ICH Quality Guidelines Summary QSEM .pdf
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May 10, 2024
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About This Presentation
STABILITY GUIDELINES
Slide Content
ICH Q GUIDELINES
Quality :
- According to Oxford Dictionary the standard of something as measured against other
things of a similar kind; the degree of excellence of something.
+ ISO defines quality as ‘the totality of features and characteristics of a product or
service that bears on its ability to meet a stated or implied need.”
- ICH defines quality as the degree to which a set of inherent properties of a product,
system or process fulfills requirements.
- According to Oxford Dictionary the standard of something as measured against other
things of a similar kind; the degree of excellence of something.
+ ISO defines quality as ‘the totality of features and characteristics of a product or
service that bears on its ability to meet a stated or implied need.”
- ICH defines quality as the degree to which a set of inherent properties of a product,
system or process fulfills requirements.
08-04-2023 3
Definitions:
“Drug substance :The unformulated drug substance that may subsequently be
formulated with excipients to produce the dosage form,
“Dosage form :A pharmaceutical product type (e.g., tablet, capsule, solution,
cream) that contains a drug substance generally, but not necessarily, in
association with excipients.
“Drug product: The dosage form in the final immediate packaging intended for
marketing.
* A new dosage form: is defined as a drug product which is a different
pharmaceutical product type, but contains the same active substance as included in
the existing drug product approved by the pertinent regulatory authority.
“+ Finished pharmaceutical product: A product that has undergone all stages of
production, including packaging in its final container and labelling.A finished
pharmaceutical product may contain one or more active pharmaceutical ingredients.
Definitions:
“Drug substance :The unformulated drug substance that may subsequently be
formulated with excipients to produce the dosage form,
“Dosage form :A pharmaceutical product type (e.g., tablet, capsule, solution,
cream) that contains a drug substance generally, but not necessarily, in
association with excipients.
“Drug product: The dosage form in the final immediate packaging intended for
marketing.
* A new dosage form: is defined as a drug product which is a different
pharmaceutical product type, but contains the same active substance as included in
the existing drug product approved by the pertinent regulatory authority.
“+ Finished pharmaceutical product: A product that has undergone all stages of
production, including packaging in its final container and labelling.A finished
pharmaceutical product may contain one or more active pharmaceutical ingredients.
* Shelf life (also referred to as expiration dating period) :
The time period during which a drug product is expected to remain within the approved
shelf life specification, provided that it is stored under the conditions defined on the
container label.
* Re-test period :
The period of time during which the drug substance is expected to remain within its
specification and, therefore, can be used in the manufacture of a given drug product, provided
that the drug substance has been stored under the defined conditions.
The time period during which a drug product is expected to remain within the approved
shelf life specification, provided that it is stored under the conditions defined on the
container label.
* Re-test period :
The period of time during which the drug substance is expected to remain within its
specification and, therefore, can be used in the manufacture of a given drug product, provided
that the drug substance has been stored under the defined conditions.
Q1A-QIF Stability
Q2 -Analytical Validation
Q3A-Q3E - Impurities
Q4A-Q4B- Pharmacopoeias
Q5A-Q5E - Quality of
Biotechnological Products
Q6A-Q6B -Specifications
Q7- Good Manufacturing
Practice
Q13-Continuous Manufacturing
for Drug Substances and Drug
Q8 — Pharmaceutical Development
Q9 - Quality Risk Managment
Q10 — Pharmaceutical Quality
System
Q11- Development and
Manufacture of Drug Substances
Q12- Lifecycle Management
qn
Q14- Analytical Procedure
Development
Q2 -Analytical Validation
Q3A-Q3E - Impurities
Q4A-Q4B- Pharmacopoeias
Q5A-Q5E - Quality of
Biotechnological Products
Q6A-Q6B -Specifications
Q7- Good Manufacturing
Practice
Q13-Continuous Manufacturing
for Drug Substances and Drug
Q8 — Pharmaceutical Development
Q9 - Quality Risk Managment
Q10 — Pharmaceutical Quality
System
Q11- Development and
Manufacture of Drug Substances
Q12- Lifecycle Management
qn
Q14- Analytical Procedure
Development
08-04-2023 6
QI-A (R2) - Stability Testing Of New Drug Substances And
Products(Parent Guideline)
Contents:
Drug Substances Drug Product
+ Stress testing » Photo stability 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.
QI-A (R2) - Stability Testing Of New Drug Substances And
Products(Parent Guideline)
Contents:
Drug Substances Drug Product
+ Stress testing » Photo stability 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.
Stress Testing
Drug substance
Studies undertaken to elucidate the
intrinsic stability of the drug substance.
Such testing is part of the development
strategy and is normally carried out
under more severe conditions than
those used for accelerated testing.
Single batch of the drug substance
The effect of temperatures (in 10°C
increments (50°C, 60°C, etc.) Above
that for accelerated testing), humidity
(75% RH or greater) where appropriate,
oxidation, and
Photostability testing should consist of
two parts: forced degradation testing
and confirmatory testing.
Hydrolysis across a wide range of pH
values when in solution or suspension.
Drug product
Studies undertaken to assess the effect
of severe conditions on the drug
product.
Such studies include photostability
testing (Q1B) and specific testing on
certain products, (Metered dose
inhalers, creams, emulsions,
refrigerated aqueous liquid products).
Least one primary batch of the drug
product
Normally, only one batch of drug
product is tested during the
development phase, and then the
photostability characteristics should be
confirmed on a single batch.
Drug substance
Studies undertaken to elucidate the
intrinsic stability of the drug substance.
Such testing is part of the development
strategy and is normally carried out
under more severe conditions than
those used for accelerated testing.
Single batch of the drug substance
The effect of temperatures (in 10°C
increments (50°C, 60°C, etc.) Above
that for accelerated testing), humidity
(75% RH or greater) where appropriate,
oxidation, and
Photostability testing should consist of
two parts: forced degradation testing
and confirmatory testing.
Hydrolysis across a wide range of pH
values when in solution or suspension.
Drug product
Studies undertaken to assess the effect
of severe conditions on the drug
product.
Such studies include photostability
testing (Q1B) and specific testing on
certain products, (Metered dose
inhalers, creams, emulsions,
refrigerated aqueous liquid products).
Least one primary batch of the drug
product
Normally, only one batch of drug
product is tested during the
development phase, and then the
photostability characteristics should be
confirmed on a single batch.
08-04-2023 8
Selection of batches
* Atleast three primary batches of Least three primary batches of the
the drug substance. drug product.
The batches should be The primary batches should be of the
manufactured to a minimum of same formulation and packaged in
pilot scale by the same synthetic the same container closure system as
route as, and using a method of proposed for marketing.
manufacture and procedure that Two of the three batches should be
simulates the final process to be at least pilot scale batches and the
used for, production batches. third one can be smaller, if justified.
Container closure system
Selection of batches
* Atleast three primary batches of Least three primary batches of the
the drug substance. drug product.
The batches should be The primary batches should be of the
manufactured to a minimum of same formulation and packaged in
pilot scale by the same synthetic the same container closure system as
route as, and using a method of proposed for marketing.
manufacture and procedure that Two of the three batches should be
simulates the final process to be at least pilot scale batches and the
used for, production batches. third one can be smaller, if justified.
Container closure system
08-04-2023 9
Specifications Drug Substance Drug Product
A list of tests, reference to ICH Q6A and Q6B ICH Q6A And Q6B
analytical procedures, and
proposed acceptance criteria
Degradation products Q3A Q3B
Factors which influence quality, Same with Preservative Content
safety, and/or efficacy. (Antioxidant, Antimicrobial
The testing should cover, as Preservative), And Functionality
appropriate, the physical, Tests (For A Dose Delivery
chemical, biological, and System).
microbiological attributes.
Analytical procedures should be Same Same
fully validated and stability
indicating. Whether and to what
extent replication should be
performed will depend on the
results of validation studies.
Specifications Drug Substance Drug Product
A list of tests, reference to ICH Q6A and Q6B ICH Q6A And Q6B
analytical procedures, and
proposed acceptance criteria
Degradation products Q3A Q3B
Factors which influence quality, Same with Preservative Content
safety, and/or efficacy. (Antioxidant, Antimicrobial
The testing should cover, as Preservative), And Functionality
appropriate, the physical, Tests (For A Dose Delivery
chemical, biological, and System).
microbiological attributes.
Analytical procedures should be Same Same
fully validated and stability
indicating. Whether and to what
extent replication should be
performed will depend on the
results of validation studies.
08-04-2023 10
Testing Frequency
For long term studies, frequency of testing should be sufficient to establish the stability
profile of the drug substance or products
For drug substances with a proposed re-test period and for drug products shelf life :
of at least 12 months, the frequency of testing at the long term storage condition should
normally be every 3 months over the first year, every 6 months over the second year, and
annually thereafter through the proposed re-test period for substances and shelf life for
products
Testing Frequency
For long term studies, frequency of testing should be sufficient to establish the stability
profile of the drug substance or products
For drug substances with a proposed re-test period and for drug products shelf life :
of at least 12 months, the frequency of testing at the long term storage condition should
normally be every 3 months over the first year, every 6 months over the second year, and
annually thereafter through the proposed re-test period for substances and shelf life for
products
08-04-2023
Storage Conditions:
Drug Substances/ Study Storage conditions Minimum period
Products covered by the data
submission
For Gencral Use 1. Long term* 25°C £2°C/ 12 months
60% RH+5% RH
or
30°C + 2°C/
65% RH + 5% RH
2.Intermediate 30°C + 2°C/65% RH + 6 months
5%
3. Accelerated 6 months
40°C + 2°C/75% RH +
5% RH
For storage in a 1. Long term 5°C+3C 12 months
refrigerator
2, Accelerated 25°C + 2°C/60% RH + 6 months
5%
For storage in a freezer Long term - 20°C + 5°C 12 months
Storage Conditions:
Drug Substances/ Study Storage conditions Minimum period
Products covered by the data
submission
For Gencral Use 1. Long term* 25°C £2°C/ 12 months
60% RH+5% RH
or
30°C + 2°C/
65% RH + 5% RH
2.Intermediate 30°C + 2°C/65% RH + 6 months
5%
3. Accelerated 6 months
40°C + 2°C/75% RH +
5% RH
For storage in a 1. Long term 5°C+3C 12 months
refrigerator
2, Accelerated 25°C + 2°C/60% RH + 6 months
5%
For storage in a freezer Long term - 20°C + 5°C 12 months
08-04-2023 12
Drug products packaged in semi-permeable containers
Aqueous-based products packaged in semi-permeable containers should be evaluated for
potential water loss in addition to physical, chemical, biological, and microbiological
stability.
This evaluation can be carried out under conditions of low relative humidity, as discussed
below.
Ultimately, it should be demonstrated that aqueous-based drug products stored in semi-
permeable containers can withstand low relative humidity environments, Other
comparable approaches can be developed and reported for non-aqueous, solvent-based
products,
Study Storage condition Minimum time period covered by data at submission
Long term* 25°C £ 2°C/40% RH 45% RH or 30°C + 2°C/35% RH + 5% RH 12
Drug products packaged in semi-permeable containers
Aqueous-based products packaged in semi-permeable containers should be evaluated for
potential water loss in addition to physical, chemical, biological, and microbiological
stability.
This evaluation can be carried out under conditions of low relative humidity, as discussed
below.
Ultimately, it should be demonstrated that aqueous-based drug products stored in semi-
permeable containers can withstand low relative humidity environments, Other
comparable approaches can be developed and reported for non-aqueous, solvent-based
products,
Study Storage condition Minimum time period covered by data at submission
Long term* 25°C £ 2°C/40% RH 45% RH or 30°C + 2°C/35% RH + 5% RH 12
08-04-2023 13
Stability Commitment
When available long term stability data on primary batches do not cover the proposed re-test
period granted at the time of approval, commitment should be made to continue the stability
studies post approval in order to firmly establish the re-test period.
