Supplements and Other Changes to an Approved Application

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 5, 206, 250, 314, 600, and 601

[Docket No. 99N-0193]

RIN 0910-AB61

Supplements and Other Changes to an Approved Application

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

-----------------------------------------------------------------------

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

its regulations on supplements and other changes to an approved

application to implement the manufacturing changes provision of the

Food and Drug Administration Modernization Act of 1997 (the

Modernization Act). The proposed rule would 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 proposal sets forth requirements for changes requiring supplement

submission and 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.

DATES: Written comments by September 13, 1999. Comments on the

collection of information by July 28, 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: Desk

Officer for FDA.

FOR FURTHER INFORMATION CONTACT:

Eric B. Sheinin, Center for Drug Evaluation and Research (HFD-800),

Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857,

301-827-5918, or

Robert A. Yetter, Center for Biologics Evaluation and Research

(HFM-10), Food and Drug Administration, 1401 Rockville Pike, Rockville,

MD 20852, 301-827-0373.

SUPPLEMENTARY INFORMATION:

I. Introduction

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

(Pub. L. 105-115) into law. 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

new drug and abbreviated new drug applications, to new and abbreviated

animal drug applications, and to license applications for biological

products. This proposed rule sets forth regulations to implement

section 506A of the act for human new drug and abbreviated new drug

applications and for licensed biological products. The Center for

Veterinary Medicine is developing separate regulations regarding

manufacturing changes for new and abbreviated animal drug applications.

This proposed rule will update and replace current Sec. 314.70 (21

CFR 314.70), which provides the requirements for manufacturing changes

for human drug applications. This proposal also proposes changes to

Sec. 601.12 (21 CFR 601.12), which provides the requirements for

manufacturing changes for licensed biological products. Although the

current Sec. 601.12 for licensed biological products is in full

compliance with the new provisions in the Modernization Act, FDA is

making the proposed changes in order to maintain harmonization with

proposed Sec. 314.70 for human drug applications.

II. Background

The requirements for reporting manufacturing changes under current

Sec. 314.70 were developed originally as part of a comprehensive effort

to improve the investigational new drug application (IND) and the new

drug application (NDA) processes. This effort began in October 1982 (47

FR 46622, October 19, 1982) and consisted of three phases. The first

phase, termed the NDA rewrite (50 FR 7452, February 22, 1985),

finalized procedures in part 314 (21 CFR part 314), including

Sec. 314.70, for FDA review of new drug and antibiotic applications.

The NDA rewrite of Sec. 314.70 created three mechanisms for reporting

manufacturing changes: Supplements requiring prior approval,

supplements not requiring prior approval, and annual reports. The

rationale behind the need for three mechanisms to report manufacturing

and controls changes is that some changes have a significant potential

to affect the safety or effectiveness of a final drug product and

should be reviewed and approved by FDA prior to distribution of the

product made with the change. Other changes have a lesser potential to

affect safety or effectiveness and could be implemented by a firm with

notification to FDA concurrently (changes being effected supplement). A

third category of changes has a minimal potential to affect safety or

effectiveness and could, therefore, be submitted in the next annual

report without compromising drug safety or effectiveness.

The second phase of the effort to improve the IND and NDA process,

termed the IND rewrite (52 FR 8831, March 19, 1987), finalized FDA

procedures in 21 CFR part 312 for reviewing IND's. The third phase

involved preparation of a series of agency guidances that elaborated on

the concepts contained in the IND and NDA regulations and provided more

detail concerning application formats and how to fulfill testing and

other regulatory requirements.

In implementing Sec. 314.70, the agency recognized both the need

for greater consistency in the approaches FDA recommended for

application holders making postapproval manufacturing and controls

changes as well as a need to reduce regulatory burden consistent with

the public health. Accordingly, FDA formed the Scale-up and

Postapproval Changes (SUPAC) Task Force. This SUPAC Task Force, which

was established by the Center for Drug Evaluation and Research (CDER)

Chemistry, Manufacturing, and Controls Coordinating Committee, oversaw

the acquisition of data on the effects of postapproval changes on the

quality and performance of drugs. Based on the data and CDER's

experience reviewing thousands of manufacturing change supplements,

CDER developed guidance documents designed to ease preapproval

requirements by categorizing certain manufacturing changes according to

whether they had a minor, moderate, or major potential to affect

product quality and performance. The SUPAC guidance documents were

issued under Sec. 314.70(a), which stated that holders of an approved

application shall make changes to the application in accordance with a

guideline, notice, or regulation published in the Federal Register that

provides for a less burdensome notification of the change.

The existing postapproval change guidances are based on the concept

that the identity, strength, quality, purity, and potency of an

approved drug should

[[Page 34609]]

remain unchanged in any important aspect as a result of any

postapproval change in manufacturing and controls. A change in any

important aspect may thus require redemonstration of pharmaceutical

equivalence and/or bioequivalence as defined in 21 CFR 320.1.

Regulations governing manufacturing changes to licensed biological

products were similar to Sec. 314.70, although they did not include the

three categories of changes provided in Sec. 314.70. In 1997, as part

of an agency initiative to reduce regulatory burden, FDA revised

Sec. 601.12 to add three categories of manufacturing changes for

licensed biological products with different reporting requirements for

each category. In addition, because certain biotechnology products were

regulated as drugs under section 505 of the act (21 U.S.C. 355), FDA

sought to harmonize regulatory approaches for those biotechnology

products that were regulated as drugs by adding new Sec. 314.70(g) that

addressed reporting changes to an approved application for certain

biotechnology products (see 61 FR 2739, January 29, 1996, and 62 FR

39890, July 24, 1997). Revised Sec. Sec. 601.12 and 314.70(g), like the

original Sec. 314.70, provided for three risk-based filing categories:

(1) Those having a substantial potential to have an adverse effect on

the identity, strength, quality, purity, and potency of a drug as those

factors relate to the safety or effectiveness of the product; (2) those

having a moderate potential to have these types of effects; and (3)

those with minimal potential to have such effects. In addition,

Sec. Sec. 601.12 and 314.70(g) provided for four different reporting

categories instead of the three originally provided in Sec. 314.70.

These categories were: (1) Prior approval supplement; (2) 30-day wait

changes being effected supplement; (3) no-wait changes being effected

supplement; and (4) annual report.

Sections 601.12 and 314.70(g) also provided that applicants could

submit as a preapproval supplement a comparability protocol that

described the specific tests and validation studies and acceptable

limits to be achieved to demonstrate the lack of adverse effect for

specified types of manufacturing changes on the identity, strength,

quality, purity, or potency of a product as they may relate to the

safety or effectiveness of the product. If approved, such a protocol

could justify a reduced reporting category for the particular change

described because the use of the protocol for the change could reduce

the potential risk of an adverse effect associated with the change.

III. Summary of the Legislation

Section 116 of the Modernization Act amended the act by adding

section 506A, which built upon the concepts embodied in the IND/NDA

rewrite, the SUPAC program, and the changes to Sec. Sec. 601.12 and

314.70(g). 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 or effectiveness of the drug (sections 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 determined to be appropriate by FDA

and include the information developed by the applicant when

``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 (parts 210 and

211 (21 CFR parts 210 and 211)). Unless otherwise specified by FDA,

some CGMP validation (e.g., process, equipment) data need not be filed

in an NDA, abbreviated new drug application (ANDA), or license

application for a biological product but should be retained at the

facility and be available for review by FDA at its discretion. Some

other CGMP validation information, in addition to the information

validating the effects of the change specified in section 506A(c)(1) of

the act, should be submitted in an NDA, ANDA, or license application

for a biological product (e.g., sterilization and advantageous agent

removal process validation).

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 FDA by regulation or

guidance; (2) a change determined by FDA by regulation or guidance to

require completion of an appropriate clinical study demonstrating

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

and (3) other changes determined by FDA 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 require submission of a supplemental application for

drugs made with manufacturing changes that are not major (section

506A(d)(1)(B) of the act) and establish categories of manufacturing

changes for which a supplemental application is required (section

506A(d)(1)(C) of the act). In such a case the applicant may begin

distribution of the drug 30 days after FDA receives a supplemental

application unless the agency notifies the applicant within the 30-day

period that 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 that permit the applicant to begin distributing a

drug made with such changes upon receipt by the agency of a

supplemental application for the change (section 506A(d)(3)(B)(ii) of

the act). If FDA disapproves 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 an annual

reporting requirement, FDA may authorize the applicant to submit a

single report containing the required information for all the changes

made during the year

[[Page 34610]]

(annual report) (section 506A(d)(2)(B) of the act).

Section 506A of the act provides FDA with considerable flexibility

to determine the information and filing mechanism required for the

agency to assess the effect of manufacturing changes in the safety and

effectiveness of the product. 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 will allow it

to be responsive to increasing knowledge of and experience with certain

types of changes and help ensure the efficacy 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 minimal or 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, further research and data collection,

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, help reduce the number of manufacturing changes specifically

identified as requiring supplements.

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. Section 506A of the act

explicitly provides FDA the authority to use guidance documents to

determine the type of changes that do or do not have a substantial

potential to adversely affect the safety or effectiveness of the drug

product. The use of guidance documents will allow FDA to more easily

and quickly modify and update important information. (FDA's use of

guidance documents under current Sec. Sec. 314.70(a) and 601.12 has

proven effective in accomplishing this goal.) Guidance documents will

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

Guidance Practices'' published in the Federal Register of February 27,

1997 (62 FR 8961 at 8967 through 8972). A notice of availability of a

draft guidance entitled ``Guidance for Industry: Changes to an Approved

NDA or ANDA'' is published elsewhere in this issue of the Federal

Register. This draft guidance covers recommended reporting categories

for various postapproval manufacturing changes. Previously published

guidances, including the SUPAC guidances, provide recommendations on

reporting categories as well as the type of information that should be

developed by the applicant to validate the effect of the change on the

identity, strength, quality, purity, or potency of a product as they

may relate to the safety or effectiveness of the product. To the extent

that the recommendations on reporting categories in this guidance, when

finalized, are inconsistent with previously published guidance, such as

the SUPAC guidances, the recommended reporting categories in such prior

guidance will be superseded by this new guidance upon its publication

in final form. CDER intends to update the previously published

guidances to make them consistent with this guidance.

