The ANDA Workshop Filing Process_May 2007

The ANDA WorkshopThe ANDA WorkshopFiling ProcessFiling Process

&&The ANDA ChecklistThe ANDA Checklist

for CTD and eCTD Formatfor CTD and eCTD Format

LCDR Stanley SheppersonFDA, CDER, Office of Generic DrugsSenior Regulatory Management Officer

May 17, 2007

Goals for DiscussionGoals for Discussion

To inform Industry of the AgencyTo inform Industry of the Agency’’s ANDA s ANDA filing processfiling processTo discuss details of the ANDATo discuss details of the ANDAChecklist for CTD and eCTD formatChecklist for CTD and eCTD formatDiscuss frequently asked questions Discuss frequently asked questions regarding CTD and eCTD submissionsregarding CTD and eCTD submissionsDiscuss progress with recently submitted Discuss progress with recently submitted electronic ANDAselectronic ANDAs

International Conference onInternational Conference onHarmonization (ICH)Harmonization (ICH)

ICH brought together the regulatory ICH brought together the regulatory authorities of Europe, Japan and the authorities of Europe, Japan and the United States to discuss scientific and United States to discuss scientific and technical aspects of product registration technical aspects of product registration

ICH developed guidelines for the Common ICH developed guidelines for the Common Technical Document for Registration of Technical Document for Registration of Pharmaceuticals for Human Use (CTD)Pharmaceuticals for Human Use (CTD)

OGD InitiativeOGD InitiativeTo conform to the ICHTo conform to the ICH--CTD formatCTD formatEncouraging all ANDAs be submitted in the CTD Encouraging all ANDAs be submitted in the CTD format and format and preferably electronic CTDpreferably electronic CTD to to support Questionsupport Question--based Reviewbased ReviewThe 1999 Guidance for Industry; Organization of The 1999 Guidance for Industry; Organization of an ANDA has been removed from the an ANDA has been removed from the Regulatory Guidance pageRegulatory Guidance pageRSB is no longer giving advice to firms on RSB is no longer giving advice to firms on submissions in the 1999 Guidance format (also submissions in the 1999 Guidance format (also referred to as the traditional format)referred to as the traditional format)

CTD GuidancesCTD Guidances

Many guidances currently exist Many guidances currently exist referencing the CTD formatreferencing the CTD formatRefer to the CDER Guidance Document Refer to the CDER Guidance Document web pageweb page

CTD and eCTD CTD and eCTD Informational LinksInformational Links

Organization of the CTDOrganization of the CTDhttp://www.fda.gov/cder/guidance/4539O.PDFhttp://www.fda.gov/cder/guidance/4539O.PDF

eCTD SubmissionseCTD Submissionshttp://www.fda.gov/cder/guidance/7087rev.pdfhttp://www.fda.gov/cder/guidance/7087rev.pdf

Drug SubstanceDrug Substancehttp://www.fda.gov/cder/guidance/3969DFT.pdfhttp://www.fda.gov/cder/guidance/3969DFT.pdf

Drug Product Drug Product http://www.fda.gov/cder/guidance/1215dft.pdfhttp://www.fda.gov/cder/guidance/1215dft.pdf

Pharmaceutical DevelopmentPharmaceutical Developmenthttp://www.fda.gov/cder/guidance/6746fnl.pdfhttp://www.fda.gov/cder/guidance/6746fnl.pdf

CTDCTD--EfficacyEfficacyhttp://www.fda.gov/cder/guidance/4539E.pdfhttp://www.fda.gov/cder/guidance/4539E.pdf

CTDCTD--QualityQualityhttp://www.fda.gov/cder/guidance/4539Q.PDFhttp://www.fda.gov/cder/guidance/4539Q.PDF

Other Helpful LinksOther Helpful LinksElectronic Common Technical Document web Electronic Common Technical Document web page: page: http://www.fda.gov/cder/regulatory/ersr/ectd.htmhttp://www.fda.gov/cder/regulatory/ersr/ectd.htmModels and more information on Quality Overall Models and more information on Quality Overall Summary (QOS) are located on the OGD web Summary (QOS) are located on the OGD web page: page: http://www.fda.gov/cder/ogd/http://www.fda.gov/cder/ogd/Comprehensive Table of Contents Comprehensive Table of Contents http://www.fda.gov/cder/regulatory/ersr/5640CTOChttp://www.fda.gov/cder/regulatory/ersr/5640CTOC--v1.2.pdfv1.2.pdfQbRQbR--Quality Overall Summary Outline in MS Word Quality Overall Summary Outline in MS Word Format, located on the OGD webpage: Format, located on the OGD webpage: http://www.fda.gov/cder/ogd/http://www.fda.gov/cder/ogd/

CTD and eCTD FormatCTD and eCTD Format

Module 1: AdministrativeModule 1: Administrative–– Required for ANDAsRequired for ANDAs–– Specific for FDASpecific for FDA–– Regulatory informationRegulatory information