Production batches Commitment
3 Proposed retest period
Fewer than 3 Proprosed retest period and 3 additional production batches
through re test period
No production batches first three production batches on long term stability studies
through the proposed re-test period,
Stability Commitment
When available long term stability data on primary batches do not cover the proposed re-test
period granted at the time of approval, commitment should be made to continue the stability
studies post approval in order to firmly establish the re-test period.
Production batches Commitment
3 Proposed retest period
Fewer than 3 Proprosed retest period and 3 additional production batches
through re test period
No production batches first three production batches on long term stability studies
through the proposed re-test period,
Statements/Labeling
A storage statement should be established for the labeling in accordance with relevant
national/regional requirements.
The statement should be based on the stability evaluation of the drug substance.
Where applicable, specific instructions should be provided, particularly for drug substances that
cannot tolerate freezing.
Terms such as “ambient conditions” or “room temperature” should be avoided.
A re-test period should be derived from the stability information, and a retest date should be
displayed on the container label if appropriate.
For product expiry date must be mentioned .
A storage statement should be established for the labeling in accordance with relevant
national/regional requirements.
The statement should be based on the stability evaluation of the drug substance.
Where applicable, specific instructions should be provided, particularly for drug substances that
cannot tolerate freezing.
Terms such as “ambient conditions” or “room temperature” should be avoided.
A re-test period should be derived from the stability information, and a retest date should be
displayed on the container label if appropriate.
For product expiry date must be mentioned .
08-04-2023 15
The purpose of this guideline or revision is to outline the changes made in Q1A(R) that result from
adoption of ICH Q1F “Stability Data Package for Registration Applications in Climatic Zones III
and IV”. These changes are:
Sr. Changes
No.
L The intermediate storage condition has been changed from 30°C + 2°C/60% RH + 5% RH to 30°C +
2°C/65% RH + 5% RH for for Drug Substance and Drug products of General Case, Drug products
packaged in semi-permeable containers and in Glossary for - “Intermediate testing”
ta
30°C + 2°C/65% RH + 5% RH can be a suitable alternative long-term storage condition to 25°C +
2°C/60% RH + 5% for Drug Substance and Drug products of General Case.
3 30°C + 2°C/35% RH + 5% RH has been added as a suitable alternative long term storage condition to
25°C + 2°C/40% RH + 5% and the corresponding example for the ratio of water-loss rates for Drug
products packaged in semi-permeable containers,
The purpose of this guideline or revision is to outline the changes made in Q1A(R) that result from
adoption of ICH Q1F “Stability Data Package for Registration Applications in Climatic Zones III
and IV”. These changes are:
Sr. Changes
No.
L The intermediate storage condition has been changed from 30°C + 2°C/60% RH + 5% RH to 30°C +
2°C/65% RH + 5% RH for for Drug Substance and Drug products of General Case, Drug products
packaged in semi-permeable containers and in Glossary for - “Intermediate testing”
ta
30°C + 2°C/65% RH + 5% RH can be a suitable alternative long-term storage condition to 25°C +
2°C/60% RH + 5% for Drug Substance and Drug products of General Case.
3 30°C + 2°C/35% RH + 5% RH has been added as a suitable alternative long term storage condition to
25°C + 2°C/40% RH + 5% and the corresponding example for the ratio of water-loss rates for Drug
products packaged in semi-permeable containers,
16
Q1-B -Stability Testing: Photo Stability Testing Of New Drug
Substances And Products
+ The guideline primarily addresses the generation of photostability information for submission in
Registration Applications for new molecular entities and associated drug products.
+ The guideline does not cover the photostability of drugs after administration (i.e. under
conditions of use) and those applications not covered by the Parent Guideline.
+ Contents :
x Light Sources like D65/1D65 emission standard such as an artificial daylight fluorescent lamp
combining visible and ultraviolet (UV) outputs, xenon, or metal halide lamp
Y Presentation of samples.
“ Analysis of samples .
* Judgment of results.
Q1-C - Stability Testing For New Dosage Forms
This subsection addresses the recommendations on what should be submitted regarding stability
of new dosage forms by the owner of the original application, after the original submission for new
drug substances and products.
Q1-B -Stability Testing: Photo Stability Testing Of New Drug
Substances And Products
+ The guideline primarily addresses the generation of photostability information for submission in
Registration Applications for new molecular entities and associated drug products.
+ The guideline does not cover the photostability of drugs after administration (i.e. under
conditions of use) and those applications not covered by the Parent Guideline.
+ Contents :
x Light Sources like D65/1D65 emission standard such as an artificial daylight fluorescent lamp
combining visible and ultraviolet (UV) outputs, xenon, or metal halide lamp
Y Presentation of samples.
“ Analysis of samples .
* Judgment of results.
Q1-C - Stability Testing For New Dosage Forms
This subsection addresses the recommendations on what should be submitted regarding stability
of new dosage forms by the owner of the original application, after the original submission for new
drug substances and products.
08-04-2023 17
QI-D - Bracketing And Matrixing Design For Stability Testing Of New
Drug Substances And Products
* This guideline is intended to address recommendations on the application of bracketing and
matrixing to stability studies conducted in accordance with principles outlined in the ICH
QIA{R) the parent guideline.
+ As defined in the glossary to the parent guideline:
Bracketing is the design of a stability * Matrixing is the design of a stability
schedule such that only samples on the
extremes of certain design factors
(e.g.. strength, container size and/or fill)
are tested at all time points as in a full
design.
* Contents:
Y Data evaluation
¥ Design factors
schedule such that a selected subset of
the total number of possible samples
for all factor combinations would be
tested at a specified time point.
At a subsequent time point, another
subset of samples for all factor
combinations would be tested.
Y” Design considerations and potential risks
Y” Design examples.
QI-D - Bracketing And Matrixing Design For Stability Testing Of New
Drug Substances And Products
* This guideline is intended to address recommendations on the application of bracketing and
matrixing to stability studies conducted in accordance with principles outlined in the ICH
QIA{R) the parent guideline.
+ As defined in the glossary to the parent guideline:
Bracketing is the design of a stability * Matrixing is the design of a stability
schedule such that only samples on the
extremes of certain design factors
(e.g.. strength, container size and/or fill)
are tested at all time points as in a full
design.
* Contents:
Y Data evaluation
¥ Design factors
schedule such that a selected subset of
the total number of possible samples
for all factor combinations would be
tested at a specified time point.
At a subsequent time point, another
subset of samples for all factor
combinations would be tested.
Y” Design considerations and potential risks
Y” Design examples.
08-04-
18
QIE -Evaluation For Stability Data
+ This guideline is intended to provide recommendations on how to use stability data generated in
accordance with the principles detailed in parent guideline to propose a retest period or shelf
life in a registration application.
18
QIE -Evaluation For Stability Data
+ This guideline is intended to provide recommendations on how to use stability data generated in
accordance with the principles detailed in parent guideline to propose a retest period or shelf
life in a registration application.
19
Q1-F -Stability Testing Of Active Pharmaceutical Ingredients And Finished
Pharmaceutical Products
ICH QI F Stability Data Package for Registration Applications in Climatic Zones I] and IV
defined storage conditions for stability testing in countries located in Climatic Zones III (hot and
dry) and IV (hot and humid), i.e. countries not located in the ICH regions and not covered by ICH
QLA(R2) Stability Testing for New Drug Substances and Drug Products.
ICH QI F described harmonised global stability testing requirements in order to facilitate access to
medicines by reducing the number of different storage conditions.
Q1-F -Stability Testing Of Active Pharmaceutical Ingredients And Finished
Pharmaceutical Products
ICH QI F Stability Data Package for Registration Applications in Climatic Zones I] and IV
defined storage conditions for stability testing in countries located in Climatic Zones III (hot and
dry) and IV (hot and humid), i.e. countries not located in the ICH regions and not covered by ICH
QLA(R2) Stability Testing for New Drug Substances and Drug Products.
ICH QI F described harmonised global stability testing requirements in order to facilitate access to
medicines by reducing the number of different storage conditions.
20
Q2(R1) Validation Of Analytical Procedures: Text And Methodology
+ Types of Analytical Procedures to be Validated The discussion of the validation of analytical
procedures is directed to the four most common types of analytical procedures:
|. Identification tests
2. Quantitative tests for impurities’ content
Limit tests for the control of impurities
‘. Quantitative tests of the active moiety in samples of drug substance or drug product
or other selected component(s) in the drug product.
+ The objective of validation of an analytical procedure is to demonstrate that it is suitable for its
intended purpose.
Q2(R1) Validation Of Analytical Procedures: Text And Methodology
+ Types of Analytical Procedures to be Validated The discussion of the validation of analytical
procedures is directed to the four most common types of analytical procedures:
|. Identification tests
2. Quantitative tests for impurities’ content
Limit tests for the control of impurities
‘. Quantitative tests of the active moiety in samples of drug substance or drug product
or other selected component(s) in the drug product.
+ The objective of validation of an analytical procedure is to demonstrate that it is suitable for its
intended purpose.
1, Identification tests are
intended to ensure the
identity of an analyte in a
sample.
* This is normally
achieved by
comparison ofa
property of the sample
(e.g., spectrum,
chromatographic
behavior, chemical
reactivity, etc) to that of
a reference standard.
2. Assay procedures are
intended to measure the analyte
present in a given sample. In the
context of this guideline . the
assay represents a quantitative
measurement of the major
component(s) in the drug
substance.
* For the drug product, similar
validation characteristics
also apply when assaying for
the active or other selected
component(s).
* The same validation
characteristics may also
apply to assays associated
with other analytical
procedures (e.g.,
3. Testing for impurities can
be cither a quantitative test
or a limit test for the
impurity in a sample.
* Either test is intended to
accurately reflect the
purity characteristics of
the sample.
Different validation
characteristics are
required for a quantitative
test than for a limit test.
intended to ensure the
identity of an analyte in a
sample.
* This is normally
achieved by
comparison ofa
property of the sample
(e.g., spectrum,
chromatographic
behavior, chemical
reactivity, etc) to that of
a reference standard.
2. Assay procedures are
intended to measure the analyte
present in a given sample. In the
context of this guideline . the
assay represents a quantitative
measurement of the major
component(s) in the drug
substance.
* For the drug product, similar
validation characteristics
also apply when assaying for
the active or other selected
component(s).
* The same validation
characteristics may also
apply to assays associated
with other analytical
procedures (e.g.,
3. Testing for impurities can
be cither a quantitative test
or a limit test for the
impurity in a sample.
* Either test is intended to
accurately reflect the
purity characteristics of
the sample.
Different validation
characteristics are
required for a quantitative
test than for a limit test.
4, The objective of the analytical procedure should be clearly understood since this will govern the
validation characteristics which need to be evaluated, Typical validation characteristics which
should be considered are listed below:
* Accuracy
Precision:
-Repeatability
-Intermediate Precision
Specificity
Detection Limit
Quantitation Limit
Linearity
Range
validation characteristics which need to be evaluated, Typical validation characteristics which
should be considered are listed below:
* Accuracy
Precision:
-Repeatability
-Intermediate Precision
Specificity
Detection Limit
Quantitation Limit
Linearity
Range
08-04-2023
Q3A(R2) Impurities in New Drug Substances
This guideline is intended to provide guidance for registration applications on the content and
qualification of impurities in new drug substances produced by chemical syntheses and not
previously registered in a region or member state.
It is not intended to apply to new drug substances used during the clinical research stage of
development.