FDA has also published a guidance entitled ``Changes to an Approved

Application for Specified Biotechnology and Specified Synthetic

Biological Products'' (62 FR 39904, July 24, 1997). FDA intends to

update this guidance as appropriate based on any final rule that may

issue as a result of this proposal.

IV. Description of the Proposed Rule

A. Definitions

FDA is proposing to amend the ``Definitions'' sections of the

regulations on applications for FDA approval to market a new drug

(Sec. 314.3) and a biological product (21 CFR 600.3) by adding

definitions for ``specification'' and ``validate the effects of the

change.'' These definitions are necessary to implement 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

materials. FDA is proposing to define ``specification'' because under

section 506A of the act a ``major change'' includes a change ``in the

specifications in the approved application or license.''

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 ``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 they relate to drug

safety or effectiveness, and may require testing beyond that in an

approved specification, such as testing to ensure pharmaceutical

equivalence and/or bioequivalence.

B. Changes to an Approved Application

Current Sec. 314.70(a) sets forth general requirements under which

an applicant must notify FDA when making 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. It also states that, depending on the type of change, the

applicant must notify FDA of it in a supplement under current

Sec. 314.70(b) or (c) or by inclusion of the information in an annual

report under current Sec. 314.70(d). FDA is proposing to retain these

general requirements under proposed Sec. 314.70(a)(1). A similar

provision is included in the regulations on changes to an approved

application for biological products under current Sec. 601.12(a). FDA

is proposing to

[[Page 34611]]

redesignate this requirement as Sec. 601.12(a)(1).

Proposed Sec. 314.70(a)(2) would require the holder of an approved

application under section 505 of the act 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) or

potency (e.g., biological activity, bioavailability, and

bioequivalence) of a drug as these factors may relate to the safety and

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. A

similar provision is included in the regulations on changes to an

approved application for biological products under current

Sec. 601.12(a). FDA is proposing to add minor wording changes for

consistency with revised Sec. 314.70 and to redesignate this

requirement as Sec. 601.12(a)(2). In addition, applicants continue to

be subject to the validation requirements of parts 210 and 211 as

mentioned previously.

Current Sec. 314.70(a) states that notwithstanding the supplement

submission requirements of current Sec. 314.70(b) and (c), an applicant

shall make a manufacturing change in accordance with ``a guideline,

notice, or regulation published in the Federal Register that provides

for a less burdensome notification of the change.'' For example, a type

of manufacturing change subject to prior approval by FDA under current

Sec. 314.70(b) might be identified in a ``guideline, notice, or

regulation'' as a change that could be reported in a supplement not

requiring prior approval or in an annual report. In the SUPAC guidance

documents, 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.

FDA is proposing to retain this requirement under proposed

Sec. 314.70(a)(3) and to add it to the regulations on changes to an

approved application for biological products as proposed

Sec. 601.12(a)(3). This exception may be used as pharmaceutical science

evolves for those changes that FDA no longer considers to have a

substantial potential to have an adverse effect on the product.

However, to ensure consistency with the principles of FDA's good

guidance practices, proposed Sec. Sec. 314.70(a)(3) and 601.12(a)(3)

would eliminate the reference to a Federal Register ``notice'' and

change the word ``guideline'' to ``guidance.'' Proposed

Sec. 314.70(a)(3) is expressly sanctioned in section 506A(c)(2)(A),

(c)(2)(B), and (c)(2)(C) of the act which permit FDA to categorize

manufacturing changes ``by regulation or guidance.''

Current Sec. 314.70(c) states, in the introductory paragraph, that

the applicant who submits a change being effected supplement to FDA

must promptly revise all promotional labeling and drug advertising to

make it consistent with any change in the labeling. FDA is proposing to

retain this provision as proposed Sec. 314.70(a)(4) and to add it to

the regulations on changes to an approved application for biological

products as proposed Sec. 601.12(a)(4). Because the prompt revision of

all promotional labeling and product advertising applies equally to all

labeling changes (see Sec. 314.81(b)(3)), FDA is proposing that this

provision expressly apply to labeling changes requiring approval prior

to the distribution of the product, labeling changes that may be

submitted in a changes being effected supplement, and those changes

that may be filed in an annual report.

Current Sec. 314.70(a) also requires that, except for a

supplemental application providing for a change in the labeling, the

applicant, other than a foreign applicant, shall include in each

supplemental application providing for a change under paragraph (b) or

(c) of current Sec. 314.70, a statement certifying that a field copy of

the supplement has been provided to the applicant's home FDA district

office. FDA is proposing to retain this requirement as proposed

Sec. 314.70(a)(5). However, as proposed, this section would omit the

phrase ``other than a foreign applicant'' because foreign applicants

now routinely supply field copies of supplements to the agency.

Proposed Sec. Sec. 314.70(a)(6) and 601.12(a)(5) 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.

C. Changes Requiring Supplement Submission and Approval Prior to

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

Certain drug or biological product manufacturing steps are so

critical that changes in these steps must be submitted in a supplement

to FDA and approved by FDA prior to distribution of the product made

using the change. Similarly, certain labeling changes must be approved

prior to distribution of the product with the new labeling. Current

regulations at Sec. Sec. 314.70(b) and (g)(1) and 601.12(b) set forth

prior approval requirements. FDA is proposing to revise these

regulations to implement section 506A of the act. Proposed

Sec. 314.70(b)(1) would implement section 506A(c)(1) and (c)(2) of the

act and would require that a preapproval supplement must be submitted

for 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.

Sometimes, during assessment of a change, an applicant will find

that the manufacturing change will have an adverse effect on the

identity, strength, quality, purity, or potency of the drug product. In

many cases, the applicant will not implement this manufacturing change,

but in some cases may still wish to do so. If an assessment concludes

that a manufacturing change has adversely affected the identity,

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

should be filed in a prior approval supplement, regardless of whether

the change is one that normally does not need FDA approval prior to

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

submit this change in a prior approval supplement with appropriate

information to support 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 prior approval supplement.

Proposed Sec. 314.70(b)(4) would retain the provision in current

Sec. 314.70(b) that provides that an applicant may request an expedited

review of a supplement if a delay in making the change would impose an

extraordinary hardship. Proposed Sec. 314.70(b)(4) would also permit a

request for an expedited review of a supplement for public health

reasons. FDA is retaining the provision

[[Page 34612]]

for expedited review for extraordinary hardship reasons but wishes to

clarify that these requests should be reserved for 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. FDA is also proposing to add this provision for expedited

review, as proposed in Sec. 314.70(b)(4), to the regulations on changes

to an approved application for biological products as proposed

Sec. 601.12(b)(4). Requests for expedited review will be assessed on a

case-by-case basis. All requests may not be granted.

Proposed Sec. 314.70(b)(2) lists changes requiring supplement

submission and FDA approval prior to distribution, including changes

designated as major manufacturing changes in section 506A(c)(2) of the

act and changes to certain biotechnology products that are currently

subject to prior approval requirements under current Sec. 314.70(g)(1).

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 believes that the filing mechanism for these significant

changes is unlikely to vary with technological advances or due to

differences among products, and that these changes should be enumerated

in the proposed regulations. The agency's continued prior review and

approval of such changes is necessary to protect the public from

products for which safety or effectiveness may have been compromised.

The changes in proposed Sec. 314.70(b)(2) would include but are not

limited to the following changes.

1. Changes in the qualitative or quantitative formulation of the

drug, including inactive ingredients, or in the specifications in the

approved application or license, except as provided in proposed

Sec. 314.70(c) and (d) (proposed Sec. 314.70(b)(2)(i)). Section

506A(c)(2)(A) of the act specifically requires that this change be

submitted in a supplement requiring FDA approval prior to distribution.

These types of changes are included under current Sec. 314.70(b) and

(g) as requiring a prior approval supplement. FDA is also proposing to

revise current Sec. 601.12(b)(2)(i) in the regulations on changes to an

approved application for biological products to be consistent with

proposed Sec. 314.70(b)(2)(i).

2. Changes requiring completion of studies in accordance with part

320 (21 CFR part 320) to demonstrate the equivalence of the drug to the

drug as manufactured without the change or to the reference listed drug

(proposed Sec. 314.70(b)(2)(ii)). A similar change is included under

current Sec. 314.70(g)(1) as requiring a prior approval supplement. FDA

is proposing that these changes be submitted in a supplement requiring

prior approval because section 506A of the act provides that a major

manufacturing change shall include a change ``determined by the

Secretary by regulation or guidance to require completion of an

appropriate clinical study demonstrating equivalence of the drug to the

drug as manufactured without the change''(section 506A(c)(2)(B) of the

act). The studies most likely to be conducted to support a

manufacturing change would be bioavailability or bioequivalence studies

conducted in humans in accordance with FDA regulations at part 320.

Well-controlled clinical trials or nonclinical tests may also be used

to establish bioavailability or bioequivalence (Sec. 320.24). These are

the types of studies the statute refers to as demonstrating the

equivalence of one drug to another. FDA proposes interpreting

``Appropriate clinical stud[ies],'' referenced in section 506A(c)(2)(B)

of the act for NDA products, to be ``studies in accordance with part

320 of this chapter'' to clarify the types of studies triggering a

prior approval supplement. This phrase is used in the proposed

regulation at Sec. 314.70(b)(2)(ii).

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. FDA is including in proposed Sec. 314.70(b)(2)(ii) the

statement that the equivalence of the drug may sometimes be

demonstrated by comparison to a reference listed drug. This is

consistent with the drug approval requirements for generic drugs

because, at the time of approval, a generic drug applicant is required

to show equivalence between the proposed generic drug and a reference

listed drug, and a proposed manufacturing change should not

significantly change the equivalence demonstrated at the time of

approval (Sec. 320.21(b)). For the more significant manufacturing

changes for generic drugs, the applicant is required to conduct a

bioequivalence study comparing the drug product made with the change to

the reference listed drug. FDA is not proposing the same changes to

Sec. 601.12 because biological products are not subject to part 320 and

have unique properties. Therefore, the agency will retain the wording

in current Sec. 601.12(b)(2)(ii).

