Guidance for Industry
Alternate Source of the
Active Pharmaceutical
Ingredient in Pending
ANDAs
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
December 2000
Office of Generic Drugs Guidance for Industry
Alternate Source of the
Active Pharmaceutical
Ingredient in Pending
ANDAs
Additional copies are available from:
Office of Training and Communications
Division of Communications Management
Drug Information Branch, HFD-210
5600 Fishers Lane
Rockville, MD  20857
(Tel) 301-827-4573
(Internet)  http://www.fda.gov/cder/guidance/index.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
December 2000
Office of Generic Drugs TABLE OF CONTENTS
I. INTRODUCTION....................................................................................................1
II. BACKGROUND......................................................................................................1
III. WHEN CAN AN ALTERNATE SOURCE BE SUBSTITUTED?....................2
IV. WHAT IS THE PROCEDURE FOR CHANGING THE SUPPLIER?.............2 1
Guidance for Industry
Alternate Source of the Active Pharmaceutical Ingredient in
Pending ANDAs
This guidance represents the Food and Drug Administration's current thinking on this
topic.  It does not create or confer any rights for or on any person and does not
operate to bind FDA or the public.  An alternative approach may be used if such
approach satisfies the requirements of the applicable statutes and regulations.
I. INTRODUCTION
This guidance is intended to describe the Office of Generic Drugs' (OGD) policy on the
use of alternate sources of the active pharmaceutical ingredients (API) in unapproved
abbreviated new drug applications (ANDAs).  The guidance describes the
circumstances under which an alternate source can be used.  This guidance is intended
to decrease the regulatory burden on industry and provide a more consistent approach
to pre- and postapproval changes in API sources.
This guidance replaces the OGD memorandum dated July 26, 1996, titled, Substitution
of an Alternate Source of the New Drug Substance in Unapproved Abbreviated
Applications.
II.  BACKGROUND
In the early 1990s, if an ANDA was approvable, except for an unsatisfactory current
good manufacturing practice (CGMP) inspection for the primary API supplier, the
application would not be approved until the CGMP issues were resolved.  In some
cases, application approval was delayed because API suppliers remained unacceptable
for months or even years.  In other cases, a supplier would close a facility thereby
                                                
1 This guidance has been prepared by the Office of Generic Drugs (OGD) in the Office of Pharmaceutical
Science in the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration
(FDA).
1 precluding approval.  To qualify an acceptable alternate API source for use in the
bioequivalence or test batch, a new batch (and depending on the dosage form, a new in
vivo bioequivalence study) based on the alternate source was requested prior to
approval.
III.  WHEN CAN AN ALTERNATE SOURCE BE SUBSTITUTED?
An ANDA applicant can propose an alternate source for the API if the applicant can
assure the Agency that the specifications and test data are essentially the same as
those of the API originally used in the bioequivalence or test batch.  Generally, a new in
vivo bioequivalence study will not be needed using the alternate source.  However,
applicants should provide comparative dissolution data depending on the dosage form
of the proposed product.  This policy conforms to existing policy regarding postapproval
changes providing for alternate sources of API.
To substitute an alternative source for the API, the following circumstances should exist:
1.  The original API source is not being withdrawn due to deficiencies specifically
relating to that API, such as:
  Lack of adequate controls
  Evidence of adulteration
  Evidence of falsification of data in the application or identified in the pre-
approval inspection
If any of these situations apply, a new acceptable bioequivalence (test) batch, an
in vivo bioequivalence study (if dictated by the dosage form), and comparative
dissolution data for all strengths (based on the dosage form) will be needed to
support the alternate source of the API (21 CFR 314.50(d)(1)(i) and (ii)).
2.  The previous bioequivalence (test) batches and bioequivalence studies were
acceptable except for the CGMP issues that were specific to the original API.
3.  The specifications of the alternate source API are essentially the same as the
original source API.
IV.  WHAT IS THE PROCEDURE FOR CHANGING THE SUPPLIER?
Applicants should submit an amendment to their pending application requesting the
withdrawal of the primary API supplier with the supporting information to add the new
supplier just as is expected for any supplier of an API.  The amendment should include
the dissolution data, waiver request, or other data necessary ( 314.50(d)(1) and
2 314.94(a)(7)).  Any potential concerns about falsification of data related to the original
source that might affect the application will be evaluated by the reviewer.  All
specifications and data for the new source will be reviewed including comparative
dissolution data.  The Agency will also perform an establishment inspection for the new
source.
3