Wei Song, Ph.D DMF Review Staff

OGD/OPS/CDER

Completeness Assessment for Type II DMF Under GDUFA

New GDUFA Requirements for DMF Review

DMF Fee Collection Basic of DMF fee: What/Why/When/Who

DMF payment process

Completeness Assessment (CA) Metrics First six-month CA submission study

Common Incomplete Comments in CA review

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What: Facts about DMF Fee Payment

It is one-time payment in the whole DMF lifecycle

The DMF fee payment will trigger the Completeness Assessment

Complete DMFs are deemed available for reference

All available for reference DMFs will be listed on a publicly available FDA website

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Why: Consequence for DMF is not Available for Reference

For referencing a DMF that fails to pay DMF fee: ANDA sponsor will receive a notification from Office of

Management (OM) that the DMF fee is due in 20 days.

After 20 days the ANDA submission will be Refuse to Receive and the application fee will be forfeited.

For referencing a DMF that fails the CA: Refuse to Receive by OGD and a 75% refund of the submission

fee could be granted.

ANDAs can only be filed by OGD if all type II DMFs for API are available for reference

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When is DMF fee Due

If the DMF fee for a Type II API DMF hasnt been paid yet, and this DMF is referenced by following submissions after October 1, 2012:

An original ANDA

Prior Approval Supplement (PAS) to an ANDA

Amendment to an ANDA (original or PAS)

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Who need pay DMF fee?

DMF holders if their Type II DMFs are first referenced on or after October 1, 2012

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DMF Fee Payment Process

Fee collection is processed in FDA for GDUFA by Office of Financial Management (OFM) and OM

DMF Holder logs into iStore and provides requested information (DMF# required)

System generates the appropriate user fee cover sheet with the required fee.

DMF Holder pays the required fee using the cover sheet (Note: Partial payment is not acceptable).

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Requirements to Initiate a DMF Completeness Assessment

FDA Central Document Room (CDR) staff perform initial Administrative Review of submitted DMF If a DMF is administratively complete, FDA sends an

acknowledgement letter to the holder and DMF status becomes Active

If a DMF is not administratively complete, FDA sends firm a letter to identify issues. DMF is Pending until issues are resolved

Office of Management (OM) confirms user fee payment and change the user fee status to Met

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DMF Queue Generation and Processing

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The Facts of Completeness Assessment

A complete DMF contains all of the information necessary for a scientific review.

The criteria of the CA review is higher than the ones used in the administrative check at CDR. It is similar to the current ANDA filing review.

CA is aimed to improve quality of the DMF submission and reduce the review cycles

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Numbers of DMF Submissions During The First GDUFA Year

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Details of DMF Submissions in the First Six Months

The first payment was received on October 25, 2012

Until April 16, 2013, FDA received 1049 DMF user fee payments

These DMFs were submitted by 300 DMF holders

1049 DMFs covered distinct 481 APIs 12

DMF Holders per DMF Submissions (N=300)

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DMF Submissions per DMF Holders (N= 1049)

14%

30% 56%

small (1 DMF)

Medium (2-5 DMFs)

Large (> 6 DMFs)

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Distributions of DMF Submission Types (N=1049)

78%

4%

18%

Paper

Papar & Electronic

Electronic

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A Snapshot of DMF CA Review Progress (10/25/2012-04/16/2013)

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Average Assignment and Review Duration By Priority

0

60

120

Assignment Duration(Oct-Dec, 2012)

Assignment Duration(Jan-Apr 2013)

Review Duration(Oct 12-Apr 13)

Expediated Normal

Day

s

17

Average Review and Response Duration By Submission Types

Day

s

0

18

36

Review Duration Response Duration

Electronic Paper

18

Submission Quality by Submission Types %

of C

ompl

eted

CA

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CA Review Outcomes

0%

50%

100%

First Cycle Second Cycle

Imcomplete Complete

Per

cent

age

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Questions are arranged according to CTD format Administrative/General Information (Item # 1~11) 2.3.S QOS (Item # 12) 3.2.S.1 General Information (Item # 13~15) 3.2.S.2 Manufacture (Item # 16~36) 3.2.S.3 Characterization (Item # 37~40) 3.2.S.4 Control of Drug Substance (Item # 41~45) 3.2.S.5 Reference Standards or Materials (Item # 46~51) 3.2.S.6 Container Closure System (Item # 52~54) 3.2.S.7 Stability (Item # 55~58) 3.2 R Regional info (Item # 59~62)

Format of Checklist

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Profile of Common Observed Incomplete Items

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Incomplete Items Observed During First Cycle CA Review - 1

Administrative/General Information Section Question # 2 (Cited by more than 10% of submissions) :

If it has been five years since the DMF has received a complete update, or there have been more than 5 amendments, a complete update may be needed. The requirement for complete update does not apply to the DMF if the entire DMF is in eCTD format.

Question # 8 (Cited by more than 25% of submissions) : The container label should include, but not limited to, the following information: weight of the material, date of manufacture, complete name and address of the manufacturer, retest date, appropriate storage conditions, temperature range, and caution statement.

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Incomplete Items Observed During First Cycle CA Review - 2

3.2. S.1 General Information Question # 15 (Cited by more than 15% of submissions) :

The general properties section (S.1) should include basic information such as chirality, polymorphism, hygroscopicity, aqueous solubility, solubility in various organic solvents, and melting range for the drug substance, etc.

