3. Drug Stability refers to the capacity of a drug
substance or product to remain within
established specifications of identity, strength,
quality, and purity in a specified period of time.
Stability is officially defined as the time lapse
during which the drug product retains the same
properties and characteristics that it possessed
at the time of manufacture.
The stability of a product is expressed as the
expiry period or technically as shelf life.
4. 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
5. To gather information during preformulation
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.
6. Chemical degradation of active drug may reduce the
quality of therapeutic indices like 5-
flurouracil, carbamazepine etc have very small
therapeutic range, slight degradation of drug may
produce sub therapeutic concentration.
After degradation a drug may produce more toxic
product(s) which may be more toxic than the parent
product.
Instability of drug product reduce bioavailability. This
may be caused by physical or chemical instability.
Instability of a product may change the physical
appearance of the product.
7. DRUG AND EXCIPIENT:
- Physical form
-particle size
-surface area
FORMULATION:
-drug excipient ratio
-Processing method
-pH
-solvent
-chelating agent
ENVIRONMENT:
-Temperature
-Relative humidity
-Packaging
-Light
-oxygen
8. Chemical : Each active ingredient retains its chemical
integrity and labeled potency within the specified limit
Physical : The original Physical properties including
appearance, palatability, uniformity, dissolution and
suspendability are retained .
Microbiological : Sterility or resistance to microbial
growth is retained according to specified requirement .
Therapeutic : Therapeutic effect remains unchanged
Toxicological : No significant increase in toxicity occurs
11. The ICH (International Conference on
Harmonization) Guidelines Q1A(R2) “Stability
testing of new drug substances and products” is
the “gold standard” for conducting stability
studies. This is valid for “new drug substances or
drug products” that are sufficient for a
registration application.
12.
13. Q1A(R2)- Stability Testing of New Drug Substances and
Products
Q1B- Stability Testing : Photostability Testing of New
Drug Substances and Products
Q1C- Stability Testing for New Dosage Forms
Q1D- Bracketing and Matrixing Designs for Stability
Testing of New Drug Substances and Products
Q1E- Evaluation of Stability Data
Q1F- Stability Data Package for Registration
Applications in Climatic Zones III and IV
Q5 C-Stability testing of biotechnological /biological
products
14. OBJECTIVE OF THE GUIDELINE:
It defines stability of drug substance and drug
product for registration of application of NCE or
associated drug, within three regions of ICH
i.e; EU, Japan, USA .
NOTE: It does not cover testing for registration of
drug substance or product intended for import
or export to other areas of the world.
15. 1. Purpose of stability testing is to provide evidence how quality varies with time under
influence of
- temperature
- humidity
- light
2. establish re-test period for drug substances
RETEST PERIOD: the period after which samples of the drug substance should be
examined to ensure that the material is still in compliance with the specification, and
thus suitable for use in manufacturing.
A retest period should be proposed on the basis of stability results and may be extended
to five years (e.g., Ethambutol 2HCl, or Isoniazid)
3. establish shelf life for drug products
SHELF LIFE: (EXPIRY DATE/EXPIRATION DATING PERIOD)
The period of time during which a pharmaceutical product, if stored correctly, is
expected to comply with the specification as determined by stability studies on a
number of batches of the product.
The shelf-life is used to establish the expiry date of DRUG PRODUCT.
16. 4. recommends storage conditions
5.Gives Test conditions based on analysis of effects
of climatic conditions in the three regions of the
EU, Japan, USA.
6. Gives mean kinetic temperature which is
derived from climatic data
7.divided world into four climatic zone I-IV
- This guideline addresses climatic zones I and II
8. And the Stability information generated in one
of the three regions is mutually acceptable to
the other two provided:
- information is consistent with this guideline,
- labelling is in accord with national/ regional requirements.
17. CLIMATIC ZONE DEFINITION STORAGE CONDITIONS
TEMPERATE CLIMATE 210C/45 % R.H
I
SUBTROPICAL AND 250C/60 % R.H
II MEDITERRANEAN CLIMATE
HOT , DRY CLIMATE 300C/35 % R.H
III
HOT , HUMID CLIMATE 300C / 70% R.H
IV
18. Stress Testing These guidelines help to
Q1 A (R2)guidelines identify the likely degradation products , to
Stress testing
establish the degradation pathway and
intrinsic stability of the molecule.
