[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2007]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR314.70]

[Page 112-116]
 
                        TITLE 21--FOOD AND DRUGS
 
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN 
                          SERVICES (CONTINUED)
 
PART 314_APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG--Table of Contents
 
                         Subpart B_Applications
 
Sec.  314.70  Supplements and other changes to an approved application.

    (a) Changes to an approved application. (1) The applicant notify FDA 
about each change in each condition established in an approved 
application beyond the variations already provided for in the 
application. The notice is required to describe the change fully. 
Depending on the type of change, the applicant must notify FDA about it 
in a supplement under paragraph (b) or (c) of this section or by 
inclusion of the information in the annual report to the application 
under paragraph (d) of this section.
    (2) The holder of an approved application under section 505 of the 
act must assess the effects of the change before distributing a drug 
product made with a manufacturing change.
    (3) Notwithstanding the requirements of paragraphs (b) and (c) of 
this section, an applicant must make a change provided for in those 
paragraphs in accordance with a regulation or guidance that provides for 
a less burdensome notification of the change (for example, by submission 
of a supplement that does not require approval prior to distribution of 
the product or in an annual report).
    (4) The applicant must promptly revise all promotional labeling and 
advertising to make it consistent with any labeling change implemented 
in accordance with paragraphs (b) and (c) of this section.
    (5) Except for a supplement providing for a change in the labeling, 
the applicant must include in each supplement and amendment to a 
supplement providing for a change under paragraph (b) or (c) of this 
section a statement certifying that a field copy has been provided in 
accordance with Sec.  314.440(a)(4).
    (6) A supplement or annual report must include a list of all changes 
contained in the supplement or annual report. For supplements, this list 
must be provided in the cover letter.
    (b) Changes requiring supplement submission and approval prior to 
distribution of the product made using the change (major changes). (1) A 
supplement must be submitted for any change in the drug substance, drug 
product, production process, quality controls, equipment, or facilities 
that has a substantial potential to have an adverse effect on the 
identity, strength, quality, purity, or potency of the drug product as 
these factors may relate to the safety or effectiveness of the drug 
product.
    (2) These changes include, but are not limited to:
    (i) Except those described in paragraphs (c) and (d) of this 
section, changes in the qualitative or quantitative formulation of the 
drug product, including inactive ingredients, or in the specifications 
provided in the approved application;
    (ii) Changes requiring completion of studies in accordance with part 
320 of this chapter to demonstrate the equivalence of the drug product 
to the drug product as manufactured without the change or to the 
reference listed drug;

[[Page 113]]

    (iii) Changes that may affect drug substance or drug product 
sterility assurance, such as changes in drug substance, drug product, or 
component sterilization method(s) or an addition, deletion, or 
substitution of steps in an aseptic processing operation;
    (iv) Changes in the synthesis or manufacture of the drug substance 
that may affect the impurity profile and/or the physical, chemical, or 
biological properties of the drug substance;
    (v) The following labeling changes:
    (A) Changes in labeling, except those described in paragraphs 
(c)(6)(iii), (d)(2)(ix), or (d)(2)(x) of this section;
    (B) If applicable, any change to a Medication Guide required under 
part 208 of this chapter, except for changes in the information 
specified in Sec.  208.20(b)(8)(iii) and (b)(8)(iv) of this chapter; and
    (C) Any change to the information required by Sec.  201.57(a) of 
this chapter, with the following exceptions that may be reported in an 
annual report under paragraph (d)(2)(x) of this section:
    (1) Removal of a listed section(s) specified in Sec.  201.57(a)(5) 
of this chapter; and
    (2) Changes to the most recent revision date of the labeling as 
specified in Sec.  201.57(a)(15) of this chapter.
    (vi) Changes in a drug product container closure system that 
controls the drug product delivered to a patient or changes in the type 
(e.g., glass to high density polyethylene (HDPE), HDPE to polyvinyl 
chloride, vial to syringe) or composition (e.g., one HDPE resin to 
another HDPE resin) of a packaging component that may affect the 
impurity profile of the drug product.
    (vii) Changes solely affecting a natural product, a recombinant DNA-
derived protein/polypeptide, or a complex or conjugate of a drug 
substance with a monoclonal antibody for the following:
    (A) Changes in the virus or adventitious agent removal or 
inactivation method(s);
    (B) Changes in the source material or cell line; and
    (C) Establishment of a new master cell bank or seed.
    (viii) Changes to a drug product under an application that is 
subject to a validity assessment because of significant questions 
regarding the integrity of the data supporting that application.
    (3) The applicant must obtain approval of a supplement from FDA 
prior to distribution of a drug product made using a change under 
paragraph (b) of this section. Except for submissions under paragraph 
(e) of this section, the following information must be contained in the 
supplement:
    (i) A detailed description of the proposed change;
    (ii) The drug product(s) involved;
    (iii) The manufacturing site(s) or area(s) affected;
    (iv) A description of the methods used and studies performed to 
assess the effects of the change;
    (v) The data derived from such studies;
    (vi) For a natural product, a recombinant DNA-derived protein/
polypeptide, or a complex or conjugate of a drug substance with a 
monoclonal antibody, relevant validation protocols and a list of 
relevant standard operating procedures must be provided in addition to 
the requirements in paragraphs (b)(3)(iv) and (b)(3)(v) of this section; 
and
    (vii) For sterilization process and test methodologies related to 
sterilization process validation, relevant validation protocols and a 
list of relevant standard operating procedures must be provided in 
addition to the requirements in paragraphs (b)(3)(iv) and (b)(3)(v) of 
this section.
    (4) An applicant may ask FDA to expedite its review of a supplement 
for public health reasons or if a delay in making the change described 
in it would impose an extraordinary hardship on the applicant. Such a 
supplement and its mailing cover should be plainly marked: ``Prior 
Approval Supplement-Expedited Review Requested.''
    (c) Changes requiring supplement submission at least 30 days prior 
to distribution of the drug product made using the change (moderate 
changes). (1) A supplement must be submitted for any change in the drug 
substance, drug product, production process, quality controls, 
equipment, or facilities that has a moderate potential to have an 
adverse effect on the identity, strength, quality, purity, or potency of 
the drug product as these factors may

