GUIDED BY PRESENTED BY

DR.VARSHA POKHARKAR DEBJANI BAIDYA

HOD OF PHARMACEUTICS M.PHARM 1ST SEM
POONA COLLEGE OF POONA COLLEGE OF
PHARMACY PHARMACY

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 CONTENT

STABILITY
STABILITY TESTING
ICH GUIDELINES
Q1 GUIDELINES
Q5 GUIDELINES
Q8 GUIDELINES
Q11 GUIDELINES

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 STABILITY

Stability is officially defined as the time lapse

during which the drug product retains the same
properties and characteristics that is possessed
at the time of manufacture.

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 STABILITY TESTING

Stability of a drug product is determined by

evaluation of quality parameters with times
under the influence of variety of environmental
factors such as temperature, humidity and light.

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Purpose of stability testing:

To gather information during pre-formulation

stage to produce a stable product.
To determine maximum expiration date.
To get an idea of storage condition.
To determine the packaging components.
To establish retest period of pharmaceuticals.
To establish transport conditions. 5
Stages of the drug product life cycle:

Stage-1: early stage stress and accelerated

testing with drug substances.
Stage-2: stability on pre-formulation batches.
Stage-3: stress testing on scale up batches.
Stage-4: accelerated and long term testing for
registration purposes.
Stage-5: on-going stability testing.
Stage-6: follow up stabilities. 6
 ICH GUIDELINES

ICH= INTERNATIONAL CONFERENCE ON

HARMONISATION
ICH
GUIDELINES

QUALITY SAFETY EFFICACY MULTIDICIPLINARY

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 The choice of test conditions defined in this
guideline is based on an analysis of the effects
of climatic conditions in the three regions of
Europe , Japan , and the United States.
The mean kinetic temperature in any part of
the world can be derived from climatic data,
and the world can be divided into various
climatic zones.
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9
MEAN KINETIC TEMPERATURE:

Single calculated temperature at which the total

amount of degradation over a particular period
is equal to the sum of the individual degradation
that would occur at various temperature

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ICH GUIDELINES: QUALITY:

Q1= STABILITY
Q2= VALLIDATION
Q3= IMPURITIES
Q4= EVALUATION AND RECOMANDATION OF
PHARMACOPOEIAL TEXTS

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Q5= BIOLOGICAL PRODUCTS
Q6= SPECIFICATIONS
Q7= GOOD MANUFACTURING PRACTICE
Q8= PHARMACEUTICAL DEVELOPMENT
Q9= QUALITY RISK MANAGEMENT
Q10= PHARMACEUTICAL QUALITY SYSTEM
Q11= DEVELOPMENT AND MANUFACTURE OF
DRUG SUBSTANCES
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ICH GUIDELINES:Q1(STABILITY):

Q1A- STABILITY SUBSTANCE OF NEW DRUG

PRODUCT.
Q1B-PHOTOSTABILITY TESTING OF NEW DRUGS AND
PRODUCTS.
Q1C- STABILITY TESTING FOR NEW DOSAGE FORMS.
Q1D- BRACKETING AND MATRIXING DESIGN FOR
STABILITY TESTING OF NEW DRUGS AND PRODUCTS.
Q1E- EVALUATION FOR STABILITY DATA.
Q1F- STABILITY DATA PACKAGE FOR REGISTRATION
APPLICATIONS IN CLIMATIC ZONES III AND IV.
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 Q1A GUIDELINE:

Testing conditions:

Accelerated Testing:

Studies designed to increase the rate of chemical

degradation or physical change of a
pharmaceutical product by using exaggerated
storage conditions as part of the formal stability
studies.
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Intermediate Testing:
Studies designed to moderately increase the
rate of chemical degradation or physical change
for a drug substance or drug product.

Long-term Testing:

Stability studies under the recommended

storage condition for the re-test period of shelf
life period for labelling.
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Q1A GUIDELINE:

PROTOCOL:
STRESS TESTING
SELECTION OF BATCHES
CONTAINER CLOSURE SYSTEM
SPECIFICATION
TESTING FREQUENCY
STORAGE CONDITION
STABILITY COMMITMENT
EVALUATION
STATEMENTS/LABELLING
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Stress Testing :

These guidelines help to identify the likely

degradation products , to establish the
degradation pathway and intrinsic stability of the
molecule.

