**SUPPORTING STATEMENT**

# Docket Number 1999N-0193

OMB Number 0910-0538

Supplements and Other Changes to an Approved Application -

Final Rule

**A. [Justification]{.underline}**

**1. [Circumstances of Information Collection]{.underline}**

This information collection approval request is for a Food and Drug
Administration (FDA) final rule to amend its regulations on supplements
and other changes to an approved application. The rule implements the
manufacturing changes provision of section 116 of the Food and Drug
Administration Modernization Act and require manufacturers to validate
the effect of any manufacturing change on the identity, strength,
quality, purity, and potency of a drug or biological product as those
factors relate to the safety or effectiveness of the product. The
respondent must report the change to FDA in one of the following ways
depending on the potential for the change to have an adverse effect on
the safety or effectiveness of the product: (1) Changes that have a
substantial potential to have an adverse effect on a product must be
submitted in a supplement requiring prior approval by FDA before
distribution of the product made using the change; (2) changes that have
a moderate potential to have an adverse effect on a product must be
submitted to FDA in a supplement not less than 30 days prior to
distribution of the product made using the change; (3) changes that have
a moderate potential to have an adverse effect on a product must be
submitted to FDA in a supplement at the time of distribution of the
product made using the change ; and (4) changes that have a minimal
potential to have an adverse effect on a product must be documented by
the respondent in the next annual report.

Sections 314.70(a)(2) and 601.12(a)(2) require the holder of an approved
application to assess the effects of a manufacturing change on the
identity, strength, quality, purity, or potency of the drug as these
factors may relate to the safety or effectiveness of the drug before
distributing a drug made with the change.

Sections 314.70(a)(4) and 601.12(a)(4) require the applicant to promptly
revise all promotional labeling and advertising to make it consistent
with any labeling change implemented. The transmittal to FDA of
advertisements and promotional labeling for drugs and biologics is
accompanied by Form FDA 2253 and regulated by 21 CFR 314.81(b)(3)(i) and
21 CFR 601.12(f)(4).

Section 314.70(a)(5) requires that the applicant include in each
supplement (except for a supplement providing for a change in the
labeling) and amendment to each supplement a statement certifying that a
field copy of the supplement has been provided to the applicant\'s home
FDA district office.

Sections 314.70(a)(6) and 601.12(a)(5) require the applicant to include,
in the cover letter for supplements, a list of all changes contained in
the supplement or annual report.

Section 314.70(b) and current \' 601.12(b) set forth requirements for
changes requiring supplement submission and approval prior to
distribution of the product made using the change (major changes).
Section 314.70(b)(1) and current § 601.12(b)(1) state that 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.

Under § 314.70(b)(3) and current § 601.12(b)(3), the applicant must
obtain approval of a supplement from FDA prior to distribution of a
product made using the change, and the following must 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 assess the effects of the change; (v) The data derived from such
studies; (vi) For a natural product, a recombinant DNA-derived
protein/polypeptide product, 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); and
(vii) For sterilization process and test methodologies, 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).

The changes requiring supplement submission and approval prior to
distribution of the product made using the change (major changes) are
listed in § 314.70(b)(2) and current § 601.12(b)(2) (including §
601.12(b)(2)(i)): (i) Except those described in paragraphs (c) and (d),
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 21 CFR 320 to demonstrate the equivalence
of the drug product to the drug product as manufactured without the
change or to the reference listed drug; (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 (c)(6)(iii), (d)(2)(ix), or (d)(2)(x); (B) If applicable,
any change to a Medication Guide required 21 CFR part 208, except for
changes in the information specified in § 208.20(b)(8)(iii) and
(b)(8)(iv); (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; and (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.

Under §§ 314.70(b)(4) and 601.12(b)(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 marked: \"Prior Approval Supplement-Expedited Review
Requested.\"

Section 314.70(c) and current § 601.12(c) set forth requirements for
changes requiring supplement submission at least 30 days prior to
distribution of the product made using the change (moderate changes).
Section 314.70(c)(1) and current § 601.12(c)(1) state that 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 product as these factors
may relate to the safety or effectiveness of the product. Under §
314.70(c)(1), the applicant must submit 12 copies of final printed
labeling for all labeling changes.

