Dive Inside the Stability Iceberg Regulatory & Scientific Affairs of Harmonized Guidance Obaid Ali Civil Service Officer, Member, ISPE, PDA 26 March 2017
Dive Inside the Stability IcebergRegulatory & Scientific Affairs of
Harmonized Guidance
Obaid AliCivil Service Officer, Member, ISPE, PDA
26 March 2017
Not the view of DRAP
Current judgment
No obligation on DRAP
Regulatory experience
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References US-FDA WHO ICH NRAs
What's the harm to give shelf life
without stability study while we have
experience of innovator drugs and
manufacturing of other drugs?
Duration
Conditions
Safety
Efficacy
Quality
How the quality varies with time
under the influence of conditions
(temperature, humidity, light)
DSDP
Selection Container Closure Specification Testing Frequency
Storage Conditions
Commitment Evaluation Claim
Stress Photo
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
DS
• Packaging may be simulated
DP
• No, should be identical
Container Closure
DS
• Physical, Chemical & Microbiological tests
DP
• + Preservative, Functionality Tests
Specifications
Should Content Uniformity be done in
Stability Study?
Should Sterility Test be done in
Injectable dosage forms?
Should Dissolution be done as a Drug
Delivery Performance Test?
Specifications
Finished Pharmaceutical Product
Specifications special for FDCs
Remember
Degradation products must be calculated in % with reference
to the parent API, not the sum of APIs,
For
FDCs
Rifampicin / isoniazidtablets
• Rifampicin quinone(degradant) as % of rifampicin
Lamivudine + Stavudine + Nevirapine
tablets
• Thymine (degradant) as % of stavudine
Example
Remember
If 2 APIs react with each other, then the degradant to be
stated with respect to worst case
Rifampicin / isoniazid tablets
• Isonicotinyl hydrazone forms from the 2 APIs.
• Specification: % hydrazonewith respect to rifampicin(worst-case in mass balance)
Example
Remember
Unknown degradants – with respect to worst case
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
Testing Frequency
Accelerated condition
Minimum of 3 time
points, including initial
and final time points
(e.g. 0, 3 & 6 months)
DS
DP
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
DS
• Bracketing, Matrixing not applicable
DP
• Bracketing, MatrixingApplicable
Testing Frequency
Storage Conditions
Accelerated40⁰C+2⁰C
75% +5%RH6 months
1 of 3
DS
DP
Storage Conditions
Long term
25⁰C+2⁰C 60%+5%RH or
30⁰C+2⁰C
65% +5%RH
12 months
2 of 3
DS
DP
Storage Conditions
Intermediate30⁰C+2⁰C
65% +5%RH6 months
3 of 3
DS
DP
Storage in a Refrigerator
Accelerated25⁰C + 2⁰C
60% + 5% RH6 months
DS
DP
Long term 5⁰C + 3⁰C 12 months
Storage in a Freezer DS
DP
Long term- 20⁰C +
5⁰C12 months
Storage below - 20⁰C : Case by case basis
Retest (DS)
• Compliance of attributes
• Suitability of use
Expiry (DP/DS)
• Expected within compliance
• No retesting
Stress (DS)
Shocks exposure
Intrinsic stability
PD
Stress (DP)
Photosensitivity
Specific products
QIB
• 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)
CompendialMethods
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
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 !!
Points to be noted
Manage knowledge from R&D to plan
stability study
Stress study for intrinsic behavior & real time for retest
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
Review
Give attention to
analysis and
calculation of
degradation products
especially in FDCs
Review
Adopt Science & Risk
based Approach
Map Product
Attributes for Stability
during Development
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