Module 2: SummariesModule 2: Summaries–– Required for ANDAsRequired for ANDAs–– Chemistry and Bioequivalence InformationChemistry and Bioequivalence Information

2.3 Quality Overall Summary (QOS)2.3 Quality Overall Summary (QOS)2.7 Clinical Summary2.7 Clinical Summary--Bioequivalence StudiesBioequivalence Studies


Module 3: Quality (Chemistry)Module 3: Quality (Chemistry)–– Required for ANDAsRequired for ANDAs–– Drug SubstanceDrug Substance–– Drug ProductDrug Product–– Product DevelopmentProduct Development–– Regional InformationRegional Information


Module 4: Nonclinical Study ReportsModule 4: Nonclinical Study Reports–– Not Required for ANDAsNot Required for ANDAs


Module 5: Clinical Study ReportsModule 5: Clinical Study Reports–– Required for ANDAsRequired for ANDAs–– Bioavailability and Bioequivalence StudiesBioavailability and Bioequivalence Studies

FormulationFormulationBA/BE study reportsBA/BE study reportsDissolutionDissolution

Non Electronic CTD Submissions Non Electronic CTD Submissions Jacket RequirementJacket Requirement

Archival Copy (Blue)Archival Copy (Blue)–– All jacketsAll jacketsField Copy (Burgundy)Field Copy (Burgundy)–– Module 3 only unless otherwise directed by Module 3 only unless otherwise directed by

your local FDA district officeyour local FDA district officeReview CopyReview Copy–– Chemistry (Red)Chemistry (Red)--Modules 1, 2 and 3Modules 1, 2 and 3–– Bioequivalence (Orange)Bioequivalence (Orange)--Modules 1, 2 and 5Modules 1, 2 and 5

Filing an ANDAFiling an ANDA

ANDAANDAFiling Filing ProcessProcess

Bioequivalence Review

Labeling Review

Chemistry & Micro Review

Request for Plant Inspection

ANDA

Acceptable &

Complete

Application Review

N

Y

Refuse to Receive Letter

The ANDA Checklist for CTD or The ANDA Checklist for CTD or eCTD Format for Completeness eCTD Format for Completeness

and Acceptability of an and Acceptability of an Application for FilingApplication for Filing

ANDA ChecklistANDA ChecklistThis checklist was created to follow the Comprehensive This checklist was created to follow the Comprehensive Table of Contents Headings and Hierarchy for the CTD Table of Contents Headings and Hierarchy for the CTD formatformatInclusive of the CFR requirements for filing an ANDAInclusive of the CFR requirements for filing an ANDAConsultation with individual divisions of OGD as well as Consultation with individual divisions of OGD as well as references to the multiple guidances for industry were references to the multiple guidances for industry were used in the developmentused in the developmentSections not listed on check list are not required for ANDA filing, but may be included if deemed necessary for reviewPlease follow the checklist and organize application Please follow the checklist and organize application accordingly.accordingly.

Module 1Module 1--AdministrativeAdministrative

1.1.2 Signed and Completed Application 1.1.2 Signed and Completed Application Form (356h)Form (356h)

314.94(a)(2)314.94(a)(2)Original signature requiredOriginal signature requiredFirms should defer to the Firms should defer to the ““Approved Drug Approved Drug Products with Therapeutic Equivalence Products with Therapeutic Equivalence Evaluations,Evaluations,”” the Electronic Orange Bookthe Electronic Orange Book when when identifying the Holder of the Approved identifying the Holder of the Approved ApplicationApplicationFirms should utilize USP nomenclature when the Firms should utilize USP nomenclature when the finished drug product is USPfinished drug product is USP

1.21.2 Cover LetterCover Letter

Only required for paper submissionOnly required for paper submissionAddress any issues or previous communication Address any issues or previous communication with the Agencywith the AgencyRefer to Control Correspondence numbers if Refer to Control Correspondence numbers if relevantrelevant

Table of ContentsTable of Contents

Only required for paper submissionOnly required for paper submissionSee Comprehensive Table of Contents See Comprehensive Table of Contents Headings and HierarchyHeadings and Hierarchy

http://www.fda.gov/cder/regulatory/ersr/5640CTOChttp://www.fda.gov/cder/regulatory/ersr/5640CTOC--v1.2.pdfv1.2.pdf

1.3.2 Field Copy Certification1.3.2 Field Copy Certification

Only required for paper submissionOnly required for paper submissionRequires original signatureRequires original signature

