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
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Guidance for Industry1

Alternate Source of the Active Pharmaceutical Ingredient in

Pending ANDAs

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).

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.
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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 preapproval 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
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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.