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) 
 
August 20061 
ICH 
 
Revision 3 
 
 
1 ICH Q3B(R2) (Revision 2) was issued with an incorrect date of July 2006 on the title pages; however, the 
guidance was issued in August 2006.  Revision 3 of this guidance reflects the correct date of August 2006.  All other 
information remains the same. 
    
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) 
 
August 2006 
ICH 
 
Revision 3
   
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 Industry2 
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) 3 
 
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.4  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 2.5  This 
guidance complements the ICH Q3A(R) guidance, which should be consulted for basic 
principles along with ICH Q3C when appropriate.  
 
 
2 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. 
3 Arabic numbers reflect the organizational breakdown in the document endorsed by the  ICH  Steering Committee 
at Step 4 of the ICH process.  
 
4 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). 
 
5 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.  
  2  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. 
  3  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 
  4  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 
  5  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. 
 
  6  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.
  7  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 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% 
 
Qualification Thresholds 
 
Maximum Daily Dose1  Threshold2,3 
< 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% 
 
 
 
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. 
  3  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.) 
Reporting
1.00
Identification
e Qualification
nc 0.80
a
t
s
b
u
S
g  0.60
u
r
D
f 
o
e 
g 0.40
a
t
n
e
c
r
e
P 0.20
0.00
0 500 1000 1500 2000 2500
Maximum Daily Dose Expressed in mg of Drug Substance
Expanded Scale: 
1.00
Reporting
Identification
0.80
e
c
an Qualification
st
b
u
S
g  0.60
u
r
D
f 
o
e 
g
a 0.40
nt
e
c
r
e
P
0.20
0.00
0 5 10 15 20
Maximum Daily Dose Expressed in mg of Drug Substance
  4  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 g 
 
'Raw' Result  Reported  Total Daily Intake 
Action 
  Result  (TDI) 
Identification  Qualification 
(%)  (%)  of the Degradation 
Threshold   Threshold  
  (Reporting  Product 
0.2%  200 g TDI 
  Threshold =  (rounded  
exceeded?  exceeded? 
0.1%)  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 Intake 
Action 
  Result  (TDI) 
Identification  Qualification 
(%)  (%)  of the Degradation 
Threshold   Threshold  
  (Reporting  Product 
2 mg TDI  3 mg TDI 
  Threshold =  (rounded  
exceeded?  exceeded? 
0.05%)  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 
  5  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). 
 
 
  6  Contains Nonbinding Recommendations 
 
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 
Greater 
to not more than  Yes  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   
relevant adverse  Qualified 
safe level 
  effects?  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