2-4 ICH Overview

2-4 ICH Quality Guidances:
an overview
PQP Assessment Training
January 18-21, 2012
Satish Mallya
1| January
Satish Mallya January 18-21,
20-22, 2010 2012
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
2| January
20-22, 20102012
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)
3| January
20-22, 2010 2012
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Climatic Zones III & IV (withdrawn – June 2006)
4| January
20-22, 2010 2012
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
5| January
20-22, 2010 2012
Stress Testing/Photostability
One primary batch One primary batch
As in ICH Q1B: 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)
6| January
20-22, 2010 2012
Selection of Batches
Data on at least three primary batches of the Data on at least three primary batches of
drug product – two pilot and third one can be minimum pilot scale manufactured by the same
smaller - same formulation and packaged in the synthetic route as used for production batches.
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.
7| January
20-22, 2010 2012
Container Closure System
Studies to be carried out in Studies to be conducted on the

container closure system identical API packaged in a container
to commercial packaging; studies closure system that is identical to
carried out in other packaging or simulates the proposed
materials can be used as commercial packaging
supporting information
8| January
20-22, 2010 2012
Specification

Studies to include attributes Studies to include attributes
susceptible to change during susceptible to change during
storage and which can influence storage and which can influence
quality, safety and efficacy: quality, safety and efficacy:
- Physical - Physical
- chemical, - Chemical
- microbiological, - Microbiological
- preservative content
- functionality tests (e.g. with
delivery systems)
Validated analytical methods to be Validated analytical methods to be

employed employed
9| January
Satish Mallya January
June 18-21,
20-22,
2010 2010 2012
Testing Frequency
For FPP with proposed re-test period/shelf-life For API with proposed re-test period/shelf-life
of at least 12 months: Every 3 months over of at least 12 months: Every 3 months over
first year, every 6 months over next 12 months first year, every 6 months over next 12 months
and annually thereafter. and annually thereafter.
Accelerated condition: Minimum of 3 time Accelerated condition: Minimum of 3 time

points, including initial and final time points points, including initial and final time points
(e.g. 0, 3 & 6 months) (e.g. 0, 3 & 6 months)
Intermediate condition (due to significant Intermediate condition (due to significant

change under accelerated condition): study change under accelerated condition): study
design should include 4 time points (e.g. 0, 6, 9 design should include 4 time points (e.g. 0, 6, 9
and 12 months) and 12 months
Matrixing or Bracketing may be applied
10 | January
June 18-21,
20-22,
2010 2010 2012
Storage Conditions
 General Case
Minimum Storage Study Minimum Storage Study
period Conditions period Conditions
covered by covered by
data at data at
submission submission
12 months 25⁰C+2⁰C /60% Long term 12 months 25⁰C+2⁰C/ 60% Long term
+5%RH or +5%RH or
30⁰C+2⁰C /65% 30⁰C+2⁰C /65%
+5%RH +5%RH
6 months 30⁰C+2⁰C /65% Intermediate 6 months 30⁰C+2⁰C /65% Intermediate

+5%RH +5%RH
6 months 40⁰C+2⁰C /75% Accelerated 6 months 40⁰C+2⁰C /75% Accelerated

+5%RH +5%RH
11 | January
June 18-21,
20-22,
2010 2010 2012
Storage Conditions
 Storage in refrigerator
period Conditions period Conditions
covered by covered by
data at data at
12months 5⁰C + 3⁰C Long term 12months 5⁰C + 3⁰C Long term
6 months 25⁰C + 2⁰C / Accelerated 6 months 25⁰C + 2⁰C / Accelerated

60% + 5% RH 60% + 5% RH
12 | January
June 18-21,
20-22,
2010 2010 2012
Storage Conditions
 Storage in freezer

period covered Conditions period covered Conditions
by data at by data at
12months - 20⁰C + 5⁰C Long 12months - 20⁰C + 5⁰C Long
term term
 Storage below - 20⁰C : Case by case basis
13 | January
June 18-21,
20-22,
2010 2010 2012
Storage Conditions – Drug Product
 Semi-permeable containers :
Minimum period Storage Conditions Study
covered by data at
submission
12 months 25⁰C+2⁰C/40%+5% RH or Long term
30⁰C+2⁰C/35%+5% RH
6 months 30⁰C+2⁰C/65%+5% RH Intermediate
6 months 40⁰C+2⁰C/NMT 25% RH Accelerated
14 | January
June 18-21,
20-22,
2010 2010 2012
Significant Change

->5% change in assay from the initial Defined as failure to meet
results specifications
-Any degradation product exceeding

its acceptance criterion
-Failure to meet acceptance criteria

for appearance, physical attributes
and functionality tests

for pH

for dissolution of 12 dosage units
15 | January
20-22, 2010 2012
Evaluation

Statistical analysis not necessary if Statistical analysis not necessary if
data exhibits little or no degradation data exhibits little or no degradation
and variability and variability
Limited extrapolation of real time data Limited extrapolation of real time data
permitted with justification permitted with justification
16 | January
June 18-21,
20-22,
2010 2010 2012
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
17 | January
20-22, 2010 2012
Q1C
Annex to Q1A (R2)
 Additional guidance on line extensions
 Reduced requirements at time of filing: 6 months

accelerated and 6 months long term
18 | January
20-22, 2010 2012
Q1D - Bracketing
19 | January
20-22, 2010 2012
Q1D - Matrixing
20 | January
20-22, 2010 2012
Q1D - Matrixing
21 | January
20-22, 2010 2012
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
22 | January
20-22, 2010 2012
Outcomes
When there is no significant change under accelerated conditions (RT)

