[Code of Federal Regulations]
[Title 21, Volume 6]
[Revised as of January 1, 2003]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR514.8]

[Page 67-71]
 
                        TITLE 21--FOOD AND DRUGS
 
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN 
                          SERVICES (CONTINUED)
 
PART 514--NEW ANIMAL DRUG APPLICATIONS--Table of Contents
 
                      Subpart A--General Provisions
 
Sec.  514.8  Supplemental new animal drug applications.

    (a)(1) After a new animal drug application is approved, a 
supplemental new animal drug application may propose changes. A 
supplemental application may omit statements made in the approved 
application concerning which no change is proposed. Each supplemental 
application shall include up-to-date reports of any of the kinds of 
information required by Sec.  510.300(a) of this chapter that has not 
previously been submitted. A supplemental application shall be 
accompanied by either a claim for categorical exclusion under Sec.  
25.30 or Sec.  25.33 of this chapter or an environmental assessment 
under Sec.  25.40 of this chapter.
    (2) A supplemental new animal drug application shall be submitted 
for any change beyond the variations provided for in the application, 
including changes in the scale of production such as from pilot-plant to 
production batch, that may alter the conditions of use, the labeling, 
safety, effectiveness, identity, strength, quality, or purity of the new 
animal drug, or the adequacy of the manufacturing methods, facilities, 
or controls to preserve them.

[[Page 68]]

    (3) If it is a prescription drug, any mailing or promotional piece 
used after the drug is placed on the market is labeling requiring a 
supplemental application, unless:
    (i) The parts of the labeling furnishing directions, warnings, and 
information for use of the drug are the same in language and emphasis as 
labeling approved or permitted; and
    (ii) Any other parts of the labeling are consistent with and not 
contrary to such approved or permitted labeling.
    (4) The supplemental application shall be submitted as follows. A 
communication proposing a change in a new animal drug application should 
provide for any one of the following kinds of changes:
    (i) Revision in labeling, such as updating information pertaining to 
effects, dosages, and side effects and contraindications, which includes 
information headed ``side effects,'' ``warnings,'' ``precautions,'' and 
``contraindications.''
    (ii) Addition of claim.
    (iii) Revision in manufacturing or control procedures; for example, 
changes in components, composition, method of manufacture, analytical 
control procedures, package or tablet size, etc.
    (iv) Change in manufacturing facilities.
    (v) Provision for outside firm to participate in the preparation, 
distribution, or packaging of a new animal drug (new distributor, 
packer, supplier, manufacturer, etc.); one firm per submission.

Any number of changes may be submitted at any one time; but if they fall 
into different categories as listed in paragraphs (a)(4) (i) through (v) 
of this section, the proposed changes should be covered by separate 
communications. Where, however, a change necessitates an overlap in 
categories, it should be submitted in a single communication. For 
example, a change in tablet potency would require other changes such as 
in components, composition, and labeling and should be submitted in a 
single communication.
    (5) The following kinds of changes may be placed into effect without 
the approval of a supplemental application, if such change is fully 
described in the next periodic report required under Sec.  510.300(b)(4) 
of this chapter or, when such a report is not required, in a written 
communication to the Food and Drug Administration within 60 days of the 
effective date of the change (this does not apply to a change proposed 
because of any mixup or any bacteriological or significant chemical, 
physical, or other change or deterioration in the drug or any failure of 
one or more distributed batches of the drug to meet its specifications):
    (i) A different container size for solid oral dosage forms where 
container and closure are of the same materials as those provided for in 
the approved application.
    (ii) Change in personnel not involving new facilities.
    (iii) Change in equipment that does not alter the method of 
manufacture of a new animal drug.
    (iv) Change from one commercial batch size to another without any 
change in manufacturing procedure.
    (v) Change to more stringent specification without altering the 
method described in the approved application.
    (vi) Inclusion of additional specifications and methods without 
deletion of those described in the approved application.
    (vii) Alteration of specifications or methods for inactive 
ingredients to bring them into compliance with new or revised 
specifications or methods in an official compendium.
    (viii) Initiation of a product identification coding system.
    (ix) Addition to labeling of a reasonable expiration date where none 
was previously used, with related conditions of drug storage when 
appropriate, except when evidence shows that a significant deterioration 
of the drug under marketing conditions has occurred which necessitates 
the immediate submission of a report under Sec.  510.300(b)(1) of this 
chapter. The report or written communication describing such change in 
labeling should include stability data justifying the expiration date 
and recommended conditions of storage.
    (x) Change from paper labels to direct printing on glass or other 
kinds of immediate containers without a change in text.

