STB. STUDY

PRESENTORS
1. Abdul Rauf
2. Tallat hussain
3. Anam Mukhtar
4. Umair Qureshi
5. Asad Ali
6. Fida Moammad

CONTENTS:
 INTRODUCTION
 Objectives.
 Scope
 Principle.
 DEFINITIONS
 CLIMATIC ZONES
 PURPOSE OF STABILITY TESTING
 TYPES OF STABILITY TESTING
 STEPS IN STABILITY TESTING OF DRUG SUBSTANCE
OR DRUG PRODUCT
 POTOSTABILITY
 STRESS TESTING
 BRACKETING AND MATRIXING
 EVALUATION STUDY
 QUESTION AND ANSWERS

OBJECTIVE OF PRESENTATION
• Clear understanding of Stability Studies
• ICH / WHO Guidelines

STABILITY………?

“For everything on the earth is
extinction.”
(Surah Rehman 55:26)

STABILITY:
• The state of being stable.
• The term “stability” with respect to a drug dosage form, refers to the
physical and chemical integrity of the dosage form unit till shelf life and
when appropriate, the ability of the dosage unit to maintain protection
against microbial contamination

Why Stability Study is
necessary…???

Stability study is necessary to determine the
SAFETY of the Product

Stability study is
necessary
to determine the
QUALITY of the
Product

HOW FDA CREATE?

ICH
Q1A(R2) –
Stability Testing of New Drug
Substances and Products

ICH GUIDELINES Q1A(R2) (STABILITY STUDIES)
 OBJECTIVE OF THE GUIDELINES
It defines the stability of drug substance and drug product for registration of
application within three regions of ICH i.e EU, Japan, USA
 SCOPE OF GUIDELINE:
Addresses information to be submitted in registration applications for new
molecular entity and associated drug products

PRINCIPLES OF THE GUIDELINES
• "…… to provide evidence on how the quality of a drug substance or drug
product varies with time under the influence of a variety of
environmental factors such as temperature, humidity & light, & enables
recommended storage conditions, re-test periods & shelf lives to be
established”
(ICH) 2003

ICH
• Climatic Zone
The divisions of the Earth's climates into general climate zones
according to average temperatures and average rainfall.
• WHO Climatic Zone Division
Climatic Zone Definition Long Term Condition
Zone I Temperate 21°C/45%
Zone II Sub Tropical 25 °C/60%
Zone III hot/dry 30 °C/35%
Zone IVA hot/humid (Pakistan) 30 °C/65%
Zone IVB hot/very humid (MM, Nepal) 30 °C/75%
(Division By Futscher & Schumacher 1972)

Purpose of the stability testing
1. Provide evidence how quality varies with time under influence of
– Temperature
– Humidity
– Light
2. Establish retest period for drug substances
– Retest Period: the period after which samples of the drug substance should
be examined to ensure that material is still in compliance with the
specification, and thus suitable for use in manufacturing.

3. Establish shelf life for drug products
– Shelf Life: the period of time after 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 expiry date of each product.
4. Recommends storage conditions.
5. gives test conditions based on effect of climatic conditions in the
three regions of the EU, Japan, USA.

Stability Chambers
1. A special chamber for each condition
2. Provide controlled temperature & humidity
conditions

IMPORTANT TERMENOLOIES
• Primary batch
A batch of an API or FPP used in a formal stability study, from which
stability data are submitted in a registration application for the purpose
of establishing a re-test period or shelf life, respectively. A primary
batch of an API should be at least a pilot scale batch. For a FPP, two of
the three batches should be at least pilot scale batch, and the third
batch a production batch.
• Commitment batches
Production batches of a drug substance or drug product for which the
stability studies are initiated or completed post approval through a
commitment made in the registration application

• Pilot (scale) batch
A batch of an API or FPP manufactured by a procedure fully
representative of and simulating that to be applied to a full
production scale batch. (For solid oral dosage forms, a pilot scale is
generally, at a minimum, one-tenth that of a full production scale or
100,000 tablets or capsules, whichever is the larger.)
• Production (scale) batch
A batch of an API or FPP manufactured at production scale by
using production equipment in a production facility as specified
in the application.

