IMPURITIES IN NEW

DRUG PRODUCTS
Q3B(R2)
ICH- dated 2 June 2006


Provides guidance for registration applications on
the content and qualification of impurities in new
drug products produced from chemically
synthesized new drug substances.
This guideline is complementary to the ICH
Q3A(R) guideline Impurities in New Drug
Substances

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.

Impurities present in the new drug substance need
not be monitored or specified in the new drug
product unless they are also degradation products.

Not covered in this guideline:
biological/biotechnological products, peptides,
fermentation products and semi-synthetic
products, herbal products.
Impurities arising from excipients present in the
new drug product .
Extraneous contaminants .







The applicant should summarize the degradation
products observed during manufacture and/or
stability studies of the new drug product.
It should be based on sound scientific appraisal of
potential degradation pathways in the new drug
product and impurities arising from the interaction
with excipients and/or the immediate container
closure system.
A justification should be provided for exclusion of
those impurities that are not degradation products
(e.g., process impurities from the drug substance and
impurities arising from excipients).



Any degradation product observed in stability
studies conducted at the recommended storage
condition should be identified when present at a
level greater than (>) the identification
thresholds.
When identification of a degradation product is
not feasible, a summary of the laboratory
studies demonstrating the unsuccessful efforts
to identify it should be included .




Degradation products present at a level lesser than
the identification threshold generally not need to be
identified. However, analytical procedures should be
developed for those degradation products that are
suspected to be unusually potent.

ANALYTICAL PROCEDURES
The registration application should include
documented evidence that the analytical procedures
have been validated and are suitable for the
detection and quantitation of degradation products.
In particular, analytical procedures should be
validated to demonstrate specificity for the specified
and unspecified degradation products.
this validation should include samples stored under
relevant stress conditions: light, heat, humidity,
acid/base hydrolysis, and oxidation.



The quantitation limit for the analytical procedure
should be less than the reporting threshold.
Degradation product levels can be measured by a
variety of techniques, including those that compare
an analytical response for a degradation product to
that of an appropriate reference standard or to the
response of the new drug substance itself.
Differences between the analytical procedures used
during development and those proposed for the
commercial product should also be discussed.



REPORTING DEGRADATION
PRODUCTS
Analytical results should be provided in the
registration application for all relevant batches of the
new drug product used for clinical, safety, and
stability testing, as well as batches that are
representative of the proposed commercial process.
Any degradation product at a level greater than the
reporting threshold and total degradation products
observed in the relevant batches of the new drug
product, should be reported with the analytical
procedures indicated.


Degradation products should be designated by
code number or by an appropriate descriptor, e.g.,
retention time.
If a higher reporting threshold is proposed, it
should be fully justified.
All degradation products at a level greater than
(>) the reporting threshold should be summed and
reported as total degradation products.



For each batch the documentation should
include:
Batch no., strength, and size
Date of manufacture
Site of manufacture
Manufacturing process
Immediate container closure
Degradation product content, individual and total
Use of batch (e.g., clinical studies, stability studies)
Reference to analytical procedure used
Batch number of the drug substance used in the new
drug product
Storage conditions for stability studies




Chromatograms with peaks labelled from
representative batches, including
chromatograms from analytical procedure
validation studies and from long-term and
accelerated stability studies, should be
provided.

LISTING OF DEGRADATION
PRODUCTS IN SPECIFICATIONS
The specification for a new drug product should
include a list of degradation products expected to
occur during manufacture of the commercial
product and under recommended storage
conditions.
Stability studies, knowledge of degradation
pathways, product development studies, and
laboratory studies should be used to characterise
the degradation profile.

Those individual degradation products with
specific acceptance criteria included in the
specification for the new drug product are
referred to as "specified degradation products"
in this guideline.
Specified degradation products can be
identified or unidentified.

In summary, the new drug product specification
should include, where applicable, the following list
of degradation products:
Each specified identified degradation product
Each specified unidentified degradation product
Any unspecified degradation product with an
acceptance criterion of not more than () the
identification threshold
Total degradation products.


QUALIFICATION OF
DEGRADATION PRODUCTS
Qualification is the process of acquiring and
evaluating data that establishes the biological safety
of an individual degradation product or a given
degradation profile at the level(s) specified.
The applicant should provide a rationale for
establishing degradation product acceptance criteria
that includes safety considerations.
The level of any degradation product present in a
new drug product that has been adequately tested
in safety and/or clinical studies would be
considered qualified.
Degradation products could be considered
qualified at levels higher than those administered
in safety studies based on a comparison between
actual doses given in the safety studies and the
intended dose of the new drug product.

Reporting Thresholds

Maximum Daily Dose Threshold
1 g 0.1%
> 1 g 0.05%


Identification Thresholds

Maximum Daily Dose1 Threshold
< 1 mg 1.0% or 5 g TDI,
whichever is lower
1 mg - 10 mg 0.5% or 20 g TDI,
whichever is lower
>10 mg - 2 g 0.2% or 2 mg TDI,
whichever is lower
> 2 g 0.10%

TDI =total daily intake of the degradation product.


