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9
ANDA Regulatory Approval Process

Timothy W. Ames, Karen A. Bernard,

Beth Fabian Fritsch, Koung Lee,
Aida L. Sanchez, Krista M. Scardina, and
Martin Shimer
U.S. Food and Drug Administration Center for Drug Evaluation and
Research, Rockville, MD, U.S.A.

The Food and Drug Administration (FDA) is organized into eight

o⁄ces=centers, the Center for Drug Evaluation and Research (CDER), the
Center for Biologics Evaluation and Research (CBER), the Center for
Devices and Radiological Health (CDRH), the Center for Food Safety and
Applied Nutrition (CFSAN), the Center for Veterinary Medicine (CVM),
the National Center for Toxicological Research (NCTR), the O⁄ce of the
Commissioner (OC), and the O⁄ce of Regulatory A¡airs (ORA).
The CDER reviews the safety and e⁄cacy of drug products.The Center
Director oversees 11 o⁄ces which include, the O⁄ce of Pharmaceutical
Science, the O⁄ce of New Drugs, the O⁄ce of Executive Programs, the
O⁄ce of Pharmacoepidemiology and Statistical Science, O⁄ce of Manage-
ment, the O⁄ce of Regulatory Policy, the O⁄ce of Medical Policy, the O⁄ce
of Counter-Terrorism and Pediatric Drug Development, the O⁄ce of
Training and Communications, the O⁄ce of Compliance, and the O⁄ce of
Information Technology. Additional information about the organization
of the CDER can be found on the FDA website at www.fda.gov=cder.
211

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212 Ames et al.

FIGURE 1 Generic drug review process.

Organizationally, the O⁄ce of Generic Drugs (OGD) is located within

the CDER under the O⁄ce of Pharmaceutical Science. It consists of the
following divisions: Chemistry, Bioequivalence, and Labeling and Program
Support. The following will provide a brief overview of the history of the
OGD.
Nearly 20 years after its enactment, The Drug Price Competition and
Patent Term Restoration Act of 1984, commonly known as the Hatch ^
Waxman Amendments (HWA), has proven to be an e¡ective piece of
legislation. One outcome of this legislation is the increased availability of
less-expensive medications to millions of Americans.The HWA to the Federal
Food, Drug and Cosmetic Act (FD&C) gave clear statutory authority to
submit Abbreviated New Drug Applications (ANDAs) for all approved
innovator drugs.With the passage of the HWA, ¢rms who sought to market
a generic version of a drug were not required to repeat the costly preclinical
and clinical testing associated with a New Drug Application (NDA).
The OGD had its origins in the early 1970s and was known as the O⁄ce
of Drug Monographs. After the passage of the HWA in 1984, the O⁄ce of
Drug Monographs became the O⁄ce of Drug Standards. The O⁄ce of Drug

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ANDA Regulatory Approval Process 213

Standards contained the Division of Generic Drugs (DGD) and the Division
of Bioequivalence. The OGD as we know it today was established in 1990 as
part of the O⁄ce of Pharmaceutical Science (OPS). Its mission is to ensure
that safe and e¡ective generic drugs are available for the American people.
The OGD ensures the safety and e⁄cacy of generic drugs by employing a
review process that is similar to the NDA process. The primary di¡erence
between the Generic Drug Review process and the NDA review process is
the study requirements. For example, an ANDA generally requires a bio-
equivalence study between the generic product and the reference listed drug
(RLD) product.The safety and e⁄cacy of the RLD product were established
previously through animal studies, clinical studies and bioavailabilty
studies. Thus, these studies need not be repeated for the ANDA.
The economic impact of the HWA is best demonstrated by the
increased market share of generic medications. In 1984, just 14% of all pre-
scriptions dispensed were for generic drugs. In contrast, 17 years later in
2001, approximately 48% of all prescriptions dispensed were for generic
drugs. Furthermore, for each 1% increase in the use of generic drugs, consu-
mers save an additional $1.32 billion per year.
The goal of this chapter is to provide an overview of the generic drug
review process for solid oral dosage forms. Each step of the review process
will be discussed from the initial submission of the application to its ¢nal
approval. As one reads through the chapter, it may be useful to refer to the
£ow diagram given in Figure 1. Since the discussion is limited to the review
of solid oral dosage forms, the microbiology review is omitted.

