ANDA Submissions — Content and CTD Format (USFDA)

TABLE OF CONTENTS

 CTD FORMAT 

A. Module 1 – Administrative Information 

• Forms and Cover Letter
• Administrative Information
• References
• Other Correspondence
• Labeling

B.Module 2 – CTD Summaries

• Quality Overall Summary
• Clinical Summary

C.Module 3 – Quality

• Drug Substance
• Drug Product
• Appendices
• Regional Information
• Literature References

D.Module 4 – Nonclinical Study Reports

E.Module 5 – Clinical Study Reports

• Complete Study Data
• Literature References

APPENDIX:  SUGGESTED COVER LETTER TEMPLATE

 

The CTD format was developed by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) in an attempt to streamline the submission requirements for Japan, the European Union, and the United States. 

The electronic CTD (eCTD) is the standard format for electronic regulatory submissions for ANDAs.

The CTD is comprised of the following modules:

• Module 1:  Administrative Information and Prescribing Information

• Module 2:  Summaries

• Module 3:  Quality

• Module 4:  Nonclinical

• Module 5:  Clinical

The sections that follow in this guidance provide additional detail about the information that should be submitted in the applicable modules, sections, and subsections

 

 

 

A. Module 1 – Administrative Information

1.0 Forms and Cover Letter
Section 1.1 contains the following forms:

• Form FDA 356h (Form 356h) –Application to Market a New or Abbreviated New Drug or Biologic for Human Use, which ANDA applicants must fully complete and sign for their submissions.

•Form FDA 3794 – Generic Drug User Fee Cover Sheet

•Form 3674 – Certification of Compliance with Requirements of Clinical Trials.gov Data Bank.

1.2 Contains a cover letter. 

For cover letter template refer the appendix.18.

FDA recommends that a cover letter clearly state in its header whether it proposes any of the following:

• A new strength of a solid oral dosage-form drug product

• A change in concentration for a parenteral dosage-form drug product

• A change in vial size, fill volume, and/or package size to a parenteral dosage-form drug product (i.e., total drug content)

• A change in concentration of an oral liquid, ophthalmic, otic, transdermal, or topical drug product

• A change in the formulation for any dosage form.

• A switch from a prescription drug product to an over-the-counter product

• The reactivation of a product listed in the discontinued section of FDA’s Approved Drug Products With Therapeutic Equivalence Evaluations (the Orange Book) .

1.2 Contains

(1) copies of any controlled correspondence from FDA related to meetings FDA holds with applicants to discuss their development of a generic drug product that is the subject of an ANDA and

(2) any copies of the minutes from those meetings.

2.0 Administrative Information:

1.3.1.2 Contains a U.S. agent letter of appointment, if applicable.  The U.S. agent letter of appointment is a separate document submitted in addition to the U.S. agent’s signature on Form 356h, if applicable

1.3.2  Contains the field copy certification.21  Applicants should notify the applicable Office of Regulatory Affairs district office by letter that their eCTD submission will be submitted to FDA

1.3.3 Contains the signed debarment certification required under the Generic Drug Enforcement Act of 1992. The applicant must certify that it did not and will not use the services of any debarred persons in connection with the application.

1.3.4  Contains a financial certification (FDA Form 3454) for any clinical investigator

1.3.5 Contains the patent and exclusivity information

1.3.5.1 Contains the patent information.

Applicants are required to provide an appropriate patent certification or statement for each patent issued by the U.S. Patent and Trademark Office and subsequently listed in the Orange Book that claims

(1) the drug substance,

(2) the drug product, and

(3) a use of the RLD that is cited by the ANDA.

1.3.5.2 Contains the patent certification(s). 

If the Orange Book does not list a patent for the RLD, the ANDA applicant must certify that such patent information has not been submitted by the NDA holder for listing in the Orange Book.

The applicant must certify to one of the following paragraphs

That the patent information has expired (Paragraph II Certification)

The date on which the patent will expire (Paragraph III Certification)

That the patent is invalid, unenforceable, or will not be infringed by the manufacture, use, or sale of the drug product for which the ANDA is submitted (Paragraph IV Certification)

Applicants submitting a Paragraph IV Certification must provide the following language:

I, (name of applicant), certify that Patent No._________ (is invalid, unenforceable, or will not be infringed by the manufacture, use, or sale of) (name of proposed drug product) for which this application is submitted.