[[Page 69]]

    (6) Approval of a supplemental new animal drug application will not 
be required to provide for an additional distributor to distribute a 
drug which is the subject of an approved new animal drug application if 
the conditions described below are met prior to putting such a change 
into effect. An order may issue refusing approval if any condition is 
not met or if any of the reasons for refusing or withdrawing approval, 
as stated in section 512(d) and (e) of the act or Sec.  514.110 applies. 
For the purposes of maintaining records and making reports under the 
requirements of Sec.  510.300 of this chapter, a distributor provided 
for under this section shall be considered an applicant within the 
meaning of Sec.  510.300(b) of this chapter. Said conditions are:
    (i) A supplemental application is furnished to the Food and Drug 
Administration to provide for a designated distributor.
    (ii) There are no changes from the conditions of the approved 
application except for a different and suitable proprietary name of the 
new animal drug (if one is used) and the name and address of the 
distributor as used on the label and labeling. The name of the 
distributor shall be accompanied by an appropriate qualifying phrase 
such as ``manufactured for'' or ``distributed by.''
    (iii) A distributor's statement is furnished to the Food and Drug 
Administration identifying the category of his operations (for example, 
wholesaler, retailer) and stating: That he will distribute the new 
animal drug only under the labeling provided for in the new animal drug 
application; that any other labeling or advertising for the drug will 
prescribe, recommend, or suggest its use only under the conditions 
stated in the labeling provided for in the application; and, if the drug 
is a prescription article, that he is regularly and lawfully engaged in 
the distribution or dispensing of prescription drugs.
    (iv) Nine copies of the printed labels and other labeling to be used 
by the distributor are submitted, identified with the new animal drug 
application number.
    (b) When necessary for the safety or effectiveness of the drug, a 
supplemental new animal drug application shall specify a period of time 
within which the proposed change will be made.
    (c) If a material change is made in the components' composition, 
manufacturing methods, facilities, or controls, or in the labeling or 
advertising, from the representations in an approved application for a 
new animal drug (except changes conforming to the conditions set forth 
in paragraph (a)(5) and (6) and/or paragraphs (d), (e), (f), and (g) of 
this section), and the drug is marketed before a supplement is approved 
for such change, approval of the application may be suspended or 
withdrawn as provided in section 512(e) of the act.
    (d) Changes of the following kinds proposed in supplemental new 
animal drug applications should be placed into effect at the earliest 
possible time:
    (1) The addition to package labeling, promotional labeling, and 
prescription drug advertising of additional warning, contraindication, 
side effect, and precaution information.
    (2) The deletion from package labeling, promotional labeling, and 
drug advertising of false, misleading, or unsupported indications for 
use or claims for effectiveness.
    (3) Changes in the methods, facilities, or controls used for the 
manufacture, processing, packing, or holding of the new animal drug 
(other than utilization of establishments not covered by the approval 
that is in effect) that give increased assurance that the drug will have 
the characteristics of identity, strength, quality, and purity which it 
purports or is represented to possess.
    (e) The Food and Drug Administration will take no action against a 
new animal drug or applicant solely because changes of the kinds 
described in paragraph (d) of this section are placed into effect by the 
applicant prior to his receipt of a written notice of approval of the 
supplemental new animal drug application if all the following conditions 
are met:
    (1) The supplemental new animal drug application providing a full 
explanation of the basis for the changes has been submitted, plainly 
marked on the mailing cover and on the supplement,

[[Page 70]]