1. FILING REVIEW OF ABBREVIATED NEW DRUG

APPLICATIONS (ANDA)
The ANDA process begins when an applicant submits an ANDA to the
OGD. The document room sta¡ processes the ANDA, assigns it an ANDA
number, and stamps a received date on the cover letter of the ANDA. The
ANDA is then sent to a consumer safety technician, who reviews the preli-
minary sections of the ANDA Checklist.
Within the ¢rst 60 days following the submission of an ANDA, a ¢ling
review is completed. The Regulatory Support Branch (RSB) is responsible
for the ¢ling review. This group, organized under the Division of Labeling
and Program Support (DLPS), consists of project managers and a support
sta¡ including technical information assistant(s), legal instruments exami-
ner(s), and consumer safety technician(s). The branch chief who reports to
the Division Director of DLPS supervises the branch.
The RSB ensures that the ANDAs contain the information necessary
to merit a technical review. To determine whether an application is

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214 Ames et al.

acceptable for ¢ling, an RSB project manager (RPM) compares the contents
of each section of the application (see Appendix A) against a list of regula-
tory requirements. An applicant may receive a ‘‘refuse to receive’’ letter
when an inactive ingredient level exceeds the level previously used in an
approved drug product via the same route of administration. Other common
reasons that a‘‘refuse to receive’’ letter may be issued to the applicant include
but are not limited to; incomplete bioequivalence studies, incomplete stabi-
lity data, incomplete packaging, and incorrect basis for submission. The ¢l-
ing date of an application is critical since it may determine the eligibility for
exclusivity. The RSB veri¢es that all applications contain a patent certi¢ca-
tion and exclusivity statement.The patent certi¢cation and exclusivity state-
ment must address all existing patents and exclusivities for the RLD
published in the ‘‘Approved Drug Products with Therapeutic Equivalence
Evaluations’’, commonly known as the ‘‘Orange Book’’. If an RLD has
expired patents, an applicant may certify that no relevant patents remain.
The review of patents and exclusivities is an ongoing process throughout
the review cycle, as new patents and exclusivities may become listed in
the ‘‘Orange Book’’. An explanation of patent certi¢cations with their
corresponding de¢nitions may be found in 21 CFR 314.94(a)(12).
Once the RSB completes the ¢ling review of the ANDA and veri¢es
that the application contains all the necessary regulatory requirements, an
‘‘acknowledgment’’ letter is issued to the applicant indicating its acceptance
for ¢ling and the o⁄cial ¢ling date. The application is then assigned
to the technical reviewers. If the ANDA does not meet the criteria for
¢ling, a ‘‘refuse-to-receive’’ letter is issued to the applicant with a list of
de¢ciencies.
Upon ¢ling an ANDA,the RPM forwards an Establishment Evaluation
Request (EER) to the O⁄ce of Compliance. The O⁄ce of Compliance then
determines if the drug product manufacturer, the drug substance manufac-
turer and the outside testing facilities are operating in compliance with
current Good Manufacturing Practice (cGMP) regulations as outlined in
21 CFR Parts 210 and 211. Each facility listed on the request is evaluated
individually and the O⁄ce of Compliance makes an overall evaluation of
all facilities listed in the application. Furthermore, a pre-approval inspec-
tion may be performed to assure the data integrity of the application.
Currently, ANDAs can be submitted entirely electronically. Appli-
cants can also submit electronic submissions of bioequivalence data along
with the traditional paper application. The electronic document room sta¡
processes the electronic ¢les, so that the reviewers can access them.The data
contained in the electronic submission are copied onto CDER’s computer
network. Additional processing may occur to populate the electronic tools
used by the reviewers.