3.0 References:

1.4.2 Contains the statement of a right of reference for each and every drug master file (DMF)

1.12.4 Contains a statement, if applicable, that a request for a proprietary name has been made.

When requesting a proprietary name, a separate electronic submission should be made and identified as a “REQUEST FOR PROPRIETARY NAME REVIEW

1.12.11 Contains the basis for submission.

The applicant should provide:

(1) the name of the RLD,

(2) the application number of the RLD, and

(3) the holder of the application for the RLD

1.12.12 Contains information demonstrating that the generic product is the same as the RL.

To demonstrate that the proposed generic drug product meets this standard, applicants should provide:
(1) A statement that the conditions of use for the generic product have been previously approved for the RLD.
(2) Information to show that the active ingredient(s) in the generic drug product is/are the same as the active ingredient(s) in the RLD.
(3) Information to show that the route of administration, dosage form, and strength of the generic drug product are the same as those of the RLD.
(4) As applicable, information to indicate the strength of the generic drug product used in the in vivo bioequivalence (BE) studies (fasting and fed) to demonstrate BE of the generic drug product to the RLD.

FDA recommends that applicants submit, within their original application, all strengths that they intend to market.  Applicants generally should not submit a new pharmacy bulk package strength or fill volume in an amendmen.

1.12.14 Contains the environmental assessment:the environmental impact statement or the claim of categorical exclusion and the justification for the exclusion.

1.12.15 Contains a request, if applicable, to waive the requirement that applicants submit evidence either measuring in vivo bioavailability (BA) or demonstrating in vivo BE of the generic product (known as a biowaiver).

5.0 Labeling:

1.14.1 Contains labeling for the generic drug product.

1.14.1.1 Contains the draft label and labeling: for each strength and container including the package size in a text-based PDF file.

1.14.1.2  Contains the annotated draft labeling text: including side-by-side labeling comparison of the generic drug product’s container(s) and carton(s) to the RLD’s container(s) and carton(s) for each strength (or total drug content and concentration for injections) and for each container closure system.  All differences should be highlighted and annotated.

1.14.1.3 Contains the prescribing and patient information in text-based PDF: Microsoft Word, and structured product labeling files.

1.14.1.4 Contains the Pharmacy Bulk Package Sterility Assurance table, if applicable

1.14.1.5 Contains the labeling history. Applicants are encouraged to review and use the Labeling Question-Based Review (QbR) model when developing labels and labeling.

1.14.3: Contains the RLD labeling and a comparison of that labeling to the draft labeling for the generic product.

1.14.3.1: Contains a side-by-side labeling comparison

In addition, applicants should do the following:

(1)  State that a sufficient number of Medication Guides will be included in each package size (i.e., an amount to ensure that the authorized dispenser is able to provide a Medication Guide to each patient receiving a prescription for the drug product)68

(2)  Confirm that the Medication Guides will be distributed in accordance with 21 CFR 208.24.

1.14.3.3 :Contains the RLD labeling, the Medication Guide, one RLD container label, and one RLD outer carton label for each strength and package size, if applicable.

1.16.1: Contains a risk management plan (non-REMS): for products that require tools to minimize risks while preserving benefits.

1.16.2: Contains, for applicants relying on an RLD with a risk evaluation and mitigation strategy (REMS), a REMS for the generic drug product and any REMS supporting documents.

B. Module 2 – CTD Summaries:

1.0: Quality Overall Summary:

2.3 Contains the Quality Overall Summary (QOS), which provides an overview of the chemistry, manufacturing, and controls (CMC) section of the application.
The QOS summarizes information from both section

Section 2.1.S about the drug substance (i.e., the active pharmaceutical ingredient (API)) and

section 2.1.P about the drug product – applicants should provide separate information on each drug substance contained in the product.

Failure to submit the QOS in text-based PDF and Microsoft Word files will result in a deficiency during the filing review conducted by FDA upon submission of the ANDA. FDA recommends against submitting a scanned PDF copy of the QOS.