Under § 314.70(c)(3) and current § 601.12(c)(1), the supplement must set
forth 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.\" Under § 314.70(c)(4)
and current § 601.12(c)(3), 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 above for § 314.70(b)(3) and current §
601.12(b)(3) must be contained in the supplement.

The changes requiring supplement submission at least 30 days prior to
distribution of the product made using the change (moderate changes) are
listed in § 314.70(c)(2) (the changes in § 314.70(c)(2)(ii)(A) and (B)
are also listed in current § 601.12(c)(2)): (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); 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.

Under § 314.70(c)(6) and current § 601.12(c)(5), FDA 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: (i)
Addition to a specification or changes in the methods or controls to
provide increased assurance that the drug substance 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 product or
from one container closure system to another; (iii) Changes in the
labeling 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 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 §
314.70(c)(3) and current § 601.12(c)(1), the supplement must be labeled
\"Supplement\--Changes Being Effected in 30 Days\" or, if applicable,
\"Supplement\--Changes Being Effected.\"

Section 314.70(d) and current § 601.12(d) set forth requirements for
changes to be described in an annual report (minor changes). Section
314.70(d)(1) and current § 601.12(d)(1) state that 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.

Under § 314.70(d)(3) and current § 601.12(d)(3) (including §
601.12(d)(3)(iii)), the applicant must submit in the annual report a
list of all products involved; and (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 (note: change consistent with proposal and current
§ 601.12(d)(3)(ii)).

The changes to be described in an annual report (minor changes) are
listed in § 314.70(d)(2) and current § 601.12(d)(2) (including §
601.12(d)(2)(i)-(v) and (vii)): (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.

The regulation reduces the overall number of manufacturing changes
subject to supplements, particularly those requiring FDA approval prior
to product distribution. Many changes that are currently reported in
supplements will be reported in annual reports. Supplement submissions
contain more burdensome reporting requirements than a submission through
an annual report. The regulation will not increase the number of annual
reports but will allow applicants to include in an annual report
information currently required to be reported to the agency in a
supplemental application. The number of manufacturing changes currently
reported in supplements that will be reported in annual reports is
approximately 1,283.

Section 314.70(e) and current § 601.12(e) state that an applicant may
submit one or more protocols describing the specific tests and 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 drug as these factors may
relate to the safety or effectiveness of the drug. 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 produced with the manufacturing change.
The supplement, if approved, 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.

Current § 601.12(f) sets forth the requirements for supplement
submission for labeling changes for biological products. Current §
601.12(f)(2)(i)(A)-(D) specify those labeling changes for which an
applicant must submit a supplement to FDA at the time the change is
made. Section 601.12(f)(2)(i)(E) adds \"any other changes specifically
requested by FDA\" to these types of changes.

Section 314.70(f) states that an applicant must comply with the patent
information requirements under section 505(c)(2) of the act. Section
314.70(g) states that an applicant must include any applicable
exclusivity information with a supplement as required under 21 CFR
314.50(j).

**2. [Purpose and Use of Information]{.underline}**

Section 505 of the Act requires that a new drug may not be marketed
unless the manufacturer provides FDA with scientific evidence that the
drug is both safe and effective. In addition, under Section 351 of the
Public Health Service Act, FDA is required to ensure the marketing of
only those biological products that are safe and effective. The
regulations at 21 CFR Parts 314 and 601 provide the means through which
pharmaceutical manufacturers can obtain FDA approval of a drug product
marketing application, and the means through which FDA can assure the
safety and effectiveness of marketed drug products. Without the
information provided by industry on the drug products they seek to
market, FDA would not be able to assure the safety and effectiveness of
marketed drug products. The submission of supplements to under 21 CFR
314.70 and 21 CFR 601.12 are also essential for FDA to assure a marketed
product\'s safety and effectiveness.

The rule affects all drug manufacturers that submit manufacturing
supplements and will result in a reduction in burdens to applicants
making manufacturing changes subject to the proposed regulation. The
rule will permit earlier implementation of the changes and quicker
marketing of products improved by manufacturing or labeling
modifications. Faster implementation can result in marked gains in
production efficiency, and generally reduces the paperwork burden
associated with reporting the changes.

