Yongtian Ni

Sino-American Regulatory Consulting Alliance

December 4, 2011

Topics
ICH and CTD
ANDA Checklist for CTD and eCTD format
CTD Modules
OGDs ANDA Filing Process
Refusal to Receive Issues
Regulations for ANDA Submissions

International Conference on
Harmonization (ICH)
ICH brought together the regulatory

authorities from Europe, Japan and the United

States to discuss scientific and technical
aspects of product registration.
ICH developed guidelines for the Common
Technical Document for Registration of
Pharmaceuticals for Human Use (CTD).

CTD and eCTD Format

New ICH-CTD format, preferably electronic to
support Question-based Review (QbR)
Pre-assigned ANDA numbers are issued only
for true electronic CTD submissions.
http://www.fda.gov/cder/ogd/request_preassi
gned_ectd.htm

CTD and eCTD Format

Module 1
Administrative
- Specific for FDA
- Contains regulatory information (356h, Cover

Letter, Debarment & Financial Cert, Patent,

LoA, Basis for Submission, Comparison to RLD,
EA, BA/BE Waiver, Labeling)
Note: FDA will soon charge user fee for
ANDA. Details have not been finalized.

CTD and eCTD Format

Module 2
Summaries
- Contains the summaries of chemistry and

bioequivalence information
- 2.3 Quality Overall Summary (QOS), QbR
(2.3.S and 2.3.P) for OGD
- 2.7 Clinical Summary- Bioequivalence Studies
http://www.fda.gov/cder/ogd/Summary_
BioTables_CTD.htm

CTD and eCTD Format

Module 3
Quality (Chemistry)
- Drug Substance
- Drug Product
- Pharmaceutical Development
- Regional Information

CTD and eCTD Format

Module 4

Nonclinical Study Reports

- Not required for ANDAs

CTD and eCTD Format

Module 5

Clinical Study Reports

Not required if there are no BA/BE studies and
if a request for waiver of BA/BE studies was
submitted in Module 1.12.15.

ANDA Filing Process

ANDA Checklist for CTD or eCTD

Format for Completeness and
Acceptability of an Application
for Filing
http://www.fda.gov/cder/ogd/anda_checklist.pdf

ANDA Checklist
This checklist was created to follow the

Comprehensive TOC Headings and Hierarchy for

the CTD format.
Inclusive of the CFR requirements for ANDA filing
Consultation with individual divisions of OGD as
well as references to the multiple guidances for
industry were used in the development of this
checklist
Sections not listed on the checklist are not
required for ANDA filing, but may be included if
deemed necessary for review

Module 1- Administrative
1.1.2 Signed and completed Application Form
21CFR314.94(a)(2)
Form 356h
Firms should defer to the Electronic Orange
Book when identifying the Holder of the
Approved Application
Firms should utilize USP nomenclature when
the finished drug product is USP.

Module 1- Administrative
1.2 Cover Letter
Only required for paper submission
Address any issues or previous
communication with the Agency
TOC
Only required for paper submission
See Comprehensive TOC (Headings &
Hierarchy)

Module 1- Administrative
1.3.2 Field Copy Certification
Only required for paper submission
Requires original signature
1.3.3 Debarment Certification-GDEA
Firms must declare that they have not and will
not use in any capacity any individual that has
been debarred pursuant to Section 306(k)(1)
and (2) of the GDEA.

Module 1- Administrative
1.3.4 Financial Certifications
BA/BE Financial Certification (Form 3454), or
BA/BE Disclosure Statement (Form 3455)
1.3.5 Patent and Exclusivity
1.3.5.1 Patent Information
Patents listed for the RLD in the Electronic
Orange Book

Module 1- Administrative
1.3.5.2
Patent Certification
Patent number/s
Certification (Paragraph based on FD&C Act)
PI
PII
PIII PIV MOU No Relevant Patents
Expiration of the Patent/s
Exclusivity Statement

NCE Exclusivity
NCE Exclusivity- only exclusivity that blocks
submission of ANDAs for a period of 5 years
from the date of approval of the first approved
NDA. If an ANDA contains a PIV certification to
a listed patent covering the NDA for which an
NCE applies, then the application may be
submitted one year prior to the expiration of
the NCE exclusivity.

