2-4 ICH Quality Guidances:
an overview
PQP Assessment Training
January 18-21, 2012
Satish Mallya
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January20-22,
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2012
Satish Mallya January
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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Focus
 Stability - Q1A, B, C, D, E & F
 Validation of Analytical Methods – Q2(R1)
 Impurities – Q3A, B & C
 Specifications – Q6A (Chemical Substances) & Q6B
(Biotechnology/Biological Products)
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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Climatic Zones III & IV (withdrawn – June 2006)
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Q1A(R2)
STABILITY TESTING OF
NEW DRUG SUBSTANCES AND PRODUCTS
Drug Substance
Drug Product
Stress testing
Photostability 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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Stress Testing/Photostability
Drug Substance
Drug Product
One primary batch
One primary batch
Effect of temperatures (in 10°C
increments (e.g., 50°C, 60°C,
etc.) above that for accelerated
testing)
As in ICH Q1B:
Effect of humidity (e.g., >
75%RH)
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Selection of Batches
Drug Substance
Data on at least three primary batches of
minimum pilot scale manufactured by the
same synthetic route as used for production
batches.
Drug Product
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.
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Container Closure System
Drug Substance
Drug Product
Studies to be conducted on the
API packaged in a container
closure system that is identical to
or simulates the proposed
commercial packaging
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
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Specification
Drug Substance
Studies to include attributes
susceptible to change during
storage and which can influence
quality, safety and efficacy:
- Physical
- Chemical
- Microbiological
Validated analytical methods to be
employed
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January
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Drug Product
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
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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January
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2012
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Storage Conditions
Drug Substance
Drug Product
 General Case
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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Satish Mallya January
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% 6 months
+ 5% RH
Accelerated
25⁰C + 2⁰C / 60% 6 months
+ 5% RH
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January
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2012
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Storage Conditions
 Storage in freezer
Drug Substance
Study
Storage
Conditions
Long
term
- 20⁰C + 5⁰C
Minimum
period covered
by data at
submission
12months
Drug Product
Study
Storage
Conditions
Long
term
- 20⁰C + 5⁰C
 Storage below - 20⁰C : Case by case basis
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Minimum
period covered
by data at
submission
12months
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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January
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Significant Change
Drug Substance
Drug Product
Defined as 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
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2012
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Evaluation
Drug Substance
Statistical analysis not necessary if
data exhibits little or no degradation
and variability
Drug Product
Statistical analysis not necessary if
data exhibits little or no degradation
and variability
Limited extrapolation of real time data Limited extrapolation of real time data
permitted with justification
permitted with justification
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2010
January
18-21,2010
2012
Satish Mallya January
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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2012
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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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Q1D - Bracketing
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Q1D - Matrixing
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Q1D - Matrixing
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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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2012
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Outcomes
When there is no significant change under accelerated conditions (RT)
Long-term and accelerated data showing
little or no change over time and little or
no variability
Retest period or shelf life can be up to
twice, but NMT 12 months beyond the
period covered by long-term data
Long-term or accelerated data showing
change over time and/or variability
Data not amenable to statistical analysis,
but relevant supporting data provided:
Retest period or shelf life can be up to
1.5 times, but NMT 6 months beyond the
period covered by long-term data
If a statistical analysis is performed:
Retest period or shelf life of up to twice,
but not more than 12 months beyond the
period covered by long-term data
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Satish Mallya January
Outcomes
When there is significant change under accelerated conditions
(RT) but no significant change at intermediate condition:
Data not amenable to statistical analysis:
Retest period or shelf life can be up to 3 months beyond the period covered
by long-term data if backed by relevant documentation
If statistical analysis is performed:
Retest period or shelf life can be up to 1.5 times, but NMT 6 months beyond
the period covered by long-term data when backed by statistical analysis
and relevant supporting data
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2012
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Q2(R1)
VALIDATION OF ANALYTICAL PROCEDURES
 Defines validation characteristics:
– Accuracy
– Precision
• Repeatability
• Intermediate Precision
– Specificity
– Detection Limit
– Quantitation Limit
– Linearity
– Range
 Robustness to be considered at appropriate stage of development of the
analytical method
 System suitability test parameters to be established for a particular
procedure depending on the type of procedure being validated Pharmacopoeias to be consulted for additional information
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VALIDATION CHARACTERISTICS
Validation
characteristics
ID
Accuracy
-
Precision
-
Impurities
Assay
Quant.