[[Page 114]]

relate to the safety or effectiveness of the drug product. If the 
supplement provides for a labeling change under paragraph (c)(6)(iii) of 
this section, 12 copies of the final printed labeling must be included.
    (2) These changes include, but are not limited to:
    (i) A change in the container closure system that does not affect 
the quality of the drug product, except those described in paragraphs 
(b) and (d) of this section; and
    (ii) Changes solely affecting a natural protein, a recombinant DNA-
derived protein/polypeptide or a complex or conjugate of a drug 
substance with a monoclonal antibody, including:
    (A) An increase or decrease in production scale during finishing 
steps that involves different equipment; and
    (B) Replacement of equipment with that of a different design that 
does not affect the process methodology or process operating parameters.
    (iii) Relaxation of an acceptance criterion or deletion of a test to 
comply with an official compendium that is consistent with FDA statutory 
and regulatory requirements.
    (3) A supplement submitted under paragraph (c)(1) of this section is 
required to give a full explanation of the basis for the change and 
identify the date on which the change is to be made. The supplement must 
be labeled ``Supplement--Changes Being Effected in 30 Days'' or, if 
applicable under paragraph (c)(6) of this section, ``Supplement--Changes 
Being Effected.''
    (4) Pending approval of the supplement by FDA, except as provided in 
paragraph (c)(6) of this section, distribution of the drug product made 
using the change may begin not less than 30 days after receipt of the 
supplement by FDA. The information listed in paragraphs (b)(3)(i) 
through (b)(3)(vii) of this section must be contained in the supplement.
    (5) The applicant must not distribute the drug product made using 
the change if within 30 days following FDA's receipt of the supplement, 
FDA informs the applicant that either:
    (i) The change requires approval prior to distribution of the drug 
product in accordance with paragraph (b) of this section; or
    (ii) Any of the information required under paragraph (c)(4) of this 
section is missing; the applicant must not distribute the drug product 
made using the change until the supplement has been amended to provide 
the missing information.
    (6) The agency may designate a category of changes for the purpose 
of providing that, in the case of a change in such category, the holder 
of an approved application may commence distribution of the drug product 
involved upon receipt by the agency of a supplement for the change. 
These changes include, but are not limited to:
    (i) Addition to a specification or changes in the methods or 
controls to provide increased assurance that the drug substance or drug 
product will have the characteristics of identity, strength, quality, 
purity, or potency that it purports or is represented to possess;
    (ii) A change in the size and/or shape of a container for a 
nonsterile drug product, except for solid dosage forms, without a change 
in the labeled amount of drug product or from one container closure 
system to another;
    (iii) Changes in the labeling, except for changes to the information 
required in Sec.  201.57(a) of this chapter (which must be made pursuant 
to paragraph (b)(2)(v)(C) of this section), to accomplish any of the 
following:
    (A) To add or strengthen a contraindication, warning, precaution, or 
adverse reaction;
    (B) To add or strengthen a statement about drug abuse, dependence, 
psychological effect, or overdosage;
    (C) To add or strengthen an instruction about dosage and 
administration that is intended to increase the safe use of the drug 
product;
    (D) To delete false, misleading, or unsupported indications for use 
or claims for effectiveness; or
    (E) Any labeling change normally requiring a supplement submission 
and approval prior to distribution of the drug product that FDA 
specifically requests be submitted under this provision.
    (7) If the agency disapproves the supplemental application, it may 
order the manufacturer to cease distribution