Contents:
1. Classification of Impurities:
Organic impurities (process- and drug-related)
Inorganic impurities
Residual solvents
2. Analytical procedures
3. Reporting impurity content of batches
- organic impurities
- each specified identified impurity
each specified unidentified impurity
any unspecified impurity with an acceptance criterion of not more than the identification threshold
- total impurities residual solvents inorganic impurities
4. Listing of impurities in specifications
5. Qualification of impurities
Q3A(R2) Impurities in New Drug Substances
This guideline is intended to provide guidance for registration applications on the content and
qualification of impurities in new drug substances produced by chemical syntheses and not
previously registered in a region or member state.
It is not intended to apply to new drug substances used during the clinical research stage of
development.
Contents:
1. Classification of Impurities:
Organic impurities (process- and drug-related)
Inorganic impurities
Residual solvents
2. Analytical procedures
3. Reporting impurity content of batches
- organic impurities
- each specified identified impurity
each specified unidentified impurity
any unspecified impurity with an acceptance criterion of not more than the identification threshold
- total impurities residual solvents inorganic impurities
4. Listing of impurities in specifications
5. Qualification of impurities
24
Q3B(R2)Impurities in New Drug Products
This guideline provides for registration applications on the content and qualification of
impurities in new drug products produced from chemically synthesised new drug substances not
previously registered in a region or member state,
This guideline addresses only those impurities in new drug products classified as degradation
products of the drug substance or reaction products of the drug substance with an excipient
and/or immediate container closure system
+ Contents:
1. Rationale for reporting and control of degradation product
2. Analytical procedures
3. Reporting impurity content of batches
4, Listing of impurities in specifications
5.Qualification of impurities
Q3B(R2)Impurities in New Drug Products
This guideline provides for registration applications on the content and qualification of
impurities in new drug products produced from chemically synthesised new drug substances not
previously registered in a region or member state,
This guideline addresses only those impurities in new drug products classified as degradation
products of the drug substance or reaction products of the drug substance with an excipient
and/or immediate container closure system
+ Contents:
1. Rationale for reporting and control of degradation product
2. Analytical procedures
3. Reporting impurity content of batches
4, Listing of impurities in specifications
5.Qualification of impurities
25
Q3C(R6) Impurities: Guideline For Residual Solvents
+ The objective of this guideline is to recommend acceptable amounts for residual solvents in
pharmaceuticals for the safety of the patient. The guideline recommends use of less toxic
solvents and describes levels considered to be toxicologically acceptable for some residual
solvents,
+ Classification of Residual Solvents :
+ They were evaluated for their possible risk to human health and placed into one of three classes
as follows:
Q3C(R6) Impurities: Guideline For Residual Solvents
+ The objective of this guideline is to recommend acceptable amounts for residual solvents in
pharmaceuticals for the safety of the patient. The guideline recommends use of less toxic
solvents and describes levels considered to be toxicologically acceptable for some residual
solvents,
+ Classification of Residual Solvents :
+ They were evaluated for their possible risk to human health and placed into one of three classes
as follows:
Class 2 solvents:
Solvents to be limited, Non-genotoxic
animal carcinogens or possible causative
agents of other i toxicity such as
neurotoxicity Solvents
suspected of other but reversible
toxicities.
e.g. Acetonitrile, Chlorobenzene,
Chloroform, Cumene, Cyclohexane ete.
Class 3 solvents:
Solvents with low toxic potential
more per day.
E.g, Acetic acid, Heptane, Acetone,
Isobutyl acetate, Anisole Isopropyl
acetate 1-Butanol, ethanol etc.
Solvents to be limited, Non-genotoxic
animal carcinogens or possible causative
agents of other i toxicity such as
neurotoxicity Solvents
suspected of other but reversible
toxicities.
e.g. Acetonitrile, Chlorobenzene,
Chloroform, Cumene, Cyclohexane ete.
Class 3 solvents:
Solvents with low toxic potential
more per day.
E.g, Acetic acid, Heptane, Acetone,
Isobutyl acetate, Anisole Isopropyl
acetate 1-Butanol, ethanol etc.
08-04-2023 27
Q3C(R8) — Residual Solvent
» The objectives of the current Maintenance procedure are to add three new solvents to the
guideline:
2-Methyltetrahydrofuran Tertiary Butyl Alcohol Cyclopentyl Methyl Ether
PDE : 50 mg/day (Class 3) PDE: 35 mg/day (Class 2) PDE: 15 mg/day (Class 2)
Q3C(R8) — Residual Solvent
» The objectives of the current Maintenance procedure are to add three new solvents to the
guideline:
2-Methyltetrahydrofuran Tertiary Butyl Alcohol Cyclopentyl Methyl Ether
PDE : 50 mg/day (Class 3) PDE: 35 mg/day (Class 2) PDE: 15 mg/day (Class 2)
28
Q3D(R1) Guideline For Elemental Impurities
The guideline applies to new finished drug products (as defined in ICH Q6A and Q6B) and new
drug products containing existing drug substances,
Contents:
+ Risk Assessment
Specifications
Reporting
Control
Element Classification :
The Elements included in this guideline have been placed into three classes based on their
toxicity (PDE) and likelihood of occurrence in the drug product,
The elemental impurity classes are:
Q3D(R1) Guideline For Elemental Impurities
The guideline applies to new finished drug products (as defined in ICH Q6A and Q6B) and new
drug products containing existing drug substances,
Contents:
+ Risk Assessment
Specifications
Reporting
Control
Element Classification :
The Elements included in this guideline have been placed into three classes based on their
toxicity (PDE) and likelihood of occurrence in the drug product,
The elemental impurity classes are:
08-04-2023
The elemental impurity classes
Class |
The elements, As, Cd,
Hg, and Pb, are human
toxicants that have
limited or no use in the
manufacture of
pharmaceuticals.
Class 2A elements:
have relatively
Class 2
Elements in this class
are generally
considered
dependent
toxicants.
high
probability of occurrence in
the drug product.
E.g: Co, Ni and V.
as
route-
human
Class 3
The elements in this class have
relatively low toxicities by the
oral route of administration (high
PDEs, generally > 500 pg/day)
but may require consideration in
the risk assessment for inhalation
and parenteral routes. Some of
the elements considered include:
Al, B, Ca, Fe, K, Mg, Mn, Na etc
y
Ru, Se and Tl.
Class 2B elements
have a reduced probability of
occurrence in the drug product.
eg Ag, Au, Ir, Os, Pd, Pt, Rh,
The elemental impurity classes
Class |
The elements, As, Cd,
Hg, and Pb, are human
toxicants that have
limited or no use in the
manufacture of
pharmaceuticals.
Class 2A elements:
have relatively
Class 2
Elements in this class
are generally
considered
dependent
toxicants.
high
probability of occurrence in
the drug product.
E.g: Co, Ni and V.
as
route-
human
Class 3
The elements in this class have
relatively low toxicities by the
oral route of administration (high
PDEs, generally > 500 pg/day)
but may require consideration in
the risk assessment for inhalation
and parenteral routes. Some of
the elements considered include:
Al, B, Ca, Fe, K, Mg, Mn, Na etc
y
Ru, Se and Tl.
Class 2B elements
have a reduced probability of
occurrence in the drug product.
eg Ag, Au, Ir, Os, Pd, Pt, Rh,
08-0:
30
Q3D(R2): Limits for Elemental Impurities by the Cutaneous and
Transcutaneous Route and Some Corrected Permitted Daily
Exposures (PDEs)
- The Guideline revision (R2) is focused on establishment of limits for elemental impurities by
the dermal route of exposure,
+ The Guideline revision (R2) also includes error corrections of the PDEs for
O Silver (oral)
Gold (oral, parenteral and inhalation)
Nickel (inhalation)
Q3E: Guideline for Extractables and Leachables (E&L)
For the purpose of this document, “extractables” are any chemical entities that will extract
from components of a manufacturing or packaging system into a solvent under forced
conditions,
This provides an effective worst case scenario in terms of what can migrate from a
component, Knowledge of these extractables is important in identifying potential
“leachables” that can migrate via contact with manufacturing systems, container-closure
systems, and drug delivery device components
30
Q3D(R2): Limits for Elemental Impurities by the Cutaneous and
Transcutaneous Route and Some Corrected Permitted Daily
Exposures (PDEs)
- The Guideline revision (R2) is focused on establishment of limits for elemental impurities by
the dermal route of exposure,
+ The Guideline revision (R2) also includes error corrections of the PDEs for
O Silver (oral)
Gold (oral, parenteral and inhalation)
Nickel (inhalation)
Q3E: Guideline for Extractables and Leachables (E&L)
For the purpose of this document, “extractables” are any chemical entities that will extract
from components of a manufacturing or packaging system into a solvent under forced
conditions,
This provides an effective worst case scenario in terms of what can migrate from a
component, Knowledge of these extractables is important in identifying potential
“leachables” that can migrate via contact with manufacturing systems, container-closure
systems, and drug delivery device components
Q4 A :Pharmacopeial Hormonization
+ The pharmacopoeial authorities, working together through the Pharmacopoeial Discussion
Group (PDG), have been closely involved with the work of ICH since the outset and
harmonisation between the major pharmacopoeias, which started before ICH, has proceeded in
parallel.
+ The pharmacopoeial authorities, working together through the Pharmacopoeial Discussion
Group (PDG), have been closely involved with the work of ICH since the outset and
harmonisation between the major pharmacopoeias, which started before ICH, has proceeded in
parallel.
08-04-2023 32
Q4B :Evaluation And Recommendation Of Pharmacopoeial Texts
For Use In The ICH Regions
This guideline describes a process for the evaluation and recommendation by the
Q4B Expert Working Group (EWG) of selected pharmacopocial texts to facilitate
their recognition by regulatory authorities for use as interchangeable in the ICH
regions. Following favourable evaluations, ICH will issue topic-specific annexes with
information about these texts and their implementation (the Q4B Outcomes).
Implementation of the Q4B annexes is intended to avoid redundant testing by
industry
Q4B :Evaluation And Recommendation Of Pharmacopoeial Texts
For Use In The ICH Regions
This guideline describes a process for the evaluation and recommendation by the
Q4B Expert Working Group (EWG) of selected pharmacopocial texts to facilitate
their recognition by regulatory authorities for use as interchangeable in the ICH
regions. Following favourable evaluations, ICH will issue topic-specific annexes with
information about these texts and their implementation (the Q4B Outcomes).
Implementation of the Q4B annexes is intended to avoid redundant testing by
industry
33
+ Each QAB party independently evaluates the documents for regulatory impact.
Additional discussion within the Q4B EWG, and/or communication/dialogue with the
submitting party (c.g., the PDG}, might be warranted to resolve any issues that
surfaced during the evaluation When the Q4B evaluation process results in a
recommendatton that the pharmacopoeial text can be used as interchangeable in the
ICH regions, the Q4B EWG prepares and signs off on a draft Q4B annex, which is
submitted to the Steering Committee for adoption at step 2.
+ Each QAB party independently evaluates the documents for regulatory impact.
Additional discussion within the Q4B EWG, and/or communication/dialogue with the
submitting party (c.g., the PDG}, might be warranted to resolve any issues that
surfaced during the evaluation When the Q4B evaluation process results in a
recommendatton that the pharmacopoeial text can be used as interchangeable in the
ICH regions, the Q4B EWG prepares and signs off on a draft Q4B annex, which is
submitted to the Steering Committee for adoption at step 2.
08-04-2023
x a
34
+ The Steering Committee agrees, based on the report of the Q4B EWG, that there is
sufficient scientific consensus on the technical issues for the draft annex to
proceed to Step 3 regulatory consultation and discussion.
* The draft Q4B annex is made available for regulatory consultation in the three
regions (generally for 3 months), The regulatory consultation and discussion
should focus on the Q4B Outcome in the annex.
* The Q4B EWG can revise the annex based on comments received and submits a
final draft of the annex to the ICH Steering Committee.
* The ICH Steering Committee adopts the annex and issues it as a stand-alone
companion document to the ICH Q4B guideline.
