Proper CMC Submission -API

Ramnarayan Randad, Ph.D.

DMF Review Staff/OGD

June 4, 2014 GPhA/FDA Bethesda, MD

1

Type II Drug Master Files (DMFs) and GDUFA

• Generic Drug User Fee Amendments (GDUFA)

– July 9, 2012 (FDASIA –PDUFA, GDUFA, BsUFA).

– Type II DMF -one-time user fee

– Pass Completeness Assessment

– “Available for Reference” -Oct 2014, ww.fda.gov/gdufa

– DMF team –pilot 2010

• Affects ANDA submission

– Risk of causing an RTR

– ANDA applicant is notified (email) of the DMF status

2

• GDUFA requires Type II API DMFs to undergo an initial CA

to ensure that the DMF is complete.

• Agency Guidance (10/1/2012), that include recommendation

on information that should be included in the DMF.

CA checklist follows CTD format:

• Has 62 questions

• DMFs that pass initial CA are published on the FDA’s public

Web site as available for reference (www.fda.gov/gdufa).

3

Completeness Assessment (CA)

4

Format of the Checklist

• Administrative/General Information (question 1-11)

• 2.3.S QOS (question 12)

• 3.2.S.1 General Information (question 13-15)

• 3.2.S.2 Manufacture (question 16-36)

• 3.2.S.3 Characterization (question 37-40)

• 3.2.S.4 Control of Drug Substance (question 41-45)

• 3.2.S.5 Reference Standards or Materials (question 46-51)

• 3.2.S.6 Container Closure System (question 52-54)

• 3.2.S.7 Stability (question 55-58)

• 3.2 R Regional info (question 59-61)

5

Is DMF Eligible for Admin CA?

Generate CA queue and prioritize.

NoAssign to reviewer for full CA

Is DMF Complete?

No

Issue Incomplete

letter to DMF holder.*

DMF holder submits

amendment

*Notification of Incomplete status is sent to ANDA applicant if the DMF has been referenced by a submitted ANDA under filing review.

DMF holder sends

notification to DMFOGD@fda.

hhs.gov

DMF holder pays the DMF

fee

ANDA applicant who references this DMF

DMFs listed as “available for reference” on FDA website

Yes Yes

DMF holder Actions

FDA Actions

CA Review Process

6

How is the Generic Industry doing with CAs?

• Overall Industry is adapting very well.

• Some metrics:

DMFs for Full CA complete on the first cycle: 17%

DMFs for Full CA complete by the second cycle: 88%

Average response time (first cycle): 45 days

• CTD format and Electronic- CTD submissions

greatly facilitate the process efficiency

Clarifications on DMF [Common Queries]

7

• API is a substance or a mixture when the substance is unstable

or cannot be transported on its own.

• DMF for a mixture (e.g. API plus an excipient) can qualify as

the API under GDUFA. We ask that a justification be

submitted to the DMF when this claim is made. Note that

these situations also have important facility fee implications.

• The CA requires that a DMF be for a single API produced by

a single manufacturing process.

Clarifications (continued)

• DMF should be limited to one process although multiple manufacturing sites

for a single drug process is permitted.

• Certain process alternatives/changes may be permissible with sufficient

supportive information provided. e.g.:

• Validated reprocess/rework procedures

• Micronization leading to different particle sizes

• Addition of a stabilizing antioxidant for stability purpose

• Alternate crystallization procedure to produce a different polymorph

• Minor process variation that is the same chemical transformation with

little risk to the impurity profile

Factors which are indicative of a second process

• Significant process alternation resulting in different impurity profile and

requiring different control strategy

• Different starting materials

• Different Intermediates

8

Clarifications (continued)

• What is the stability data requirement to pass

the CA? Do the provisions of the new stability

guidance apply?

The guidance requirements apply to the full scientific

review. To pass the CA the firm needs to demonstrate that

stability studies have started (i.e. one batch with a time

point beyond initial).

9

Policy Change for FY 2015

• DMF must be “Available for Reference” at the time

of ANDA submission or the ANDA will be “Refuse

to Receive”

• For FY 2013 and 2014 this was not the case – DMF

holders had the entire ANDA filing window to

become “Available for Reference”

• Firm’s will need to coordinate DMF fee payment and

ANDA submission to allow the DMF to pass the CA

(we recommend 6 months) 10

Average time to CA Completion by Payment

Month (Full CA, first cycle)

• Large influence of

the bolus’ on

timelines

• Impact was partially

muted do to hiring

• September 2013

bolus has been

cleared so another

downward trend is

expected 0

40

80

120

160

200

0

50

100

150

200

250

300

350

# of Paid DMFs Avg Days of 1st CA Review

Initial Bolus Cleared

Backlog > 400

Backlog : 78

Backlog > 300

Avoid an RTR due to the DMF-Suggestions

• Make sure the DMF is on the “Available for Reference”

list prior to ANDA submission

• Communicate with the DMF holder so they know the

ANDA submission timeframe.

• Pay the DMF fee six-months in advance of the planned

ANDA submission date

This will allow sufficient time for two cycles of CA review (if

needed)

• Submit a high-quality DMF (preferably in eCTD

format) 12

• Know if the DMF is eligible for an administrative CA

• Make sure the choice of starting materials is appropriately

justified

• For older DMFs, know whether a complete update needs to be

submitte and submit ahead of payment!

• Make sure FDA has the current contact information (fax

number)

• Respond to Incomplete letters as quickly as possible (30 days or

less is ideal) Provide notification of amendment as instructed on

the fax cover sheet!

• Contact us with CA status requests if the DMF is not on the list

or you have not received a “DMF Incomplete” communication

(DMFOGD@FDA.HHS.GOV)

13

Avoid an RTR due to the DMF-– Be Proactive!

Resources from Oct 1, 2012

• Large increase in resources

since Oct 1, 2012

• 14 GDUFA hires in

FY2013

• 25 GDUFA hires in

2014

• Total review Staff of 61

by end of 2014

• Increased capability to cope

with large and variable

workload. Will result in

much lower and predictable

CA timelines

0

5

10

15

20

25

30

35

40

Oct-12 Dec-12 Feb-13 Apr-13 Jun-13 Aug-13 Oct-13 Dec-13 Feb-14 Apr-14

Growth in DMF Staff Since Oct 1, 2012

15

Thank you