The ANDA Workshop Filing Process

&
The ANDA Checklist for CTD and eCTD Format

LCDR Stanley Shepperson FDA, CDER, Office of Generic Drugs Senior Regulatory Management Officer May 17, 2007

Goals for Discussion

To inform Industry of the Agencys ANDA filing process To discuss details of the ANDA Checklist for CTD and eCTD format Discuss frequently asked questions regarding CTD and eCTD submissions Discuss progress with recently submitted electronic ANDAs

International Conference on Harmonization (ICH)

ICH brought together the regulatory authorities of 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)

OGD Initiative
To conform to the ICH-CTD format Encouraging all ANDAs be submitted in the CTD format and preferably electronic CTD to support Question-based Review The 1999 Guidance for Industry; Organization of an ANDA has been removed from the Regulatory Guidance page RSB is no longer giving advice to firms on submissions in the 1999 Guidance format (also referred to as the traditional format)

CTD Guidances
Many guidances currently exist referencing the CTD format Refer to the CDER Guidance Document web page

CTD and eCTD Informational Links

Organization of the CTD http://www.fda.gov/cder/guidance/4539O.PDF eCTD Submissions http://www.fda.gov/cder/guidance/7087rev.pdf Drug Substance http://www.fda.gov/cder/guidance/3969DFT.pdf Drug Product http://www.fda.gov/cder/guidance/1215dft.pdf Pharmaceutical Development http://www.fda.gov/cder/guidance/6746fnl.pdf CTD-Efficacy http://www.fda.gov/cder/guidance/4539E.pdf CTD-Quality http://www.fda.gov/cder/guidance/4539Q.PDF

Other Helpful Links

Electronic Common Technical Document web page: http://www.fda.gov/cder/regulatory/ersr/ectd.htm Models and more information on Quality Overall Summary (QOS) are located on the OGD web page: http://www.fda.gov/cder/ogd/
Comprehensive Table of Contents http://www.fda.gov/cder/regulatory/ersr/5640CTOCv1.2.pdf QbR-Quality Overall Summary Outline in MS Word Format, located on the OGD webpage: http://www.fda.gov/cder/ogd/

CTD and eCTD Format

Module 1: Administrative
Required for ANDAs Specific for FDA Regulatory information

CTD and eCTD Format

Module 2: Summaries
Required for ANDAs Chemistry and Bioequivalence Information
2.3 Quality Overall Summary (QOS) 2.7 Clinical Summary-Bioequivalence Studies

CTD and eCTD Format

Module 3: Quality (Chemistry)
Required for ANDAs Drug Substance Drug Product Product 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
Required for ANDAs Bioavailability and Bioequivalence Studies
Formulation BA/BE study reports Dissolution

Non Electronic CTD Submissions Jacket Requirement

Archival Copy (Blue)
All jackets

Field Copy (Burgundy)

Module 3 only unless otherwise directed by your local FDA district office

Review Copy
Chemistry (Red)-Modules 1, 2 and 3 Bioequivalence (Orange)-Modules 1, 2 and 5

Filing an ANDA

ANDA Filing Process

ANDA
Application Review

Refuse to Receive Letter

Acceptable & Complete

Y Request for Plant Inspection Chemistry & Micro Review Labeling Review Bioequivalence Review

The ANDA Checklist for CTD or eCTD Format for Completeness and Acceptability of an Application for Filing

ANDA Checklist
This checklist was created to follow the Comprehensive Table of Contents Headings and Hierarchy for the CTD format Inclusive of the CFR requirements for filing an ANDA Consultation with individual divisions of OGD as well as references to the multiple guidances for industry were used in the development Sections not listed on check list are not required for ANDA filing, but may be included if deemed necessary for review Please follow the checklist and organize application accordingly.