Module 1- Administrative
1.4.1 Letters of Authorization
Allows FDA to review the referenced DMF
- Type II (API)
- Type III (CC)
- US Agent LoA must be submitted by all firms
residing outside of US. US Agent is granted
authority by the DMF holder to act as an
intermediary between FDA and the applicant

Module 1- Administrative
1.12.11
Basis for Submission
Must include name of RLD as designated by
the Orange Book
Include the NDA number on the Basis for
submission
If utilizing an approved Suitability Petition as
Basis of Submission, the applicant must
provide a copy of the approval letter for the
Suitability Petition. 21 CFR 314.93

Module 1-Administrative
1.12.11
Basis for Submission (Contd)
314.122 ANDAs that rely upon an RLD that is
no longer marketed.
An application may be filed pending the
outcome of the Agencys determination that a
drug product was removed from the market for
reasons other than safety or efficacy. This
petition must be submitted under 10.25(a) and
10.30.

Module 1- Administrative
1.12.12
Comparison Between Generic Drug
and RLD- 505(j)(2)(A)
Conditions of Use
Active Ingredients- must be same as
innovator
Inactive Ingredients
Route of Administration
Dosage Form
Strength

Module 1- Administrative
1.12.14
Environmental Analysis
Firms should submit a statement that they are
in compliance with all federal, state and local
environmental laws
Categorical exclusion under 25.31 (a)
Environmental Assessment for substances that
occurs naturally in the environment

http://www.fda.gov/cder/guidance/1730fnl
.pdf

Module 1- Administrative
1.12.15
Request for Waiver of In-Vivo BA
Studies
For certain drug products, the in vivo BA/BE of
the drug product may be self-evident and
meets one of the criteria defined in 21CFR
320.22(b)(1).

Module 1- Administrative
1.14.1
Draft Labeling
Proposed draft labeling (electronic format);
including SPL
S X S container labeling with differences
annotated and explained
Electronic submission requirements
ANDAs submitted after June 8, 2004 are
required to provide their labeling in electronic
format

Module 1- Administrative
1.14.3
Listed Drug Labeling (RLD)
S X S Labeling of Package and Patient Insert
with all differences annotated and explained
1 RLD label and 1 RLD container label

Module 2- Summaries
2.3 Quality Overall Summary
QOS should include sufficient information
from each section in Module 3 to provide the
reviewer an overview of the application
Chemistry/Bio Division requests submission
in PDF and MS format
Model QOS and Model Bio Summary Tables
available in OGD website

Module 2- Summaries
2.7 Clinical Summary (Bioequivalence)
Summary of results of BA/BE studies
Bioequivalence Division request submission in
PDF and MS format

Module 3- Quality
3.2.S.1
General Information (Drug
Substance)
Nomenclature
Structure
General Properties

Module 3- Quality
3.2.S.2
Manufacture (Drug Substance)
Name and full address of facilities
(Summary table of all facilities- contacts,
addresses, phone/fax numbers, CFN #, etc.)
Function or Responsibility
Type II DMF No. for API
* DMF for API must be stamped received by
Agency prior to submission of an ANDA that
relies upon said DMF.

Module 3- Quality
3.2.S.4
Control of Drug Substance
Specifications
Test Procedures
Validation
Spectra and chromatograms
Sample statement in accord with 21 CFR
314.50 (e)(i)
CoA/Batch Analysis
Justification of Specifications

Module 3- Quality
3.2.P.1
Description and Composition of
the Drug
Product
Unit composition
Inactive ingredients and amounts as
compared to IIG

Components and Composition of

the Drug Product
Inactive ingredients not previously approved

or higher than previously approved (Most

prevalent RTR issue)
OGD will not consider GRAS/GRAE status
conclusive evidence; use in food products will
not persuade FDA to allow its use in drug
products
Exception Excipients: changes in preservative,
buffer or antioxidant: 314.94(a)(9)(iii)
Note that pH adjusters in parenterals are not
exception excipients.

