Stability studies

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Stability Studies:

Stability Studies On Drug Substances Author: Srikanth N 1


Terminology Re-test date 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. Re-test period The 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 batch A 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. 6/17/2017 2


Terminology Mass balance The 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. 6/17/2017 3

Objective :

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. 6/17/2017 4


Types Three 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. 6/17/2017 5

Stability Protocol:

Stability Protocol Batch selection Container Closure System Specifications Testing frequency Storage conditions Sample Quanity Statements and labelling Stability commitment 6/17/2017 6

Batch Selection:

Batch Selection Three Primary batches of drug susbtance are to be kept for stability studies Usually 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 6/17/2017 7

Container Closure System:

Container Closure System Stability 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]. 6/17/2017 8


Specification Stability 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. 6/17/2017 9

Testing Frequency:

Testing Frequency Testing frequency for accelerated and long term as follows Accelerated: 0,1,2,3 and 6 Months Long term: 0,3,6,9,12,18,24,36,48 and 60 Months 6/17/2017 10

Storage Conditions:

Storage Conditions Type 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 -- -- 6/17/2017 11

Sample Quantity:

Sample Quantity Sample 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 6/17/2017 12

Sample Quantity:

Sample Quantity Specification 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) 6/17/2017 13

Sample Quantity:

Sample Quantity For accelerated Studies Time points: 0,1,2,3 and 6 Months [Total 4 time point excluding intial] For each time point: 4 g Total: 4 x 4 g = 16 g For Long term Studies Time points: 0,3,6,9,12,18,24,36,48 and 60 Months [Total 9 time point excluding intial] For each time point: 4 g Total: 9 x 4 g = 36 g 6/17/2017 14

Sample Quantity:

Sample Quantity Accelerated : 16 g+ 5 g extra= 21 g Long term: 36 g + 10g =46 g Total = 67 g [rounded to 70 grams] 6/17/2017 15

Storage Statements and Labelling:

Storage Statements and Labelling Statement 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 6/17/2017 16

Stability Commitment:

Stability Commitment It 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. 6/17/2017 17

Stress Testing:

Stress Testing Stress 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 Humidity Photodegradation 6/17/2017 18


Conditions Study Chanllenge conditions Time 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 6/17/2017 19


Others Stability Evaluation Data Variability and many more refer to 6/17/2017 20

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