Guidance for Industry 

Q3B(R2) Impurities in New 

Drug Products

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

Center for Biologics Evaluation and Research (CBER) 

July 2006 

ICH 

Revision 2 
Guidance for Industry 

Q3B(R2) Impurities in New 

Drug Products

Additional copies are available from: 

Office of Training and Communication 

Division of Drug Information, HFD-240 

Center for Drug Evaluation and Research 

Food and Drug Administration 

5600 Fishers Lane 

Rockville, MD 20857 

(Tel) 301-827-4573 

 http://www.fda.gov/cder/guidance/index.htm 

or 

Office of Communication, Training and 

Manufacturers Assistance, HFM-40 

Center for Biologics Evaluation and Research 

 Food and Drug Administration 

1401 Rockville Pike, Rockville, MD 20852-1448 

 http://www.fda.gov/cber/guidelines.htm. 

 (Tel) Voice Information System at 800-835-4709 or 301-827-1800

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

Center for Biologics Evaluation and Research (CBER) 

July 2006 

ICH 

Revision 2
TABLE OF CONTENTS 

I. INTRODUCTION (1.0)........................................................................................................ 1 

II. RATIONALE FOR THE REPORTING AND CONTROL OF DEGRADATION 

PRODUCTS (2.0).......................................................................................................................... 2 

III. ANALYTICAL PROCEDURES (3.0) ................................................................................ 3 

IV. REPORTING DEGRADATION PRODUCTS, CONTENT OF BATCHES (4.0)......... 4 

V. LISTING OF DEGRADATION PRODUCTS IN SPECIFICATIONS (5.0).................. 4 

VI. QUALIFICATION OF DEGRADATION PRODUCTS (6.0).......................................... 6 

GLOSSARY................................................................................................................................... 1 

ATTACHMENT 1 ........................................................................................................................ 3 

ATTACHMENT 2 ........................................................................................................................ 5 

ATTACHMENT 3 ........................................................................................................................ 7 
Contains Nonbinding Recommendations

Guidance for Industry1

Q3B(R2) Impurities in New Drug Products 

This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It 

does not create or confer any rights for or on any person and does not operate to bind FDA or the public. 

You can use an alternative approach if it satisfies the requirements of the applicable statutes and 

regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for 

implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate 

number listed on the title page of this guidance. 

I. INTRODUCTION (1.0) 2

This guidance provides recommendations for registration applications on the content and 

qualification of impurities in new drug products produced from chemically synthesized new drug 

substances not previously registered in a region or member state. This guidance revises the ICH 

guidance of the same title that was issued in May 1997 and first revised in February 2003. The 

first revision clarified the 1997 guidance and included other changes.3 The revision also 

provided consistency with more recently published ICH guidances (e.g., Q3A(R) Impurities in 

New Drug Substances, Q3C Impurities: Residual Solvents, and Q6A Specifications: Test 

Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: 

Chemical Substances). This second revision provides clarification to Attachment 2.4 This 

guidance complements the ICH Q3A(R) guidance, which should be consulted for basic 

principles along with ICH Q3C when appropriate. 

 

1 This guidance was developed within the Q3B(R) Expert Working Group of the International Conference on 

Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been 

subject to consultation by the regulatory parties, in accordance with the ICH process. This document was endorsed 

by the ICH Steering Committee at Step 4 of the ICH process, June 2, 2006. At Step 4 of the process, the final draft is 

recommended for adoption to the regulatory bodies of the European Union, Japan, and the United States. 

2 Arabic numbers reflect the organizational breakdown in the document endorsed by the ICH Steering Committee 

at Step 4 of the ICH process. 

3 For example, addressing reporting, identification, and qualification thresholds; listing impurities in specifications 

and making a clear distinction between ICH Q3B (listing impurities) and Q6A (setting specifications); and deleting 

the exception to conventional rounding practice (i.e., the provision recommending no rounding up to 0.1 percent for 

values between 0.05 and 0.09 percent). 

4

 Specifically, footnote 2 of Attachment 2 was revised to explain why the degradation product in Case 3, Example 2, 

does not have to be qualified. In addition, the reporting, identification, and qualification thresholds are clearly 

indicated for both examples in the attachment. 

1
Contains Nonbinding Recommendations

This guidance 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 guidance). Generally, impurities present in a new drug substance need not be monitored or 

specified in new drug product unless they are also degradation products (see ICH Q6A guidance 

on specifications). 

Impurities arising from excipients present in a new drug product or extracted or leached from the 

container closure system are not covered by this guidance. This guidance 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 guidance: 

• Biological/biotechnological products 

• Peptides 

• Oligonucleotides 

• Radiopharmaceuticals 

• Fermentation products and semi-synthetic products derived therefrom 

• Herbal products 

• 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. 

