The document discusses terminology, objectives, types, protocols, and procedures for drug substance stability studies. It defines key terms like re-test date and period. It describes the three types of studies - accelerated, intermediate, and long term. It outlines the stability protocol including batch selection, storage conditions, testing frequency, and commitments. It also discusses stress testing to identify degradation products and evaluate the stability of molecules under various challenge conditions.

1. On Drug Substances
Author: Srikanth N
http://stabilitystudies.blogspot.com
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2. 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.
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3. 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.
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4. 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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5. 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.
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6. Stability Protocol
 Batch selection
 Container Closure System
 Specifications
 Testing frequency
 Storage conditions
 Sample Quanity
 Statements and labelling
 Stability commitment
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7. 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
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8. 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].
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9. 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.
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10. 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
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11. Storage Conditions
Type of study Accelerated Long term Intermediate
General 40°C±2°C, 25°C±2°C, 30°C±2°C,
Case 70±5% RH 60±5% RH 65±5% RH
Refrigeraed 25°C±2°C, 5°C±3°C --
60±5% RH
Freezer -20°C±5°C -- --
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12. Sample Quantity
 Sample Quantity is determined on the analytical
parameters under study
Specification Accepatance Quantity[G]
Crieteria
Description White to almost white 1 g [reusable]
power
Identification by IR Sample spectrum 300 mg
should be
concorddant with that
of the sample
spectrum
Loss on drying NMT 0.05% 1g
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13. Sample Quantity
Specification Acceptance Crieteria Quantity{G}
Related Substances Monaamide impurity –NMT 0.15% 1g
Dimer Impurity-NMT 0.15%
Unknown impurity-NMT 0.10%
Total Impurity-NMT 1,0%
Assay by HPLC Between 98.0-102.0 % 1g
Total 3.3 g(rounded
to 4 g)
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14. 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
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15. Sample Quantity
 Accelerated : 16 g+ 5 g extra= 21 g
 Long term: 36 g + 10g =46 g
 Total = 67 g [rounded to 70 grams]
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16. Storage Statements and Labelling
Statement condition Label statement
25ºC / 60% RH (Long term) Do not store above 25°C
40ºC / 75% RH (Accelerated term)
25ºC / 60% RH (Long term) Do not store above 25°C
30ºC / 65% RH (Intermediate, failure
at long term)
30ºC / 65% RH (Long term) Do not store above 30ºC
40ºC / 75% RH (Accelerated term)
5ºC +/- 3ºC Store in a refrigerator (2 to 8ºC)
-20ºC +/-5ºC Store in freezer
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17. 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.
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18. 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
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19. 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 6 x 106 lux hrs, R.T. 5 X ICH
light)*
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20. Others
 Stability Evaluation
 Data Variability and many more refer to
 http://stabilitystudies.blogspot.com
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