limit
+
-
+
Repeatibility
-
+
-
+
Int.Precision
+
+
-
+
Specificity
-
+
+
+
LOD
-
-
+
-
LOQ
-
+
-
-
Linearity
-
+
-
+
+
-
+
Range
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2012
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Q3
Impurities
 Impurities in New Drug Substances Q3A(R2): Defines thresholds
for reporting, identification and qualification of impurities in DS
 Impurities in New Drug Products Q3B(R2): Defines thresholds for
reporting, identification and qualification of impurities in DP
 Guideline for Residual Solvents Q3C (R5): Classifies residual
solvents by risk assessment:
– Class 1 solvents: solvents to be avoided
– Class 2 solvents: solvents to be limited
– Class 3 solvents: solvents with low toxic potential
 Guideline for Metal Impurities Q3D (Concept paper – July 2009)
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Q3A(R2)
CLASSIFICATION OF IMPURITIES
 Organic Impurities
–
–
–
–
–
Starting materials
By-products
Intermediates
Degradation products
Reagents, ligands, catalysts
 Inorganic Impurities
–
–
–
–
Reagents, ligands, catalysts
Heavy metals or other residual metals
Inorganic salts
Other materials (e.g., filter aids, charcoal)
 Residual Solvents
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Q3A(R2)
Definitions
 Qualification: The process of acquiring and evaluating data that establishes
the biological safety of an individual impurity or a given impurity profile at
the level(s) specified.
 Reporting Threshold: A limit above (>) which an impurity should be
reported.
 Specified Impurity: An impurity that is individually listed and limited with a
specific acceptance criterion in the new drug substance specification. A
specified impurity can be either identified or unidentified.
 Unidentified Impurity: An impurity for which a structural characterisation
has not been achieved and that is defined solely by qualitative analytical
properties (e.g., chromatographic retention time)
 Unspecified impurity: An impurity that is limited by a general acceptance
criterion, but not individually listed with its own specific acceptance
criterion, in the new drug substance specification
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Q3A(R2)
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Q3A(R2)
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Q3B(R2)
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Q3B(R2)
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Q3C(R5)
 Provides 2 options for describing limits of Class 2 Solvents
 Option 1: As per the table provided - calculated using TDI of 10 g
and the calculation – Concentration (ppm) = 1000 x Permitted Daily Exposure (PDE)/ Dose
– PDE is given in terms of mg/day and dose is given in g/day.
Solvent
PDE (mg/day)
Acetonitrile
4.1
410
Chlorobenzene
3.6
360
 If TDI is more than 10 g use option 2
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Concentration
limit (ppm)
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Satish Mallya January
Example for Option 2
 Option 2: It is not considered necessary for each component of the drug product to
comply with the limits given in Option 1. The PDE in terms of mg/day can be used
with the known maximum daily dose and equation (Concentration (ppm) = 1000 x
PDE/ Dose) to determine the concentration of residual solvent allowed in drug
product
Example: PDE of acetonitrile is 4.1mg/day
Component
exposure
Amount in formulation
Acetonitrile content
Daily
Drug substance
0.3 g
800 ppm
0.24 mg
Excipient 1
0.9 g
400 ppm
0.36 mg
Excipient 2
3.8 g
800 ppm
3.04 mg
Drug Product
5.0 g
728 ppm
3.64 mg
 The sum of the amounts of solvent per day should be less than that given by the
PDE.
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Q6A
 Addresses aspects such as:
–
–
–
–
–
–
–
–
–
–
–
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Periodic or skip testing
Release vs shelf-life criteria
In-process tests
Design and development considerations
Limited data available at filing
Parametric release
Alternative procedures
Pharmacopoeial tests and acceptance criteria
Evolving technologies
Impact of drug substance on drug product specifications
Reference standard
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Satish Mallya January
Q6A
Decision Trees
 #1 – Establishing acceptance criteria for specified impurity In DS
 #2 – Establishing acceptance criteria for degradation product in DP
 #3 – Establishing acceptance criteria for PSD in DS
 #4 – Investigating need to set acceptance criteria for polymorphism in DS
and DP
 #5 – Establishing ID, Assay and enantiomeric impurity procedures for
chiral DS and chiral DS in DP
 #6 – Microbiological Quality Attributes of DS and Excipients
 #7 – Setting acceptance criteria for DP dissolution
 #8 – Microbiological Quality Attributes of non sterile DP
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Periodic or Skip Testing
 Should be justified.
 May be applied to certain tests only (e.g. residual
solvents and microbiological test for solid oral products)
 Recommend that it should be applied post approval
 Batch to batch retesting to be restored in the event of
failure
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Design and Development Considerations
 It may be possible to propose excluding or replacing
certain tests based on experience and data accumulated:
– microbiological testing for drug substances and solid
dosage forms which have been shown during development
not to support microbial viability or growth (Decision Trees
#6 and #8)
– extractables from product containers where it has been
reproducibly shown that either no extractables are found in
the drug product or the levels meet accepted standards for
safety
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Design and Development Considerations
– particle size testing may be performed as an in-process
test, or may be performed as a release test, depending on
its relevance to product performance
– dissolution testing for immediate release solid oral drug
products made from highly water soluble drug substances
may be replaced by disintegration testing, if these
products have been demonstrated during development to
have consistently rapid drug release characteristics
(Decision Tree #7) (only accepted in exceptional
circumstances and all conditions must be met including
substantial development data)
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