FDA's guidance documents, including this guidance, do not establish legally enforceable 

responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should 

be viewed only as recommendations, unless specific regulatory or statutory requirements are 

cited. The use of the word should in Agency guidances means that something is suggested or 

recommended, but not required. 

II. RATIONALE FOR THE REPORTING AND CONTROL OF DEGRADATION 

PRODUCTS (2.0) 

The applicant should summarize the degradation products observed during manufacture and/or 

stability studies of a 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 summarize any laboratory studies conducted to detect degradation products in 

the new drug product. This summary also should 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 should be discussed. 

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Contains Nonbinding Recommendations

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 infeasible, 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 part of the justification for selection of alternative thresholds based on manufacturing 

experience with the proposed commercial process. 

III. ANALYTICAL PROCEDURES (3.0) 

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 guidances 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 characterized 

according to their intended uses. The drug substance can be used to estimate the levels of 

degradation products. In cases when 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. 

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Contains Nonbinding Recommendations

IV. REPORTING DEGRADATION PRODUCTS, CONTENT OF BATCHES (4.0) 

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.” 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 percent, the results should be 

reported to the number of decimal places (e.g., 0.06 percent) in the applicable reporting 

threshold; at and above 1.0 percent, the results should be reported to one decimal place (e.g., 1.3 

percent). 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 labeled (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 (5.0) 

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 characterize the degradation profile. The selection of 

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Contains Nonbinding Recommendations

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 guidance. 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 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 identification threshold given in Attachment 1. For 

degradation products known to be unusually potent or to produce toxic or unexpected 

pharmacological effects, the quantitation or 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 guidance on specifications, decision tree #2, for establishing an 

acceptance criterion for a specified degradation product in a new drug product). 

In this guidance, 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 

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Contains Nonbinding Recommendations

VI. QUALIFICATION OF DEGRADATION PRODUCTS (6.0) 

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 levels 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. 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 may be appropriate (see Attachment 3). 

Higher or lower thresholds for qualification of degradation products may 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 may be appropriate. Conversely, a higher qualification 

threshold may 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. 

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Contains Nonbinding Recommendations

Although this guidance is not intended to apply during the clinical research stage of 

development, in the later stages of development, the thresholds in this guidance may 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.

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Contains Nonbinding Recommendations

GLOSSARY 

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, optimize, 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 characterization 

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 levels 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 

characterization has not been achieved and that is defined solely by qualitative analytical 

properties (e.g., chromatographic retention time) 

1
Contains Nonbinding Recommendations

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 

2
Contains Nonbinding Recommendations

ATTACHMENT 1 

THRESHOLDS FOR DEGRADATION PRODUCTS 

IN NEW DRUG PRODUCTS

Reporting Thresholds 

Maximum Daily Dose1 Threshold2,3

≤ 1 g 0.1% 

> 1 g 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 

> 2 g 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 

> 2 g 0.15% 

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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Contains Nonbinding Recommendations

Illustration of Thresholds for Reporting, Identification, and Qualification of Degradation 

Products in New Drug Products as a Function of Maximum Daily Dose 

(Note: Actual threshold values should be taken from the preceding table in this attachment.) 

0.00

0.20

0.40

0.60

0.80

1.00

0 500 1000 1500 2000 2500

Maximum Daily Dose Expressed in mg of Drug Substance

Percentage of Drug Substance

Reporting

Identification

Qualification

Expanded Scale: 

0.00

0.20

0.40

0.60

0.80

1.00

Percentage of Drug Substance

4

0 5 10 15 20

Maximum Daily Dose Expressed in mg of Drug Substance

Reporting

Identification

Qualification
Contains Nonbinding Recommendations

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 for 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 μg 

Action 'Raw' Result 

(%) 

Reported 

Result 

(%) 

(Reporting 

Threshold = 

0.1%) 

Total Daily Intake 

(TDI) 

of the Degradation 

Product 

(rounded 

result in μg) 

Identification

Threshold 

0.2% 

exceeded? 

Qualification

Threshold 

200 μg TDI 

exceeded? 

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 

Action 'Raw' Result 

(%) 

Reported 

Result 

(%) 

(Reporting 

Threshold = 

0.05%) 

Total Daily Intake 

(TDI) 

of the Degradation 

Product 

(rounded 

result in mg) 

Identification

Threshold 

2 mg TDI 

exceeded? 

Qualification

Threshold 

3 mg TDI 

exceeded? 

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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Contains Nonbinding Recommendations

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 should 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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Contains Nonbinding Recommendations

ATTACHMENT 3 

DECISION TREE FOR IDENTIFICATION AND QUALIFICATION OF A 

DEGRADATION PRODUCT

7
Contains Nonbinding Recommendations

Notes to 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 maximize 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?

8