Supplements and Other Changes to Approved New Animal Drug Applications

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 5, 25, 500, 510, 514, and 558

[Docket No. 99N-1415]

RIN 0910-AB49

Supplements and Other Changes to Approved New Animal Drug

Applications

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend

its regulations on supplements and other changes to an approved new

animal drug application (NADA) or abbreviated new animal drug

application (ANADA) to implement the manufacturing changes provision of

the Food and Drug Administration Modernization Act of 1997 (the

Modernization Act). This proposed rule would require manufacturers to

validate the effect of any manufacturing change on the identity,

strength, quality, purity, and potency of a new animal drug as those

factors relate to the safety or effectiveness of the product. The

proposal identifies changes requiring submission and approval of a

supplement prior to the distribution of the new animal drug made using

the change, changes requiring the submission of a supplement at least

30 days prior to the distribution of the new animal drug, changes

requiring the submission of a supplement at the time of distribution,

and changes to be described in an annual report.

DATES: Written comments by December 15, 1999.

ADDRESSES: Submit written comments to the Dockets Management Branch

(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,

Rockville, MD 20852. Submit written comments on the information

collection requirements to the Office of Information and Regulatory

Affairs, Office of Management and Budget (OMB), New Executive Office

Bldg., 725 17th St. NW., rm. 10235, Washington, DC 20503, Attn.: Wendy

Taylor, Desk Officer for FDA.

kets Management Branch

(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,

Rockville, MD 20852. Submit written comments on the information

collection requirements to the Office of Information and Regulatory

Affairs, Office of Management and Budget (OMB), New Executive Office

Bldg., 725 17th St. NW., rm. 10235, Washington, DC 20503, Attn.: Wendy

Taylor, Desk Officer for FDA.

FOR FURTHER INFORMATION CONTACT: Dennis M. Bensley, Jr., Center for

Veterinary Medicine (HFV-140), Food and Drug Administration, 7500

Standish Pl., Rockville, MD 20855, 301-827-6956.

SUPPLEMENTARY INFORMATION:

I. Introduction

On November 21, 1997, the President signed the Modernization Act

into law (Public Law 105-115). Section 116 of the Modernization Act

amended the Federal Food, Drug, and Cosmetic Act (the act) by adding

section 506A (21 U.S.C. 356a), which describes requirements and

procedures for making and reporting manufacturing changes to approved

NADA's and ANADA's, new drug applications (NDA's) and abbreviated new

drug applications (ANDA's), and to license applications for biological

products. This proposed rule sets forth regulations to implement

section 506A of the act for NADA's and ANADA's. The Center for Drug

Evaluation and Research (CDER) and the Center for Biologics Evaluation

and Research (CBER) are issuing separate proposed regulations regarding

manufacturing changes for NDA's and ANDA's and for licensed biological

products.

Section 506A of the act makes no distinction between the

requirements for reporting manufacturing changes for human drug and

biological products regulated by CDER and CBER and for new animal drug

products regulated by the Center for Veterinary Medicine (CVM). CVM is

proposing this rule to harmonize the reporting requirements of

manufacturing changes for new animal drug products with those reporting

requirements for human drug and biological products

equirements for reporting manufacturing changes for human drug and

biological products regulated by CDER and CBER and for new animal drug

products regulated by the Center for Veterinary Medicine (CVM). CVM is

proposing this rule to harmonize the reporting requirements of

manufacturing changes for new animal drug products with those reporting

requirements for human drug and biological products.

The Modernization Act, section 116, becomes effective on the

effective date of these final regulations or 24 months after the

enactment of the Modernization Act (November 21, 1999), whichever

occurs first. This proposed rule updates and will replace Sec. 514.8

(21 CFR 514.8), which provides the current requirements for

manufacturing changes for NADA's.

II. Background

A. CVM's Current Rule

CVM currently evaluates all manufacturing changes to approved

NADA's under the regulations found in Sec. 514.8. Manufacturing changes

are currently submitted as permitted changes (Sec. 514.8(a)(5)),

changes being effected (CBE's) (Sec. 514.8(d), or changes requiring

approval prior to implementation (Sec. 514.8(a)(4)).

Under current Sec. 514.8(a)(5), permitted changes may be put into

effect without the approval of a supplemental application but must be

reported in the next annual drug experience report (DER). Section

514.8(a)(5) lists the types of manufacturing changes that are

considered permitted changes.

CBE's under current Sec. 514.8(d) include manufacturing changes

that would ``give increased assurance that the drug will have the

characteristics of identity, strength, quality, and purity which it

purports or is represented to possess.'' Such changes are to be placed

into effect at the earliest possible time with concurrent submission of

a supplemental application; hence such changes do not require CVM

approval before implementation.

Changes requiring approval of a supplemental application prior to

implementation are set out in current Sec. 514.8(a)(4) of the

regulations

ity which it

purports or is represented to possess.'' Such changes are to be placed

into effect at the earliest possible time with concurrent submission of

a supplemental application; hence such changes do not require CVM

approval before implementation.

Changes requiring approval of a supplemental application prior to

implementation are set out in current Sec. 514.8(a)(4) of the

regulations. Most manufacturing changes are currently reported in

preapproval supplemental applications under Sec. 514.8(a)(4).

B. Section 116 of The Modernization Act

Many of the concepts included in the Modernization Act were

incorporated from earlier rulemaking and guidance documents issued by

CDER and CBER. A discussion of CDER's earlier rulemaking, guidance

documents, and their underlying rationale can be found in the preamble

to CDER's proposed rulemaking to comply with section 506A of the act.

CDER had issued a series of guidance documents to ease preapproval

requirements for certain manufacturing changes that are unlikely to

have a detectable impact on a drug product's quality and performance as

distinguished from those that could have a significant impact. These

guidance documents were issued under a provision in current 21 CFR

314.70(a) that permits holders of an approved application to make

changes to the application in accordance with a guideline, notice, or

regulation published in the Federal Register that provides a less

burdensome notification of the change.

As of this date, CDER has issued several guidances addressing the

requirements relating to postapproval changes in manufacturing and

controls. These are known as the SUPAC (Scale-Up and Postapproval

Changes) documents. The first of these guidance documents was published

in November 1995 and is entitled ``Immediate Release Solid Oral Dosage

Forms; Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and

Controls; In Vitro Dissolution Testing; In Vivo Bioequivalence

Documentation'' (SUPAC-IR)

es in manufacturing and

controls. These are known as the SUPAC (Scale-Up and Postapproval

Changes) documents. The first of these guidance documents was published

in November 1995 and is entitled ``Immediate Release Solid Oral Dosage

Forms; Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and

Controls; In Vitro Dissolution Testing; In Vivo Bioequivalence

Documentation'' (SUPAC-IR). This guidance provides recommendations to

holders of approved drug applications who intend, during the

postapproval period, to change: (1) The components or composition, (2)

the site of manufacture, (3) the scale of manufacture, and/or (4)

the manufacturing (process and/or equipment) of an immediate release

solid oral dosage form.

