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 Industry1

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 (FDA’s) 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.
Contains Nonbinding Recommendations

2

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 requireme nts of 21 CFR 314.70(c)(2)(iii).