1.3.3 Debarment Certification1.3.3 Debarment Certification--GDEAGDEA

Requires original signatureRequires original signatureFirm must declare that they have not and will not Firm must declare that they have not and will not use in any capacity any individual that has been use in any capacity any individual that has been debarred pursuant to Section 306(k)(1) and (2) debarred pursuant to Section 306(k)(1) and (2) of the GDEAof the GDEAFirm must declare that no one responsible for Firm must declare that no one responsible for the development or submission of the ANDA has the development or submission of the ANDA has been convicted of a crime as defined by Section been convicted of a crime as defined by Section 306(k)(1) and (2) with in the last 5 years306(k)(1) and (2) with in the last 5 years

1.3.4 Financial Certifications1.3.4 Financial Certifications

Bioavailability/Bioequivalence Financial Bioavailability/Bioequivalence Financial Certification (Form 3454)Certification (Form 3454)

OROR

Bioavailability/Bioequivalence Disclosure Bioavailability/Bioequivalence Disclosure Statement (Form 3455)Statement (Form 3455)

1.3.5 Patent and Exclusivity1.3.5 Patent and Exclusivity

1.3.5.1 Patent Information1.3.5.1 Patent InformationPatents listed for the RLD in Patents listed for the RLD in ““Approved Approved Drug Products with Therapeutic Drug Products with Therapeutic Equivalence Evaluations,Equivalence Evaluations,”” the Electronic the Electronic Orange BookOrange Book

1.3.5 Patent and Exclusivity1.3.5 Patent and Exclusivity (Cont.)(Cont.)

1.3.5.2 Patent Certification1.3.5.2 Patent Certification

Patent number (s) Patent number (s)

Certification Certification Paragraph based on the FD&C ACT Paragraph based on the FD&C ACT PI PII PIII PIV MOU No Relevant PatentsPI PII PIII PIV MOU No Relevant Patents

Expiration of Patent (s) Expiration of Patent (s)

1.3.5 Patent and Exclusivity1.3.5 Patent and Exclusivity (Cont.)(Cont.)

1.3.5.2 Patent Certification1.3.5.2 Patent Certification

Exclusivity StatementExclusivity Statement (Included in this section)(Included in this section)–– ExclusivityExclusivity statements must be included even if the product is not statements must be included even if the product is not

entitled to any marketing exclusivityentitled to any marketing exclusivity–– NCENCE exclusivity is the only exclusivity that blocks submission of ANexclusivity is the only exclusivity that blocks submission of ANDAs. DAs.

NCE may block submission of an ANDA for a period of 5 years fromNCE may block submission of an ANDA for a period of 5 years from the the date of approval of the first approved NDA. However, if an ANDA date of approval of the first approved NDA. However, if an ANDA contains a PIV certification to a listed patent covering the NDAcontains a PIV certification to a listed patent covering the NDA for which for which NCE applies then an application may be submitted one year prior NCE applies then an application may be submitted one year prior to to expiration of NCEexpiration of NCE

–– Pediatric Exclusivity may attach to NCE and further extend thesePediatric Exclusivity may attach to NCE and further extend thesetimeframes to 5 & timeframes to 5 & ½½ years and 4 & years and 4 & ½½ years respectivelyyears respectively

1.4.1 Letters of Authorization1.4.1 Letters of Authorization

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

US Agent Letters of AuthorizationUS Agent Letters of Authorization–– Letter of Authorization (U.S. Agent) must be Letter of Authorization (U.S. Agent) must be

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

1.12.11 Basis for Submission1.12.11 Basis for Submission

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

1.12.11 Basis for Submission (cont.)1.12.11 Basis for Submission (cont.)

314.122 ANDAs that rely upon a listed 314.122 ANDAs that rely upon a listed drug that is no longer marketed. An drug that is no longer marketed. An application may be filed pending the application may be filed pending the outcome of the Agencyoutcome of the Agency’’s determination s determination that a drug product was removed from the that a drug product was removed from the market for reasons other than safety or market for reasons other than safety or efficacy. This petition must be submitted efficacy. This petition must be submitted under 10.25(a) and 10.30.under 10.25(a) and 10.30.

1.12.12 Comparison Between Generic 1.12.12 Comparison Between Generic Drug and RLDDrug and RLD--505(j)(2)(A)505(j)(2)(A)

Conditions of use Conditions of use Active ingredients Active ingredients –– Active Ingredients must be the same, this Active Ingredients must be the same, this

means precisely the same salt must be means precisely the same salt must be used as the innovator. Applicants wishing used as the innovator. Applicants wishing to pursue approval of an application to pursue approval of an application utilizing a different salt of the same active utilizing a different salt of the same active moiety must submit their application as a moiety must submit their application as a 505(b)(2) 505(b)(2)

Inactive ingredientsInactive ingredients

1.12.12 Comparison Between Generic 1.12.12 Comparison Between Generic Drug and RLDDrug and RLD--505(j)(2)(A) (Cont.)505(j)(2)(A) (Cont.)

