European Medicines Agency

June 2006
CPMP/ICH/2738/99

ICH Topic Q 3 B (R2)

Impurities in New Drug Products

Step 5

NOTE FOR GUIDANCE ON IMPURITIES IN NEW DRUG PRODUCTS

(CPMP/ICH/2738/99)

TRANSMISSION TO CHMP November 1999

TRANSMISSION TO INTERESTED PARTIES November 1999

RELEASE FOR CONSULTATION November 1999

DEADLINE FOR COMMENTS May 2000

APPROVAL BY CPMP February 2003

DATE FOR COMING INTO OPERATION August 2003

REVISED ATTACHMENT 2 June 2006

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Tel. (44-20) 74 18 85 75 Fax (44-20) 75 23 70 40
E-mail: mail@emea.eu.int http://www.emea.eu.int
EMEA 2006 Reproduction and/or distribution of this document is authorised for non commercial purposes only provided the EMEA is acknowledged
 TABLE OF CONTENTS

I. INTRODUCTION 3
1.1 OBJECTIVE OF THE GUIDELINE 3
1.2 BACKGROUND 3
1.3 SCOPE OF THE GUIDELINE 3
II. RATIONALE FOR THE REPORTING AND CONTROL OF DEGRADATION
PRODUCTS 3

III. ANALYTICAL PROCEDURES 4

IV REPORTING DEGRADATION PRODUCTS CONTENT OF BATCHES 4

V. LISTING OF DEGRADATION PRODUCTS IN SPECIFICATIONS 5

VI QUALIFICATION OF DEGRADATION PRODUCTS 6

VII GLOSSARY 7
ATTACHMENT 1: THRESHOLDS FOR DEGRADATION PRODUCTS IN NEW DRUG PRODUCTS 9
EXAMPLE 1: 50 MG MAXIMUM DAILY DOSE 11
EXAMPLE 2: 1.9 GRAM MAXIMUM DAILY DOSE 11
ATTACHMENT 3: DECISION TREE FOR IDENTIFICATION AND QUALIFICATION OF A
DEGRADATION PRODUCT 13

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 IMPURITIES IN NEW DRUG PRODUCTS

I. INTRODUCTION

1.1 Objective of the guideline

This document provides guidance 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.

1.2 Background

This guideline is complementary to the ICH Q3A(R) guideline “Impurities in New Drug
Substances”, which should be consulted for basic principles. The ICH Q3C guideline
“Residual Solvents” should also be consulted, if appropriate.
1.3 Scope of the guideline

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 (collectively referred to as “degradation products”
in this guideline). Generally, impurities present in the new drug substance need not be
monitored or specified in the new drug product unless they are also degradation products (see
ICH Q6A guideline on specifications).
Impurities arising from excipients present in the new drug product or extracted or leached
from the container closure system are not covered by this guideline. This guideline also does
not apply to new drug products used during the clinical research stages of development. The
following types of products are not covered in this guideline: biological/biotechnological
products, peptides, oligonucleotides, radiopharmaceuticals, fermentation products and semi-
synthetic products derived therefrom, herbal products, and crude products of animal or plant
origin. Also excluded from this document are: (1) extraneous contaminants that should not
occur in new drug products and are more appropriately addressed as good manufacturing
practice (GMP) issues, (2) polymorphic forms, and (3) enantiomeric impurities.

II. RATIONALE FOR THE REPORTING AND CONTROL OF DEGRADATION

PRODUCTS

The applicant should summarise the degradation products observed during manufacture
and/or stability studies of the new drug product. This summary 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. In
addition, the applicant should summarise any laboratory studies conducted to detect
degradation products in the new drug product. This summary should also include test results
of batches manufactured during the development process and batches representative of the
proposed commercial process. A rationale 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). The impurity profiles of the batches representative of
the proposed commercial process should be compared with the profiles of batches used in
development and any differences discussed.

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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 given in Attachment 1. 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 in the registration application.
Degradation products present at a level of not more than (≤) the identification threshold
generally would not need to be identified. However, analytical procedures should be
developed for those degradation products that are suspected to be unusually potent, producing
toxic or significant pharmacological effects at levels not more than (≤) the identification
threshold. In unusual circumstances, technical factors (e.g., manufacturing capability, a low
drug substance to excipient ratio, or the use of excipients that are crude products of animal or
plant origin) can be considered as part of the justification for selection of alternative
thresholds based upon manufacturing experience with the proposed commercial process.

