Stability of phrmaceutical product

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 zonesClimatic

Zone

Zone – I Zone – II Zone – III Zone – IVa Zone - IVb

Moderate Mediterranean Hot & Dry Hot & Humid Hot & High Humid

Temperature (±2°C) - MKT

21 25 30 30 30

Yearly avg. Humidity (±5%RH)

45 60 35 65 75

European All Countries -

American Chile, Canada & US Brazil, Jamaica

Asian China, Japan & Turkey India, Srilanka & Philippines

African South Africa, Zambia & Zimbabwe Botswana, Ghana & Uganda

Australia / Oceanic Australia, Newzelannd Fiji, Papua & New guinea

What is Mean Kinetic Temperature?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.”

Synthesis

Stability of Pharmaceutical productFormulatio

nsPackagi

ng

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

Drug Instability could lead to………

Stability during various stages of drug development

Clinical Studies - PhasesEach 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 SUBSTANCEPhysical Properties:Color / Appearance / pH / Solubility / Melting Pt. / Optical Rotation / Density / ViscosityParticle Size / MorphologyCrystal Structure, etc.,

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

Microbial Properties:Sterility, Microbial limits

***** Validated analytical method should be used.

DRUG PRODUCTPhysical Properties:Color / Appearance / pH / Viscosity, etc.,

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

Microbial Properties:Sterility, Microbial limits

Functional Properties:Dissolution / Disintegration / Brittleness / Preservative content / Wt. loss / Dose uniformity, etc.,

***** Validated analytical method should be used.

CONTAINER CLOSUREPhysical Properties:Moisture / Vapor transmission / Light permeation / Adhesion / Scaling / Elasticity / Fragility / Corrosion, etc.,

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

ICH – Stability Guidelines

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



General Case (Drug Substances / Products

Label Storage Condition Stability Studies Study Condition Minimum Data

required for Filing

Room Temperature(General customary

requirements)

Long Term25±2°C / 60±5%RH

or30±2°C / 65±5%RH

12 Months

Intermediate 30±2°C / 65±5%RH 6 Months

Accelerated 40±2°C / 75±5%RH 6 Months

RefrigeratorLong Term 5±3°C 12 Months


Freezer Long Term -20±5°C 12 Months


For Aqueous-Based Drug Products (Packaged in Semi-permeable Containers)

Label Storage Condition Stability Studies Study Condition Minimum Data

required for Filing

Room Temperature(General customary

requirements)

Long Term25±2°C / 40±5%RH

or30±2°C / 35±5%RH

12 Months

Intermediate 30±2°C / 65±5%RH 6 Months


*** No intermediate condition for Refrigerator storage condition.

*** No accelerated condition for Freezer storage condition.

*** Storage below -20°C should be treated case-by-case.


NUMBER OF BATCHES and SELECTION OF BATCHES

Material Number of Batches / Scale Formulation

API At least 3 batches / Pilot scale N/A

Drug ProductAt least 3 batches

2 of them should be pilot scale3rd can be smaller

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.



Low-Humidity testing conditions

Alternative testing conditions

Ratio of water loss rates

Calculation Formula

R A RWL RWL = (100-R)/100-A)

25°C / 40% RH 25°C / 60% RH 1.5 (100 – 40)/(100 – 60)

30°C / 35% RH 30°C / 65% RH 1.9 (100 – 35)/(100 – 65)

30°C / 35% RH 30°C / 75% RH 2.6 (100 – 35)/(100 – 75)

40°C / NMT 25% RH 40°C / 75% RH 3.0 (100 – 25)/(100 – 75)

Ex., at 40°C 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.



Q1B – Photo Stability Testing of New Drug Substances and Products


Study design and Number of batches

MaterialForced Photo degradation

study

Confirmatory Studies

No. of Batches * Conditions

Drug Substance YES 1 1.2 Million lux hours:Near-UV energy of ≥ 200 watts hours / sq.

meterDrug Product ** NO 1

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



Photo stability study ofDrug Product **

Q1C – Stability Testing of New Dosage Forms

Q1D – Bracketing and Matrixing designs for Stability Testingof New Dosage Forms



Example for Bracketing DesignStrength S1 = 50 mg S2 = 75 mg S3 = 500 mg

Batch B1 B2 B3 B1 B2 B3 B1 B2 B3

Container Size (C)

15 ml T T T T T T

100 ml

500 ml T T T T T T

T = Samples tested

C1 – S1 – B1 C3 – S1 – B1 C1 – S3 – B1 C3 – S3 – B1

C1 – S1 – B2 C3 – S1 – B2 C1 – S3 – B2 C3 – S3 – B2

C1 – S1 – B3 C3 – S1 – B3 C1 – S3 – B3 C3 – S3 – B3


Example for Matrixing Design – “One-Half reduction”Time points (M) 0 3 6 9 12 18 24 36

