Pharmaceutical StabilityPharmaceutical Stability

Bujji Kanchi

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Routine LifeRoutine Life

� we use food and drugs

� Has any one ensure whether the drugs expired before buying or consuming ?

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Keep in placeKeep in place

� Manufacturers and retailers should ensure the storage conditions of DRUGS.

� Drugs to be stored in refrigerator. Keep it in refrigerator only.

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Mr.StabilityMr.Stability

� The Expiry date/Retest of the drugs under recommended storage conditions is Revealed by Mr. Stability.

� Nothing but stability studies

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What is Stability studiesWhat is Stability studies

� What is light ?Which is not dark

� Stability means which is not instability

� the state or quality of being stable.

� resistance or the degree of resistance to chemical change.

� No significant change in quality

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What is stabilityWhat is stability

� The change in quality leads to instability.� The change in stability due to storage

conditions over time.� The change in stability leads to expiry of the

drugs.� To be stable, the conditions for stability must

be adjusted enough to be stable� Packing conditions will effects the drugs

stability� Utterly stability means quality remains same

until the expiry / retest date.

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Changes in stability can beChanges in stability can be

� There are three major types of “changes”:

� Physical changes, which might effect the appearance, melting point, clarity and color of solution, water, crystal modification (polymorphism) or particle size

� Chemical changes, which can be observed in an increase in degradation products or decrease of assay

� Microbial changes, like growth of microorganism, change in the efficiency of preservative contents (e.g., antioxidant, antimicrobial preservative)

�Last but not least…..

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Last but not leastLast but not least

� Last but not least, some changes are due to the Packing or container closure system

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Picture :Picture :Shouting FDA inspector Shouting FDA inspector PerspectivePerspective--Lack of proper Stability study.Lack of proper Stability study.

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Why stabilityWhy stability

� Every study has a purpose,

� Every purpose has a requirement,

� Every requirement calls

the stakeholders to alert for compliance.

� Stability studies has a very important and great purpose to fulfill the patient safety and regulatory requirements

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Why stabilityWhy stability

� To know the drug

1. Storage conditions

2. Retest/Expiry date

3. Packing style

THAT IS IT.

nothing more than that

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Definition Definition

� Stability

To provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity, and light, and to establish a re-test period for the drug substance or a shelf life for the drug product and recommended storage conditions.

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Definition Definition

� Retest

The date after which samples of the drug

substance should be examined to ensure that the material is still in compliance with the specification and thus suitable for use in the manufacture of a given drug product.

� Expiry date/Shelf life

The date after which it must not be used.

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Conditions of storage Conditions of storage

� Long term or Real time or Storage condition

25°/60%RH or 30°/65%RH

or Refrigerator(2-8°C)

or Zone-IV(30°/75%RH)

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Long term storageLong term storage

� Long term storage is the storage condition to store the materials.

� Often called Real time condition

� These storage conditions are real climatic conditions

� The world is divided into 4 climatic zones

� As a true convention these conditions are available in the world climate and the stability of the drugs are evaluated in this conditions only, unless and otherwise justified.

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World Climatic ZonesWorld Climatic Zones

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Climatic zonesClimatic zones

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Conventional ProcedureConventional Procedure

� Pack and incubate the samples in stability chamber and test it frequently

� observe the changes by comparing the results at each interval of testing with the initial results or consecutive results and find the changes.

� Showing variation / No variation

� Confirm the stableness.

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By LawBy Law (unless and otherwise justified)(unless and otherwise justified)

� For every long-term condition, There is a need of accelerated or Intermediate study supports to

� Giving Retest by Extrapolating

� To know the long term degradation elements early.

� During transport, an evidence of extreme high temperature stability

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What is accelerated storageWhat is accelerated storage

� Keeping the temperature higher than long term and study as per the procedure for six months.

� Studies designated to increase rate of degradation.

� Intermediate study(30°C/65%RH) is designated to increase the rate of degradation moderately.

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Requirement of Studies for the products stored at Requirement of Studies for the products stored at 2525°°C/60%RHC/60%RH

Study Storage condition Minimum time period covered by

data at submission

Long term*

25°C ± 2°C/60% RH ± 5% RH

or

30°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

*It is up to the applicant to decide whether long term stability studies are performed at 25 ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH.

