Stability studies

04/12/2023 http://stabilitystudies.blogspot.com 1

Stability StudiesOn Drug Substances

Author: Srikanth N

http://stabilitystudies.blogspot.com


TerminologyRe-test dateThe 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.

Re-test periodThe period of time during which the drug substance is expected to

remain within its specification and, therefore, can be used in the manufacture of a given drug product, provided that the drug substance has been stored under the defined conditions.

Primary batchA batch of a drug substance used in a formal stability study, from

which stability data are submitted in a registration application for the purpose of establishing a re-test period .A primary batch of a drug substance should be at least a pilot scale batch.


TerminologyMass balanceThe process of adding together the assay

value and levels of degradation products to see how closely these add up to 100% of the initial value, with due consideration of the margin of analytical error.


Objective Stability studies are conducted to assesses

the effect of Tempeature, Humidity and Light and to assign the retest period and to recommend the storage conditions.


TypesThree types of Stability Studies

Accelerated Studies designed to know the shortterm Excursions

of temperature on the drug Substances Intermediate

Studies conducted, incase of failure in accelerated studies and the conditions of temperature and humidity are in between long term and accelerated.

Long term Studies designed to check the stability of the drug

substnace.


Stability ProtocolBatch selectionContainer Closure SystemSpecificationsTesting frequencyStorage conditionsSample QuanityStatements and labellingStability commitment


Batch SelectionThree Primary batches of drug susbtance are

to be kept for stability studiesUsually three commercial batches to be kept

in studies and the batches may be first three batches.

One add-on batch for every year. This might be the first batch of that year


Container Closure SystemStability Studies to be conducted in the

container closures that are similar to the containers in which the Drug susbtance is marketting.

For example, Itraconazole is stored in trasparent polyethylene bag[primary packing] and which inturn stored in black polyehtylene bag and finally in HDPE container[secondary packing].


SpecificationStability analysis is perfomed for the test

parameters which are prone to change during the storage and are likely to influence the Qality, safety and Efficacy.


Testing FrequencyTesting frequency for accelerated and long

term as followsAccelerated: 0,1,2,3 and 6 MonthsLong term: 0,3,6,9,12,18,24,36,48 and 60

Months


Storage ConditionsType of study

Accelerated Long term Intermediate

General Case

40°C±2°C, 70±5% RH

25°C±2°C, 60±5% RH

30°C±2°C, 65±5% RH

Refrigeraed

25°C±2°C, 60±5% RH

5°C±3°C --

Freezer -20°C±5°C

-- --


Sample QuantitySample Quantity is determined on the

analytical parameters under study

Specification Accepatance Crieteria

Quantity[G]

Description White to almost white power

1 g [reusable]

Identification by IR

Sample spectrum should be concorddant with that of the sample spectrum

300 mg

Loss on drying NMT 0.05% 1g


Sample QuantitySpecification Acceptance Crieteria Quantity{G

}

Related Substances Monaamide impurity –NMT 0.15%Dimer Impurity-NMT 0.15%Unknown impurity-NMT 0.10%Total Impurity-NMT 1,0%

1g

Assay by HPLC Between 98.0-102.0 % 1g

Total 3.3 g(rounded to 4 g)


Sample QuantityFor accelerated Studies

Time points: 0,1,2,3 and 6 Months [Total 4 time point excluding intial]

For each time point: 4 gTotal: 4 x 4 g = 16 g

For Long term StudiesTime points: 0,3,6,9,12,18,24,36,48 and 60

Months [Total 9 time point excluding intial]For each time point: 4 gTotal: 9 x 4 g = 36 g


Sample QuantityAccelerated : 16 g+ 5 g extra= 21 gLong term: 36 g + 10g =46 gTotal = 67 g [rounded to 70 grams]


Storage Statements and LabellingStatement condition Label statement

25ºC / 60% RH (Long term)40ºC / 75% RH (Accelerated term)

Do not store above 25°C

25ºC / 60% RH (Long term)30ºC / 65% RH (Intermediate, failure at long term)

Do not store above 25°C

30ºC / 65% RH (Long term)40ºC / 75% RH (Accelerated term)

Do not store above 30ºC

5ºC +/- 3ºC Store in a refrigerator (2 to 8ºC)

-20ºC +/-5ºC Store in freezer


Stability CommitmentIt is commitment given to the reulatory

authorities or customers.All three batches of stability from

production, studies to be conducted through the assigned retest period.

Less than 3 batches, commitment to add the immediate prodcution batches to make 3 batches and continue through the retest period assigned.

No match from production, first three production batches to be kept for stability studies continue through the retest period assigned.


Stress TestingStress testing of the drug substance can help identify

the likely degradation products, which can in turn help establish the degradation pathways and the intrinsic stability of the molecule and/or validate the stability indicating power of the analytical procedures used.

Stress testing to be carried out on a single batch of the drug substance.

Parameters in stress testing Acid Hydrolysis[0.1N HCl]Base Hydrolysis[0.1N NaoH]Oxidation[3% H2O2]Temperature with HumidityPhotodegradation


ConditionsStudy Chanllenge

conditionsTime Points

Acid/solution HCl (1.0N, RT, 70°C) Initial –7 days

Basic/Solution NaOH (1.0N, RT, 70°C)

Initial –7 days

Oxidative/Solution H2O2+ Initiator 7 Days

Thermal 70°C/30% RH 6 weeks

Thermal/Humidity 70°C/75% RH 6 weeks

Photo (UV light)* 1,000 watt hrs/m2, RT

5 X ICH

Photo (Fluorescent light)*

6 x 106 lux hrs, R.T. 5 X ICH


OthersStability EvaluationData Variability and many more refer to

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Stability studies