[Code of Federal Regulations]
[Title 21, Volume 7]
[Revised as of April 1, 2008]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR601.12]

[Page 24-28]
 
                        TITLE 21--FOOD AND DRUGS
 
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN 
                          SERVICES (CONTINUED)
 
PART 601_LICENSING--Table of Contents
 
                      Subpart C_Biologics Licensing
 
Sec. 601.12  Changes to an approved application.


    (a) General. (1) As provided by this section, an applicant must 
inform the Food and Drug Administration (FDA) (see mailing addresses in 
Sec. 600.2 of this chapter) about each change in the product, 
production process, quality controls, equipment, facilities, responsible 
personnel, or labeling established in the approved license 
application(s).
    (2) Before distributing a product made using a change, an applicant 
must assess the effects of the change and demonstrate through 
appropriate validation and/or other clinical and/or nonclinical 
laboratory studies the lack of adverse effect of the change on the 
identity, strength, quality, purity, or potency of the product as they 
may relate to the safety or effectiveness of the product.
    (3) Notwithstanding the requirements of paragraphs (b), (c), and (f) 
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

[[Page 25]]

(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 (f)(1) and (f)(2) of this section.
    (5) 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 shall be submitted for any change in the product, production 
process, quality controls, equipment, facilities, or responsible 
personnel that has a substantial potential to have an adverse effect on 
the identity, strength, quality, purity, or potency of the product as 
they may relate to the safety or effectiveness of the product.
    (2) These changes include, but are not limited to:
    (i) Except as provided in paragraphs (c) and (d) of this section, 
changes in the qualitative or quantitative formulation, including 
inactive ingredients, or in the specifications provided in the approved 
application;
    (ii) Changes requiring completion of an appropriate human study to 
demonstrate the equivalence of the identity, strength, quality, purity, 
or potency of the product as they may relate to the safety or 
effectiveness of the product;
    (iii) Changes in the virus or adventitious agent removal or 
inactivation method(s);
    (iv) Changes in the source material or cell line;
    (v) Establishment of a new master cell bank or seed; and
    (vi) Changes which may affect product sterility assurance, such as 
changes in product or component sterilization method(s), or an addition, 
deletion, or substitution of steps in an aseptic processing operation.
    (3) The applicant must obtain approval of the supplement from FDA 
prior to distribution of the product made using the change. Except for 
submissions under paragraph (e) of this section, the following shall be 
contained in the supplement:
    (i) A detailed description of the proposed change;
    (ii) The product(s) involved;
    (iii) The manufacturing site(s) or area(s) affected;
    (iv) A description of the methods used and studies performed to 
evaluate the effect of the change on the identity, strength, quality, 
purity, or potency of the product as they may relate to the safety or 
effectiveness of the product;
    (v) The data derived from such studies;
    (vi) Relevant validation protocols and data; and
    (vii) A reference list of relevant standard operating procedures 
(SOP's).
    (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 product made using the change. (1) A supplement 
shall be submitted for any change in the product, production process, 
quality controls, equipment, facilities, or responsible personnel that 
has a moderate potential to have an adverse effect on the identity, 
strength, quality, purity, or potency of the product as they may relate 
to the safety or effectiveness of the product. The supplement shall be 
labeled ``Supplement--Changes Being Effected in 30 Days'' or, if 
applicable under paragraph (c)(5) of this section, ``Supplement--Changes 
Being Effected.''
    (2) These changes include, but are not limited to:
    (i) [Reserved]
    (ii) An increase or decrease in production scale during finishing 
steps that involves different equipment; and
    (iii) Replacement of equipment with that of similar, but not 
identical, design and operating principle that does