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Requirement of Studies for the products Requirement of Studies for the products stored at 5stored at 5°°CC

Study Storage condition Minimum time period covered by

data at submission

Long term 5°C ± 3°C 12 months

Accelerated 25°C ± 2°C/60% RH ± 5% RH 6 months

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Frequency of testingFrequency of testing

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Studies Studies ––Frequency of testingFrequency of testing� Accelerated- 6 months

Every month up to six months

� Long term- 5 years

Testing points in months-(1-6 months, then quarterly up to one year, half yearly in second year, there after annually

� Intermediate- 12 months

Quarterly over the year

If significant change(Fail to meet the specification) at any testing interval, No need further testing.

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PackingPacking� No. of sample to be packed and kept in stability chamber

Storage conditions

Months 5°

25°/60% OR

30°/65% 30°/65 40°/75%

1 * * * *

2 * * * *

3 * * * *

4 * * * *

5 * * * *

6 * * * *

7 - - *

8 - - *

9 * * *

10 - - *

11 - - *

12 * * *

18 * *

24 * *

36 * *

48 * *

60 * *

* Indicates Sample packed- Not required to pack

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Analysis at the intervalsAnalysis at the intervals

� Start the studies at Long term at 25°, Intermediate 30°, accelerated 40° as per the schedules.

� If there is no failure at accelerated and intermediate, continue the 25° up to 5 years

� Failure at any interval 30° or 25°, then only start 5° interval study

� Stop the testing at the interval from its failure.

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Analysis at the intervalsAnalysis at the intervals

� If any significant change at accelerated study.

Call for intermediate testing from the point of accelerated every month up to 12 months.

� If no significant change at accelerated study.

Study at intermediate condition 3,6,9,12 months only(4 testing intervals)

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Testing parametersTesting parametersWhat test to be done in stability studiesWhat test to be done in stability studies--

� No need to test all tests as per release specifications

� In general, appearance, assay and degradation products should be evaluated

� for all active pharmaceutical ingredients (APIs).

� Other API parameters that may be susceptible to change should also be studied where applicable.

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Retest evaluationRetest evaluationRetest period alloment

Long term at 25°C/60%RH

Accelerated

Long

Term Intermediate Retest

X is Y=

GOOD GOOD GOOD 2X

Little Degradation, Not failed GOOD GOOD 1.5X

Significant change GOOD GOOD X+3

Significant change GOOD Significant change X

Long term at 5°C

Accelerated

Long

Term Retest

X is Y=

GOOD GOOD 1.5X

Little Degradation, Not failed GOOD X+3

Significant change GOOD X

y=2X is invalid when X>12 Months, In this case Y=X+12 Months is assigned.

y=1.5X is invalid when X>12 Months, In this case Y=X+6 Months is assigned. 29

Stability chambersStability chambers

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Integrated systems for data controlIntegrated systems for data control

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Stability chambersStability chambers

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Stability chambersStability chambers

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Check list Check list S.No. Activity Remarks

1 Check the Entry in Stability analysis schedules from respective chamber Ok Not ok

2 Check the Entry in charging and with drawl record, Does The record should

reflect the samples present in the chamber.

Ok Not ok

3 Charging the samples in to the chamber with in 20 days from the T0 Point(Batch

Release)

Ok Not ok

4 Are with drawl of the samples from the chamber with in the relaxation period. Ok Not ok

5 Analysis and data sheets must be ready with in 5 days from the date of with

drawl

Ok Not ok

6 After analysis , Check the analytical results entry in Data sheets and

verification of data

Ok Not ok

7 One batch added to the long term stability programme every year(unless none

is produced during that year)

Ok Not ok

8 Retest date Annexure, Updating the retest based on Long term data at Every

time point of long term study

Ok Not ok

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Ensure stability chambers MaintenanceEnsure stability chambers Maintenance

Stability Chamber Check list

S.No. Activity Remarks

1 Daily Chamb er log( yesterday 9 am to Today 9 am), Print daily in the mo rning. Ok Not ok

2 Observe the deviatio ns; all deviations must be entered in the chamber histo ry

card.

Ok Not ok

3 Any ch amber sh owing deviat ions more than t hree consecu tive time poin ts, Call

for CAPA.

Ok Not ok

4 Mo re th an 24 hours, Necessary actio n to switch into the st andby chamb er o r

oth er facility.

Ok Not ok

5 Ch ambers m ust be cleaned fo r every three mo nths and entered in Cleaning

record.

Ok Not ok

6 Ch eck the Annul calibration to the chamber is done or n ot Ok Not ok

7 Alarm verification record OK Not ok

8 Annual calibration of stability chambers as per schedule (External Calibratio n) Ok Not ok

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It’s All About stabilityIt’s All About stability

� Questions

� Discussions

Reference:

ICH-Q1, WHO annex-2.

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