The regulation will reduce the overall number of manufacturing changes
subject to supplements, particularly those requiring FDA approval prior
to product distribution. Many changes that are currently reported in
supplements would be reported in annual reports. Supplement submissions
contain more burdensome reporting requirements than a submission through
an annual report. The regulation will not increase the number of annual
reports but will allow applicants to include in an annual report
information currently required to be reported to the agency in a
supplemental application. The number of manufacturing changes currently
reported in supplements that would be reported in annual reports is
approximately 1,283.

**3. [Use of Improved Information Technology]{.underline}**

In the [Federal Register]{.underline} of December 11, 2003 (68 FR
69009), FDA required the submission of labeling for human prescription
drugs and biologics in electronic format. In addition, the agency has
issued several guidances describing how to make voluntary electronic
submissions to the agency. In January 1999, FDA issued a guidance on
general considerations for electronic submissions entitled "Providing
Regulatory Submissions in Electronic Format\--General Considerations."
The general considerations guidance included a description of the types
of electronic file formats that we are able to accept for processing,
reviewing, and archiving electronic documents. In January, 1999, FDA
announced the availability of a guidance entitled "Providing Regulatory
Submissions in Electronic Format\--NDAs," which provided information on
how to submit a complete archival copy of an NDA in electronic format,
including the provisions of this final rule in §§ 314.70 and 601.12. In
November 1999, FDA published a guidance to assist applicants in
submitting documents in electronic format for review and archive
purposes as part of a BLA, product license application (PLA), or
establishment license application (ELA). Most recently, FDA published a
guidance for ANDAs, "Providing Regulatory Submission in Electronic
Format---ANDAs" (June 27, 2002), and "Providing Regulatory Submission in
Electronic Format--- Annual Reports for NDAs and ANDAs\" (August 2003).

**5. [Involvement of Small Entities]{.underline}**

Although new drug development is typically an activity completed by
large multinational drug firms, the information collection required
under 21 CFR 314 and 21 CFR 601 applies to small as well as large
companies submitting marketing applications. Under the Regulatory
Flexibility Act, FDA regularly analyzes regulatory options that would
minimize any significant impact on small entities. FDA also assists
small businesses in complying with regulatory requirements.

Due to the multiplicity of products and manufacturing changes, the
agency has not estimated the total savings to industry as a result of
the rule, but anticipates that they would increase over time. New
information and technology will allow a greater number of changes to be
reported in supplements that do not require prior approval or in annual
reports. Because the rule benefits manufacturers regardless of size and
impose no additional costs, the agency has certified that the rule will
not have a significant adverse economic impact on a substantial number
of small entities.

**6. [Consequences If Information Collected Less
Frequently]{.underline}**

Parts 314 and 601 establishes a reporting frequency that is dictated by
the need to focus on potential problems concerning the safety and
effectiveness of human drugs. Less frequent data collection would hinder
early detection of such threats to the public health.

**7. [Consistency with the Guidelines in 5 CFR
1320.5(d)(2)]{.underline}**

Proposed § 314.70(c)(1) requires applicants to send 12 copies of
labeling to FDA. This is necessary to facilitate FDA review of these
supplements in a timely manner. This provision is already required under
current § 314.70.

**8. [Consultation Outside the Agency]{.underline}**

Comments received on FDA\'s proposed information collection burden
estimates for this rule, published in the [Federal Register]{.underline}
of June 28, 1999, and how the comments\' suggestions have increased the
burden estimates for the final rule, are discussed in detail in section
12 of this supporting statement.

**9. [Remuneration of Respondents]{.underline}**

FDA has not provided and has no intention to provide any payment or gift
to respondents under these requirements.

**10. [Assurance of Confidentiality]{.underline}**

Confidentiality of the information submitted under these reporting
requirements is protected under 21 CFR 314.430 and under 21 CFR part 20.
The unauthorized use or disclosure of trade secrets required in
applications is specifically prohibited under Section 310(j) of the Act.

**11. [Questions of a Sensitive Nature]{.underline}**

There are no questions of a sensitive nature.