ICH
Types of Stability Testing
 Long Term/Ambient/Real Time
 Accelerated
 Stress (one time
during development)
 In use Stability
(If required)
 On going
 Follow Up Stability Study
(one Batch per year)

- Accelerated testing
- Studies designed to increase the rate of chemical degradation or
physical change by means of exaggerated storage conditions
- Intermediate testing
- Studies at 30degC/60%RH, intended for extrapolation to long term
storage at 25degC [provided that 25degC is appropriate for the
market in question]
- Stress testing
- API: Studies which elucidate intrinsic stability of API. Normally
during development. Normally more stressful than ‘accelerated’
testing.
- Finished product: Studies of effect of ‘severe’ conditions. E.g
freeze/thaw cycling for suspensions & emulsions, low humidity for
aqueous liquids in moisture-permeable containers.

-In-use stability testing:
– Establishes the “period of time during which a
multidose product can be used whilst retaining quality
within an accepted specification once the container is
opened”
• For example:
– liquids that are reconstituted prior to use
– effervescent tablets in a moisture-proof container (eg Al screw-cap
tube)
– ophthalmic products (especially with respect to preservative
efficacy

STEPS IN STABILITY TESTING OF DRUG SUBSTANCE OR
DRUG PRODUCT
DRUG SUBSTANCE DRUG PRODUCT
Stress Testing Photostability Testing
Selection of Batches Selection of Batches
Container Closure System Container Closure System
Specification Specification
Testing Frequency Testing Frequency
Storage Conditions Storage Conditions
Stability Commitment Stability Commitment
Evaluation Evaluation
Statements/Labelling Statements/Labelling

STRESS TESTING
DEGRADATION FACTOR CONDITIONS
Thermal ≥ 50°C, 60 °C (10°C above accelerated
conditions)
Humidity ≥ 75% RH
Acid 0.1N HCl
Base 0.1N NaOH
Oxidative Oxygen gas, or 3% H2O2
Photolytic Metal halide, Hg, Xe lamp, or UV-B
fluorescent

What is the Use of Stress Testing?????
• To validate the stability indicating power of the analytical procedures.
• To identify stability-affecting factors such as ambient temperature,
humidity and light and to select packing materials which protects the
formulation against such effects.
• To identify potential degradants of the API and assess if they can be
formed during manufacture or storage of the formulation.
• To select manufacturing process for particular drug substance.

• Selection of Batches:
Drug Substance Drug Product
Number of
Batches
at least three primary batches
of the DS
at least three primary batches of
the DP
Scale minimum of pilot scale two of the three batches should
be at least pilot scale, third batch
may be smaller
Process same synthetic route that
simulates the final process for
production
simulate that to be applied to
production batches
Container
Closure
the same as or simulates the
packaging proposed for storage
and distribution
in the packaging proposed for
marketing

Container Closure System
• Container closure system same or simulates packaging proposed for
storage and distribution.
Specification:
• list of tests
• reference to analytical procedure
• proposed acceptance criteria

Analytical Procedures
• validated stability indicating
• replication depending on results from validation studies
Test Attributes
• attributes that are susceptible to changed storage,
• Influence quality, safety and/or efficacy
• Should cover physical, chemical, biological and microbiological attributes

• Testing Frequency:
– long term condition:
• normally every three months over the first year, every six
months over the second year, and then annually through the
proposed shelf life
• (e.g., 0, 3, 6, 9, 12, 18, 24, 36 ... months)
– intermediate storage condition (if called for):
• a minimum of four time points, including the initial and final time
points, from a 12-month study
• (e.g., 0, 6, 9, 12 months)
– accelerated storage condition:
• a minimum of three time points, including the initial and final
time points, from a 6-month study
• (e.g., 0, 3, 6 months)

• Storage Conditions – General Case:
* testing at the Intermediate Storage Condition is conducted if there is
“significant change” (as defined in Q1A) at the Accelerated Storage Condition
Study Storage condition Minimum time period
covered by data at
submission
Long term 25°C ± 2°C/60% RH ± 5% RH
or
30°C ± 2°C/65% RH ± 5% RH
12 months
Intermediate* 30°C ± 2°C/65% RH ± 5% RH 6 months
Accelerated 40°C ± 2°C/75% RH ± 5% RH 6 months

• Storage Conditions - Semi-permeable containers:
– aqueous-based products packaged in semi-permeable
containers should be evaluated for potential water loss
Study Storage condition Minimum time period
covered by data at
submission
Long term 25°C ± 2°C/40% RH ± 5% RH
Or 30°C ± 2°C/35% RH ± 5% RH
12 months
Intermediate 30°C ± 2°C/65% RH ± 5% RH 6 months
Accelerated 40°C ± 2°C/Not More Than (NMT)
25% RH ± 5% RH
6 months

• Storage Conditions (continued):
– refrigerator:
– freezer:
– below -20°C:
• treated on a “case-by-case basis”
Study Storage Condition
Minimum Time Period
at Submission
Long term 5°C ± 3°C 12 months
Accelerated 25°C ± 2°C / 60% RH ± 5% RH 6 months
Study Storage Condition
Minimum Time Period
at Submission
Long term -20°C ± 5°C 12 months

STABILITY TEST PARAMETERS FOR VARIOUS TYPES OF PRODUCTS
• Tablets –
Appearance, colour, odour, assay, disintegration/dissolution, 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, microbial limits, pH , leakage and pellicle formation.

