Guidance for Industry 
 
Changes to an Approved NDA or ANDA; 
Specifications  Use of Enforcement 
Discretion for Compendial Changes  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
November 2004 
CMC 
   
Guidance for Industry 
 
Changes to an Approved NDA or ANDA; 
Specifications  Use of Enforcement 
Discretion for Compendial Changes  
 
 
 
 
 
 
 
 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 November 2004 
CMC 
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION.............................................................................................................1 
II.  BACKGROUND...............................................................................................................2 
III.  EXERCISE OF ENFORCEMENT DISCRETION.......................................................2  Contains Nonbinding Recommendations 
1
Guidance for Industry  
 
Changes to an Approved NDA or ANDA; Specifications  Use of 
Enforcement Discretion for Compendial Changes  
 
 
 
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 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 
telephone number listed on the title page of this guidance. 
 
 
 
 
I.  INTRODUCTION  
 
This guidance is intended to inform new drug application (NDA) and abbreviated new drug 
application (ANDA) holders of the Food and Drug Administration's (FDAs) plan to use 
enforcement discretion with regard to section 314.70(c)(2)(iii) of the final rule entitled 
Supplements and Other Changes to an Approved Application (21 CFR 314.70(c)(2)(iii)).2  This 
subsection describes the filing requirement that a relaxation of acceptance criteria or deletion of a 
test to comply with an official compendium must be reported in a changes-being-effected-in-30-
days supplement (CBE-30). In the exercise of its enforcement discretion, FDA does not intend to 
take enforcement action if manufacturers continue to submit such changes in their annual reports.  
The use of enforcement discretion will give the Agency time to clarify that some of these types 
of postapproval changes can be submitted in an annual report, rather than in a CBE-30.  The 
Agency intends to clarify this issue in an upcoming revision to the guidance for industry 
Changes to an Approved NDA or ANDA; Questions and Answers. 
 
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.  
 
 
                                                 
1 This guidance has been prepared by the Office of Compliance and the Office of Pharmaceutical Science in the 
Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration. 
  
2 See the Federal Register, Vol. 69, p. 18728, April 8, 2004. 
1 Contains Nonbinding Recommendations 
II.  BACKGROUND 
 
On April 8, 2004, FDA published in the Federal Register (69 FR 18728) the final rule entitled 
Supplements and Other Changes to an Approved Application.  In the same issue of the Federal 
Register (69 FR 18768), FDA announced the availability of the guidance for industry entitled 
Changes to an Approved NDA or ANDA (the Changes guidance).  The final rule sets forth 
requirements for postapproval changes.  
 
Under section 314.70(c)(2)(iii) of the final rule, the relaxation of acceptance criteria or deletion 
of a test to comply with an official compendium that is consistent with FDA statutory and 
regulatory requirements must be submitted as a supplement  changes-being-effected-in-30 days 
(CBE-30) (see section VIII.C.1.e of the Changes guidance).  Under 314.70(d)(2)(i) of the final 
rule, any change in a specification made to comply with an official compendium, except the 
relaxation of acceptance criteria or deletion of a test that is consistent with FDA statutory and 
regulatory requirements, is to be submitted as an Annual Report (see section VIII.D.1 of the 
Changes guidance).  
 
Since publication of the final rule, the Agency has received communications from NDA and 
ANDA holders requesting clarification of the regulation as it applies to changes such as excipient 
monographs and general chapters.  As written now, the regulations could be interpreted to 
require a CBE for any compendial change to relax or delete a test, resulting in an increase in the 
number of supplements, something that was not intended. The Agency plans to revise the 
Guidance for Industry:  Changes to an Approved NDA or ANDA; Questions and Answers to 
provide more specific recommendations as to what types of changes can be submitted in an 
annual report instead of a CBE-30 supplement.   
 
In addition, the Agency is aware that stakeholders have expressed concern that the final rule (i.e., 
21 CFR 314.70), which published on April 8, 2004, and the accompanying Changes guidance do 
not take into consideration the recent FDA Pharmaceutical CGMP Initiative for the 21st Century.  
Accordingly, the Agency plans to align this guidance with the initiative in order to facilitate 
manufacturing changes to enhance product quality.  
 
 
III.  EXERCISE OF ENFORCEMENT DISCRETION 
 
FDA intends to exercise enforcement discretion and does not intend to take action to enforce 
compliance with the compendial changes requirement as stated in 21 CFR 314.70(c)(2)(iii) if 
manufacturers submit such changes in their annual reports.  FDA intends to develop further 
guidance to clarify the requirements of 21 CFR 314.70(c)(2)(iii). 
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