**12. [Estimates of Annualized Hour Burden]{.underline}**

The final rule sets forth requirements for manufacturing changes
requiring supplement submission and FDA approval prior to the
distribution of the product made using the change, changes requiring
supplement submission at least 30 days prior to the distribution of the
product, changes requiring supplement submission at the time of
distribution, and changes to be described in an annual report. The
regulation reduces the rate of increase in the number of manufacturing
changes subject to supplements and the overall number of supplements
requiring FDA approval prior to product distribution. Many changes that
are currently reported in supplements will be able to be reported in
annual reports. Supplement submissions contain more burdensome reporting
requirements than a submission through an annual report. The regulation
will not increase the number of annual reports but will allow applicants
to include in an annual report information currently required to be
reported to the agency in a supplemental application. The number of
manufacturing changes currently reported in supplements that will be
reported in annual reports is approximately 1,283.

Sections 314.70(a)(2) and 601.12(a)(2) require, generally, that the
holder of an approved application must assess the effects of a
manufacturing change before distributing a drug product made with the
change. This section implements sections 506A(a)(1) and 506A(b) of the
act, which require the holder of an approved application to validate the
effects of a manufacturing change on the identity, strength, quality,
purity, or potency of the drug as these factors may relate to the safety
or effectiveness of the drug before distributing a drug made with the
change. Under section 506A(d)(3)(A), information developed by the
applicant to validate the effects of the change regarding identity,
strength, quality, purity, and potency is required to be submitted to
FDA as part of the supplement or annual report. Thus, estimates for
validation requirements are included in the estimates for supplements
and annual reports; no separate estimates are provided for §§
314.70(a)(2) and 601.12(a)(2) in Table 1 of this document. Furthermore,
no estimates are required for the guidance entitled \"Changes to an
Approved NDA or ANDA,\" because it does not provide recommendations on
the specific information that should be developed by the applicant to
validate the effect of the change on the identity, strength (e.g.,
assay, content uniformity), quality (e.g., physical, chemical, and
biological properties), purity (e.g., impurities and degradation
products), or potency (e.g., biological activity, bioavailability,
bioequivalence) of a product as they may relate to the safety or
effectiveness of the product.

Sections 314.70(a)(4) and 601.12(a)(4) require, generally, that the
applicant must promptly revise all promotional labeling and advertising
to make it consistent with any labeling changes implemented. The
transmittal to FDA of advertisements and promotional labeling for drugs
and biologics is accompanied by Form FDA 2253 and regulated by §§
314.81(b)(3)(i) and 601.12(f)(4). This information collection is
approved by OMB until October 31, 2004, under OMB control number
0910‑0376. Therefore, the burden for this requirement is not estimated
in Table 1 of this document.

Section 314.70(a)(5) requires the applicant to include in each
supplement (except for a supplement providing for a change in the
labeling) and amendment to each supplement a statement certifying that a
field copy has been provided in accordance with § 314.440(a)(4). The
information collection for submitting a field copy under § 314.440(a)(4)
is approved by OMB until March 15, 2005, under OMB control number
0910‑0001. Based on data concerning the number of supplements and
amendments to supplements currently received by the agency, FDA
estimates that approximately 8,556 certifications will be submitted
annually as required by § 314.70(a)(5). FDA estimates that approximately
594 applicants will submit these certifications. FDA estimates that
preparation of a statement certifying the field copy will take
applicants an average of 5 minutes.

Sections 314.70(a)(6) and 601.12(a)(5) require the applicant to include
a list of all changes contained in the supplement or annual report; for
supplements, this list must be provided in the cover letter. The
information collection for submitting an annual report under §
314.81(b)(2) is approved by OMB until March 15, 2005, under OMB control
number 0910‑0001. Based on data concerning the number of supplements
currently received by the agency, FDA estimates that approximately 4,984
lists of all changes in the supplement will be submitted annually as
required by § 314.70(a)(6). FDA estimates that approximately 594
applicants will submit these lists. Because the information required
would be generated in preparing the supplement, the agency estimates
that, under § 314.70(a)(6), it will take approximately 1 hour to include
a list of changes in a cover letter for a supplement. FDA estimates that
approximately 2,983 lists of all changes in the supplement or annual
report will be submitted annually as required by § 601.12(a)(5). FDA
estimates that approximately 190 applicants will submit these lists.
Because the information required would be generated in preparing the
supplement or annual report, the agency estimates that, under §
601.12(a)(5), it will take approximately 1 hour to include a list of
changes for a supplement or an annual report.

