ICH International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use

Now our concern is QUALITY guideline, in that stability guidelines.

STABILITY: The ability of a pharmaceutical product to retain its properties within specified limits throughout its shelf life.
To provide evidence on how the quality of pharmaceutical product varies with time under the influence of variety of environmental factors such as temperature, humidity and light. In order to demonstrate that the clinical effect, the quality and patient safety of the drug is maintained during its maximal time of storage and intended use. Aspects of stability that are to be considered includes physical, chemical, microbiological and bio-pharmaceutical attributes.
Objectives: To understand basic properties of the product. To assure integrity/quality of the product. Product development. To recommend storage conditions. To recommend re-test date and assigning shelf life To review the product quality. To full fill the requirements for dossier quality.

World divided into climatic zones

Climatic Zone
Temperature (2C) - MKT
Yearly avg. Humidity (5%RH) European American Asian African Australia / Oceanic

Zone I
Moderate
21 45

Zone II
Mediterranean
25 60

Zone III
Hot & Dry
30 35

Zone IVa
Hot & Humid
30 65 Brazil, Jamaica

Zone - IVb
Hot & High Humid
30 75

All Countries Chile, Canada & US China, Japan & Turkey South Africa, Zambia & Zimbabwe Australia, Newzelannd

India, Srilanka & Philippines Botswana, Ghana & Uganda Fiji, Papua & New guinea

What is Mean Kinetic Temperature?

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.

Stability of Pharmaceutical product

Synthesis Formulations Packaging

Q: Why do pharmaceutical properties change under storage/ over time? A: The drug substance is chemical entity with many reactive functional groups (e.g.: -OH, -NH2, -COOH, etc..). Similarly the excipients used in formulations are also chemicals with reactive functional groups.

Oxidation, Reduction, Hydrolysis, Photolysis, Aggregation, Precipitation, morphology change, Microbial Growth etc.,

Chemical Reactivity Check List

API/Excipient Functional Groups

Alcohols (-OH) Thiols (-SH) Amines (-NH2) Halides (-X = Cl, Br, F, I) Carboxylic acid (-COOH) Esters, Lactones (-COOR) Amides, Peptides, Lactam (-COONRR) Imines, Ethers (-C=N-R, R-O-R) Aldehydes (-COH) - unsaturated ketones (-C=C-COR) Chiral Centers (-C*-) Double bond (C=C, N=N)

Oxidation, Esterification, Etherification Disulphide formation Addition rxn, N-Oxidation, Q-ium-salts Alkylation Decarboxylation, Esterification Hydrolysis, trans-esterification Hydrolysis Hydrolysis Reaction with amines (Schiffs base) Additions, adduct formation. Racemisation Oxidation ---Rearrangements, Polymerization

Reactivity that can affect stability

Drug Instability could lead to

Results

Reduction of labeled quantity.

Sub-potent drug products. Super-potent drug products. Change in content uniformity.

Change in Bio-availability.
Toxicity due to degradation. Loss of Container closure integrity. Loss of Microbial integrity / sterility. Loss of Cosmetic aspects. Loss of Functional aspects.

Stability during various stages of drug development

Development Phase Pre-IND Preclinical Research Phase I Phase II Phase III (File NDA) Phase IV

* API * Drug Product * Analytical Development (Medicinal / Process Chem)

* Provide material for Pharm/Tox Studies * Preliminary CMC development (API AM) * API/Solution Stability

CMC Activities

* Process Development - API - Drug Product * Analytical Development

* Scale-up / Validation - API - Drug Product * Analytical Development

* Post approval - CMC commitments - CMC Changes - Line extensions

* Provide Phase I & II Clinical supplies * Understand & Optimize -- API process -- Formulation -- Analytical Methods * Developmental Stability -- API -- Drug Product

* Provide Phase III Clinical supplies * Develop Commercial -- API process -- Formulation -- Analytical Methods * NDA Stability (ICH) -- API, Drug Product

* CMC Comments -- Post approval stability -- Annual stability * CMC Changes -- Improvement in process, Scale, Site, Vendors etc., -- API/DP * Stability (ICH) -- API/DP *New dosage forms Development & Stability

Objectives

* Set API/DP specs, Retest date, Shelf Life

Clinical Studies - Phases

Each clinical trial is conducted in four phases. The Food and Drug Administration (FDA) must approve each phase before the study can continue.