3. Changes that may affect product sterility assurance, such as

changes in product or component sterilization method(s) or an addition,

deletion, or substitution of steps in an aseptic processing operation

(proposed Sec. 314.70(b)(2)(iii)). Current Sec. Sec. 314.70(g)(1) and

601.12(b)(2)(vi) require a prior approval supplement for this change.

4. 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 (proposed

Sec. 314.70(b)(2)(iv)). A similar change in current Sec. 314.70(b)(1)

requires a prior approval supplement.

5. Changes in labeling, except those described in proposed

Sec. 314.70(c)(6)(iii) (changes to add or strengthen certain warnings

or statements), Sec. 314.70(d)(2)(ix) (certain changes in the

description or information about a drug), and Sec. 314.70(d)(2)(x)

(certain editorial or minor changes) (proposed Sec. 314.70(b)(2)(v)).

This change requires a prior approval supplement under current

Sec. 314.70(b)(3).

6. Changes in a container closure system that controls drug

delivery or that may affect the impurity profile of the drug product

(proposed Sec. 314.70(b)(2)(vi)). Significant changes in container

closure systems require a prior approval supplement under current

Sec. 314.70(b)(2).

7. Changes solely affecting a natural product, a recombinant

deoxyribonucleic acid (DNA)-derived protein/polypeptide product, or a

complex or conjugate of a drug with a monoclonal antibody for: (1)

Changes in the virus or adventitious agent removal or inactivation

method(s); (2) changes in the source material or cell line; and (3)

establishment of a new master cell bank or seed (proposed

Sec. 314.70(b)(2)(vii)). This change requires a prior approval

supplement under current Sec. 314.70(g)(1).

8. Changes to a product under an application subject to a validity

assessment because of significant questions regarding the integrity of

the data supporting that application (proposed

Sec. 314.70(b)(2)(viii)). 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 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

[[Page 34613]]

questions resolved, the holder of an approved application may submit

supplements for manufacturing changes as otherwise provided in

Sec. 314.70.

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 this proposed regulation. As discussed previously, section 116

of the Modernization Act expressly states that the agency may through

guidance categorize the manufacturing changes. FDA anticipates that

scientific advances and future experience may reduce the need for

premarket approval of 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: Changes to an Approved NDA or ANDA'' 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 guidance as well as on the

proposed rule.

Current Sec. 314.70(b)(1) requires that supplements requiring prior

approval be submitted for the following changes in a drug substance:

(1) Relaxing the limits for a specification (Sec. 314.70(b)(1)(i)); (2)

establishing a new regulatory analytical method

(Sec. 314.70(b)(1)(ii)); (3) deleting a specification or regulatory

analytical method (Sec. 314.70(b)(1)(iii)); (4) changing the synthesis

of the drug substance, including a change in solvents and a change in

the route of synthesis (Sec. 314.70(b)(1)(iv)); and (5) using a

different facility or establishment to manufacture the drug substance

(Sec. 314.70(b)(1)(v)). FDA is proposing to revoke current

Sec. 314.70(b)(1)(i), (b)(1)(ii), and (b)(1)(iii) because these relate

to a change in a specification which is already covered under proposed

Sec. 314.70(b)(1). FDA is proposing to revoke current

Sec. 314.70(b)(1)(iv) and (b)(1)(v) 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 has decided not to include these changes

in this proposed rule, but plans to provide recommendations on the

filing mechanisms for these types of changes in the guidance documents

discussed previously.

Current Sec. 314.70(b)(2) requires that supplements requiring prior

approval be submitted for the following changes in a drug product: (1)

Adding or deleting an ingredient, or otherwise changing the composition

of the drug product, other than deletion of an ingredient intended only

to affect the color of the drug product (Sec. 314.70(b)(2)(i)); (2)

relaxing the limits for a specification (Sec. 314.70(b)(2)(ii)); (3)

establishing a new regulatory analytical method

(Sec. 314.70(b)(2)(iii)); (4) deleting a specification or regulatory

analytical method (Sec. 314.70(b)(2)(iv)); (5) changing the method of

manufacture of the drug product, including changing or relaxing an in-

process control (Sec. 314.70(b)(2)(v)); (6) using a different facility

or establishment, including a different contract laboratory or labeler,

to manufacture, process, or pack the drug product

(Sec. 314.70(b)(2)(vi)); (7) changing the container and closure system

for the drug product or changing a specification or regulatory

analytical method for the container and closure system

(Sec. 314.70(b)(2)(vii)); (8) changing the size of the container,

except for solid dosage forms, without a change in the container and

closure system (Sec. 314.70(b)(2)(viii)); (9) extending the expiration

date of the drug product based on data obtained under a new or revised

stability testing protocol that has not been approved in the

application (Sec. 314.70(b)(2)(ix)); (10) establishing a new procedure

for reprocessing a batch of the drug product that fails to meet

specifications (Sec. 314.70(b)(2)(x)); (11) adding a code imprint by

printing with ink on a solid oral dosage form drug product

(Sec. 314.70(b)(2)(xi)); (12) adding a code imprint by embossing,

debossing, or engraving on a modified release solid oral dosage form

drug product (Sec. 314.70(b)(2)(xii)). FDA is proposing to revoke

Sec. 314.70(b)(2)(i) through (b)(2)(iv) because these provisions relate

to a change in qualitative or quantitative formulation or a

specification that is already covered under proposed Sec. 314.70(b)(1).

FDA is proposing to revoke current Sec. 314.70(b)(2)(v) through

(b)(2)(xii) because some changes would fall into the proposed major

manufacturing changes category while others would fall into other

proposed categories. FDA plans to provide recommendations on the filing

mechanism for these changes in the guidance documents discussed

previously.

Proposed Sec. 314.70(b)(3) states that the applicant must obtain

approval of a supplement from FDA before distributing a product using a

change under Sec. 314.70(b), and specifies information to be included

in the supplement. The supplement must include: (1) A detailed

description of the proposed change; (2) the product(s) involved; (3)

the manufacturing site(s) or area(s) affected; (4) a description of the

methods used and studies performed to evaluate the effect of the change

on the identity, strength, quality, purity, or potency of the product

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

product (validating the effects of the change); (5) data derived from

such studies; (6) for a natural product, a recombinant DNA-derived

protein/polypeptide product, or a complex or conjugate of a drug with a

monoclonal antibody, relevant validation protocols must be provided in

addition to the requirements under Sec. 314.70(b)(3)(iv) and (b)(3)(v);

(7) for sterilization process and test methodologies, relevant

validation protocols must be provided in addition to the requirements

under Sec. 314.70(b)(3)(iv) and (b)(3)(v); and (8) if applicable, a

reference list of relevant standard operating procedures (SOP's). These

supplement content requirements are already required under current

Sec. Sec. 314.70(g)(1)(iii) and 601.12(b)(3), and FDA is proposing to

retain the requirements in this rule, except that the proposal

specifies that relevant validation protocols and data apply to a

natural product, a recombinant DNA-derived protein/polypeptide product,

or a complex or conjugate of a drug with a monoclonal antibody, as well

as protocols and data for sterilization processes and test

methodologies.

Current Sec. 314.70(g)(1)(iii) only applies to recombinant DNA-

derived protein/polypeptide products or complexes or conjugates of a

drug with a monoclonal antibody. Some information requirements listed

under current Sec. 314.70(g)(1)(iii) are not applicable to all CDER

drug products. FDA is proposing to clarify the requirements in current

Sec. 314.70(g)(1)(iii) to describe the limited circumstances under

which certain information would be required.

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

Distribution of the Drug Product Made Using the Change (Moderate

Changes)

Current Sec. 314.70(c) describes changes that may be made before

FDA approval of a supplement. These include changes to enhance the safe

use of a drug by adding specifications to strengthen warnings, or to

delete false, misleading, or unsupported indications for use. Current

Sec. 314.70(g)(2) describes changes requiring supplement submission at

least 30 days prior to distribution of the

[[Page 34614]]

product made using the change. These include changes in the site of

testing from one facility to another, an increase or decrease in

production scale during finishing steps that involves new or different

equipment, and replacement of equipment with that of similar, but not

identical, design and operating principle that does not affect the

process methodology or process operating parameters. FDA recognizes

that 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 there is a

mechanism for assessing the consequences of the change and that the

agency approve such changes. Ready access to information regarding such

changes through submission of a supplement 30 days before distribution

of the product would protect against the distribution of unsafe or

ineffective products while speeding the availability of improved

products.

Proposed Sec. 314.70(c) implements section 506A(d)(1)(B) and

(d)(3)(B)(i) of the act and provides that products made using changes

listed under this section may be distributed not sooner than 30 days

after receipt of a supplement by FDA. Proposed Sec. 314.70(c)(1) 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. 314.70(c)(3) states that a supplement submitted under paragraph

(c)(1) 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'' or, if applicable under paragraph (c)(6) of this

section, ``Supplement--Changes Being Effected.''

Proposed Sec. 314.70(c)(2) describes the types of changes that

would be included under this section:

1. A change in the container closure system that does not affect

the quality of the final drug product (proposed Sec. 314.70(c)(2)(i)).

2. Changes solely affecting a natural protein product, a

recombinant DNA-derived protein/polypeptide product or a complex or

conjugate of a drug with a monoclonal antibody, including: (1) An

increase or decrease in production scale during finishing steps that

involves new or different equipment and (2) replacement of equipment

with that of similar, but not identical, design and operating principle

that does not affect the process methodology or process operating

parameters (proposed Sec. 314.70(c)(2)(ii)). These changes are listed

in current Sec. 314.70(g)(2) as requiring the submission of a

supplement at least 30 days prior to distribution.

Current Sec. 314.70(g)(2) lists a change in the site of testing

from one facility to another as a change that must be filed in a

supplement submitted at least 30 days prior to distribution. FDA has

decided not to include a similar change in proposed Sec. 314.70(c) and

is proposing to delete this change from current Sec. 601.12(c)(2)(i).

FDA plans to provide recommendations on the filing mechanism for this

change in the guidance documents discussed previously.

Proposed Sec. 314.70(c)(4) states that distribution of a product

made using a change under this section may begin not less than 30 days

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

that the same information listed in paragraph (b)(3), discussed

previously, must be contained in the supplement required under proposed

Sec. 314.70(c).