The annex moves to the regional regulatory implementation step.
x a
34
+ The Steering Committee agrees, based on the report of the Q4B EWG, that there is
sufficient scientific consensus on the technical issues for the draft annex to
proceed to Step 3 regulatory consultation and discussion.
* The draft Q4B annex is made available for regulatory consultation in the three
regions (generally for 3 months), The regulatory consultation and discussion
should focus on the Q4B Outcome in the annex.
* The Q4B EWG can revise the annex based on comments received and submits a
final draft of the annex to the ICH Steering Committee.
* The ICH Steering Committee adopts the annex and issues it as a stand-alone
companion document to the ICH Q4B guideline.
The annex moves to the regional regulatory implementation step.
Q4B ANNEX I(R1)
Q4B ANNEX 2(R1)
Residue On
Ignition/Sulphated Ash
General Chapter.
Test for extractable volume of
parenteral preparations
general chapter
35
European Pharmacopoeia (Ph.
Eur.): Supplement 5.6 (official
on January 2007) {reference
Sulphated Ash 01/2007:204 14);
Japanese Pharmacopoeia (JP):
2.44 Residue on Ignition Test as
it appears in the JP Fifteenth
Edition (March 31, 2006, The
Ministry of Health, Labour and
Welfare Ministerial Notification
No. 285}:
United States Pharmacopeia
(USP): Residue on Ignition
official in USP 29, 2nd
Supplement, August 2006.
Test for Extractable Volume of
Parenteral Preparations, JP 6.05
Test for Extractable Volume of
Parenteral Preparations, and
The section in USP Injections
General Chapter entitled
"Volume in Containers” can be
used as interchangeable in the
ICH regions.
Q4B ANNEX 2(R1)
Residue On
Ignition/Sulphated Ash
General Chapter.
Test for extractable volume of
parenteral preparations
general chapter
35
European Pharmacopoeia (Ph.
Eur.): Supplement 5.6 (official
on January 2007) {reference
Sulphated Ash 01/2007:204 14);
Japanese Pharmacopoeia (JP):
2.44 Residue on Ignition Test as
it appears in the JP Fifteenth
Edition (March 31, 2006, The
Ministry of Health, Labour and
Welfare Ministerial Notification
No. 285}:
United States Pharmacopeia
(USP): Residue on Ignition
official in USP 29, 2nd
Supplement, August 2006.
Test for Extractable Volume of
Parenteral Preparations, JP 6.05
Test for Extractable Volume of
Parenteral Preparations, and
The section in USP Injections
General Chapter entitled
"Volume in Containers” can be
used as interchangeable in the
ICH regions.
36
Q4B ANNEX 3(R1)
‘Test for particulate
contamination: sub-visible
particles general chapter
+ Except for nominal 100-milliliter (ml)
parenteral products, the acceptance
criteria are interchangeable.
* At the 100-ml nominal volume, the
criteria specified in JP are more
stringent than those in the other two
pharmacopocias; therefore, the
criteria are not interchangeable in all
three regions at that volume,
Q4B ANNEX 4A(R1)
Microbiological examination of
Non-sterile Products: Microbial
Enumerations Tests General
Chapter
The ICH steering committee, based on the
evaluation by the Q4B expert working
group (EWG), recommends that the official
pharmacopoeial texts,
* Ph,Eur.2.6,12, Microbiological
examination of non-sterile products:
microbial enumeration tests,
+ JP-4.05 microbiological examination of
non-sterile products: 1. Microbiological
examination of non-sterile products:
microbial enumeration tests, and
* USP microbiological examination of
nonsterile products; microbial
‘enumeration tests can be used as
interchangeable in the ICH
+ The proposed texts evaluated did not
contain acceptance criteria,
Q4B ANNEX 3(R1)
‘Test for particulate
contamination: sub-visible
particles general chapter
+ Except for nominal 100-milliliter (ml)
parenteral products, the acceptance
criteria are interchangeable.
* At the 100-ml nominal volume, the
criteria specified in JP are more
stringent than those in the other two
pharmacopocias; therefore, the
criteria are not interchangeable in all
three regions at that volume,
Q4B ANNEX 4A(R1)
Microbiological examination of
Non-sterile Products: Microbial
Enumerations Tests General
Chapter
The ICH steering committee, based on the
evaluation by the Q4B expert working
group (EWG), recommends that the official
pharmacopoeial texts,
* Ph,Eur.2.6,12, Microbiological
examination of non-sterile products:
microbial enumeration tests,
+ JP-4.05 microbiological examination of
non-sterile products: 1. Microbiological
examination of non-sterile products:
microbial enumeration tests, and
* USP microbiological examination of
nonsterile products; microbial
‘enumeration tests can be used as
interchangeable in the ICH
+ The proposed texts evaluated did not
contain acceptance criteria,
+ Q4B ANNEX 4B(R1)
+ Microbiological Examination Of
Non-sterile Products; Test For
Specified Micro-organisms ¡General
Chapter.
+ The ICH Steering Commitee, based on the
evaluation by the Q4B Ben Working Group
(EWG), recommends the official
pharmacopocial texts,
- Ph.Eur. 2.6.13. Microbiological Examination of
Non-Sterile Products: Tests for Specified
Microorganisms,
+ JP 4.05 Microbiological Examination of Non-
Sterile Products: IL Microbiological Examination
of Non-Sterile Products: Tests for Specified
Microorganisms, and
+ USP Microbiological Examination of Nonsterile
Products: Tests for Specified Microorganisms can
be used as interchangeable in the ICH regions
+ The proposed texts evaluated did not contain
tance criteria.
+ Q4B ANNEX 4C(RI)
- Microbiological Examination Of
Non-sterile Products: Acceptance
Criteria For Pharmaceutical
Preparations And Substances For
Pharmaceutical Use :General
Chapter.
+ The ICH Steering Committee, based on the
evaluation by the Q4B Expert Working Group
(EWG), recommends that the official
pharmacopoeial texts,
Ph.Eur. 5.1.4, Microbiological Quality of Non-
Sterile Pharmaceutical Preparations and
Substances for Pharmaceutical Use,
+ JP General Information 12. Microbial Attributes of
Nonsterile Pharmaceutical Products, and
+ USP Microbiological Attributes of Nonsterile
Pharmaceutical Products, can be used as
interchangeable in the ICH regions,
+ Microbiological Examination Of
Non-sterile Products; Test For
Specified Micro-organisms ¡General
Chapter.
+ The ICH Steering Commitee, based on the
evaluation by the Q4B Ben Working Group
(EWG), recommends the official
pharmacopocial texts,
- Ph.Eur. 2.6.13. Microbiological Examination of
Non-Sterile Products: Tests for Specified
Microorganisms,
+ JP 4.05 Microbiological Examination of Non-
Sterile Products: IL Microbiological Examination
of Non-Sterile Products: Tests for Specified
Microorganisms, and
+ USP Microbiological Examination of Nonsterile
Products: Tests for Specified Microorganisms can
be used as interchangeable in the ICH regions
+ The proposed texts evaluated did not contain
tance criteria.
+ Q4B ANNEX 4C(RI)
- Microbiological Examination Of
Non-sterile Products: Acceptance
Criteria For Pharmaceutical
Preparations And Substances For
Pharmaceutical Use :General
Chapter.
+ The ICH Steering Committee, based on the
evaluation by the Q4B Expert Working Group
(EWG), recommends that the official
pharmacopoeial texts,
Ph.Eur. 5.1.4, Microbiological Quality of Non-
Sterile Pharmaceutical Preparations and
Substances for Pharmaceutical Use,
+ JP General Information 12. Microbial Attributes of
Nonsterile Pharmaceutical Products, and
+ USP Microbiological Attributes of Nonsterile
Pharmaceutical Products, can be used as
interchangeable in the ICH regions,
08-04-2023
38
Q4B Annex 5 (R1) : Disintegration Test General Chapter
This test is not interchangeable in ICH
regions :
For tablets and
capsules larger
than 18 millimeters
long for
(mm)
which a different
apparatus is used.
For dosage forms
referred to in the
régional compendia
as delayed-release,
gastro-resistant,
orenteric-coated.
Product-specific
parameters such as
media and the use of
discs should be
specified in the
No testing conditions
application dosserier .
38
Q4B Annex 5 (R1) : Disintegration Test General Chapter
This test is not interchangeable in ICH
regions :
For tablets and
capsules larger
than 18 millimeters
long for
(mm)
which a different
apparatus is used.
For dosage forms
referred to in the
régional compendia
as delayed-release,
gastro-resistant,
orenteric-coated.
Product-specific
parameters such as
media and the use of
discs should be
specified in the
No testing conditions
application dosserier .
08-04-2023 39
Q4B Annex 6 : Uniformity Of Dosage Units General Chapter
Unless the 25 milligrams (mg)/25% threshold limit is met, the use of the Mass/Weight
Variation test as an alternative test for Content Uniformity is not considered interchangeable
in all ICH regions,
For specific dosage forms that appear in local text in the pharmacopoeias by enclosing the text
in black diamond symbols, application of the Uniformity of Dosage Units test is not
considered interchangeable in all ICH regions.
Olf a correction factor is called for when different procedures are used for assay of the
preparation and for the Content Uniformity Test, the correction factor should be specified and
justified in the application dossier.
*( black diamonds indicate non harmonise
attributes/provisions,white diamonds indicate local requirements)
Q4B Annex 6 : Uniformity Of Dosage Units General Chapter
Unless the 25 milligrams (mg)/25% threshold limit is met, the use of the Mass/Weight
Variation test as an alternative test for Content Uniformity is not considered interchangeable
in all ICH regions,
For specific dosage forms that appear in local text in the pharmacopoeias by enclosing the text
in black diamond symbols, application of the Uniformity of Dosage Units test is not
considered interchangeable in all ICH regions.
Olf a correction factor is called for when different procedures are used for assay of the
preparation and for the Content Uniformity Test, the correction factor should be specified and
justified in the application dossier.
*( black diamonds indicate non harmonise
attributes/provisions,white diamonds indicate local requirements)
The declaration of interchangeability
applies to the Basket Apparatus
(Apparatus 1), the Paddle Apparatus
(Apparatus 2), and the Flow-Through
Cell.
The Flow-Through Cell should be
referred to in the dossier by an
unambiguous descriptive title or
compendial reference because it is
referred to by different numbers in the
three pharmacopoeias.
40
Not Interchangeable for :
Dosage forms referred to in the regional compendia as
delayed-release, gastro-resistant, or enteric-coated.
JP Interpretation 2,
Use of large vessels (greater than 1 liter).
When enzymes are used in the media.
applies to the Basket Apparatus
(Apparatus 1), the Paddle Apparatus
(Apparatus 2), and the Flow-Through
Cell.
The Flow-Through Cell should be
referred to in the dossier by an
unambiguous descriptive title or
compendial reference because it is
referred to by different numbers in the
three pharmacopoeias.
40
Not Interchangeable for :
Dosage forms referred to in the regional compendia as
delayed-release, gastro-resistant, or enteric-coated.
JP Interpretation 2,
Use of large vessels (greater than 1 liter).
When enzymes are used in the media.
08-04-2023 41
The dissolution apparatus should be appropriately calibrated to ensure compliance with regional good
manufacturing practice (GMP) requirements. For example, an appropriately designed and executed
mechanical calibration strategy should be in compliance with good manufacturing practice
requirements.
Product-specific parameters such as media, stirring rate, sampling time, and the use and type of
sinkers should be specified and justified in the application dossier. Acceptance criteria should be
specified in the application dossier.
* Analytical Procedures The ICH Steering Committee, based on the evaluation by the Q4B Expert
Working Group (EWG), recommends that the official pharmacopocial texts, Ph.Eur. 2.9.3.