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ANDA Regulatory Approval Process 215

All applicants who plan to submit ANDAs electronically should con-

sult CDER’s website for electronic submissions at www.fda.gov=cder=
regulatory=rsr=default.htm.

2. COORDINATION OF THE GENERIC DRUG REVIEW

PROCESS
Once the ANDA is accepted for ¢ling, the application enters the review
queue. This means that the application is assigned to a bioequivalence
reviewer, a chemist, and a labeling reviewer.
Each chemistry team consists of a team leader, a project manager,
and several reviewers. In this section, the emphasis will be placed on the
chemistry project manager’s role in the generic drug review process.
The chemistry project manager serves as the ‘‘Application’’ Project
Manager (APM). While APMs are located within the Chemistry review
teams, they are actually a part of the Review Support Branch within the
DLPS. Speci¢cally, they plan, organize, and coordinate all of the review
activities for the applications that they manage. This requires the coordina-
tion of all discipline reviews which include chemistry, bioequivalence, and
labeling.
The APMs serve as co-leaders for the chemistry review teams. They
assure timely resolution of scienti¢c and regulatory con£icts to prevent
delays in the review process. The APMs also make every e¡ort to meet the
review goals set by the OGD management.
The APMs manage and coordinate the work of the review teams to
assure that reviews are performed in a timely manner. In addition, the APMs
identify and resolve potential problems such as the inequality of individual
workload and regulatory issues. The OGD makes a concerted e¡ort to
comply with the statutory 180 day review cycle mandated by the Federal
FD&C Act.The APMs play a key role in coordinating the various disciplines
to review the applications within 180 days from the submission date. In
attempt to achieve OGD’s management goals, the APMs may recommend
redistribution of work according to the policies and procedures within the
OGD.
The APMs enter key information about their applications into a pro-
ject management database. This database allows the OGD sta¡ to access
the status and outcome of discipline reviews and the status of the ¢eld and
compliance inspection reports. The APMs use the information to provide
applicants and OGD management the status of applications.
Since communication plays a large role in the generic drug review
process, the APMs are designated as the primary contacts for all issues relat-
ing to the review of the application. As such, they communicate the status of

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216 Ames et al.

all aspects of the applications that they manage. The APMs attempt to
address all applicant inquiries within 2 working days of receiving a request.
If the questions from the applicant are of a technical nature and require
further evaluation by a reviewer and=or team leader, the APMs make the
appropriate arrangements for either a telephone conference and=or a meet-
ing. The APMs generally request applicants to submit a proposed agenda
prior to the telephone conference or meeting. The APMs and the review
teams work with the applicants to resolve scienti¢c issues that may delay
the approval of applications.

3. BIOEQUIVALENCE REVIEW PROCESS

After an ANDA is accepted for ¢ling by the RSB, the bioequivalence section
is assigned to the Division of Bioequivalence to review. The Bioequivalence
Project Managers (BPM) access a list of pending ANDAs and assign them
to individual reviewers according to the ‘‘¢rst-in, ¢rst-reviewed’’ policy. The
BPMs also randomly assign other review documents such as Bio-INDs,
protocols, and correspondence.
The DBE’s responsibilities include the review of the bioequivalence
section of ANDAs, supplemental ANDAs, Bio-Investigational New Drug
Applications (Bio-INDs), protocols, and controlled correspondence. It is
worth mentioning that more than half of all correspondence submitted to
the OGD requests guidance from the DBE.
Structurally, the DBE is organized into three review branches; each
branch consists of approximately six reviewers,who are supervised by a team
leader. The team leaders complete a secondary review of all bioequivalence
submissions assigned to their branch. In addition, they ensure the consis-
tency of the recommendations provided to the applicants. A BPM is assigned
to each branch and is responsible for processing all reviews and managing
the bioequivalence review process. A statistician is also available to resolve
statistical issues.
The bioequivalence review process establishes bioequivalence
between a proposed generic drug and the RLD. Bioequivalence is estab-
lished when the ratio of the means of the test product compared to the refer-
ence product (T=R) of the pharmacokinetic parameters for rate (Cmax) and
extent of absorption (AUC) of log transformed data meet the 90%
con¢dence intervals of 80^125%. Refer to Chapters 10 and 11 for a more
detailed discussion of bioequivalence testing requirements and statistical
considerations.
The BPMs provide regulatory guidance on bioequivalence issues
through correspondence and teleconferences. In addition, the BPMs coordi-
nate the resolution of all regulatory and scienti¢c issues regarding the