Section 314.70(b) and current § 601.12(b) set forth requirements for
changes requiring supplement submission and approval prior to
distribution of the product made using the change (major changes).
Section 314.70(b)(1) and current § 601.12(b)(1) provide, generally, that
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. Section 314.70(b)(3) and current § 601.12(b)(3) specify the
information that must be contained in the supplement.

Based on data concerning the number of supplements currently received by
the agency, FDA estimates that approximately 1,744 supplements will be
submitted annually under § 314.70(b)(1) and (b)(3). FDA estimates that
approximately 594 applicants will submit such supplements, and that it
will take approximately 150 hours to prepare and submit to FDA each
supplement. FDA estimates that approximately 903 supplements will be
submitted annually under § 601.12(b)(1) and (b)(3). FDA estimates that
approximately 190 applicants will submit such supplements, and that it
will take approximately 150 hours to prepare and submit to FDA each
supplement.

Under §§ 314.70(b)(4) and 601.12(b)(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 marked: \"Prior Approval Supplement‑Expedited Review
Requested.\" The burden for an applicant\'s request for an expedited
review of a supplement by marking the mailing cover is minimal and is
included in the burden hour estimates for submitting a supplement under
§§ 314.70(b)(1) and (b)(3) and §§ 601.12(b)(1) and (b)(3).

Section 314.70(c) and current § 601.12(c) set forth requirements for
changes requiring supplement submission at least 30 days prior to
distribution of the product made using the change (moderate changes).
Section 314.70(c)(1) and current § 601.12(c)(1) require, generally, that
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 relate to the safety or effectiveness of the drug
product. Under § 314.70(c)(3) and current § 601.12(c)(1), the supplement
must 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.\" Under §
314.70(c)(4) and § 314.70(b)(3) and current § 601.12(b)(3) must be
contained in the supplement.

Based on data concerning the number of supplements currently received by
the agency, FDA estimates that approximately 2,754 supplements will be
submitted annually under § 314.70(c)(1), (c)(3), and (c)(4). FDA
estimates that approximately 594 applicants will submit such
supplements, and that it will take approximately 95 hours to prepare and
submit to FDA each supplement. FDA estimates that approximately 255
supplements will be submitted annually under § 601.12(c)(1) and (c)(3).
FDA estimates that approximately 98 applicants will submit such
supplements, and that it will take approximately 95 hours to prepare and
submit to FDA each supplement.

Under § 314.70(c)(6) and current § 601.12(c)(5), FDA 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 upon receipt by the agency of
a supplement for the change. The supplement must be labeled
\"Supplement‑‑Changes Being Effected.\" If the supplement provides for a
labeling change, 12 copies of the final printed labeling must be
included. Based on data concerning the number of supplements currently
received by the agency, FDA estimates that approximately 486 supplements
will be submitted annually under § 314.70(c)(6). FDA estimates that
approximately 486 applicants will submit such supplements, and that it
will take approximately 95 hours to prepare and submit to FDA each
supplement. FDA estimates that approximately 47 supplements will be
submitted annually under § 601.12(c)(5). FDA estimates that
approximately 34 applicants will submit such supplements, and that it
will take approximately 95 hours to prepare and submit to FDA each
supplement.

Section 314.70(d) and current § 601.12(d) set forth requirements for
changes to be described in an annual report (minor changes). Section
314.70(d)(1) and current § 601.12(d)(1) provide, generally, that 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 in the next annual
report. Section 314.70(d)(3) and current § 601.12(d)(3) (including
proposed § 601.12(d)(3)(iii)) list the information that must be included
in the annual report for describing changes under this section.