Qualification Thresholds
Maximum Daily Dose Threshold
< 10 mg 1.0% or 50 g
TDI, whichever is
lower

10 mg - 100 mg 0.5% or 200 g TDI,
whichever is
lower
>100 mg - 2 g 0.2% or 3 mg TDI,
whichever is
lower
> 2 g 0.15%


IMPURITIES: GUIDELINE FOR
RESIDUAL SOLVENTS -Q3C(R4)
Current Step 4 version dated February 2009
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.

Residual solvents in pharmaceuticals are defined
here as organic volatile chemicals that are used or
produced in the manufacture of drug substances or
excipients, or in the preparation of drug products.
Since there is no therapeutic benefit from residual
solvents, all residual solvents should be removed
to the extent possible


Appropriate selection of the solvent for the
synthesis of drug substance may enhance the
yield, or determine characteristics such as crystal
form, purity, and solubility.
Therefore, the solvent may sometimes be a
critical parameter in the synthetic process.
However, the content of solvents in such
products should be evaluated and justified.


ICH Q3C
ICH Q3C guides in determining, on a safety basis,
acceptable residual solvent levels for intake by use
of the term permitted daily exposure (PDE).
This Guidance classifies residual solvents used in
the synthesis and processing into four categories.
The Guidance recommends that

Class I solvents be avoided. These include benzene,
carbon tetrachloride, 1,2-dichloromethane,1,1-
dichloroethane, and 1,1,1-trichloroethane.
Class II solvents that should be limited because of
their inherent toxicity either by calculation of
concentration (PPM) or by PDE
Class 3 solvents with low toxic potential
Class 4 solvents with no safety data.
Class 1 solvents: Solvents to be avoided
Known human carcinogens, strongly suspected
human carcinogens, and environmental hazards.
Benzene - Carcinogen
Carbon tetrachloride -Toxic and environmental
hazard
1,2-Dichloroethane - Toxic
1,1-Dichloroethene - Toxic
1,1,1-Trichloroethane - Environmental hazard



Class 2 solvents: Solvents to be limited
Non-genotoxic animal carcinogens or possible
causative agents of other irreversible toxicity such as
neurotoxicity or teratogenicity.

PDE (mg/day)
Acetonitrile 4.1
Chlorobenzene 3.6
Chloroform 0.6
Cyclohexane 38.8
1,2-Dichloroethene 18.7




Pyridine 2.0
Toluene 8.9
Hexane 2.9
Methanol 30.0
1,1,2-Trichloroethene 0.8
Xylene 21.7
Methylbutyl ketone 0.5
Methylcyclohexane 11.8
N-Methylpyrrolidone1 5.3
Nitromethane 0.5
Pyridine 2.0 200
Sulfolane 1.6 Tetrahydrofuran2 7.2









Solvents in Class 3 (shown in Table 3) may be
regarded as less toxic and of lower risk to human
health. Class 3 includes no solvent known as a
human health hazard at levels normally accepted
in pharmaceuticals.
However, there are no long-term toxicity or
carcinogenicity studies for many of the solvents. It
is considered that amounts of these residual
solvents of 50 mg per day or less (corresponding
to 5000 ppm or 0.5% under Option 1) would be
acceptable without justification.


Class 3 solvents: Solvents with low toxic
potential
Solvents with low toxic potential to man; no health-
based exposure limit is needed. Class 3 solvents
have PDEs of 50 mg or more per day.
Acetic acid , Heptane, Acetone,
Ethanol, 1-Pentanol ,
Ethyl acetate, 1-Propanol ,
Ethyl ether, 2-Propanol






Ethyl acetate
Ethyl ether
Ethyl formate
Propyl acetate
Formic acid
Cumene
2-Methyl-1-propanol
Dimethyl sulfoxide
Pentane



Class 4 solvents :Solvents for which No
Adequate Toxicological Data was Found

1,1-Diethoxypropane ,
Methyl isopropyl ketone,
1,1-Dimethoxymethane,Methyltetrahydrofuran
2,2-Dimethoxypropane, Petroleum ether
Isooctane , Trichloroacetic acid
Isopropyl ether, Trifluoroacetic acid


It is only necessary to test for solvents that are used
or produced in the manufacture or purification of
drug substances, excipients, or drug product.
Although manufacturers may choose to test the drug
product, a cumulative method may be used to
calculate the residual solvent levels in the drug
product from the levels in the ingredients used to
produce the drug product.

If the calculation results in a level equal to or below
that recommended in this guideline, no testing of the
drug product for residual solvents need be
considered.
If, however, the calculated level is above the
recommended level, the drug product should be
tested to ascertain whether the formulation process
has reduced the relevant solvent level to within the
acceptable amount..
Drug product should also be tested if a solvent is
used during its manufacture.

Options for Describing Limits of Class 2
Solvents
Option 1:
Concentration (ppm) =1000 x PDE/dose
Here, PDE is given in terms of mg/day and dose is
given in g/day.
If all excipients and drug substances in a formulation
meet the limits given in Option 1, then these
components may be used in any proportion. No
further calculation is necessary provided the daily
dose does not exceed 10 g .


