Agency Emergency Processing Request Under OMB Review; Guidance for Industry; Changes to an Approved NDA or ANDA

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 99N-4614]

Agency Emergency Processing Request Under OMB Review; Guidance

for Industry; Changes to an Approved NDA or ANDA

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing that a

collection of information has been submitted to the Office of

Management and Budget (OMB) for emergency processing under the

Paperwork Reduction Act of 1995 (the PRA). The collection of

information is contained in a guidance for industry entitled ``Changes

to an Approved NDA or ANDA.'' The guidance is intended to assist

applicants in determining how they should report changes to an approved

new drug application (NDA) or abbreviated new drug application (ANDA)

under section 116 of the Food and Drug Administration Modernization Act

(the Modernization Act), which provides requirements for making and

reporting manufacturing changes to an approved application and for

distributing a drug product made with such changes.

DATES: Submit written comments on the collection of information by

November 10, 1999.

ADDRESSES: Submit written comments on the collection of information to

the Office of Information and Regulatory Affairs, OMB, New Executive

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

Desk Officer for FDA. All comments should be identified with the docket

number found in brackets in the heading of this document.

FOR FURTHER INFORMATION CONTACT: Karen L. Nelson, Office of Information

Resources Management (HFA-250), Food and Drug Administration, 5600

Fishers Lane, Rockville, MD 20857, 301-827-1482.

SUPPLEMENTARY INFORMATION: On November 21, 1997, the President signed

the Modernization Act (Public Law 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 NDA's and ANDA's, to new and abbreviated animal

drug applications, and to license applications for biological products.

The guidance for industry entitled ``Changes to an Approved NDA or

ANDA'' provides recommendations to holders of NDA's and ANDA's who

intend to make postapproval changes in accordance with section 506A of

the act. The guidance covers recommended reporting categories for

postapproval changes for drugs, other than specified biotechnology and

specified synthetic biological products. Recommendations are provided

for postapproval changes in: (1) Components and composition, (2) sites,

(3) manufacturing process, (4) specification(s), (5) package, (6)

labeling, and (7) miscellaneous changes.

With respect to the collection of information described below, FDA

invites comment on: (1) Whether the proposed collection of information

is necessary for the 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,

[[Page 59777]]

when appropriate, and other forms of information technology.

Title: Changes to an Approved NDA or ANDA

Section 116 of the Modernization Act amended the act by adding

section 506A, which 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.

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).

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 (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 guidance on 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 guidance

enables the agency to respond more readily to knowledge gained from

manufacturing experience, further research and data collection, and

advances in technology. The guidance describes the agency's current

interpretation of specific changes falling into the four filing

categories. 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 allows FDA to more easily and quickly modify and update

important information.

Description of Respondents: Businesses or other for-profit

organizations.

As explained below, FDA estimates the burden of this collection of

information as follows:

Table 1.--Estimated Annual Reporting Burden \1\

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Number of

Federal Food, Drug, and Cosmetic No. of Responses per Total Annual Hours per Total Hours

Act Sections Respondents Respondent Responses Response

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506A(c)(1)

506A(c)(2)

Prior approval supplement

(supp.)

594 3 1,744 120 209,280

506A(d)(1)(B)

506A(d)(1)(C)

[[Page 59778]]

506A(d)(3)(B)(i)

Changes being effected (CBE) in

30-day supp.

594 5 2,754 80 220,320

506A(d)(1)(B)

506A(d)(1)(C)

506A(d)(3)(B)(ii)

CBE supp.

486 1 486 80 38,880

506A(d)(1)(A)

506A(d)(1)(C)

506A(d)(2)(A)

506A(d)(2)(B)

Annual Report 704 10 6,929 25 173,225

Total 641,705

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

information.

Sections 506A(a)(1) and 506A(b) of the act require the holder of an

approved application to validate the effects of a manufacturing change

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

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

before distributing a drug made with the change. Under section

506A(d)(3)(A), information developed by the applicant to validate the

effects of the change regarding identity, strength, quality, purity,

and potency is required to be submitted to FDA as part of the

supplement or annual report. Thus, no separate estimates are provided

for these sections in the Table 1; estimates for validation

requirements are included in the estimates for supplements and annual

reports. The guidance does not provide recommendations on the specific

information that should be developed by the applicant to validate the

effect of the change on the identity, strength (e.g., assay, content

uniformity), quality (e.g., physical, chemical, and biological

properties), purity (e.g., impurities and degradation products), or

potency (e.g., biological activity, bioavailability, bioequivalence) of

a product as they may relate to the safety or effectiveness of the

product.