Module 3- Quality
3.2.P.2
Pharmaceutical Development
Should contain information on the
development studies conducted to establish
that the dosage form, formulation,
manufacturing process, container closure
system, microbiological attributes and usage
instructions are appropriate for the purpose
specified in the application.
See Guidance for Industry Q8

Module 3- Quality
3.2.P.3
Manufacture (Drug Product)
Name and full address of manufacturers,
contract labs, contacts and specific functions
All firms performing any testing, packaging,
sterilization, etc. of DS or DP must be IDed so
that a request may be initiated for inspection
cGMP certification with signature
FDA inspection information

Module 3- Quality
3.2.P.3.2 Batch Formula (Drug Product)
List of all components of the dosage form to
be used in the manufacturing process,
amounts on a per batch basis, including
overages and a reference to their quality
standards.

Module 3- Quality
3.2.P.3.3 Description of Manufacturing Process
and
Process Controls (Drug Product)
Flow Diagram showing the process steps and
where materials enter the process
Blank Master Production Batch Records
- Maximum production scale-up of 10 x the
theoretical yield of the exhibit batch may be
requested.

Module 3- Quality
3.2.P.3.3 Description of Manufacturing
Process and Process Controls (Contd)
Reprocessing Statement
- Forms should certify that it does not utilize
reprocessing procedures in the
manufacturing of the drug product. If the
firm does wish to reprocess the drug
product, they will submit a Prior Approval
Supplement to the Agency describing the
process. Release of the reprocessed
product will be withheld until the PAS is
approved by the Agency.

Module 3- Quality
3.2.P.3.4 Controls of Critical Steps and
Intermediates
(Drug Product)
All critical process controls and their

associated numeric ranges, limits, or

acceptance criteria should be identified and
justified and a brief description of the test
provided

Module 3- Quality
3.2.P.3.5 Process Validation and/or Evaluation
(Drug Product)
Description, documentation, and results of
the validation and/or evaluation should be
provided for critical steps or critical assays
used in the manufacturing process
- Microbiological sterilization validation
- Filter Validation
Must have complete filter validation present
upon submission of an ANDA, this information
may not be submitted at a later date.

Module 3- Quality
3.2.P.4

Controls of Excipients (Inactive

Ingredients)
Identify source of supplier for all inactive
ingredients (tabular format)
CoA
3.2.P.4.1 Specifications
Testing Specifications

Module 3- Quality
3.2.P.4.2 Analytical Procedures
Test procedures should be provided, when
appropriate
3.2.P.4.3 Validation of Analytical Procedures
Normally not needed for excipients
Should be submitted in special circumstances
(i.e., characteristic of excipient is critical to
product quality)

Module 3- Quality
3.2.P.4.4 Justification of Specifications
Applicants CoA
Pharm/Tox studies when appropriate to justify
the safety of an inactive ingredient
IIG database, compendial, etc.

Module 3- Quality
3.2.P.5
Controls of Drug Product
3.2.P.5.1 Specifications
3.2.P.5.2 Analytical Procedures
3.2.P.5.3 Validation of Analytical Procedures
Sample statement- Sample drug product will
be submitted upon request from FDA in accord
with 21CFR 314.50(e)(1)

Module 3- Quality
3.2.P.5.4 Batch Analysis
CoA for each executed batch
3.2.P.5.5 Characterization of Impurities
List all expected impurities
Identification of impurities
3.2.P.5.6 Justification of Specifications
Pharm/Tox studies to justify the safety of an
impurity

Module 3- Quality
3.2.P.7
Container Closure System
1. Summary of CC System (if new resin,
provide data)
2. Components Specification (including
Engineering Drawing) and Test Data
3. Packaging Configuration and Sizes
4. Container Closure testing
5. Source of Supply and Suppliers Address

Module 3- Quality
3.2.P.8
Stability
3.2.P.8.1 Stability Summary and Conclusion
Stability Protocol
Proposed expiration dating period
- Tentative 24 month expiration date based
upon 3 months of accelerated stability

Module 3- Quality
3.2.P.8.2 Post-approval Stability Protocol and
Stability Commitment
Firm must commit to placing first 3
production lots as packaged in the largest
and smallest container on long term stability
Each year thereafter, a minimum of one lot
packaged in the largest and smallest
container will be added to long term stability.
Firm must report the stability data as it
becomes available (periodic reports).