``Special new animal drug application Supplement--changes being 
effected.''
    (2) The applicant specifically informs the Food and Drug 
Administration of the date on which such changes are being effected and 
submits to the Administration nine printed copies of any revised 
labeling to be placed in use, identified with the new animal drug 
application number.
    (3) All promotional labeling and all drug advertising are promptly 
revised consistent with the changes made in the labeling on or within 
the new animal drug package.
    (f) When a supplemental new animal drug application proposes changes 
only of the kinds described in paragraph (d) of this section, and the 
applicant informs the Food and Drug Administration that the changes are 
being put into effect, such notification will be regarded as an 
agreement by the applicant to an extension of the time for formal action 
on the application.
    (g) In addition to changes as permitted by paragraphs (d) and (e) of 
this section, an applicant may place into effect changes proposed in a 
supplement to a new animal drug application that became effective prior 
to October 10, 1962, upon written notification from the Food and Drug 
Administration that such action is permitted, without approval of the 
supplemental application, pending the completion of the review of the 
effectiveness of such drug by the National Academy of Sciences-National 
Research Council and a determination as to whether there are grounds for 
refusing approval under section 512(d) of the act or for invoking 
section 512(e) of the act. The Food and Drug Administration will take no 
action against a new animal drug or an applicant solely because changes 
that have been permitted in a written communication are placed into 
effect by the applicant prior to his receipt of a written notice of 
approval of the supplemental new animal drug application.
    (h) Except as provided in paragraphs (e) and (g) of this section, no 
provision of this section shall limit the authority of the Secretary or 
of the Commissioner to suspend or withdraw approval of a new animal drug 
application in accord with the provisions of section 512(e) of the act 
or to initiate any other regulatory proceedings with respect to a drug 
or applicant under provisions of the act.
    (i) Changes from the conditions of an approved new animal drug 
application in accord with the provisions of paragraphs (d), (e), and 
(g) of this section are permitted on the basis of a temporary deferral 
of final action on the supplemental application under the provisions of 
section 512 (c), (d), or (e) of the act.
    (j) When an applicant receives written notification from the Food 
and Drug Administration, under the provisions of paragraph (g) of this 
section, that he may place into effect changes proposed in a 
supplemental application without approval of the supplemental 
application, he may within 30 days submit a written request that the 
Food and Drug Administration process the supplemental application. In 
such case, the change shall not be put into effect until approved. 
Within 180 days of the receipt of such written request, the Food and 
Drug Administration will approve the supplemental application or furnish 
notice of an opportunity for a hearing under the provisions of section 
512 (d) or (e), or both, of the act on a proposal to refuse approval of 
the supplemental application or to withdraw approval of the application 
and supplements thereto.
    (k) A supplement to an application that became effective prior to 
October 10, 1962, may include a written statement to the effect that a 
temporary deferral of final action under the provisions of paragraph 
(d), (e), or (g) of this section is unacceptable to the applicant and 
that the applicant requests action as provided in section 512(c) of the 
act. Final action on such supplemental applications will be expedited in 
accord with applicable provisions of section 512 of the act and 
regulations in this subchapter E. In such cases, if the applicant places 
into effect any of the proposed changes prior to his receipt of a 
written notice of approval of the supplemental new animal drug 
application, such action may be regarded by the Food and Drug 
Administration as a basis for invoking the provisions of section 
512(e)(1)(D) of the act; that

[[Page 71]]

is, the applicant may be furnished notice of an opportunity for a 
hearing on a proposal to withdraw approval of the application on the 
ground that the application contains an untrue statement of a material 
fact related to the changes from the conditions approved in the 
application.
    (l) A supplemental application that contains nonclinical laboratory 
studies shall include, with respect to each nonclinical study, either a 
statement that the study was conducted in compliance with the 
requirements set forth in part 58 of this chapter, or, if the study was 
not conducted in compliance with such regulations, a brief statement of 
the reason for the noncompliance.

[40 FR 13825, Mar. 27, 1975, as amended at 50 FR 7517, Feb. 22, 1985; 50 
FR 16668, Apr. 26, 1985; 62 FR 40600, July 29, 1997]

    Effective Date Note: At 68 FR 15365, Mar. 31, 2003, Sec.  514.8 was 
amended in paragraph (a)(1) by removing ``Sec.  510.300(a) of this 
chapter'' and by adding in its place ``Sec.  514.80''; in paragraph 
(a)(5) by removing ``Sec.  510.300(b)(4) of this chapter'' and by adding 
in its place ``Sec.  514.80(b)(4)''; in paragraph (a)(5)(ix) by removing 
``Sec.  510.300(b)(1) of this chapter'' and by adding in its place 
``Sec.  514.80 (b)(1)''; and by revising paragraph (a)(6), effective 
June 30, 2003. For the convenience of the user, the revised text is set 
forth as follows:

Sec.  514.8  Supplemental new animal drug applications.

    (a) * * *
    (6) Approval of a supplemental new animal drug application will not 
be required to provide for an additional distributor to distribute a 
drug which is the subject of an approved new animal drug application if 
the conditions described in Sec.  514.80(b)(5)(iii) are met before 
putting such a change into effect.

                                * * * * *