[[Page 26]]

not affect the process methodology or process operating parameters.
    (iv) 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) Pending approval of the supplement by FDA, and except as 
provided in paragraph (c)(5) of this section, distribution of the 
product made using the change may begin not less than 30 days after 
receipt of the supplement by FDA. The information listed in paragraph 
(b)(3)(i) through (b)(3)(vii) of this section shall be contained in the 
supplement.
    (4) 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 
product in accordance with paragraph (b) of this section; or
    (ii) Any of the information required under paragraph (c)(3) of this 
section is missing; the applicant shall not distribute the product made 
using the change until FDA determines that compliance with this section 
is achieved.
    (5) In certain circumstances, FDA may determine that, based on 
experience with a particular type of change, the supplement for such 
change is usually complete and provides the proper information, and on 
particular assurances that the proposed change has been appropriately 
submitted, the product made using the change may be distributed 
immediately upon receipt of the supplement by FDA. These circumstances 
may include substantial similarity with a type of change regularly 
involving a ``Supplement--Changes Being Effected'' supplement or a 
situation in which the applicant presents evidence that the proposed 
change has been validated in accordance with an approved protocol for 
such change under paragraph (e) of this section.
    (6) If the agency disapproves the supplemental application, it may 
order the manufacturer to cease distribution of the products made with 
the manufacturing change.
    (d) Changes to be described in an annual report (minor changes). (1) 
Changes in the product, production process, quality controls, equipment, 
facilities, or responsible personnel that have a minimal potential to 
have an adverse effect on the identity, strength, quality, purity, or 
potency of the product as they may relate to the safety or effectiveness 
of the product shall be documented by the applicant in an annual report 
submitted each year within 60 days of the anniversary date of approval 
of the application. The Director, Center for Biologics Evaluation and 
Research or the Director, Center for Drug Evaluation and Research, may 
approve a written request for an alternative date to combine annual 
reports for multiple approved applications into a single annual report 
submission.
    (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)(iv) of this 
section, that is consistent with FDA statutory and regulatory 
requirements.
    (ii) The deletion or reduction of an ingredient intended only to 
affect the color of the product, except that a change intended only to 
affect Blood Grouping Reagents requires supplement submission and 
approval prior to distribution of the product made using the change in 
accordance with the requirements set forth in paragraph (b) of this 
section;
    (iii) An extension of an expiration dating period based upon full 
shelf life data on production batches obtained from a protocol approved 
in the application;
    (iv) A change within the container closure system for a nonsterile 
product, based upon a showing of equivalency to the approved system 
under a protocol approved in the application or published in an official 
compendium;
    (v) A change in the size and/or shape of a container containing the 
same number of dosage units for a nonsterile solid dosage form product, 
without a change from one container closure system to another;
    (vi) The addition by embossing, debossing, or engraving of a code 
imprint

[[Page 27]]

to a solid dosage form biological product other than a modified release 
dosage form, or a minor change in an existing code imprint; and
    (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.
    (3) The following information for each change shall be contained in 
the annual report:
    (i) A list of all products involved; and
    (ii) A full description of the manufacturing and controls changes 
including: the manufacturing site(s) or area(s) involved; the date the 
change was made; a cross-reference to relevant validation protocols and/
or SOP's; and relevant data from studies and tests performed to evaluate 
the effect of the change on the identity, strength, quality, purity, or 
potency of the product as they may relate to the safety or effectiveness 
of the product.
    (iii) A statement by the holder of the approved application or 
license that the effects of the change have been assessed.
    (4) The applicant shall submit the report to the FDA office 
responsible for reviewing the application. The report shall include all 
the information required under this paragraph for each change made 
during the annual reporting interval which ends on the anniversary date 
in the order in which they were implemented.
    (e) An applicant may submit one or more protocols describing the 
specific tests and validation studies and acceptable limits to be 
achieved to demonstrate the lack of adverse effect for specified types 
of manufacturing changes on the identity, strength, quality, purity, or 
potency of the product as they may relate to the safety or effectiveness 
of the product. Any such protocols, or change to a protocol, shall be 
submitted as a supplement requiring approval from FDA prior to 
distribution of the product which, if approved, may 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) Labeling changes. (1) Labeling changes requiring supplement 
submission--FDA approval must be obtained before distribution of the 
product with the labeling change. Except as described in paragraphs 
(f)(2) and (f)(3) of this section, an applicant shall submit a 
supplement describing a proposed change in the package insert, package 
label, container label, or, if applicable, a Medication Guide required 
under part 208 of this chapter, and include the information necessary to 
support the proposed change. An applicant cannot use paragraph (f)(2) of 
this section to make any change to the information required in Sec. 
201.57(a) of this chapter. An applicant may report the minor changes to 
the information specified in paragraph (f)(3)(i)(D) of this section in 
an annual report. The supplement shall clearly highlight the proposed 
change in the labeling. The applicant shall obtain approval from FDA 
prior to distribution of the product with the labeling change.
    (2) Labeling changes requiring supplement submission--product with a 
labeling change that may be distributed before FDA approval. (i) An 
applicant shall submit, at the time such change is made, a supplement 
for any change in the package insert, package label, or container label, 
except for changes to the package insert required in Sec. 201.57(a) of 
this chapter (which must be made pursuant to paragraph (f)(1) 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 abuse, dependence, 
psychological effect, or overdosage;
    (C) To add or strengthen an instruction about dosage and 
administration that is intended to increase the safety of the use of the 
product; and
    (D) To delete false, misleading, or unsupported indications for use 
or claims for effectiveness.
    (E) Any labeling change normally requiring a supplement submission 
and approval prior to distribution of the product that FDA specifically 
requests be submitted under this provision.