Route of administrationRoute of administration–– Route 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 FormDosage FormStrengthStrength

1.12.14 Environmental Analysis1.12.14 Environmental Analysis

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

1.12.15 Request for Waiver of In1.12.15 Request for Waiver of In--Vivo Vivo Bioavailability StudiesBioavailability 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 Labeling1.14.1 Draft Labeling

4 copies of draft labeling if not 4 copies of draft labeling if not electronic electronic 1 side by side by side labeling comparison of 1 side by side by side labeling comparison of containers and carton with all differences containers and carton with all differences annotated and explainedannotated and explained1 package insert (content of labeling) 1 package insert (content of labeling) submitted electronicallysubmitted electronicallyElectronic submission requirementsElectronic 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)1.14.3 Listed Drug Labeling (RLD)

1 side by side labeling comparison of 1 side by side labeling comparison of package and patient insert with all package and patient insert with all differences annotated and explaineddifferences annotated and explained1 RLD label and 1 RLD container label1 RLD label and 1 RLD container label

Module 2Module 2--SummariesSummaries

ChemistryChemistry&&

BioequivalenceBioequivalence

2.3 Quality Overall Summary2.3 Quality Overall Summary

Quality Overall Summary should include sufficient Quality Overall Summary should include sufficient information from each section in Module 3 to provide the information from each section in Module 3 to provide the reviewer with an overviewreviewer with an overview

Chemistry Division request submission in PDF format Chemistry Division request submission in PDF format and Word Processed (MS Word)and Word Processed (MS Word)

A model Quality Overall Summary for an immediate A model Quality Overall Summary for an immediate release tablet and an extended release capsule can be release tablet and an extended release capsule can be found on the OGD webpage found on the OGD webpage http://www.fda.gov/cder/ogd/http://www.fda.gov/cder/ogd/

2.7 Clinical Summary (Bioequivalence)2.7 Clinical Summary (Bioequivalence)

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

Module 3Module 3--QualityQuality

ChemistryChemistry

3.2.S Drug Substance3.2.S Drug Substance

3.2.S.1 General Information3.2.S.1 General Information(Drug Substance)(Drug Substance)

NomenclatureNomenclatureStructureStructureGeneral PropertiesGeneral Properties

3.2.S.2 Manufacture3.2.S.2 Manufacture(Drug Substance)(Drug Substance)

Name and full address of facilitiesName and full address of facilities–– Helpful to provide summary table of all facilities Helpful to provide summary table of all facilities

(contacts, addresses, phone/fax numbers, etc., CFN#, (contacts, addresses, phone/fax numbers, etc., CFN#, etc.)etc.)

–– Specific functions performedSpecific functions performedFunction or ResponsibilityFunction or ResponsibilityType II DMF number for APIType II DMF number for API–– Note DMF for Active Pharmaceutical Ingredients must Note DMF for Active Pharmaceutical Ingredients must

be stamped received by the Agency prior to be stamped received by the Agency prior to submission of an ANDA that relies upon said DMFsubmission of an ANDA that relies upon said DMF

3.2.S.4 Control of Drug 3.2.S.4 Control of Drug SubstanceSubstance

Testing specificationsTesting specificationsSpectra and chromatogramsSpectra and chromatogramsSample statementSample statement–– Samples of drug substance will be submitted upon Samples of drug substance will be submitted upon

request from FDA in accord with 21 CFR 314.50(e)(i)request from FDA in accord with 21 CFR 314.50(e)(i)

Certificate of Analysis (COA)Certificate of Analysis (COA)–– API supplierAPI supplier–– ApplicantApplicant

3.2.P Drug Product3.2.P Drug Product

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

Unit composition of the proposed productUnit composition of the proposed productInactive ingredients and amounts are Inactive ingredients and amounts are appropriate per IIGappropriate per IIG

Components and Composition of Components and Composition of the Drug Productthe Drug Product

Use of inactive ingredients that have not been previously Use of inactive ingredients that have not been previously approved or that are being used at a higher level than approved or that are being used at a higher level than previously approved is the most prevalent RTR issue.previously approved is the most prevalent RTR issue.

RSB needs a complete breakdown of all components used in RSB needs a complete breakdown of all components used in the proposed formulation. This includes flavors and colors thatthe proposed formulation. This includes flavors and colors thatmay contain proprietary information. may contain proprietary information.

Suggestion: If you know that your firm is proposing to use a Suggestion: If you know that your firm is proposing to use a flavor/color that has not been previously approved ask your flavor/color that has not been previously approved ask your vendor to fax a copy of the formulation to OGD at (301) 443vendor to fax a copy of the formulation to OGD at (301) 443--3847. Have the vendor request that FDA evaluate the 3847. Have the vendor request that FDA evaluate the formulation and itformulation and it’’s use at XXX mg. The request will be s use at XXX mg. The request will be assigned a control number which your firm may cite in its assigned a control number which your firm may cite in its submission as proof that the proposed level is acceptable.submission as proof that the proposed level is acceptable.