In May 1997 and August 1997, CDER issued two related guidances

entitled ``Semisolid Dosage Forms Scale-Up and Postapproval Changes:

Chemistry, Manufacturing, and Controls; In Vitro Release Testing; In

Vivo Bioequivalence Documentation'' (SUPAC-SS) and ``Modified Release

Solid Oral Dosage Forms Scale-Up and Postapproval Changes: In Vitro

Dissolution Testing; In Vivo Bioequivalence Documentation'' (SUPAC-MR).

These two guidances cover the same general topics and use the same

general approaches as SUPAC-IR. The current series of guidance

documents relating to scale-up and postapproval changes focuses on

changes to manufacturing and controls for drug products. Future

guidances will consider changes in manufacturing and controls for the

drug substance, product containers and closures, and other topics as

well.

The underlying rationale of these guidances already completed or in

preparation is that the identity, strength, quality, purity, and

potency of an approved drug should remain unchanged in any important

aspect as a result of any postapproval change in manufacturing and

controls. This unchanged performance extends to changes that might

affect in vivo bioavailability and relative bioavailability

(bioequivalence)

ionale of these guidances already completed or in

preparation is that the identity, strength, quality, purity, and

potency of an approved drug should remain unchanged in any important

aspect as a result of any postapproval change in manufacturing and

controls. This unchanged performance extends to changes that might

affect in vivo bioavailability and relative bioavailability

(bioequivalence).

CDER's guidance documents, described previously, originally applied

only to drug products approved under sections 505 (new and abbreviated

new drug applications) and 507 (antibiotic applications; revoked by the

Modernization Act) of the act (21 U.S.C. 355 and 357). However, CVM

adopted many of the concepts described in these guidance documents by

permitting the reporting of minor manufacturing changes in a biennial

supplement instead of in a preapproval supplement submitted in

accordance with the current regulation (Sec. 514.8). The biennial

supplement does not require CVM approval prior to the distribution of

the drug product made using the changes.

CDER's and CBER's proposed rulemaking and supporting guidance

documents allow for many moderate manufacturing changes to be reported

as CBE's that are not provided for in CVM's current regulations

(Sec. 514.8). CVM is proposing regulations that harmonize the reporting

of manufacturing changes for new animal drug products with the

reporting of manufacturing changes for human drug products, because:

and CBER's proposed rulemaking and supporting guidance

documents allow for many moderate manufacturing changes to be reported

as CBE's that are not provided for in CVM's current regulations

(Sec. 514.8). CVM is proposing regulations that harmonize the reporting

of manufacturing changes for new animal drug products with the

reporting of manufacturing changes for human drug products, because:

(1) The act makes no distinction between the requirements for the

reporting of manufacturing changes for human drug products and for new

animal drug products, (2) the act does not provide for the reporting of

minor manufacturing changes in biennial supplements, (3) the proposed

rulemaking allows for flexibility in reporting many moderate changes as

CBE's, and (4) CVM and the animal drug industry can benefit from CDER's

expertise and resources to issue specific guidances on manufacturing

and controls changes used for drugs, generally.

CVM is currently collaborating with CDER on a number of guidance

documents addressing manufacturing and controls changes, including the

draft guidance document entitled ``Chemistry, Manufacturing and Control

Changes to an Approved NADA or ANADA'' to be made available for comment

along with this proposed rulemaking. On the effective date of these

final regulations or on November 21, 1999, whichever occurs first,

CVM's previous practices will be superseded by section 506A of the act

and/or the final regulations and the reporting of minor manufacturing

changes in biennial supplements will no longer be permitted. CVM

proposes to adopt CDER's current guidance documents for manufacturing

changes (SUPAC-IR, SUPAC-SS and SUPAC-MR). These documents will be

updated to reflect changes resulting from the proposed rulemaking, and

CVM intends to participate with CDER in the drafting of any guidance

documents covering manufacturing changes. In addition, CVM will also

issue guidance documents for specific new animal drug products such as

Type A medicated articles.

ts for manufacturing

changes (SUPAC-IR, SUPAC-SS and SUPAC-MR). These documents will be

updated to reflect changes resulting from the proposed rulemaking, and

CVM intends to participate with CDER in the drafting of any guidance

documents covering manufacturing changes. In addition, CVM will also

issue guidance documents for specific new animal drug products such as

Type A medicated articles.

III. Summary of the Legislation

Section 116 of the Modernization Act amended the act by adding

section 506A, which provides requirements for making and reporting

manufacturing changes to an approved application and for distributing a

drug made with such changes. Section 506A of the act includes the

following provisions:

1. A drug made with a manufacturing change, whether a major

manufacturing change or otherwise, may be distributed only after the

applicant validates the effects of the change on the identity,

strength, quality, purity, and potency of the drug as these factors may

relate to the safety and effectiveness of the drug (section 506A(a)(1)

and (b) of the act). This section recognizes that additional testing,

beyond testing to ensure that an approved specification is met, is

required to ensure unchanged identity, strength, quality, purity, or

potency as these factors may relate to the safety or effectiveness of

the drug.

2. A drug made with a major manufacturing change may be distributed

only after the applicant submits a supplemental application to FDA and

the supplemental application is approved by the agency. The application

is required to contain information that FDA deems appropriate and

include the information developed by the applicant validating the

effects of the change (section 506A(c)(1) of the act). The phrase

``validating the effects of the change,'' as used in this proposed

rule, is not the same as ``validation'' required in FDA's current good

manufacturing practice (CGMP) regulations (21 CFR parts 210 and 211).

o contain information that FDA deems appropriate and

include the information developed by the applicant validating the

effects of the change (section 506A(c)(1) of the act). The phrase

``validating the effects of the change,'' as used in this proposed

rule, is not the same as ``validation'' required in FDA's current good

manufacturing practice (CGMP) regulations (21 CFR parts 210 and 211).

3. A major manufacturing change is a manufacturing change

determined by FDA to have substantial potential to adversely affect the

identity, strength, quality, purity, or potency of the drug as these

factors may relate to the safety or effectiveness of the drug. Such

changes include: (1) A change made in the qualitative or quantitative

formulation of the drug involved or in the specifications in the

approved application or license unless exempted by regulation or

guidance, (2) a change determined by FDA through regulation or guidance

to require completion of an appropriate clinical study demonstrating

equivalence of the drug to the drug manufactured without the change or

a reference listed drug, and (3) other changes determined by regulation

or guidance to have a substantial potential to adversely affect the

safety or effectiveness of the drug (section 506A(c)(2) of the act).

4. FDA may establish categories of manufacturing changes, other

than major manufacturing changes, and require submission of a

supplemental application for drugs made with such manufacturing changes

(section 506A(d)(1)(B) and (d)(1)(C) of the act). For changes, other

than major changes, that require submission of a supplemental

application, the applicant may begin distribution of the drug 30 days

after FDA receives the supplemental application unless the agency

notifies the applicant within the 30-day period that FDA review and

prior approval of the application is required (section 506A(d)(3)(B)(i)

of the act)

nd (d)(1)(C) of the act). For changes, other

than major changes, that require submission of a supplemental

application, the applicant may begin distribution of the drug 30 days

after FDA receives the supplemental application unless the agency

notifies the applicant within the 30-day period that FDA review and

prior approval of the application is required (section 506A(d)(3)(B)(i)

of the act). FDA may also designate a category of manufacturing changes

for which the applicant may begin distributing a drug made with such

changes upon receipt by the agency of the supplemental application for

the change (section 506A(d)(3)(B)(ii) of the act). If FDA fails

to approve a supplemental application, the agency may order the

manufacturer to cease the distribution of drugs that have been made

with the disapproved change (section 506A(d)(3)(B)(iii) of the act).

