[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