[[Page 28]]

    (ii) Pending approval of the supplement by FDA, the applicant may 
distribute a product with a package insert, package label, or container 
label bearing such change at the time the supplement is submitted. The 
supplement shall clearly identify the change being made and include 
necessary supporting data. The supplement and its mailing cover shall be 
plainly marked: ``Special Labeling Supplement--Changes Being Effected.''
    (3) Labeling changes requiring submission in an annual report. (i) 
An applicant shall submit any final printed package insert, package 
label, container label, or Medication Guide required under part 208 of 
this chapter incorporating the following changes in an annual report 
submitted to FDA each year as provided in paragraph (d)(1) of this 
section:
    (A) Editorial or similar minor changes;
    (B) A change in the information on how the product is supplied that 
does not involve a change in the dosage strength or dosage form;
    (C) A change in the information specified in Sec. 208.20(b)(8)(iii) 
and (b)(8)(iv) of this chapter for a Medication Guide; and
    (D) A change made pursuant to an exception or alternative granted 
under Sec. 201.26 or Sec. 610.68 of this chapter.
    (ii) The applicant may distribute a product with a package insert, 
package label, or container label bearing such change at the time the 
change is made.
    (4) Advertisements and promotional labeling. Advertisements and 
promotional labeling shall be submitted to the Center for Biologics 
Evaluation and Research or Center for Drug Evaluation and Research in 
accordance with the requirements set forth in Sec. 314.81(b)(3)(i) of 
this chapter, except that Form FDA-2567 (Transmittal of Labels and 
Circulars) or an equivalent form shall be used.
    (5) The submission and grant of a written request for an exception 
or alternative under Sec. 201.26 or Sec. 610.68 of this chapter 
satisfies the requirements in paragraphs (f)(1) through (f)(2) of this 
section.
    (g) Failure to comply. In addition to other remedies available in 
law and regulations, in the event of repeated failure of the applicant 
to comply with this section, FDA may require that the applicant submit a 
supplement for any proposed change and obtain approval of the supplement 
by FDA prior to distribution of the product made using the change.
    (h) Administrative review. Under Sec. 10.75 of this chapter, an 
applicant may request internal FDA review of FDA employee decisions 
under this section.

[62 FR 39901, July 24, 1997, as amended at 63 FR 66399, Dec. 1, 1998. 
Redesignated at 65 FR 59718, Oct. 6, 2000, and amended at 69 FR 18766, 
Apr. 8, 2004; 70 FR 14983, Mar. 24, 2005; 71 FR 3997, Jan. 24, 2006; 72 
FR 73600, Dec. 28, 2007]