Module 1-Administrative

1.1.2 Signed and Completed Application Form (356h)

314.94(a)(2) Original signature required Firms should defer to the Approved Drug Products with Therapeutic Equivalence Evaluations, the Electronic Orange Book when identifying the Holder of the Approved Application Firms should utilize USP nomenclature when the finished drug product is USP

1.2 Cover Letter

Only required for paper submission Address any issues or previous communication with the Agency Refer to Control Correspondence numbers if relevant

Table of Contents
Only required for paper submission See Comprehensive Table of Contents Headings and Hierarchy
http://www.fda.gov/cder/regulatory/ersr/5640CTOC-v1.2.pdf

1.3.2 Field Copy Certification

Only required for paper submission Requires original signature

1.3.3 Debarment Certification-GDEA

Requires original signature Firm 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 Firm must declare that no one responsible for the development or submission of the ANDA has been convicted of a crime as defined by Section 306(k)(1) and (2) with in the last 5 years

1.3.4 Financial Certifications

Bioavailability/Bioequivalence Financial Certification (Form 3454) OR Bioavailability/Bioequivalence Disclosure Statement (Form 3455)

1.3.5 Patent and Exclusivity 1.3.5.1 Patent Information Patents listed for the RLD in Approved Drug Products with Therapeutic Equivalence Evaluations, the Electronic Orange Book

1.3.5 Patent and Exclusivity (Cont.)

1.3.5.2 Patent Certification Patent number (s) Certification
Paragraph based on the FD&C ACT PI PII PIII PIV MOU No Relevant Patents

Expiration of Patent (s)

1.3.5 Patent and Exclusivity (Cont.)

1.3.5.2 Patent Certification
Exclusivity Statement (Included in this section)
Exclusivity statements must be included even if the product is not entitled to any marketing exclusivity NCE exclusivity is the only exclusivity that blocks submission of ANDAs. NCE may block submission of an ANDA for a period of 5 years from the date of approval of the first approved NDA. However, if an ANDA contains a PIV certification to a listed patent covering the NDA for which NCE applies then an application may be submitted one year prior to expiration of NCE Pediatric Exclusivity may attach to NCE and further extend these timeframes to 5 & years and 4 & years respectively

1.4.1 Letters of Authorization

DMF Letters of Authorization
Type II for API (allowing FDA to review DMF) Type III for container closure components

US Agent Letters of Authorization

Letter of Authorization (U.S. Agent) must be submitted by all firms residing outside of the United States. This letter must be on the applicants letterhead and grant authority for a designated U.S. firm and individual to act as an intermediary between FDA and the applicant

1.12.11 Basis for Submission

Must include name of the Reference Listed Drug as designated by the Approved Drug Products with Therapeutic Equivalence Evaluations, the Electronic Orange Book Helpful to include NDA number on Basis for Submission For utilizing an approved Suitability Petition as Basis of Submission the applicant must provide a copy of the approval letter for the Suitability Petition. 314.93

1.12.11 Basis for Submission (cont.) 314.122 ANDAs that rely upon a listed drug 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.

1.12.12 Comparison Between Generic Drug and RLD-505(j)(2)(A) Conditions of use Active ingredients
Active Ingredients must be the same, this means precisely the same salt must be used as the innovator. Applicants wishing to pursue approval of an application utilizing a different salt of the same active moiety must submit their application as a 505(b)(2)

Inactive ingredients

1.12.12 Comparison Between Generic Drug and RLD-505(j)(2)(A) (Cont.) Route of administration
Route of administration: a change in container/closure system that limits the routes of administration when compared to the RLD must be previously authorized via the Suitability Petition process.

Dosage Form Strength

1.12.14 Environmental Analysis

Firm should submit a statement that they are in compliance with all federal, state and local environmental laws Must have a signature ANDA applicants may claim a categorical exclusion under 25.31(a)

1.12.15 Request for Waiver of In-Vivo Bioavailability Studies Firm should submit a BA/BE waiver request for any strength or dosage form in which In-Vivo BA/BE studies is not performed

1.14.1 Draft Labeling

4 copies of draft labeling if not electronic 1 side by side by side labeling comparison of containers and carton with all differences annotated and explained 1 package insert (content of labeling) submitted electronically Electronic submission requirements
All ANDAs submitted after June 8, 2004, are required to provide their labeling in electronic format

1.14.3 Listed Drug Labeling (RLD)

1 side by side labeling comparison of package and patient insert with all differences annotated and explained 1 RLD label and 1 RLD container label

Module 2-Summaries
Chemistry & Bioequivalence

2.3 Quality Overall Summary

Quality Overall Summary should include sufficient information from each section in Module 3 to provide the reviewer with an overview Chemistry Division request submission in PDF format and Word Processed (MS Word) A model Quality Overall Summary for an immediate release tablet and an extended release capsule can be found on the OGD webpage http://www.fda.gov/cder/ogd/

2.7 Clinical Summary (Bioequivalence) Summary of Results of Bioavailability/ Bioequivalence studies should be included in this section Bioequivalence Division request submission in PDF format and Word Processed (MS Word)

