Introduction to LPC - Facility Design And Re-Engineering
4 OARO - ICH Dive Inside Stability Iceberg
1. Dive Inside the Stability Iceberg
Regulatory & Scientific Affairs of
Harmonized Guidance
Obaid Ali
Civil Service Officer, Member, ISPE, PDA
26 March 2017
7. DS
• 3 Primary Batches of pilot
scale
• Same synthetic route
DP
• 3 Primary Batches, two, of
pilot scale, one may be
smaller
• Same formulation & CC
Batch Selection
15. Rifampicin / isoniazid
tablets
• Rifampicin quinone
(degradant) as % of
rifampicin
Lamivudine +
Stavudine + Nevirapine
tablets
• Thymine (degradant)
as % of stavudine
Example
16. Remember
If 2 APIs react with each other, then the degradant to be
stated with respect to worst case
17. Rifampicin / isoniazid tablets
• Isonicotinyl hydrazone forms
from the 2 APIs.
• Specification: % hydrazone
with respect to rifampicin
(worst-case in mass balance)
Example
19. Testing Frequency
For API with proposed re-test
period/shelf-life of at least 12
months
Every 3 months over first year,
every 6 months over next 12
months and annually
thereafter.
DS
DP
21. Testing Frequency
Intermediate condition (due to
significant change under
accelerated condition)
Study design should include 4
time points (e.g. 0, 6, 9 and 12
months
DS
DP
30. • Must be stability indicating e.g.
• Assay of API
• Determination of Degradants
• Determination of Preservatives
Analytical
Methods
• May not be suitable (e.g. non-
specific like titration) i.e. Non-
specific
• May not exist for the particular
purpose (e.g. degradants)
Compendial
Methods
31. Significant Change
Drug Substance
Failure to meet
specifications
>5% change in assay from the initial results
Any degradation product exceeding its acceptance
criterion
Failure to meet acceptance criteria for appearance,
physical attributes and functionality tests
Failure to meet acceptance criteria for pH
Failure to meet acceptance criteria for dissolution of 12
dosage units
32. Pitfall/Downside
The assay value is still within the limits
but the change during stability is
more than 5.0%
Example
Release assay limit: 95.0 –
105.0%
Stability assay limit: 92.5 –
105.0%
Release assay:101.0% (within
spec)
24-Month assay: 93.0% (within
spec)
Loss in potency: 8.0% !!This is a significant change !!
33. Points to be noted
Manage knowledge
from R&D to plan
stability study
Stress study for
intrinsic behavior &
real time for retest
34. Review
Stability testing is an
essential part of the process
of ensuring that the patient
receives a product that
meets established standards
of safety, efficacy and
quality
36. Review
Adopt Science & Risk
based Approach
Map Product
Attributes for Stability
during Development
37. Review
Sound planning and execution of stability studies are important:
•Valuable time may be lost if the data are insufficient
•Always include all attributes which may change with
time (e.g. water content, friability & tablet strength in the
case of uncoated tablets) – pay upfront and save later