Proposed Sec. 314.70(c)(5) states that 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. 314.70(c). If the proposed change is determined to be a major

change that should be submitted under proposed Sec. 314.70(b), the

agency would inform the applicant and the applicant would be required

to receive FDA 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. 314.70(c), 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. These provisions are

provided in section 506A(d)(3) of the act. These requirements are

included under current Sec. Sec. 314.70(g)(2)(iv) and 601.12(c)(4) and

FDA is retaining and expanding this requirement to cover all drugs.

Under proposed Sec. 314.70(c)(7), 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. FDA is also proposing to add this provision to the regulations

on changes to an approved application for biological products as

proposed Sec. 601.12(c)(6).

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

(Moderate Changes)

Under proposed Sec. 314.70(c)(6), FDA may designate a category of

changes for which the holder of an approved application making such a

change may begin distribution of the drug upon receipt by FDA of a

supplemental application for the change. This provision implements

section 506A(d)(3)(B)(ii) of the act. FDA recognizes that 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 there is a mechanism for

assessing the consequences of the changes and for the agency to 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. 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. Ready access to information by FDA regarding such

changes, through the submission of a supplement, would protect against

the distribution of unsafe or ineffective products while speeding the

availability of improved products.

These changes include, but are not limited to:

1. The addition to a specification or changes in the methods or

controls to provide increased assurance that the drug will have the

characteristics of identity, strength, quality, purity, or potency that

it purports or is represented to possess (proposed

Sec. 314.70(c)(6)(i)). A similar change is listed under current

Sec. 314.70(c). Proposed Sec. 314.70(c)(6)(i) revises current

Sec. 314.70(c) to provide clarification based on the proposed

definition of specification and to delete the reference to facilities.

FDA plans to provide recommendations on the filing mechanism for

facility changes in the guidance documents discussed previously.

2. A change in the size and/or shape of a container (containing the

same

[[Page 34615]]

labeled amount of product) for a nonsterile drug product, except for

solid dosage forms, without a change from one container closure system

to another (proposed Sec. 314.70(c)(6)(ii)). A similar change is listed

under current Sec. 314.70(b) as requiring prior approval. The proposal

differs from the existing rule in that it only applies to nonsterile

drug products, thereby reducing the potential risks and eliminating the

need for a prior approval requirement. FDA is also clarifying that

changes in container size relate to changes in the physical size of the

container and do not include changes in the labeled amount of the drug.

3. Changes in the labeling to add or strengthen a contraindication,

warning, precaution, or adverse reaction, or to add or strengthen a

statement about drug abuse, dependence, psychological effect, or

overdosage, or to add or strengthen an instruction about dosage and

administration that is intended to increase the safe use of the product

(proposed Sec. 314.70(c)(6)(iii)(A), (c)(6)(iii)(B), and

(c)(6)(iii)(C)). These changes are required under current

Sec. 314.70(c)(2), except that FDA is proposing to include labeling

changes relating to adding or strengthening a statement about

psychological effects to maintain consistency with current

Sec. 601.12(f)(2)(B).

4. The deletion of false, misleading, or unsupported indications

for use or claims for effectiveness (proposed

Sec. 314.70(c)(6)(iii)(D)). This change is required under current

Sec. 314.70(c)(2).

5. Any other labeling changes specifically requested by FDA

(proposed Sec. 314.70(c)(6)(iii)(E)). FDA is proposing to include this

change under this section to enable the agency to allow for labeling

changes that normally require prior approval to be submitted in a

changes being effected supplement when FDA specifically requests the

change. FDA is also proposing to add this requirement to the

regulations on changes to an approved application for biological

products as proposed Sec. 601.12(f)(2)(i)(E).

Current Sec. 314.70(c)(3) lists the following changes to use a

different facility or establishment to manufacture the drug substance

that may be made before FDA approval: (1) Where the manufacturing

process in the new facility or establishment does not differ materially

from that in the former facility or establishment, and (2) where the

new facility or establishment has received a satisfactory CGMP

inspection within the previous 2 years covering that manufacturing

process. FDA is proposing not to include these changes in this proposed

rule but plans to provide recommendations on the filing mechanism for

these changes in the guidance documents discussed previously.

F. Changes To Be Described in the Next Annual Report (Minor Changes)

Proposed Sec. 314.70(d) 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 of the product as these factors

may relate to the safety or effectiveness of the product would be

documented by the applicant in the next annual report in accordance

with current Sec. 314.81(b)(2). This provision is provided in section

506A(d)(2) of the act. FDA recognizes that there are manufacturing

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

product's safety or effectiveness. FDA believes that prior agency

approval of these changes is unnecessary and is proposing in

Sec. 314.70(d) 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 there is a mechanism for

assessing the consequences of the change. FDA can effectively assess

compliance with Sec. 314.70(d) 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.

Under proposed Sec. 314.70(d)(2), these changes would include, but

are not limited to:

1. Any change made to comply with an official compendium that is

consistent with FDA requirements and provides increased assurance that

the drug will have the characteristics of identity, strength, quality,

purity, or potency that it purports or is represented to possess

(proposed Sec. 314.70(d)(2)(i)). Similar changes are listed in current

Sec. 314.70(d) and (g) as changes to be described in the next annual

report. FDA is limiting the situations in which these changes can be

submitted in an annual report because certain changes in a

specification (e.g., deleting a test, relaxing acceptance criteria) are

not considered to have minimal potential to effect a product's safety

or effectiveness. FDA is also proposing to revise current

Sec. 601.12(d)(2)(i) in the regulations on changes to an approved

application for biological products to be consistent with proposed

Sec. 314.70(d)(2)(i).

2. The deletion or reduction of an ingredient intended only to

affect the color of the product (proposed Sec. 314.70(d)(2)(ii)). A

similar change is listed in current Sec. 314.70(d) and (g)(3) which

states that the deletion of an ingredient intended only to affect the

color of the drug product should be submitted in an annual report. FDA

is proposing to broaden this provision to include changes that reduce

the quantity of an ingredient intended only to affect the color of the

product. FDA is also proposing to revise current Sec. 601.12(d)(2)(ii)

in the regulations on changes to an approved application for biological

products to be consistent with proposed Sec. 314.70(d)(2)(ii).

3. The replacement of equipment with that of the same design and

operating principles except for equipment used with a natural protein

product, a recombinant DNA-derived protein/polypeptide product, or a

complex or conjugate of a drug with a monoclonal antibody (proposed

Sec. 314.70(d)(2)(iii)). FDA is proposing to add this change to clarify

when certain changes in equipment could be reported in an annual

report. In general, under current regulations (e.g.,

Sec. 314.70(b)(2)(v)), changes in process, which may include changes in

equipment, require a prior approval supplement and this proposal would

reduce the regulatory burden without adversely affecting the quality of

the drug product.

4. A change in the size and/or shape of a container containing the

same number of dose units for a nonsterile solid dosage form, without a

change from one container closure system to another (proposed

Sec. 314.70(d)(2)(iv)). A similar change is listed in current

Sec. 314.70(d) and (g)(3) which states that a change in the size of a

container for a solid dosage form without a change from one container

and closure system to another must be filed in an annual report. FDA is

proposing to broaden this provision to include a change in the shape of

the container. FDA is also clarifying that a change in container size

relates to a change in the physical size of the container and does not

include a change involving the number of dosage units. FDA is also

proposing to revise current Sec. 601.12(d)(2)(v) in the regulations on

changes to an approved application for biological products to be

consistent with proposed Sec. 314.70(d)(2)(iv).

5. 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

[[Page 34616]]

compendium (proposed Sec. 314.70(d)(2)(v)). A similar change is listed

in current Sec. 314.70(d) and (g)(3) which states that a change within

the container and closure system for the drug product (for example, a

change from one high density polyethylene (HDPE) to another HDPE),

except a change in container size for nonsolid dosage forms, based upon

a showing of equivalency to the approved system under a protocol

approved in the application or published in an official compendium,

should be submitted in an annual report. The current regulations limit

this provision by excluding a change in container size for nonsolid

dosage forms. FDA is proposing to broaden this provision to allow such

changes for all nonsterile drug products. FDA is also proposing to

revise current Sec. 601.12(d)(2)(iv) in the regulations on changes to

an approved application for biological products to be consistent with

proposed Sec. 314.70(d)(2)(v).

6. An extension of an expiration dating period based upon full

shelf life data on full production batches obtained from a protocol

approved in the application (proposed Sec. 314.70(d)(2)(vi)). A similar

change is listed under current Sec. 314.70(d) and (g)(3) as one to be

filed in an annual report. FDA is clarifying that the extension of an

expiration date in an annual report should be based on data from full

production batches. FDA is also proposing to revise current

Sec. 601.12(d)(2)(iii) regarding changes to an approved application for

biological products to be consistent with proposed

Sec. 314.70(d)(2)(vi).

7. The addition, deletion, or revision of an alternate 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 (proposed Sec. 314.70(d)(2)(vii)). A similar change is

listed in current Sec. 314.70(d) and (g)(3) which state that the

addition or deletion of an alternate analytical method should be filed

in an annual report. FDA is proposing to broaden this provision to

include revisions of alternate analytical procedures. FDA is also

clarifying that any changes in alternate analytical procedures should

provide 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. FDA is also

proposing to revise current Sec. 601.12(d)(2)(vii) in the regulations

on changes to an approved application for biological products to be

consistent with proposed Sec. 314.70(d)(2)(vii).

8. 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

(proposed Sec. 314.70(d)(2)(viii)). These changes are listed in current

Sec. 314.70(d) and (g)(3) as changes to be described in the next annual

report.

9. A change in the labeling concerning the description of the drug

product or in the information about how the drug is supplied, that does

not involve a change in the dosage strength or dosage form (proposed

Sec. 314.70(d)(2)(ix)). These changes are listed in current

Sec. 314.70(d) as changes to be described in the next annual report.

10. An editorial or similar minor change in labeling (proposed

Sec. 314.70(d)(2)(x)). These changes are listed in current

Sec. 314.70(d) as changes to be described in the next annual report.