Module 3-Quality
Chemistry

3.2.S Drug Substance

3.2.S.1 General Information (Drug Substance)

Nomenclature Structure General Properties

3.2.S.2 Manufacture (Drug Substance)

Name and full address of facilities
Helpful to provide summary table of all facilities (contacts, addresses, phone/fax numbers, etc., CFN#, etc.) Specific functions performed

Function or Responsibility Type II DMF number for API

Note DMF for Active Pharmaceutical Ingredients must be stamped received by the Agency prior to submission of an ANDA that relies upon said DMF

3.2.S.4 Control of Drug Substance

Testing specifications Spectra and chromatograms Sample statement
Samples of drug substance will be submitted upon request from FDA in accord with 21 CFR 314.50(e)(i)

Certificate of Analysis (COA)

API supplier Applicant

3.2.P Drug Product

3.2.P.1 Description and Composition of the Drug Product

Unit composition of the proposed product Inactive ingredients and amounts are appropriate per IIG

Components and Composition of the Drug Product

Use of inactive ingredients that have not been previously approved or that are being used at a higher level than previously approved is the most prevalent RTR issue. RSB needs a complete breakdown of all components used in the proposed formulation. This includes flavors and colors that may contain proprietary information. Suggestion: If you know that your firm is proposing to use a flavor/color that has not been previously approved ask your vendor to fax a copy of the formulation to OGD at (301) 4433847. Have the vendor request that FDA evaluate the formulation and its use at XXX mg. The request will be assigned a control number which your firm may cite in its submission as proof that the proposed level is acceptable.

Components and Composition of the Drug Product (Cont.)

OGD will not consider GRAS/GRAE status conclusive evidence that an excipient may be used in a drug product at a given level. Furthermore, use of an excipient in food products will not persuade FDA to allow its use in drug products. Exception Excipients: minor changes in formulation of a drug product for which an applicant may seek approval. Parenterals: 314.94(a)(9)(iii): changes in preservative, buffer and antioxidant Ophthalmic/Otic: 314.94(a)(9)(iv): changes in preservative, buffer, substance to adjust tonicity and thickening agent Topical Use: 314.94(a)(9)(v): changes are not specified by the Regulations Note the use of pH adjusters in parenterals is not an exception excipient

3.2.P.2 Pharmaceutical Development

The Pharmaceutical Development section should contain information on the development studies conducted to establish that the dosage form, the formulation, manufacturing process, container closure system, microbiological attributes and usage instructions are appropriate for the purpose specified in the application. See the Guidance for Industry; Q8 Pharmaceutical Development

3.2.P.3 Manufacture (Drug Product)

Name and full address of facility
This section includes manufacturers of drug product as well as outside contract testing labs Please provide a summary table of all lab addresses, contacts, and specific functions performed

Function or Responsibility
Provide a detailed description of outside firms responsibilities and functions. All firms performing any testing, packaging, sterilization, etc. of the finished drug product and/or active pharmaceutical ingredient must be identified so that a request may be initiated for inspection

cGMP Certification
Certification should include signature

3.2.P.3.2 Batch Formula (Drug Product)

A batch formula should be provided that includes a list of all components of the dosage form to be used in the manufacturing process, their amounts on a per batch basis, including overages and a reference to their quality standards.

3.2.P.3.3 Description of Manufacturing Process and Process Controls (Drug Product) A flow diagram should be presented giving the steps of the process and showing where materials enter the process Blank Master Production Batch Records
Firms may request a maximum production scale-up of 10X the Theoretical yield of the exhibit batch

3.2.P.3.3 Description of Manufacturing Process and Process Controls (Cont.) (Drug Product) Reprocessing Statement
Firm should certify that it does not utilize reprocessing procedures in the manufacture on 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

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

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

3.2.P.4 Controls of Excipients

Inactive Ingredients

3.2.P.4 Controls of Excipients (Inactive Ingredients)

Identify source of supplier for all inactive ingredients
It is helpful if the applicant provides a table indicating the source of all active and inactive ingredients

3.2.P.4.1 Specifications (Inactive Ingredients)

Testing Specifications Suppliers COA
Minimally OGD needs the COA, specifications and test results from the drug substance manufacturer and the applicants COA. We also like to have the applicants testing specifications and data from the drug product manufacturers 3.2.P.4.4

3.2.P.4.2 Analytical Procedures (Inactive Ingredients)

Analytical procedures used for testing the excipients should be provided, when appropriate

3.2.P.4.3 Validation of Analytical Procedures (Inactive Ingredients)

Submission of validation information in the application is normally not needed for excipients Validation information should be submitted if there are special circumstances
Characteristic of the excipient or the excipient itself is critical to product quality

3.2.P.4.4 Justification of Specifications (Inactive Ingredients)

Applicants Certificate of Analysis Pharm/Tox studies can be submitted in this section when appropriate to justify the safety of an inactive ingredient Other justification of inactive ingredients (IIG database, etc.)

