STB. STUDY

BY RND TEAM

STABILITY STUDIES

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?

Q1A(R2) – Stability Testing of New Drug

Substances and Products

ICH GUIDELINES Q1A(R2) (STABILITY STUDIES)

OBJECTIVE OF THE GUIDELINESIt 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

• 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 ConditionZone 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 testing1. 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 condition2. Provide controlled temperature & humidity

conditions

IMPORTANT TERMENOLOIES

• Primary batchA 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.

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 TESTINGDEGRADATION 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

or30°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% RHOr 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 monthsAccelerated 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 Substances and Products

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).

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 pointsReduced 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 mgBatch B1 B2 B3

15 mL T T T100 mL

Container Size

500 mL T T TKey: 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

Q1D - Bracketing and Matrixing

• 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)

Q1D - Bracketing and Matrixing• MATRIXING - Simple design on time points:

– A practical, “one-half reduction”:

Time point (months) 0 3 6 9 12 18 24 36Batch 1 T T T T T TBatch 2 T T T T T T

Strength 1

Batch 3 T T T T TBatch 1 T T T T TBatch 2 T T T T T T

Strength 2

Batch 3 T T T T TT = 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

Substances and Products • Q1D: Bracketing and Matrixing Designs for Stability Testing of

Drug Substances and Drug Products • Q1E: Evaluation for Stability Data

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