Based on data concerning the number of supplements and annual reports
currently received by the agency, FDA estimates that approximately 6,929
annual reports will include documentation of certain manufacturing
changes as required under § 314.70(d)(1) and (d)(3). FDA estimates that
approximately 704 applicants will submit such information, and that it
will take approximately 35 hours to prepare and submit to FDA the
information for each annual report. FDA estimates that approximately 227
annual reports will include documentation of certain manufacturing
changes as required under current § 601.12(d)(1) and (d)(3). FDA
estimates that approximately 166 applicants will submit such
information, and that it takes approximately 35 hours to prepare and
submit to FDA the information for each annual report.

Section 314.70(e) and current § 601.12(e) state, generally, that 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, 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.

Based on data concerning the number of supplements currently received by
the agency, FDA estimates that approximately 50 protocols will be
submitted annually under § 314.70(e). FDA estimates that approximately
50 applicants will submit such protocols, and that it will take
approximately 200 hours to prepare and submit to FDA each protocol. FDA
estimates that approximately 20 protocols will be submitted annually
under § 601.12(e). FDA estimates that approximately 14 applicants will
submit such protocols, and that it will take approximately 200 hours to
prepare and submit to FDA each protocol.

Current § 601.12(f) sets forth the requirements for supplement
submission for labeling changes for biological products. Current §
601.12(f)(2)(i)(A) through (f)(2)(i)(D) specify those labeling changes
for which an applicant must submit a supplement to FDA at the time the
change is made. Section 601.12(f)(2)(i)(E) adds to these types of
changes \"any labeling change normally requiring a supplement submission
and approval prior to distribution of the product that FDA specifically
requests be filed under this provision.\" Based on data concerning the
number of supplements currently received by the agency, FDA estimates
that approximately 12 labeling supplements will be submitted annually
under current § 601.12(f)(1). FDA estimates that approximately 12
applicants will submit these supplements, and that it will take
approximately 40 hours to prepare and submit to FDA each supplement. FDA
estimates that approximately 10 labeling supplements will be submitted
annually under current § 601.12(f)(2), including those that will be
submitted under new § 601.12(f)(2)(i)(E). FDA estimates that
approximately 10 applicants will submit these supplements, and that it
will take approximately 20 hours to prepare and submit to FDA each
supplement. FDA estimates that approximately 100 annual reports for
labeling changes will be submitted under current § 601.12(f)(3). FDA
estimates that approximately 70 applicants will submit these reports,
and that it will take approximately 10 hours to prepare and submit to
FDA each report. FDA estimates that approximately 1,495 labeling
supplements will be submitted annually under current § 601.12(f)(4). FDA
estimates that approximately 61 applicants will submit these
supplements, and that it will take approximately 10 hours to prepare and
submit to FDA each supplement.

Section 314.70(f) states that an applicant must comply with the patent
information requirements under section 505(c)(2) of the act. Section
314.70(g) states that an applicant must include any applicable
exclusivity information with a supplement as required under Sec.
314.50(j). Patent and exclusivity information collection requirements
are approved by OMB until March 15, 2005, under OMB control number
0910‑0001. Therefore, this requirement is not estimated in Table 1 of
this document.

[Comments received on FDA\'s proposed information collection burden
estimates]{.underline}:

Concerning the accuracy of FDA\'s estimate of the burden of the proposed
collection of information, including the validity of the methodology and
assumptions used, one comment said that FDA has underestimated the
information collection burden. The comment suggested the following
revised estimates: For § 314.70(b)(1) and (b)(3), the comment estimated
160 hours per response; for § 314.70(c)(1), (c)(3), and (c)(4), 80 hours
per response; for § 314.70(c)(6), 80 hours per response; for §
314.70(d)(1) and (d)(3), 25 hours per response; for § 314.70(e), 240
hours per response. The comment assumed that the number of hours
estimated refers to the number of hours required by regulatory affairs
personnel to collect, assemble, and prepare data required for a
submission. Other related activities, such as manufacturing validation
lots and conducting stability studies, are not part of the estimates,
since they are manufacturing activities that would be conducted, as
appropriate, regardless of the reporting requirements. The comment said
its estimates are based on an average time required for submissions, and
the actual time required for a particular submission can vary, based on
the complexity of the submitted change. The comment said that although
the proposal would change the reporting level of changes, the associated
\"paperwork\" for these changes is not significantly reduced and in some
cases is increased.