Under proposed Sec. 314.70(d)(3), an applicant must submit in the

annual report a list of all products involved and: (1) A statement by

the holder of the approved application that the effects of the change

have been validated; (2) a full description of the manufacturing and

controls changes, including the manufacturing site(s) or area(s)

involved; and (3) the date each change was made, a cross-reference to

relevant validation protocol(s) and/or SOP's, and relevant data from

studies and tests performed to evaluate the effect of the change on the

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

factors may relate to the safety or effectiveness of the product

(validating the effects of the change). FDA is also proposing to revise

current Sec. 601.12(d)(3) in the regulations on changes to an approved

application for biological products to add, as proposed

Sec. 601.12(d)(3)(iii), the requirement that the applicant must submit

a statement that the effects of the change have been validated.

G. Other Information

Under proposed Sec. 314.70(e), 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 prior approval

from FDA prior to distribution of the drug. If the supplement is

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. This proposed requirement is

provided for in current Sec. Sec. 314.70(g)(4) and 601.12(e).

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 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.

Under proposed Sec. 314.70(f), an applicant would be required to

comply with the patent information requirements under section 505(c)(2)

of the act. This proposed requirement is identical to the current

requirement at Sec. 314.70(e).

Proposed Sec. 314.70(g) would require an applicant claiming

exclusivity under Sec. 314.108 to include, with the supplemental

application, information required under Sec. 314.50(j). This proposed

requirement is identical to the current requirement at Sec. 314.70(f).

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

authorize FDA to revise Sec. Sec. 314.70 and 601.12. Sections 301 and

501 of the act (21 U.S.C. 331 and 351) prohibit the manufacture,

processing, packing, or holding of drugs that do not conform to CGMP;

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. Sections 301 and 502 of the act (21 U.S.C. 352) prohibit

false or misleading labeling of drugs, including, under section 201(n)

of the act (21 U.S.C. 321(n)), failure to reveal material facts

relating to potential consequences under customary conditions of use;

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 their labeling. Under section 505 of the act, FDA

will approve an NDA if the drug is shown to be safe and effective for

its intended use and if, among other things, the methods used

[[Page 34617]]

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

processing and packing of the 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.

The Public Health Service Act (the PHS Act) provides additional

authority for FDA to revise Sec. 601.12. Section 351(a) of the PHS Act

(42 U.S.C. 262(a)) provides that license applications for biological

products may be approved upon a showing that the product is safe, pure,

and potent and that the manufacturing facility meets standards designed

to ensure continued safety, purity, and potency of the product. In

addition, under section 351(b) of the PHS Act, biological products and

their containers or packages may not be falsely labeled or marked.

V. Conforming Amendments

The regulations on supplements and changes to an approved

application or license are cited throughout FDA's regulations. Because

FDA is proposing to revise these regulations, the agency is taking this

opportunity to make conforming amendments to 21 CFR parts 5, 206, 250,

314, 600, and 601 to reflect these proposed regulations. These

conforming amendments will ensure the accuracy and consistency of the

regulations.

VI. 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 (Pub. L. 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. Under the Regulatory Flexibility

Act, if a rule has a significant economic impact on a substantial

number of small entities, an agency must analyze regulatory options

that would minimize any significant impact of the rule on small

entities. Title II of the Unfunded Mandates Reform Act (in section 202)

requires that agencies prepare a written assessment of anticipated

costs and benefits before proposing any rule that may result in an

expenditure in any one year by State, local, and tribal governments, in

the aggregate, or by the private sector of $100 million (adjusted

annually for inflation).

The agency believes that this proposed rule is consistent with the

regulatory philosophy and principles identified in Executive Order

12866 and in these two statutes. As shown in the following paragraphs,

the rule will not be significant as defined by the Executive Order and

the Unfunded Mandates Reform Act, and the agency certifies that the

proposed rule will not have a significant economic impact on a

substantial number of small entities.

The purpose of the proposed rule is to implement section 506A of

the act and to reduce the number of manufacturing changes subject to

supplements requiring FDA approval prior to product distribution. The

proposed rule would affect all drug manufacturers that submit

manufacturing supplements and would result in a substantial reduction

in burdens to applicants making manufacturing changes subject to the

proposed regulation. The proposed rule would 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 to the agency. For example, a report by the Eastern Research

Group (ERG), an FDA contractor, on the effects of the SUPAC guidance

for immediate release solid oral dosage forms (SUPAC-IR) found that

reducing the number of changes that require preapproval gives companies

greater control over their production resources, which could lead to

significant net savings to industry (Eastern Research Group,

Pharmaceutical Industry Cost Savings Through Use of the Scale-Up and

Post-Approval Guidance for Immediate Release Solid Oral Dosage Forms

(SUPAC-IR), January 7, 1998, Contract No. 223-94-8301). Such economic

incentives may encourage manufacturers to improve their products,

product labeling, and methods of manufacture.

Due to the multiplicity of products and manufacturing changes, the

agency has not estimated the total savings to industry as a result of

this 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. ERG estimated that companies may already have saved $71

million in 1997 due to the agency's implementation of more flexible

reporting procedures for chemistry, manufacturing, and control changes.

This proposed rule would broaden the potential scope of such savings.

Because the proposal would benefit manufacturers regardless of size and

impose no additional costs, the agency certifies that this rule will

not have a significant adverse economic impact on a substantial number

of small entities.

VII. Paperwork Reduction Act of 1995

This proposed rule contains collections of information that are

subject to review by OMB under the Paperwork Reduction Act of 1995 (the

PRA) (44 U.S.C. 3501-3520). ``Collection of information'' includes any

request or requirement that persons obtain, maintain, retain, or report

information to the agency, or disclose information to a third party or

to the public (44 U.S.C. 3502(3) and 5 CFR 1320.3(c)). The title,

description, and respondent description of the information collection

are shown under this section VII with an estimate of the annual

reporting burden. Included in the estimate is the time for reviewing

instructions, gathering and maintaining the data needed, and completing

and reviewing the collection of information.

FDA invites comments on: (1) Whether the proposed collection of

information is necessary for proper performance of FDA's functions,

including whether the information will have practical utility; (2) the

accuracy of FDA's estimate of the burden of the proposed collection of

information, including the validity of the methodology and assumptions

used; (3) ways to enhance the quality, utility, and clarity of the

information to be collected; and (4) ways to minimize the burden of the

collection of information on respondents, including through the use of

automated collection techniques, when appropriate, and other forms of

information technology.

Title: Supplements and Other Changes to an Approved Application.

Description: The proposed rule would implement the manufacturing

changes provision of section 116 of the 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 would report the change to

[[Page 34618]]

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 would 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 would 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 would 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 would be documented by the respondent in the next annual

report.

Proposed Sec. Sec. 314.70(a)(2) and 601.12(a)(2) would 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. This proposed requirement implements the statutory requirement

for information collection under section 506A(a) and (b) of the act

and, therefore, no burden estimate has been calculated for this

regulation.

Proposed Sec. Sec. 314.70(a)(4) and 601.12(a)(4) would 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

Sec. Sec. 314.81(b)(3)(i) and 601.12(f)(4). This information collection

is approved by OMB until August 31, 2001, under OMB control number

0910-0376. Therefore, this requirement is not estimated in Table 1 of

this document.

Proposed Sec. 314.70(a)(5) would require that the applicant include

in each supplement (except for a supplement providing for a change in

the labeling) a statement certifying that a field copy of the

supplement has been provided to the applicant's home FDA district

office. Based on data concerning the number of supplements received by

the agency, FDA estimates that approximately 4,278 certifications and

field copies will be submitted annually as required by proposed

Sec. 314.70(a)(5). FDA estimates that approximately 594 applicants will

submit these certifications and field copies. Preparation of a field

copy would involve copying material already prepared for the

supplement, and FDA estimates that it will take an average of 1 hour

for applicants to include an additional field copy for FDA.

Proposed Sec. Sec. 314.70(a)(6) and 601.12(a)(5) would require the

applicant to include in the cover letter a list of all changes

contained in the supplement or annual report. Based on data concerning

the number of supplements and annual reports received by the agency,

FDA estimates that approximately 11,913 lists of all changes in the

supplement or annual report will be submitted annually as required by

proposed Sec. 314.70(a)(6). FDA estimates that approximately 704

applicants will submit these lists. Because the information required

would be generated in preparing the supplement or annual report, the

agency estimates that, under proposed Sec. 314.70(a)(6), it will take

approximately 1 hour to include a list of changes in a cover letter for

a supplement or an annual report. FDA estimates that approximately

2,983 lists of all changes in the supplement or annual report will be

submitted annually as required by proposed Sec. 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 proposed

Sec. 601.12(a)(5), it will take approximately 1 hour to include a list

of changes in a cover letter for a supplement or an annual report.

Proposed Sec. 314.70(b) and current Sec. 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). Proposed Sec. 314.70(b)(1) and current Sec. 601.12(b)(1)

state that a supplement must be submitted for 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.

Under proposed Sec. 314.70(b)(3) and current Sec. 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 evaluate the effect of the change on the identity,

strength, quality, purity, or potency of the product as these factors

may relate to the safety or effectiveness of the product (validating

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 with a

monoclonal antibody, relevant validation protocols must be provided;

(vii) For sterilization process and test methodologies, relevant

validation protocols must be provided; and (viii) A reference list of

relevant standard operating procedures when applicable.

The changes requiring supplement submission and approval prior to

distribution of the product made using the change (major changes) are

listed in proposed Sec. 314.70(b)(2) and current Sec. 601.12(b)(2)

(including proposed Sec. 601.12(b)(2)(i)): (i) Changes in the

qualitative or quantitative formulation of the drug, including inactive

ingredients, or in the specifications provided in the approved

application; (ii) Changes requiring completion of studies in accordance

with 21 CFR part 320 to demonstrate the equivalence of the drug to the

drug as manufactured without the change or to the reference listed

drug; (iii) Changes that may affect product sterility assurance, such

as changes in product or component sterilization method(s) or an

addition, deletion, or substitution of steps in an aseptic processing

operation; (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) Certain

changes in labeling; (vi) Changes in a container closure system that

controls drug delivery or that may affect the impurity profile of the

drug product; (vii) Changes solely affecting a natural product, a

recombinant DNA-derived protein/polypeptide product, or a complex or

conjugate of a drug 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; (viii) 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 that application.

Under proposed Sec. Sec. 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

[[Page 34619]]

hardship on the applicant. Such a supplement and its mailing cover

should be marked: ``Prior Approval Supplement-Expedited Review

Requested.''

