ANDA Filing and

Refuse to Receive
Issues

Johnny Young,
M.A.L.A. 1
Planned Implementation Date:

January 2, 2014

6
An ANDA containing less than 10 easily remedied
deficiencies will be contacted regarding the same. A
response must be provided within 5 U.S. business days.
Day 1 of the 5 U.S. business days will commence the
day after notification is provided to the applicant.

An ANDA will be Refused-for-Receipt if:

- The number of easily remedied deficiencies is equal to

or more than 10

- A response to the fewer than 10 deficiencies is not

received within 5 U.S. business days

8
Module 3: Drug Substance (3.2.S)
-Type II API DMFs (cont.)

The time frame between the date of submission of a

Type II API DMF and its “accompanying” ANDA
submission was analyzed for approximately 75 NCE-1
submissions.
 Only 30% of these API DMFs were submitted beyond 60 days
prior to the ANDA submission
 38% were submitted within 30 days of the ANDA submission
 Of the 38% subset above, 43% were submitted within 10 days of
the ANDA submission!

20
Module 3: Drug Substance (3.2.S)
-Type II API DMFs (cont.)

The trend needs to be reversed, so that ample time is

allowed for the Initial Completeness Assessment
determination to be made and any identified
deficiencies addressed, all prior to the ANDA
submission, to ensure that the Type II API DMF is
determined to be available for reference at the time of
receipt (refer to 744B(a)(2)(D)(ii)(II) of the Act).

Otherwise…

21
Module 3: Drug Substance (3.2.S)
-Type II API DMFs (cont.)

the ANDA will be Refused for Receipt, if the

referenced Type II API DMF is not on FDA’s Available
for Reference list* at the time a receipt decision is to be
made.
(*http://www.fda.gov/downloads/ForIndustry/UserFees/GenericDrugUserFees/UCM332875.pdf)

Therefore, our best practice recommendation is that a Type II API

DMF be submitted at least 6 months in advance of the ANDA
submission.

22
Module 3: Drug Product (3.2.P)
– Justifying oral liquids
• Do not rely on percentages that are listed in the IID for
justification of a level of use for an inactive

– Q/Q sameness evaluations

• With these types of justifications, also justify the proposed
concentration/amount via the IID
• Provide evidence that any changes permitted by 21 CFR
314.94(a)(9)(iii)(iv) do not affect safety and/or efficacy of the drug
product

– Flavoring agents
• Provide qualitative and quantitative breakdown of components

23
Module 3: Drug Product (3.2.P)
– For any inactive ingredient that cannot be justified via
the IID, submit or provide any of the following:
• Pharm/tox information
• Evidence of a CDER-approved drug product of the same route of
administration as the test product that contains the inactive
ingredient in question at or above the proposed level of use
• A Controlled Correspondence requesting an evaluation of the
acceptability of the proposed level of use
(http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/u
cm120610.htm)

If the proposed level of use cannot be justified via the

IID and none of the above support is provided at the
time of submission, the ANDA will be Refused for
Receipt. 24
 RTR Draft Guidance
• Excipient justifications for oral liquid drug products,
– FDA recommends - justification not be based on a listed percentage in
the IID.
– Calculate the amount of inactive ingredient that is delivered per dose or
per day (MDI) on dosing recommendations indicated in the RLD label
– Justify the calculated amount based on an amount-per-unit IID listing
that corresponds to a solid oral dosage form.
• Furthermore, inactive ingredients that are included in powders
for oral suspension should be justified as described above,
with calculations of amounts delivered per dose based on the
dry powder composition (i.e., prior to reconstitution).

19
Module 5: Clinical Study Reports (cont.)
– In-Vitro Dissolution
• Provide the RLD certificate of analysis for all strengths (place these in
Module 2.7 as well)
• Check specific bioequivalence drug product guidances for dissolution
recommendations
Dissolution Recommendations (If incomplete or absent, Refuse to
Receive)
• 12 unit vs 12 unit for all strengths in all recommended media
• 12 half-tablet units for any dosage form for which this information is
necessary
• Don’t forget about alcohol dose-dumping studies, if applicable!

35
 RTR Deficiencies
 Major  Minor
• No 356h • Not all info on 356h
• Failure to pay GUDFA fees • Little viii statement that
• Type II DMF submitted after includes protected use
ANDA or DMF fails C&A • Appropriate DMF LOA
• Missing sterility data • Labeling- side-by-side
• Inadequate stability data comparison
• Orientation of liquids and SS • PI in word format
on stability • Appropriate cGMP
• Batch records for pilot and certifications from 3rd parties
commercial batches • Elemental iron calculations
• Inconsistent scoring • Post approval stability
configuration commitment

9
Stability Guidance & Draft
Q&A Guidance -
considerations
Radhika Rajagopalan, Ph.D.,
Team Leader
Chemistry Division 2
Office of Generic Drugs, FDA

FDA Small Business WEBINAR

November 4, 2013

1
 Common Considerations

• Sterile drug product batches (supporting ANDA submission) should be

manufactured in a sterile facility (sterility is a critical product quality attribute)

• Time points for various storage conditions:

– 0 = initial release
– Accelerated time points: 0, 3, 6, and one additional time point
– Intermediate time points (0, 6, 9, and 12 months)
– Long-term time points (0, 3, 6, 9, 12, 18, 24, 36 months)

