2-4 ICH Quality Guidances:

an overview

PQP Assessment Training

January 18-21, 2012
Satish Mallya

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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)
Products

Stability Testing of New Drug Substances and

Q1B
Products

Photostability Testing of New Drug Substances and

Q1C

Stability Testing for New Dosage Forms

Q1DBracketing 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Climatic Zones III & IV (withdrawn June 2006)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 10C

increments (e.g., 50C, 60C,
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

Drug Product

Data on at least three primary batches of

Data on at least three primary batches of the
minimum pilot scale manufactured by the same drug product two pilot and third one can be
synthetic route as used for production batches. 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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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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Storage Conditions
Drug Substance

General Case

Drug Product

Study

Storage
Conditions

Minimum
period
covered by
data at
submission

Study

Storage
Conditions

Minimum
period
covered by
data at
submission

Long term

25C+2C/ 60%
+5%RH or
30C+2C /65%
+5%RH

12 months

Long term

25C+2C /60%
+5%RH or
30C+2C /65%
+5%RH

12 months

Intermediate

30C+2C /65%
+5%RH

6 months

Intermediate

30C+2C /65%
+5%RH

6 months

Accelerated

40C+2C /75%
+5%RH

6 months

Accelerated

40C+2C /75%
+5%RH

6 months

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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

5C + 3C

12months

Long term

5C + 3C

12months

Accelerated

25C + 2C / 60% 6 months

+ 5% RH

Accelerated

25C + 2C / 60% 6 months

+ 5% RH

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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

- 20C + 5C

12months

Long
term

- 20C + 5C

12months

Storage below - 20C : Case by case basis

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Storage Conditions Drug Product

Semi-permeable containers :
Study

Storage Conditions

Minimum period
covered by data at
submission

Long term

25C+2C/40%+5% RH or
30C+2C/35%+5% RH

12 months

Intermediate

30C+2C/65%+5% RH

6 months

Accelerated

40C+2C/NMT 25% RH

6 months

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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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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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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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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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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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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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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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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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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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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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