Based on data concerning the number of supplements received by the

agency, FDA estimates that approximately 1,744 supplements will be

submitted annually under proposed Sec. 314.70(b)(1) and (b)(3). FDA

estimates that approximately 594 applicants will submit such

supplements, and that it will take approximately 80 hours to prepare

and submit to FDA each supplement. FDA estimates that approximately 903

supplements are submitted annually under Sec. 601.12(b)(1) and (b)(3).

FDA estimates that approximately 190 applicants submit such

supplements, and that it takes approximately 80 hours to prepare and

submit to FDA each supplement. The burden for an applicant's request,

under proposed Sec. Sec. 314.70(b)(4) and 601.12(b)(4), for FDA to

expedite its review of a supplement is negligible and has not been

estimated in Table 1 of this document.

Proposed Sec. 314.70(c) and current Sec. 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). Proposed Sec. 314.70(c)(1) and current

Sec. 601.12(c)(1) state that a supplement must 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. Under proposed Sec. 314.70(c)(1), the applicant must submit 12

copies of final printed labeling for all labeling changes.

Under proposed Sec. 314.70(c)(3) and current Sec. 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 proposed Sec. 314.70(c)(4) and current Sec. 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 previously for proposed Sec. 314.70(b)(3) and current

Sec. 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 proposed Sec. 314.70(c)(2) (the changes in

Sec. 314.70(c)(2)(ii)(A) and (c)(2)(ii)(B) are also listed in current

Sec. 601.12(c)(2)): (i) A change in the container closure system that

does not affect the quality of the final drug product; and (ii) Changes

solely affecting a natural protein product, a recombinant DNA-derived

protein/polypeptide product or a complex or conjugate of a drug with a

monoclonal antibody, including: (A) An increase or decrease in

production scale during finishing steps that involves new or different

equipment; and (B) Replacement of equipment with that of similar, but

not identical, design and operating principle that does not affect the

process methodology or process operating parameters.

Based on data concerning the number of supplements received by the

agency, FDA estimates that approximately 2,754 supplements will be

submitted annually under proposed Sec. 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 50 hours to

prepare and submit to FDA each supplement. FDA estimates that

approximately 255 supplements are submitted annually under

Sec. 601.12(c)(1) and (c)(3). FDA estimates that approximately 98

applicants submit such supplements, and that it takes approximately 50

hours to prepare and submit to FDA each supplement.

Under proposed Sec. 314.70(c)(6) and current Sec. 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 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 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 other changes

specifically requested by FDA. Under proposed Sec. 314.70(c)(3) and

current Sec. 601.12(c)(1), the supplement must be labeled

``Supplement--Changes Being Effected.''

Based on data concerning the number of supplements received by the

agency, FDA estimates that approximately 486 supplements will be

submitted annually under proposed Sec. 314.70(c)(6). FDA estimates that

approximately 486 applicants will submit such supplements, and that it

will take approximately 50 hours to prepare and submit to FDA each

supplement. FDA estimates that approximately 47 supplements are

submitted annually under Sec. 601.12(c)(5). FDA estimates that

approximately 34 applicants submit such supplements, and that it takes

approximately 50 hours to prepare and submit to FDA each supplement.

Proposed Sec. 314.70(d) and current Sec. 601.12(d) set forth

requirements for changes to be described in an annual report (minor

changes). Proposed Sec. 314.70(d)(1) and current Sec. 601.12(d)(1)

state that changes in 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 of the product as these factors may relate to the safety or

effectiveness of the product must be documented by the applicant in the

next annual report.

Under proposed Sec. 314.70(d)(3) and current Sec. 601.12(d)(3)

(including proposed Sec. 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 validated; (ii) A full description of the

manufacturing and controls changes, including the manufacturing site(s)

or area(s) involved; and (iii) The date each change was made, a cross-

reference to relevant validation protocols and/or SOP's, and relevant

data from studies and tests performed to evaluate the effect of the

change on the identity, strength, quality, purity, or potency of the

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

the product (validation).

The changes to be described in an annual report (minor changes)

are listed in proposed Sec. 314.70(d)(2) and current Sec. 601.12(d)(2)

(including proposed Sec. 601.12(d)(2)(i) through (d)(2)(v) and

(d)(2)(vii)): (i) Any change made to comply with an official compendium

that is consistent with FDA requirements and provides increased

assurance that the drug will have the

[[Page 34620]]

characteristics of identity, strength, quality, purity, or potency that

it purports or is represented to possess; (ii) The deletion or

reduction of an ingredient intended to affect only the color of the

product; (iii) Replacement of equipment with that of the same design

and operating principles except for equipment used with a natural

protein product, a recombinant DNA-derived protein/polypeptide product,

or a complex or conjugate of a drug with a monoclonal antibody; (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, 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 obtained from a protocol approved in the

application; (vii) The addition, deletion, or revision of an alternate

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; (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 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.

Based on data concerning the number of supplements and annual

reports received by the agency, FDA estimates that approximately 6,929

annual reports will include documentation of certain manufacturing

changes as required under proposed Sec. 314.70(d)(1) and (d)(3). FDA

estimates that approximately 704 applicants will submit such

information, and that it will take approximately 10 hours to prepare

and submit to FDA the information for each annual report. FDA estimates

that approximately 227 annual reports include documentation of certain

manufacturing changes as required under current Sec. 601.12(d)(1) and

(d)(3). FDA estimates that approximately 166 applicants submit such

information, and that it takes approximately 10 hours to prepare and

submit to FDA the information for each annual report. Proposed

Sec. 314.70(d)(3) and current Sec. 601.12(d)(3) require a statement by

the applicant that the effects of the change have been validated. This

information is developed by the applicant to validate the effects of

the change regarding identity, strength, quality, purity, and potency,

and is expressly required to be submitted under section 506A(d)(3)(A)

of the act. Therefore, the burden associated with such collection of

information is not included in the estimates of Table 1 of this

document.

The proposed regulation would 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 proposed

regulation would not increase the number of annual reports but would

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.

Proposed Sec. 314.70(e) and current Sec. 601.12(e) state that an

applicant may submit one or more protocols describing the specific

tests and validation studies and acceptable limits to be achieved to

demonstrate the lack of adverse effect for specified types of

manufacturing changes on the identity, strength, quality, purity, or

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

effectiveness of the drug. Any such protocols, or changes to a

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.

Based on data concerning the number of supplements received by the

agency, FDA estimates that approximately 50 protocols will be submitted

annually under proposed Sec. 314.70(e). FDA estimates that

approximately 50 applicants will submit such protocols, and that it

will take approximately 20 hours to prepare and submit to FDA each

protocol. FDA estimates that approximately 20 protocols are submitted

annually under Sec. 601.12(e). FDA estimates that approximately 14

applicants submit such protocols, and that it takes approximately 20

hours to prepare and submit to FDA each protocol.

Current Sec. 601.12(f) sets forth the requirements for supplement

submission for labeling changes for biological products. Current

Sec. 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. Proposed Sec. 601.12(f)(2)(i)(E) would add

``any other changes specifically requested by FDA'' to these types of

changes. FDA estimates that approximately 12 labeling supplements are

submitted annually under current Sec. 601.12(f)(1). FDA estimates that

approximately 12 applicants submit these supplements, and that it takes

approximately 40 hours to prepare and submit to FDA each supplement.

FDA estimates that approximately 10 labeling supplements are submitted

annually under current Sec. 601.12(f)(2), including those that would be

submitted under proposed Sec. 601.12(f)(2)(i)(E). FDA estimates that

approximately 10 applicants submit these supplements, and that it takes

approximately 20 hours to prepare and submit to FDA each supplement.

FDA estimates that approximately 100 annual reports for labeling

changes are submitted under current Sec. 601.12(f)(3). FDA estimates

that approximately 70 applicants submit these reports, and that it

takes approximately 10 hours to prepare and submit to FDA each report.

FDA estimates that approximately 1,495 labeling supplements are

submitted annually under current Sec. 601.12(f)(4). FDA estimates that

approximately 61 applicants submit these supplements, and that it takes

approximately 10 hours to prepare and submit to FDA each supplement.

Proposed Sec. 314.70(f) states that an applicant must comply with

the patent information requirements under section 505(c)(2) of the act.

Proposed Sec. 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 May 31, 2001, under OMB control

number 0910-0305. Therefore, this requirement is not estimated in Table

1 of this document.

Description of Respondents: Business or other for-profit

organizations.

In compliance with section 3507(d) of the PRA (44 U.S.C. 3507(d)),

the agency has submitted a copy of this proposed rule to OMB for its

review and approval of these information collections.

[[Page 34621]]

Interested persons are requested to send comments regarding this

collection of information, including suggestions for reducing this

burden, to the Office of Information and Regulatory Affairs, OMB

(address above), Attn: Wendy Taylor, Desk Officer for FDA. Submit

written comments on the collection of information by July 28, 1999.

Table 1.--Estimated Annual Reporting Burden1

----------------------------------------------------------------------------------------------------------------

No. of

21 CFR Section No. of Responses per Total Annual Hours per Total Hours

Respondents Respondent Responses Response

----------------------------------------------------------------------------------------------------------------

314.70(a)(5) 594 7 4,278 1 4,278

314.70(a)(6) 704 17 11,913 1 11,913

314.70(b)(1) and (b)(3) 594 3 1,744 80 139,520

314.70(c)(1),(c)(3), and 594 5 2,754 50 137,700

(c)(4)

314.70(c)(6) 486 1 486 50 24,300

314.70(d)(1) and (d)(3) 704 10 6,929 10 69,290

314.70(e) 50 1 50 20 1,000

601.12(a)(5) 190 16 2,983 1 2,983

601.12(b)(1) and (b)(3) 190 5 903 80 72,240

601.12(c)(1) and (c)(3) 98 3 255 50 12,750

601.12(c)(5) 34 1 47 50 2,350

601.12(d)(1) and (d)(3)6 1 227 10 2,270

601.12(e) 14 1 20 20 400

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 1,000

601.12(f)(4) 61 25 1,495 10 14,950

Total 497,624

----------------------------------------------------------------------------------------------------------------

\1\There are no capital costs or operating and maintenance costs associated with this collection of information.

VIII. Environmental Impact

The agency has determined under 21 CFR 25.30(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.