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ANDA Regulatory Approval Process 217

bioequivalence of drug products submitted for marketing approval. All

meetings and teleconferences regarding bioequivalence issues are scheduled
and documented by the BPM.
The BPMs request and track inspections of the clinical and analytical
sites through the Division of Scienti¢c Investigations (DSI). Inspection
requests to the DSI are sent immediately after the ANDA is assigned to a
reviewer. The clinical and analytical sites are inspected for two reasons: (1)
to verify the quality and integrity of the scienti¢c data submitted in bioequi-
valence studies and (2) to ensure that the rights and welfare of human sub-
jects participating in the studies are protected in accordance with the
regulations (21 CFR 312, 320, 50, and 56). Signi¢cant problems, such as
research misconduct or fraud (see MaPP 5210.7) are promptly acted upon.
One of the most common ¢ndings on an DSI inspection is the absence of
retention samples by the testing facility (refer to 21 CFR 320.38 and 320.63
and the draft guidance ‘‘Handling and Retention of BA and BE Testing
Samples’’ for more information). If problems are discovered during these
inspections, additional studies from the applicant may be requested.
If a bioequivalence reviewer requires additional information to com-
plete their review, they will ¢rst consult with their team leader and then
request the BPM to obtain the information from the applicant. If an issue
can be resolved within 10 working days, a teleconference with the applicant
is initiated by the BPM. The BPM maintains a record of all teleconferences
with the applicants. The applicant’s response to the teleconference is labeled
as a ‘‘Bioequivalence Telephone Amendment’’. A de¢ciency letter is issued
to the applicant when a review contains numerous de¢ciencies that require
more than 10 days to resolve.
The reviewer prepares a draft or primary review, which is then
forwarded to the team leader for a secondary review and=or revisions. Dur-
ing the secondary review, the team leader provides comments on the primary
review, discusses regulatory or scienti¢c issues with the Division Director
and assesses the need for additional data from the applicant. Once all unre-
solved or outstanding issues are addressed, the team leader sends the review
back to the reviewer with his comments. The reviewer then ¢nalizes the
review and forwards it to the Division Director. The Division Director per-
forms a tertiary review and documents his concurrence.
Once the bioequivalence review is completed and all bioequivalence
requirements are addressed, the DBE forwards an acceptable letter that
states that there are no further questions at this time. The bioequivalence
review is then forwarded to the APM. If the bioequivalence review indicates
de¢ciencies, a de¢ciency letter is issued to the applicant.
Bioequivalence studies with clinical endpoints are often recom-
mended to establish bioequivalence between dosage forms intended to

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218 Ames et al.

deliver the active ingredient(s) locally, (i.e., topical creams and ointments)
and between dosage forms that are not intended to be absorbed (i.e., Sucral-
fate)(21 CFR 320.24(b)(4)). The OGD’s Associate Director of Medical
A¡airs (ADMA) and the clinical team review these studies for the DBE.
The ADMA also forwards all comments and recommendations to the Direc-
tor of the DBE for concurrence. The ADMA consults with the O⁄ce of New
Drugs for input on the appropriateness of clinical endpoints (see MaPP
5210.4). For this reason, it is strongly advised that applicants submit proto-
cols or Bio-INDs prior to the initiation of bioequivalence studies to ensure
the appropriateness of study designs and endpoints (see MaPP 5240.4).