The nature of the stress testing will depend on the

individual API and the type of FPP involved.

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Selection of batches :

At least 3 primary Storage condition batches

of the drug substance should be selected.

The quality should be representative to

quality of material used for production scale.

For existing active substances that are

known to be stable, data from at least two
primary batches should be provided.
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Container Closure system:
The stability studies should be conducted on the API
packaged in a container closure system that is the same
as , or simulates, the packaging proposed for storage and
distribution.
Specification:
list of tests
reference to analytical procedure
proposed acceptance criteria
Test Attributes :
attributes that are susceptible to changed evaluation
influence quality, safety and/or efficacy
Should cover physical, chemical, biological and
microbiological attributes 19
Specification:

list of tests
reference to analytical procedure
proposed acceptance criteria

Test Attributes :

attributes that are susceptible to changed

evaluation
influence quality, safety and/or efficacy
Should cover physical, chemical, biological and
microbiological attributes
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TESTING FREQUENCY:
Testing frequency For products with a proposed shelf
life of at least 12 months:
First year------------------3 month
Second --------------------6 month
Thereafter------------------annually through out the
proposed re-test system period.

At accelerated storage condition :Testing frequency

minimum of three time points (0, 3 and 6 months),
from a 6- month study.
At Intermediate storage condition :minimum of four
time points (0, 6, 9 and 12 months), from a 12- month
study. 21
 STORAGE CONDITIONS:

STUDY STORAGE DURATION

CONDITION

Long term* 25C 2C/60% 12 months

5% or
30C 2C/65%
5%
Intermediate** 30C 2C/65% 6 months
5%
Accelerated 40C 2C/75% 6 months
5%
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DRUG SUBSTANCES INTENDED FOR STORAGE
IN A REFRIGERATOR

STUDY STORAGE DURATION

CONDITION

Long term 5C 3C 12 months

Accelerated 25C 2C/60% 6 months

5%

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DRUG SUBSTANCES INTENDED FOR STORAGE
IN A FREEZER:

STUDY STORAGE DURATION

CONDITIONS

LONG TERM - 20 C 5C 12 MONTHS

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Stability Commitment:

When Re-test period not covered or not mentioned

long term stability data do not cover proposed re-test
period granted at time of approval, commitment
should be made to continue post approval to establish
re-test period.

Not required for Submission which includes data from

3 production system batches, commitment to continue
through proposed re-test period.

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Fewer than three production batches
commitment continue with these studies
through proposed re-test period and place
additional production batches to a total of three
on long term stability through proposed re-test
period.

No Production batches commitment to place

first three production batches on long term
stability studies through proposed re-test period.

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EVALUATION:

A systematic approach should be adopted in the

presentation and evaluation of the stability
information which covers the physical , chemical &
biological parameter.

A minimum of 3 batches of drug product was

tested.
The analyst must found the batch to batch
variability & if it is small than only it is accepted & it
can be done by different statistical tests ( P value
for level of significance for rejection).
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 Where the data shows so little degradation & so little
variability that is apparent from looking the data that
the requested shelf life will be granted. & it is
normally unnecessary to go through the formal
statistical analysis.

Any evaluation also consider the not only the assay

but also consider the other parameter testing & also
the different stability and degradation performance.

The stability of the drug product after reconstitution

or diluting according to labelling , should be
addressed to provide appropriate and supportive
information.
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STATEMENTS AND LEBELLING:

A storage statement should be established for display

on the label based on the stability evaluation of the
API. Where applicable specific instructions should be
provided, particularly for APIs that cannot tolerate
freezing or excursions in temperature. Terms such as
ambient conditions or room temperature should
be avoided.
A re-test period should be derived from the stability
information, and a retest date should be displayed on
the container label if appropriate.

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 Q1B

The photostability guidance provides

recommendation for the light exposure options
to which the drug or drug product should be
exposed.