IX. Request for Comments

Interested persons may, on or before September 13, 1999, submit to

the Dockets Management Branch (address above) written comments

regarding this proposal. Two copies of any comments are to be

submitted, except that individuals may submit one copy. Comments are to

be identified with the docket number found in brackets in the heading

of this document. Received comments may be seen in the office above

between 9 a.m. and 4 p.m., Monday through Friday. Submit written

comments on the information collection requirements as described in

paragraph VII of this document by July 28, 1999.

List of Subjects

21 CFR Part 5

Authority delegations (Government agencies), Imports, Organization

and functions (Government agencies).

21 CFR Parts 206 and 250

Drugs.

21 CFR Part 314

Administrative practice and procedure, Confidential business

information, Drugs, Reporting and recordkeeping requirements.

21 CFR Part 600

Biologics, Reporting and recordkeeping requirements.

21 CFR Part 601

Administrative practice and procedure, Biologics, Confidential

business information.

Therefore, under the Federal Food, Drug, and Cosmetic Act and under

authority delegated to the Commissioner of Food and Drugs, it is

proposed that 21 CFR parts 5, 206, 250, 314, 600, and 601 be amended as

follows:

PART 5--DELEGATIONS OF AUTHORITY AND ORGANIZATION

1. The authority citation for 21 CFR part 5 continues to read as

follows:

Authority: 5 U.S.C. 504, 552, App. 2; 7 U.S.C. 138a, 2271; 15

U.S.C. 638, 1261-1282, 3701-3711a; 15 U.S.C. 1451-1461; 21 U.S.C.

41-50, 61-63, 141-149, 321-394, 467f, 679(b), 801-886, 1031-1309; 35

U.S.C. 156; 42 U.S.C. 241, 242, 242a, 242l, 242n, 243, 262, 263,

264, 265, 300u-300u-5, 300aa-1; 1395y, 3246b, 4332, 4831(a), 10007-

10008, E.O. 11921, 41 FR 24294, 3 CFR, 1977 Comp., p. 124-131; E.O.

12591, 52 FR 13414, 3 CFR, 1988 Comp., p. 220-223.

Sec. 5.80 [Amended]

2. Section 5.80 Approval of new drug applications and their

supplements is amended in the first sentence of paragraphs (d) and (f)

by removing the phrase ``Sec. Sec. 314.70(b)(1), (b)(2)(ii) through

(b)(2)(x), (c)(1), and (c)(3)'' and by adding in its place the phrase

``Sec. 314.70(b)(1), (b)(2)(i) excluding changes in qualitative or

quantitative formulation, (b)(2)(iii), (b)(2)(iv), (b)(2)(vi),

(b)(2)(vii), (c)(2)(i), (c)(2)(ii), (c)(6)(i), and (c)(6)(ii)''; and in

the first sentence of paragraph (e) by removing the phrase

``Sec. Sec. 314.70(b)(3) and (c)(2)(i) through (c)(2)(iv)'' and by

adding in its place the phrase ``Sec. 314.70(b)(2)(v) and

(c)(6)(iii)''.

PART 206--IMPRINTING OF SOLID ORAL DOSAGE FORM DRUG PRODUCTS FOR

HUMAN USE

3. The authority citation for 21 CFR part 206 is revised to read as

follows:

Authority: 21 U.S.C. 321, 331, 351, 352, 355, 371; 42 U.S.C.

262.

Sec. 206.10 [Amended]

4. Section 206.10 Code imprint required is amended in the first

sentence of paragraph (b) by removing the phrase

``Sec. 314.70(b)(2)(xi) or (b)(2)(xii)'' and by adding in its place the

phrase ``Sec. 314.70(b)''.

PART 250--SPECIAL REQUIREMENTS FOR SPECIFIC HUMAN DRUGS

5. The authority citation for 21 CFR part 250 continues to read as

follows:

Authority: 21 U.S.C. 321, 336, 342, 352, 353, 355, 361(a),

362(a) and (c), 371, 375(b).

[[Page 34622]]

Sec. 250.250 [Amended]

6. Section 250.250 Hexachlorophene, as a component of drug and

cosmetic products is amended in the last sentence of paragraph

(c)(4)(ii) by removing the phrase ``Sec. 314.70(c)(2)'' and by adding

in its place the phrase ``Sec. 314.70(c)(6)(iii)''.

PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG

7. The authority citation for 21 CFR part 314 is revised to read as

follows:

Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 356a, 371,

374, 379e.

8. Section 314.3 is amended in paragraph (b) by alphabetically

adding the definitions for ``Specification'' and ``Validate the effects

of the change'' to read as follows:

Sec. 314.3 Definitions.

* * * * *

(b) * * *

Specification means 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 materials. For the purpose of

this definition, acceptance criteria means numerical limits, ranges, or

other criteria for the tests described.

* * * * *

Validate the effects of the change means to assess 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.

9. Section 314.50 is amended in paragraph (d)(1)(ii)(b) by removing

the phrase ``specifications and test procedures'' and by adding in its

place the word ``specification''; in paragraph (d)(1)(v) by removing

the phrase ``Except for a foreign applicant, the'' and by adding in its

place the word ``The''; in paragraph (d)(3)(i) by adding the word

``procedures'' after the word ``analytical''; in paragraph (d)(3)(ii)

by removing the phrases ``specifications or analytical methods'' and

``specification or analytical methods'' each time they appear and by

adding in their places the phrase ``tests, analytical procedures, and

acceptance criteria''; in paragraph (d)(4)(iv) by removing the word

``methods'' and by adding in its place the word ``procedures''; in the

last sentence of paragraph (e)(1) introductory text and in the first

sentence of paragraph (e)(2)(i) by removing the word ``methods'' each

time it appears and by adding in its place the word ``procedures''; and

by revising the first two sentences of paragraphs (d)(1)(i) and

(d)(1)(ii)(a) to read as follows:

Sec. 314.50 Content and format of an application.

* * * * *

(d) * * *

(1) * * *

(i) Drug substance. A full description of the drug substance

including its physical and chemical characteristics and stability; the

name and address of its manufacturer; the method of synthesis (or

isolation) and purification of the drug substance; the process controls

used during manufacture and packaging; and the specifications necessary

to ensure the identity, strength, quality, and purity of the drug

substance and the bioavailability of the drug products made from the

substance, including, for example, tests, analytical procedures, and

acceptance criteria relating to stability, sterility, particle size,

and crystalline form. The application may provide additionally for the

use of alternatives to meet any of these requirements, including

alternative sources, process controls, and analytical procedures. * * *

(ii)(a) Drug product. A list of all components used in the

manufacture of the drug product (regardless of whether they appear in

the drug product) and a statement of the composition of the drug

product; the specifications for each component; the name and address of

each manufacturer of the drug product; a description of the

manufacturing and packaging procedures and in-process controls for the

drug product; the specifications necessary to ensure the identity,

strength, quality, purity, potency, and bioavailability of the drug

product, including, for example, tests, analytical procedures, and

acceptance criteria relating to sterility, dissolution rate, containers

and closure systems; and stability data with proposed expiration

dating. The application may provide additionally for the use of

alternatives to meet any of these requirements, including alternative

components, manufacturing and packaging procedures, in-process

controls, and analytical procedures. * * *

* * * * *

Sec. 314.60 [Amended]

10. Section 314.60 Amendments to an unapproved application is

amended in paragraph (c) by removing the phrase ``, other than a

foreign applicant,''.

11. Section 314.70 is revised to read as follows:

Sec. 314.70 Supplements and other changes to an approved application.

(a) Changes to an approved application. (1) The applicant shall

notify FDA about each change in each condition established in an

approved application beyond the variations already provided for in the

application. The notice is required to describe the change fully.

Depending on the type of change, the applicant shall notify FDA about

it in a supplement under paragraph (b) or (c) of this section or by

inclusion of the information in the annual report to the application

under paragraph (d) of this section.

(2) The holder of an approved application under section 505 of the

act shall validate the effects of the 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 a manufacturing change.

(3) Notwithstanding the requirements of paragraphs (b) and (c) of

this section, an applicant shall make a change provided for in those

paragraphs in accordance with a regulation or guidance that provides

for a less burdensome notification of the change (for example, by

submission of a supplement that does not require approval prior to

distribution of the product or in an annual report).

(4) The applicant shall promptly revise all promotional labeling

and advertising to make it consistent with any labeling change

implemented in accordance with this section.

(5) Except for a supplement providing for a change in the labeling,

the applicant shall include in each supplemental application providing

for a change under paragraph (b) or (c) of this section a statement

certifying that a field copy of the supplement has been provided to the

applicant's home FDA district office.

(6) A supplement or annual report shall include in the cover letter

a list of all changes contained in the supplement or annual report.

(b) Changes requiring supplement submission and approval prior to

distribution of the product made using the change (major changes). (1)

A supplement shall be submitted for any change in the product,

production process, quality controls, equipment, 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.

[[Page 34623]]

(2) These changes include, but are not limited to:

(i) Except as provided in paragraphs (c) and (d) of this section,

changes in the qualitative or quantitative formulation of the drug,

including inactive ingredients, or in the specifications provided in

the approved application;

(ii) Changes requiring completion of studies in accordance with

part 320 of this chapter to demonstrate the equivalence of the drug to

the drug as manufactured without the change or to the reference listed

drug;

(iii) Changes that may affect product sterility assurance, such as

changes in product or component sterilization method(s) or an addition,

deletion, or substitution of steps in an aseptic processing operation;

(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) Changes in labeling, except those described in paragraphs

(c)(6)(iii), (d)(2)(ix), or (d)(2)(x) of this section;

(vi) Changes in a container closure system that controls drug

delivery or that may affect the impurity profile of the drug product;

(vii) Changes solely affecting a natural product, a recombinant

DNA-derived protein/polypeptide product, or a complex or conjugate of a

drug 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.

(viii) 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 that application.