• Emulsions –
Appearance including phase separation, colour, odour, assay, pH,
viscosity, preservative content, weight loss and microbial limits.
• Ophthalmic/otic solution or suspension-
Appearance, colour, odour, assay,PH.

Significant Change
• 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., color, phase separation,
hardness).
• As appropriate for the dosage form, e.g., failure to
meet the acceptance criteria for dissolution for 12 dosage units.

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 batches, commitment to continue through proposed
• re-test period. 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.

• Extrapolation
• Limited extrapolation of the real time data beyond the observed range
to extend the re-test period can be undertaken at approval time, if
justified.
• Justification should be based on
• Knowledge on mechanism of degradation
• results of accelerated testing,
• goodness of fit of mathematical model
• existence of supporting data and batch size

Q1B- Photostability Testing of New Drug

Photostability Testing: Q1-B
A systematic approach to photostability testing is recommended
covering, as appropriate, studies such as :
 Tests on the active substance;
 Tests on the exposed product outside of the immediate pack,
and if necessary ;
 Tests on the product in the immediate pack; and if necessary
 Tests on the product in the marketing pack.

Photostability Testing: Q1-B
• Light Sources
• 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).

ICH
Q1D - Bracketing and Matrixing

Q1D – Bracketing
 Outlines recommendations, principles, and considerations
for reduced designs.
 Terms:
 Full Design: samples for every combination of all design
factors are tested at all time points
 Reduced Design: not all samples for every factor
combination are tested at all time points (Bracketing &
Matrixing)

Q1D – Bracketing
• Bracketing: testing samples on the extremes of certain design
factors (e.g., strengths, container sizes and/or fills)
• Basic Principles:
– some reduced designs may need minimal justification, some
designs may require more justification
– assumptions should be assessed and justified
– potential risks should be taken into consideration

Q1D – Bracketing
Strength 50 mg 75 mg 100 mg
Batch B1 B2 B3 B4 B5 B6 B7 B8 B9
Tested? T T T T T T
Key: B1 – B9 indicate batches, T = sample tested
BRACKETING – Strengths:

Q1D – Bracketing
• BRACKETING - Container Closure Sizes and Fills:
Strength 50 mg
Batch B1 B2 B3
15 mL T T T
100 mL
Container Size
500 mL T T T
Key: B1 – B3 indicate batches, T = sample tested

Q1D - Matrixing
– Matrixing: 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
– not applicable:
• different storage conditions
• different test attributes

• Matrixing - Considerations:
– 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)

• MATRIXING - Simple design on time points:
– A practical, “one-half reduction”:
Time point (months) 0 3 6 9 12 18 24 36
Batch 1 T T T T T T
Batch 2 T T T T T T
Strength 1
Batch 3 T T T T T
Batch 1 T T T T T
Batch 2 T T T T T T
Strength 2
Batch 3 T T T T T
T = sample tested

Evaluation for Stability Data (Q1E)
 Data Presentation
Should be presented in an appropriate format( e.g. Tabular, graphical
format)
A tabular summary of outcome statistical analysis and/or graphical
presentation of long term data should be indicated.
 Data Evaluation
Use statistical analysis approach to verify product shelf life.
Statistical approach tell us ;
How to analyze long term data for appropriate qualitative attributes.
How to use regression analysis for shelf life .

Statements/Labelling
• Storage Statement Storage statement established for labelling should
be in accordance with national/regional requirements.
• Statement based on stability evaluation ˆ Re-test date Re-test date
derived from stability information. The re-test date should be displayed
on the container label.

ICH
 REFERENCES:
• Q1A(R2): Stability Testing of New Drug Substances and
Products
• Q1B: Stability Testing: Photostability Testing of New Drug
• Q1D: Bracketing and Matrixing Designs for Stability Testing of
Drug Substances and Drug Products
• Q1E: Evaluation for Stability Data

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