Supplements to New Drug Applications, Abbreviated New Drug Applications, or Abbreviated Antibotic Applications for Nonsterile Drug Products; Draft Guideline; Notice

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 93D-0403]

Supplements to New Drug Applications, Abbreviated New Drug

Applications, or Abbreviated Antibiotic Applications for Nonsterile

Drug Products; Draft Guideline

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is publishing a draft

guideline entitled ``Draft Guideline on Supplements to NDA's, ANDA's,

or AADA's for Nonsterile Drug Products.'' This draft guideline is

intended to help distinguish between manufacturing changes that require

prior approval through a supplement to an approved new drug application

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

antibiotic application (AADA), manufacturing changes that require a

supplement but that may be made prior to approval of the supplement,

and those manufacturing changes that need only to be described in an

annual report. The draft guideline covers certain changes in the method

of manufacture that involve equipment changes, reprocessing of drug

products that fail to meet specifications, and changes made to the

physical facility. The draft guideline also advises manufacturers of

their statutory obligation to comply with the current good

manufacturing practice regulations regardless of whether or not they

submit a supplement to an application.

DATES: Written comments by March 14, 1995.

ADDRESSES: Submit written comments on the draft guideline to the

Dockets Management Branch (HFA-305), Food and Drug Administration, rm.

1-23, 12420 Parklawn Dr., Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: Walter A. Brown, Center for Drug

Evaluation and Research (HFD-323), Food and Drug Administration, 7500

Standish Pl., Rockville, MD 20855, 301-594-1089.

SUPPLEMENTARY INFORMATION: FDA regulations, in Sec. 314.70 (21 CFR

314.70), require applicants to notify FDA about each change in

condition established in an approved NDA, ANDA, or AADA. Applicants

notify FDA of such changes through a supplemental application and,

depending on the type of change, may or may not need FDA approval

before the change may be implemented (see Sec. 314.70(b) and (c)).

Examples of changes to a drug product that require prior FDA approval

include: (1) Adding or deleting an ingredient or otherwise changing the

composition of the drug product; (2) relaxing the limits for a

specification; (3) establishing a new regulatory analytical method or

deleting a specification or regulatory analytical method; (4) changing

the method of manufacturing of the drug product, including changing or

relaxing an in-process control; (5) using a different facility or

establishment; and (6) establishing a new procedure for reprocessing a

batch of the drug product that fails to meet specifications (see

Sec. 314.70(b)(2)). Examples of changes to a drug product that may be

made before FDA approval of a supplemental application include adding a

new specification or test method or changing the methods, facilities,

or controls to provide increased assurance that the drug will have the

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

purports or is represented to possess (see Sec. 314.70(c)(1)).

The regulations also permit applicants to make some changes,

including, but not limited to, changes to comply with an official

compendium or an editorial or minor change in labeling, without

submitting a supplemental application; instead, these changes are

described in an annual report (see Sec. 314.70(d)).

FDA has prepared the draft guideline to help distinguish between

some manufacturing changes that require prior approval through a

supplement to an approved NDA, ANDA, or AADA, some changes that require

a supplement but that may be made prior to approval of the supplement,

and some changes that ordinarily may be described only in an annual

report. The guideline covers changes in the method of manufacture that

involve certain equipment changes, reprocessing of drug products, and

certain changes made to the physical facility. For example, the draft

guideline explains that changing to equipment of different design or

operating principles from previously utilized equipment would require

prior FDA approval, but changing to equipment of the same design and

operating principles from the same or a different manufacturer could be

described in the annual report.

FDA is making this draft guideline available for public comment

before issuing a final guideline. If, following receipt of comments,

the agency concludes that a guideline will assist firms in complying

with the supplement regulations at Sec. 314.70, FDA will prepare a

final guideline and will announce its availability in the Federal

Register.

A person may follow the guideline or may choose to use alternative

procedures even though they are not provided for in the guideline. If a

person chooses to use alternative procedures, that person may wish to

discuss the matter further with the agency to prevent an expenditure of

money and effort on activities that FDA may later determine to be

unacceptable.

Guidelines are generally issued under Sec. 10.90(b) (21 CFR

10.90(b)), which provides for the use of guidelines to establish

procedures or standards of general applicability that are not legal

requirements but that are acceptable to FDA. The agency is now in the

process of revising Sec. 10.90(b). Therefore, this draft guideline is

not being issued under the authority of Sec. 10.90(b), and it does not

create or confer any rights, privileges, obligations, or benefits for

or on any person, nor does it operate to bind FDA in any way.

Interested persons may, on or before March 14, 1995, submit to the

Dockets Management Branch (address above) written comments on the draft

guideline. 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. The

draft guideline and received comments may be seen in the office above

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

The text of the draft guideline follows:

Draft Guideline on Supplements to NDA's, ANDA's, or AADA's for

Nonsterile Drug Products

I. Purpose

This guideline informs interested persons of certain practices

and procedures for notifying the Food and Drug Administration (FDA)

of changes in approved applications for nonsterile drug products.