Concerning the proposed requirement in § 314.70(e) that an applicant may
submit one or more protocols, the comment noted that these protocols
must be submitted as a supplement requiring approval from FDA prior to
distribution of a drug produced with the manufacturing change. The
comment said that, based on its experience, the estimate of 20 hours for
these protocol submissions is significantly underestimated and that 240
hours is a more reasonable estimate. The comment said that these
protocols are, in effect, supplements requiring prior approval and,
therefore, would require the same number of hours to prepare as a prior
approval supplement under § 314.70(b)(1) and (b)(3). Additionally, once
the data for the change has been generated, the change requires an
additional submission in order to implement the change. Assuming the
data generated could be submitted under § 314.70(c), the number of hours
to submit changes under proposed § 314.70(e) would be a combination of
the number of hours required to submit a change under §§ 314.70(b) and
314.70(c).

Another comment said that the estimated time in the proposal to collect
the requested information for each type of supplement is low. The
comment said that FDA underestimated the time to prepare the documents
addressed in the proposal and that FDA should take greater care in
evaluating the necessary steps required in preparing a supplement or
report, not just the document preparation. For prior approved
supplements under § 314.70(b), the comment said that the estimate of 80
hours is low and should be increased by at least 10 hours. The only time
saving that can be gained under this requirement is when a firm can
submit multiple supplements for the same change (site change), which is
an uncommon occurrence; smaller firms submit one supplement at a time.
For changes-being-effected supplements under § 314.70(c), the comment
said that 50 hours for these types of supplements is low. The comment
asked what is the difference between this type of supplement and prior
approval supplements other than the filing mechanism. For annual reports
under § 314.70(d), the comment said that 10 hours is low and that the
data that go into such a report is collected over the entire year before
the report may be put together. The comment said that an average of 20
hours is more reasonable. Concerning protocols under § 314.70(e), the
comment said that 20 hours to prepare a suitability protocol is a large
underestimate, and that firms will spend a large amount of time to
determine just which tests and specifications to include in the
protocol, in addition to preparing the protocol itself. The comment also
said that the analysis and reporting of the results of the completed
protocols was not included in the estimate.

FDA has considered the above comments as well as other information it
has received and has revised the proposed information collection burden
estimates. The estimate for \"hours per response\" for §§ 314.70(b)(1)
and (b)(3) and 601.12(b)(1) and (b)(3) has been increased from 80 hours
to 150 hours; the estimate for §§ 314.70(c)(1), (c)(3), and (c)(4) and
601.12(c)(1) and (c)(3) has been increased from 50 hours to 95 hours;
the estimate for §§ 314.70(c)(6) and 601.12(c)(5) has been increased
from 50 hours to 95 hours; the estimate for §§ 314.70(d)(1) and (d)(3)
and 601.12(d)(1) and (d)(3) has been increased from 10 hours to 35
hours; and the estimate for §§ 314.70(e) and 601.12(e) has been
increased from 20 hours to 200 hours.