2.0 Clinical Summary:

2.7: Contains summary data critical to the determination of BE – FDA has developed model summary tables to assist applicants in summarizing the BE data.The tables provide a format for applicants to summarize various aspects of the BE submission such as the design and outcome of in vivo and in vitro BE studies as well as the results of in vitro dissolution testing.

2.7.1: Contains a summary of biopharmaceutic studies and associated analytical methods, as well as summary tables in a standardized format for data to be submitted, including, but not necessarily limited to: BE summary tables for in vitro feeding tube testing, clinical endpoint summary tables, topical dermatologic corticosteroid in vivo BE study summary tables, in vitro binding BE study summary tables, and BE summary tables for aqueous nasal spray solutions.

Section 2.2 also contains dissolution data testing for the whole tablet and the half tablet (if applicable), comparing the test product to the RLD.

C. Module 3 – Quality:

Module 3 contains all of the CMC information necessary to support the application,including the information supporting and verifying what was summarized in section 2.1.

The specific placement of product quality microbiology information in Module 3 is listed in CDER’s Manual of Policies and Procedures (MAPP) 5040.1 Product Quality Microbiology Information in the Common Technical Document — Quality (CTD-Q).

It is recommended that applicants review the following three guidances for industry to assist in the preparation of Module 3:

(1) ANDAs: Impurities in Drug Products.

(2) ANDAs: Impurities in Drug Substances, and

(3) ANDAs: Stability Testing of Drug Substances and Products.

1.0: Drug Substance:

3.2.S: contains the CMC information specific to the drug substance(s).

For a drug product containing more than one drug substance, the information requested for part “S” should be provided in its entirety for each drug substance as a separate Module 3.2.S.

3.2.S.1: Contains general information about the drug substance, including:

(1) the nomenclature

(2) the structure, and

(3) general properties. Section 3.2.S.1 should not include any references to the DMF.

3.2.S.2 Contains information related to the manufacture of the drug substance. This section should include all intermediate and final drug substance manufacturing facilities listed on the Form 356h as well as all research and development manufacturing and testing sites that generated data to support the application in accordance with 21 CFR 314.50(d)(1)(ii)(b).

All testing labs that perform functions integral to the control strategy— including, but not limited to,a characterization and comparison of molecules and comparability testing — should be listed.

3.2.S.2.1 Contains information about each drug substance manufacturer, including the:
(1) Name and full address of the facility(ies) of each manufacturer, including the contractors, and each proposed production site or facility involved in the manufacturing and testing
(2) Contact information for an agent at the facility (including phone and fax numbers and email addresses)
(3) U.S. agent’s name, if applicable
(4) Function or responsibility of the manufacturer
(5) Type II DMF number for the API or any critical or final intermediates, if applicable
(6) Central File Number, Facility Establishment Identifier, and Data Universal Numbering System numbers, if known

Subsections 3.2.S.2.2 through 3.2.S.2.6 may refer to the DMF. If there is no DMF referenced in the application, detailed information should be provided in these subsections.

3.2.S.2.2 Contains a complete description of the manufacturing process and process controls, including the manufacturing and sterilization processes for the sterile substance(s) used in the sterile drug product.
3.2.S.2.3 Contains the control of materials used in the manufacture of the drug substance.
3.2.S.2.4 Contains controls of critical steps and intermediates.
3.2.S.2.5 Contains process validation and/or evaluation, including the manufacturing and sterilization processes for the sterile drug substance(s) used in the sterile drug product.

3.2.S.2.6 Contains the manufacturing process development.

3.2.S.3 Contains characterization information for the API.

3.2.S.3.1 Contains an elucidation of the API structure and other characteristics.
3.2.S.3.2 Contains all potential impurities.FDA recommends that applicants complete the Summary Tables for the Listing and Characterization of Impurities and Justification of Limits in Drug Substance and Drug Products.

