[Code of Federal Regulations]
[Title 21, Volume 7]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR601.12]

[Page 23-26]
 
                        TITLE 21--FOOD AND DRUGS
 
          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. As provided by this section, an applicant shall inform 
Food and Drug Administration (FDA) about each change in the product, 
production process, quality controls, equipment, facilities, responsible 
personnel, or labeling, established in the approved license 
application(s). Before distributing a product made using a change, an 
applicant shall demonstrate through appropriate validation and/or other 
clinical and/or non-clinical 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.
    (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) Changes in the qualitative or quantitative formulation or other 
specifications as provided in the approved application or in the 
regulations;
    (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).

[[Page 24]]

    (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) Change in the site of testing from one facility to another;
    (ii) An increase or decrease in production scale during finishing 
steps that involves new or different equipment; and
    (iii) Replacement of equipment with that of similar, but not 
identical, design and operating principle that does not affect the 
process methodology or process operating parameters.
    (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.
    (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, 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 an official compendium that is 
consistent with FDA requirements;
    (ii) The deletion 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 date based upon full shelf-life 
data obtained from a protocol approved in the application;
    (iv) A change within the container and closure system for solid 
dosage forms, based upon a showing of equivalency to the approved system 
under a

[[Page 25]]

protocol approved in the application or published in an official 
compendium;
    (v) A change in the size of a container for a solid dosage form, 
without a change from one container and closure system to another;
    (vi) The addition by embossing, debossing, or engraving of a code 
imprint 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 deletion of an alternate analytical method.
    (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.
    (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. 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 
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.
    (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

[[Page 26]]

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; and
    (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.
    (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 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.
    (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.]