The information may be useful to persons seeking to comply with

certain regulations on supplements and other changes to an approved

application (Sec. 314.70 (21 CFR 314.70)).

II. Introduction

Guidelines are generally issued under 21 CFR 10.90, and, as

such, state principles and practices of general applicability that

are not legal requirements but are acceptable to FDA. However, FDA

is now in the process of revising Sec. 10.90(b). This guideline is

not, therefore, being issued under the authority of Sec. 10.90(b),

and it does not create or confer any rights, privileges,

obligations, or benefits for or on any person, nor does it bind FDA

in any way.

The agency advises that this guideline represents its current

position on the requirements for filing supplements to applications

set forth at Sec. 314.70. If a person chooses to depart from the

practices and procedures set forth in this guideline, that person

may wish to discuss the matter further with FDA to prevent an

expenditure of money and effort on activities that FDA may later

determine to be unacceptable.

This guideline may be amended from time to time if FDA

determines that an amendment would be useful based on its experience

in using this guideline, through its regulatory efforts, and through

comments submitted by interested persons.

III. Background

Applicants with an approved application must notify FDA about

each change in an approved application that is beyond any variation

already provided for in that application (see Sec. 314.70). The

purpose of this guideline is to help clarify the provisions of

Sec. 314.70 in order to distinguish between those manufacturing

changes that need to be submitted as a preapproval supplement (i.e.,

a supplement that requires FDA approval before the change is made)

to the approved new drug application (NDA), abbreviated new drug

application (ANDA), or abbreviated antibiotic application (AADA),

those that require a supplement but that may be made prior to

approval of the supplement, and those that only need to be described

in the annual report.

The applicant may wish to consider this guideline when deciding

whether to submit a preapproval supplement, a supplement for a

change that may be implemented prior to approval of the supplement,

or an annual report for the following changes that may affect the

manufacture of nonsterile drug products:

1. A change in the equipment that affects the method of

manufacture,

2. A change in reprocessing a batch that fails to meet

specifications, or

3. The use of different facilities.

Regardless of whether a supplement or an annual report is filed,

the manufacturer in making such changes must conform to the current

good manufacturing practice (CGMP) requirements of the Federal Food,

Drug, and Cosmetic Act (21 U.S.C. 351(a)(2)(B)) regulations (21 CFR

parts 210 and 211). Therefore, changes affecting the method of

manufacture, such as changed equipment, new reprocessing procedures,

or the use of different facilities, require validation under the

CGMP regulations before the drug product may be shipped.

IV. Guidance

A. Changes in Methods of Manufacture That Involve Changes of Equipment

(Sec. 314.70(b)(2)(v)).

1. Changes That Require Filing a Preapproval Supplement.

(i) Changing to equipment of different design or operating

principles from previously utilized equipment (e.g., changing from a

V blender to a ribbon blender).

(ii) Changing to equipment that changes the basic methodology of

manufacturing (e.g., changing from a tray dryer to a fluid bed dryer

or spray dryer).

2. Changes That Ordinarily May be Described Only in the Annual

Report.

(i) Changing to equipment of the same design and operating

principles from the same or a different manufacturer.

(ii) Changing to the same equipment with a different capacity;

however, the capacity should not exceed 10 times the test batch

size. (See Office of Generic Drugs Policy and Procedure Guide #22-90

(revised), dated September 13, 1990, on scale-up batch size

production requirements for nonantibiotic, solid, oral dosage form

drug products.)

Usually changes in volume require a change and validation of

parameters such as mixing time and speed. Such validation studies

should reflect no change in product formulation or quantitative

composition. The applicant should also perform comparative multiple-

point dissolution profiles for solid oral dosage forms as part of

the validation.

B. Reprocessing of Drug Products That Fail to Meet Specifications

(Sec. 314.70(b)(2)(x)).

1. Changes that Require Filing a Preapproval Supplement;

Establishing New Procedures for Reprocessing of Drug Products That

Fail to Meet Specifications.

(i) Applicants should submit proposed, detailed reprocessing

procedures when requesting authorization to reprocess. Applicants

may propose such procedures as part of their original applications

or they may submit them as preapproval supplements.

(ii) Reprocessing procedures submitted with the original

application normally cover only procedures which can be anticipated

reasonably, are not materially influenced by the type of drug

involved (i.e., there is no definite or potential effect on the

manufacturing process or performance characteristics of the drug),

and are ones with which the applicant has experience. Preapproval

supplement submissions may also cover such procedures, but are more

likely to cover a deficiency where the type of drug may have a

material influence, and the reprocessing may be product specific or

specific to the problem causing the need for the reprocessing. (See

Office of Generic Drugs Policy and Procedure Guide #23-90, dated

August 9, 1990.)