3.2.S.4 Contains information about the control of the drug substance, including the validation procedures and the results of the microbiological analytical tests, as applicable.
3.2.S.4.1 Contains the drug substance specification. The specification includes the tests, acceptance criteria, and references to methods in tabular form, including any microbiological attributes for the drug substance (e.g., sterility for a sterile product or microbial limits for a non-sterile product), as appropriate.
3.2.S.4.2 Contains the analytical procedures (compendial and/or in-house), including, if appropriate, the analytical procedures used to perform microbiological tests of the drug substance.
3.2.S.4.3 Contains a validation of the analytical procedures, including:
(1) The full validation reports for the in-house methods and their equivalence to USP procedures, if available for the drug substance
(2) A verification of USP General Chapter <1226> or DMF procedures, if referenced
(3) Legible spectra and chromatograms for reference standards and test samples
(4) The Sample Statement(s) of Availability and identification of the drug substance.

3.2.S.4.4 Contains the batch analysis, including the COAs from both the drug substance manufacturer(s) and the drug product manufacturer(s) for the batches used to produce the exhibit batch(es) of the drug product. Applicants should clearly identify the drug substance lot(s) used in any BE studies.

3.2.S.4.5 Contains a justification of the specification, including, but not limited to, references to compendia (e.g., the USP, the European Pharmacopeia, and the Japanese Pharmacopeia), the ICH, and/or the RLD analysis. FDA recommends that applicants complete the Summary Tables for the Listing and Characterization of Impurities and Justification of Limits in Drug Substance and Drug Products.

3.2.S.5 Contains information about the reference standards or materials. Appropriate certification, characterization, and qualification information should be provided for the reference standards of the drug substance and impurities.
3.2.S.6 Contains information about the container closure systems. If the application contains a sterile substance for use in a sterile drug product, this section will also contain both a description of the container closure system used for the drug substance and a validation of the container closure integrity. The applicant may refer to the DMF.

3.2.S.7 Contains stability information.
3.2.S.7.1 Contains stability summary and conclusions. The applicant may refer to the DMF for complete stability data. However, the retest date or expiration date of the API should, at a minimum, be provided at both the drug product manufacturing site and the drug substance manufacturing site.102
3.2.S.7.2 Contains the post-approval stability protocol. The applicant may refer to the DMF.
3.2.S.7.3 Contains stability data. The applicant may refer to the DMF.

2. Drug Product:

3.2.P contains detailed information known about the drug product. During the development of the application, applicants should review as per

• ICH guidance for industry Q8 (R2) Pharmaceutical Development (Rev. 2),
• Guidance for industry Submission Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products,
• Product-specific CMC guidances for industry (e.g., metered dose inhalers and nasal sprays), as applicable.

3.2.P.1 Contains the description and composition of the drug product. For each drug strength,applicants should provide:
(1) The quantitative composition and function of each component in their generic drug product, include any solvents and processing aids that are used during the manufacture of the drug product
(2) Information related to the physical description of the product (tablet size, scoring) and comparison to the RLD.
(3) The quality standards (e.g., the USP or the National Formulary) of components; the composition of colors, flavors and imprinting ink, if applicable
(4) The amounts of their inactive ingredients that are appropriate per the Inactive Ingredient Database (per dose or unit dose) and a justification, preferably in a tabular format, for those amounts
(5) A conversion from percentage to milligram (mg)/dose values for all components, as applicable
(6) A conversion from percentage to mg/milliliter (mL) and/or mg/vial for injectable and injection products, indicating the unit of percentage (weight/weight or weight/volume) for liquid dosage forms
(7) A conversion from percentage to mg/mL for oral solution products
(8) A conversion from percentage to mg/dose for dry powder to oral solution or oral suspension
(9) An identification and justification of any formulation overages or overfills that appear in the final product.

(10) A daily elemental iron calculation or statement of adherence to 21 CFR 73.1200
(11) If the proposed product is packaged with a specific diluent, a demonstration that the diluent is qualitatively and quantitatively the same as the diluent packaged with the RLD
(12) For products that contain aspartame, a calculation of the amount of phenylalanine (mg per dosage unit).
(13) For nonprescription products that contain potassium, calcium, magnesium, and/or sodium, a calculation for the potassium, calcium, magnesium, and/or sodium content of a single maximum recommended dose.
(14) For products that contain alcohol, a calculation of the absolute alcohol in terms of percent volume (volume/volume).
(15) For antibiotics that contain sodium, a calculation for the sodium content (per tablet/capsule or per unit dose).