III. 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 (see ICH Q2A and Q2B guidelines on analytical validation). In
particular, analytical procedures should be validated to demonstrate specificity for the
specified and unspecified degradation products. As appropriate, this validation should include
samples stored under relevant stress conditions: light, heat, humidity, acid/base hydrolysis,
and oxidation. When an analytical procedure reveals the presence of other peaks in addition to
those of the degradation products (e.g., the drug substance, impurities arising from the
synthesis of the drug substance, excipients and impurities arising from the excipients), these
peaks should be labeled in the chromatograms and their origin(s) discussed in the validation
documentation.

The quantitation limit for the analytical procedure should be not more 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. Reference standards used in the
analytical procedures for control of degradation products should be evaluated and
characterised according to their intended uses. The drug substance can be used to estimate the
levels of degradation products. In cases where the response factors are not close, this practice
can still be used if a correction factor is applied or the degradation products are, in fact, being
overestimated. Acceptance criteria and analytical procedures, used to estimate identified or
unidentified degradation products, are often based on analytical assumptions (e.g., equivalent
detector response). These assumptions should be discussed in the registration application.

Differences between the analytical procedures used during development and those proposed
for the commercial product should also be discussed.

IV REPORTING DEGRADATION PRODUCTS CONTENT OF BATCHES

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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. Quantitative results should be presented
numerically, and not in general terms such as “complies”, “meets limit” etc. Any degradation
product at a level greater than (>) the reporting threshold (see Attachment 1), and total
degradation products observed in the relevant batches of the new drug product, should be
reported with the analytical procedures indicated. Below 1.0%, the results should be reported
to the number of decimal places (e.g., 0.06%) in the applicable reporting threshold; at and
above 1.0%, the results should be reported to one decimal place (e.g., 1.3%). Results should
be rounded using conventional rules (see Attachment 2). A tabulation (e.g., spreadsheet) of
the data is recommended. 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.
Chromatograms with peaks labelled (or equivalent data if other analytical procedures are
used) from representative batches, including chromatograms from analytical procedure
validation studies and from long-term and accelerated stability studies, should be provided.
The applicant should ensure that complete degradation product profiles (e.g., chromatograms)
of individual batches are available, if requested.
For each batch of the new drug product described in the registration application, the
documentation should include:
• Batch identity, 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

V. 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. The selection of degradation products in the new drug product specification should
be based on the degradation products found in batches manufactured by the proposed
commercial process. 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.
A rationale for the inclusion or exclusion of degradation products in the specification should
be presented. This rationale should include a discussion of the degradation profiles observed

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in the safety and clinical development batches and in stability studies, together with a
consideration of the degradation profile of batches manufactured by the proposed commercial
process. Specified identified degradation products should be included along with specified
unidentified degradation products estimated to be present at a level greater than (>) the identi-
fication threshold given in Attachment 1. For degradation products known to be unusually
potent or to produce toxic or unexpected pharmacological effects, the quantitation/detection
limit of the analytical procedures should be commensurate with the level at which the
degradation products should be controlled. For unidentified degradation products, the
procedure used and assumptions made in establishing the level of the degradation product
should be clearly stated. Specified unidentified degradation products should be referred to by
an appropriate qualitative analytical descriptive label (e.g., “unidentified A", “unidentified
with relative retention of 0.9”). A general acceptance criterion of not more than (≤) the
identification threshold (Attachment 1) for any unspecified degradation product and an
acceptance criterion for total degradation products should also be included.
For a given degradation product, its acceptance criterion should be established by taking into
account its acceptance criterion in the drug substance (if applicable), its qualified level, its
increase during stability studies, and the proposed shelf life and recommended storage
conditions for the new drug product. Furthermore, each acceptance criterion should be set no
higher than the qualified level of the given degradation product.
Where there is no safety concern, degradation product acceptance criteria should be based on
data generated from batches of the new drug product manufactured by the proposed
commercial process, allowing sufficient latitude to deal with normal manufacturing and
analytical variation and the stability characteristics of the new drug product. Although normal
manufacturing variations are expected, significant variation in batch-to-batch degradation
product levels can indicate that the manufacturing process of the new drug product is not
adequately controlled and validated (see ICH Q6A guideline on specifications, decision tree
#2, for establishing an acceptance criterion for a specified degradation product in a new drug
product).
In this guideline, the use of two decimal places for thresholds (See Attachment 1) does not
necessarily indicate the precision of the acceptance criteria for specified degradation products
and total degradation products.
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.