Phase I: In this phase, a new drug or treatment is tested on a small group of healthy people to
determine safe dosage, study how the drug works in the body, and see if it has any side effects. The overall safety of the drug is not known during this phase.

Phase II: The drug or treatment can now be tested on a larger group of people to see if it is effective
and to further test its overall safety. Rating scales are developed and used to record data during this phase.

Phase III: Now the drug or treatment is ready to be tested on even larger numbers of people. The study
will look even more closely at the drug's effectiveness, if it has any side effects, overall safety, and how it can improve a person's quality of life. Most drugs that reach this phase are considered for FDA approval.

Phase IV: Once given FDA approval, the trial can enter into the final phase, which involves monitoring
the drug after it has been released to the public. In this phase, researchers look for additional information such as risks, benefits, and optimal or additional uses of the drug. In some cases this phase is used to test the drug on a sub-group of people (such as patients over a certain age).

Stability Specification (Test Method Limit) Attributes investigated

DRUG SUBSTANCE Physical Properties:

Color / Appearance / pH / Solubility / Melting Pt. / Optical Rotation / Density / Viscosity Particle Size / Morphology Crystal Structure, etc.,

DRUG PRODUCT Physical Properties:

Color / Appearance / pH / Viscosity, etc.,

CONTAINER CLOSURE Physical Properties:

Moisture / Vapor transmission / Light permeation / Adhesion / Scaling / Elasticity / Fragility / Corrosion, etc.,

Chemical Properties:
Assay / Moisture content / Degradation products, etc.,

Chemical Properties:
Reactivity / Solvent content / Purity / Degradation products, etc.,

Chemical Properties:
Chemical interaction / Degradation / Extraction & leaching of additives / Chemicals into drug product

Microbial Properties:
Sterility, Microbial limits

Microbial Properties:
Sterility, Microbial limits
***** Validated analytical method should be used.

Functional Properties:
Dissolution / Disintegration / Brittleness / Preservative content / Wt. loss / Dose uniformity, etc., ***** Validated analytical method should be used.

ICH Stability Guidelines

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

Key Features:
-- Covers stability information needed for marketing application in EU, Japan & USA. (Zone I & II) -- Outlines the core stability data package for New drug substances and products.

Major points:
-- Stress testing ( to understand the degradation pattern, intrinsic stability and defining SIM) -- Number of batches / Selection of batches / Storage conditions. -- Amount of data required at the time of filing.

SIM Stability indicating method:

A validated method that can accurately and precisely quantitate the decrease in the quantity of drug substance due to degradation.

Specification:
It is a list of tests, reference to analytical procedures and proposed acceptance criteria, addressed based on ICH Q6A, Q6B, Q3A, Q3B & Q5C

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

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.

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 labeling.

Shelf-Life:

The time period during which a drug product is expected to remain within the approved shelflife specification.

Re-test date: The date after which samples of the drug substance should be examined to ensure that the
material is still in compliance with the specification.

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

General Case (Drug Substances / Products Label Storage Condition
Room Temperature (General customary requirements)

Stability Studies
Long Term Intermediate Accelerated Long Term

Study Condition
252C / 605%RH or 302C / 655%RH 302C / 655%RH 402C / 755%RH 53C 252C / 605%RH -205C

Minimum Data required for Filing

12 Months 6 Months 6 Months 12 Months 6 Months 12 Months

Refrigerator
Accelerated

Freezer

Long Term

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

For Aqueous-Based Drug Products (Packaged in Semi-permeable Containers) Label Storage Condition
Room Temperature (General customary requirements)

Stability Studies
Long Term Intermediate Accelerated

Study Condition
252C / 405%RH or 302C / 355%RH 302C / 655%RH 402C / 255%RH

Minimum Data required for Filing

12 Months 6 Months 6 Months

*** No intermediate condition for Refrigerator storage condition. *** No accelerated condition for Freezer storage condition. *** Storage below -20C should be treated case-by-case.