Selection of batches
Container closure
system
specifications
Testing frequency Selection of batches At least 3 primary
Storage condition
batches of the drug substance should be
selected. The quality should be
Stability commitment
representative to quality of material used
evaluation for production scale.
Statements/labelling
19. Container Closure system:
Should simulate packaging proposed for
Q1 A (R2)guidelines storage and distribution.
Stress testing
Selection of batches Specification:
Container closure specification:
system • list of tests,
Specifications • reference to analytical procedure,
• proposed acceptance criteria
Testing frequency
Storage condition Test Attributes
• attributes that are susceptible to changed
Stability commitment
storage,
evaluation • influence quality, safety and/or efficacy
Statements/labelling
• Should cover physical, chemical, biological
and microbiological attributes
20. TESTING FREQUENCY:
TestingfrequencyFor productswitha proposed shelflifeof at least 12 months:
Q1 A (R2)guidelines First year------------------3 month
Stress testing Second --------------------6 month
Selection of batches
Thereafter------------------annually
Container closure through out the proposed re-test
system period
specifications
At accelerated storage condition
Testing frequency minimum of three time points (0, 3 and 6 months), from a 6-
month study.
Storage condition
Stability commitment At Intermediate storage condition
minimum of four time points (0, 6, 9 and 12 months), from a 12-
evaluation month study.
Statements/labelling
21. STORAGE CONDITIONS:
Long term testing should cover a minimum of 12 months duration
on at least three primary batches at time of submission and should
Q1 A (R2)guidelines be continued sufficient to cover the proposed re-test period.
Stress testing GENERAL:
Selection of batches STUDY STORAGE CONDITION DURATION
Container closure
system Long term* 25°C ± 2°C/60% ± 12 months
5%
specifications
or
30°C ± 2°C/65% ±
Testing frequency
5%
Storage conditions
Intermediate** 30°C ± 2°C/65% ± 6 months
5%
Stability commitment
Accelerated 40°C ± 2°C/75% ± 6 months
evaluation 5%
Statements/labelling
23. STUDY STORAGE CONDITION DURATION
Long term 5°C ± 3°C 12 months
Accelerated 25°C ± 2°C/60% ± 5% 6 months
If significant change between 3 and 6 months at accelerated
testing propose re-test data based on real time data. (LONG TERM STUDY)
If significant change within 3 months discussion should address excursions outside label
storage. Single batch shorter than 3 months with more frequent testing.
24. STUDY STORAGE DURATION
CONDITIONS
Long term - 20 °C ± 5°C 12 months
Re-test period based on real time data at long term storage
condition.
In absence of accelerated storage condition testing on a single
batch at an elevated temperature e.g. 5°C ± 3°C address short
term excursions
25. Stability Commitment:
When Re-test period not covered or not mentioned
Q1 A (R2)guidelines
long term stability data do not cover proposed re-test period granted at
Stress testing
time of approval, commitment should be made to continue post
approval to establish re-test period
Selection of batches
Container closure Not required for Submission which includes data from 3 production
system batches, commitment to continue through proposed re-test period.
specifications
Fewer than three production batches commitment continue with
Testing frequency these studies through proposed re-test period and place additional
production batches to a total of three on long term stability through
Storage condition proposed re-test period
Stability commitment No Production batches commitment to place first three production
batches on long term stability studies through proposed re-test period.
evaluation
Statements/labelling
26. 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 test's ( P value for level
of significance for rejection).
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
labeling ,should be addressed to provide appropriate and supportive
information.
27. 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.
28. STATEMENTS /LABELLING:
Q1 A (R2)guidelines
Stress testing
A storage statement should be
Selection of batches established based on the stability
Container closure evaluation of the drug substance.
system
specifications
Terms such as “ambient conditions” or
Testing frequency “room temperature” should be
avoided.
Storage condition
Stability commitment Retest date should be displayed on
the container label if appropriate.
evaluation
Statements /labelling
29. Light can affect drugs, causing chemical changes
so…
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.
30. A systematic approach to photostability testing
is recommended covering, as appropriate,
studies such as :
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.