(3) The applicant must obtain approval of a supplement from FDA

prior to distribution of a product made using a change under paragraph

(b) of this section. Except for submissions under paragraph (e) of this

section, the following shall be contained in the supplement:

(i) A detailed description of the proposed change;

(ii) The product(s) involved;

(iii) The manufacturing site(s) or area(s) affected;

(iv) A description of the methods used and studies performed to

evaluate the effect of the change on the identity, strength, quality,

purity, or potency of the product as these factors may relate to the

safety or effectiveness of the product (validating 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 with a

monoclonal antibody, relevant validation protocols shall be provided in

addition to the requirements in paragraphs (b)(3)(iv) and (b)(3)(v) of

this section; and

(vii) For sterilization process and test methodologies, relevant

validation protocols shall be provided in addition to the requirements

in paragraphs (b)(3)(iv) and (b)(3)(v) of this section; and

(viii) A reference list of relevant standard operating procedures

(SOP's) when applicable.

(4) An applicant may ask FDA to expedite its review of a supplement

for public health reasons or if a delay in making the change described

in it would impose an extraordinary hardship on the applicant. Such a

supplement and its mailing cover should be plainly marked: ``Prior

Approval Supplement-Expedited Review Requested.''

(c) Changes requiring supplement submission at least 30 days prior

to distribution of the drug product made using the change (moderate

changes). (1) A supplement shall 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. If

the change concerns labeling, include 12 copies of final printed

labeling.

(2) These changes include, but are not limited to:

(i) A change in the container closure system that does not affect

the quality of the final drug product; and

(ii) Changes solely affecting a natural protein product, a

recombinant DNA-derived protein/polypeptide product or a complex or

conjugate of a drug with a monoclonal antibody, including:

(A) An increase or decrease in production scale during finishing

steps that involves new or different equipment; and

(B) Replacement of equipment with that of similar, but not

identical, design and operating principle that does not affect the

process methodology or process operating parameters.

(3) A supplement submitted under paragraph (c)(1) of this section

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. The supplement

shall be labeled ``Supplement--Changes Being Effected in 30 Days'' or,

if applicable under paragraph (c)(6) of this section, ``Supplement--

Changes Being Effected.''

(4) Pending approval of the supplement by FDA, except as provided

in paragraph (c)(6) of this section, distribution of the product made

using the change may begin not less than 30 days after receipt of the

supplement by FDA. The information listed in paragraphs (b)(3)(i)

through (b)(3)(viii) of this section shall be contained in the

supplement.

(5) The applicant shall not distribute the product made using the

change if within 30 days following FDA's receipt of the supplement, FDA

informs the applicant that either:

(i) The change requires approval prior to distribution of the

product in accordance with paragraph (b) of this section; or

(ii) Any of the information required under paragraph (c)(4) of this

section is missing; the applicant shall not distribute the product made

using the change until FDA determines that compliance with this section

is achieved.

(6) The agency 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

involved upon receipt by the agency of a supplement for the change.

These changes include, but are not limited to:

(i) Addition to a specification or changes in the methods or

controls to provide increased assurance that the drug 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

[[Page 34624]]

(E) Any other changes specifically requested by FDA.

(7) If the agency disapproves the supplemental application, it may

order the manufacturer to cease distribution of the drug products made

with the manufacturing change.

(d) Changes to be described in an annual report (minor changes).

(1) Changes in the product, production process, quality controls,

equipment, or facilities that have a minimal 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 shall be documented by the applicant in

the next annual report in accordance with Sec. 314.81(b)(2).

(2) These changes include, but are not limited to:

(i) Any change made to comply with an official compendium that is

consistent with FDA requirements and provides increased assurance that

the drug will have the characteristics of identity, strength, quality,

purity, or potency that it purports or is represented to possess;

(ii) The deletion or reduction of an ingredient intended to affect

only the color of the product;

(iii) Replacement of equipment with that of the same design and

operating principles except for equipment used with a natural protein

product, a recombinant DNA-derived protein/polypeptide product, or a

complex or conjugate of a drug with a monoclonal antibody;

(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,

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 full production batches obtained from a protocol

approved in the application;

(vii) The addition, deletion, or revision of an alternate

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;

(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 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.

(3) For changes under this category, the applicant is required to

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 validated;

(ii) A full description of the manufacturing and controls changes,

including the manufacturing site(s) or area(s) involved; and

(iii) The date each change was made, a cross-reference to relevant

validation protocols and/or SOP's, and relevant data from studies and

tests performed to evaluate the effect of the change on the identity,

strength, quality, purity, or potency of the product as these factors

may relate to the safety or effectiveness of the product (validation).

(e) Protocols. An applicant may submit one or more protocols

describing the specific tests and validation studies and acceptable

limits to be achieved to demonstrate the lack of adverse effect for

specified types of manufacturing changes on the identity, strength,

quality, purity, or potency of the drug as these factors may relate to

the safety or effectiveness of the drug. Any such protocols, or changes

to a protocol, shall 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.

(f) Patent information. The applicant shall comply with the patent

information requirements under section 505(c)(2) of the act.

(g) Claimed exclusivity. If an applicant claims exclusivity under

Sec. 314.108 upon approval of a supplement for change to its previously

approved drug product, the applicant shall include with its supplement

the information required under Sec. 314.50(j).

Sec. 314.81 [Amended]

12. Section 314.81 Other postmarketing reports is amended in

paragraph (b)(1)(ii) by removing the word ``specifications'' and by

adding in its place the word ``specification''.

Sec. 314.94 [Amended]

13. Section 314.94 Content and format of an abbreviated application

is amended in the second sentence of paragraph (d)(2) by removing the

word ``methods'' each time it appears and by adding in its place the

word ``procedures''.

Sec. 314.410 [Amended]

14. Section 314.410 Imports and exports of new drugs is amended in

paragraph (b)(2) by removing the word ``specifications'' and by adding

in its place the word ``specification''.

Sec. 314.430 [Amended]

15. Section 314.430 Availability for public disclosure of data and

information in an application or abbreviated application is amended in

paragraph (e)(6) by removing the word ``method'' and by adding in its

place the word ``procedure''.

PART 600--BIOLOGICAL PRODUCTS: GENERAL

16. The authority citation for 21 CFR part 600 is revised to read

as follows:

Authority: 21 U.S.C. 321, 351, 352, 353, 355, 356a, 360, 360i,

371, 374; 42 U.S.C. 216, 262, 263, 263a, 264, 300aa-25.

17. Section 600.3 is amended by adding paragraphs (hh) and (ii) to

read as follows:

Sec. 600.3 Definitions.

* * * * *

(hh) Specification, as used in Sec. 601.12 of this chapter, means

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 materials. For the purpose of this definition,

acceptance criteria means numerical limits, ranges, or other criteria

for the tests described.

(ii) Validate the effects of the change, as used in Sec. 601.12 of

this chapter, means to assess 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.

PART 601--LICENSING

18. The authority citation for 21 CFR part 601 is revised to read

as follows:

Authority: 15 U.S.C. 1451-1561; 21 U.S.C. 321, 351, 352, 353,

355, 356a, 360c-360f, 360h-360j, 371, 374, 379e, 381; 42 U.S.C. 216,

241, 262, 263.

[[Page 34625]]

19. Section 601.12 is amended by revising paragraphs (a),

(b)(2)(i), (d)(2)(i) through (d)(2)(v), and (d)(2)(vii); by adding

paragraph (b)(4), (c)(6), (d)(3)(iii), and (f)(2)(i)(E); and by

removing and reserving paragraph (c)(2)(i) to read as follows:

Sec. 601.12 Changes to an approved application.

(a) General. (1) As provided by this section, an applicant shall

inform the Food and Drug Administration (FDA) about each change in the

product, production process, quality controls, equipment, facilities,

responsible personnel, or labeling established in the approved license

application(s).

(2) Before distributing a product made using a change, an applicant

shall validate the effects of the change and demonstrate through

appropriate validation and/or other clinical and/or nonclinical

laboratory studies the lack of adverse effect of the change on the

identity, strength, quality, purity, or potency of the product as they

may relate to the safety or effectiveness of the product.

(3) Notwithstanding the requirements of paragraphs (b), (c), and

(f) of this section, an applicant shall make a change provided for in

those paragraphs in accordance with a regulation or guidance that

provides for a less burdensome notification of the change (for example,

by submission of a supplement that does not require approval prior to

distribution of the product or in an annual report).

(4) The applicant shall promptly revise all promotional labeling

and advertising to make it consistent with any labeling change

implemented in accordance with this section.

(5) A supplement or annual report shall include in the cover letter

a list of all changes contained in the supplement or annual report.

(b) * * *

(2) * * *

(i) Except as provided in paragraphs (c) and (d) of this section,

changes in the qualitative or quantitative formulation, including

inactive ingredients, or in the specifications provided in the approved

application;

* * * * *

(4) An applicant may ask FDA to expedite its review of a supplement

for public health reasons or if a delay in making the change described

in it would impose an extraordinary hardship on the applicant. Such a

supplement and its mailing cover should be plainly marked: ``Prior

Approval Supplement-Expedited Review Requested.''

(c) * * *

(2) * * *

(i) [Reserved]

* * * * *

(6) If the agency disapproves the supplemental application, it may

order the manufacturer to cease distribution of the products made with

the manufacturing change.

(d) * * *

(2) * * *

(i) Any change made to comply with an official compendium that is

consistent with FDA requirements and provides increased assurance that

the drug will have the characteristics of identity, strength, quality,

purity, or potency that it purports or is represented to possess;

(ii) The deletion or reduction of an ingredient intended only to

affect the color of the product, except that a change intended only to

affect Blood Grouping Reagents requires supplement submission and

approval prior to distribution of the product made using the change in

accordance with the requirements set forth in paragraph (b) of this

section;

(iii) An extension of an expiration dating period based upon full

shelf life data on full production batches obtained from a protocol

approved in the application;

(iv) 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;

(v) A change in the size and/or shape of a container containing the

same number of dosage units for a nonsterile solid dosage form, without

a change from one container closure system to another;

* * * * *

(vii) The addition, deletion, or revision of an alternate

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.

(3) * * *

(iii) A statement by the holder of the approved application or

license that the effects of the change have been validated.

* * * * *

(f) * * *

(2) * * *

(i) * * *

(E) Any other changes specifically requested by FDA.

* * * * *

Dated: June 18, 1999.

William K. Hubbard,

Acting Deputy Commissioner for Policy.

[FR Doc. 99-16191 Filed 6-25-99; 8:45 am]

BILLING CODE 4160-01-F