___________________  
 
 
Guidance for Industry 

ANDAs:  Impurities in Drug 

Products 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

 
 
November 2010 

OGD 

 
   
 
Guidance for Industry 

 
ANDAs:  Impurities in Drug 

Products 

 
 
 
 
 
 
 
 
Additional copies are available from: 

Office of Communications 
 
Division of  Drug Information, WO 51, Room 2201 
 
Center for Drug Evaluation  and Research  

Food and  Drug Administration 

10903 New Hampshire Ave. 

Silver Spring, MD   20993-0002 
 
Phone: 301-796-3400;  Fax: 301-847-8714 
 
druginfo@fda.hhs.gov 

 http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

 
November 2010 

OGD 

 
  Contains Nonbinding Recommendations 
 
 
 
TABLE OF CONTENTS 
 
I.	          INTRODUCTION............................................................................................................. 1 
 
II.	         BACKGROUND ............................................................................................................... 1 
 
III. 	  LISTING OF DEGRADATION PRODUCTS AND SETTING ACCEPTANCE 

CRITERIA FOR DEGRADATION PRODUCTS IN DRUG PRODUCT 

SPECIFICATIONS.................................................................................2 

 
A.   Listing of Degradation Products........................................................2
 
  B.   Setting Acceptance Criteria for Degradation Products............................3  
IV.       QUALIFICATION OF DEGRADATION PRODUCTS....................................4
 
  A.   Qualification Thresholds.................................................................4 

  B.   Qualification Procedures.................. ..............................................5 
 
    1.   	 Comparative Analytical Studies... ................................................... 5
  
    2.   	 Scientific Literature and Significant Metabolite............ ......................5  
    3.   	 Toxicity Studies................................................ ................... .........5  
ATTACHMENT:    IDENTIFICATION AND QUALIFICATION OF DEGRADATION 
PRODUCTS IN GENERIC DRUG PRODUCTS...................................................................... 6 
 
  Contains Nonbinding Recommendations 
 
Guidance for Industry 

ANDAs:  Impurities in Drug Products 

 
 
 
This guidance represents the Food and Drug Administrations (FDAs) 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 the approach 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 
 
This guidance provides recommendations on what chemistry, manufacturing, and controls (CMC)  
information sponsors should include regarding the reporting, identification, and qualification of 
impurities that are classified as degradation products in drug products when submitting:1, 2  
 
	   Original abbreviated new drug applications (ANDAs) 
 
	   ANDA supplements for changes that may affect the quantitative or qualitative 

degradation product profile 

 
The guidance also provides recommendations for establishing acceptance criteria for degradation  
products (specifically, degradation products  of the active ingredient or reaction products  of the 
active ingredient with an excipient(s) and/or immediate container/closure system) in generic drug 
products. The guidance will replace an existing 1998 draft guidance of the same name. 
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities. Instead, guidances describe the Agencys 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.  BACKGROUND 
 
On August 29, 2005, FDA published a revised of the draft guidance for industry titled ANDAs: 
Impurities in Drug Products, originally issued in December 1998.   
                                                           
1 The recommendations in this guidance are limited to drug  products that are manufactured  from drug substances  
produced  by chemical synthesis. 
 
2 See 21 CFR 314.94(a)(9)    
  Contains Nonbinding Recommendations 
 
 
We are issuing this final guidance for the following reasons: 
 
1. 	 To update information on listing of degradation products, setting acceptance criteria, 
and qualifying degradation products (thresholds and procedures) in ANDAs in 
conformance with the revision of the guidance for industry on Q3B(R) Impurities in 
New Drug Products. 
 
2. 	  To remove those sections of the 1998 draft guidance containing recommendations 
that are no longer needed because they are addressed in the more recent Q3B(R)  (see 
the list below). 
    
The Q3B(R) was developed by the International Conference on Harmonisation (ICH) to provide 
guidance on impurities in drug products for new drug applications (NDAs).  However, the 
Agency believes that many of the recommendations provided on impurities in drug products also 
apply to ANDAs. Please refer to the following specific sections in the Q3B(R) for these 
recommendations: 
 
	   Section I, Introduction 
	   Section II, Rationale for the Reporting and Control of Degradation Products 
	   Section III, Analytical Procedures 
	   Section IV, Reporting Degradation Products, Content of Batches 
	   Attachment 1, Thresholds for Degradation Products 
 
 
III. 	  LISTING OF DEGRADATION PRODUCTS AND SETTING ACCEPTANCE 
CRITERIA FOR DEGRADATION PRODUCTS IN DRUG PRODUCT 
SPECIFICATIONS 
 