Components and Composition of Components and Composition of the Drug Product (Cont.)the Drug Product (Cont.)

OGD will not consider GRAS/GRAE status conclusive evidence that OGD will not consider GRAS/GRAE status conclusive evidence that an excipient may be used in a drug product at a given level. an excipient may be used in a drug product at a given level. Furthermore, use of an excipient in food products will not persuFurthermore, use of an excipient in food products will not persuade ade FDA to allow its use in drug products. FDA to allow its use in drug products.

Exception Excipients: minor changes in formulation of a drug Exception Excipients: minor changes in formulation of a drug product for which an applicant may seek approval. product for which an applicant may seek approval. –– Parenterals: 314.94(a)(9)(iii): changes in preservative, buffer Parenterals: 314.94(a)(9)(iii): changes in preservative, buffer and and

antioxidant antioxidant –– Ophthalmic/Otic: 314.94(a)(9)(iv): changes in preservative, Ophthalmic/Otic: 314.94(a)(9)(iv): changes in preservative,

buffer, substance to adjust tonicity and thickening agentbuffer, substance to adjust tonicity and thickening agent–– Topical Use: 314.94(a)(9)(v): changes are not specified by theTopical Use: 314.94(a)(9)(v): changes are not specified by the

Regulations Regulations –– Note the use of pH adjusters in parenterals is not an exception Note the use of pH adjusters in parenterals is not an exception

excipient excipient

3.2.P.2 Pharmaceutical 3.2.P.2 Pharmaceutical DevelopmentDevelopment

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

See the Guidance for Industry; See the Guidance for Industry; Q8 Pharmaceutical Development Q8 Pharmaceutical Development

3.2.P.3 Manufacture3.2.P.3 Manufacture(Drug Product)(Drug Product)

Name and full address of facilityName and full address of facility–– This section includes manufacturers of drug product as well as This section includes manufacturers of drug product as well as

outside contract testing labsoutside contract testing labs–– Please provide a summary table of all lab addresses, contacts, Please provide a summary table of all lab addresses, contacts,

and specific functions performedand specific functions performedFunction or ResponsibilityFunction or Responsibility–– Provide a detailed description of outside firms responsibilitiesProvide a detailed description of outside firms responsibilities

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

cGMP CertificationcGMP Certification–– Certification should include signatureCertification should include signature

3.2.P.3.2 Batch Formula3.2.P.3.2 Batch Formula(Drug Product)(Drug Product)

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

3.2.P.3.3 Description of Manufacturing 3.2.P.3.3 Description of Manufacturing Process and Process ControlsProcess and Process Controls

(Drug Product)(Drug Product)

A flow diagram should be presented giving A flow diagram should be presented giving the steps of the process and showing the steps of the process and showing where materials enter the processwhere materials enter the processBlank Master Production Batch RecordsBlank Master Production Batch Records–– Firms may request a maximum production Firms may request a maximum production

scalescale--up of 10X the Theoretical yield of the up of 10X the Theoretical yield of the exhibit batchexhibit batch

3.2.P.3.3 Description of Manufacturing 3.2.P.3.3 Description of Manufacturing Process and Process Controls (Cont.)Process and Process Controls (Cont.)


Reprocessing StatementReprocessing Statement–– Firm should certify that it does not utilize Firm should certify that it does not utilize

reprocessing procedures in the manufacture reprocessing procedures in the manufacture on the drug product. If the firm does wish to on the drug product. If the firm does wish to reprocess the drug product they will submit a reprocess the drug product they will submit a Prior Approval Supplement to the Agency Prior Approval Supplement to the Agency describing the process. Release of the describing the process. Release of the reprocessed product will be withheld until the reprocessed product will be withheld until the PAS is approved by the AgencyPAS is approved by the Agency

3.2.P.3.4 Controls of Critical 3.2.P.3.4 Controls of Critical Steps and IntermediatesSteps and Intermediates


All critical process controls and their All critical process controls and their associated numeric ranges, limits, or associated numeric ranges, limits, or acceptance criteria should be identified acceptance criteria should be identified and justified and a brief description of the and justified and a brief description of the test providedtest provided

3.2.P.3.5 Process Validation 3.2.P.3.5 Process Validation and/or Evaluationand/or Evaluation


Description, documentation, and results of Description, documentation, and results of the validation and/or evaluation should be the validation and/or evaluation should be provided for critical steps or critical assays provided for critical steps or critical assays used in the manufacturing processused in the manufacturing process–– Microbiological sterilization validationMicrobiological sterilization validation–– Filter validationFilter validation

Must have complete filter validation present upon Must have complete filter validation present upon submission of an ANDA, this information may not submission of an ANDA, this information may not be submitted at a later datebe submitted at a later date

