDY HUMIDITY DURATION
Long term 25°C ± 2°C /60% RH ± 5% 12 months
RH
Intermediate 30°C± 2°C /65% RH ± 5% 6 months
RH
Accelerated 40°C± 2°C/ 75% RH ± 5% 6 months
RH
DIFFERENT TEMPERATURE REQUIREMENT DEPEND UPON

TYPE OF DOSAGE FORMS
FOR TYPE OF STUDY

DISTINCT
PRODUCTS AST IST LST
Solid oral DF, 40°C ± 2°C 40°C±2°C 40°C±2°C
solids for 75 % ± 5%RH 75 % ± 5% RH 75 % ± 5% RH
reconstitution,
dry
&lyophilized
powders in glass
vials
Liquids in glass 40°C ± 2°C 30°C±2°C 25°C±2°C
bottles ,vials, Ambient Ambient Ambient
sealed glass Humidity humidity Humidity
ampoules which
provide an
impermeable
barrier to water
loss
Drug products 40°C ± 2°C 30°C±2°C 25°C±2°C
in NMT 25 % 65 % ± 5% 40 % ± 5% RH
semipermeable RH RH Or 30°C±2°C
containers 35 % ± 5% RH

Page 74
SUPAC GUIDELINES[1,2,3,4]
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.
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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.
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 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

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PHOTOSTABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS[1,4]
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 photolabile drug substances and drug products are
established by national/regional requirements.
B. Light Sources
 The light sources described below may be used for photostability 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.

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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.
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 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 photostable 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 photostability characteristics should be confirmed on a single batch if the drug is
clearly photostable or photolabile.
 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

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 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.

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BRACKETING AND MATRIXING DESIGNS FOR STABILITY TESTING OF NEW

DRUG SUBSTANCES AND PRODUCTS[1,4]
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,
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(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 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
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.

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 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) 0 3 6 9 12 18 24 36

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S S1 Batch 1 T T T T T T
t
Batch 2 T T T T T T
r
e Batch 3 T T T T T
n S2 Batch 1 T T T T T
g
t Batch 2 T T T T T T
h Batch 3 T T T T T
“One-Third Reduction”
Time point (months) 0 3 6 9 12 18 24 36
S S1 Batch 1 T T T T T T
t
Batch 2 T T T T T T
r
e Batch 3 T T T T T T T
n S2 Batch 1 T T T T T T T
g
t Batch 2 T T T T T T
h Batch 3 T T T T T T
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
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

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Time-point 0 3 6 9 12 18 24 36
(months)
T1 T T T T T T T
T2 T T T T T T
T3 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.

Page 86
IMPURITY PROFILE[1,4]
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 therefrom,
 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)

Page 87
 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.

Page 88
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.

Page 89
 Stability studies, knowledge of degradation pathways, product development studies, and

laboratory studies should be used to characterise 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.

Page 90
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, chapter-
4. 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-Info-
FDA. May 6, 1998.
6. Chemical Works of Gedeon Richter Ltd., P.O.B. 27, H-1475 Budapest, Hungary(Talanta
44 (1997) 1517-1526)

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5.regulatory Req For Stability

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SEMINAR on

PREPARED BY: MANAVADRIYA HIMANSHU

GUIDED BY: Dr R.K PARIKH

DEPARTMENT OF PHARMACEUTICS AND

L. M. COLLEGE OF PHARMACY, AHMEDABAD- 09

Over view of ICH guidelines

Photo stability testing of new drug

Bracketing and metrixing of new drug

Department of pharmaceutics and pharmaceutical technology,LMCP

STABILITY[2,3,4]: “The capacity of a drug product to remain within specifications

PURPOSE OF STABILITY STUDY[2,3,4]:

Most important guidelines are[2,3,4]

Overview of ICH guideline for stability testing…

Pharmacopeias Q4 Pharmacopeial harmonization

Department of pharmaceutics and pharmaceutical technology,LMCP

Biotechnology Q5A Viral Safety Evaluation

STABILITY S1(A) Guidelines on The Need For

Department of pharmaceutics and pharmaceutical technology,LMCP

EFFICACY E1 The Extent of Population Exposure

Department of pharmaceutics and pharmaceutical technology,LMCP

E13 Definations of genomic biomarkers,

INTERNATIONAL CLIMATIC ZONES AND CLIMATIC

Climatic Zone I Zone II Zone III Zone IV

Department of pharmaceutics and pharmaceutical technology,LMCP

REQUIREMENT OF TEMPERATURE DEPENDED ON TYPE OF

TYPE OF TEMPERATURE RELATIVE TIME

DIFFERENT TEMPERATURE REQUIREMENT DEPEND UPON

FOR TYPE OF STUDY

Department of pharmaceutics and pharmaceutical technology,LMCP

1) Stability Testing for New Drug Applications(NDA)

3) Stability Testing For Investigational New Drug Applications

C. Change in Manufacturing Site

I. Change in Container and Closure of the Drug Product

Department of pharmaceutics and pharmaceutical technology,LMCP

PHOTOSTABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS[1,4]

Department of pharmaceutics and pharmaceutical technology,LMCP

DECISION FLOW CHART FOR PHOTOSTABILITY TESTING OF DRUG PRODUCTS

Department of pharmaceutics and pharmaceutical technology,LMCP

 The forced degradation studies should be designed to provide suitable information to

Shape and Dimensions for ampoule specifications.

Option 2: Use 1 cm quartz cell.

Department of pharmaceutics and pharmaceutical technology,LMCP

BRACKETING AND MATRIXING DESIGNS FOR STABILITY TESTING OF NEW

(2) tablets of different strengths manufactured by compressing varying amounts of the

Table 1: Example of a Bracketing Design

Department of pharmaceutics and pharmaceutical technology,LMCP

Department of pharmaceutics and pharmaceutical technology,LMCP

3a Matrixing on Time Points

3b Matrixing on Time Points and Factors

Department of pharmaceutics and pharmaceutical technology,LMCP

1.4.4 Applicability and Degree of Reduction

Department of pharmaceutics and pharmaceutical technology,LMCP

Impurities Q3A Impurity Testing in New Drug

IMPURITIES IN NEW DRUG SUBSTANCES

Impurities in new drug substances are addressed from two perspectives:

Department of pharmaceutics and pharmaceutical technology,LMCP

IMPURITIES IN NEW DRUG PRODUCTS

Department of pharmaceutics and pharmaceutical technology,LMCP

2. RATIONALE FOR THE REPORTING AND CONTROL OF DEGRADATION

4. REPORTING DEGRADATION PRODUCTS CONTENT OF BATCHES

5. LISTING OF DEGRADATION PRODUCTS IN SPECIFICATIONS

Department of pharmaceutics and pharmaceutical technology,LMCP