An Outline Discussion on ICH Q1

1. Dive Inside the Stability Iceberg
Regulatory & Scientific Affairs of
Harmonized Guidance
Obaid Ali
Civil Service Officer, Member, ISPE, PDA
26 March 2017

2. Not the
view of
DRAP
Current
judgment
No
obligation
on DRAP
Regulatory
experience
D
I
S
C
L
A
I
M
E
R
References US-FDA WHO ICH NRAs

3. What's the harm to give shelf life
without stability study while we have
experience of innovator drugs and
manufacturing of other drugs?

4. Duration
Conditions
Safety
Efficacy
Quality

5. How the quality varies with time
under the influence of conditions
(temperature, humidity, light)

6. DS
DP
Selection Container Closure Specification Testing Frequency
Storage
Conditions
Commitment Evaluation Claim
Stress Photo

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

8. DS
• Packaging may
be simulated
DP
• No, should be
identical
Container Closure

9. DS
• Physical, Chemical
& Microbiological
tests
DP
• + Preservative,
Functionality Tests
Specifications

10. Should Content Uniformity be done in
Stability Study?

11. Should Sterility Test be done in
Injectable dosage forms?

12. Should Dissolution be done as a Drug
Delivery Performance Test?

13. Specifications
Finished Pharmaceutical Product
Specifications special for FDCs

14. Remember
Degradation products must be calculated in % with reference
to the parent API, not the sum of APIs,
For
FDCs

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

18. Remember
Unknown degradants – with respect to worst case

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

20. Testing Frequency
Accelerated condition
Minimum of 3 time
points, including initial
and final time points
(e.g. 0, 3 & 6 months)
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

22. DS
• Bracketing,
Matrixing not
applicable
DP
• Bracketing,
Matrixing
Applicable
Testing Frequency

23. Storage Conditions
Accelerated 40⁰C+2⁰C
75% +5%RH 6 months
1 of 3
DS
DP

24. Storage Conditions
Long
term
25⁰C+2⁰C
60%+5%RH or
30⁰C+2⁰C
65% +5%RH
12
months
2 of 3
DS
DP

25. Storage Conditions
Intermediate 30⁰C+2⁰C
65% +5%RH 6 months
3 of 3
DS
DP

26. Storage in a Refrigerator
Accelerated 25⁰C + 2⁰C
60% + 5% RH 6 months
DS
DP
Long term 5⁰C + 3⁰C 12 months

27. Storage in a Freezer DS
DP
Long term
- 20⁰C +
5⁰C
12 months
Storage below - 20⁰C : Case by case basis

28. Retest (DS)
• Compliance of
attributes
• Suitability of
use
Expiry (DP/DS)
• Expected
within
compliance
• No retesting

29. Stress
(DS)
Shocks
exposure
Intrinsic
stability
PD
Stress
(DP)
Photosensitivity
Specific
products
QIB

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

35. Review
Give attention to
analysis and
calculation of
degradation products
especially in FDCs

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