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

NUMBER OF BATCHES and SELECTION OF BATCHES Material
API

Number of Batches / Scale

At least 3 batches / Pilot scale At least 3 batches 2 of them should be pilot scale 3rd can be smaller

Formulation
N/A

Drug Product

Same as proposed commercial product

(Pilot Scale = 10% of production scale; or 1,00,000 units, which ever is larger for solid orals) Process: API and Drug Product should be manufactured by a process representative of commercial process. Container Closure: Same as proposed commercial packaging. Testing Frequency: Long-term testing: 0, 3, 6, 9, 12, 18, 24 months, then yearly (36M). Intermediate testing: 0, 6, 9 & 12 months. Accelerated testing: 0, 3 & 6 months.

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

Significant Change in Drug substance
Failure to meet in specification

Significant Change in Drug Product

5% change in assay value from its initial value. Any degradation product exceeding its acceptance criteria. Failure to meet the acceptance criteria for dissolution 12 units. Failure to meet the acceptance criteria for pH. Failure to meet the acceptance criteria for appearance, physical attributes and functional tests.

Significant Change in Pharmaceutical Product packed in semi-permeable container

5% water loss from its initial value.

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

Pharmaceutical product packed in semi-permeable container Water loss
Low-Humidity Alternative testing Ratio of water testing conditions conditions loss rates R A RWL Calculation Formula RWL = (100-R)/100-A)

25C / 40% RH
30C / 35% RH 30C / 35% RH 40C / NMT 25% RH

25C / 60% RH
30C / 65% RH 30C / 75% RH 40C / 75% RH

1.5
1.9 2.6 3.0

(100 40)/(100 60)

(100 35)/(100 65) (100 35)/(100 75) (100 25)/(100 75)

Ex., at 40C the calculated rate of water loss during storage at NMT 25% RH is the rate of
water loss measured at 75% RH multiplied by 3.0.

Q1A (R2) Stability Testing of New Drug Substances and Products Stability Commitment Drug Substance and Product Primary Batches
If the submitted data do not cover the proposed shelf life at the time of approval, commitment should be made to continue the studies to firmly establish the shelf life.

Production scale batches

No Commitment required if full term production scale data provided. If production scale batch on stability but full term data not provided, commitment to continue studies. If data provided on less than 3 production scale batches, commitment to add additional batches to study.* If no production scale data, commitment to put first 3 production scale batches.* ***For drug substance = Long term stability. ***For drug product = Long term and accelerated stability.

Q1A (R2) Stability Testing of New Drug Substances and Products Labeling Additional labeling Limiting Factors statement, where relevant
Pharmaceutical products that cannot tolerate refrigerating. Pharmaceutical products that cannot tolerate freezing. Light-sensitive pharmaceutical products. Do not keep in refrigerator or freeze. Do not freeze. Protect from light. Store & transport always below 30C.

Pharmaceutical products that cannot tolerate excessive heat.

Highly hygroscopic pharmaceutical products.

Store in dry condition

Q1B Photo Stability Testing of New Drug Substances and Products

Key Features:
-- Covers the photo stability information for application. -- Photo stability testing conditions for exposing drug substance and products. (Photo sensitivity)

Major points:
-- Light sources -- Photo stability conditions. -- Study Design. -- Number of batches.

Light Sources:
-- Option 1: Artificial daylight (out put similar to D65 [outdoor daylight] & DI65 [indoor indirect daylight]) combining visible and UV outputs, Xenon or metal halide lamp. -- Option 2: (a) Cool white fluorescent lamp. (b) Near UV Fluorescent lamp with spectral distribution between 320 400 nm, Emax emission between 350 370 nm.