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Purpose of photostability testing:

To Evaluate that light exposure does not result in

unacceptable change.

Provides means of screening drug early in the

development process & allows identification of
particular photo labile drug.

Gives idea about how to store drug

For generation of photo stability information for

submission in Registration Applications for new
molecular entities and associated drug products.
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A systematic approach to photostability
testing:

i) Tests on the active substance

ii) Tests on the exposed product outside of
the immediate pack, and if necessary
iii) Tests on the product in the immediate
pack; and if necessary
iv) Tests on the product in the marketing
pack.
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Recommended light sources:

I. Artificial daylight fluorescent lamp with a

combination of ultraviolet(near UV lamp having
spectral distribution from 320-400nm) and visible
outputs, xenon or metal halide lamps.

II. Cool white fluorescent and near UV lamp.

For confirmatory studies, the samples should be

exposed to light ,providing an overall illumination of not
less than 1.2 million lux hours and an integrated near
UV energy of not less than 200 watt hours/ square
meter.
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The drug product is said to be undergo a significant
change if the following factors are observed:

A 5% change in assay from its initial value.

Any degradation product exceeding its acceptance
criterion.
Failure to meet the acceptance criteria for
appearance, physical attributes, and functionality
test (e.g., colour, phase separation , hardness).
As appropriate for the dosage form, e.g., failure to
meet the acceptance criteria for dissolution for 12
dosage units.

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 Q1C

Definition:
A new dosage form is defined as a medicinal product which is a
different pharmaceutical product type, but containing the same
active substance as included in an existing product approved by
the pertinent regulatory authority.

Include:
products of a different route of administration (e.g., oral to
parenteral), new specific functionality/delivery systems (e.g.,
immediate release tablet to modified release tablet) and
different dosage forms of the same route of administration
(e.g., capsule to tablet, solution to suspension). 35
 Stability protocols for new dosage forms should
follow the guidance in the parent stability
guideline in principle. However, a reduced
stability database at submission time may be
acceptable with proper justification. e.g.,6
months accelerated and 6 months long term data
from on going studies may be acceptable in
certain justified cases.

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 Q1D

Study design:

Full Study Design: samples for every combination

of all design factors are tested at all time points.

Reduced Study Design: not all samples for every

factor combination are tested at all time points ex:
bracketing, matrixing.
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Bracketing:

Bracketing is the design of a stability schedule such

that only the extremes of certain design factors are
tested at all time points.

- different strengths
- different container size and/or fill

Stability of intermediate levels represented by

stability or tested extremes.
Bracketing design not appropriate, if tested samples
are not the extremes.
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BRACKETING Strengths:

Applicable: strengths of identical or closely related

formulations.
Applicable with additional justification (e.g., supporting
data): strengths where the relative amounts of the drug
substance and excipients vary within the product line
Not applicable: different excipients among strengths

Bracketing Container Size, Fill:

Applicable: same container closure system where either the
container size or fill varies while the other remains constant
Applicable with additional justification (e.g., supporting
data): same container closure system but both the container
size and fill vary
Not applicable: different container closure systems
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MATRIXING:

Definition: testing a selected subset of the total

number of possible samples for all factor
combinations at a specified time point, while
testing another subset of samples at a subsequent
time point

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 applicable: strengths with identical or closely
related formulations container sizes or fills of the
same C/C system different batches made with the
same equipment and process

applicable with additional justification: where

the relative amounts of excipients change or
different excipients are used

not applicable: different storage conditions

different test attributes

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 Q1E

It describes:
How to propose a retest period for drug substances
and a shelf life for drug products in the registration
application
When and how a extrapolation beyond available
data can be considered.

EXTRAPOLATION : extrapolation is the practice of

using a known data set to infer the information about
a future data.
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 Q1F

Stability Data Package for Registration Applications

in Climatic Zones III and IV Climatic conditions in
the countries where the product is to be marketed
should be carefully considered during the
development phase

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 Tests at elevated temperatures and/or extremes
of humidity Special transportation and climatic
conditions outside the storage conditions
recommended in this guideline should be
supported by the additional data.

Stability testing at a high humidity condition, e.g.