4. CHEMISTRY REVIEW PROCESS

After an ANDA has been accepted for ¢ling by the RSB, the Chemistry,
Manufacturing and Controls (CMC) section of the application is assigned
to the appropriate Chemistry Division and Team, based on the therapeutic
category of the drug product. Once the application is assigned to the team,
the application is designated as ‘‘random’’ and placed on the team leader’s
queue. The team leader assigns the application to a reviewer on his or her
team according to the ‘‘¢rst-in, ¢rst reviewed policy’’. The Chemistry Divi-
sions review the CMC section of ANDAs, Drug Master Files, Supplemental
ANDAs, Annual Reports, and Controlled Correspondence.
The Chemistry Divisions are organized into review teams consisting of
¢ve or six reviewers and a team leader. Team leaders perform a secondary
review of all chemistry submissions. An APM assigned to each team coordi-
nates the entire review process and acts as the primary point of contact for
the application. Each division is led by a Division Director and Deputy
Director. A tertiary review is often performed by the Deputy Director, but
may be performed by the Division Director, to ensure consistent recommen-
dations to applicants. Inter-divisional consistency is also emphasized
through regular meetings between the Chemistry Divisions and the OGD
management.
The goal of the chemistry review process is to assure that the generic
drug will be manufactured in a reproducible manner under controlled condi-
tions. Areas such as the applicant’s manufacturing procedures, raw material
speci¢cations and controls, sterilization process, container and closure
systems, and stability data are reviewed to assure that the drug will perform
in an acceptable manner.
The chemistry reviewer drafts a primary review that is forwarded to the
team leader for secondary review. The secondary review may require little
or no revision from the ¢rst draft or it may require major revision. Team lea-
ders provide comments and corrections to the primary reviewer. The APM

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ANDA Regulatory Approval Process 219

also assists in the correction process. Once the team resolves the issues
internally, the review is ¢nalized and signed by the team leader, primary
reviewer and APM. The ¢nalized review, including a list of de¢ciencies, is
forwarded to the Deputy Director for concurrence. The Deputy Director,
or in some cases the Division Director, completes the tertiary review. If the
application is a ‘‘¢rst generic drug product’’, the Associate Director for
Chemistry performs a quality control audit. This function is completed
outside of the Chemistry Divisions at the O⁄ce level.
After all issues are resolved within the Chemistry Divisions, it is the
responsibility of the APM to communicate the status of the application to
the applicant. After designating the chemistry de¢ciencies as ‘‘Minor’’ or
‘‘Major,’’ the APM faxes them to the applicant.When the application is ready
for ¢nal approval, the approval package is processed through the immediate
o⁄ce and the applicant is contacted. The Chemistry Divisions coordinate
with all of the disciplines for each application prior to full approval.
Since the Chemistry Divisions generate the ¢nal approval letter for the
O⁄ce Director, the other disciplines must be found acceptable with respect
to the approval of the application.

5. LABELING REVIEW PROCESS

After an ANDA has been accepted for ¢ling by the RSB, the Labeling section
of the application is assigned to the appropriate labeling reviewer based on
the therapeutic category of the drug product. The Labeling Review Branch
is part of the DLPS. A team leader oversees the work of 4^6 reviewers.
The basis for the labeling review is to ensure that the generic drug label-
ing is the ‘‘same as’’ the RLD labeling. There are several exceptions to the
‘‘same as’’ regulation. Exceptions are allowed for: di¡erences due to changes
in the manufacturer or distributor, unexpired patents, or exclusivities and
other characteristics inherent to the generic drug product, such as tablet
size, shape, or color.
The labeling reviewer also identi¢es and resolves concerns that may
contribute to medication errors. For example, the labeling reviewer may
identify drug names that are similar or that sound alike. In addition, the
labeling reviewer may address concerns associated with the prominence
and=or legibility of drug names on a container label. To ensure that the
proposed labeling in an ANDA is the ‘‘same as’’ the RLD, the labeling
reviewer must ¢rst identify the RLD. The next step is to ¢nd the most
recently approved labeling for the RLD. If the RLD labeling is not the most
recently approved, it is considered discontinued labeling. Hence, it is not
acceptable for the labeling review. It is very important to monitor FDA’s