S1

B1 T T T T T T

B2 T T T T T T

B3 T T T T T

S2

B1 T T T T T

B2 T T T T T T

B3 T T T T T

T = Sample Tested


Example for Matrixing Design – “One-Third reduction”Time points (M) 0 3 6 9 12 18 24 36

S1

B1 T T T T T T

B2 T T T T T T

B3 T T T T T T T

S2

B1 T T T T T T T

B2 T T T T T T

B3 T T T T T T

T = Sample Tested


For Product with three strengths and three container sizes

“On time points”Strength S1 S2 S3

Container Size A B C A B C A B C

Batch 1 T1 T2 T3 T2 T3 T1 T3 T1 T2




For Product with three strengths and three container sizes

“On time points and Factors”Strength S1 S2 S3

Container Size A B C A B C A B C

Batch 1 T1 T2 T2 T1 T1 T2



KeyTime Point (M) 0 3 6 9 12 18 24 36

T1 T T T T T T T

T2 T T T T T T

T3 T T T T T T

Q1E – Evaluation of Stability Data



1. No Significant change in accelerated condition data within 6 months1.1 Long term & Accelerated data showing little or no variability / change over time

Room temperature Y = up to “2X”, NMT “X + 12”

Refrigerator temperature Y = up to “1.5X”, NMT “X + 6”

1.2 Long term & Accelerated data showing variability / change over time

1.2.1 Data not amenable to statistical analysis.

Room temperature Y = up to “1.5X”, NMT “X + 6”

Refrigerator temperature Y = up to “X + 3”

1.2.2 Data amenable to statistical analysis.

Room temperature Y = up to “2X”, NMT “X + 12”

Refrigerator temperature Y = up to “1.5X”, NMT “X + 6”

Data evaluation for RTP / SL estimation for Pharmaceutical productData evaluation for RTP / SL estimation for Pharmaceutical product


2. Significant change in accelerated condition data within 6 months2.1 Intended to be stored in refrigerator.

No Extrapolation, shorter RTP / SL.

2.2 Significant change at intermediate condition

No Extrapolation, shorter RTP / SL.

2.3 No significant change at intermediate condition

2.3.1 If long term data amenable to statistical analysis.

Y = up to “1.5X”, NMT “X + 6”

2.3.2 If long term data amenable to statistical analysis.

Y = up to “X + 3”

Y = Proposed RTP /SL X = Period covered by Long term data

Data evaluation for RTP / SL estimation for Pharmaceutical productData evaluation for RTP / SL estimation for Pharmaceutical product

Q1E – Evaluation of Stability DataNo 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) 9 M 12 M 18 M 24 M 36 M

Formula (Y = ) 2X 2X X + 12 X + 12 X

SL / RTP 18 M 24 M 30 M 36 M 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) 9 M 12 M 18 M 24 M 36 M

Formula (Y = ) 1.5X 1.5X X + 6 X + 6 X

SL / RTP 13.5 M 18 M 24 M 30 M 36 M

No extrapolation after 36 months

Q1E – Evaluation of Stability DataSignificant 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) 9 M 12 M

Formula (Y = ) 1.5X 1.5X

SL / RTP 1.35 M 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) 9 M

Formula (Y = ) X + 3

SL / RTP 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.


Statistical MethodsA Linear regression analysis (Y = mX + C)

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

C 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.

Statistical approaches for RTP / SL estimation for Pharmaceutical productStatistical approaches for RTP / SL estimation for Pharmaceutical product

Changes in ICH – Q1A parent guideline

Case Q1A Q1A (R) Q1A(R2) Remarks

Testing Frequency(Accelerated Condition)

0, 1, 2, 3 & 6 months

0, 3 & 6 months

0, 3 & 6 months

5 point study to 3 point study

Stability storage

condition

Long Term 25±2°C / 60±5%RH

25±2°C / 60±5%RH

25±2°C / 60±5%RH

(or) 30±2°C / 65±5%RH

Decision is left to applicant

Intermediate 30±2°C / 60±5%RH

30±2°C / 60±5%RH

30±2°C / 65±5%RH -

Nov - 2000Nov - 2000

Feb - 2003Feb - 2003

Feb - 2003Feb - 2003

Stability challenge for Zone – III & IV

Withdrawn in June 2006 - Reasons Several countries / regions have revised their own stability testing guidelines for larger safety margin (e.g., 30°C / 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: 30°C / 65% RH. 30°C / 75% RH is acceptable, should the applicant decide to use them.

ICH – Q1F - Stability Data Package for Registration in Climatic Zones III & IV

Stability Study Long Term Accelerated

Condition 30±2°C / 65±5% RH 40±2°C / 75±5%

Data Required 12 months 6 months

Stress Condition: 50°C at ambient humidity to cover extremely hot & dry conditions; 25°C / 80% RH to cover extremely high humidity condition.

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, registration and commercialization.

Documents

Stability of phrmaceutical product