5. FDA may authorize applicants to distribute drugs without

submitting a supplemental application (section 506A(d)(1)(A) of the

act) and may establish categories of manufacturing changes that may be

made without submitting a supplemental application (section

506A(d)(1)(C) of the act). The applicant is required to submit a report

to FDA on such a change, and the report is required to contain

information the agency deems to be appropriate and information

developed by the applicant when validating the effects of the change.

FDA may also specify the date on which the report is to be submitted

(section 506A(d)(2)(A) of the act). If during a single year an

applicant makes more than one manufacturing change subject to a

reporting requirement, the act permits FDA to authorize the applicant

to submit a single annual report containing the required information

for all the changes made during the year (section 506A(d)(2)(B) of the

act).

Section 506A of the act recognizes that the amount of testing and

the data to be included in a submission and the appropriate method for

reporting the data are related to the scope and the type of change

being made

s FDA to authorize the applicant

to submit a single annual report containing the required information

for all the changes made during the year (section 506A(d)(2)(B) of the

act).

Section 506A of the act recognizes that the amount of testing and

the data to be included in a submission and the appropriate method for

reporting the data are related to the scope and the type of change

being made. Four methods of reporting changes (i.e., supplements that

require FDA review and prior approval, CBE's supplements with a 30-day

wait, CBE's supplements with no wait, and annual reports) are discussed

in section 506A of the act and in this proposal. The appropriate method

for reporting any specific change depends on the potential for that

change to impact the fundamental safety or effectiveness of the product

by adversely affecting the basic aspects of the drug product--its

identity, strength, quality, purity, and potency.

The main objective of a review of a supplemental application that

documents postapproval changes to an NADA or ANADA is to ensure

``sameness'' or ``equivalence'' between the pre- and post-change

product. ``Sameness or equivalence'' do not mean ``identical'' since

certain manufacturing changes lead to differences. Such differences

should not, however, affect the safety or effectiveness of the drug

product. Also, a proposed manufacturing change should not be so

extensive that a new drug product is created. If a manufacturing change

does produce a fundamental alteration (i.e., a pharmaceutically

inequivalent dose form), a new application may be required for the

resulting product.

Generally, in the case of NADA products, the pre- and post-change

drug product should be compared. In the case of ANADA products, the

pre- and post-change drug products should be compared to the reference

listed drug, typically the pioneer drug product

duce a fundamental alteration (i.e., a pharmaceutically

inequivalent dose form), a new application may be required for the

resulting product.

Generally, in the case of NADA products, the pre- and post-change

drug product should be compared. In the case of ANADA products, the

pre- and post-change drug products should be compared to the reference

listed drug, typically the pioneer drug product. Confirmation of

``sameness'' or ``equivalence'' is particularly important when changes

are made that involve the active pharmaceutical ingredient or affect

critical manufacturing steps. Examples of such changes include, but are

not limited to, components and overall composition of the formulation;

manufacturing site, scale, equipment, process, or specifications; and

analytical procedures.

Many factors should be considered in determining whether a change

has a substantial, moderate, or 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. Some types of manufacturing changes have a greater potential

to cause unwanted or unexpected changes to the product that may be

difficult to assess by merely testing to specifications. The type of

product is also a factor to consider in determining the potential risk

of a manufacturing change having an adverse effect on the product. Some

products may be substantially affected by what appear to be small

manufacturing changes.

Therefore, defining ``substantial,'' ``moderate,'' and ``minimal''

in the regulations with such specificity that they exhaustively

describe all of the many individual changes that may occur is not

feasible

rmining the potential risk

of a manufacturing change having an adverse effect on the product. Some

products may be substantially affected by what appear to be small

manufacturing changes.

Therefore, defining ``substantial,'' ``moderate,'' and ``minimal''

in the regulations with such specificity that they exhaustively

describe all of the many individual changes that may occur is not

feasible. FDA is planning, however, to provide greater detail in

guidance about the types or categories of changes that the agency

believes should be considered ``substantial,'' ``moderate,'' or

``minimal.''

Section 506A of the act provides FDA with considerable flexibility

to establish required information and filing requirements for

manufacturing changes. There is a corresponding need to retain such

flexibility in the proposed regulations implementing section 506A of

the act to ensure that the least burdensome means for reporting changes

are available. FDA believes that such flexibility is necessary to be

responsive to increasing knowledge of and experience with certain types

of changes and to help ensure the effectiveness and safety of the

products involved. For example, a change that may currently be

considered to have a substantial potential to have an adverse effect on

the safety or effectiveness of the product may, at a later date, based

on new information or advances in technology, be determined to have a

lesser potential to have such an adverse effect. Conversely, a change

originally considered to have a moderate potential to have an adverse

effect on the safety or effectiveness of the product may later, as a

result of new information, be found to have an increased, substantial

potential to adversely affect the product

sed

on new information or advances in technology, be determined to have a

lesser potential to have such an adverse effect. Conversely, a change

originally considered to have a moderate potential to have an adverse

effect on the safety or effectiveness of the product may later, as a

result of new information, be found to have an increased, substantial

potential to adversely affect the product.

The agency believes it can more readily respond to knowledge gained

from manufacturing experience, and advances in technology by issuing

regulations that set out broad, general categories of manufacturing

changes and by using guidance documents to provide FDA's current

thinking on the specific changes that fall into those general

categories. The proposed rule would, therefore, reduce the number of

manufacturing changes specifically identified as being subject to

supplements requiring or not requiring review and approval. The agency

also understands that applicants expect some predictability on what

type of reporting will be expected for specific changes. FDA intends to

make available guidance documents to describe the agency's current

interpretation of specific changes falling into the four filing

categories and to modify the documents as needed to reflect changes

based on new information. The use of guidance documents as provided for

in section 506A of the act will allow FDA to more easily and quickly

modify and update important information. Guidance documents will be

developed according to the procedures set out in FDA's Good Guidance

Practices as published in the Federal Register of February 27, 1997 (62

FR 8961 at 8967 to 8972). A notice of availability for a draft guidance

entitled ``Chemistry, Manufacturing and Control Changes to an Approved

NADA or ANADA'' is published elsewhere in this issue of the Federal

various postapproval manufacturing changes

ent the provisions of

section 506A of the act.

FDA is proposing to define ``specification'' as the quality

standard (i.e., tests, analytical procedures, and acceptance criteria)

provided in an approved application to confirm the quality of drug

substances, drug products, intermediates, raw materials, reagents, and

other components including container closure systems, and in-process

controls. FDA is proposing to define ``specification'' because section

506A of the act includes a change ``in the specifications in the

approved application or license'' as a major change. To clarify the

meaning of the term ``acceptance criteria'' as used in the definition

of ``specification,'' FDA is including in the proposed definition of

``specification'' the statement that ``acceptance criteria'' refers to

numerical limits, ranges, or other criteria for the tests described. To

determine if a material being tested complies with a specification,

there must be predetermined criteria. These criteria may include

numerical limits or ranges (e.g., not more than 1 percent) or other

criteria (e.g., white to off-white in color).