Dissolution Test for Solid Dosage Forms,
JP 6.10 Dissolution Test, and USP Dissolution can be used as interchangeable in the ICH regions
subject to the following conditions:
The dissolution apparatus should be appropriately calibrated to ensure compliance with regional good
manufacturing practice (GMP) requirements. For example, an appropriately designed and executed
mechanical calibration strategy should be in compliance with good manufacturing practice
requirements.
Product-specific parameters such as media, stirring rate, sampling time, and the use and type of
sinkers should be specified and justified in the application dossier. Acceptance criteria should be
specified in the application dossier.
* Analytical Procedures The ICH Steering Committee, based on the evaluation by the Q4B Expert
Working Group (EWG), recommends that the official pharmacopocial texts, Ph.Eur. 2.9.3.
Dissolution Test for Solid Dosage Forms,
JP 6.10 Dissolution Test, and USP Dissolution can be used as interchangeable in the ICH regions
subject to the following conditions:
42
Q4 B Annex 8 (R1) Sterility Test General Chapter
+ Diluting and rinsing fluids should not have antibacterial or antifungal properties if they are to be
considered suitable for dissolving, diluting, or rinsing an article under test for sterility,
+ When testing liquid parenteral preparations with a nominal volume of 100 milliliters in batches
of more than 500 containers, the test is considered interchangeable if the minimum number of
containers selected is cither 20 or is 2 percent of the total number of containers, whichever is
lower.
Q4 B Annex 8 (R1) Sterility Test General Chapter
+ Diluting and rinsing fluids should not have antibacterial or antifungal properties if they are to be
considered suitable for dissolving, diluting, or rinsing an article under test for sterility,
+ When testing liquid parenteral preparations with a nominal volume of 100 milliliters in batches
of more than 500 containers, the test is considered interchangeable if the minimum number of
containers selected is cither 20 or is 2 percent of the total number of containers, whichever is
lower.
08-04-2023 43
Q4B Annex 9(R1) Tablet Friability General Chapter
+ For interchangeability, the loss of mass for a single determination should be not more than 1,0
percent, unless otherwise specified in the dossier,
» When three determinations are conducted, then the mean loss of mass for the three
determinations should be not more than 1.0 percent, unless otherwise specified in the dossier,
Q 4B Annex 10 (R1) Polyacrylamide Gel Electrophoresis
General Chapter
This annex is the result of the Q4B process for the polyaeryl electrophoresis entitled
sodium dodecyl! sulphate polyacrylamide gel electrophoresis (SDS-PAGE),
+ JP general information 23. SDS-polyacrylamide gel electrophoresis.
+ USP biotechnology-derived articles — polyacrylamide gel electrophoresis.
+ Can be used as interchangeable in the ICH regions amide gel electrophoresis general
chapter.
Q4B Annex 9(R1) Tablet Friability General Chapter
+ For interchangeability, the loss of mass for a single determination should be not more than 1,0
percent, unless otherwise specified in the dossier,
» When three determinations are conducted, then the mean loss of mass for the three
determinations should be not more than 1.0 percent, unless otherwise specified in the dossier,
Q 4B Annex 10 (R1) Polyacrylamide Gel Electrophoresis
General Chapter
This annex is the result of the Q4B process for the polyaeryl electrophoresis entitled
sodium dodecyl! sulphate polyacrylamide gel electrophoresis (SDS-PAGE),
+ JP general information 23. SDS-polyacrylamide gel electrophoresis.
+ USP biotechnology-derived articles — polyacrylamide gel electrophoresis.
+ Can be used as interchangeable in the ICH regions amide gel electrophoresis general
chapter.
08-04-2023 44
Q4BAnnex 11: Capillary Electrophoresis General Chapter
» Capillary Electrophoresis, JP General Information.
- Capillary Electrophoresis, and USP General Information Chapter Biotechnology-derived
Articles.
+ can be used as interchangeable in the ICH regions.
Q4B Annex 12: Analytical Sieving General Chapter
Particle-size Distribution Estimation by Analytical Sieving,
JP 3.04 ¿Particle Size Determination entitled Method 2. Analytical Sieving Method,
USP General Chapter Particle Size Distribution Estimation by Analytical Sieving,
can be used as interchangeable in the ICH regions.
Q4BAnnex 11: Capillary Electrophoresis General Chapter
» Capillary Electrophoresis, JP General Information.
- Capillary Electrophoresis, and USP General Information Chapter Biotechnology-derived
Articles.
+ can be used as interchangeable in the ICH regions.
Q4B Annex 12: Analytical Sieving General Chapter
Particle-size Distribution Estimation by Analytical Sieving,
JP 3.04 ¿Particle Size Determination entitled Method 2. Analytical Sieving Method,
USP General Chapter Particle Size Distribution Estimation by Analytical Sieving,
can be used as interchangeable in the ICH regions.
Q4B Annex 13 :Bulk Density And Tapped Density Of Powders
General Chapter .
+ Bulk Density and Tapped Density of Powders, JP 3.01 Determination of Bulk and Tapped
Densities, and USP General Chapter Bulk Density and Tapped Density of Powders, can be used
as interchangeable in the ICH regions.
General Chapter .
+ Bulk Density and Tapped Density of Powders, JP 3.01 Determination of Bulk and Tapped
Densities, and USP General Chapter Bulk Density and Tapped Density of Powders, can be used
as interchangeable in the ICH regions.
46
Q4B Annex 14: Bacterial Endotoxins Test General Chapter
+ Any of the three techniques can be used for the test Kinetic turbidimetric, Kinetic clot
- „In the event of doubt or dispute, the gel-clot limit test should be used to make the final
decision on compliance for the product being tested.
+ The USP, JP, and Ph.Eur. reference standards are considered interchangeable as they have been
suitably calibrated against the WHO (World Health Organization) International Standard for
Endotoxin.
+ In the section Photometric quantitative techniques, Preparatory testing,
- Test for interfering factors, the user should perform the test on solutions A, B, C, and D on at
least 2 replicates using the optimal conditions as recommended by the lysate manufacturer
The evaluated texts did not contain acceptance criteria, Endotoxin limits should be specified in
the application dossier unless otherwise specified in an individual monograph.
Q4B Annex 14: Bacterial Endotoxins Test General Chapter
+ Any of the three techniques can be used for the test Kinetic turbidimetric, Kinetic clot
- „In the event of doubt or dispute, the gel-clot limit test should be used to make the final
decision on compliance for the product being tested.
+ The USP, JP, and Ph.Eur. reference standards are considered interchangeable as they have been
suitably calibrated against the WHO (World Health Organization) International Standard for
Endotoxin.
+ In the section Photometric quantitative techniques, Preparatory testing,
- Test for interfering factors, the user should perform the test on solutions A, B, C, and D on at
least 2 replicates using the optimal conditions as recommended by the lysate manufacturer
The evaluated texts did not contain acceptance criteria, Endotoxin limits should be specified in
the application dossier unless otherwise specified in an individual monograph.
47
Q5A(R1)Viral Safety Evaluation Of Biotechnology Products Derived
From Cell Lines Of Human Or Animal Origin
* Testing and evaluation of the viral safety of biotechnology products derived from
characterized cell lines of human or animal origin (i.e.. mammalian, avian, insect) and outlines
data that should be submitted in the marketing application/registration package.
* The term virus excludes nonconventional transmissible agents like those associated with
Bovine Spongiform Encephalopathy (BSE) and scrapie.
Viruses that could occur Adventitious viruses that
in the Master Cell Bank could be introduced during
(MCB). Production.
Q5A(R1)Viral Safety Evaluation Of Biotechnology Products Derived
From Cell Lines Of Human Or Animal Origin
* Testing and evaluation of the viral safety of biotechnology products derived from
characterized cell lines of human or animal origin (i.e.. mammalian, avian, insect) and outlines
data that should be submitted in the marketing application/registration package.
* The term virus excludes nonconventional transmissible agents like those associated with
Bovine Spongiform Encephalopathy (BSE) and scrapie.
Viruses that could occur Adventitious viruses that
in the Master Cell Bank could be introduced during
(MCB). Production.
0B-04-
2023
+ Cell Line Qualification:
+ Testing for viruses is an important part of qualifying a cell line for use in the production of a
biotechnology product is the appropriate testing for the presence of virus.
A. Suggested Virus Tests for
1.MCB 2.Working Cell Bank 3. Cells at the Limit of in vitro Cell
Endogenous (WCB) Age Used for Production
Non-endogenous + Adventitious virus either by || * This is for pilot-plant scale or
viral contamination direct testing or by analysis of commercial-scale conditions to the
Mouse Antibody cells at the limit of in vitro proposed in vitro cell age or beyond.
Production (MAP) cell age. * For viruses undetected in MCB and
Test Antibody production tests are WCB If any adventitious viruses are
usually not necessary detected at this level, the process
should be carefully checked in order
to determine the cause of the
contamination, and completely
redesigned if necessary.
2023
+ Cell Line Qualification:
+ Testing for viruses is an important part of qualifying a cell line for use in the production of a
biotechnology product is the appropriate testing for the presence of virus.
A. Suggested Virus Tests for
1.MCB 2.Working Cell Bank 3. Cells at the Limit of in vitro Cell
Endogenous (WCB) Age Used for Production
Non-endogenous + Adventitious virus either by || * This is for pilot-plant scale or
viral contamination direct testing or by analysis of commercial-scale conditions to the
Mouse Antibody cells at the limit of in vitro proposed in vitro cell age or beyond.
Production (MAP) cell age. * For viruses undetected in MCB and
Test Antibody production tests are WCB If any adventitious viruses are
usually not necessary detected at this level, the process
should be carefully checked in order
to determine the cause of the
contamination, and completely
redesigned if necessary.
49
B. Recommended Viral Detection and Identification Assays
+ Assays should include appropriate controls to ensure adequate sensitivity and specificity,
+ Wherever a relatively high possibility of the presence of a specific virus can be predicted from
the species of origin of the cell substrate, specific tests and/or approaches may be necessary.
If the cell line used for production is of human or non-human primate origin, additional tests
for human viruses, such as those causing immunodeficiency diseases and hepatitis, should be
performed unless otherwise justified. The polymerase chain reaction (PCR) may be
appropriate for detection of sequences of these human viruses as well as for other specific
viruses,
B. Recommended Viral Detection and Identification Assays
+ Assays should include appropriate controls to ensure adequate sensitivity and specificity,
+ Wherever a relatively high possibility of the presence of a specific virus can be predicted from
the species of origin of the cell substrate, specific tests and/or approaches may be necessary.
If the cell line used for production is of human or non-human primate origin, additional tests
for human viruses, such as those causing immunodeficiency diseases and hepatitis, should be
performed unless otherwise justified. The polymerase chain reaction (PCR) may be
appropriate for detection of sequences of these human viruses as well as for other specific
viruses,
1. Tests for Retroviruses
For | and 3 :infectivity assays in sensitive
cell cultures and electron microscopy (EM)
studies,
If infectivity is not detected and no
retrovirus or retrovirus-like particles have
been observed by EM, reverse transcriptase
(RT) or other appropriate assays should be
performed to detect retroviruses which may
be noninfectious.
Induction studies have not been found to be
useful,
50
2. In vitro Assays
By the inoculation of a test article into
various susceptible indicator cell cultures
capable of detecting a wide range of
human and relevant animal viruses.
The choice of cells used in the test is
governed by the species of origin of the
cell bank to be tested, but should include
a human and/or a non-human primate cell
line susceptible to human viruses.
The nature of the assay and the sample to
be tested are governed by the type of
virus which may possibly be present
based on the origin or handling of the
cells.
Both cytopathic(Adeno viruses Jand
hemadsorbing (Influenza) viruses should
be sought.
For | and 3 :infectivity assays in sensitive
cell cultures and electron microscopy (EM)
studies,
If infectivity is not detected and no
retrovirus or retrovirus-like particles have
been observed by EM, reverse transcriptase
(RT) or other appropriate assays should be
performed to detect retroviruses which may
be noninfectious.