3.2.P.4 Controls of Excipients3.2.P.4 Controls of Excipients

Inactive IngredientsInactive Ingredients

3.2.P.4 Controls of Excipients3.2.P.4 Controls of Excipients(Inactive Ingredients)(Inactive Ingredients)

Identify source of supplier for all inactive Identify source of supplier for all inactive ingredientsingredients–– It is helpful if the applicant provides a table It is helpful if the applicant provides a table

indicating the source of all active and inactive indicating the source of all active and inactive ingredientsingredients

3.2.P.4.1 Specifications3.2.P.4.1 Specifications(Inactive Ingredients)(Inactive Ingredients)

Testing SpecificationsTesting SpecificationsSuppliers COASuppliers COA– Minimally OGD needs the COA, specifications

and test results from the drug substance manufacturer and the applicant’s COA. We also like to have the applicant’s testing specifications and data from the drug product manufacturers 3.2.P.4.4

3.2.P.4.2 Analytical Procedures3.2.P.4.2 Analytical Procedures(Inactive Ingredients)(Inactive Ingredients)

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

3.2.P.4.3 Validation of Analytical 3.2.P.4.3 Validation of Analytical ProceduresProcedures

(Inactive Ingredients)(Inactive Ingredients)Submission of validation information in the Submission of validation information in the application is normally not needed for application is normally not needed for excipientsexcipientsValidation information should be submitted Validation information should be submitted if there are special circumstancesif there are special circumstances–– Characteristic of the excipient or the excipient Characteristic of the excipient or the excipient

itself is critical to product qualityitself is critical to product quality

3.2.P.4.4 Justification of 3.2.P.4.4 Justification of SpecificationsSpecifications

(Inactive Ingredients)(Inactive Ingredients)

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

3.2.P.5 Controls of Drug 3.2.P.5 Controls of Drug ProductProduct

3.2.P.5.13.2.P.5.1–– Specification (s)Specification (s)

3.2.P.5.23.2.P.5.2–– Analytical ProceduresAnalytical Procedures

3.2.P.5.33.2.P.5.3–– Validation of Analytical ProceduresValidation of Analytical Procedures

Sample StatementSample Statement--Sample drug product will be submitted Sample drug product will be submitted upon request from FDA in accord with 21 CFR 314.50(e)(i)upon request from FDA in accord with 21 CFR 314.50(e)(i)

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

3.2.P.5.43.2.P.5.4–– Batch AnalysisBatch Analysis

COA for Finished Dosage Form needed for each COA for Finished Dosage Form needed for each executed batchexecuted batch

3.2.P.5.53.2.P.5.5–– Characterization of ImpuritiesCharacterization of Impurities

List all expected impuritiesList all expected impuritiesIdentification of impuritiesIdentification of impurities

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

3.2.P.5.63.2.P.5.6–– Justification of SpecificationsJustification of Specifications

Pharm/Tox studies can be submitted in this section Pharm/Tox studies can be submitted in this section when appropriate to justify the safety of an impuritywhen appropriate to justify the safety of an impurity

3.2.P.7 Container Closure 3.2.P.7 Container Closure SystemSystem

3.2.P.7 Container Closure 3.2.P.7 Container Closure SystemSystem

1. Summary of Container/Closure 1. Summary of Container/Closure System (if System (if new resin, provide data) new resin, provide data) 2. Components Specification and Test 2. Components Specification and Test Data Data 3. Packaging Configuration and Sizes3. 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 4. Container/Closure Testing 5. Source of supply and suppliers address 5. Source of supply and suppliers address

3.2.P.8 Stability3.2.P.8 Stability

3.2.P.8.1 Stability Summary and 3.2.P.8.1 Stability Summary and ConclusionConclusion

Stability ProtocolStability ProtocolProposed expiration dating periodProposed expiration dating period– Firm may propose a tentative 24 month

expiration date based upon 3 months of accelerated stability

3.2.P.8.2 Post3.2.P.8.2 Post--approval Stability Protocol approval Stability Protocol and Stability Commitmentand Stability Commitment

Post Approval Stability Protocols and CommitmentsPost 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 Data3.2.P.8.3 Stability Data

Data from four time points should be submitted Data from four time points should be submitted -- 0, 1, 2, and 3 0, 1, 2, and 3 months months Must submit 3 months of accelerated stability conducted under Must submit 3 months of accelerated stability conducted under stressed conditions of 40stressed conditions of 40˚̊C and 75% relative humidityC and 75% relative humidityThis data should be provided even if the product fails under strThis data should be provided even if the product fails under stressed essed conditions. RSB will file an ANDA with failing accelerated stabconditions. RSB will file an ANDA with failing accelerated stability ility but may not file an ANDA if only unstressed stability is providebut may not file an ANDA if only unstressed stability is provided.d.If a firm is utilizing the same container closure system for mulIf a firm is utilizing the same container closure system for multiple tiple package amounts/sizes then a firm may bracket intermediate package amounts/sizes then a firm may bracket intermediate package amount/sizes and only perform stability on the largest apackage amount/sizes and only perform stability on the largest and nd smallest package amount/sizes.smallest package amount/sizes.Batch number must be the same as the exhibit batchBatch number must be the same as the exhibit batch

3.2.R Regional Information3.2.R Regional Information

3.2.R Drug Substance3.2.R Drug Substance

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

types of post approval manufacturing changestypes of post approval manufacturing changesMethods Validation PackageMethods Validation Package–– 3 copies needed for paper submission3 copies needed for paper submission

3.2.R Drug Product3.2.R Drug Product

Executed batch records for drug productExecuted 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 batchMust 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 marketingScale-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.)3.2.R Drug Product (Cont.)