FDA is proposing to define the phrase ``validate the effects of the

change'' as an assessment of the effect of a manufacturing change on

the identity, strength, quality, purity, or potency of a drug as these

factors relate to the safety or effectiveness of the drug. FDA is

proposing to define this phrase because section 506A of the act

includes a requirement that a drug made with a manufacturing change may

only be distributed after the applicant validates the effects of the

change. Validating the effects of the change is important in

determining whether manufacturing changes alter the identity, strength,

quality, purity, or potency of a drug product as these factors may

relate to drug safety or effectiveness, and includes testing beyond

that in an approved specification, such as redocumentation of the

pharmaceutical equivalence or bioequivalence

effects of the

change. Validating the effects of the change is important in

determining whether manufacturing changes alter the identity, strength,

quality, purity, or potency of a drug product as these factors may

relate to drug safety or effectiveness, and includes testing beyond

that in an approved specification, such as redocumentation of the

pharmaceutical equivalence or bioequivalence.

``Minor changes and stability report'' would mean a report that is

submitted once each year within 60 days of the anniversary of the

application's original approval or a mutually agreed upon date for

minor manufacturing changes made according to proposed Sec. 514.8(b)(4)

or a statement that no changes were made, and updated stability data

generated on commercial or production batches according to an approved

stability protocol.

The MCSR is the annual report described in section 506A(d)(2)(B) of

the act, and it is different and distinct from the annual report

described and submitted in accordance with current Sec. 510.300 (21 CFR

510.300) (i.e., periodic DER's). The MCSR is a type of ``annual''

report for manufacturing changes only. The MCSR would be submitted to

and reviewed by CVM's Office of New Animal Drug Evaluation (ONADE)

rather than by CVM's Office of Surveillance and Compliance (OSC). The

MCSR must include minor manufacturing changes implemented over the past

year and an update of ongoing stability data generated on production

lots. Currently, ongoing stability data are submitted as part of DER's

to OSC. CVM has decided that it is more efficient to allow the

administrative review of information relating to manufacturing changes

and stability to reside in one group. Information regarding labeling

changes and product defects would continue to be submitted to CVM's

OSC.

FDA is proposing to define ``listed drug'' and ``the list'' to

clarify ``reference listed drug'' cited in proposed

Sec. 514.8(b)(2)(ii)(B).

B. Manufacturing Changes to an Approved Application

ive review of information relating to manufacturing changes

and stability to reside in one group. Information regarding labeling

changes and product defects would continue to be submitted to CVM's

OSC.

FDA is proposing to define ``listed drug'' and ``the list'' to

clarify ``reference listed drug'' cited in proposed

Sec. 514.8(b)(2)(ii)(B).

B. Manufacturing Changes to an Approved Application

Proposed Sec. 514.8(b) sets forth general requirements under which

an applicant must notify FDA when making a change to an approved

application and replaces current Sec. 514.8(a). This paragraph states

that an applicant must notify FDA about each change in each condition

established in an approved application beyond the variations already

provided for in the application, and that the notice is required to

describe the change fully. It also states that the applicant must,

depending on the type of change, notify FDA of the change in a

supplement under proposed Sec. 514.8(b)(2) or (b)(3) or by the

inclusion of the information in an annual report (the MCSR) under

proposed Sec. 514.8(b)(4). Reference in current Sec. 514.8(a)(1) to

current regulations, Sec. 510.300, has been deleted and, instead,

proposed Sec. 514.8(b)(1)(i) makes reference to annual reports

described under proposed Sec. 514.8(b)(4). Manufacturing changes and/or

updated stability data generated according to an approved stability

commitment would no longer be reported in periodic DER's (i.e., annual

reports under current Sec. 510.300) but be reported under proposed

Sec. 514.8(b)(4) in an MCSR. CVM intends to publish a final rule

revising Sec. 510.300, which will be renumbered as Sec. 514.80. Since

CVM expects to publish the final rule for Sec. 514.80 (Records and

reports concerning experience with new animal drugs for which an

approved application is in effect. (56 FR 65581, December 17, 1991))

before the final rule for Sec

t be reported under proposed

Sec. 514.8(b)(4) in an MCSR. CVM intends to publish a final rule

revising Sec. 510.300, which will be renumbered as Sec. 514.80. Since

CVM expects to publish the final rule for Sec. 514.80 (Records and

reports concerning experience with new animal drugs for which an

approved application is in effect. (56 FR 65581, December 17, 1991))

before the final rule for Sec. 514.8, CVM will, if necessary, amend the

rule for Records and reports concerning experience with new animal

drugs for which an approved application is in effect. after the final

rule for Sec. 514.8 publishes.

Proposed Sec. 514.8(b)(1)(ii) would require the holder of an

approved application under section 512 of the act (21 U.S.C. 360b) to

validate the effects of manufacturing changes on the identity, strength

(e.g., assay and content uniformity), quality (e.g., physical,

chemical, and biological properties), purity (e.g., impurities and

degradation products) and potency (e.g., biological activity,

bioavailability, and bioequivalence) of a drug as these factors may

relate to the safety or effectiveness of the drug. These validation

requirements must be met before a product made with a manufacturing

change may be distributed. This amendment implements section 506A(a)(1)

and (b) of the act.

Proposed Sec. 514.8(b)(1)(iii) states that notwithstanding the

requirements of Sec. 514.8(b)(2) and (b)(3), an applicant must report 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, a type of manufacturing change subject to review

and approval by FDA under proposed Sec. 514.8(b)(2) might be identified

in regulation or guidance as a change that could be reported in a

supplement not requiring review and approval or in an annual report

in those paragraphs in accordance with a regulation

or guidance that provides for a less burdensome notification of the

change. For example, a type of manufacturing change subject to review

and approval by FDA under proposed Sec. 514.8(b)(2) might be identified

in regulation or guidance as a change that could be reported in a

supplement not requiring review and approval or in an annual report.

CDER used this provision to reduce the regulatory burden for submission

of supplements for manufacturing changes that were not likely to

adversely affect drug product quality or performance in the SUPAC

guidance documents.

Proposed Sec. 514.8(b)(1)(iv) requires the applicant to include in

each supplemental application providing for a change under proposed

Sec. 514.8(b)(2) or (b)(3), a statement that a copy of the supplement

has been provided to the appropriate FDA district office whose

jurisdiction includes the facility where the manufacturing change is

implemented.

Proposed Sec. 514.8(b)(1)(v) would add a requirement that a list of

all changes contained in the supplement or annual report must be

included in the cover letter for the supplement or annual report. For

many years, most supplements and annual reports have routinely included

such cover letters. Including a list of all changes in the cover

letters will enable FDA to more efficiently locate and evaluate changes

in what are often substantial documents, thus facilitating FDA review

of supplements and annual reports.

Proposed Sec. 514.8(b)(2)(iii) describes the information that must

be included in a supplement. References to regulations for categorical

exclusion or an environmental assessment have been updated and included

in Sec. 514.8(b)(2)(iii)(K).