25C/80%RH, is recommended for solid dosage
forms in water- vapour permeable packaging viz.,
tablets in PVC/ aluminium blisters, intended to be
marketed in territories with extremely high
humidity conditions in Zone IV.
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 Q5C

ICH Q5C intends to give guidance to

applicants regarding the type of stability
studies to be provided in support of marketing
authorisation applications for biological
medicinal products.

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Selection of batches

Drug substance (Bulk material)

When bulk material is stored after manufacture stability data should be
provided On atleast 3 batches for which manufacture & storage are
representative of the manufacturing scale of production . A minimum of 6
months stability data at the Time of submission should be submitted in cases
where storage period greater than 6 months.

Intermediate
During manufacture of biotechnological product the quality & control of
intermediate may be critical to the production of final product.

Drug Product (final container product)

Stability information should be provided on atleast 3 batches of final container
product which will be used at manufacturing scale. A minimum of 6 months
data at The time of submission should be submitted in case where storage
period greater than 6 month.
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ICH Q5C applies to well characterised proteins and
polypeptides isolated or manufactured by rDNA
technology.
COVER DOES NOT COVER
cytokines (IFN, IL, CSF, TNF) antibiotics
EPO allergenic extracts
plasminogen activators heparins
blood products vitamins
growth hormones whole blood
insulins cellular/ blood components
monoclonal antibodies
vaccines

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Testing frequency:

Shelf life biologicals can vary

ICH Guidance is based on a 0.5-5 years shelf life for most
biologicals .
The recommended intervals for long term studies in pre
licensing

SHELF TESTING FREQUENCY TESTING

LIFE POINTS
<1 YEAR MONTHLY FOR THE 1ST 3 MONTHS 0,1,2,3,6,9, AND
3 MONTHS INTERVAL 12
THEREAFTER
>1 YEAR EVERY 3 MONTHS DURING 1ST 0,3,6,9,12,15,18
YEAR ..
EVERY 6 MONTHS DURING 2ND 48
YEAR
Storage condition

Temp.- The storage condition for the real time/ real

temp. stability study may be confined to the proposed
storage temperature.

Humidity : Biotechnological product are distributed

in container protecting them against humidity.

Container/Closure : Change in the quality of product

may occur due to interaction b/w formulated
biotechnological product and container/closure.
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 Q8

Objective To describe the regulatory submission in

the ICH M4 CTD(Common Technical Document)
format.
Aim - 1. To design a quality product and
manufacturing process
2. Inf. From pceutical development
studies can be basis for quality risk management.
3. It describe the knowledge that
establish the type of dosage form selected and
formulation proposed are suitable for intended use.
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Component of drug product
Drug Substance- To evaluate the potential effect of drug
substance physicochemical properties on the performance of
the product.

Excipient The excipient chosen their conc. & characteristics

of drug product performance (e.g. stability, bioavailability).

Container Closure System

The choice of primary packaging material should consider e.g.
choice of material, production from moisture and light, safety
of material. For secondary packaging material should be
included when relevant

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 Q11

Describes approaches to developing process and

drug substance understanding.
Provides guidance on what information should be
provided.
Provides further clarification on the principles and
concepts described in ICH guidelines on
pharmaceutical development(Q8),quality risk
management (Q9) and pharmaceutical quality
system (Q10) as they pertain to the development and
manufacture of the drug substances.
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 Q11 is not intended as a guide to what to submit
in applications during the clinical development of
investigational medicinal products but the
principles described may be taken into
consideration during this time in order to provide
information for inclusion in any later marketing
authorisation submission.

Q11 does not provide guidance on how to

comply with requirements for good
manufacturing practice (GMP).

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 REFERANCES:

www.ich.org/products/guidelines/quality.
htmlwww.ema.europa.eu/pdfs/human/ich/27
3699en.pdf
www.ich.org/fileadmin/.../ICH.../Guidelines/...
/Q1B_Guideline.pdf
apps.who.int/prequal/trainingresources/pq.../
stabilitystudies.ppt
Jens T cartensen, C.T Rhodes Drug stability
Principles and Practices, Third Edition
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