Pharmacy, Quality Assurance, Sem- VI, B pharm

1. ICH QUALITY GUIDANCES
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2. ICH Topics
Stability - Q1A – Q1F
Analytical Validation – Q2
Impurities – Q3A - Q3C (Q3D – concept paper)
Pharmacopoeias – Q4A - Q4B (and annexes)
Quality of Biotechnological Products – Q5A – Q5E
Specifications – Q6A – Q6B
Good Manufacturing Practice – Q7
Pharmaceutical Development – Q8
Quality Risk Management - Q9
Pharmaceutical Quality System – Q10
Development and Manufacturing of Drug Substances – Q11
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3. STABILITY
Q1A(R2) Stability Testing of New Drug Substances and
Products
Q1B Photostability Testing of New Drug Substances and
Products
Q1C Stability Testing for New Dosage Forms
Q1D Bracketing and Matrixing Designs for Stability Testing
of New Drug Substances and Products
Q1E Evaluation of Stability Data
Q1F Stability Data Package for Registration Applications in
Climatic Zones III & IV (withdrawn – June 2006)
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4. Q1A(R2) STABILITY TESTING OF NEW DRUG SUBSTANCES AND
PRODUCTS
Drug Product
Drug Substance
Photostability testing
Stress testing
Selection of batches
Selection of batches
Container closure system
Container closure system
Specification
Specification
Testing frequency
Testing frequency
Storage conditions
Storage conditions
Stability commitment
Stability commitment
Evaluation
Evaluation
Statements/Labeling
Statements/Labeling
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5. STRESS TESTING/PHOTOSTABILITY
Drug Product
Drug Substance
One primary batch
As in ICH Q1B:
One primary batch
Effect of temperatures (in 10°C
increments (e.g., 50°C, 60°C, etc.)
above that for accelerated testing)
Effect of humidity (e.g., > 75%RH)
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6. SELECTION OF BATCHES
Drug Product
Drug Substance
Data on at least three primary batches of
the drug product – two pilot and third one
can be smaller - same formulation and
packaged in the same container closure
system as proposed for marketing.
The manufacturing process used for
primary batches should simulate that to be
applied to production batches
Where possible, use different batches of the
drug substance.
Should be performed on each individual
strength and container size of the drug
product unless bracketing or matrixing is
applied.
Data on at least three primary batches of
minimum pilot scale manufactured by the
same synthetic route as used for
production batches.
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7. CONTAINER CLOSURE SYSTEM
Drug Product
Drug Substance
Studies to be carried out in container
closure system identical to
commercial packaging; studies
carried out in other packaging
materials can be used as supporting
information
Studies to be conducted on the API
packaged in a container closure
system that is identical to or
simulates the proposed commercial
packaging
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8. SPECIFICATION
Drug Substance Drug Product
Studies to include attributes
susceptible to change during
storage and which can influence
quality, safety and efficacy:
- Physical
- Chemical
- Microbiological
Studies to include attributes
susceptible to change during
storage and which can influence
quality, safety and efficacy:
- Physical
- chemical,
- microbiological,
- preservative content
- functionality tests (e.g. with
delivery systems)
Validated analytical methods to be
employed
Validated analytical methods to be
employed
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9. TESTING FREQUENCY
Drug Substance Drug Product
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.
For FPP 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.