C. Changes Requiring Supplement Submission and Approval Prior to

Distribution of the Product Made Using the Change (Major Change)

ments and annual reports.

Proposed Sec. 514.8(b)(2)(iii) describes the information that must

be included in a supplement. References to regulations for categorical

exclusion or an environmental assessment have been updated and included

in Sec. 514.8(b)(2)(iii)(K).

C. Changes Requiring Supplement Submission and Approval Prior to

Distribution of the Product Made Using the Change (Major Change)

Certain drug manufacturing steps are so critical that changes in

these steps must be subject to the submission of a supplement to FDA

that is approved by FDA prior to distribution of the drug product made

using the change. Current Sec. 514.8(a)(4) sets forth changes for which

such review and approval are required.

Proposed Sec. 514.8(b)(2) would revise the current sections to

implement section 506A of the act. Proposed Sec. 514.8(b)(2)(i)

implements section 506A(c)(2) of the act and would require a

preapproval supplement to be submitted for any major change, i.e., any

change in the 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

product as these factors may relate to the safety or effectiveness of

the product.

Also, there are times when manufacturing changes are demonstrated

to have an adverse effect on the identity, strength, quality, purity,

or potency of the drug product. In many cases the applicant chooses not

to implement these manufacturing changes, but in other cases the

applicant may still wish to do so

the

product as these factors may relate to the safety or effectiveness of

the product.

Also, there are times when manufacturing changes are demonstrated

to have an adverse effect on the identity, strength, quality, purity,

or potency of the drug product. In many cases the applicant chooses not

to implement these manufacturing changes, but in other cases the

applicant may still wish to do so. If an assessment by the sponsor

shows that a manufacturing change has adversely affected the identity,

strength, quality, purity, or potency of the drug product and the

sponsor wants to make the change, the change should be filed in a

supplement that requires review and approval by FDA before distribution

of the product, regardless of whether the change is listed as an

example of one that normally does not need FDA approval prior to

distribution of the product made with the change. The applicant should

submit this change in a supplement that requires review and approval

with appropriate information to demonstrate that the manufacturing

change has not altered the continued safety and effectiveness of the

product. The agency will assess the effect of any adverse change in a

drug product, as the change may relate to the safety or effectiveness

of the product, during the review of the supplement that requires

approval prior to distribution of the product.

Proposed Sec. 514.8(b)(2)(ii) lists examples of those changes

requiring submission and approval of a supplement prior to

distribution, including those designated as major manufacturing changes

in section 506A(c)(2) of the act, and changes to certain biotechnology

products. These changes have a substantial 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

val of a supplement prior to

distribution, including those designated as major manufacturing changes

in section 506A(c)(2) of the act, and changes to certain biotechnology

products. These changes have a substantial 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. The agency's continued review and approval of these

changes prior to product distribution is necessary to protect the

animals and the public from products for which safety or effectiveness

may have been compromised.

FDA is proposing to describe additional specific examples of

changes that have substantial, moderate, and minimal potential to

adversely affect a product in guidance documents rather than enumerate

them in the proposed regulations. As discussed previously, section 506A

of the act expressly states that the agency, through guidance, may

categorize the manufacturing changes. FDA anticipates that scientific

advances and future experience may reduce the need for approval of

supplements providing for certain changes, and the agency will respond

to changed circumstances by revising the guidance documents. A notice

of availability of a draft guidance document entitled ``Guidance for

Industry: Chemistry, Manufacturing and Controls Changes to an Approved

NADA or ANADA,'' that provides more detailed recommendations on how to

report proposed changes, is being published elsewhere in this issue of

the Federal Register, and the agency is soliciting comments on the

draft guidance in addition to the proposed rule.

In regard to proposed Sec. 514.8(b)(2)(ii)(B), section 506A of the

act also states in part that ``* * * equivalence of the drug to the

drug as manufactured without the change'' should be demonstrated

how to

report proposed changes, is being published elsewhere in this issue of

the Federal Register, and the agency is soliciting comments on the

draft guidance in addition to the proposed rule.

In regard to proposed Sec. 514.8(b)(2)(ii)(B), section 506A of the

act also states in part that ``* * * equivalence of the drug to the

drug as manufactured without the change'' should be demonstrated. For

those generic drug products for which, at the time of approval, a

generic drug applicant was required to show equivalence between the

proposed generic drug and a reference listed drug (typically the

referenced pioneer drug product), a proposed manufacturing change

should not significantly change the equivalence demonstrated at the

time of approval. In addition, for the more significant manufacturing

changes for generic drugs the approval of which relied on a

demonstration of bioequivalence to a reference listed drug, the

applicant is required to conduct a bioequivalence study comparing the

drug product made with the change to the reference listed drug,

typically the pioneer drug product.

Under proposed Sec. 514.8 (b)(2)(ii)(G) changes to a product under

an application that is subject to a validity assessment because of

significant questions regarding the integrity of the data supporting

the application require approval prior to distribution. Until questions

about the integrity of the data in the application have been resolved,

there are inadequate assurances that any change will not adversely

affect the safety or effectiveness of the product. Moreover, a change

to a product cannot be validated, as required under 506A(b) of the act,

until the integrity of the underlying data in such an application is

validated. Consequently, there is a significant potential that the

change will have an adverse effect on the identity, strength, quality,

purity, or potency of the product

t adversely

affect the safety or effectiveness of the product. Moreover, a change

to a product cannot be validated, as required under 506A(b) of the act,

until the integrity of the underlying data in such an application is

validated. Consequently, there is a significant potential that the

change will have an adverse effect on the identity, strength, quality,

purity, or potency of the product. After a validity assessment has been

completed, and data integrity questions resolved, the holder of an

approved application may submit supplements for manufacturing changes

as otherwise provided in Sec. 514.8.

Current Sec. 514.8(a)(4)(iii), (a)(4)(iv), and (a)(4)(v) regarding

general manufacturing and control changes requiring approval prior to

distribution are not included in proposed Sec. 514.8(b)(2), because

some of these changes would fall into the proposed major manufacturing

change category while others would fall into other proposed categories

depending on whether the change is considered to have a substantial,

moderate, or minimal potential to adversely affect the

identity, strength, quality, purity, or potency of the drug as they may

relate to the safety or effectiveness of the drug. FDA plans to provide

recommendations on how to submit the supplements in guidance documents,

including the draft guidance document mentioned previously. Current

Sec. 514.8(a)(4)(v) relating to identification of distributors has been

updated and reproposed as Sec. 514.8(c)(4).

Proposed Sec. 514.8(b)(2)(iii) states that the applicant must

obtain approval of a supplement from FDA before distributing a product

using a change under Sec. 514.8(b)(2), and it specifies information to

be included in the supplement.

Proposed Sec. 514.8(b)(2)(iv) permits a request for an expedited

review of a supplement for public health reasons or if a delay in

making the change described in the supplement would impose an

extraordinary hardship on the applicant

oval of a supplement from FDA before distributing a product

using a change under Sec. 514.8(b)(2), and it specifies information to

be included in the supplement.