Q1B Photo Stability Testing of New Drug Substances and Products

Photo stability conditions:
-- Fluorescent light: Minimum 1.2 million lux hours at 25C / 60% RH. -- UV light: Minimum 200 Watts hours per square meter.

Study design and Number of batches

Material Drug Substance Drug Product **

Forced Photo degradation study

YES NO

Confirmatory Studies No. of Batches *

1 1

Conditions
1.2 Million lux hours: Near-UV energy of 200 watts hours / sq. meter

* Two additional batches should be studied if the results are equivocal.

Q1B Photo Stability Testing of New Drug Substances and Products

Photo stability conditions:
-- Fluorescent light: Minimum 1.2 million lux hours at 25C / 60% RH. -- UV light: Minimum 200 Watts hours per square meter.

A D G

B E H

C F I

Calibration - Calculation:
Fluorescent light: with Lux meter Avg lux = (A + B + C + D + E + F + G + H + I) / 9 Light Exposure for Fluorescent light = 1.2 X 1000000 hrs Avg.Lux

UV light: with Radio meter Avg lux = (A + B + C + D + E + F + G + H + I) / 9 Light Exposure for UV light = 200 X 1000000 Avg.Lux X 10000

Q1B Photo Stability Testing of New Drug Substances and Products

Photo stability study of Drug Product **

Immediate Pack Market Pack

Drug Product

Q1C Stability Testing of New Dosage Forms

Key Features:
-- Covers what should be submitted regarding stability of new dosage forms by the owner of the original application, after the original submission for new drug substances and products.

New Dosage Form:

A pharmaceutical product, containing the same active substance as include in the existing approved drug product, differing in -- rout of administration (e.g., oral to parenteral). -- new functionality / delivery systems (e.g., IR to MR). -- dosage form / same administration (e.g., capsule to tablet, solution to suspensions).

****
A reduced stability database at submission time (e.g., 6 months accelerated and 6 months long term data from ongoing studies) may be acceptable in certain justified cases.

Q1D Bracketing and Matrixing designs for Stability Testing of New Dosage Forms
Key Features:
-- Provides guidance on bracketing and matrixing study designs to stability studies.
STUDY DESIGN REDUCED FULL

BRACKETING

MATRIXING

Bracketing:
Design of a stability schedule whereby 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, assuming that the stability of any intermediate levels is represented by the stability of the extremes tested.

Matrixing:
Design of a stability schedule where testing is performed on a selected subset of samples for one time point and or another subset of samples for a subsequent time point. ** Effect on retest date and shelf life should be checked before going to reduced study design.

Q1D Bracketing and Matrixing designs for Stability Testing of New Dosage Forms
Bracketing Applicable
Multiple Strengths of identical or closely related formulations. Same container closure system (if only size & fill varies)

Bracketing Not Applicable

Drug Substances Different strengths with different excipients

Matrixing Applicable
Different Batches / Strengths / size of same container closure system. (in
some different) cases

Matrixing Not Applicable

Limited utility for Drug Substance. Supporting data with more variability.

Multiple Strengths of identical or closely related formulations

Q1D Bracketing and Matrixing designs for Stability Testing of New Dosage Forms

Example for Bracketing Design

Strength Batch B1 15 ml T T S1 = 50 mg B2 T T B3 T T T = Samples tested C1 S1 B1 C1 S1 B2 C1 S1 B3 C3 S1 B1 C3 S1 B2 C3 S1 B3 C1 S3 B1 C1 S3 B2 C1 S3 B3 C3 S3 B1 C3 S3 B2 C3 S3 B3 B1 S2 = 75 mg B2 B3 B1 T T S3 = 500 mg B2 T T B3 T T

Container Size (C)

100 ml
500 ml

Q1D Bracketing and Matrixing designs for Stability Testing of New Dosage Forms Example for Matrixing Design One-Half reduction
Time points (M) B1 S1 B2 B3 B1 S2 B2 B3 0 T T T T T T T T T = Sample Tested 3 T T T T T 6 9 T T 12 T T T T T T T T T T T 18 24 T 36 T T T T T T