Induction studies have not been found to be
useful,
50
2. In vitro Assays
By the inoculation of a test article into
various susceptible indicator cell cultures
capable of detecting a wide range of
human and relevant animal viruses.
The choice of cells used in the test is
governed by the species of origin of the
cell bank to be tested, but should include
a human and/or a non-human primate cell
line susceptible to human viruses.
The nature of the assay and the sample to
be tested are governed by the type of
virus which may possibly be present
based on the origin or handling of the
cells.
Both cytopathic(Adeno viruses Jand
hemadsorbing (Influenza) viruses should
be sought.
3, In vivo Assays :
A test should be inoculated into animals,
including suckling and adult mice, and in
embryonated eggs to reveal viruses that
cannot grow in cell cultures. Additional
animal species may be used.
51
a. Antibody Production Tests:
Species-specific viruses present in rodent
cell lines may be detected by inoculating
test article into virus-free animals, and
examining the serum antibody level or
enzyme activity after a specified period.
Examples of such tests are the
® Mouse Antibody Production (MAP)
Test- Ectromelia Virus
Rat Antibody Production (RAP) Test-
Hantaan Virus
Hamster Antibody Production (HAP)
Test- Lymphocytic Choriomeningitis
Virus
A test should be inoculated into animals,
including suckling and adult mice, and in
embryonated eggs to reveal viruses that
cannot grow in cell cultures. Additional
animal species may be used.
51
a. Antibody Production Tests:
Species-specific viruses present in rodent
cell lines may be detected by inoculating
test article into virus-free animals, and
examining the serum antibody level or
enzyme activity after a specified period.
Examples of such tests are the
® Mouse Antibody Production (MAP)
Test- Ectromelia Virus
Rat Antibody Production (RAP) Test-
Hantaan Virus
Hamster Antibody Production (HAP)
Test- Lymphocytic Choriomeningitis
Virus
ol
2023 52
Testing For Viruses In Unprocessed Bulk
Unprocessed bulk means one or multiple pooled harvests of cells and culture media.
When cells are not readily accessible (e.g.. hollow fiber or similar systems), the unprocessed bulk
would constitute fluids harvested from the fermenter.
Data from at least 3 lots of unprocessed bulk at pilot-plant scale or commercial scale should be
submitted as part of the marketing application/registration package.
Tests performed during the qualification of the cell lines, the cultivation method, raw material
sources and results of viral clearance studies. In vitro screening tests, using one or several cell
lines, are generally employed to test unprocessed bulk. If appropriate, a PCR test or other
suitable methods may be used.
Rationale And Action Plan For Viral Clearance Studies And Virus Tests On Purified Bulk :
+ Case A: where no virus, virus-like particle or retrovirus-like particle has been demonstrated,
+ Case B : where only a rodent retrovirus (or a retrovirus-like particle which is believed to be non-
pathogenic, such as rodent A- and R-type particles) is present.
* Case C: when the cells or unprocessed bulk are known to contain a virus, other than a rodent
retrovirus, for which there is no evidence of capacity for infecting humans.
* Case D: where a known human pathogen, such as (or “relevant” or specific “model.
* Case E: when a virus, which cannot be classified by currently available methodologies
2023 52
Testing For Viruses In Unprocessed Bulk
Unprocessed bulk means one or multiple pooled harvests of cells and culture media.
When cells are not readily accessible (e.g.. hollow fiber or similar systems), the unprocessed bulk
would constitute fluids harvested from the fermenter.
Data from at least 3 lots of unprocessed bulk at pilot-plant scale or commercial scale should be
submitted as part of the marketing application/registration package.
Tests performed during the qualification of the cell lines, the cultivation method, raw material
sources and results of viral clearance studies. In vitro screening tests, using one or several cell
lines, are generally employed to test unprocessed bulk. If appropriate, a PCR test or other
suitable methods may be used.
Rationale And Action Plan For Viral Clearance Studies And Virus Tests On Purified Bulk :
+ Case A: where no virus, virus-like particle or retrovirus-like particle has been demonstrated,
+ Case B : where only a rodent retrovirus (or a retrovirus-like particle which is believed to be non-
pathogenic, such as rodent A- and R-type particles) is present.
* Case C: when the cells or unprocessed bulk are known to contain a virus, other than a rodent
retrovirus, for which there is no evidence of capacity for infecting humans.
* Case D: where a known human pathogen, such as (or “relevant” or specific “model.
* Case E: when a virus, which cannot be classified by currently available methodologies
08-04-2023 53
Evaluation And Characterisation Of Viral Clearance Procedures
A. The Choice of Viruses for the Evaluation and Characterisation of Viral Clearance
2. "Model" Viruses
Herpes virus (e.g., HSV-1 ora
pseudorabies virus)
1."Relevant" Viruses
Non-specific “model”:
Extremes of virus properties.
Anticipated to Specific “model”
Physically and chemically
occur in
similar to relevant virses.
system.
B. Design and Implications of Viral Clearance Evaluation and Characterisation Studies
€. Interpretation of Viral Clearance Studies Acceptability
D. Limitations of Viral Clearance Studies
E. Statistics F. Re-Evaluation of Viral Clearance
* Specific Precautions
+ Minimum Quantity
* Parallel Control Assays
Evaluation And Characterisation Of Viral Clearance Procedures
A. The Choice of Viruses for the Evaluation and Characterisation of Viral Clearance
2. "Model" Viruses
Herpes virus (e.g., HSV-1 ora
pseudorabies virus)
1."Relevant" Viruses
Non-specific “model”:
Extremes of virus properties.
Anticipated to Specific “model”
Physically and chemically
occur in
similar to relevant virses.
system.
B. Design and Implications of Viral Clearance Evaluation and Characterisation Studies
€. Interpretation of Viral Clearance Studies Acceptability
D. Limitations of Viral Clearance Studies
E. Statistics F. Re-Evaluation of Viral Clearance
* Specific Precautions
+ Minimum Quantity
* Parallel Control Assays
54
QSA{R2): Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines
of Human or Animal Origin
It is proposed to revise the QSA(R1) Guideline “Viral Safety Evaluation of Biotechnology Products
Derived from Cell Lines of Human or Animal Origin” to reflect new biotechnology product types,
advances in manufacturing technology, analytical methods for virus testing, and scientific
knowledge that have occurred since publication of the original document in 1999,
Classes Of Biotechnology
Products
Using virus-like particles
(VLPs), subunit proteins, and
viral-vectored products have
been developed for vaccines
and gene therapies.
Aspects of virus clearance
validation that have emerged
or evolved
Virus assays and alternative
analytical methods nucleic
acid-based assays such as
Polymerase Chain Reaction
(PCR) and Next Generation
Sequencing (NGS)
QSA{R2): Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines
of Human or Animal Origin
It is proposed to revise the QSA(R1) Guideline “Viral Safety Evaluation of Biotechnology Products
Derived from Cell Lines of Human or Animal Origin” to reflect new biotechnology product types,
advances in manufacturing technology, analytical methods for virus testing, and scientific
knowledge that have occurred since publication of the original document in 1999,
Classes Of Biotechnology
Products
Using virus-like particles
(VLPs), subunit proteins, and
viral-vectored products have
been developed for vaccines
and gene therapies.
Aspects of virus clearance
validation that have emerged
or evolved
Virus assays and alternative
analytical methods nucleic
acid-based assays such as
Polymerase Chain Reaction
(PCR) and Next Generation
Sequencing (NGS)
08-04-2023 55
Q5B: Quality Of Biotechnological Products: Analysis Of The Expression Construct In Cells
Used For Production Of R-DNA Derived Protein Products
This document is intended to describe the types of information that are considered valuable in assessing
the structure of the expression construct used to produce recombinant DNA derived proteins, This
document is not intended to cover the whole quality aspect of R-DNA derived medicinal products.
Q5C :Quality Of Biotechnological Products: Stability Testing Of
Biotechnological/Biological Products
* This document covers the generation and submission of stability data for products such as
cytokines (interferons, interleukins, colony-stimulating 2 factors, tumour necrosis factors),
erythropoietins, plasminogen activators, blood plasma factors, growth hormones and growth
factors, insulins, monoclonal antibodies, and vaccines consisting of well-characterised proteins or
polypeptides.
* In addition, the guidance outlined in the following sections may apply to other types of products,
such as conventional vaccines, after consultation with the appropriate regulatory authorities. The
document does not cover antibiotics, allergenic extracts, heparins, vitamins, whole blood, or
cellular blood components.
Q5B: Quality Of Biotechnological Products: Analysis Of The Expression Construct In Cells
Used For Production Of R-DNA Derived Protein Products
This document is intended to describe the types of information that are considered valuable in assessing
the structure of the expression construct used to produce recombinant DNA derived proteins, This
document is not intended to cover the whole quality aspect of R-DNA derived medicinal products.
Q5C :Quality Of Biotechnological Products: Stability Testing Of
Biotechnological/Biological Products
* This document covers the generation and submission of stability data for products such as
cytokines (interferons, interleukins, colony-stimulating 2 factors, tumour necrosis factors),
erythropoietins, plasminogen activators, blood plasma factors, growth hormones and growth
factors, insulins, monoclonal antibodies, and vaccines consisting of well-characterised proteins or
polypeptides.
* In addition, the guidance outlined in the following sections may apply to other types of products,
such as conventional vaccines, after consultation with the appropriate regulatory authorities. The
document does not cover antibiotics, allergenic extracts, heparins, vitamins, whole blood, or
cellular blood components.
Q5 D :Derivation And Characterisation Of Cell Substrates Used For Production Of
Biotechnological/Biological Products
It is important to provide supportive documentation which describes the history of the cell
substrate that is used in the manufacture of a biotechnological/biological product, as well as
any parental cell line from which it was totally or partially derived.
Events during the research and development phases of the cell substrate may contribute
significantly to assessment of the risks associated with the use of that particular cell substrate
for production.
The information supplied in this regard is meant to facilitate an overall evaluation which will
ensure the quality and safety of the product.
+ Origin, Source, And History Of Cells
- Generation Of The Cell Substrate
+ Cell Banking
+ Systems Procedure
- General Principles Of Characterisation And Testing Of Cell Bankstests Of Identity
+ Metazoan Cells
+ Microbial Cells
+ Cell Substrate
+ Stability
+ Purity
+ Tests For Karyology And Tumorigenicity
Biotechnological/Biological Products
It is important to provide supportive documentation which describes the history of the cell
substrate that is used in the manufacture of a biotechnological/biological product, as well as
any parental cell line from which it was totally or partially derived.
Events during the research and development phases of the cell substrate may contribute
significantly to assessment of the risks associated with the use of that particular cell substrate
for production.
The information supplied in this regard is meant to facilitate an overall evaluation which will
ensure the quality and safety of the product.
+ Origin, Source, And History Of Cells
- Generation Of The Cell Substrate
+ Cell Banking
+ Systems Procedure
- General Principles Of Characterisation And Testing Of Cell Bankstests Of Identity
+ Metazoan Cells
+ Microbial Cells
+ Cell Substrate
+ Stability
+ Purity
+ Tests For Karyology And Tumorigenicity
57
Q 5 E :Comparability Of Biotechnological/Biological Products Subject To
Changes In Their Manufacturing Process
* The objective of this document is to provide principles for assessing the comparability of
biotechnological/biological products before and after changes are made in the manufacturing
process for the drug substance or drug product,
Q 5 E :Comparability Of Biotechnological/Biological Products Subject To
Changes In Their Manufacturing Process
* The objective of this document is to provide principles for assessing the comparability of
biotechnological/biological products before and after changes are made in the manufacturing
process for the drug substance or drug product,
08-04-2023
58
Q6A -Specifications: Test Procedures And Acceptance Criteria For New Drug
Substances And New Drug Products: Chemical Substances
This guideline is intended to assist to the extent possible, in the establishment of a single set of global
specifications for new drug substances and new drug products.