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

Comparability Protocols (optional)Comparability Protocols (optional)–– Used to demonstrate the lack of adverse effect for specified Used to demonstrate the lack of adverse effect for specified

types of post approval manufacturing changestypes of post approval manufacturing changesMethods Validation PackageMethods Validation Package–– 3 copies needed for paper submission3 copies needed for paper submission

Module 4Module 4--Nonclinical Study Nonclinical Study ReportsReports

Not needed for ANDAsNot needed for ANDAs

Module 5Module 5--Clinical Study Clinical Study ReportsReports

BioequivalenceBioequivalence

5.3.1 Bioavailability Study 5.3.1 Bioavailability Study ReportsReports

FormulationFormulation–– Comparison of all strengthsComparison of all strengths–– Qualitative and Quantitative comparisons of Qualitative and Quantitative comparisons of

parenterals, ophthalmics, otics and topicalsparenterals, ophthalmics, otics and topicalsQ1/Q2?Q1/Q2?Exception excipientsException excipients

5.3.1.2 Comparative BA/BE 5.3.1.2 Comparative BA/BE Study ReportsStudy Reports

Study(ies) meet BE criteria (90% CI of 80Study(ies) meet BE criteria (90% CI of 80--125, C max, AUC)125, C max, AUC)–– Automatic refuse to receive issue if BA/BE Automatic refuse to receive issue if BA/BE

study fails criteriastudy fails criteria

5.3.1.3 In Vitro5.3.1.3 In Vitro--InIn--Vivo Vivo Correlation Study ReportsCorrelation Study Reports

InIn--Vitro DissolutionVitro 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 5.3.1.4 Reports of Bioanalytical and Analytical Methods for Human StudiesAnalytical Methods for Human Studies

5.3.1.45.3.1.4–– Reports of Bioanalytical and Analytical Reports of Bioanalytical and Analytical

Methods for Human Studies Methods for Human Studies Bioanalytical validation reportBioanalytical validation reportSee M4E: The CTDSee M4E: The CTD--Efficacy GuidanceEfficacy Guidance

5.3.7 Case Reports Forms and 5.3.7 Case Reports Forms and Individual Patient ListingIndividual Patient Listing

5.3.75.3.7–– Case Reports Forms and Individual Case Reports Forms and Individual

Patient ListingPatient ListingSee M4E: The CTDSee M4E: The CTD--Efficacy Efficacy GuidanceGuidance

Refusal to Receive IssuesRefusal to Receive Issues

Incomplete bioequivalence studiesIncomplete bioequivalence studiesNo dissolution dataNo dissolution dataDMF not present or received by the DMF not present or received by the Agency by the date the ANDA was Agency by the date the ANDA was stamped receivedstamped receivedMissing or incomplete stability dataMissing or incomplete stability dataNo patent certificationsNo patent certificationsMissing CitizenMissing Citizen’’s Petition or Suitability s Petition or Suitability Petition Petition

Refusal to Receive Issues (Cont.)Refusal to Receive Issues (Cont.)

Inactive IngredientsInactive IngredientsMaster production batch records not in Master production batch records not in accord with 10X scaleaccord with 10X scale--upupNo information demonstrating that No information demonstrating that differences in inactive ingredients do not differences in inactive ingredients do not impact safety and efficacyimpact safety and efficacy

Questions and AnswersQuestions and Answers

Q:Q: Can an ANDA be refused for filing if Can an ANDA be refused for filing if submitted in the traditional format submitted in the traditional format addressed in the 1999 Guidance and addressed in the 1999 Guidance and not submitted in the CTD or eCTD not submitted in the CTD or eCTD format?format?

A:A: No. At this time, the FDA can not No. At this time, the FDA can not refuse to file an ANDA for using the refuse to file an ANDA for using the traditional format. traditional format.

Questions and AnswersQuestions and AnswersQ: Q: Should the Quality Overall Summary Should the Quality Overall Summary

(QOS) be provided as separate files or (QOS) be provided as separate files or as one complete file? as one complete file?

