Presentation on: stability study of pharmaceutical products

Presented To:

Department of Pharmacy

Northern university Bangladesh

Supervised by:

Dr. Harun AR Rashid

Associate professor & Head

Department of Pharmacy

Presented By:

Md.Mohsin &

Khadija Tut Tahera

NORTHERN UNIVERSITYB A N G L A D E S H

Contents

stability

Stability study

Types of stability

Pharmaceutical degradation

Testing conditions

Climate zone

Guidelines

Types of stability testing

Activation energy

Shelf life prediction

Limitation of accelerated

study

Current trend in stability

testing

Stability

.

Stability of pharmaceutical product may be defined as the capability of a particular formulation in a specific container/closure system to remain within its physical, chemical, microbiological, therapeutic and toxicological specification.

Stability study

Stability testing/study is termed as a complex process because of involvement of a variety of

factors including

1

stability of the active ingredients

3

heat and moisture conditions

encountered during shipment,

storage and handling.

4

type of dosage form

5

interaction between active ingredients and

excipients

2

container/closure system used for packaging

Need for stability study

Provide evidence as to how the quality of

the drug product varies with time.

Establish shelf life for the drug product.

Determine recommended

storage conditions

Determine container and closure system

suitability.

Safety point of view of patient.

Ultimate achievement

Assurance to the patient

Economic considerations

Legal requirement

THEARAPEUTICAL

STABILITY

PHYSICAL

STABILITY

TOXICOLOGIC

STABILITY

MICROBIOLOGICAL

STABILITY

CHEMICAL

STABILITY

Stability

PHARMACEUTICAL DEGRADATION

1. Physical degradation

2. Chemical degradation

3.Microbiological degradation

TYPES OF PHARMACEUTICAL DEGRADATION

FACTORS AFFECTING PHYSICAL DEGRADATION

PHYSICAL DEGRADATION

Polymorphic changes

Crystal growth

Absorption of H2O

Loss of H2O

Loss of volatile

components

Color changes

chemical degradation

Hydrolysis oxidation Decarboxylation Isomerization Polymerization

MICROBIAL DEGRADATION

MICROBIAL DEGRADATION

EndotoxinPyrogen

What happens if drug is degraded?

Lowering of concentration/potency

Active to toxic product

appearance

Reduction in bioavailability

TYPES OF STABILITY TESTING

stability testing

Real-Time stability testing

Accelerated stability testing

Retained sample/ongoing stability

testing

GUIDELINES

guidelines

ICH

FDAWHO

Climate zone

Four climatic zones can be distinguished for the purpose of worldwide stability testing, as follows: ICH Stability Zones

Zone Type of Climate

Zone I Temperate zone

Zone II Mediterranean/subtropical zone

Zone III Hot and dry zone

Zone IV Hot humid/tropical zone

Zone IVb ASEAN testing conditions hot/higher humidity

Testing Conditions

Long Term/Real-Time stability testing

Climatic Zone Temperature Humidity Minimum Duration

Zone I 21ºC ± 2ºC 45% RH ± 5% RH 12 Months

Zone II 25ºC ± 2ºC 60% RH ± 5% RH 12 Months

Zone III 30ºC ± 2ºC 35% RH ± 5% RH 12 Months

Zone IV 30ºC ± 2ºC 65% RH ± 5% RH 12 Months

Zone IVb 30ºC ± 2ºC 75% RH ± 5% RH 12 Months

Refrigerated 5ºC ± 3ºC No Humidity 12 Months

Frozen -15ºC ± 5ºC No Humidity 12 Months

Testing Conditions

Accelerated and Intermediate Testing Conditions

Climatic Zone Temperature Humidity Minimum Duration

Accelerated

Ambient

40ºC ± 2ºC 75% RH ± 5% RH 6 Months

Accelerated

Refrigerated

25ºC ± 2ºC 60% RH ± 5% RH 6 Months

Accelerated Frozen 5ºC ± 3ºC No Humidity 6 Months

Intermediate 30ºC ± 2ºC 65% RH ± 5% RH 6 Months

Sampling Frequency

For Long term testing, during first year sampling should be done every three months, during second year, sampling should be done every six months and after two years, sampling should be done once a year.

Accelerated testing should be done at least six months and it suggests sampling points of 0, 3, 6 months.

Testing parameters of different dosage forms

Tablets Capsules Oral solutions, suspensions and

emulsions

Topical & Ophthalmic and

Preparation

Powders and granules for oral solution or suspension

Metered-dose Inhalations and Nasal Aerosols

Examples of testing parameters contd

Suppositories Freeze-dried Products

Transdermal Patches

large volume parenterals (LVPs)

Small volume parenterals (SVPs)

ACCELERATED STABILITY TESTING AND ACTIVATION ENERGY

Activation energy is the energy that must be overcome in order for a chemical reaction to occur. Activation energy may also be defined as the minimum energy required to start a chemical reaction. The activation energy of a reaction is usually denoted by Ea.