Q1D Bracketing and Matrixing designs for Stability Testing of New Dosage Forms Example for Matrixing Design One-Third reduction
Time points (M) 0 3 6 T T T T T T T 9 12 18 T T T T T T 24 36

B1
S1 B2 B3 B1 S2 B2

T
T T T T

T
T

T
T T T T

T
T T T T

B3

T = Sample Tested

Q1D Bracketing and Matrixing designs for Stability Testing of New Dosage Forms
For Product with three strengths and three container sizes On time points
Strength Container Size A S1 B C A S2 B C A S3 B C

Batch 1
Batch 2 Batch 3

T1
T2 T3

T2
T3 T1

T3
T1 T2

T2
T3 T1

T3
T1 T2

T1
T2 T3

T3
T1 T2

T1
T2 T3

T2
T3 T1

Q1D Bracketing and Matrixing designs for Stability Testing of New Dosage Forms
For Product with three strengths and three container sizes On time points and Factors
Strength Container Size A S1 B C T1 T2 A S2 B T1 T2 T3 C A T1 T2 T3 S3 B C

Batch 1
Batch 2 Batch 3

T1
T3

T2
T3

T2
T3

T1

T1

T2
T3

Key
Time Point (M) T1 0 T 3 6 T 9 T 12 T 18 T T 24 T 36 T

T2
T3

T
T

T
T T

T
T

T
T

Q1E Evaluation of Stability Data

Key Features:
-- How to propose a retest period for drug substance and shelf life for drug product in the registration application. -- When and how a extrapolation beyond available data can be considered.

General Principles:
The purpose of a stability study is to establish, based on testing a minimum of three batches of the drug substance or product, a retest period of shelf life and label storage instructions applicable to all future batches manufactured and packaged under similar circumstances.

Presentation and evaluation of the stability information. Physical, chemical, biological and microbiological tests. Mass balance should be considered. Single vs. multifactor designs and full vs. reduced design studies. Data from formal stability studies & supporting data - critical quality attributes. Appendix A: Decision Tree. Appendix B: Statistical approach.

Q1E Evaluation of Stability Data

General Principles (Contd.,):
Quantitative critical attributes Assay, Degradation products, Preservative content. Qualitative attributes are not amenable to statistical analysis. Statistical analysis is not intended to imply when it can be justified to be unnecessary

Data presentation:
Data of all attributes should be presented in an appropriate format: Tabulated, Graphical , Narrative.

Extrapolation:
Extrapolation is the practice of using a known data set to infer the information about a future data. -to extend retest period / shelf life beyond the period covered by long term data.

Mass Balance:
The process of adding the assay value and levels of degradation products to see how closely those add up to 100% of the initial value, with due consideration of the margin of analytical error.

Q1E Evaluation of Stability Data

Data evaluation for RTP / SL estimation for Pharmaceutical product
1. No Significant change in accelerated condition data within 6 months
1.1 Long term & Accelerated data showing little or no variability / change over time

Room temperature
Refrigerator temperature 1.2

Y = up to 2X, NMT X + 12
Y = up to 1.5X, NMT X + 6

Long term & Accelerated data showing variability / change over time Room temperature Refrigerator temperature Y = up to 1.5X, NMT X + 6 Y = up to X + 3

1.2.1 Data not amenable to statistical analysis.

1.2.2 Data amenable to statistical analysis.

Room temperature
Refrigerator temperature

Y = up to 2X, NMT X + 12
Y = up to 1.5X, NMT X + 6

Q1E Evaluation of Stability Data

Data evaluation for RTP / SL estimation for Pharmaceutical product
2. Significant change in accelerated condition data within 6 months
2.1 2.2 2.3 Intended to be stored in refrigerator.

No Extrapolation, shorter RTP / SL.