VI 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

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would be considered qualified. Therefore, it is useful to include any available information on
the actual content of degradation products in the relevant batches at the time of use in safety
and/or clinical studies. Degradation products that are also significant metabolites present in
animal and/or human studies are generally 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. Justification of such higher levels should include consideration of factors such
as: (1) the amount of degradation product administered in previous safety and/or clinical
studies and found to be safe; (2) the increase in the amount of the degradation product; and
(3) other safety factors, as appropriate.
If the qualification thresholds given in Attachment 1 are exceeded and data are unavailable to
qualify the proposed acceptance criterion of a degradation product, additional studies to
obtain such data can be appropriate (see Attachment 3).
Higher or lower thresholds for qualification of degradation products can be appropriate for
some individual new drug products based on scientific rationale and level of concern,
including drug class effects and clinical experience. For example, qualification can be
especially important when there is evidence that such degradation products in certain new
drug products or therapeutic classes have previously been associated with adverse reactions in
patients. In these instances, a lower qualification threshold can be appropriate. Conversely, a
higher qualification threshold can be appropriate for individual new drug products when the
level of concern for safety is less than usual based on similar considerations (e.g., patient
population, drug class effects, and clinical considerations). Proposals for alternative
thresholds would be considered on a case-by-case basis.
The "Decision Tree for Identification and Qualification of a Degradation Product"
(Attachment 3) describes considerations for the qualification of degradation products when
thresholds are exceeded. In some cases, reducing the level of degradation product (e.g., use
of a more protective container closure or modified storage conditions) to not more than (≤)
the threshold can be simpler than providing safety data. Alternatively, adequate data could be
available in the scientific literature to qualify a degradation product. If neither is the case,
additional safety testing should be considered. The studies considered appropriate to qualify a
degradation product will depend on a number of factors, including the patient population,
daily dose, and route and duration of new drug product administration. Such studies can be
conducted on the new drug product or substance containing the degradation products to be
controlled, although studies using isolated degradation products can sometimes be
appropriate.
Although this guideline is not intended to apply during the clinical research stage of
development, in the later stages of development the thresholds in this guideline can be useful
in evaluating new degradation products observed in new drug product batches prepared by the
proposed commercial process. Any new degradation product observed in later stages of
development should be identified (see the “Decision Tree for Identification and Qualification
of a Degradation Product” in Attachment 3) if its level is greater than (>) the identification
threshold given in Attachment 1. Similarly, qualification of the degradation product should be
considered if its level is greater than (>) the qualification threshold given in Attachment 1.
Safety studies should provide a comparison of results of safety testing of the new drug
product or drug substance containing a representative level of the degradation product with
previously qualified material, although studies using the isolated degradation products can
also be considered.

VII GLOSSARY

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Degradation Product: An impurity resulting from a chemical change in the drug substance
brought about during manufacture and/or storage of the new drug product by the effect of, for
example, light, temperature, pH, water, or by reaction with an excipient and/or the immediate
container closure system.
Degradation Profile: A description of the degradation products observed in the drug
substance or drug product.
Development Studies: Studies conducted to scale-up, optimise, and validate the
manufacturing process for a drug product.
Identification Threshold: A limit above (>) which a degradation product should be
identified.
Identified Degradation Product: A degradation product for which a structural
characterisation has been achieved.
Impurity: Any component of the new drug product that is not the drug substance or an
excipient in the drug product.
Impurity Profile: A description of the identified and unidentified impurities present in a drug
product.
New Drug Substance: The designated therapeutic moiety that has not been previously
registered in a region or member state (also referred to as a new molecular entity or new
chemical entity). It can be a complex, simple ester, or salt of a previously approved
substance.
Qualification: 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.
Qualification Threshold: A limit above (>) which a degradation product should be qualified.
Reporting Threshold: A limit above (>) which a degradation product should be reported.
Specified Degradation Product: A degradation product that is individually listed and limited
with a specific acceptance criterion in the new drug product specification. A specified
degradation product can be either identified or unidentified.
Unidentified Degradation Product: A degradation product for which a structural
characterisation has not been achieved and that is defined solely by qualitative analytical
properties (e.g., chromatographic retention time).
Unspecified Degradation Product: A degradation product that is limited by a general
acceptance criterion, but not individually listed with its own specific acceptance criterion, in
the new drug product specification.

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Attachment 1: Thresholds for Degradation Products in New Drug Products

Reporting Thresholds

Maximum Daily Dose1 Threshold2,3

≤1 g 0.1%
>1g 0.05%

Identification Thresholds

Maximum Daily Dose1 Threshold2, 3

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

Qualification Thresholds

Maximum Daily Dose1 Threshold2,3

< 10 mg 1.0% or 50 µg TDI, whichever is lower
10 mg - 100 mg 0.5% or 200 µg TDI, whichever is lower
>100 mg - 2 g 0.2% or 3 mg TDI, whichever is lower
>2g 0.15%

Notes on Attachment 1

1 The amount of drug substance administered per day

2 Thresholds for degradation products are expressed either as a percentage of the drug
substance or as total daily intake (TDI) of the degradation product. Lower thresholds
can be appropriate if the degradation product is unusually toxic.
3 Higher thresholds should be scientifically justified.