3.2.P.5 Controls of Drug Product

3.2.P.5.1
Specification (s)

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 21 CFR 314.50(e)(i)

3.2.P.5 Controls of Drug Product (Cont.)

3.2.P.5.4
Batch Analysis
COA for Finished Dosage Form needed for each executed batch

3.2.P.5.5
Characterization of Impurities
List all expected impurities Identification of impurities

3.2.P.5 Controls of Drug Product (Cont.)

3.2.P.5.6
Justification of Specifications
Pharm/Tox studies can be submitted in this section when appropriate to justify the safety of an impurity

3.2.P.7 Container Closure System

3.2.P.7 Container Closure System

1. Summary of Container/Closure System (if new resin, provide data) 2. Components Specification and Test Data 3. Packaging Configuration and Sizes
RSB is looking for engineers drawings with exact dimensions and specifications of all components of the Container/Closure system. This should be provided for all dosage unit sizes.

4. Container/Closure Testing 5. Source of supply and suppliers address

3.2.P.8 Stability

3.2.P.8.1 Stability Summary and Conclusion

Stability Protocol Proposed expiration dating period
Firm may propose a tentative 24 month expiration date based upon 3 months of accelerated stability

3.2.P.8.2 Post-approval Stability Protocol and Stability Commitment

Post Approval Stability Protocols and Commitments
Post Approval Commitments: Firm must commit to placing first three 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 this stability data as it becomes available (in periodic reports)

3.2.P.8.3 Stability Data

Data from four time points should be submitted - 0, 1, 2, and 3 months Must submit 3 months of accelerated stability conducted under stressed conditions of 40C and 75% relative humidity This data should be provided even if the 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. If a firm is utilizing the same container closure system for multiple package amounts/sizes then a firm may bracket intermediate package amount/sizes and only perform stability on the largest and smallest package amount/sizes. Batch number must be the same as the exhibit batch

3.2.R Regional Information

3.2.R Drug Substance

Executed batch records for drug substance (if available) Comparability Protocols (optional) (See Drug Substance Guidance)
Used to demonstrate the lack of adverse effect for specified types of post approval manufacturing changes

Methods Validation Package

3 copies needed for paper submission

3.2.R Drug Product

Executed batch records for drug product Solid Oral Dosage Forms: Exhibit Batch must be a minimum of 100,000 units or 10% of the proposed production batch Must completely package the exhibit batch in containers proposed for marketing Parenteral Products: Must package a minimum of 10% of the exhibit bulk in each vial size (container) proposed for marketing Scale-up should be based upon actual packaged amounts For all dosage forms you must provide a complete reconciliation detailing the disposition of all dosage units
Very helpful to provide a reconciliation summary table and list in Table of Contents

3.2.R Drug Product (Cont.)

Information on Components (See Drug Product Guidance)
Manufacturer information Function of contract facilities COA (s)

Comparability Protocols (optional)

Used to demonstrate the lack of adverse effect for specified types of post approval manufacturing changes

Methods Validation Package

3 copies needed for paper submission

Module 4-Nonclinical Study Reports

Not needed for ANDAs

Module 5-Clinical Study Reports

Bioequivalence

5.3.1 Bioavailability Study Reports

Formulation
Comparison of all strengths Qualitative and Quantitative comparisons of parenterals, ophthalmics, otics and topicals

Q1/Q2? Exception excipients

5.3.1.2 Comparative BA/BE Study Reports

Study(ies) meet BE criteria (90% CI of 80125, C max, AUC)
Automatic refuse to receive issue if BA/BE study fails criteria

5.3.1.3 In Vitro-In-Vivo Correlation Study Reports

In-Vitro Dissolution
Dissolution data must be provided for 12 dosage units. The dissolution data should compare the proposed product to the reference listed drug for each strength that the applicant is seeking approval. Applicant must also provide mean, range and standard deviation for each time point. Lot and or batch numbers must correspond to the exhibit batch Dissolution data is required for all solid oral dosage forms, suppositories and oral suspensions

