Presented By : Guided By :Ch.Mahesh Babu. Mrs.McthelM.PHARMACY Asst.professor

Dept of pharmaceutics

NIRMALA COLLEGE OF PHARMACY

Stability testing is an integral part of pharmaceutical development.

The primary purpose of stability testing is to provide supporting evidence on stability behavior of pharmaceutical drug products.

Many factors drive the process of industrial stability testing for pharmaceutical development.

It is an evolutionary concept covering the life cycle of pharmaceutical product development.

In early discovery phase the primary focus is to generate stability characteristics of a chemical /biological entity.

In later stages ,the goal is to establish shelf life for formulations packaged in final package intended for commercial introduction.

Discovery phase Pre clinical stage Pre-IND stage IND stage Product development stage NDA stage Approved product stage Revised product stage

DISCOVERY PHASE To help select the most satisfactory chemical

entity possessing the right pharmacological, toxicological & pharmaceutical profile.

The pharmaceutical profile is mostly focused towards the optimum chemical and physical stability characteristics.

To select the right physical form(base, salt ,ester)

These studies help establish the boundaries with in which one must operate to design formulations.

The development of early dosage form for pre clinical testing in humans require an extensive stability evaluation.

Preliminary stability testing on all formulations must be carried out using stability indicating assays in accordance with GLPs.

It requires an entrance assay prior to the initiation of toxicological testing and an exit assay, must be performed at the end of the studies.

Pre-formulation & stability evaluation of chemical entity is carried out according to ICH guidelines.

In addition to normal preformulation evaluations ,forced degradation studies under highly stressed stability conditions is under taken.

DOSAGE FORM PARAMETERS

SOLID Temperature, humidity,photo degradation.

solutions pH, ionic strength, additives

Accelerated and normal storage temperature testing of drug substance and for clinical formulation must be initiated.

The goal of these studies should be to generate information to insure that the clinical formulations are likely to remain stable during the planned clinical studies.

Intermediate stability testing is done in this stage.

Interim stability testing is conducted to establish the maximum time for which a drug product can be stored in interim containers for further processing.

Formal stability program is established for generation of stability data for registration applications.

The stability of drugs should be evaluated in containers used for marketing.

Care should be exercised in selection of the size, surface-to volume ratio of the container.

The goal of the stability evaluation program during this phase is to confirm or extending the expiration date.

The commitment in this stage mandates that any batch that is found out of specification will be with drawn from the market.

Most products undergo post approval changes.

They may be internally driven or externally driven.

Internally driven : changing size & shape of dosage forms, changes in package design and others.

Externally driven : deletion of dyes, formulation changed and others.

Establishment of stability testing function requires an extensive development of documentation to maximize the compliance and to minimize the regulatory citations.

The guidelines in section 211.166 of 21 CFR states “ there shall be a written stability testing program designed to assess the stability characteristics of drug product”.

a written stability testing program is critical for the establishment of the stability testing function.

The stability protocol should record the purpose for conducting the stability test the method used, the testing frequency ,storage conditions and several other factors.

The commitment requires submission of stability data at periodic intervals as specified in the application.

Current good manufacturing practices mandate that every organization develops a set of SOP’s to describe their operations.

It is almost impossible to develop a stability management function with out having a comprehensive set of SOP’s

Regulations require that “each person engaged in the manufacturing processing should have education or training to enable that person to perform the assigned functions”.

Training shall be in the particular operations that the employees performs.

Training must be conducted by qualified individual on a continuous basis with sufficient frequency.

During discovery phase stability evaluation is used in the conduct of pre-clinical safety.

This data helps to establish retest period for drug substances .

Selection of three pilot batches is used for statistical evaluation.

Based on the analysis the world is divided in to 4 climatic zones.

WORLDWIDE ZONES AND THE TEMPERATURE AND HUMIDITY

CONDITIONS Zone Mean kinetic

temperatureYearly average humidity (%RH)

Zone I ( Moderate) 21 �C 45

Zone II (Mediterranean) 25 �C 60

Zone III (Hot, dry) 30 �C 35

Zone IV (Very hot, moist)

30� C 70

COUNTRIES BELONGING TO VARIOUS ZONES

Regions Zone I &II Zone III&IV

EUROPE All countries

AMERICA Argentina, Bolivia, Canada, Mexico, US

Brazil, Columbia, Cuba, Jamaica

ASIA Afghanistan, China, Iran, Nepal, Turkey

Bahrain , Hong Kong, India, Oman , Pakistan,

Srilanka,UAE

AFRICA Egypt, Algeria, South Africa, Libya

Angola, Benin, Congo, Uganda, Sudan, Somalia,

Senegal

Study Storage conditionMinimum time period covered by data at submission

Long Term

(Ambient)

25º C ± 2º C

60%RH ± 5%

12 months

Intermediate

(controlled)

30º C ± 2º C

60%RH ± 5%

6 months

Accelerated 40º C ± 2º C

75%RH ± 5%

6 months

To simulate the transportation and shipment conditions in the stability studies thermal cycling is done

Testing parameters for those studies should include not only the chemical analysis but also physical changes.