31. Combination of visible and UV light.
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 recognised 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.
32. 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.
Protected samples (e.g., wrapped in aluminum
foil) are used as dark controls to evaluate the
contribution of thermally induced change to the
total observed change
[ LUX = Is the unit which indicates the intensity
or the brightness of the light]
33. 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).
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 ongoing studies may be
acceptable in certain justified cases.
34. Tablets –
Appearance, colour, odour, assay, disintegration/dissol
ution, moisture and friability or hardness testing.
Hard gelatin capsules - Appearance, colour, odour of
contents, assay, disintegration/dissolution, moisture
and microbial limits
Soft gelatin capsules - Appearance, colour, odour of
contents, assay, disintegration/dissolution, moisture, m
icrobial limits, ph , leakage and pellicle formation.
Emulsions – Appearance including phase
separation, colour, odour, assay, pH, viscosity, preserva
tive content, weight loss and microbial limits.
35. Suppositories – Appearance, colour, assay,
particle size, softening range, appearance,
dissolution and microbial limits.
Small volume parenteral: Drug injection –
Appearance, colour, assay, ph, preservative,
content, particulate matter, sterility and
pyrogenicity.
Large volume parenteral - Appearance, colour,
assay, ph, preservative content, particulate
matter, sterility and pyrogenicity
Transdermals – Appearance, assay, leakage,
microbial limit/sterility, peel and adhesive
forces, drug release rate.
36. Outlines recommendations, principles, and
considerations for reduced designs.
Terms:
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.
37. Applicability of Reduced Designs
Applicable to formal stability studies of most
types of drug products
Drug substances: matrixing limited, bracketing
generally not applicable
Whether bracketing or matrixing depends on
circumstances
Any reduced design should be justified.
Type and level of justification depends on
avaiable supporting data.
Careful consideration and scientific
justification, if bracketing and matrixing in one
design.
38. 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.
39. 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
40. Three strengths and three container sizes:
Container size Dosage strength
50 mg 75 mg 100mg
1 2 3 1 2 3 1 2 3
15 ml T T T T T T
100 ml
500 ml T T T T T T
41. MATRIXING:
Def: 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
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
42. Design should be balanced as far as possible so
that each combination is tested to the same
extent over the intended duration of the study
and through the last time point prior to
submission
Where time points are matrixed, all selected
factor combinations should be tested at the
initial and final time points (and the last time
point prior to submission)
43. Type Storage period in months(time points) Total
number
0 3 6 9 12 18 24 36 48 60
A × × - - × - - × - × 5
B × - × - × × - - × × 6
C × - - × × - × - - × 5
44. 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.
45. CASE 1:
NO SIGNIFICANT CHANGE AT ACCELERATED
CONDITION:
Long term and accelerated Long term/accelerated data
data showing a little or no showing change over
change over time and time/variability
little /no variability
Drug substance/product will remain within the Stability analysis of long term data can
acceptance criteria during the proposed retest be useful attribute to establish retest
period/shelf life period
Statistical analysis is not required
46. CASE 2:
SIGNIFICANT CHANGE AT ACCELERATED CONDITION:
No significant change at intermediate
Significant change at intermediate
The extent of extrapolation wpould depend on
whether LT data for attributes are amenable to The proposed retest period or shelf
statistical analysis life should not exceed the period
covered by long term data
Data not amenable to data amenable to
statistical analysis statistical analysis
The proposed retest The proposed retest period or
period/shelf life can be shelf life can be upto one &half
upto 3 months beyond the times but should not be more than
period covered by LT data 6 months beyond the period
covered by LT data
47. REGRESSION ANALYSIS: appropriate approach
for evaluation of stability data
Upper and lower confidence limit(95%) should
be calculated and compared to acceptance
criterion
APPENDICES:
APPENDIX –A:decision tree for data evaluation
for retest period or shelf life estimation of drug
substance and drug product
APPENDIX –B:examples of statistical approaches
to stability data analysis.
48. 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 . So
the world has been divided into four climatic
zones based on the prevalent annual climatic
conditions.
Temperature and humidity determine the storage
conditions and so they greatly affect the
stability of the product.
49. 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. 25°C/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.