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220 Ames et al.

database and website on a regular basis to determine the most recent labeling
approvals.
One allowed di¡erence between the generic and the RLD labeling is
the omission of information protected by patents and exclusivity. The label-
ing reviewer ensures that the applicant properly addresses all patents and
exclusivities by verifying the information in the ‘‘Orange Book.’’ The appli-
cant’s patent certi¢cation and exclusivity statement determines the way the
proposed labeling will be drafted.
The applicant may submit four copies of draft labeling or 12 copies of
¢nal printed labeling as proposed labeling. Draft copies may also be sub-
mitted for tentative approval. The labeling branch supports the submission
of electronic labeling. This practice is preferred and strongly encouraged.
For USP products, the labeling reviewer uses the United States Phar-
macopeia (USP) to evaluate the established name, molecular structure,
molecular weight, structural formula, chemical name, and the storage
conditions of the proposed drug product.
As the container label or carton label is reviewed, the labeling reviewer
decides if the labeling is easy to read and positioned in accordance with the
regulations. In addition, the labeling reviewer encourages applicants to
revise their labeling to decrease the likelihood of confusion with other drug
products.
After completing the review of the proposed labeling, the labeling
reviewer drafts a review that either identi¢es labeling de¢ciencies or recom-
mends approval. A tentative approval may be issued for an application with
outstanding patent and exclusivity issues. The team leader completes a sec-
ondary review of the application. If he or she is in agreement with the review,
the review is sent back to the labeling reviewer to ¢nalize. The labeling
reviewer then forwards the review back to the team leader for concurrence.
If the proposed labeling is de¢cient, the APM or the labeling reviewer
communicates the de¢ciencies to the applicant. If the proposed labeling is
acceptable, an approval or tentative approval summary is forwarded to the
APM.

6. PUTTING IT ALL TOGETHER

After the ¢nal O⁄ce level administrative review and individual disciplines
have resolved their de¢ciencies, the application will either receive a full
approval or a tentative approval letter (See ANDA Approval Chart).
The APMs are instrumental in assembling an approval package. This
package includes all reviews supporting ¢nal or tentative approval. When
the review of an ANDA is completed, the APMs draft the appropriate
approval letter and circulate it with the reviews and application for

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ANDA Regulatory Approval Process 221

concurrence. The APMs communicate with the OGD management on a

weekly basis to update them on the progress of reviews.
A full approval letter details the conditions of approval and allows the
applicant to market the generic drug product. A tentative approval letter is
issued if there are unexpired patents or exclusivities accorded to the RLD.
The tentative approval letter details the circumstances associated with the
tentative approval and delays the marketing of the product until all patents
and=or exclusivities expire. Once the O⁄ce Director or his designee has
signed the ¢nal approval letter, the APM calls and faxes a copy of the
approval letter to the applicant.The document room sta¡ then mails the ¢nal
approval letter to the applicant.
As one can see, the generic drug review process incorporates a series of
checks and balances to ensure the integrity of the reviews. The OGD is
comprised of bioequivalence reviewers, chemists, labeling reviewers, and
project managers. These individuals work together as a team to accomplish
the OGD’s mission of providing safe and e¡ective generic drugs to the
American People.