A. 	 Listing of Degradation Products 
 
We recommend that the specification for a drug product include a list of degradation products.  
Stability studies, chemical development studies, and routine batch analyses can be used to 
predict the degradation profile for the commercial product.  It is important that the list of 
degradation products for the drug product specification be based on degradation products found 
in the batch(es) manufactured by the proposed commercial process.  
We recommend that you include in your submission a rationale for the inclusion or exclusion of 
degradation products in the drug product specification.  It is important that the rationale include a 
discussion of the degradation profiles observed in stability studies and any other batch(es) 
manufactured in support of the application.  
Individual degradation products with specific acceptance criteria that are included in the 
specification for the drug product are referred to as "specified degradation products" in this 
guidance. Specified degradation products can be identified or unidentified.  
  2
  Contains Nonbinding Recommendations 
 
We recommend that specified identified degradation products be included in the list of  
degradation products along with specified unidentified degradation products that are estimated to 
be present at a level greater than the identification threshold given in Q3B(R). For degradation 
products known to be unusually potent or to produce toxic or unexpected pharmacological 
effects, we recommend that the quantitation and/or detection limit of the analytical procedures 
correspond to the level at which the degradation products are expected to be controlled.   
For unidentified degradation products to be listed in the drug product specification, we 
recommend that you clearly state the procedure used and assumptions made in establishing the 
level of the degradation product.  It is important that specified unidentified degradation products 
be referred to by an appropriate qualitative analytical descriptive label (e.g., unidentified A, 
unidentified with relative retention of 0.9).  We recommend that you also include general 
acceptance criteria of not more than the identification threshold (see Q3B(R), Attachment 1) for 
any unspecified degradation product and acceptance criteria for total degradation products.  
We recommend that the drug product specification include, where applicable, a list of the 
following types 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 figure in the identification threshold in Attachment 1, Q3B(R)  
	   Total degradation products 
 
B.  Setting Acceptance Criteria for Degradation Products 
 
We recommend that the acceptance criterion be set no higher than the qualified level (see section 
IV, Qualification of Degradation Products).  In establishing degradation product acceptance 
criteria, the first critical consideration is whether a degradation product is specified in the United 
States Pharmacopeia (USP).  If there is a monograph in the USP that includes a limit for a 
specified identified degradation product, we recommend that the acceptance criterion be set no 
higher than the official compendial limit.   
 
If the level of the degradation product is above the level specified in the USP, we recommend 
qualification.  Then, if appropriate qualification has been achieved, an applicant may wish to 
petition the USP for revision of the degradation products acceptance criterion.  
 
If the acceptance criterion for a specified degradation product does not exist in the USP and this 
degradation product can be qualified by comparison to the reference listed drug (RLD), the 
acceptance criterion should be similar to the level observed in the RLD.  In other circumstances, 
the acceptance criterion may need to be set lower than the qualified level to ensure drug product 
quality.  For example, if the level of the significant metabolite impurity is too high, other quality 
attributes, like potency, could be seriously affected.  In this case, we would recommend that the 
degradation product acceptance criterion be set lower than the qualified level.  
 
We recommend that ANDA sponsors develop robust formulations and manufacturing processes 
that are based on sound state-of-the-art scientific and engineering principles and knowledge.   
  3
  Contains Nonbinding Recommendations 
 
Although routine manufacturing variations are expected, significant variation in batch-to-batch 
degradation product levels or an unusually high level of degradation products may indicate that 
the manufacturing process of the drug product is not adequately controlled or designed.  
IV.  QUALIFICATION OF DEGRADATION PRODUCTS 
 
Qualification is the process of acquiring and evaluating data that establish the biological safety 
of an individual degradation product or a given degradation profile at the level(s) being 
considered. When appropriate, we recommend that applicants provide a rationale for establishing 
degradation product acceptance criteria that includes safety considerations.    
 
A specified identified degradation product is considered qualified when it meets one or more of 
the following conditions: 
 
 	  When the observed level and proposed acceptance criterion for the degradation product 
do not exceed the level observed in the RLD. 
 	  When the degradation product is a significant metabolite of the drug substance. 
	   When the observed level and the proposed acceptance criterion for the degradation 
product are adequately justified by the scientific literature. 
 	  When the observed level and proposed acceptance criterion for the degradation product 
do not exceed the level that has been adequately evaluated in toxicology studies. 
 
Although quantitative structure activity relationships (QSAR) programs may be used for 
prediction of toxicity of an individual degradation product or a given degradation profile, the 
results are not generally considered conclusive for qualification purposes. 
 
A.  Qualification Thresholds 
 
Recommended qualification thresholds3 for degradation products based on the maximum daily 
dose of the drug are provided in Q3B(R). When these qualification thresholds are exceeded, we 
recommend that degradation product levels be qualified.  In some cases, it may be appropriate to 
increase or decrease the qualification threshold for qualifying degradation products.  For 
example, when there is evidence that a degradation product in certain drug classes or therapeutic 
classes has previously been associated with adverse reactions in patients, it may be important to 
establish a lower qualification threshold.  Conversely, when the concern for safety is low, a 
higher threshold for qualifying degradation products may be appropriate.  The FDA will consider  
proposals for applications for alternative qualification thresholds on a case-by-case basis after 
considering issues such as patient population, drug class effects, and historical safety data.   
 