Retest period or shelf life can be up to Long-term and accelerated data showing
twice, but NMT 12 months beyond the little or no change over time and little or
period covered by long-term data no variability
Data not amenable to statistical analysis, Long-term or accelerated data showing

but relevant supporting data provided: change over time and/or variability
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
23 | January
20-22, 2010 2012
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
24 | January
20-22, 2010 2012
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
25 | January
20-22, 2010 2012
VALIDATION CHARACTERISTICS
Assay Impurities ID Validation

characteristics
Quant. limit
+ + - - Accuracy
- Precision
+ + - - Repeatibility
+ + - + Int.Precision
+ + + - Specificity
- - + - LOD
- + - - LOQ
+ + - - Linearity
+ + - Range
26 | January
20-22, 2010 2012
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)
27 | January
20-22, 2010 2012
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
28 | January
20-22, 2010 2012
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
29 | January
20-22, 2010 2012
Q3A(R2)
30 | January
20-22, 2010 2012
Q3A(R2)
31 | January
20-22, 2010 2012
Q3B(R2)
32 | January
20-22, 2010 2012
Q3B(R2)
33 | January
20-22, 2010 2012
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.
Concentration PDE (mg/day) Solvent
limit (ppm)
410 4.1 Acetonitrile
360 3.6 Chlorobenzene
 If TDI is more than 10 g use option 2
34 | January
20-22, 2010 2012
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 Amount in formulation Acetonitrile content Daily
exposure
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.
35 | January
20-22, 2010 2012
Q6A
 Addresses aspects such as:

– 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
36 | January
20-22, 2010 2012
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
37 | January
20-22, 2010 2012
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
38 | January
20-22, 2010 2012
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
39 | January
January
Satish Mallya January 18-21
20102012
18-21,
20-22, 2012
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)
40 | January
20-22, 2010 2012
41 | January
20-22, 2010 2012

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2-4 ICH Quality Guidances:

PQP Assessment Training

January 18-21, 2012

 Impurities – Q3A - Q3C (Q3D – concept paper)

 Pharmacopoeias – Q4A - Q4B (and annexes)

 Quality of Biotechnological Products – Q5A – Q5E

 Specifications – Q6A – Q6B

 Good Manufacturing Practice – Q7

 Quality Risk Management - Q9

 Pharmaceutical Quality System – Q10

 Development and Manufacturing of Drug Substances – Q11

 Stability - Q1A, B, C, D, E & F

 Validation of Analytical Methods – Q2(R1)

 Impurities – Q3A, B & C

 Specifications – Q6A (Chemical Substances) & Q6B

 Q1A(R2) Stability Testing of New Drug Substances and

 Q1B Photostability Testing of New Drug Substances and

 Q1C Stability Testing for New Dosage Forms

 Q1D Bracketing and Matrixing Designs for Stability Testing

 Q1E Evaluation of Stability Data

Drug Product Drug Substance

Selection of batches Selection of batches

Container closure system Container closure system

Testing frequency Testing frequency

Storage conditions Storage conditions

Stability commitment Stability commitment

Drug Product Drug Substance

One primary batch One primary batch

As in ICH Q1B: Effect of temperatures (in 10°C

Effect of humidity (e.g., >

Drug Product Drug Substance

The manufacturing process used for primary

Where possible, use different batches of the

Should be performed on each individual

Drug Product Drug Substance

Studies to be carried out in Studies to be conducted on the

Drug Product Drug Substance

Validated analytical methods to be Validated analytical methods to be

Accelerated condition: Minimum of 3 time Accelerated condition: Minimum of 3 time

Intermediate condition (due to significant Intermediate condition (due to significant

Matrixing or Bracketing may be applied

6 months 30⁰C+2⁰C /65% Intermediate 6 months 30⁰C+2⁰C /65% Intermediate

6 months 40⁰C+2⁰C /75% Accelerated 6 months 40⁰C+2⁰C /75% Accelerated

6 months 25⁰C + 2⁰C / Accelerated 6 months 25⁰C + 2⁰C / Accelerated

Drug Product Drug Substance

 Storage below - 20⁰C : Case by case basis

6 months 30⁰C+2⁰C/65%+5% RH Intermediate

6 months 40⁰C+2⁰C/NMT 25% RH Accelerated

Drug Product Drug Substance

-Any degradation product exceeding

-Failure to meet acceptance criteria

-Failure to meet acceptance criteria

-Failure to meet acceptance criteria

Drug Product Drug Substance

 Test on API first – if not photosensitive then no further testing is

 Where appropriate, impact of light during manufacturing

 Reduced requirements at time of filing: 6 months

 Provides recommendations for: (at RT, Refrigerated and

When there is no significant change under accelerated conditions (RT)

Data not amenable to statistical analysis, Long-term or accelerated data showing

If a statistical analysis is performed:

When there is significant change under accelerated conditions

Data not amenable to statistical analysis:

If statistical analysis is performed: