1. ich jntu pharmacy

1
ICH Quality Guidance for Regulatory Requirements for
Preformulation Study
BY
Dr. Suman Pattanayak
Associate Professor
Department of Pharma Analysis & QA.
Vijaya Institute of Pharmaceutical Sciences for Women
B. Pharm IV year/ II Sem
DRA, IPR & Patents

ICH Topics
• Stability - Q1A – Q1F
• Analytical Validation – Q2
• Impurities – Q3A - Q3C (Q3D – concept paper)
• Pharmacopoeias – Q4A - Q4B (and annexes)
• Quality of Biotechnological Products – Q5A – Q5E
• Specifications – Q6A – Q6B
• Good Manufacturing Practice – Q7
• Pharmaceutical Development – Q8
• Quality Risk Management - Q9
• Pharmaceutical Quality System – Q10
• Development and Manufacturing of Drug Substances – Q11
January 18-21, 2012

Focus
• Stability - Q1A, B, C, D, E & F
• Validation of Analytical Methods – Q2(R1)
• Impurities – Q3A, B & C
• Specifications – Q6A (Chemical Substances) &
Q6B (Biotechnology/Biological Products)
January 18-21, 2012

Stability
• Q1A(R2) Stability Testing of New Drug Substances and
Products
• Q1B Photostability Testing of New Drug Substances and
Products
• Q1C Stability Testing for New Dosage Forms
• Q1D Bracketing and Matrixing Designs for Stability Testing
of New Drug Substances and Products
• Q1E Evaluation of Stability Data
• Q1F Stability Data Package for Registration Applications in
Climatic Zones III & IV (withdrawn – June 2006)
January 18-21, 2012

Q1A(R2)
STABILITY TESTING OF
NEW DRUG SUBSTANCES AND PRODUCTS
Drug ProductDrug Substance
Photostability testingStress testing
Selection of batchesSelection of batches
Container closure systemContainer closure system
SpecificationSpecification
Testing frequencyTesting frequency
Storage conditionsStorage conditions
Stability commitmentStability commitment
EvaluationEvaluation
Statements/LabelingStatements/Labeling
January 18-21, 2012

Stress Testing/Photostability
One primary batch
As in ICH Q1B:
One primary batch
Effect of temperatures (in 10°C
increments (e.g., 50°C, 60°C,
etc.) above that for accelerated
testing)
Effect of humidity (e.g., >
75%RH)
January 18-21, 2012

Selection of Batches
Data on at least three primary batches of
the drug product – two pilot and third one
can be smaller - same formulation and
packaged in the same container closure
system as proposed for marketing.
The manufacturing process used for
primary batches should simulate that to be
applied to production batches
Where possible, use different batches of
the drug substance.
Should be performed on each individual
strength and container size of the drug
product unless bracketing or matrixing is
applied.
Data on at least three primary batches of
minimum pilot scale manufactured by the
same synthetic route as used for
production batches.
January 18-21, 2012

Container Closure System
Studies to be carried out in
container closure system
identical to commercial
packaging; studies carried out
in other packaging materials
can be used as supporting
information
Studies to be conducted on the
API packaged in a container
closure system that is identical
to or simulates the proposed
commercial packaging
January 18-21, 2012

Specification
Drug Substance Drug Product
Studies to include attributes
susceptible to change during
storage and which can influence
quality, safety and efficacy:
- Physical
- Chemical
- Microbiological
Studies to include attributes
susceptible to change during
storage and which can influence
quality, safety and efficacy:
- Physical
- chemical,
- microbiological,
- preservative content
- functionality tests (e.g. with
delivery systems)
Validated analytical methods to be
employed
Validated analytical methods to be
employed
June 2010January 18-21, 2012

Testing Frequency
For API with proposed re-test period/shelf-
life of at least 12 months: Every 3 months
over first year, every 6 months over next 12
months and annually thereafter.
For FPP with proposed re-test period/shelf-
life of at least 12 months: Every 3 months
over first year, every 6 months over next 12
months and annually thereafter.
Accelerated condition: Minimum of 3 time
points, including initial and final time points
(e.g. 0, 3 & 6 months)
Accelerated condition: Minimum of 3 time
points, including initial and final time points
(e.g. 0, 3 & 6 months)
Intermediate condition (due to significant
change under accelerated condition): study
design should include 4 time points (e.g. 0, 6,
9 and 12 months
Intermediate condition (due to significant
change under accelerated condition): study
design should include 4 time points (e.g. 0, 6,
9 and 12 months)
Matrixing or Bracketing may be applied
June 2010January 18-21, 2012

Storage Conditions
• General Case
Drug
Substance
Drug Product
Study Storage
Conditions
Minimum
period
covered by
data at
submission
Study Storage
Conditions
Minimum
period
covered by
data at
submission
Long term 25⁰C+2⁰C/
60%+5%RH
or
30⁰C+2⁰C /65%
+5%RH
12 months Long term 25⁰C+2⁰C
/60%+5%RH
or
30⁰C+2⁰C /65%
+5%RH
12 months
Intermediat
e
30⁰C+2⁰C /65%
+5%RH
6 months Intermediat
e
30⁰C+2⁰C /65%
+5%RH
6 months
Accelerated 40⁰C+2⁰C /75%
+5%RH
6 months Accelerated 40⁰C+2⁰C /75%
+5%RH
6 months
June 2010January 18-21, 2012

Storage Conditions
• Storage in refrigerator
Study Storage
Conditions
Minimum
period
covered by
data at
submission
Study Storage
Conditions
Minimum
period
covered by
data at
submission
Long term 5⁰C + 3⁰C 12months Long term 5⁰C + 3⁰C 12months
Accelerate
d
25⁰C + 2⁰C /
60% + 5% RH
6 months Accelerate
d
25⁰C + 2⁰C /
60% + 5% RH
6 months
June 2010January 18-21, 2012

Storage Conditions
• Storage in freezer
• Storage below - 20⁰C : Case by case basis
Study Storage
Conditions
Minimum
period covered
by data at
submission
Study Storage
Conditions
Minimum
period
covered by
data at
submission
Long
term
- 20⁰C + 5⁰C 12months Long
term
- 20⁰C + 5⁰C 12months
June 2010January 18-21, 2012

Storage Conditions – Drug Product
• Semi-permeable containers :
Study Storage Conditions Minimum period
covered by data at
submission
Long term 25⁰C+2⁰C/40%+5% RH or
30⁰C+2⁰C/35%+5% RH
12 months
Intermediate 30⁰C+2⁰C/65%+5% RH 6 months
Accelerated 40⁰C+2⁰C/NMT 25% RH 6 months
June 2010January 18-21, 2012

Significant Change
->5% change in assay from the
initial results
-Any degradation product
exceeding its acceptance criterion
-Failure to meet acceptance criteria
for appearance, physical attributes
and functionality tests
for pH
for dissolution of 12 dosage units
Defined as failure to meet
specifications
January 18-21, 2012

Evaluation
Statistical analysis not necessary if
data exhibits little or no
degradation and variability
Statistical analysis not necessary if
data exhibits little or no
degradation and variability
Limited extrapolation of real time
data permitted with justification
Limited extrapolation of real time
data permitted with justification
June 2010January 18-21, 2012

Q1B
PHOTOSTABILITY TESTING OF
NEW DRUG SUBSTANCES AND PRODUCTS
• Provides 2 options for sources of light:
– artificial daylight fluorescent lamp combining visible and ultraviolet (UV)
outputs, xenon, or metal halide lamp
– sample should be exposed to both the cool white fluorescent and near
ultraviolet lamp
• Test on API first – if not photosensitive then no further testing is
required
• If API is photosensitive then testing to be continued on (as
appropriate):
– Tests on the exposed drug product outside of the immediate pack
– Tests on the drug product in the immediate pack
– Tests on the drug product in the marketing pack
• Where appropriate, impact of light during manufacturing
January 18-21, 2012

Q1C
Annex to Q1A (R2)
• Additional guidance on line extensions
• Reduced requirements at time of filing: 6
months accelerated and 6 months long term
January 18-21, 2012

Q1D - Bracketing
January 18-21, 2012

Q1D - Matrixing
January 18-21, 2012

Q1E
EVALUATION OF STABILITY DATA
• Provides recommendations for: (at RT, Refrigerated and
Freezer storages)
– treating stability data
– Extending re-test period or shelf-life beyond period
covered by long-term data
– Statistical approaches to analysis of stability data
• Progression:
– Start with data under accelerated condition
– Then assess data under intermediate condition, if
appropriate
– Finally evaluate trends and variability of the long-term
data
January 18-21, 2012

Outcomes
When there is no significant change under accelerated conditions (RT)
Retest period or shelf life can be up to
twice, but NMT 12 months beyond the
period covered by long-term data
Long-term and accelerated data
showing little or no change over time
and little or no variability
Data not amenable to statistical
analysis, but relevant supporting data
provided: Retest period or shelf life can
be up to 1.5 times, but NMT 6 months
beyond the period covered by long-
term data
If a statistical analysis is performed:
Retest period or shelf life of up to twice,
but not more than 12 months beyond
the period covered by long-term data
Long-term or accelerated data showing
change over time and/or variability
January 18-21, 2012

Outcomes
When there is significant change under accelerated conditions (RT)
but no significant change at intermediate condition:
Data not amenable to statistical analysis:
Retest period or shelf life can be up to 3 months beyond the period covered by
long-term data if backed by relevant documentation
If statistical analysis is performed:
Retest period or shelf life can be up to 1.5 times, but NMT 6 months beyond the
period covered by long-term data when backed by statistical analysis and
relevant supporting data
January 18-21, 2012

Q2(R1)
VALIDATION OF ANALYTICAL PROCEDURES
• Defines validation characteristics:
– Accuracy
– Precision
• Repeatability
• Intermediate Precision
– Specificity
– Detection Limit
– Quantitation Limit
– Linearity
– Range
• Robustness to be considered at appropriate stage of development of the
analytical method
• System suitability test parameters to be established for a particular procedure
depending on the type of procedure being validated - Pharmacopoeias to be
consulted for additional information
January 18-21, 2012

VALIDATION CHARACTERISTICS
AssayImpurities
Quant. limit
IDValidation
characteristics
+
+
+
+
-
-
+
+
+ -
+ -
+ -
+ +
- +
+ -
+ -
+ -
-
-
-
+
-
-
-
-
Accuracy
Precision
Repeatibility
Int.Precision
Specificity
LOD
LOQ
Linearity
Range
January 18-21, 2012

Q3
Impurities
• Impurities in New Drug Substances Q3A(R2): Defines thresholds for
reporting, identification and qualification of impurities in DS
• Impurities in New Drug Products Q3B(R2): Defines thresholds for
reporting, identification and qualification of impurities in DP
• Guideline for Residual Solvents Q3C (R5): Classifies residual solvents by
risk assessment:
– Class 1 solvents: solvents to be avoided
– Class 2 solvents: solvents to be limited
– Class 3 solvents: solvents with low toxic potential
• Guideline for Metal Impurities Q3D (Concept paper – July 2009)
January 18-21, 2012

Q3A(R2)
CLASSIFICATION OF IMPURITIES
• Organic Impurities
– Starting materials
– By-products
– Intermediates
– Degradation products
– Reagents, ligands, catalysts
• Inorganic Impurities
– Reagents, ligands, catalysts
– Heavy metals or other residual metals
– Inorganic salts
– Other materials (e.g., filter aids, charcoal)
• Residual Solvents
January 18-21, 2012

Q3A(R2)
Definitions
• Qualification: The process of acquiring and evaluating data that establishes the
biological safety of an individual impurity or a given impurity profile at the
level(s) specified.
• Reporting Threshold: A limit above (>) which an impurity should be reported.
• Specified Impurity: An impurity that is individually listed and limited with a
specific acceptance criterion in the new drug substance specification. A specified
impurity can be either identified or unidentified.
• Unidentified Impurity: An impurity for which a structural characterisation has not
been achieved and that is defined solely by qualitative analytical properties (e.g.,
chromatographic retention time)
• Unspecified impurity: An impurity that is limited by a general acceptance
criterion, but not individually listed with its own specific acceptance criterion, in
the new drug substance specification
January 18-21, 2012

Q3C(R5)
• Provides 2 options for describing limits of Class 2 Solvents
• Option 1: As per the table provided - calculated using TDI of 10 g and
the calculation -
– Concentration (ppm) = 1000 x Permitted Daily Exposure (PDE)/ Dose
– PDE is given in terms of mg/day and dose is given in g/day.
• If TDI is more than 10 g use option 2
Concentration
limit (ppm)
PDE (mg/day)Solvent
410
360
4.1
3.6
Acetonitrile
Chlorobenzene
January 18-21, 2012

Example for Option 2
• Option 2: It is not considered necessary for each component of the drug product to comply
with the limits given in Option 1. The PDE in terms of mg/day can be used with the known
maximum daily dose and equation (Concentration (ppm) = 1000 x PDE/ Dose) to determine
the concentration of residual solvent allowed in drug product
Example: PDE of acetonitrile is 4.1mg/day
Component Amount in formulation Acetonitrile content Daily exposure
Drug substance 0.3 g 800 ppm 0.24 mg
Excipient 1 0.9 g 400 ppm 0.36 mg
Excipient 2 3.8 g 800 ppm 3.04 mg
Drug Product 5.0 g 728 ppm 3.64 mg
• The sum of the amounts of solvent per day should be less than that given by the PDE.
January 18-21, 2012

Q6A
• Addresses aspects such as:
– Periodic or skip testing
– Release vs shelf-life criteria
– In-process tests
– Design and development considerations
– Limited data available at filing
– Parametric release
– Alternative procedures
– Pharmacopoeial tests and acceptance criteria
– Evolving technologies
– Impact of drug substance on drug product specifications
– Reference standard
January 18-21, 2012

Q6A
Decision Trees
• #1 – Establishing acceptance criteria for specified impurity In DS
• #2 – Establishing acceptance criteria for degradation product in DP
• #3 – Establishing acceptance criteria for PSD in DS
• #4 – Investigating need to set acceptance criteria for polymorphism in DS
and DP
• #5 – Establishing ID, Assay and enantiomeric impurity procedures for chiral
DS and chiral DS in DP
• #6 – Microbiological Quality Attributes of DS and Excipients
• #7 – Setting acceptance criteria for DP dissolution
• #8 – Microbiological Quality Attributes of non sterile DP
January 18-21, 2012

Periodic or Skip Testing
• Should be justified.
• May be applied to certain tests only (e.g.
residual solvents and microbiological test for
solid oral products)
• Recommend that it should be applied post
approval
• Batch to batch retesting to be restored in the
event of failure
January 18-21, 2012

Design and Development
Considerations
• It may be possible to propose excluding or
replacing certain tests based on experience and
data accumulated:
– microbiological testing for drug substances and solid
dosage forms which have been shown during
development not to support microbial viability or
growth (Decision Trees #6 and #8)
– extractables from product containers where it has
been reproducibly shown that either no extractables
are found in the drug product or the levels meet
accepted standards for safety
January 18-21 2012January 18-21, 2012

Design and Development
Considerations
– particle size testing may be performed as an in-
process test, or may be performed as a release test,
depending on its relevance to product performance
– dissolution testing for immediate release solid oral
drug products made from highly water soluble drug
substances may be replaced by disintegration
testing, if these products have been demonstrated
during development to have consistently rapid drug
release characteristics (Decision Tree #7) (only
accepted in exceptional circumstances and all
conditions must be met including substantial
development data)
January 18-21, 2012

Impurities
• Impurities are unwanted chemicals present in
the API or FPP arising from normal
manufacture.
• They are not chemicals accidently or
maliciously introduced.
• Impurities have no therapeutic value and are
potentially harmful. Therefore they need to
be controlled.

Impurities (2)
Question:
If a manufacturer controls impurity content in
accordance with a pharmacopoeial monograph
can we accept the specifications?

Impurity (3)
Question:
If a manufacturer controls impurity content in accordance with a
pharmacopoeial monograph can we accept the specifications?
Unfortunately no, monographs are developed based upon how
the API was prepared historically.
A particular manufacturer's manufacturing method may lead to
unexpected impurities, due to a different route of synthesis,
different reagents, etc.

Overview
Setting an impurity limit
1. What are the potential impurities?
2. What impurities actually occur?
3. When to specify impurities.
4. Setting limits for impurities.

What are the potential impurities?

• The first step in setting impurity specifications
is to consider what potential impurities might
be present, based upon all available
information.
• This step is often poorly performed by
applicants.
• There is a tendency to skip this step in
discussions and just adopt pharmacopoeial
specifications if a monograph exists.

API SM
Reaction
intermediate
Final API
FPP
Potential Impurities
What are the potential impurities? (2)

API SM
Reaction
intermediate
Final API
FPP
Residue of the API SM
Residue of the intermediate

API SM
Reaction
intermediate
Final API
FPP
SM
impurities
Residue of the SM
Impurities in the SM

API SM
Reaction
intermediate
Final API
FPP
Reagents
Solvents
Catalysts
Solvents
SM
impurities
Residue of the SM
Reagents
Solvents
Catalysts
Reagents
Solvents
Catalysts

API SM
Reaction
intermediate
Final API
FPP
Reagents
Solvents
Catalysts
Solvents
By-products
By-products
SM
impurities
Residue of the SM
Reagents
Solvents
Catalysts
Reaction by-products
Reagents
Solvents
Catalysts

API SM
Reaction
intermediate
Final API
FPP
Reagents
Solvents
Catalysts
Solvents
Degradation
By-products
By-products
SM
impurities
Reagents
Solvents
Catalysts
Residue of the SM
Reagents
Solvents
Catalysts
Degradation products

API SM
Reaction
intermediate
Final API
FPP
Reagents
Solvents
Catalysts
Solvents
Degradation
By-products
By-products
SM
impurities
Excipient-API
interactions
Reagents
Solvents
Catalysts
Residue of the SM
Impurities in the SM Reagents
Solvents
Catalysts
Excipient-API interactions

API SM
Reaction
intermediate
Final API
FPP
Reagents
Solvents
Catalysts
Solvents?
Degradation
By-products
By-products
SM
impurities
Container-API
interactions
Excipient-API
interactions
Reagents
Solvents
Catalysts
Residue of the SM
Reagents
Solvents
Catalysts
Excipient-API interactions
Container closure interactions

• It is essential to have a detailed knowledge of
the preparation of the API and the controls
place upon the API starting materials, reaction
intermediates, reagents and solvents.
• It is essential to know how the API degrades.
• Similarly, the manner of preparation of the
FPP is important. Are there solvents involved,
heat, water etc?

• Most of the potential impurities arise during the
preparation of the API and its subsequent
degradation.
• The focus of FPP impurities is usually limited to
degradation products, or occasionally API-
Excipient and API-API interactions
(isoniazid/rifampicin).
• Typically FPP impurity specifications only control
for API degradation products.
• Consequently, there is a large focus on the
control of impurities in the API.

• Impurities introduced during manufacture
• API degradation products
• API reaction by-products
Determining most of the potential impurities does not
require a great deal of chemistry knowledge. Impurities
can be divided into:

What impurities are introduced during
manufacture?
• These can be determined from the detailed
manufacturing process description.
• They are the solvents, reagents, catalysts,
residue starting material, reaction
intermediates used in manufacture.

What are the possible degradation impurities?
• These can be determined from the results of
stress studies.
• Significant degradation products should be
identified and treated as potential impurities.

What are the possible reaction by-products?
• Here some chemistry knowledge would be
helpful.
Advice:
• Look for areas of functionality, particularly C-O, C-
N, and double bonds.
• Consider all the impurities specified in relevant
pharmacopoeial monographs.
• Remember, it is the applicant's job to do this not
yours.

O
O
O
OR
OH
DimerisationO
HO
O
O
O
OO
O
OR
OH
DimerisationO
HO
OO
OROR
OH
DimerisationO
HO
OO
HO
At C-O bonds oxidation, reduction, cleavage, addition and
elimination can readily occur.

(10)
Additions to double bonds within the molecule may occur
unintentionally, and even if intentional are not 100% specific.
X X
XX
X
X
+
+
+
[X]
[X]
98% 1.5% 0.5%
80% 20%
X X
XX
X
X
+
+
+
[X]
[X]
98% 1.5% 0.5%
80% 20%

(11)
Stereochemical impurities can arise.
O
OH
O
OCH3
O
OCH3
+
CH3OH
O
OH
O
OCH3
O
OCH3
+
O
OH
OO
OH
O
OCH3
OO
OCH3
O
OCH3
OO
OCH3
+
CH3OH

(12)
Certain chemical structures "alert structures" are considered to be genotoxic.

(13)
• Genotoxins must be considered carefully due to
their toxicity at even very low levels.
• The most common situation that arises is the use
of the reagents methylsulphonic acid or toluene
sulphonic acid.
• In the presence of alcohols like methanol or
ethanol they can form sulphonate esters. These
esters are genotoxic.
• Remember, if the impurity and the API share the
same alert structure then the impurity does not
need to be controlled as a genotoxin.

What impurities actually occur?

What impurities actually occur?
API SM
Step 1
Step 3
Final API
Step 2
Chance
Chance of an impurity occurring
Step impurity is introduced
Enantiomers

What impurities actually occur? (2)
• Investigation of batch analysis and long-term stability data is required.
• Impurities present at levels greater than the ICH reporting threshold
should be reported by the manufacturer.
• Potential impurities can be excluded by either testing the final API or FPP,
or a relevant proceeding molecule.
• Some pharmacopoeial impurities may not be present if a different
manner of preparation,( reagents, synthesis) is used.
• For degradants, look to long-term stability data. The presence of an
impurity under accelerated conditions does not mean it will appear
under long-term conditions

What impurities actually occur? (3)
Analytical methods
• If you are looking for an impurity using a test
method that can not detect the impurity then
you are wasting your time. Demonstrated
specificity and appropriate LOD/LOQs are
important, especially for genotoxins.
• It is important for the manufacturer to detail the
methods used. This is often not clear in
submitted dossiers if different test methods have
been used at different times.

When to specify impurities
The ICH divides impurities into
• Organic impurities (process- and drug-related)
• Residual solvents
• Inorganic impurities

When to specify impurities (2)
Organic impurities
• Any impurity routinely observed in batch data
or long-term stability trials should be controlled
by the impurity specifications.
• Impurities observed below the ICH
identification threshold need not be
individually specified in the specifications.
They can be controlled under the limit for any
unspecified impurity.
• Impurities above the ICH identification
threshold need to be identified and individually
specified in the specifications.

• Regardless of the related substance requirements of an applicable
pharmacopoeial monograph, a test for any unspecified impurity and total
impurities should be included.
Maximum daily dose Identification Threshold - The lower of:
% of API TDI
API < 2 g 0.10% 1.0 mg
> 2 g 0.05% -
FPP < 1 mg 1.0% 5 ug
1 mg – 10 mg 0.5% 20 ug
> 10 mg – 2 g 0.2% 2 mg
> 2 g 0.10% -

Genotoxins
• If a genotoxin is formed or is likely to be formed during manufacture or
storage then a limit for this impurity should be included in specifications.
• If batch data (6 pilot or 3 production) demonstrate that levels of the
impurity are at or below 30% of the allowable limit then non-routine testing
may be adopted. It should still be specified.
– For instance, if methylsulphonic acid and methanol were used in the last
step, but methane methylsulphonate was not detected then it may be
appropriate to test once annually.
– if methylsulphonic acid and methanol were used in the first of three
steps, but methane methylsulphonate was not detected then it may be
appropriate to specify the test is to be applied when there is a change in
manufacture.

Residual solvents
• The absence of specific test should be demonstrated on at least 3
production batches or 6 pilot scale batches.
Used in last step Prior to the last step
Class I Specify Specify if detected
Class II Specify Specify if >10% of the ICH
Q3C limit (option I)
Class III Not specified if controlled to less than 0.5%. Control
by Loss on Drying test permissible.

Metals either used in the last step or not consistently
removed from previous steps.
> 30% of applicable limit < 30% of applicable limit
Class I Specify Non-routine test permitted
Class II Specify Non-routine test permitted
Class III Specify Not required to be specified
Metal residues: EMEA/CHMP/SWP/4446/2000

Setting limits for impurities
• The limits must be qualified as safe.
• The limits should realistically reflect batch
and stability data.

Setting limits for impurities (2)
Organic Impurities
An organic impurity above the applicable ICH qualification threshold
needs to be qualified.
Maximum daily dose Qualification Threshold - The lower of:
% of API TDI
API < 2g 0.15% 1.0 mg
> 2g 0.05% -
FPP < 10 mg 1.0% 50 ug
10 mg - 100 mg 0.5% 200 ug
> 100 mg - 2 g 0.2% 3 mg
> 2 g 0.15% -

• Through toxicological trials.
• By comparison to a limit specified in the Ph.Int., Ph.Eur., or USP for a
specific impurity. It could even be in a monograph for another
substance. A statement in a monograph of "any other impurity NMT
0.5%" can not be used as justification for an impurity limit, as it is not
specific.
• By comparison to levels found in an innovator or prequalified FPP.
• By comparison to a limit previously approved in a prequalified FPP. This
is a last resort.
If the impurity limit is greater than the ICH qualification threshold then it should
be qualified:

• The limit for any unspecified impurity should be at the ICH identification
threshold.
• The limit for total impurity content should reflect batch data.
• These concepts are applicable to synthetic APIs, but could be used on a
case by case basis for semi-synthetic APIs.

Genotoxins: EMEA/CHMP/QWP/251344/2006
• Are considered unsafe at any level.
• A limit for a genotoxin with an understood toxicity can be calculated based
upon the known PDE.
• A limit for a genotoxin without sufficient toxicity information must
determine based upon a TTC of 1.5ug/day.
Max limit = TTC/maximum dose.
• Levels above this limit need to justified toxicologically.
• Limits for genotoxins like aflatoxins, N-nitroso-, and azoxy-compounds are
considered so toxic they must be justified using toxicological study data.
TTC = Threshold of Toxological Concern

Residual solvents
ICH limits apply – Q3C(R4)
• Class I solvents – See table 1, Q3C(R4)
• Class III solvents – 5000 ppm is acceptable without further
justification; might be controlled by LOD (0.5%)
• Class III solvent limits above 5000 ppm are permissible, but it would tend
to indicate poor manufacturing control.

Class II solvents – 2 methods for calculating limits
• Option 1 – Table of Q3C(R4) - predefined limits.
Good for APIs and FPPs
• Option 2 – A limit based upon the calculated total
exposure to the solvent in the FPP.

For instance: Acetonitrile
• The option 1 limit is 410 ppm based on a PDE of 4.1 mg/day.
• The option 2 limit allows potentially a limit higher than 410 ppm.
• Option 2 permits up to 4.1 mg of acetonitrile in the FPP.
• The limit of 410 ppm may be exceeded in the API provided the total
amount of residual acetonitirile in the FPP does not exceed 4.1 mg.

This can lead to API manufacturers justifying limits like this:
Acetonitrile (PDE 4.1 mg/day) in zidovudine (300 mg per day)
Using the ICH formula:
Max limit = 1000 x 4.1/0.3
= 13,660 ppm (seems a little excessive).

BUT
"provided that it has been demonstrated that the residual solvent has been
reduced to the practical minimum. The limits should be realistic in relation to
analytical precision, manufacturing capability, reasonable variation in the
manufacturing process, and the limits should reflect contemporary
manufacturing standards." – ICHQ3C(R4)
Basically, we might accept 1000 ppm (i.e. >410 ppm) if supported by batch
data, but not 20 times this value.
Also, option 2 applies to the total amount of solvent in the FPP. If the amount
of solvent in the API is excessive it may cause problems for the setting FPP
limits.

Metal residues: EMEA-CHMP-SWP-4446-2000

• Either adopt the stated concentration (ppm) limits (dose <10 g), or
• Set a limit for each metal such that the content of all metals of a
particular subclass, based on maximum dose, do not exceed the
recommended PDE. Metal contamination from all sources in the FPP
must be considered.

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