• For Supplemental ANDA submission requirements – refer to SUPAC

IR/MR/SS, and Changes to an approved NDA or ANDA guidance, and Q&A
to Changes guidance

4
 Amendments to pending ANDAs
• Q&A guidance section D
– “All amendments submitted to pending ANDAs after
the effective date of the final stability guidance (June
20, 2014) will be held to the standards in place at the
time of the original ANDA submission, unless there is
a concern with the submitted stability data.”
• An original ANDA which is filed prior to the June 20, 2014 implementation
date would only require stability data for one batch per strength for
submission. If additional strengths are amended to this ANDA after the June
20, 2014 implementation date, the assumption is that stability data for only a
single batch per strength would be required for submission. - Yes, but will
be considered a major amendment
• If a firm were to submit an original ANDA after the June 20, 2014
implementation date, and additional strengths are to be submitted as an
amendment, how many batches of stability data will be required? - # 3
batches will be required and it will be considered a major amendment; if all
strengths are filed with the original anda then see slide # 14.

15
GPhA/FDA
FALL TECHNICAL
CONFERENCE

393 Days into GDUFA:

What Should Industry Be Doing Today?
Marcie McClintic Coates, JD, MBA
GPhA GDUFA Negotiating Team
Head of Global Regulatory Affairs, Mylan
 Thoughts for Industry:
Strive for High Quality Applications
• Starting Oct 1, 2014 metrics begin, amendments become
more important

• Multiple amendments or certain types of amendments may

extend or negate CR goal date

• For Industry, incentive to:

– Be more selective when making post submission changes
to pending ANDAs
– Stay engaged with 3rd parties listed in your application
– Turnaround open comments as quickly as possible
 Thoughts for Industry:
Implement Continuous Improvement
• Avoid repeating deficiencies
– When comments are given on an application, implement
this feedback into future filings where applicable to avoid
repeat deficiencies

• Stay engaged
– Fall Tech Conference is great forum to learn more about
FDA’s expectations to improve submission quality
– Additional guidance expected to provide greater clarity to
avoid repeating issues and provide needed guidance on
complex products
– Provide ideas on how FDA can improve efficiency in the
review process
GPhA/FDA
FALL TECHNICAL
CONFERENCE

GDUFA 2012-2017
Industry Perspective
Richard J. Stec Jr., Ph.D.
October 29, 2013
 FDA – Industry Communication
Disappointments
• Recent change in OGD communication of
ANDA review status a disappointing step
backwards in achieving predictability
• Limiting Q/Q controlled correspondence
inquiries only to formulations that are
required to be Q/Q equivalent delays access
– Greater chance of an RTR, waste drug & resources
– Potentially expose subjects unnecessarily to drug
– May increase law suits on lost PIV opportunities
 Updates Regarding the OGD
Division of Microbiology
&
ANDA Sterility Assurance Review

Dr. Lynne A. Ensor

U.S. Food & Drug Administration
Center for Drug Evaluation & Research
Office of Pharmaceutical Science/Office of Generic Drugs
Division of Microbiology
Acting Division Director/Deputy Division Director

2013 GPhA/FDA Fall Technical Conference

October 29, 2013 1
 Bulk Drug Solution Bioburden

• No alert or action levels for bulk drug solution

bioburden
– Recommend setting bulk drug solution bioburden
alert and action levels for the solution prior to any
filtration step.

10
Sterilizing Filtration of Drug Solution
• During the filtration sterilization validation study it is
unclear if/how the positive control (0.45 um rated filter)
was included in the bacterial retention studies and/or
positive control results are not provided
– It is recommended that the 0.45 um rated filter is challenged parallel
with the test (0.22 um rated) filters

• Viability data for B. diminuta in the drug solution are not

provided with the bacterial retention study results
– Please provide this information with bacterial retention study summaries

11
Container Closure Integrity Testing
• The container closure system used for
validation study is not stated and/or dimensional
specifications are not provided
– Please indicate the manufacturer of the components used in
validation testing
– If different components are used than those proposed for
production, please indicate the inner neck diameter
specifications of the vials and/or are different from proposed drug
product vial, or stoppers are not identical/equivalent (i.e., same
formulation and dimensions, but perhaps different coating) to the
proposed drug product stoppers.
12
Antimicrobial Effectiveness Testing
• Antimicrobial Effectiveness testing results are
not provided for the drug solution formulated
with preservative at the lowest specified
concentration, or not provided at all for multi-
dose drug products that are preservative-free.
- Provide AET summary and results for the drug product
containing the minimum API concentration (either release or
stability [lowest])

13
 Drug Product Labeling
• The drug product label does not indicate if
the product is intended to be single or
multiple dose. The volume of the drug
product could allow for multiple dose.
– Clearly indicate single or multiple dose
– If multi-dose, please provide AET summary and
results (per USP <51> or equivalent)

14
Drug Product Labeling (2)
– Microbiological quality following product
penetration

– Post-reconstitution or dilution

– Risk assessment data to support the

proposed post-penetration holding
parameters per product labeling
15
 Product Labeling
– Risk assessment study & data
• Maximum hold duration during worst-case holding
conditions/diluent
• Minimum inoculum (≤100 cfu/mL)
– USP <51> strains
– Typical skin flora
– Nosocomial infection causing organism(s)
– Psychrophilic organism(s)
• Acceptance criteria
– No growth (LT 0.5 log10)
16