APPENDIX A
ANDA CHECKLIST FOR COMPLETENESS and
ACCEPTABILITYof an APPLICATION

ANDA# ____________________________________ FIRM NAME _____________________________________

RELATED APPLICATION(S)_________________________ FIRST GENERIC?_________________________

DRUG NAME: _________________________________________

DOSAGE FORM: __________________________________________________

Electronic Submission: E-mail noti¢cation sent: Comments: ____________________________

Random Assignment Queue: Chem Team Leader: PM: _______________________________________________
Labeling Reviewer: ________________Micro Review: _________________PD study (Med Ofcr): _________________
Letter Date Received Date

Comments On Cards Therapeutic Code

MethodsValidation Package(3 copies)
(Required for Non-USP drugs)
Archival, and Review copies Field Copy
Certification (Original Signature)
Cover Letter
Table of Contents

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ACCEPTABLE

Sec. I Signed and Completed Application Form (356h) &

(Statement regarding Rx=OTC Status)
Sec. II Basis for Submission NDA: &
RLD: Firm:
ANDA suitability petition required? If yes, consult needed
for pediatric study requirement.
Sec. III Patent Certification &
1. Paragraph:
2. Expiration of Patent:
A. Pediatric Exclusivity Submitted?
B. Pediatric ExclusivityTracking System checked?
Exclusivity Statement
Sec. IV Comparison between Generic Drug and &
RLD- 505(j)(2)(A)
1. Conditions of use
2. Active ingredients
3. Route of administration
4. Dosage Form
5. Strength
Sec.V Labeling &
1. 4 copies of draft (each strength and container) or 12
copies of FPL
2. 1RLD label and 1RLD container label
3. 1side by side labeling comparison with all differences
annotated and explained
Sec.VI Bioavailability=Bioequivalence &
1. Financial Certification (Form FDA 3454) and
Disclosure Statement (Form 3455)
2. Request forWaiver of In-Vivo Study(ies):
3. Formulation data same? (Comparison of all
Strengths)(Ophthalmics, Otics,Topicals Perenterals)
4. Lot Numbers of Products used in BE Study(ies):
5. StudyType: (Continue with the appropriate study
type box below)
StudyType IN-VIVO PK STUDY(IES)(i.e., fasting=fed=sprinkle) &
a. Study(ies) meets BE criteria (90% CI or 80^125,
Cmax, AUC)
b. Data Files (Computer Media) Submitted
c. In-Vitro Dissolution
StudyType IN-VIVO BE STUDY with CLINICAL ENDPOINTS &
a. Properly defined BE endpoints (eval. by Clinical Team)
b. Summary results meet BE criteria (90% CI
within
20% or 80^120)

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ANDA Regulatory Approval Process 223

c. Summary results indicate superiority of active

treatments (test & reference) over vehicle=placebo
(p < 0.05)(eval. by Clinical Team)
d. Data Files (Computer Media) Submitted
StudyType TRANSDERMAL DELIVERY SYSTEMS &
a. In-Vivo PK Study
1. Study(ies) meet BE Criteria (90% CI or 80^125,
Cmax, AUC)
2. In-Vitro Dissolution
3. Data Files (Computer Media) Submitted
b. Adhesion Study
c. Skin Irritation=Sensitization Study
StudyType NASALLY ADMINISTERED DRUG PRODUCTS &
a. Solutions (Q1=Q2 sameness):
1. In- Vitro Studies (Dose=Spray Content Uniformity,
Droplet=Drug Particle Size Distrib., Spray Pattern,
Plume Geometry, Priming & Repriming,Tail Off Profile)
b. Suspensions (Q1=Q2 sameness):
1. In-Vivo PK Study
a. Study(ies) meets BE Criteria (90% CI or 80^125,
Cmax, AUC)
b. Data Files (Computer Media) Submitted
2. In-Vivo BE Study with Clinical EndPoints
a. Properly defined BE endpoints (eval. by ClinicalTeam)
b. Summary results meet BE criteria (90% CI within
þ=- 20% or 80^120)
c. Summary results indicate superiority of active
treatments (test & reference) over vehicle=placebo
(p < 0.05)(eval. by ClinicalTeam)
d. Data Files (Computer Media) Submitted
3. In-Vitro Studies (Dose=Spray Content Uniformity,
Droplet=Drug Particle Size Distrib., Spray Pattern,
Plume Geometry, Priming & Repriming,Tail Off Profile)
StudyType TOPICAL CORTICOSTEROIDS (VASOCONSTRICTOR &
STUDIES)
a. Pilot Study (determination of ED50)
b. Pivotal Study (study meets BE criteria 90%^CI or
80^125)
Sec.VII Components and Composition Statements &
1. Unit composition and batch formulation
2. Inactive ingredients as appropriate
Sec.VIII Raw Materials Controls &
1. Active Ingredients
a. Addresses of bulk manufacturers
b. Type II DMF authorization letters or synthesis