A:A: Please note that the QOS is a Please note that the QOS is a reviewerreviewer’’s tool and is most useful as s tool and is most useful as one complete document (in both MS one complete document (in both MS Word and pdf files) for ANDAs. Word and pdf files) for ANDAs.

Questions and AnswersQuestions and AnswersA:A: Page 3 of the Page 3 of the ““Guidance for Industry Granularity Guidance for Industry Granularity

Document Annex to M4: Organization of the CTDDocument Annex to M4: Organization of the CTD”” is is a diagram that provides a visual layout of how to a diagram that provides a visual layout of how to prepare a summary of the application. prepare a summary of the application.

The QOS is Module 2.3 and can be submitted in The QOS is Module 2.3 and can be submitted in multiple files but there is the option of submitting as multiple files but there is the option of submitting as one document (highlighted in pink). one document (highlighted in pink).

Please note comment #2 about submitting one Please note comment #2 about submitting one document for each drug substance. OGD directors document for each drug substance. OGD directors and reviewers have requested one document with and reviewers have requested one document with the two different DS identified separately. the two different DS identified separately.


Q:Q: Is Module 5 required if a request for Is Module 5 required if a request for waiver of BA/BE studies was submitted waiver of BA/BE studies was submitted within the ANDA submission and no within the ANDA submission and no tests were performed?tests were performed?

A:A: No. If there are no BA/BE studies No. If there are no BA/BE studies Module 5 is not needed.Module 5 is not needed.


Q:Q: Can hyperlinks be used to refer to Can hyperlinks be used to refer to duplicate information submitted in an duplicate information submitted in an electronic submission?electronic submission?

A:A: Yes. Caution: if submitting an Yes. Caution: if submitting an amendment, make sure to also amend amendment, make sure to also amend your hyperlink if appropriate.your hyperlink if appropriate.

Questions and AnswersQuestions and AnswersQ:Q: In the CTD format, where should theIn the CTD format, where should the

16 Bioequivalence Summary Tables be 16 Bioequivalence Summary Tables be placed?placed?

A:A: Module 2.7.1.1 should include:Module 2.7.1.1 should include:Table 1. Submission SummaryTable 1. Submission Summary

Table 4. Bioanalytical Method ValidationTable 4. Bioanalytical Method Validation

Table 6. Formulation DataTable 6. Formulation Data

Module 2.7.1.2 should include:Module 2.7.1.2 should include:Table 5. Summary of InTable 5. Summary of In--vitro Dissolution Studies vitro Dissolution Studies

Questions and AnswersQuestions and AnswersQ:Q: In the CTD format, where should theIn the CTD format, where should the

16 Bioequivalence Summary Tables be 16 Bioequivalence Summary Tables be placed?placed?

A:A: Module 2.7.1.3 should include:Module 2.7.1.3 should include:Table 2.Table 2. Summary of Comparative Bioavailability (BA) StudiesSummary of Comparative Bioavailability (BA) StudiesTable 3.Table 3. Statistical Summary of the Comparative BA DataStatistical Summary of the Comparative BA Data

Module 2.7.4.1.3 should include:Module 2.7.4.1.3 should include:Table 7. Demographic Profile of Subjects Completing the BE StudyTable 7. Demographic Profile of Subjects Completing the BE Study


Q:Q: In the CTD format, where should theIn the CTD format, where should the16 Bioequivalence Summary Tables be 16 Bioequivalence Summary Tables be placed?placed?

A:A: Module 2.7.4.2.1.1 should include:Module 2.7.4.2.1.1 should include:Table 8.Table 8. Incidence of Adverse Events in Individual StudiesIncidence of Adverse Events in Individual Studies

Questions and AnswersQuestions and AnswersA:A: Module 5.3.1.2 should include:Module 5.3.1.2 should include:

Table 10. Study Information Table 10. Study Information Table 12. Dropout InformationTable 12. Dropout Information

Module 5.3.1.3 should include:Module 5.3.1.3 should include:Table 11. Product Information Table 11. Product Information Table 13. Protocol DeviationsTable 13. Protocol DeviationsTable 16. Composition of Meal Used in Fed BE StudyTable 16. Composition of Meal Used in Fed BE Study

Module 5.3.1.4 should include:Module 5.3.1.4 should include:Table 9. Reanalysis of Study Samples Table 9. Reanalysis of Study Samples Table 14. Summary of Standard Curve and QC Data for BE Sample AnTable 14. Summary of Standard Curve and QC Data for BE Sample AnalysesalysesTable 15. SOPs dealing with Bioanalytical Repeats of Study SamplTable 15. SOPs dealing with Bioanalytical Repeats of Study Sampleses

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 submissionsPre-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:RSB contact information:

Phone number: (301) 827Phone number: (301) 827--58625862

Fax number: (301) 443Fax number: (301) 443--38473847

The ANDA Workshop Filing Process_May 2007

Documents

therapeutic

long term

container

electronic

finished drug

approved drug

specific functions

reference