(A) Reprocessing procedures submitted in an original application

should be accompanied by supporting data.

(B) The applicant may choose to submit the reprocessing

information after approval of the NDA, ANDA, or AADA; however, the

supplement regulations require that the reprocessing procedures and

the supporting data be approved by FDA prior to release for shipment

of products made with the new procedure.

(C) Examples of supporting data needed for reprocessing

procedures may include, but are not limited to:

(1) A copy of the full investigative report pertaining to the

out-of-specification result including all corrective actions.

(2) Full analytical data and results regarding the reprocessed

material.

(3) A 3-month accelerated stability study, including multipoint

dissolution profiles, conducted before the drug product is released

into commerce, with a commitment to conduct long-term studies and

submit the resulting data to FDA.

(4) Data previously generated for similar products, such as data

to allow adjustment for appearance and physical parameters for other

tablets or capsules.

(iii) Applicants may reprocess a drug product using a procedure

approved in an NDA, ANDA, or AADA, but the CGMP regulations require

that the resulting product not be shipped until there is validation

of the specific reprocessing procedures for that drug product.

2. Changes That Ordinarily May be Described Only in the Annual

Report.

The repetition of one step a single time per batch in the

approved sequence of the manufacturing process does not require a

supplemental application and may be described in the next annual

report. For example, where in-process material does not meet

specifications, a firm could repeat the pertinent step, such as the

filtering, drying, milling, or blending procedure. Such reprocessing

must be done in conformance with the CGMP regulations.

FDA notes the following limitations and caveats regarding the

repetition of one step of the manufacturing process.

(i) The repeated step should be done within the manufacturing

parameters and the variations provided for in the approved

formulation.

(ii) The output should conform to established specifications

based on in-process testing.

(iii) The repetition of one step should be a random and

infrequent event. If a manufacturer finds that a step must be

consistently repeated to meet specifications, this constitutes a

change in the manufacturing process and requires a preapproval

supplement.

C. Changes Made to the Physical Facility (Sec. 314.70(b)(1)(v),

(b)(2)(vi), and (c)(3)).

1. Changes That Require Filing a Preapproval Supplement

(Sec. 314.70(b)(1)(v) and (b)(2)(vi)).

(i) A preapproval supplement must be filed for changes regarding

the use of a different, separate facility or establishment to

manufacture the drug substance, where:

(A) ``[T]he manufacturing process in the new facility or

establishment differs materially from that in the former facility or

establishment'' (Sec. 314.70(b)(1)(v)(a)), or

(B) ``[T]he new facility or establishment has not received a

satisfactory * * * CGMP inspection within the previous 2 years

covering that manufacturing process'' (Sec. 314.70(b)(1)(v)(b)).

(ii) Use of a different, separate facility or establishment for

the manufacture of the drug product (Sec. 314.70(b)(2)(vi)).

(iii) The addition to, or relocation of structures within, any

portion of the existing facility or establishment used to

manufacture a drug product or drug substance that results in a

materially different manufacturing process.

2. Changes That Require Filing a Supplement, but Which May be Made

Before Receiving FDA Approval (Sec. 314.70(c)(3)).

The manufacturer must file a supplement for the use of a

different, separate facility or establishment to manufacture the

drug substance. However, that change may be implemented prior to FDA

approval where:

(i) ``[T]he manufacturing process in the new facility or

establishment does not differ materially from that in the former

facility or establishment'' (Sec. 314.70(c)(3)), and

(ii) The new facility or establishment has received a

satisfactory CGMP inspection covering the manufacturing process

within the previous 2 years.

3. Changes That Ordinarily May be Described Only in the Annual

Report (Sec. 314.70(d)).

The following changes are examples of those that generally do

not adversely affect product processing or plant utility systems, do

not usually require prior notice to FDA, are generally not

considered to create ``different facility or establishment'' and

therefore may be described in the next annual report.

(i) Relocating processing areas or structures within, or through

addition to, any portion of the existing facility or establishment

used to manufacture the drug product or drug substance where:

(A) The manufacturing process in the changed facility or

establishment does not differ materially from that in the former

facility or establishment, and

(B) The changed facility or establishment has received a

satisfactory CGMP inspection within the previous 2 years covering

the manufacturing process related to the portion of the facility

that was changed.

(ii) Relocating equipment within the approved facility or

establishment.

(iii) Relocating nonprocessing rooms or areas within the

approved facility or establishment.

(iv) Adding new interior partitions or walls to increase control

over the environment. For example, the separation of processing

areas to prevent cross-contamination.

(v) Replacing or adding new surfaces to enhance cleaning.

(vi) Replacing or adding improved lighting.

Dated: November 23, 1994.

William K. Hubbard,

Interim Deputy Commissioner for Policy.

[FR Doc. 94-30405 Filed 12-9-94; 8:45 am]

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