Ich guidelines for Stability

CONTENTS

INTRODUCTION

STRUCTURAL FEATURES OF ICH GUIDELINES FOR STABILITY

PREDICTION OF SHELF LIFE

PARAMETERS EVALUATED

ICH

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

ICH is a joint initiative involving both regulators and research-based industry representatives of the European Union, Japan and the USA in scientific and technical discussions of the testing procedures required to assess and ensure the safety, quality and efficacy of medicines.

Objective of ICH

To increase international harmonisation of technical requirements to ensure the safe, effective, and high quality medicines

Developement and registration of these drugs in the most efficient and cost-effective manner

Prevent unnecessary duplication of clinical trials in humans

To promote public health

Minimize the use of animal testing without compromising safety and effectiveness

Make information available on ICH, ICH activities and ICH guidelines to any country or company that requests the information

Promote harmonisation processes related to ICH guidelines regionally and globally

To strengthen the capacity of drug regulatory authorities and industry to utilise them.

STABILITY The capacity of a drug substance or drug product to remain within the established specifications to maintain its identity, strength, quality and purity through out the retest or expiration dating period.

NEED OF STABILITY STUDIES# To determine the shelf life# To determine quality, safety and efficacy of a drug product.

GLOBAL CLIMATIC ZONES

ZONES(CONDITION)

MEAN KINETIC TEMPERATURE

AVERAGE YEARLY % RH

ZONE I(Moderate)

21 45

ZONE II(Mediterranian)

25 60

ZONE III(Hot, Dry)

30 35

ZONE IV(Very hot, Moist)

30 70

PREDICTION OF SHELF LIFE

SHELF LIFE :- The time during which the dosage form is supposed to

retain its original qualities.

STEPS INVOLVED IN PREDICTION OF SHELF LIFE :-

1. Division of formulation and storage at different elevated temperatures like 400C, 500C, 600C and 700C to accelerate degradation.

2. Withdrawal of samples at various intervals of time and measurement of remaining concentration of active ingredients

3. Determination of order of reaction

4. Calculation of reaction rate constant K for the degradation at each elevated temperature.

5. Determination of K at room temperature from linear plot of log K values at different elevated temperatures against the reciprocal of absolute temperature

6. Extrapolation of curve to 25 0C and obtain K value at 250C

7. Substitution of K value in appropriate rate equation and shelf life is estimated

8. Calculation for determination of overage

GENERAL STRUCTURAL FEATURES OF ICH GUIDELINES FOR STABILITY

SELECTION OF BATCHESCONTAINER AND CLOSURE SYSTEMTESTING FREQUENCYFor long-term studies – every 3 months over the first year every 6 months over the second year annually thereafter through the proposed re-test

period.

for accelerated storage condition - minimum of three time points, including the initial

and final time points (e.g., 0, 3, and 6 months), from a 6-month study

for intermediate storage condition - four time points, including the

initial and final time points (e.g., 0, 6, 9, 12 months), from a 12-month study

STORAGE CONDITIONS:-

Study Storage condition Minimum time period covered bydata at submission

Long term* 25°C ± 2°C/60% RH ± 5% RHor30°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

*studies are performed at 25 ±2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH.

** If 30°C ± 2°C/65% RH ± 5% RH is the long-term condition, there is no intermediate condition.

Drug substances intended for storage in a refrigerator

Study Storage condition Minimum time period covered bydata at submission

Long term 5°C ± 3°C 12 months

Accelerated 25°C ± 2°C/60% RH ± 5% RH

6 months

Long term** - 20°C ± 5°C 12 months

*FOR STORAGE IN FREEZER

EVALUATION

PHYSICAL TEST

CHEMICAL TEST BIOLOGICAL TEST

MICROBIOLOGICAL TEST

GENERAL PARAMETERS EVALUATED APPEARANCE

PHYSICAL PARAMETERS

CHEMICAL PARAMETERS

- MOISTURE CONTENT - OXYGEN CONSUMPTION

DRUG CONTENT

pH

PARAMETERS EVALUATED FOR DIFFERENT DOSAGE FORMS

Tablets :-

• Dissolution (or disintegration, if justified)

• Water content

• Hardness/Friability

• Tests for texture and colour stability (For coated and coloured tablets)

Capsules :-

• Brittleness

• dissolution (or disintegration, if justified)

• water content

• level of microbial contamination

Emulsions :-

• Phase separation

• pH

• Viscosity

• Level of microbial contamination

• Mean size

• Distribution of dispersed globules

Oral solutions and suspensions :-

• Formation of precipitate• clarity for solutions• pH• Viscosity• Extractables• level of microbial contamination • Redispersibility• rheological properties• mean size• distribution of particles • polymorphic conversion (if applicable)

Nasal sprays: solutions and suspensions :-

• Clarity (for solution)• level of microbial contamination• pH• particulate matter• unit spray medication content uniformity• number of actuations meeting unit spray content

uniformity per container• droplet and/or particle size distribution• weight loss• pump delivery• microscopic evaluation (for suspensions)• foreign particulate matter extractable/leachable from

plastic and elastomeric components of the container, closure andpump.

Powders and granules for oral solution or suspension :-

• Water content• Reconstitution time

Suppositories :-

• Softening range• Dissolution (at 37°C).

Topical, ophthalmic and otic preparations :-

• Clarity• Homogeneity• pH• resuspendability (for lotions)• Consistency• Viscosity• particle size distribution (for suspensions

when feasible) • level of microbial contamination/sterility• weight loss (when appropriate).

Cutaneous sprays :-

• pressure• weight loss• net weight dispensed• delivery rate• level of microbial contamination• spray pattern• water content• particle size distribution (for suspensions)..

Parenterals :-

• Colour• clarity (for solutions)• particulate matter• pH• Sterility• Endotoxins• Volume*

REFERENCES

1. Sinko patrick J, “Martin’s Physical Pharmacy & Pharmaceutical Sciences”, published by Waulters kluwer health (India) pvt ltd, New Delhi, 5th edition, 2006

2. www.ema.europa.eu /docs.

THANKS