Significant change at intermediate condition No Extrapolation, shorter RTP / SL. No significant change at intermediate condition Y = up to 1.5X, NMT X + 6 2.3.2 If long term data amenable to statistical analysis. 2.3.1 If long term data amenable to statistical analysis.

Y = up to X + 3
Y = Proposed RTP /SL X = Period covered by Long term data

Q1E Evaluation of Stability Data

No significant change at Accelerated condition within 6 months
General case: The proposed retest period / shelf life can be up to twice, but should be NMT 12
months beyond the period covered by long term data.
Long Term (X) Formula (Y = ) SL / RTP 9M 2X 18 M 12 M 2X 24 M 18 M X + 12 30 M 24 M X + 12 36 M 36 M X 36 M

Refrigerated case: The proposed retest period / shelf life can be up to one and half times, but
should be NMT 6 months beyond the period covered by long term data.
Long Term (X) Formula (Y = ) SL / RTP 9M 1.5X 13.5 M 12 M 1.5X 18 M 18 M X+6 24 M 24 M X+6 30 M 36 M X 36 M

No extrapolation after 36 months

Q1E Evaluation of Stability Data

Significant change at Accelerated condition within 6 months
General case: The proposed retest period / shelf life can be up to one and half times, but
should be NMT 6 months beyond the period covered by long term data.
Long Term (X) Formula (Y = ) SL / RTP 9M 1.5X 1.35 M 12 M 1.5X 18 M

Refrigerated case: The proposed retest period / shelf life can be up to 3 months beyond the
period covered by long term data.
Long Term (X)
Formula (Y = ) SL / RTP

9M
X+3 12 M

If accelerated stability data for 6 months is not ok, consider intermediate condition as long-term. If any significant change occur at any time during 6 months testing at the accelerated storage condition, additional testing at the intermediate storage condition should be conducted and evaluated.

Q1E Evaluation of Stability Data

Statistical approaches for RTP / SL estimation for Pharmaceutical product
Statistical Methods
A
B C

Linear regression analysis (Y = mX + C)

Poolability tests:
Pooling the data from several batches to estimate a RTP / SL. ANCOVA Analysis of Co-variance method.

Statistical modeling

These procedures can be used in the analysis of stability data that are amenable to statistical analysis for a quantitative attribute for which there is a proposed criterion.

Changes in ICH Q1A parent guideline

Case
Testing Frequency (Accelerated Condition)

Q1A
0, 1, 2, 3 & 6 months

Q1A (R)
0, 3 & 6 months

Q1A(R2)
0, 3 & 6 months

Remarks
5 point study to 3 point study

Nov - 2000
252C / 605%RH (or) 302C / 655%RH

Stability storage condition

Long Term

252C / 605%RH

252C / 605%RH

Decision is left to applicant

Feb - 2003

Intermediate

302C / 605%RH

302C / 605%RH

302C / 655%RH

Feb - 2003

Stability challenge for Zone III & IV

ICH Q1F - Stability Data Package for Registration in Climatic Zones III & IV
Stability Study Condition Data Required Long Term 302C / 655% RH 12 months Accelerated 402C / 755% 6 months

Stress Condition: 50C at ambient humidity to cover extremely hot & dry conditions; 25C / 80% RH to cover extremely high humidity condition.
Withdrawn in June 2006 - Reasons Several countries / regions have revised their own stability testing guidelines for larger safety margin (e.g., 30C / 75%RH a long term storage condition). Respective regions and WHO responsible for defining of storage conditions. Impact on ICH Q1A (R2) Intermediate testing condition is unchanged: 30C / 65% RH. 30C / 75% RH is acceptable, should the applicant decide to use them.

Conclusion
Pharmaceutical stability is a critical quality attribute. Any deviation from the established stability profile could affect the quality, safety and efficacy. Through understanding of the stability of the pharmaceutical product is important to build the quality in
-Design the optimal pharmaceutical product, define efficient API / DP process and establish appropriate specifications and Expiry dates. Successful development, commercialization. registration and

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