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 Illustration of Thresholds for Reporting, Identification, and Qualification of
Degradation Products in New Drug Products as a Function of Maximum Daily Dose1

1.00 Reporting
Identification
Qualification
Percentage of Drug Substance

0.80

0.60

0.40

0.20

0.00
0 500 1000 1500 2000 2500
Maximum Daily Dose Expressed in mg of Drug Substance

Expanded Scale:

1.00

Reporting
0.80 Identification
Percentage of Drug Substance

Qualification

0.60

0.40

0.20

0.00
0 5 10 15 20
Maximum Daily Dose Expressed in mg of Drug Substance
1 Note: Actual threshold values should be taken from the preceding table in this attachment.

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Attachment 2: Illustration of Reporting Degradation product Results for Identification
and Qualification in an Application

The attachment is only illustrative and is not intended to serve as a template how results on
degradation products should be presented in an application file. Normally raw data are not
provided.

Example 1: 50 mg Maximum Daily Dose

Reporting threshold: 0.1%

Identification threshold: 0.2%
Qualification threshold: 200 g

'Raw' Result Reported Total Daily Action

Result Intake (TDI)
(%) (%) of the Identification Qualification
(Reporting Degradation Threshold Threshold
Threshold = Product 0.2% 200 g TDI
0.1%) (rounded exceeded? exceeded?
result in g)
0.04 Not reported 20 None None

0.2143 0.2 100 None None

0.349 0.31 150 Yes None1

0.550 0.61 300 Yes Yes1

Example 2: 1.9 gram Maximum Daily Dose

Reporting threshold: 0.05%

Identification threshold: 2 mg
Qualification threshold: 3 mg

'Raw' Result Reported Total Daily Action

Result Intake (TDI)
(%) (%) of the Identification Qualification
(Reporting Degradation Threshold Threshold
Threshold = Product 2 mg TDI 3 mg TDI
0.05%) (rounded exceeded? exceeded?
result in mg)
0.049 Not reported 1 None None

0.079 0.08 2 None None

0.183 0.181 3 Yes None1, 2

0.192 0.191 4 Yes Yes1

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Notes on attachment 2

1 After identification, if the response factor is determined to differ significantly from the
original assumptions, it can be appropriate to re-measure the actual amount of the degradation
product present and re-evaluate against the qualification threshold (see Attachment 1).

2 To verify if a threshold is exceeded, a reported result has to be evaluated against the

thresholds as follows: when the threshold is described in %, the reported result rounded to the
same decimal place as the threshold should be compared directly to the threshold. When the
threshold is described in TDI, the reported result should be converted to TDI, rounded to the
same decimal place as the threshold and compared to the threshold e.g. an amount of 0.18%
degradation level corresponds to a TDI of 3.4 mg impurity (absolute amount) which is then
rounded down to 3 mg; so the qualification threshold expressed in TDI (3 mg) is not
exceeded.

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Attachment 3: Decision Tree for Identification and Qualification of a Degradation
Product

Is degradation
product greater than
identification
thresholdc?

Yes No
No action

Any
Structure Yes known human Yes Reduce to
identified? relevant risksd? safe level

No
No

Reduce
to not more than Yes No further
(≤) identification action
thresholdc?

Yes
No

Reduce
to not more than Yes Greater No
(≤) qualification than qualification No action
thresholdc? thresholdc?

No

Consider patient population and duration of use

and consider conducting:
• Genotoxicity studies (point mutation,
chromosomal aberration)a
• General toxicity studies (one species, usually
14 to 90 days)b
• Other specific toxicity endpoints, as
appropriate

Any
Reduce to Yes clinically No
safe level relevant adverse Qualified
effects?

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Notes on Attachment 3
a) If considered desirable, a minimum screen (e.g., genotoxic potential), should be
conducted.
A study to detect point mutations and one to detect chromosomal aberrations, both in
vitro, are considered an appropriate minimum screen.

b) If general toxicity studies are desirable, one or more studies should be designed to allow
comparison of unqualified to qualified material. The study duration should be based on
available relevant information and performed in the species most likely to maximise the
potential to detect the toxicity of a degradation product. On a case-by-case basis, single-
dose studies can be appropriate, especially for single-dose drugs. In general, a minimum
duration of 14 days and a maximum duration of 90 days would be considered
appropriate.

c) Lower thresholds can be appropriate if the degradation product is unusually toxic.

d) For example, do known safety data for this degradation product or its structural class
preclude human exposure at the concentration present?

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