Proposed Sec. 514.8(b)(2)(iv) permits a request for an expedited

review of a supplement for public health reasons or if a delay in

making the change described in the supplement would impose an

extraordinary hardship on the applicant. FDA is including this

provision for expedited review for extraordinary hardship reasons but

wishes to clarify that these requests should focus on manufacturing

changes made necessary by catastrophic events (e.g., fire) or by events

that could not be reasonably foreseen and for which the applicant could

not plan. Requests for expedited review will be assessed on a case-by-

case basis. All requests may not be granted.

Under proposed Sec. 514.8(b)(2)(v), an applicant may submit one or

more protocols describing specific tests, validation studies, and

acceptable limits to be achieved to demonstrate the lack of an 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. Such protocols, or

changes to a protocol, would be submitted as a supplement requiring

approval from FDA prior to distribution. If approved, the use of such a

protocol in making the specified changes may justify a reduced

reporting category for the change because of the reduced risk of an

adverse effect.

Generally, when considering a change in the manufacture of a

product, the manufacturer will prepare a protocol, often called a

``comparability protocol,'' identifying tests to be performed in

evaluating the change and its effect on the product and defining the

criteria against which the impact of the change will be evaluated

ry for the change because of the reduced risk of an

adverse effect.

Generally, when considering a change in the manufacture of a

product, the manufacturer will prepare a protocol, often called a

``comparability protocol,'' identifying tests to be performed in

evaluating the change and its effect on the product and defining the

criteria against which the impact of the change will be evaluated. By

providing FDA an opportunity to review and approve the comparability

protocol before it is used by the applicant to evaluate a change, FDA

can have a greater assurance that the change is being properly

evaluated and there is, therefore, less potential for the change to

have an adverse effect on the safety or effectiveness of the product.

D. Changes Requiring Supplement Submission at Least 30 Days Prior to

Distribution of the Drug Product Made Using the Change (Moderate

Changes)

Current Sec. 514.8(d)(3) provides for manufacturing changes that

give an increased assurance that the drug will have the characteristics

of identity, strength, quality, and purity that it purports or is

represented to possess to be placed into effect at the earliest

possible time. Proposed Sec. 514.8(b)(3) implements section

506A(d)(1)(B) and (d)(3) of the act and provides that products made

using the changes listed under this section may only be distributed not

sooner than 30 days after receipt of a supplement by FDA. FDA

recognizes that animal and the public health can be adequately

protected without requiring approval of certain manufacturing changes

prior to distribution of the product made with the change. FDA

continues to believe that it is important that such changes be

documented and validated so that there is a mechanism for assessing the

consequences of the change and that the agency approve such changes

ognizes that animal and the public health can be adequately

protected without requiring approval of certain manufacturing changes

prior to distribution of the product made with the change. FDA

continues to believe that it is important that such changes be

documented and validated so that there is a mechanism for assessing the

consequences of the change and that the agency approve such changes.

The requirement to submit a supplement 30 days before distribution of

the product balances FDA's need to review applications to protect

against the distribution of unsafe or ineffective products and the need

to make improved products available.

Proposed Sec. 514.8(b)(3)(i) would require that a supplement be

submitted for any change in the 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. Proposed Sec. 514.8(b)(3)(iii) states

that a supplement submitted under Sec. 514.8(b)(3)(i) is required to

give a full explanation of the basis for the change and identify the

date on which the change is to be made, and that the supplement must be

labeled ``Supplement--Changes Being Effected in 30 Days.''

Proposed Sec. 514.8(b)(3)(ii) describes the types of changes that

require submission of a supplement 30 days before distribution.

Proposed Sec. 514.8(b)(3)(iv) states that distribution of a product

made using a change listed under this section may not begin until 30

days after receipt of a supplement by FDA. This section would also

require that the same information listed in proposed

Sec. 514.8(b)(2)(iii), discussed previously, must be contained in the

supplement required under proposed Sec. 514.8(b)(3).

According to proposed Sec

c. 514.8(b)(3)(iv) states that distribution of a product

made using a change listed under this section may not begin until 30

days after receipt of a supplement by FDA. This section would also

require that the same information listed in proposed

Sec. 514.8(b)(2)(iii), discussed previously, must be contained in the

supplement required under proposed Sec. 514.8(b)(3).

According to proposed Sec. 514.8(b)(3)(v), during the 30-day period

following receipt of the supplement, FDA would perform a preliminary

review to determine whether the supplement is complete and whether the

type of change is appropriate for review as a supplement under proposed

Sec. 514.8(b)(3). If the proposed change is determined to be a major

change that should appropriately be submitted under proposed

Sec. 514.8(b)(2), the agency would inform the applicant and the

applicant would be required to receive FDA's approval before a product

produced with the change could be distributed. If FDA determines that

the change is properly submitted as a supplement under

Sec. 514.8(b)(3)(i), but the required information is incomplete, the

applicant would be required to supply the missing information and wait

until FDA has determined that the supplement is in compliance before

distributing the product.

Under proposed Sec. 514.8(b)(3)(vii), if FDA disapproves a

supplemental application under this section, the agency may order the

manufacturer to cease distribution of the drug products made with the

manufacturing change. This amendment would implement section

506A(d)(3)(B)(iii) of the act.

E. Changes That May Be Implemented When FDA Receives a Supplement

(Moderate Changes)

ting the product.

Under proposed Sec. 514.8(b)(3)(vii), if FDA disapproves a

supplemental application under this section, the agency may order the

manufacturer to cease distribution of the drug products made with the

manufacturing change. This amendment would implement section

506A(d)(3)(B)(iii) of the act.

E. Changes That May Be Implemented When FDA Receives a Supplement

(Moderate Changes)

Section 506A(d)(3)(B)(ii) of the act gives FDA authority to

designate a category of changes for which the holder of an approved

application making such change may begin distribution of the drug upon

receipt by FDA of a supplemental application for the change. FDA

recognizes that animals and the public can be adequately protected

without requiring approval of certain manufacturing changes prior to

distribution of the product made with the change. FDA continues to

believe that it is important that such changes be documented and

validated so that there is a mechanism for assessing the consequences

of the change and that the agency approve such changes. However, based

on FDA's experience, certain changes may be implemented when FDA

receives the supplement, rather than delaying distribution for 30 days

because, in general, these changes provide the same or increased

assurance that the product will have the characteristics of identity,

strength,

quality, purity, or potency that it purports or is represented to have.

Submission of a supplement gives FDA ready access to information

regarding such changes. The requirement for approval of such

supplements allows FDA to protect against the distribution of unsafe or

ineffective products while allowing products that are likely to be

improved to be available more quickly. Examples of such changes are

listed in proposed Sec. 514.8(b)(3)(vi). The supplement submitted under

this paragraph is required to give a full explanation of the basis for

the change and the supplement must be labeled ``Supplement--Changes

Being Effected.''

Under proposed Sec

unsafe or

ineffective products while allowing products that are likely to be

improved to be available more quickly. Examples of such changes are

listed in proposed Sec. 514.8(b)(3)(vi). The supplement submitted under

this paragraph is required to give a full explanation of the basis for

the change and the supplement must be labeled ``Supplement--Changes

Being Effected.''

Under proposed Sec. 514.8(b)(3)(vii), if FDA disapproves a

supplemental application under this section, the agency may order the

manufacturer to cease distribution of the drug products made with the

manufacturing change.