 
 
 
                                                           
3  Qualification threshold is  defined as a limit above (>) which a degradation product should be qualified.  
 
  4
  Contains Nonbinding Recommendations 
 
B.  Qualification Procedures 
 
The decision tree in the attachment describes considerations for the qualification of degradation 
products when the usual qualification threshold recommended in ICH Q3B(R) is exceeded. In 
some cases, decreasing the level of the degradation product below the threshold rather than 
providing additional data can be the simplest course of action.  Alternatively, adequate data 
could be available in the scientific literature to qualify the degradation product.   The studies 
considered appropriate to qualify the degradation product will depend on a number of factors, 
including the patient population, daily dose, and route and duration of drug administration.  Such 
studies can be conducted on the drug product containing the degradation product to be controlled,  
although studies using isolated degradation products can sometimes be appropriate.  The 
following are descriptions of methods for qualifying degradation products. 
 
1.  Comparative Analytical Studies 
 
A degradation product present in a drug product covered by an ANDA can be qualified by 
comparing the analytical profiles of a generic drug product with those in an RLD using the same  
validated, stability-indicating analytical procedure (e.g., comparative HPLC studies).  However, 
the profile may be compared to a different drug product with the same route of administration 
and similar characteristics (e.g., tablet versus capsule) if samples of the reference listed drug are 
unavailable or in the case of an ANDA submitted pursuant to a suitability petition.  It is essential 
that maximum daily doses of the degradation product and routes of administration be taken into 
account for qualification by comparative analytical studies. The qualified threshold of a 
degradation product in a dosage form may not be applicable to all drug products containing that 
degradation product if the maximum daily doses or the routes of administration are different.  We  
recommend that you conduct the stability studies on comparable samples (e.g., age of samples) 
to get a meaningful comparison of degradation profiles.   
 
A degradation product present in the generic drug product is considered qualified if the amount 
of identified degradation product in the generic drug product is similar to the levels observed in 
the RLD. 
 
2.  Scientific Literature and Significant Metabolites 
 
If the level of the specified identified degradation product is adequately justified by the scientific 
literature, no further qualification is considered necessary.  In addition, a degradation product 
that is also a significant metabolite of the drug substance is generally considered qualified. 
 
3.  Toxicity Studies 
 
Toxicity tests are the least preferred method to qualify degradation products.  We recommend the 
tests be used only when degradation products cannot be qualified by either of the above 
procedures (section IV.B.1 or 2). The tests are designed to detect compounds that induce general 
toxic or genotoxic effects in experimental systems.  If performed, such studies should be 
conducted on the drug product or drug substance containing the degradation products to be 
controlled, although studies using isolated degradation products may also be used.  
  
  5
  Contains Nonbinding Recommendations 
 
ATTACHMENT:  IDENTIFICATION AND QUALIFICATION OF DEGRADATION 
PRODUCTS IN GENERIC DRUG PRODUCTS 
 
 
Is degradation 
 
product greater 
  than identification 
  thresholda? 
   
Yes  No 
No action 
Any
Structure  Yes  known human  Yes 
identified?   relevant risksb?  Reduce to 
safe level 
No 
No 
Greater than 
Reduce  qualification 
 No
to not more than   Yes  No further   thresholda? 
 No action 
() identification  action 

thresholda? 

Yes 
Yes 
No 
Is the degradation product Reduce  Yes 
observed in a reference listed drug at  No  to not more than  
a similar level or is it  adequately 
() qualification  No Action 
qualified by  other acceptable 
approachesc?  thresholda? 
No 
Consider patient population and duration of use 
and consider conducting: 
   Genotoxicity studies (point mutation, 
chromosomal aberration)d  
   General toxicity  studies (one species, usually  
14 to 90 days)e  
   Other specific toxicity  endpoints, as 
appropriate 
 
Any 
Reduce to   Yes  clinically  No   
relevant adverse  Qualified 
safe level 
effects?  
  Contains Nonbinding Recommendations 
 
Notes on the Attachment  
 
a	   Lower thresholds can be appropriate if the degradation product is unusually toxic. 
 
b	   For example, do  known safety data  for this degradation product  or its structural class preclude human exposure at  
the observed level?   
 
c   A degradation product is considered qualified for ANDAs when one or  more of the following conditions are met: 
 
 	  When the observed level and proposed acceptance criterion for the degradation product do not exceed the 
level justified by the RLD. 
 	  When the degradation product is a significant metabolite of  the drug substance. 
 	  When the observed level and the proposed acceptance  criterion for the degradation product are adequately 
justified  by the scientific literature. 
 	  When the observed level and proposed acceptance criterion for the degradation product do not exceed the 
level that has been adequately evaluated in toxicity studies. 
 
d 	 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 for genotoxicity. 
 
e 	 If general toxicity studies are  appropriate, 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 for detecting 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. 
 
 
  7