Module 3- Quality
3.2.P.8.3
Stability Data*
Data from 4 timepoints should be submitted- 0, 1, 2,
and 3 months
3 months of accelerated stability conducted per ICH
Q1A, even if product fails under stressed conditions.
RSB will file an ANDA with failing accelerated stability
but may not file an ANDA if only unstressed stability is
provided.
Firm can bracket intermediate package sizes and only
perform stability on largest and smallest package sizes
if same CC system is used for multiple package sizes
Batch number must be the same as the exhibit batch
*FDA soon will require 12 months RT data and 6 months
Accelerated/Intermediate data for three lots for each Package configuration.

Module 3- Quality
3.2.R Regional Information
3.2.R Drug Substance
Executed Batch Records (if available)
Comparability Protocols (optional)
-used to demonstrate the lack of adverse
effect for specified types of post-approval
manufacturing changes
Methods Validation Package

Module 3- Quality
3.2.R Drug Product
Executed Batch Records
- Parenteral products:
Must package a minimum of 10% of the
exhibit bulk size in each vial size proposed for
marketing; scale-up based upon actual
packaged amounts
- Provide reconciliation detailing the disposition
of all dosage units

Module 3- Quality
3.2.R
Drug Product (Contd)
Information on Components
Manufacturer Information
Function of Contract Facilities (Sterilization,
etc.)
CoA
Comparability Protocols
- used to demonstrate the lack of adverse
effect for specified types of post-approval
manufacturing changes
Methods Validation Package

Certification to Accompany Drug, Biological

Product,
and Device Applications or Submissions
The recently enacted U.S. Public Law 110-85 (Food and Drug
Administration Amendments Act of 2007), Title VIII, Section 801
mandates the expansion of the clinical trials data bank (
ClinicalTrials.gov). The new provisions require additional information
to be submitted to the databank, including expanded information
on clinical trials and information on the results of clinical trials.
Beginning no later than December 26, 2007, one FDAAA provision in
Section 801, 42 U.S.C. 282(j)(5)(B), requires that a certification form (FDA
3674) accompany certain human drug, biological, and device product
submissions made to FDA. At the time of submission of an application
under sections 505, 515, or 520(m) of the Federal Food, Drug, and
Cosmetic Act (FD&C Act) (21 U.S.C. 355, 360e, or 360j(m)), or under
section 351 of the Public Health Service Act (PHS Act) (21 U.S.C. 262), or
submission of a report under section 510(k) of the FD&C Act (21 U.S.C.
360(k)), such application or submission must be accompanied by a
certification that all applicable requirements of section 402(j) of the PHS
Act have been met. Where available, such certification must include the
appropriate ClinicalTrials.gov identifiers (NCT numbers).

Refusal to Receive Issues

Incomplete BE studies
No dissolution data
DMF not present or received by Agency by the

stamped ANDA receipt date

Missing or incomplete stability data
No patent certifications
Missing Citizens Petition or Suitability Petition

Refusal to Receive Issues

(Contd)
Inactive Ingredients
Master production batch records not in accord

with 10 x scale-up
No information demonstrating that differences
in inactive ingredients do not impact safety
and efficacy.

Regulations for ANDA

submissions
21 CFR 5.80
Approvals of New Drug
Applications and their
Supplements
21 CFR 10.30
Citizen Petition
21 CFR 50 Protection of Human Subjects
21 CFR 56 Institutional Review Boards
21 CFR 310.305 Records and reports concerning
ADEs
on marketed prescription
drugs for
human use without
approved new drug
applications
21 CFR 314.70
Supplements and other changes
to an approved
application
21 CFR 320 BA/BE Requirements