Current Sec. 514.8(d) describes the types of changes that can be

placed into effect at the earliest possible time. Such changes are

being described in proposed Sec. 514.8(b)(3)(vi) and (c)(3).

F. Changes and Updated Stability Data to Be Described and Submitted in

an Annual Report (Minor Changes)

Minor manufacturing changes are currently submitted in an annual

report under Sec. 510.300(b)(6) as referenced in current

Sec. 514.8(a)(5) or in a biennial supplement. Proposed Sec. 514.8(b)(4)

would provide that changes to the 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 as these factors may relate to the safety or effectiveness of

the product be documented by the applicant in the next annual report,

i.e., ``Minor Changes and Stability Report,'' as described under

proposed Sec. 514.8(b)(4). FDA recognizes that there are manufacturing

changes that have a minimal potential to have an adverse affect on a

product's safety or effectiveness. FDA believes that agency approval of

these changes prior to product distribution is unnecessary and is

proposing in Sec. 514.8(b)(4) that such changes would not be required

to be approved by the agency

s described under

proposed Sec. 514.8(b)(4). FDA recognizes that there are manufacturing

changes that have a minimal potential to have an adverse affect on a

product's safety or effectiveness. FDA believes that agency approval of

these changes prior to product distribution is unnecessary and is

proposing in Sec. 514.8(b)(4) that such changes would not be required

to be approved by the agency. FDA continues to believe that it is

important that such changes be documented and validated so that FDA can

assess the consequences of the change. FDA can effectively assess

compliance with this section and CGMP requirements for changes that

have a minimal potential to adversely affect the product's safety or

effectiveness by having ready access to information regarding such

changes through submission of an annual report and by inspection.

Section 506A(d)(1)(C) of the act authorizes FDA to establish

reporting categories (i.e., annual report) of manufacturing changes

(i.e., minor changes) that may be made without submitting a

supplemental application. Section 506A(d)(2)(A) of the act permits

minor changes to be reported separately or in an annual report. Section

506A of the act has no provisions for reporting minor manufacturing

changes in biennial supplements as permitted by CVM's pilot program.

Therefore, all minor manufacturing changes described in regulations or

guidance should be submitted in an MCSR to the application annually.

The MCSR will be reviewed by the appropriate CVM office that reviews

manufacturing supplements. No manufacturing changes or updated

stability data are to be reported in the periodic DER that is submitted

to CVM's OSC. But reports of manufacturing defects must continue to be

submitted to OSC. The MCSR must be submitted each year within 60 days

of the anniversary of approval of the application or mutually agreed

upon date. Proposed Sec. 514.8(b)(4)(ii) lists examples of changes that

can be reported in the MCSR.

Proposed Sec

tability data are to be reported in the periodic DER that is submitted

to CVM's OSC. But reports of manufacturing defects must continue to be

submitted to OSC. The MCSR must be submitted each year within 60 days

of the anniversary of approval of the application or mutually agreed

upon date. Proposed Sec. 514.8(b)(4)(ii) lists examples of changes that

can be reported in the MCSR.

Proposed Sec. 514.8(b)(4)(iii) states that the MCSR must list all

products to which minor changes were made.

Proposed Sec. 514.8(b)(4) replaces current Sec. 514.8(a)(5).

G. Labeling and Other Changes Requiring Submission and Approval of a

Supplement Prior to Distribution of the Product Made Using the Change

(Major Changes)

Labeling changes addressed in current Sec. 514.8(a) and (b) are

newly addressed by proposed Sec. 514.8(c). Proposed Sec. 514.8(c)(1)

describes when an applicant must notify FDA that the applicant is

making such a change to an approved application. This section states

that an applicant must notify FDA about each change in each condition

established in an approved application beyond the variations already

provided for in the application, and that the notice is required to

describe the change fully.

Proposed Sec. 514.8(c)(2) updates current Sec. 514.8(a)(3),

(a)(4)(i) and (a)(4)(ii) regarding labeling changes and addition of

intended use requiring preapproval supplements. Labeling and other

changes requiring submission of a supplemental application are

described in proposed Sec. 514.8(c)(2)(i).

Proposed Sec. 514.8(c)(2)(ii) requires an applicant to obtain

approval of a supplement by FDA before distributing a product subject

to a change listed under Sec. 514.8(c)(2)(i), and specifies information

to be included in the supplement.

Current Sec. 514.8(a)(3) regarding mailing or promotional pieces

for a prescription drug has been updated and is included under proposed

Sec. 514.8(c)(2). Current Sec

ec. 514.8(c)(2)(ii) requires an applicant to obtain

approval of a supplement by FDA before distributing a product subject

to a change listed under Sec. 514.8(c)(2)(i), and specifies information

to be included in the supplement.

Current Sec. 514.8(a)(3) regarding mailing or promotional pieces

for a prescription drug has been updated and is included under proposed

Sec. 514.8(c)(2). Current Sec. 514.8(a)(4)(i) and (a)(4)(ii) regarding

revisions in labeling and addition of claim, respectively, have been

updated and included under proposed Sec. 514.8(c)(2)(i)(A) and

(c)(2)(i)(B).

H. Labeling Changes To Be Placed Into Effect Prior to Receipt of a

Written Notice of Approval of a Supplemental Application

Proposed Sec. 514.8(c)(3) updates and redesignates current

Sec. 514.8(d) regarding labeling changes to be placed into effect prior

to receipt of a written notice of approval of a supplemental

application.

Proposed Sec. 514.8(c)(3)(i) requires labeling changes that

increase the assurance of product safety, such as additional warnings,

contraindications, or side effects or deletions of false, misleading,

or unsupportive statements; and any other changes as directed by FDA to

be placed into effect immediately. These changes, proposed

Sec. 514.8(c)(3)(i)(A) and (c)(3)(i)(B), are listed in current

Sec. 514.8(d)(1) and (d)(2).

Proposed Sec. 514.8(c)(3)(ii) permits labeling changes to the style

and format that do not decrease the safety of product approved in

supplemental applications to be placed into effect prior to written

notice of approval from FDA of a supplemental application.

Proposed Sec. 514.8(c)(3)(iii) updates current Sec. 514.8(e) and

describes what must be included in a supplement submitted under

Sec. 514.8(c)(3). FDA will not take action against products or sponsors

solely because a change in labeling described in Sec. 514.8(c)(3) is

implemented prior to FDA receipt and approval of a supplement if the

information listed in Sec. 514.8(c)(3)(iii) has been submitted to the

agency

)(3)(iii) updates current Sec. 514.8(e) and

describes what must be included in a supplement submitted under

Sec. 514.8(c)(3). FDA will not take action against products or sponsors

solely because a change in labeling described in Sec. 514.8(c)(3) is

implemented prior to FDA receipt and approval of a supplement if the

information listed in Sec. 514.8(c)(3)(iii) has been submitted to the

agency.

Proposed Sec. 514.8(c)(4) would require applicants to notify CVM of

additional designated distributors under proposed Sec. 514.80(a)(2),

(b)(3), and (b)(5)(iii) (Records and reports concerning experience with

new animal drugs for which an approved application is in effect.--as

noted in section IV.B of this document, CVM expects to publish the

final rule for Sec. 514.80 before the final rule for this document).