Accelerated condition: Minimum of 3
time points, including initial and final
time points (e.g. 0, 3 & 6 months)
Accelerated condition: Minimum of 3
time points, including initial and final
time points (e.g. 0, 3 & 6 months)
Intermediate condition (due to
significant change under accelerated
condition): study design should include 4
time points (e.g. 0, 6, 9 and 12 months
Intermediate condition (due to
significant change under accelerated
condition): study design should include 4
time points (e.g. 0, 6, 9 and 12 months)
Matrixing or Bracketing may be applied
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10. STORAGE CONDITIONS
General Case
Drug Substance Drug Product
Study Storage
Conditions
Minimum
period
covered by
data at
submission
Study Storage
Conditions
Minimum
period
covered by
data at
submission
Long term 25⁰C+2⁰C/
60%+5%RH
or
30⁰C+2⁰C /65%
+5%RH
12 months Long term 25⁰C+2⁰C
/60%+5%RH
or
30⁰C+2⁰C /65%
+5%RH
12 months
Intermediate 30⁰C+2⁰C /65%
+5%RH
6 months Intermediate 30⁰C+2⁰C /65%
+5%RH
6 months
Accelerated 40⁰C+2⁰C /75%
+5%RH
6 months Accelerated 40⁰C+2⁰C /75%
+5%RH
6 months
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11. STORAGE CONDITIONS
Storage in refrigerator:
Drug Substance Drug Product
Study Storage
Conditions
Minimum
period
covered by
data at
submission
Study Storage
Conditions
Minimum
period
covered by
data at
submission
Long term 5⁰C + 3⁰C 12months Long term 5⁰C + 3⁰C 12months
Accelerated 25⁰C + 2⁰C /
60% + 5%
RH
6 months Accelerated 25⁰C + 2⁰C /
60% + 5%
RH
6 months
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12. STORAGE CONDITIONS
Storage in freezer:
Drug Substance Drug Product
Study Storage
Conditions
Minimum
period covered
by data at
submission
Study Storage
Conditions
Minimum
period
covered by
data at
submission
Long
term
- 20⁰C + 5⁰C 12months Long
term
- 20⁰C + 5⁰C 12months
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13. STORAGE CONDITIONS – DRUG PRODUCT
Semi-permeable containers :
Study Storage Conditions Minimum period covered
by data at submission
Long term 25⁰C+2⁰C/40%+5% RH
or
30⁰C+2⁰C/35%+5% RH
12 months
Intermediate 30⁰C+2⁰C/65%+5% RH 6 months
Accelerated 40⁰C+2⁰C/NMT 25% RH 6 months
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14. Significant Change
Drug Product
Drug Substance
->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
Defined as failure to meet
specifications
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15. EVALUATION
Drug Substance Drug Product
Statistical analysis not necessary if
data exhibits little or no degradation
and variability
Statistical analysis not necessary if
data exhibits little or no degradation
and variability
Limited extrapolation of real time
data permitted with justification
Limited extrapolation of real time
data permitted with justification
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LABELING:
*Based on the stability evaluation of drug product, a storage
temperature range may be decided.
*Where ever applicable specific instructions should be provided,
particularly for drug products that can not tolerate freezing.
*Terms such as ambient conditions or room temperature are
unacceptable

17. Q1B: PHOTOSTABILITY TESTING OF NEW
DRUG SUBSTANCES AND PRODUCTS
Provides 2 options for sources of light:
◦ artificial daylight fluorescent lamp combining visible and ultraviolet (UV)
outputs, xenon, or metal halide lamp
◦ sample should be exposed to both the cool white fluorescent and near
ultraviolet lamp
Test on API first – if not photosensitive then no further testing is required
If API is photosensitive then testing to be continued on (as appropriate):
◦ Tests on the exposed drug product outside of the immediate pack
◦ Tests on the drug product in the immediate pack
◦ Tests on the drug product in the marketing pack
Where appropriate, impact of light during manufacturing
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18. Q1C Annex to Q1A (R2)
Additional guidance on line extensions
Reduced requirements at time of filing: 6 months accelerated and 6
months long term
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19. Q1D - Bracketing
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20. Q1D - Matrixing
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21. Q1D - Matrixing
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22. Q1E EVALUATION OF STABILITY DATA
Provides recommendations for: (at RT, Refrigerated and Freezer storages)
◦ treating stability data
◦ Extending re-test period or shelf-life beyond period covered by long-
term data
◦ Statistical approaches to analysis of stability data
Progression:
◦ Start with data under accelerated condition
◦ Then assess data under intermediate condition, if appropriate
◦ Finally evaluate trends and variability of the long-term data
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