For sterile products, applicants should include a brief description of the primary container closure system, as well as any secondary packaging, for each configuration in section 3.2.P.1, and detailed information on the primary container closure system and secondary packaging should be included in section 3.2.P.7.

For generic drug products containing inactive ingredient changes permitted in accordance with § 314.94(a)(9)(iii)-(v), applicants must also identify and characterize the changes and provide information that demonstrates that these changes do not affect the safety or efficacy of the drug product.

3.2.P.2 Contains the pharmaceutical development report (for the product and the manufacturing process) and the microbial attributes (container closure integrity testing report for sterile product and the antimicrobial effectiveness testing for multi-dose sterile products, and if the sterile drug product is packaged, single-use/dose/multi-dose and/or pharmacy bulk.)

If the applicant has moved toward a Quality by Design approach,applicants may demonstrate this approach in section 3.2.P.2. Applicants are encouraged to review FDA’s Quality by Design for ANDAs:An Example for Modified Release Dosage Forms and An Example for Immediate-Release Dosage Forms.

For sterile products that are reconstituted (or further diluted) and stored prior to administration, the applicant should provide microbiological studies to support the worst-case post-constitution or post-dilution storage times, diluents, and conditions that are stated in the product package insert labeling. The study should be a risk assessment that shows that adventitious microbial contamination does not grow (generally accepted as no more than 0.5 log10 growth) under the specified storage conditions.

The applicant should include:
(1) A table comparing the equipment, process parameters, and in-process controls for all exhibit and commercial batches
(2) The procedures for reprocessing/reworking, if applicable
(3) The batch reconciliation data
The applicant should clearly indicate which manufacturing process:
(1) Was used in the preparation of the BE batch(es)
(2) Is proposed for commercial production

3.2.P.3 Contains information about the manufacture of the generic drug product.
3.2.P.3.1 Contains information about the drug product manufacturer(s), including the:
(1) Name and full address of the facilities of each manufacturer, including the contractors, and each proposed production site or facility involved in the manufacturing and testing
(2) Contact information for an agent at the facility (including phone and fax numbers and email addresses)
(3) U.S. agent’s name, if applicable.

(4) Function or responsibility of the manufacturer.
(5) Current good manufacturing practice certifications for both the applicant and the drug product manufacturer (if they are different entities)
(6) Central File Number, Facility Establishment Identifier, and Data Universal Numbering System numbers, if known

This section should also contain all facilities listed on Form 356h as well as all research and development manufacturing and testing sites that generated data to support the application in accordance with § 314.50(d)(1)(ii)(b).

For testing sites, applicants should include any testing sites that (1) generate stability testing/release data and BE data to support the application and (2) are used for commercial testing.

3.2.P.3.2 Contains the batch formula for the generic drug product, including:

(1) the amounts of the components including processing aids, if any, that come into contact with the drug substance or product during any stage of the manufacture (quantitative comparison, including the total numbers of dosage units, between the pilot scale and commercial scale in a tabular form recommended) and

(2) an indication and justification of any overage(s) or weight adjustment(s) used. The applicant should clearly identify the formulation used in any BE studies, including the study identification number.

3.2.P.3.3 Contains a complete description of the manufacturing process and controls, including:
(1) A description of the manufacturing process and facility. (For a sterile drug product,description of the manufacturing and sterilization processes (e.g., the sterilization and/or dehydrogenation of the primary packaging, the product contact manufacturing equipment, and the bulk drug product) and the associated manufacturing in-process controls.)
(2) A manufacturing process flowchart showing the process flow, applicable process parameters, and in-process controls. If process analytical technology methods are used, applicants should indicate those methods in the manufacturing flowchart.
(3) The master production batch record(s) for the largest intended production runs (i.e., commercial batch records) that is/are no more than 10 times the exhibit batch(es).

(4) The master packaging record(s) for the intended marketing container(s). (If commercial scale batch records are not written in English, applicants must submit an English translation for them)
(5) An indication whether the drug product is a sterile product.
(6) A reprocessing statement in accordance with 21 CFR 211.115.