[[Page 115]]

of the drug product(s) made with the manufacturing change.
    (d) Changes to be described in an annual report (minor changes). (1) 
Changes in the drug substance, drug product, production process, quality 
controls, equipment, or facilities that have a minimal potential to have 
an adverse effect on the identity, strength, quality, purity, or potency 
of the drug product as these factors may relate to the safety or 
effectiveness of the drug product must be documented by the applicant in 
the next annual report in accordance with Sec.  314.81(b)(2).
    (2) These changes include, but are not limited to:
    (i) Any change made to comply with a change to an official 
compendium, except a change described in paragraph (c)(2)(iii) of this 
section, that is consistent with FDA statutory and regulatory 
requirements.
    (ii) The deletion or reduction of an ingredient intended to affect 
only the color of the drug product;
    (iii) Replacement of equipment with that of the same design and 
operating principles except those equipment changes described in 
paragraph (c) of this section;
    (iv) A change in the size and/or shape of a container containing the 
same number of dosage units for a nonsterile solid dosage form drug 
product, without a change from one container closure system to another;
    (v) A change within the container closure system for a nonsterile 
drug product, based upon a showing of equivalency to the approved system 
under a protocol approved in the application or published in an official 
compendium;
    (vi) An extension of an expiration dating period based upon full 
shelf life data on production batches obtained from a protocol approved 
in the application;
    (vii) The addition or revision of an alternative analytical 
procedure that provides the same or increased assurance of the identity, 
strength, quality, purity, or potency of the material being tested as 
the analytical procedure described in the approved application, or 
deletion of an alternative analytical procedure;
    (viii) The addition by embossing, debossing, or engraving of a code 
imprint to a solid oral dosage form drug product other than a modified 
release dosage form, or a minor change in an existing code imprint;
    (ix) A change in the labeling concerning the description of the drug 
product or in the information about how the drug product is supplied, 
that does not involve a change in the dosage strength or dosage form; 
and
    (x) An editorial or similar minor change in labeling, including a 
change to the information allowed by paragraphs (b)(2)(v)(C)(1) and (2) 
of this section.
    (3) For changes under this category, the applicant is required to 
submit in the annual report:
    (i) A statement by the holder of the approved application that the 
effects of the change have been assessed;
    (ii) A full description of the manufacturing and controls changes, 
including the manufacturing site(s) or area(s) involved;
    (iii) The date each change was implemented;
    (iv) Data from studies and tests performed to assess the effects of 
the change; and,
    (v) For a natural product, recombinant DNA-derived protein/
polypeptide, complex or conjugate of a drug substance with a monoclonal 
antibody, sterilization process or test methodology related to 
sterilization process validation, a cross-reference to relevant 
validation protocols and/or standard operating procedures.
    (e) Protocols. An applicant may submit one or more protocols 
describing the specific tests and studies and acceptance criteria to be 
achieved to demonstrate the lack of adverse effect for specified types 
of manufacturing changes on the identity, strength, quality, purity, and 
potency of the drug product as these factors may relate to the safety or 
effectiveness of the drug product. Any such protocols, if not included 
in the approved application, or changes to an approved protocol, must be 
submitted as a supplement requiring approval from FDA prior to 
distribution of a drug product produced with the manufacturing change. 
The supplement, if approved,

[[Page 116]]

may subsequently justify a reduced reporting category for the particular 
change because the use of the protocol for that type of change reduces 
the potential risk of an adverse effect.
    (f) Patent information. The applicant must comply with the patent 
information requirements under section 505(c)(2) of the act.
    (g) Claimed exclusivity. If an applicant claims exclusivity under 
Sec.  314.108 upon approval of a supplement for change to its previously 
approved drug product, the applicant must include with its supplement 
the information required under Sec.  314.50(j).

[69 FR 18764, Apr. 8, 2004, as amended at 71 FR 3997, Jan. 24, 2006]