Table 1. Estimated Annual Reporting Burden

+---------------+-----------+---------+----------+---------+---------+
| 21 CFR        | Number of | Number  | Total    | Hours   | Total   |
| Section       | Re        | of      | Annual   | per     |         |
|               | spondents | Re      | R        | R       | Hours   |
|               |           | sponses | esponses | esponse |         |
|               |           | per     |          |         |         |
|               |           | Res     |          |         |         |
|               |           | pondent |          |         |         |
+---------------+-----------+---------+----------+---------+---------+
| 314.70(a)(5)  | 594       | 14      | 8,556    | 5 min.  | 713     |
+---------------+-----------+---------+----------+---------+---------+
| 314.70(a)(6)  | 594       | 8       | 4,984    | 1       | 4,984   |
+---------------+-----------+---------+----------+---------+---------+
| 314.70        | 594       | 3       | 1,744    | 150     | 261,600 |
| (b)(1),(b)(3) |           |         |          |         |         |
+---------------+-----------+---------+----------+---------+---------+
| 314.70(c)(1), | 594       | 5       | 2,754    | 95      | 261,630 |
| (c)(3),(c)(4) |           |         |          |         |         |
+---------------+-----------+---------+----------+---------+---------+
| 314.70(c)(6)  | 486       | 1       | 486      | 95      | 46,170  |
+---------------+-----------+---------+----------+---------+---------+
| 314.70        | 704       | 10      | 6,929    | 35      | 242,515 |
| (d)(1),(d)(3) |           |         |          |         |         |
+---------------+-----------+---------+----------+---------+---------+
| 314.70(e)     | 50        | 1       | 50       | 200     | 10,000  |
+---------------+-----------+---------+----------+---------+---------+
| 601.12(a)(5)  | 190       | 16      | 2,983    | 1       | 2,983   |
+---------------+-----------+---------+----------+---------+---------+
| 601.12        | 190       | 5       | 903      | 150     | 135,450 |
| (b)(1),(b)(3) |           |         |          |         |         |
+---------------+-----------+---------+----------+---------+---------+
| 601.12        | 98        | 3       | 255      | 95      | 24,225  |
| (c)(1),(c)(3) |           |         |          |         |         |
+---------------+-----------+---------+----------+---------+---------+
| 601.12(c)(5)  | 34        | 1       | 47       | 95      | 4,465   |
+---------------+-----------+---------+----------+---------+---------+
| 601.12        | 166       | 1       | 227      | 35      | 7,945   |
| (d)(1),(d)(3) |           |         |          |         |         |
+---------------+-----------+---------+----------+---------+---------+
| 601.12(e)     | 14        | 1       | 20       | 200     | 4,000   |
+---------------+-----------+---------+----------+---------+---------+
| 601.12(f)(1)  | 12        | 1       | 12       | 40      | 480     |
+---------------+-----------+---------+----------+---------+---------+
| 601.12(f)(2)  | 10        | 1       | 10       | 20      | 200     |
+---------------+-----------+---------+----------+---------+---------+
| 601.12(f)(3)  | 70        | 1       | 100      | 10      | 1000    |
+---------------+-----------+---------+----------+---------+---------+
| 601.12(f)(4)  | 61        | 25      | 1495     | 10      | 14,950  |
+---------------+-----------+---------+----------+---------+---------+
| Total         |           |         |          |         | 1,      |
|               |           |         |          |         | 023,310 |
+---------------+-----------+---------+----------+---------+---------+

~There\ are\ no\ capital\ costs\ or\ operating\ and\ maintenance\ costs\ associated\ with\ this\ collection\ of\ information~

**13. [Estimates of Annualized Cost Burden to Respondents]{.underline}**

FDA\'s Economics Staff estimates an average industry wage rate of
\$50.00 per hour for preparing and submitting the information collection
requirements under 21 CFR Parts 314 and 601. This figure is an average
of the following wage rates (based on the percentage of time required
for each type of employee): Upper management at \$70.00 per hour; middle
management at \$35.00 per hour; and clerical assistance at \$23.00 per
hour. Using the averaged wage rate of \$50.00 per hour, and multiplied
times the total hour burden estimated above, the total cost burden to
respondents is \$51,165,500.

**14. [Estimates of Annualized Cost Burden to the
Government]{.underline}**

Using the estimate of \$50.00 per hour as the hourly wage for FDA
reviewers to review supplement submissions under the proposal, and
estimating that it takes an average of approximately 120 hours to review
each submission, the annualized cost to FDA as a result of this proposed
rulemaking would be \$ 189,330,000 (31,555 x 120 x \$50).

**15. [Changes in Burden]{.underline}**

The burden estimate has increased from the proposed rule. This increase
results from suggestions made in the comments on the burden estimate in
the proposed rule, and is discussed in detail under section 12 above.

**16. [Time Schedule, Publication, and Analysis Plans]{.underline}**

There are no publications.

**17. [Displaying of OMB Expiration Date]{.underline}**

The agency is not seeking to display the expiration date for OMB
approval of the information collection.

**18. [Exception to the Certification Statement - Item 19]{.underline}**

There are no exceptions to the certification statement identified in
Item 19, \"Certification for Paperwork Reduction Act Submission,\" of
OMB Form 83-I.