ARRHENIUS EQUATION

Reaction rates are proportional to the number of collisions per unit time (of reactant molecules). The number of collisions increases as the temperature increases. Therefore, the reaction rate increases as the temperature increases according to Arrhenius equation

K = A e-Ea/RT

logK = logA - (Ea/2.303RT)

K = reaction rate constant

A = frequency factor constant i.e maximum number of collisions at infinite temperature

Ea = Energy of activation

T = absolute temperature (Kelvin)

Estimation of energy of activation

Fig. Arrhenius plot

A graph can be drawn by taking log k on y-axis and reciprocal temperature (1/T) on x-axis.

A straight line is obtained, the slope of the line is negative and the magnitude is Ea / 2.303 R.

The intercept corresponds to logA

All the constants in the Arrhenius equation can be obtained from the graph.

Estimation of k value

The reaction is conducted at several temperatures.

Concentration of reactants is determined.

Appropriate graphs are drawn for the kinetic data.

Data is processed for all the orders.

The order of the reaction is identified and from the slopes of the lines, k values are calculated for all temperatures.

Arrhenius plot for elevated temperatures

SHELF LIFE EXTENSION

To support a shelf life extension, a report must be generated documenting stability data (for the proposed interval) for three batches which meet all the following criteria:

Same product / potency

Same manufacturing

process.

Same primary packaging material

Same formulation

No significant change in the manufacturing procedure

Re-stability test after registration

Once the pharmaceutical product has been registered, additional stability studies are required whenever variations that may affect the stability of

the active pharmaceutical substance or pharmaceutical product are made, such as major variations like the following:

a. Change in the manufacturing process.

b. Change in the composition of the

pharmaceutical product.

c. Change of the immediate packaging.

PHOTOSTABILITY

Photo degradation may be observed as bleaching or as discoloration of products. The other effects include cloudy appearance of the product, a loss in viscosity of formulation, precipitation of active principle, alteration in dissolution rate, Although many drugs are found to decompose when exposed to light.

Light Source

Xenon lamps

Tungsten-mercury lamps

Natural Light

Artificial daylight tubes

By exposing drug substance to 400 & 900 (FC)of illumination for 4 & 2 weeks to light and another sample examined protected from light .

e.g. cycloprofen becomes very yellow after five days under 900 foot candles of light

Limitation of Arrhenius relationship for stability prediction

Stability predictions based on Arrhenius equation are valid only when the break down depends on temperature

The energy of activation obtained in the study should be between 10 to 30 kcal/mole

When degradation is due to Microbial contamination or Photochemical reactions

When the product looses its physical integrity at higher temperatures

When the order changes at elevated temperatures

In case of disperse systems, when temperature is elevated viscosity is decreased and this may introduce errors in the prediction of stability

STABILITY CHAMBER

CURRENT TRENDS IN STABILITY TESTING

Current trend, especially amongst the multinational pharmaceutical companies, is to define conditions for stability testing for global marketing. For this the companies are orienting their protocols to single set of conditions that covers extreme environmental conditions. The specific changes for global testing include increase in duration of accelerated testing period from 6 to 12 months, and conduct of additional tests at 50°C/75% RH for 3 months.

The concept behind this change is to avoid repetition of stability testing for other regions and efficient and optimum use of resources as all tests are done in one laboratory. Moreover testing under combination of three environmental factors ; temperature, humidity and light, has been reported to result in stronger deleterious effect on drug substances and products, than under temperature and humidity conditions only.

Reference

1.Stability testing for hot and humid climates, WHO Drug Information Vol 18,

2, 2004, page 113-156

2. World Health Organization :Stability Testing Of Active Pharmaceutical

Ingredients and Finished Pharmaceutical Products; WHO Technical Report

Series, No. 953, 2009 ; Page No.87-123.

3. ICH Q1A: “Stability Testing of New Drug Substances and Products”

http://www.ich.org/LOB/media/MEDIA419.pdf

4.ICH Q1C: “Stability Testing of New Dosage Forms”

http://www.ich.org/LOB/media/MEDIA413.pdf

5.ICH Q1E: “Evaluation for Stability Data”

http://www.ich.org/LOB/media/MEDIA415.pdf

http://www.ich.org/LOB/media/MEDIA427.pdf

http://www.ich.org/LOB/media/MEDIA430.pdf

6.Handbook of modern pharmaceutical analysis, Volume III, page: 445-483

Reference 7. Ali J., Khar RK., Ahuja A. Dosage form and design.3rd ed. Delhi. Birla

Publications Pvt. Ltd ( 2008) 100-123

8.International Conference on Harmonization, guidelines Q1A and Q1F,

www.ich.org/

9.CVS Subrahmanyam, Textbook of Physical Pharmacy, Second Edition; 15

May 2000;Page No-51-58,366-426

10. Grimm W. Extension of the international conference on harmonization

tripartite guideline for stability testing of new drug substances and products

to countries of climatic zones 3 and 4. Drug Dev.Ind. Pharm. 1998; 24:313-

325

11.http://www.fda.gov/ICECI/Inspections/InspectionGuides/InspectionTechnical

Guides/ucm072919.htm

12. http://www.authorstream.com/Presentation/sachins_patil16-1564811-ich-

guidelines-stability-studies-accelerated/

13. http://apps.who.int/medicinedocs/en/d/Jh1808e/