It provides guidance on the setting and justification of acceptance criteria and the selection of test
procedures for new drug substances of synthetic chemical origin, and new drug products produced from
them, which have not been registered previously in the United States, the European Union, or
Japan.
General New Drug New Drug Products
Substances
+ Description * Physicochemical + Dissolution
* Identification properties * Disintegration
+ Assay * Particle size + Friability
* Impurities Polymorphic + Hardness
* Microbial limits forms. + Osmolality
+ Water content + Endotoxin
* Sterility
.
Redispersibility
58
Q6A -Specifications: Test Procedures And Acceptance Criteria For New Drug
Substances And New Drug Products: Chemical Substances
This guideline is intended to assist to the extent possible, in the establishment of a single set of global
specifications for new drug substances and new drug products.
It provides guidance on the setting and justification of acceptance criteria and the selection of test
procedures for new drug substances of synthetic chemical origin, and new drug products produced from
them, which have not been registered previously in the United States, the European Union, or
Japan.
General New Drug New Drug Products
Substances
+ Description * Physicochemical + Dissolution
* Identification properties * Disintegration
+ Assay * Particle size + Friability
* Impurities Polymorphic + Hardness
* Microbial limits forms. + Osmolality
+ Water content + Endotoxin
* Sterility
.
Redispersibility
59
Q6B Test Procedures And Acceptance Criteria For Biotechnological/Biological
Products
This guidance document provides general principles on the setting and justification, to the extent possible,
of a uniform set of international specifications for biotechnological and biological products to support
new marketing applications.
Principles For Consideration In Setting Specifications:
+ Characterization
* Physicochemical properties
+ Biological activity
* Immunochemical properties
+ Purity, Impurities and contaminants
* Analytical Considerations
+ Reference standards and reference materials
* Process Controls
* Process-related considerations
+ Raw materials and excipient specifications
* Justification for specifications
Q6B Test Procedures And Acceptance Criteria For Biotechnological/Biological
Products
This guidance document provides general principles on the setting and justification, to the extent possible,
of a uniform set of international specifications for biotechnological and biological products to support
new marketing applications.
Principles For Consideration In Setting Specifications:
+ Characterization
* Physicochemical properties
+ Biological activity
* Immunochemical properties
+ Purity, Impurities and contaminants
* Analytical Considerations
+ Reference standards and reference materials
* Process Controls
* Process-related considerations
+ Raw materials and excipient specifications
* Justification for specifications
60
Q7 :Good Manufacturing Practice Guide For Active Pharmaceutical
Ingredients
This Guide applies to the manufacture of APIs for use in human drug (medicinal) products.
It applies to the manufacture of sterile APIs only up to the point immediately prior to the
APIs being rendered sterile.
The sterilization and aseptic processing of sterile APIs are not covered by this guidance,
but should be performed in accordance with GMP guidelines for drug (medicinal) products
as defined by local authorities.
(a) personnel
(b) premises including personnel facilities
(e) maintenance of buildings and equipment
(d) storage of starting materials and finished products
(e) equipment
(f) production and in-process controls
(g) QC
(h) documentation
(i) sanitation and hygiene
(j) validation and revalidation programmes
(k) calibration of instruments or measurement systems
(1) recall procedures
(m) complaints management
(n) labels control
(0) results of previous self-inspections and any corrective steps taken,
Q7 :Good Manufacturing Practice Guide For Active Pharmaceutical
Ingredients
This Guide applies to the manufacture of APIs for use in human drug (medicinal) products.
It applies to the manufacture of sterile APIs only up to the point immediately prior to the
APIs being rendered sterile.
The sterilization and aseptic processing of sterile APIs are not covered by this guidance,
but should be performed in accordance with GMP guidelines for drug (medicinal) products
as defined by local authorities.
(a) personnel
(b) premises including personnel facilities
(e) maintenance of buildings and equipment
(d) storage of starting materials and finished products
(e) equipment
(f) production and in-process controls
(g) QC
(h) documentation
(i) sanitation and hygiene
(j) validation and revalidation programmes
(k) calibration of instruments or measurement systems
(1) recall procedures
(m) complaints management
(n) labels control
(0) results of previous self-inspections and any corrective steps taken,
42023
Q8(R2) Pharmaceutical Development :
This guideline describes the suggested contents for the (Pharmaceutical Development) section of a
regulatory submission in the ICH M4 Common Technical Document (CTD) formatprovides an
opportunity to present the knowledge gained through the application of scientific approaches and
quality risk management to the development of a product and its manufacturing process.
It is first produced for the original marketing application and can be updated to support new
knowledge gained over the lifecycle* of a product.
intended to provide a comprehensive understanding of the product and manufacturing process for
reviewers and inspectors.
The guideline also indicates areas where the demonstration of greater understanding of
pharmaceutical and manufacturing sciences can create a basis for flexible regulatory approaches.
The degree of regulatory flexibility is predicated on the level of relevant scientific knowledge
provided.
Q8(R2) Pharmaceutical Development :
This guideline describes the suggested contents for the (Pharmaceutical Development) section of a
regulatory submission in the ICH M4 Common Technical Document (CTD) formatprovides an
opportunity to present the knowledge gained through the application of scientific approaches and
quality risk management to the development of a product and its manufacturing process.
It is first produced for the original marketing application and can be updated to support new
knowledge gained over the lifecycle* of a product.
intended to provide a comprehensive understanding of the product and manufacturing process for
reviewers and inspectors.
The guideline also indicates areas where the demonstration of greater understanding of
pharmaceutical and manufacturing sciences can create a basis for flexible regulatory approaches.
The degree of regulatory flexibility is predicated on the level of relevant scientific knowledge
provided.
08-04-2023 62
Part | Pharmaceutical Development Part 2: Annex
Formulation Development: A summary * Approaches To Pharmaceutical
should be provided describing the Development
development of the formulation, including * Elements Of Pharmaceutical Development
identification of those attributes that are - Quality target product profile
critical to the quality of the drug product, - Critical quality attributes
taking into consideration intended usage -Risk assessment: linking material
and route of administration, Information attributes and process parameters to drug
from formal experimental designs can be product eqas
useful in identifying critical or interacting - Design space
variables that might be important to * Submission Of Pharmaceutical
ensure the quality of the drug product. Development And Related Information In
Components of the Drug Product : Common Technical Documents (CTD)
= Drug Substance Format
+ Excipients
* Drug substances
Part | Pharmaceutical Development Part 2: Annex
Formulation Development: A summary * Approaches To Pharmaceutical
should be provided describing the Development
development of the formulation, including * Elements Of Pharmaceutical Development
identification of those attributes that are - Quality target product profile
critical to the quality of the drug product, - Critical quality attributes
taking into consideration intended usage -Risk assessment: linking material
and route of administration, Information attributes and process parameters to drug
from formal experimental designs can be product eqas
useful in identifying critical or interacting - Design space
variables that might be important to * Submission Of Pharmaceutical
ensure the quality of the drug product. Development And Related Information In
Components of the Drug Product : Common Technical Documents (CTD)
= Drug Substance Format
+ Excipients
* Drug substances
63
ICH Implementation Working Group (IWG) on ICH Q8, Q9 and
Q10
Technical issues & related documentation:
common understanding of terminology;
address inter-relationship between Q8, Q9 and Q10; applicability to both review and
inspection;
final status after partial implementation is established (e.g. level of details in the dossier);
Additional implementation issues: influence on existing [CH guidelines;
Communication and training; ¢.g. Q&A, briefing packs from ICH; external collaborations;
workshops.
ICH Implementation Working Group (IWG) on ICH Q8, Q9 and
Q10
Technical issues & related documentation:
common understanding of terminology;
address inter-relationship between Q8, Q9 and Q10; applicability to both review and
inspection;
final status after partial implementation is established (e.g. level of details in the dossier);
Additional implementation issues: influence on existing [CH guidelines;
Communication and training; ¢.g. Q&A, briefing packs from ICH; external collaborations;
workshops.
08-04-2023 64
Q9 Quality Risk Management
+ Risk is defined as the combination of the probability of occurrence of harm and the severity of that
harm.
* In relation to pharmaceuticals, although there are a variety of stakeholders, including patients and
medical practitioners as well as government and industry, the protection of the patient by managing
the risk to quality should be considered of prime importance.
* The purpose of this document is to offer a systematic approach to quality risk management.
* Itserves as a foundation or resource document that is independent of, yet supports, other ICH Quality
documents and complements existing quality practices, requirements, standards, and guidelines
within the pharmaceutical industry and regulatory environment, It specifically provides guidance on
the principles and some of the tools of quality risk management that can enable more effective and
consistent risk based decisions, both by regulators and industry, regarding the quality of drug
substances and drug (medicinal) products across the product lifecycle.
Q9 Quality Risk Management
+ Risk is defined as the combination of the probability of occurrence of harm and the severity of that
harm.
* In relation to pharmaceuticals, although there are a variety of stakeholders, including patients and
medical practitioners as well as government and industry, the protection of the patient by managing
the risk to quality should be considered of prime importance.
* The purpose of this document is to offer a systematic approach to quality risk management.
* Itserves as a foundation or resource document that is independent of, yet supports, other ICH Quality
documents and complements existing quality practices, requirements, standards, and guidelines
within the pharmaceutical industry and regulatory environment, It specifically provides guidance on
the principles and some of the tools of quality risk management that can enable more effective and
consistent risk based decisions, both by regulators and industry, regarding the quality of drug
substances and drug (medicinal) products across the product lifecycle.
08-04-2023 65
Principles Of Quality Risk Management
Two primary principles of quality risk management are:
“The evaluation of the risk to quality should be based on scientific knowledge and ultimately
link to the protection of the patient; and
* The level of effort, formality and documentation of the quality risk management process should
be commensurate with the level of risk.
Annex | :Risk Management methods and Annex 2: Potential Applications for Quality
tools: Risk Management-
Facilitation Methods * Quality risk management as part of
Failure Mode Effects Analysis(FMEA) Integrated quality management
Failure Mode, Effects And Criticality Regulatory operations
Analysis(FMECA) Part of development
Fault Tree Analysis(FTA) Facilities,equipments,utilities
Hazard Analysis And Critical Control Material management
Points( HACCP) Production
Hazard Operability Analysis(HOA) Laboratory control
Preliminary Hazard Analysis(PHA) Stability studies
Packaging and labelling
Principles Of Quality Risk Management
Two primary principles of quality risk management are:
“The evaluation of the risk to quality should be based on scientific knowledge and ultimately
link to the protection of the patient; and
* The level of effort, formality and documentation of the quality risk management process should
be commensurate with the level of risk.
Annex | :Risk Management methods and Annex 2: Potential Applications for Quality
tools: Risk Management-
Facilitation Methods * Quality risk management as part of
Failure Mode Effects Analysis(FMEA) Integrated quality management
Failure Mode, Effects And Criticality Regulatory operations
Analysis(FMECA) Part of development
Fault Tree Analysis(FTA) Facilities,equipments,utilities
Hazard Analysis And Critical Control Material management
Points( HACCP) Production
Hazard Operability Analysis(HOA) Laboratory control
Preliminary Hazard Analysis(PHA) Stability studies
Packaging and labelling
Flow chart of Risk
Management
Management
Q9(R1) - Quality Risk Management
* Limited and specific adjustments would be made to specific chapters and annexes of the
current ICH Q9 Guideline on Quality Risk Management (QRM). The adjustments would
address four areas for improvement.
High levels of subjectivity in risk assessments and in QRM outputs —
Product availability risks
Lack of clarity on risk-based decision-making
Lack of understanding as to what constitutes formality in QRM work
Specific official ICH training materials (with examples)would be developed to supplement
the existing ICH briefing pack on ICH Q9 as well as to explain and facilitate the
implementation and application of the proposed revisions.