3.2.P.3.4 Contains the controls of the critical steps and intermediates, including:

(1) the acceptance criteria and test results for the exhibit batches.

(2) a comparison of the controls and equipment between the exhibit and commercial batch manufacture and

(3) information about the holding periods.

3.2.P.3.5 Contains information to demonstrate that the manufacturing process produces a dosage form that meets the product specifications, including an evaluation of the data generated for the critical material attributes and the critical process parameters that were found to meet the established scale-up guideline and/or acceptance criteria.

(For a sterile product, this section should contain a validation of the sterilization processes (such as validation (bacterial retention studies) of the sterilizing grade filters) and/or the depyrogenation processes (such as the processes for the sterilization and/or depyrogenation of the primary packaging, the product contact manufacturing equipment, and the bulk drug product) and the manufacturing processes that impact the sterility assurance of the drug product.)

3.2.P.4 Contains information on the control of the excipients, including the identity of the source of inactive ingredients (including the supplier and the supplier’s address) and the grades (e.g., compendial or non-compendial).
3.2.P.4.1 Contains the testing specifications, including the retest schedule and the excipient manufacturer’s or supplier’s COA(s).
3.2.P.4.2 Contains the analytical procedures for the non-compendial methods used for testing the excipients. For compendial excipients, applicants should reference the USP or the National Formulary but need not mention the analytical procedure.
3.2.P.4.3 Contains the validation data of the non-compendial or in-house analytical procedures.
3.2.P.4.4 Contains a justification of the specifications and includes:

(1) the applicant’s or the drug product manufacturer’s COA(s),

(2) the residual solvents statement(s) from the manufacturer(s), and

(3) the bovine spongiform encephalopathy, transmissible spongiform encephalopathy, and melamine certifications, as applicable.

3.2.P.5 Contains information on the control of the drug product.
3.2.P.5.1 Contains the specifications for the drug product, including the microbiological specifications (e.g., the microbial limits, sterility, and bacterial endotoxins), as applicable. These specifications should include the tests, acceptance criteria, and references to methods in a tabular format.
3.2.P.5.2 Contains a description of the analytical procedures (compendial and/or in-house) used for testing the drug product, including any microbiological tests, as applicable. For sterile drug products, this section should contain the methods for the product release tests (e.g., sterility tests or bacterial endotoxins tests (if applicable)).
3.2.P.5.3 Contains the validation of the analytical procedure, including:
(1) The full validation reports for the in-house methods and their equivalence to USP procedures, if available for the drug product
(2) A verification of USP General Chapter <1226> procedures, if referenced
(3) The legible spectra and chromatograms for reference standards and test samples
(4) The Sample Statement(s) of Availability and identification of the finished dosage form of the drug products.
For sterile drug products, this section should contain the validation procedures and results for the microbiological analytical tests (e.g., sterility tests or bacterial endotoxins tests (if applicable)).
3.2.P.5.4 Contains the batch analysis, including the executed COAs for all presentations and/or strengths of the finished dosage form. The applicant should clearly identify the drug product batch(es) used in any BE studies, including the study identification number.

3.2.P.5.5 Contains the characterization of impurities.
FDA recommends that applicants control all degradation products and process solvents if they are used during the manufacture of the finished dosage form. FDA also recommends that applicants complete the Summary Tables for the Listing and Characterization of Impurities and Justification of Limits in Drug Substance and Drug Products.

3.2.P.5.6 Contains the justification of the specifications, including but not limited to references to compendia (e.g., the USP or the Japanese Pharmacopeia), the ICH, and/or the RLD analysis. FDA recommends that applicants complete the Summary Tables for the Listing and Characterization of Impurities and Justification of Limits in Drug Substance and Drug Products.

3.2.P.6 Contains information about the reference standards or reference materials used for testing the drug product.
3.2.P.7 Contains information on the container closure system, including:
(1) A summary of the primary and secondary container closure system (including data for any resin used and technical diagrams/drawings of the container closure components, a statement whether the closure for each proposed packaging configuration is child resistant or non-child resistant, and a description of markings on the cap/ferrule overseals)
(2) The component specifications, including dimensional (drawing) and test data for each packaging component received by the applicant.
(3) The packaging configuration(s) and size(s)
(4) The container closure testing data in accordance with USP General Chapters <660>, <661>, and <671> (for solid oral, dosage forms, test for water permeation and light transmission; for liquids, test for leachable, extractables, and light transmission)
(5) The source of the container closure system supply and the supplier’s address.

