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04/12/2023 http://stabilitystudies.blogspot.com 1
Stability StudiesOn Drug Substances
Author: Srikanth N
http://stabilitystudies.blogspot.com
04/12/2023 http://stabilitystudies.blogspot.com 2
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.
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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.
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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.
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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.
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Stability ProtocolBatch selectionContainer Closure SystemSpecificationsTesting frequencyStorage conditionsSample QuanityStatements and labellingStability commitment
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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
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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].
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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.
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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
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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
-- --
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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
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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)
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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
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Sample QuantityAccelerated : 16 g+ 5 g extra= 21 gLong term: 36 g + 10g =46 gTotal = 67 g [rounded to 70 grams]
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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
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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.
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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
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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
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OthersStability EvaluationData Variability and many more refer to
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