* Harmonized training material and its comprehensive roll out is a key component of this
revision.
* Limited and specific adjustments would be made to specific chapters and annexes of the
current ICH Q9 Guideline on Quality Risk Management (QRM). The adjustments would
address four areas for improvement.
High levels of subjectivity in risk assessments and in QRM outputs —
Product availability risks
Lack of clarity on risk-based decision-making
Lack of understanding as to what constitutes formality in QRM work
Specific official ICH training materials (with examples)would be developed to supplement
the existing ICH briefing pack on ICH Q9 as well as to explain and facilitate the
implementation and application of the proposed revisions.
* Harmonized training material and its comprehensive roll out is a key component of this
revision.
68
Q10 -Pharmaceutical Quality System
ICH Q10 describes one comprehensive model for an effective pharmaceutical quality system
that is based on International Standards Organisation (ISO) quality concepts, includes
applicable Good Manufacturing Practice (GMP) regulations and complements ICH Q8
“Pharmaceutical Development” and ICH Q9 “Quality Risk Management”.
ICH Q10 is a model for a pharmaceutical quality system that can be implemented throughout
the different stages of a product lifecycle. Much of the content of ICH Q10 applicable to
manufacturing sites is currently specified by regional GMP requirements. ICH Q10 is not
intended to create any new expectations beyond current regulatory requirements.
Consequently, the content of ICH Q10 that is additional to current regional GMP
requirements is optional.
Corrective action and preventive action (CAPA) system
Q10 -Pharmaceutical Quality System
ICH Q10 describes one comprehensive model for an effective pharmaceutical quality system
that is based on International Standards Organisation (ISO) quality concepts, includes
applicable Good Manufacturing Practice (GMP) regulations and complements ICH Q8
“Pharmaceutical Development” and ICH Q9 “Quality Risk Management”.
ICH Q10 is a model for a pharmaceutical quality system that can be implemented throughout
the different stages of a product lifecycle. Much of the content of ICH Q10 applicable to
manufacturing sites is currently specified by regional GMP requirements. ICH Q10 is not
intended to create any new expectations beyond current regulatory requirements.
Consequently, the content of ICH Q10 that is additional to current regional GMP
requirements is optional.
Corrective action and preventive action (CAPA) system
Annex I:
69
Scenario Potential Opportunity
4. Comply with GMPs Compliance - status quo
E. Demonstrate effective Opportunity to:
pharmaceutical quality system, including
effective use of quality risk management
principles (e.g., ICH Q9 and ICH Q10).
3. Demonstrate product and process
understanding, including effective use of
quality risk management principles (e.g.,
ICH Q8 and ICH Q9).
4. Demonstrate effective
pharmaceutical quality system and product
and process understanding, including the
use of quality risk management principles
(e.9., ICH Q8, ICH Q9 and ICH Q10).
increase use of risk based approaches for
regulatory inspections.
Opportunity to:
facilitate science based pharmaceutical
quality assessment;
enable innovative approaches to process
validation;
establish real-time release mechanisms.
Opportunity to:
increase use of risk based approaches for
regulatory inspections;
facilitate science based pharmaceutical
quality assessment;
optimise science and risk based post-
approval change processes to maximise
benefits from innovation and continual
improvement;
enable innovative approaches to process
validation;
establish real-time release mechanisms.
69
Scenario Potential Opportunity
4. Comply with GMPs Compliance - status quo
E. Demonstrate effective Opportunity to:
pharmaceutical quality system, including
effective use of quality risk management
principles (e.g., ICH Q9 and ICH Q10).
3. Demonstrate product and process
understanding, including effective use of
quality risk management principles (e.g.,
ICH Q8 and ICH Q9).
4. Demonstrate effective
pharmaceutical quality system and product
and process understanding, including the
use of quality risk management principles
(e.9., ICH Q8, ICH Q9 and ICH Q10).
increase use of risk based approaches for
regulatory inspections.
Opportunity to:
facilitate science based pharmaceutical
quality assessment;
enable innovative approaches to process
validation;
establish real-time release mechanisms.
Opportunity to:
increase use of risk based approaches for
regulatory inspections;
facilitate science based pharmaceutical
quality assessment;
optimise science and risk based post-
approval change processes to maximise
benefits from innovation and continual
improvement;
enable innovative approaches to process
validation;
establish real-time release mechanisms.
08-04-2023 70
Annex 2 :
‚ICH Q10 Pharmaceutical Quality System
Management Responsibilities
Process Performance & Product Quality Monitoring System
PQS Corrective Action / Preventive Action (CAPA) System
elements ‘Change Management System
Management Review
Knowledge Management
Quality Risk Management
Annex 2 :
‚ICH Q10 Pharmaceutical Quality System
Management Responsibilities
Process Performance & Product Quality Monitoring System
PQS Corrective Action / Preventive Action (CAPA) System
elements ‘Change Management System
Management Review
Knowledge Management
Quality Risk Management
08-04-2023 71
Q11- Development And Manufacture Of Drug Substances (Chemical
Entities And Biotechnological/Biological Entities)
This guideline describes approaches to developing and understanding the manufacturing process of the
drug substance, and also provides guidance on what information should be provided in Module 3 of
the Common Technical Document (CTD) Sections 3.2.8.2.2 - 3.2.8.2.6 (ICH M4Q).
It addresses aspects of development and manufacture that pertain to drug substance, including the
presence of steps designed to reduce impurities. In addition, ICH Q11 provides further clarification on
the principles and concepts described in ICH Guidelines on Pharmaceutical Development (Q8),
‘Quality Risk Management (Q9) and Pharmaceutical Quality System (Q10) as they pertain to the
development and manufacture of drug substance.
Q11- Development And Manufacture Of Drug Substances (Chemical
Entities And Biotechnological/Biological Entities)
This guideline describes approaches to developing and understanding the manufacturing process of the
drug substance, and also provides guidance on what information should be provided in Module 3 of
the Common Technical Document (CTD) Sections 3.2.8.2.2 - 3.2.8.2.6 (ICH M4Q).
It addresses aspects of development and manufacture that pertain to drug substance, including the
presence of steps designed to reduce impurities. In addition, ICH Q11 provides further clarification on
the principles and concepts described in ICH Guidelines on Pharmaceutical Development (Q8),
‘Quality Risk Management (Q9) and Pharmaceutical Quality System (Q10) as they pertain to the
development and manufacture of drug substance.
08-04-2023 72
Q12- Technical And Regulatory Considerations For
Pharmaceutical Product Lifecycle Management
+ This guideline provides a framework to facilitate the management of post-approval CMC
changes in a more predictable and efficient manner. A harmonised approach regarding technical
and regulatory considerations for lifecycle management will benefit patients, industry, and
regulatory authorities by promoting innovation and continual improvement in the
pharmaceutical sector, strengthening quality assurance and improving supply of medicinal
products
Q12- Technical And Regulatory Considerations For
Pharmaceutical Product Lifecycle Management
+ This guideline provides a framework to facilitate the management of post-approval CMC
changes in a more predictable and efficient manner. A harmonised approach regarding technical
and regulatory considerations for lifecycle management will benefit patients, industry, and
regulatory authorities by promoting innovation and continual improvement in the
pharmaceutical sector, strengthening quality assurance and improving supply of medicinal
products
73
Q12: Regulatory and Technical Considerations for Pharmaceutical
Product Lifecycle Management Endorsed by the Management
Committee (30 March 2020)
+ Establishment of an Implementation Working Group (WG) to prepare a comprehensive
training programme and associated materials to facilitate an aligned interpretation and a
harmonized implementation of ICH Q12 in ICH and non-ICH regions, Statement of the
Perceived Problem: ICH Q12 Regulatory and Technical Considerations for
Q12: Regulatory and Technical Considerations for Pharmaceutical
Product Lifecycle Management Endorsed by the Management
Committee (30 March 2020)
+ Establishment of an Implementation Working Group (WG) to prepare a comprehensive
training programme and associated materials to facilitate an aligned interpretation and a
harmonized implementation of ICH Q12 in ICH and non-ICH regions, Statement of the
Perceived Problem: ICH Q12 Regulatory and Technical Considerations for
T4
Q13: Continuous Manufacturing for Drug Substances and Drug
Products
» The proposed guideline will harmonise regulatory expectations for drug substance and drug
product production using continuous manufacturing, which will increase the likelihood of its
implementation by industry internationally. This will result in the following likely benefits: -
Enable the development of new methods for production of new molecules to address therapeutic
needs
~ Increased manufacturing options available to address public health needs
- Improved access of medicines to patients
- Development of new approaches for the control of drug manufacturing to enhance assurance of
quality
- Increase operator safety (process safety risk reductions) for manufacturing
- Reduce resource consumption (for example, materials) and waste generation by shrinking
equipment and facility footprints - Improve the robustness, efficiency, and capability of
manufacturing processes
Q13: Continuous Manufacturing for Drug Substances and Drug
Products
» The proposed guideline will harmonise regulatory expectations for drug substance and drug
product production using continuous manufacturing, which will increase the likelihood of its
implementation by industry internationally. This will result in the following likely benefits: -
Enable the development of new methods for production of new molecules to address therapeutic
needs
~ Increased manufacturing options available to address public health needs
- Improved access of medicines to patients
- Development of new approaches for the control of drug manufacturing to enhance assurance of
quality
- Increase operator safety (process safety risk reductions) for manufacturing
- Reduce resource consumption (for example, materials) and waste generation by shrinking
equipment and facility footprints - Improve the robustness, efficiency, and capability of
manufacturing processes
08-04-2023 75
Q14: Analytical Procedure Development and Revision of
Q2(R1) Analytical Validation
+ The new guideline is proposed for harmonising the scientific approaches of Analytical
Procedure Development, and providing the principles relating to the description of Analytical
Procedure Development process. Applying this guideline will improve regulatory
communication between industry and regulators and facilitate more efficient, sound scientific
and risk-based approval as well as post-approval change management of analytical procedureln
addition to the current guideline, the revised guideline will define the common validation
characteristics for procedures, like NIR, nuclear magnetic resonance spectroscopy (NMR), and
hyphenated techniques, for example CE-MS, CE-ICP-MS, LC-NMR, GC-MS, LC-MS.
Although these techniques utilize very different instrumentation, the data output is an intensity
across a frequency range or mass to charge ratio range.
Q14: Analytical Procedure Development and Revision of
Q2(R1) Analytical Validation
+ The new guideline is proposed for harmonising the scientific approaches of Analytical
Procedure Development, and providing the principles relating to the description of Analytical
Procedure Development process. Applying this guideline will improve regulatory
communication between industry and regulators and facilitate more efficient, sound scientific
and risk-based approval as well as post-approval change management of analytical procedureln
addition to the current guideline, the revised guideline will define the common validation
characteristics for procedures, like NIR, nuclear magnetic resonance spectroscopy (NMR), and
hyphenated techniques, for example CE-MS, CE-ICP-MS, LC-NMR, GC-MS, LC-MS.
Although these techniques utilize very different instrumentation, the data output is an intensity
across a frequency range or mass to charge ratio range.
76
Conclusion :
Harmonisation achievements in the Quality area include pivotal milestones such as
the conduct of stability studies, defining relevant thresholds for impurities testing
and a more flexible approach to pharmaceutical quality based on Good
Manufacturing Practice (GMP) risk management.
Reference :
https://www.ich.org/page/quality-guidelines,
Conclusion :
Harmonisation achievements in the Quality area include pivotal milestones such as
the conduct of stability studies, defining relevant thresholds for impurities testing
and a more flexible approach to pharmaceutical quality based on Good
Manufacturing Practice (GMP) risk management.
Reference :
https://www.ich.org/page/quality-guidelines,
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