3.2. S.2 Manufacture Question # 16 (Cited by more than 10% of submissions) :

The complete name, address, function, and contact information, including the name of on-site responsible individual is needed for the manufacture. If the intermediate is outsourced, the manufacturing site of the intermediate should be provided. Separate facilities, used for additional processing and release testing, should also be included in this section.

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Incomplete Items Observed During First Cycle CA Review - 3

3.2. S.2 Manufacture Question # 17 (Cited by more than 20% of submissions) :

A true starting material should be a substance of defined chemical properties and structure. It should be a commercially available chemical in a pre-existing, non-pharmaceutical market in addition to its proposed use as starting material per ICH Q 11. If a late stage intermediates is designated as regulatory starting material, a determination should be made if information is provided in the DMF to adequately evaluate their controls and impact on the drug substance quality and purity. Further discussion regarding regulatory starting materials : FDA Perspectives: Designation of Regulatory Starting Materials in the Manufacturing of Drug Substances: Impact on ANDA Review Time Scott, B., Pharm Tech 36(1) pp. 63-66 (2011)

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Incomplete Items Observed During First Cycle CA Review - 4

3.2.S.2.3. Control of Materials: Question # 23, 24, and 27 (cited by more than 20% of submissions) :

For each starting material, a representative in-house CoA and the corresponding vendors CoA from the each approved supplier are needed. For each reagent and solvent used in the manufacture of the drug substance, a representative in-house CoA or the corresponding vendors CoA from the each approved supplier is required.

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Incomplete Items Observed During First Cycle CA Review - 5

3.2.S.2.5 -2.6 Process Validation: Question # 34 (Cited by more than 10% of submissions) :

A summary of your process validation for the manufacturing process is needed. The summary should include basically the description for the validation batches, starting material analysis, in process controls, intermediate and final API analysis which can be presented in a tabular format.

Question # 36 (Cited by more than 20% of submissions) : A summary of the manufacturing process development for your manufacturing process is needed. The summary should include the rational of starting material designation, critical material attribute identification, process optimization, justification of control strategy..

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Incomplete Items Observed During First Cycle CA Review - 6

3.2.S.3. Characterization Question # 37 (Cited by more than 20% of submissions) :

The characterization information should sufficiently to elucidate the structure of the drug substance. 2D NMR, Chiral HPLC comparison, specific optical rotation, single crystal XRD, etc. may be needed to address regio/stereo-chemical features. PXRD, DSC, FTIR data may be required to address Polymorph character. Peak assignment tables are helpful for interpreting IR, NMR, MS spectra. The representative spectra should be legible to read.

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Incomplete Items Observed During First Cycle CA Review - 7

3.2.S.5 Reference Standards and Materials Question # 49 (Cited by more than 25% of submissions) :

For each identified impurity, the source, the lot number, and the CoA for both reference standard and working standard should be provided.

Question # 50 (Cited by more than 25% of submissions) : Non-compendial reference standard should be characterized and quantified.

Question # 50 (Cited by more than 25% of submissions) : For impurities with compendial RS available, comparative data, like over-laid IR spectra, between the USP RS and the in-house WS should be provided. For the representative spectra should be legible to read.

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Incomplete Items Observed During First Cycle CA Review - 8

3.2.S.6 Container/Closure System: Question # 54 (Cited by more than 25% of submissions) :

For each packing component, the corresponding source information, specification, and representative COA is needed

3.2.S.R Regional information: Question # 59 (Cited by more than 30% of submissions) :

The representative Executed Batch Records translated in to English, where appropriate, is needed.

Question # 60 (Cited by more than 30% of submissions) : For exhibit batch(es), required information includes yields, results of in-process controls, and analytical results for intermediates.

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Suggestions for a Successful CA Review

Proactively initiate the DMF completeness assessment by paying the DMF fee as early as possible

Follow the draft CA guidance and checklist

Provide high quality submissions and include sufficient data to support your justification

Submit the DMF in CTD format and preferably in eCTD

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Slide Number 1New GDUFA Requirements for DMF ReviewWhat: Facts about DMF Fee PaymentWhy: Consequence for DMF is not Available for ReferenceWhen is DMF fee DueWho need pay DMF fee?DMF Fee Payment ProcessRequirements to Initiate a DMF Completeness AssessmentDMF Queue Generation and Processing The Facts of Completeness AssessmentNumbers of DMF Submissions During The First GDUFA YearDetails of DMF Submissions in the First Six MonthsDMF Holders per DMF Submissions (N=300) DMF Submissions per DMF Holders (N= 1049)Distributions of DMF Submission Types (N=1049)A Snapshot of DMF CA Review Progress (10/25/2012-04/16/2013)Average Assignment and Review Duration By PriorityAverage Review and Response Duration By Submission TypesSubmission Quality by Submission TypesCA Review OutcomesSlide Number 21Profile of Common Observed Incomplete ItemsIncomplete Items Observed During First Cycle CA Review - 1Incomplete Items Observed During First Cycle CA Review - 2Incomplete Items Observed During First Cycle CA Review - 3Incomplete Items Observed During First Cycle CA Review - 4Incomplete Items Observed During First Cycle CA Review - 5Incomplete Items Observed During First Cycle CA Review - 6Incomplete Items Observed During First Cycle CA Review - 7Incomplete Items Observed During First Cycle CA Review - 8Suggestions for a Successful CA Review