[Federal Register Volume 59, Number 237 (Monday, December 12, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-30405]


[[Page Unknown]]

[Federal Register: December 12, 1994]


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Part III





Department of Health and Human Services





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Food and Drug Administration



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Supplements to New Drug Applications, Abbreviated New Drug 
Applications, or Abbreviated Antibotic Applications for Nonsterile Drug 
Products; Draft Guideline; Notice
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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]
BILLING CODE 4160-01-F