0338 21cfr601 12 2007

§ 601.8

21 CFR Ch. I (4–1–05 Edition)

(c) When a license has been suspended
pursuant to § 601.6 and a hearing request has been granted, the hearing
shall proceed on an expedited basis.

(see mailing addresses in § 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
(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,

[42 FR 4718, Jan. 25, 1977, as amended at 42
FR 15676, Mar. 22, 1977; 42 FR 19143, Apr. 12,
1977]

§ 601.8 Publication of revocation.
Notice of revocation of a license,
with statement of the cause therefor,
shall be issued by the Commissioner
and published in the FEDERAL REGISTER.
[42 FR 4718, Jan. 25, 1977]

§ 601.9 Licenses; reissuance.
(a) Compliance with requirements. A
biologics license, previously suspended
or revoked, may be reissued or reinstated upon a showing of compliance
with requirements and upon such inspection and examination as may be
considered necessary by the Director,
Center for Biologics Evaluation and
Research or the Director, Center for
Drug Evaluation and Research.
(b) Exclusion of noncomplying location.
A biologics license, excluding a location or locations that fail to comply
with the requirements in this chapter,
may be issued without further application and concurrently with the suspension or revocation of the license for
noncompliance at the excluded location or locations.
(c) Exclusion of noncomplying product(s). In the case of multiple products
included under a single biologics license application, a biologics license
may be issued, excluding the noncompliant product(s), without further
application and concurrently with the
suspension or revocation of the biologics license for a noncompliant product(s).
[64 FR 56451, Oct. 20, 1999, as amended at 70
FR 14983, Mar. 24, 2005]

Subpart B [Reserved]
Subpart C—Biologics Licensing
§ 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)

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Food and Drug Administration, HHS

§ 601.12
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
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,

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

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§ 601.12

21 CFR Ch. I (4–1–05 Edition)

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
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

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Food and Drug Administration, HHS

§ 601.12

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.
(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.
(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; and
(C) A change in the information specified in § 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 or Center for Drug Evaluation and Research in accordance
with the requirements set forth in
§ 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.

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§ 601.14

21 CFR Ch. I (4–1–05 Edition)

(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 § 10.75
of this chapter, an applicant may request internal FDA review of FDA employee decisions under this section.

mailing addresses in § 600.2 of this chapter) must be at least two final containers of each lot of product. A copy
of the associated documents which describe and identify the shipment must
accompany the shipment for forwarding with the samples to the Director, Center for Biologics Evaluation
and Research or the Director, Center
for Drug Evaluation and Research (see
mailing addresses in § 600.2). For shipments of 20 or less final containers,
samples need not be forwarded, provided a copy of an official release from
the Center for Biologics Evaluation
and Research or Center for Drug Evaluation and Research accompanies each
shipment.

[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]

[70 FR 14983, Mar. 24, 2005]

§ 601.14 Regulatory submissions in
electronic format.
(a) General. Electronic format submissions must be in a form that FDA
can process, review, and archive. FDA
will periodically issue guidance on how
to provide the electronic submission
(e.g., method of transmission, media,
file formats, preparation and organization of files.)
(b) Labeling. The content of labeling
required under § 201.100(d)(3) of this
chapter (commonly referred to as the
package insert or professional labeling), including all text, tables, and figures, must be submitted to the agency
in electronic format as described in
paragraph (a) of this section. This requirement is in addition to the provisions of §§ 601.2(a) and 601.12(f) that require applicants to submit specimens
of the labels, enclosures, and containers, or to submit other final printed labeling. Submissions under this
paragraph must be made in accordance
with part 11 of this chapter except for
the requirements of § 11.10(a), (c)
through (h), and (k), and the corresponding requirements of § 11.30.

§ 601.20 Biologics licenses; issuance
and conditions.
(a) Examination—compliance with requirements. A biologics license application shall be approved only upon examination of the product and upon a determination that the product complies
with the standards established in the
biologics license application and the
requirements prescribed in the regulations in this chapter including but not
limited to the good manufacturing
practice requirements set forth in
parts 210, 211, 600, 606, and 820 of this
chapter.
(b) Availability of product. No biologics license shall be issued unless:
(1) The product intended for introduction into interstate commerce is
available for examination, and
(2) Such product is available for inspection during all phases of manufacture.
(c) Manufacturing process—impairment
of assurances. No product shall be licensed if any part of the process of or
relating to the manufacture of such
product, in the judgment of the Director, Center for Biologics Evaluation
and Research or the Director, Center
for Drug Evaluation and Research,
would impair the assurances of continued safety, purity, and potency as provided by the regulations contained in
this chapter.
(d) Inspection—compliance with requirements. A biologics license shall be
issued or a biologics license application
approved only after inspection of the

[68 FR 69020, Dec. 11, 2003]

§ 601.15 Foreign establishments and
products: samples for each importation.
Random samples of each importation, obtained by the District Director
of Customs and forwarded to the Director, Center for Biologics Evaluation
and Research or the Director, Center
for Drug Evaluation and Research (see

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