Sections 506A(c)(1) and 506A(c)(2) of the act set forth

requirements for changes requiring supplement submission and approval

prior to distribution of the product made using the change (major

changes). Under these sections, 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. The applicant must obtain approval of a supplement from

FDA prior to distribution of a product made using the change.

Based on data concerning the number of supplements received by the

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

submitted annually under sections 506A(c)(1) and 506A(c)(2) of the act.

FDA estimates that approximately 594 applicants will submit such

supplements, and that it will take approximately 120 hours to prepare

and submit to FDA each supplement.

Under section 506A(d)(1)(B), 506A(d)(1)(C), and 506A(d)(3)(B)(i) of

the act set forth requirements for changes requiring supplement

submission at least 30 days prior to distribution of the product made

using the change (moderate changes). Under these sections, 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. Distribution of the product

made using the change may begin not less than 30 days after receipt of

the supplement by FDA.

Based on data concerning the number of supplements received by the

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

submitted annually under sections 506A(d)(1)(B), 506A(d)(1)(C), and

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

Under section 506A(d)(3)(B)(ii) of the act, 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. Based on data concerning the number of

supplements received by the agency, FDA estimates that approximately

486 supplements will be submitted annually under section

506A(d)(3)(B)(ii) of the act. FDA estimates that approximately 486

applicants will submit such supplements, and that it will take

approximately 80 hours to prepare and submit to FDA each supplement.

Sections 506A(d)(1)(A), 506A(d)(1)(C), 506A(d)(2)(A), and

506A(d)(2)(B) of the act set forth requirements for changes to be

described in an annual report (minor changes). Under these sections,

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.

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 sections 506A(d)(1)(A), 506A(d)(1)(C),

506A(d)(2)(A), and 506A(d)(2)(B) of the act. FDA estimates that

approximately 704 applicants will submit such information, and that it

will take approximately 25 hours to prepare and submit to FDA the

information for each annual report.

In the Federal Register of June 28, 1999 (64 FR 34608), FDA

published a

[[Page 59779]]

proposed rule to implement section 116 of the Modernization Act by

revising current regulations at 21 CFR 314.70 on supplements and other

changes to an approved application. In that same issue of the Federal

Register (64 FR 34660), FDA published a notice of availability of a

draft guidance for industry entitled ``Changes to an Approved NDA or

ANDA.'' On August 19, 1999, FDA held a public meeting to discuss and

receive comments on the proposed regulations and the draft guidance.

(On August 5, 1999, a notice of the meeting was published in the

Federal Register (64 FR 42625).)

The period for public comment on the proposed regulations closed on

September 13, 1999, and FDA is currently reviewing the comments and

preparing a final rule. The comment period for the draft guidance

closed on August 27, 1999, and FDA has considered these comments when

preparing the guidance that is the subject of this request for

emergency processing.

FDA is requesting emergency processing of this proposed collection

of information under section 3507(j) of the PRA and 5 CFR 1320.13. The

information is needed immediately to implement section 506A of the act,

which provides requirements for making and reporting manufacturing

changes to an approved application and for distributing a drug product

made with such changes. The use of normal information clearance

procedures would likely result in the prevention or disruption of this

collection of information because section 506A takes effect on November

21, 1999. After November 20, 1999, and until final regulations are

issued revising 21 CFR 314.70, section 506A of the act will be the sole

basis for FDA's regulation of postapproval manufacturing changes for

products approved under NDA's or ANDA's. The guidance provides

recommendations to holders of approved NDA's and ANDA's who intend to

make postapproval changes in accordance with section 506A of the act.

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.

Dated: October 29, 1999.

Margaret M. Dotzel,

Acting Associate Commissioner for Policy.

[FR Doc. 99-28793 Filed 11-2-99; 8:45 am]

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