For controlled substances, the applicant should provide a description of the tamper-evident properties of the container closure system as described in 21 CFR 1302.06.

For OTC products, the applicant should confirm that the container closure system meets the requirements of 21 CFR 211.132.

3.2.P.8 Contains the stability data:
3.2.P.8.1 Contains the stability summary and conclusions for the finished dosage form, including:
(1) The preapproval stability protocol
(2) The proposed expiration dating period for marketing packaging
(3) The proposed expiration dating period for bulk packaging, if applicable
(4) A storage temperature statement
3.2.P.8.2 Contains the post-approval stability protocol. If the applicant and drug product manufacturer are different entities, stability protocols should be provided by the applicant. This section should also contain analytical procedures and testing schedules for maintenance of the microbial product quality (e.g., the container closure integrity/sterility, bacterial endotoxins, and microbial limits), as appropriate.

3.2.P.8.3 Contains stability data, including:
(1) Accelerated and long-term data
(2) Intermediate stability data, if applicable.
(3) The batch numbers on the stability records that are the same as the test batch
(4) The date the stability studies were initiated.

5) The date that each stability sample was removed from the stability chamber for each testing time point.
(6) Data on all presentations of the container-closure system.

For primary batches of liquids, solutions, semi-solids, and suspensions, the product should be placed into worst-case and non-worst-case scenarios.

For post-approval stability studies, the applicant should pick the worst-case orientation for the study.

The following information and data can also be included in this section:
(1) One-time special stability studies conducted to confirm the quality of the constituted drug products (for example, parenterals and/or powders reconstituted with diluents and/or drug admixtures) per the labeling’s instructions
(2) One-time thermal cycling studies (freeze-thaw/heat-cool), as applicable
(3) One-time in-use stability studies for oral liquids and other dosage forms (e.g., a solution to be used within a certain period of opening the container per labeling instructions, compatibility with a dropper when provided as part of the container closure system), as applicable.

• Appendices:

3.2.A.2 Contains an appendix for the Adventitious Agents Safety Evaluation for sterile products.

A description of the processes used to control for potential contamination with adventitious agents (e.g., transmissible spongiform encephalopathy and viruses).

These processes may include assays to detect adventitious agents and actions taken to avoid them, as well as procedures to eliminate or inactivate them.

4. Regional Information

3.2.R Contains regional information for the drug substance and the drug product.

3.2.R.1.S Contains the executed batch records for the drug substance.

Applicants may refer to the DMF(s) for this information. If no DMF is referenced in the application, applicants should provide the executed and blank master batch records. The executed records should clearly identify the drug substance lot(s) used in any BE studies.
3.2.R.2.S Contains any comparability protocols proposed for the drug substance.

3.2.R.3.S Contains the methods validation package for non-USP drugs. This information may also be placed in section 3.2.S.4.3.

3.2.R.1.P.1 Contains the executed batch records that include:

(1) a copy of the executed batch record(s) with equipment specified and the packaging records (the packaging and labeling procedures);

(2) the batch reconciliation and label reconciliation for the theoretical yield, the actual yield, and the packaged yield, all in a tabular format; and

(3) the bulk package reconciliation for any bulk packaging that is considered a commercial container. The bulk package reconciliation is recommended if the bulk packaging is used to achieve the minimum package requirement. As part of the bulk package reconciliation recommendation, the applicant should submit bulk package stability data in section 3.2.P.8.3.

3.2.R.1.P.2 Contains information on components including but not limited to the applicants’ and suppliers’ COAs for the drug substance lots, inactive ingredients lots, and packaging components lots that are contained in the exhibit batches of the drug product, as well as the supplier’s address.

3.2.R.2.P Contains the comparability protocols for the drug product, if applicable.
3.2.R.3.P Contains the methods validation package. This package may also be contained in section 3.2.P.5.3.