This notification will be accompanied by a Form FDA 2301, submitted to

DER, and reported at the time of initial product distribution by the

new distributor. This type of change is not considered a

manufacturing change, rather a type of labeling change to be reported

to the Division of Epidemiology and Surveillance in the OSC, CVM.

In addition to section 506A of the act, other sections of the act

authorize FDA to propose Sec. 514.8. Section 501 of the act (21 U.S.C.

351) prohibits the manufacture, processing, packing, or holding of

drugs that do not conform to CGMP; the use of an unsafe new animal drug

under the meaning of section 512 of the act; the use of unsafe color

additives in or on a drug under section 721 of the act (21 U.S.C.

379e); and the distribution of a drug that differs in the strength,

purity, or quality that it purports or is represented to possess.

Section 502 of the act (21 U.S.C. 352) prohibits false or misleading

labeling of drugs, drugs that lack adequate directions for use and

adequate warnings, and the distribution of drugs that are dangerous to

health when used in the manner suggested in the labeling

9e); and the distribution of a drug that differs in the strength,

purity, or quality that it purports or is represented to possess.

Section 502 of the act (21 U.S.C. 352) prohibits false or misleading

labeling of drugs, drugs that lack adequate directions for use and

adequate warnings, and the distribution of drugs that are dangerous to

health when used in the manner suggested in the labeling. Under section

512 of the act, FDA will approve an application for a new intended use

of a new animal drug if, among other things, the methods used in, and

the facilities and controls used for, the manufacture, processing, and

packing of such drug are adequate to preserve its identity, strength,

quality, and purity. Section 701 of the act (21 U.S.C. 371) authorizes

FDA to issue regulations for the efficient enforcement of the act.

I. Other Information.

Proposed Sec. 514.8(d) regarding patent information is included to

comply with section 512(c)(3) of the act. Proposed Sec. 514.8(e)

regarding claimed exclusivity is included to comply with section

512(c)(2)(F) of the act. Proposed Sec. 514.8(f) regarding good

laboratory practice for nonclinical laboratory studies is redesignated

as current Sec. 514.8(l).

J. Sections Proposed for Removal

The agency is proposing that a number of paragraphs be removed

after reevaluation of the regulations covering changes to an approved

application because the agency has determined that these paragraphs are

no longer relevant to current practices. These regulations are

described in the next two paragraphs.

FDA has determined that the regulations covering special

circumstances of NADA's effective prior to October 10, 1962, are no

longer needed. Thus FDA is proposing to eliminate current

Sec. 514.8(g), (k), and (j).

Current Sec. 514.8(h) stating that nothing in Sec

ined that these paragraphs are

no longer relevant to current practices. These regulations are

described in the next two paragraphs.

FDA has determined that the regulations covering special

circumstances of NADA's effective prior to October 10, 1962, are no

longer needed. Thus FDA is proposing to eliminate current

Sec. 514.8(g), (k), and (j).

Current Sec. 514.8(h) stating that nothing in Sec. 514.8 limits the

Secretary of Health and Human Services's authority to suspend or

withdraw approval of a new animal drug application is adequately

addressed in section 512(c)(1)(F) of the act and need not be addressed

in the proposed regulations. Similarly, FDA is removing current

Sec. 514.8(i) that provides for a deferral of final action on

supplemental applications as described under current Sec. 514.8(d),

(e), and (g).

K. Section 514.106 Approval of Supplemental Applications

This proposal would modify Sec. 514.106(b) regarding the

administrative categorization of supplemental applications to provide

for proper references to proposed Sec. 514.8.

V. Conforming Amendments

A number of sections in the regulations covering new animal drugs

are affected by these proposed changes. Conforming changes are being

proposed in Secs. 5.83, 25.33, 500.25, 510.300, 514.106, and 558.5

because of the reorganization of the existing information or

introduction of new requirements.

VI. Environmental Impact

The agency has determined under 21 CFR 25.24(h) that this action is

of a type that does not individually or cumulatively have a significant

effect on the human environment. Therefore, neither an environmental

assessment nor an environmental impact statement is required.

VII. Analysis of Impacts

zation of the existing information or

introduction of new requirements.

VI. Environmental Impact

The agency has determined under 21 CFR 25.24(h) that this action is

of a type that does not individually or cumulatively have a significant

effect on the human environment. Therefore, neither an environmental

assessment nor an environmental impact statement is required.

VII. Analysis of Impacts

FDA has examined the impacts of the proposed rule under Executive

Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the

Unfunded Mandates Reform Act of 1995 (Public Law 104-4). Executive

Order 12866 directs agencies to assess all costs and benefits of

available regulatory alternatives and, when regulation is necessary, to

select regulatory approaches that maximize net benefits (including

potential economic, environmental, public health and safety, and other

advantages; distributive impacts; and equity). Executive Order 12866

classifies a rule as significant if it meets any one of a number of

specified conditions, including having an annual effect on the economy

of $100 million or adversely affecting in a material way a sector of

the economy, competition, or jobs. The agency believes that this

proposed rule is consistent with the regulatory philosophy and

principles identified in the Executive Order. The Office of Management

and Budget (OMB) has determinied that this proposed rule is a

significant regulatory action subject to review under the Executive

Order.

The agency is proposing to amend current Sec. 514.8 to implement

section 116 of the Modernization Act. This section establishes

reporting procedures and requirements for making major and other

manufacturing changes to an approved NADA or ANADA. The intent of

section 506A of the act and this proposed rule is to permit sponsors to

use a less burdensome notification procedure for some types of changes,

while also clarifying the regulations and harmonizing them, where

possible, with CDER's and CBER's regulations

ablishes

reporting procedures and requirements for making major and other

manufacturing changes to an approved NADA or ANADA. The intent of

section 506A of the act and this proposed rule is to permit sponsors to

use a less burdensome notification procedure for some types of changes,

while also clarifying the regulations and harmonizing them, where

possible, with CDER's and CBER's regulations. Downgrading the level of

agency review for some of these supplements will lead to compliance

cost savings due to the resulting improvement in manufacturing

efficiencies.

The agency has not estimated the value of the expected improvements

in manufacturing efficiencies due to the myriad of factors affecting

the production schedules of new animal drugs. FDA believes, however,

that these changes will result in shorter average lag times between the

decision to make certain minor changes to the manufacturing process for

a new animal drug and the time at which that change can be implemented.

A report by the Eastern Research Group, an FDA contractor, on the

effects of the human drug scale-up and postapproval change guidance for

immediate release solid oral dosage form (SUPAC-IR), concluded that

this type of supplement change can result in significant net savings to

industry. In particular, the report found that companies gain greater

control over their production resources and ``shorter waiting times for

changes that can now be filed as Changes Being Effected (CBE's) or

annual reports.''

The proposed rule contains four reporting categories for

supplemental chemistry, manufacturing and control (CMC) changes,

whereas the current regulation Sec. 514.8 contains three. The first

category concerns those changes requiring approval prior to

implementation and defines what is included in a ``major'' change.

These requirements are very similar to those in the existing

regulation, but clarify some of the existing language. The second

category is a new ``30-day changes being effected,'' or 30-day CBE