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224 Ames et al.

c. COA(s) specifications and test results from drug

substance mfgr(s)
d. Applicant certificate of analysis
e.Testing specifications and data from drug product
manufacturer(s)
f. Spectra and chromatograms for reference standards
and test samples
g. CFN numbers
2. Inactive Ingredients
a. Source of inactive ingredients identified
b.Testing specifications (including identification and
characterization)
c. Suppliers’COA (specifications and test results)
d. Applicant certificate of analysis
Sec.IX Description of Manufacturing Facility &
1. Full Address(es)of the Facility(ies)
2. CGMP Certification
3. CFN numbers
Sec. X Outside Firms Including ContractTesting Laboratories &
1. Full Address
2. Functions
3. CGMP Certification=GLP
4. CFN numbers
Sec. XI Manufacturing and Processing Instructions &
1. Description of the Manufacturing Process (including
MicrobiologicalValidation, if Appropriate)
2. Master Production Batch Record(s) for largest
intended production runs (no more than 10x pilot
batch) with equipment specified
3. If sterile product: Aseptic fill=Terminal sterilization
4. Filter validation (if aseptic fill)
5. Reprocessing Statement
Sec. XII In-Process Controls &
1. Copy of Executed Batch Record (Antibiotics=3
Batches if bulk product produced by fermentation)
with Equipment Specified, including Packaging
Records (Packaging and Labeling Procedures), Batch
Reconciliation and Label Reconciliation
2. In-process Controls - Specifications and data
Sec. XIII Container &
1. Summary of Container=Closure System (if new resin,
provide data)
2. Components Specification and Test Data (Type III DMF
References)
3. Packaging Configuration and Sizes

Copyright © 2005 by Marcel Dekker, Inc.

 5460-3 Shargel Ch09 R1 102504

ANDA Regulatory Approval Process 225

4. Container=ClosureTesting
5. Source of supply and suppliers address
Sec. XIV Controls for the Finished Dosage Form &
1. Testing Specifications and Data
2. Certificate of Analysis for Finished Dosage Form
Sec. XV Stability of Finished Dosage Form &
1. Protocol submitted
2. Post Approval Commitments
3. Expiration Dating Period
4. Stability Data Submitted
a. 3 month accelerated stability data
b. Batch numbers on stability records the same
as the test batch
Sec. XVI Samples
Statement of Availability and Identification of: &
1. Drug Substance
2. Finished Dosage Form
3. Same lot numbers
Sec. XVII Environmental Impact Analysis Statement &
Sec. XVIII GDEA (Generic Drug Enforcement Act)=Other: &
1. Letter of Authorization (U.S. Agent [if needed,
countersignature on 356h])
2. Debarment Certification (original signature)
3. List of Convictions statement (original signature)

Reviewing Recommendation:
CSO=CST
Date & FILE &REFUSE to RECEIVE
Supervisory Concurrence=Date: ____ ____ _ _ _ _ _ _ _ _ ____ _ _ _ _ _ _ _ Date:____ _ _ _ _ _ _ ____ _ _ _ _ _ _ _ ___
Duplicate copy sent to bio:
(Hold if RF and send when acceptable)
Duplicate copy to HFD- for consult:Type:

Copyright © 2005 by Marcel Dekker, Inc.