5. Literature References:

3.3 Contains copies of any documents referred to in the application. The documents may include published articles, official meeting minutes, or other regulatory guidance or advice provided to the applicant. FDA recommends that these documents be provided in text-based PDF files.

D. Module 4 – Nonclinical Study Reports

ANDAs generally do not contain data that are typically included in Module 4. If nonclinical study reports or safety assessments are submitted in support of a proposed specification (i.e., toxicology studies to qualify

(1) impurities per the ICH guidances for industry Q3A140 and Q3B(R2),
(2) residual solvents,

(3) leachables, or

(4) excipients)

These reports or assessments should be included in Module 4.

E. Module 5 – Clinical Study Reports:

Module 5 contains all of the clinical study report data needed to support the application and to demonstrate that the generic drug product is bioequivalent to the RLD.

To facilitate the submission of complete data, FDA develops product-specific guidances,summary data tables (as referenced in section III.B.2 of this guidance),and multiple guidances on biopharmaceutics.Applicants should use an eCTD Study Tagging File for each study submitted

1. Complete Study Data

5.2 Contains the tabular listing of all clinical studies (e.g., pivotal, pilot, and failed studies) conducted.
5.3 Contains the clinical study reports and related information.
5.3.1 Contains the complete study data for the biopharmaceutic studies147 and the lot numbers and strength of the products used in the BE studies. Applicants should document the study type.
5.3.1.2 Contains reports of the comparative BA and BE studies (e.g., fasting or fed studies). This section should also contain information of in vivo BE studies including, but not limited to:
• A synopsis of the study
• A study report
• The study’s protocol and amendments.

All case report forms
• A list of the independent ethics committees or institutional review boards and consent and/or assent forms
• The institutional review boards’ approval letters for the protocol, amendments, and consent/assent forms
• A list and description of the investigators
• The number of subjects enrolled in each study site
• The signatures of the principal or coordinating investigator(s) or the sponsor’s responsible medical officer
• A listing of the subjects receiving the test drug(s) from a specified batch
• The randomizations scheme
• The audit certificates and reports
• A statistical analysis plan and amendments
• Documentation of interlaboratory standardization methods of quality assurance procedures, if used.
• The publications based on the study.
• The important publications referenced in the report.
• A list of the discontinued patients, including the specific reason for each discontinuation.
• A list of subjects included in the per protocol (PP), modified/intent-to treat ((M)ITT), and safety populations153
• A list of subjects excluded from the PP, (M)ITT, and safety populations.

• A reason for excluding the PP, (M)ITT, and safety populations for each subject
• Any protocol deviations, including the specific reason for each deviation
• Demographic data
• Drug concentration data
• Treatment compliance rate data
• The individual subject’s response scores/data per visit
• The adverse event listings
• The concomitant medication listings
• A listing of the individual laboratory measurements by subject
• The site (identifier)
• The individual subject data listings
• The in vivo and/or in vitro BE study datasets
• A summary dataset containing a separate line listing for each subject.
• An analysis dataset containing a separate line listing for each visit per subject.
• The individual analysis datasets (e.g., adverse events or concomitant medications).
• The analysis programs
• The annotated case report form
• The annotated electrocardiogram waveform datasets
• The image files
• The narrative safety reports for serious adverse events
• Source data

• In vitro BE study information.

5.3.1.3 Contains in vitro-in vivo correlation study reports.
5.3.1.4 Contains reports of bioanalytical and analytical methods.

If a method is used in multiple studies, the method and its validation should be included only once in section 5.3.1.4 and then referenced again in the individual study reports. Additionally, 100% raw numerical data and 20% chromatograms should be provided for each study.
Case report forms should be placed under the study to which they pertain and appropriately tagged.
The data provided in all of these sections should support the summary tables submitted in section 2.7.

All comparative dissolution data from the in vitro-in vivo correlation study reports should be placed in section 2.7 with the dissolution summary tables.

2. Literature References

5.4 Contains copies of any documents referred to in the application.

The documents may include published articles, official meeting minutes, or other regulatory guidance or advice provided to the applicant. Applicants should submit one copy of all important references cited in the QOS or the individual technical reports contained in section 5.3.162 FDA recommends that these documents be provided in text-based PDF files.