Photostability testing studies include:• Test on drug substance.• Test on exposed drug product outside the immediate

pack.• Test on drug product in the immediate pack.• Test on drug product in the marketing pack.

Light sourceOption 1: Artificial daylight lamp combining both visible &

UV output similar to D65 & ID65.Option 2: Cool white fluorescent & near UV lamp

output max. energy emitted

Sample exposed to light source/actinometric systemEg: Quinine chemical actinometry 2%w/v aq.solution of quinine monohydrochloride

dihydrate

Option 1: In 20ml colourless ampoule at 400 nm Option 2: In 1cm quartz cell-(sample) and control wrapped with

Aluminium foil Change in absorbance calculated by A = AT-A0

Photostability testing

Forced degradation Confirmatory testing

Evaluate the photosensitivity Its used alone or in solution Placed in chemically inert &

transparent containers. Variety of exposure condition

Information necessary for handling, packaging and labeling

To study, identify precautionary measures needed in manufacturing or in formulation

The containers should be tested in all directions i.e..up right ,inverted ,on the side positions.

This is done for long term and accelerated stability testing.

This is to ensure that there are no adverse effects from any interaction is produced.

For long-term storage 12 month study

◦ Testing frequency 0 3 6 9 12

For accelerated storage 6 month study

◦ Testing frequency 0 3 6(initial) (final)

If significant change occur◦ Increase the testing by adding

sample at final time point◦ Include 4th time point in study

design

For intermediate storage 12 month study - Testing frequency 0 6 12

If significant change occur - A 4th time point can be

included

According to the section 211.166 of 21 CFR states that “testing of drug products for re constitution at the time of dispensing as well as after they are reconstituted”.

For reconstituted products two distinct stability periods are in operation.

First period : long term and accelerated stability testing prior to reconstitution.

Second period: short term stability after reconstitution

Dosage form Evaluation

Tablets Appearance,colour,odour,assay,degradation

products,dissolution,moisture and friability.

Hard gelatin capsules Appearance,colour,odour,assay,degradation

products,dissolution,moisture and microbial limits

Soft gelatin capsules Appearance,colour,odour,assay,degradation

products,dissolution,moisture and microbial limits,pH,leakage.

Emulsions Appearance,colour,odour,assay,degradation products, microbial

limits,PH,viscosity,preservative content and distribution of dispersed

phase globules.

Dosage form Evaluation

Oral solutions Appearance,colour,odour,assay,degradation products, PH,microbial limits,

preservative content.

Oral suspensions Appearance,colour,odour,assay,degradation products, PH,microbial limits,

preservative content,redispersibility,rheological

properties, mean size and distribution of particle.

Oral powders Appearance,colour,moisture,and reconstitution time.

Inhalations and nasal sprays Appearance,colour,odour,assay,degradation products, dose content

uniformity, microscopic evalution,water content, leak rate,

microbial limits.

Topical,opthalamic,ointments,creams,lotions,pastes,gels,solutions

.

Appearance,clarity,colour,homgeneity,odour,ph,resuspendibility,viscosity,p

article size distribution,assy,degraation

products,preservatives,microbial limits, weight loss.

Dosage form Evaluation

Small volume parenterals Appearance,colour,clarity, assay,presarvative

content, degradation products, particulate

matter, sterility,

Large volume parenterals Appearance,colour,clarity, assay,presarvative

content,degradation products,particulate

matter,sterility,pH,pyrogenicity,volume.

Bracketing is the design of a stability schedule such that samples on the extremes of certain design factors are tested at all time points.

Protocols for bracketing designs should be endorsed by the FDA prior to initiation of primary stability studies (FDA 1998).

Bracketing design is suitable and applicable to identical or closely related formulations packaged in different size identical container/closure system.

MATRIXING Matrixing is the design of a stability schedule such that the

selected subset of the total number of possible samples for all factor combinations would be tested at a specified time point.

3rd

month6th month