5.3.1.4 Reports of Bioanalytical and Analytical Methods for Human Studies

5.3.1.4
Reports of Bioanalytical and Analytical Methods for Human Studies
Bioanalytical validation report See M4E: The CTD-Efficacy Guidance

5.3.7 Case Reports Forms and Individual Patient Listing

5.3.7 Case Reports Forms and Individual Patient Listing See M4E: The CTD-Efficacy Guidance

Refusal to Receive Issues

Incomplete bioequivalence studies No dissolution data DMF not present or received by the Agency by the date the ANDA was stamped received Missing or incomplete stability data No patent certifications Missing Citizens Petition or Suitability Petition

Refusal to Receive Issues (Cont.)

Inactive Ingredients Master production batch records not in accord with 10X scale-up No information demonstrating that differences in inactive ingredients do not impact safety and efficacy

Questions and Answers

Q: Can an ANDA be refused for filing if submitted in the traditional format addressed in the 1999 Guidance and not submitted in the CTD or eCTD format? No. At this time, the FDA can not refuse to file an ANDA for using the traditional format.

A:

Questions and Answers

Q: Should the Quality Overall Summary (QOS) be provided as separate files or as one complete file? Please note that the QOS is a reviewers tool and is most useful as one complete document (in both MS Word and pdf files) for ANDAs.

A:

Questions and Answers

A: Page 3 of the Guidance for Industry Granularity Document Annex to M4: Organization of the CTD is a diagram that provides a visual layout of how to prepare a summary of the application. The QOS is Module 2.3 and can be submitted in multiple files but there is the option of submitting as one document (highlighted in pink). Please note comment #2 about submitting one document for each drug substance. OGD directors and reviewers have requested one document with the two different DS identified separately.

Questions and Answers

Q: Is Module 5 required if a request for waiver of BA/BE studies was submitted within the ANDA submission and no tests were performed? No. If there are no BA/BE studies Module 5 is not needed.

A:

Questions and Answers

Q: Can hyperlinks be used to refer to duplicate information submitted in an electronic submission? Yes. Caution: if submitting an amendment, make sure to also amend your hyperlink if appropriate.

A:

Questions and Answers

Q: In the CTD format, where should the 16 Bioequivalence Summary Tables be placed? Module 2.7.1.1 should include:
Table 1. Submission Summary Table 4. Bioanalytical Method Validation Table 6. Formulation Data

A:

Module 2.7.1.2 should include:

Table 5. Summary of In-vitro Dissolution Studies

Questions and Answers

Q: In the CTD format, where should the 16 Bioequivalence Summary Tables be placed? Module 2.7.1.3 should include:
Table 2. Summary of Comparative Bioavailability (BA) Studies Table 3. Statistical Summary of the Comparative BA Data

A:

Module 2.7.4.1.3 should include:

Table 7. Demographic Profile of Subjects Completing the BE Study

Questions and Answers

Q: In the CTD format, where should the 16 Bioequivalence Summary Tables be placed? Module 2.7.4.2.1.1 should include:
Table 8. Incidence of Adverse Events in Individual Studies

A:

Questions and Answers

A: Module 5.3.1.2 should include:
Table 10. Study Information Table 12. Dropout Information

Module 5.3.1.3 should include:

Table 11. Product Information Table 13. Protocol Deviations Table 16. Composition of Meal Used in Fed BE Study

Module 5.3.1.4 should include:

Table 9. Reanalysis of Study Samples Table 14. Summary of Standard Curve and QC Data for BE Sample Analyses Table 15. SOPs dealing with Bioanalytical Repeats of Study Samples

Helpful Hint
Please follow the checklist as closely as possible
Eases regulatory and scientific review. Reduces number of contacts to locate information

Electronic Submissions
Many firms have converted to the CTD format using electronic or paper submissions; and some hybrid. CTD is the preferred format for electronic submissions Pre-assigned ANDA numbers are issued ONLY for true electronic CTD submissions

Electronic Submissions
Electronic submissions in hybrid format
Need to include a comprehensive table of contents Make sure all hyperlinks link to the specific information cited Do not mix traditional formatting with CTD numbering system

RSB contact information:

Phone number: (301) 827-5862 Fax number: (301) 443-3847