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 as stated in
Table 2 can be used with the known maximum daily
dose and equation (1) above to determine the
concentration of residual solvent allowed in drug
product.

Analytical Procedures
Residual solvents are typically determined using
chromatographic techniques such as gas
chromatography. Any harmonized procedures for
determining levels of residual solvents as described
in the pharmacopoeias should be used, if feasible.
Otherwise, manufacturers would be free to select the
most appropriate validated analytical procedure for a
particular application.
If only Class 3 solvents are present, a non-specific
method such as loss on drying may be used.


Validation of methods for residual solvents
should conform to ICH guidelines Text on
Validation of Analytical Procedures
Reporting levels of residual solvents

The supplier might choose one of the following as
appropriate:
Only Class 3 solvents are likely to be present.
Loss on drying is less than 0.5%.
Only Class 2 solvents X, Y, ... are likely to be
present.
All are below the Option 1 limit. (Here the supplier
would name the Class 2 solvents represented by
X, Y, ...)


Only Class 2 solvents X, Y, ... and Class 3
solvents are likely to be present.
Residual Class 2 solvents are below the Option 1
limit and residual Class 3 solvents are below 0.5%.

If Class 1 solvents are likely to be present, they
should be identified and quantified.

ANALYTICAL METHOD
DEVELOPMENT
Analytical methods employed for detection and
quantification of impurities should be sufficiently
sensitive to measure low levels of impurities.
There are a great variety of methods used for
monitoring impurities. The primary requirement for
such techniques is the capacity to differentiate
between the compounds of interest. This
requirement frequently necessitates utilization of
separation methods in combination with a variety of
detectors


Separation Methods
The following methods can be used for separation
of impurities and degradation products:
Capillary electrophoresis (CE)
Chiral separations
Gas chromatography (GC)
High-pressure liquid chromatography (HPLC)
Supercritical fluid chromatography (SFC)
Thin-layer chromatography (TLC)

The nature and complexity of the separation
problem determines which method should be used.
The primary goal of a good separation method is
resolution of all impurities of interest.

Capillary electrophoresis is an effective
technique in situations where very low quantities
of samples are available and high resolution is
essential. Its relatively lower reproducibility is the
principal difficulty of this procedure.


Gas chromatography is an extremely useful
technique for quantification. It can afford the
desired resolution, selectivity, and ease of
quantification.
The chief limitation, however, is that the sample
must be volatile or must be made volatile by
derivatization.
This technique is very practical for organic volatile
impurities (OVI).

High-pressure liquid chromatography is often
referred to as high performance liquid
chromatography today.. The applications of this
very effective technique have been significantly
expanded for the pharmaceutical chemist by the use
of a variety of detectors such as fluorescence,
electrometric, MS, and so forth.

Supercritical fluid chromatography (SFC) offers
some of the advantages of GC in terms of detection
and of HPLC in terms of separations, in that
volatility of the sample is not of paramount
importance.
SFC is generally performed in the normal phase
(NP) mode, and often NP-TLC or NP-HPLC
methods can be readily adapted to SFC methods.
Because of the similarity to HPLC in the
chromatographic measurement process, this
technique can be used to accurately quantify
nonpolar impurities of the sample of interest.



Thin-layer chromatography coupled with
densitometric detection is a highly sensitive method
for quick assessment of the purity of various
compounds
High-performance TLC (HPTLC) is an improved
version of TLC that uses stationary phases of
decreased thickness and lower particle size,
providing improved resolution over shorter elution
distances.
TLC can resolve a large range of compounds by
employing a variety of different plates and mobile
phases. Limited resolution ,detection, and ease of
quantification are the main problems associated with
this method.


Spectroscopic Methods
The following spectroscopic measurement
techniques have been used for characterizing
impurities; most of these are very useful as detectors
for chromatographic methods:
Ultraviolet (UV)
Infrared (IR)
Raman spectroscopy
Mass spectrometry (MS)
Nuclear magnetic resonance (NMR)

Ultraviolet spectrophotometry coupled with diode
array detectors, is capable to obtain sufficient
simultaneous information at various wavelengths to
assure greater reliability.
Infrared spectrophotometry (IR) affords specific
information on some functional groups. However,
low-level delectability is difficult.



Raman spectroscopy is based on the measurement of
scattered electromagnetic radiation resulting from
the irradiation of matter. Specifically, when a
material is irradiated with a strong monochromatic
light source (e.g., laser), difference in vibrational
energy between the scattered beam and incident
beam that is measured.
Raman spectroscopy is an extremely powerful tool
in characterizing the presence of polymorphs



Mass spectrometry (MS) provides excellent
structural information, and, based on the resolution
of the instrument, it may be an effective tool for
differentiating molecules with small differences in
molecular weight
Nuclear magnetic resonance spectroscopy (NMR)
provides reasonably detailed structural information
on a molecule and is an extremely useful method for
characterization of impurities. Its use as a
quantitative method is limited.




THANKS