CENTER FOR DRUG EVALUATION AND

RESEARCH

APPLICATION NUMBER:

205636Orig1s000
CHEMISTRY REVIEW(S)
 CHEMISTRY REVIEW

NDA 205636

ProAir RespiClick (Albuterol Inhalation Powder)

Teva Branded Pharmaceutical Products R&D, Inc.

Yong Hu, Ph.D.

Division of New Drug Quality Assessment III

Office of New Drug Quality Assessment

For

Division of Pulmonary, Allergy, and Rheumatology Products

 CHEMISTRY REVIEW

Table of Contents
Table of Contents.....................................................................................................2
Chemistry Review Data Sheet................................................................................3
The Executive Summary.........................................................................................7
I. Recommendations.......................................................................................................................7
A. Recommendation and Conclusion on Approvability......................................................................7
B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk Management Steps, if
Approvable........................................................................................................................................7
II. Summary of Chemistry Assessments.........................................................................................7
A. Description of the Drug Product(s) and Drug Substance(s).............................................................7
B. Description of How the Drug Product is Intended to be Used.........................................................9
C. Basis for Approvability or Not-Approval Recommendation...........................................................9
Chemistry Assessment...........................................................................................11
I. Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body Of Data.......11
(b) (4)
S DRUG SUBSTANCE [Albuterol sulfate, ]................................................11
P DRUG PRODUCT [Albuterol, Inhalation Powder].....................................................................17
R REGIONAL INFORMATION....................................................................................................99
II. Review Of Common Technical Document-Quality (Ctd-Q) Module 1..................................99
A. Labeling & Package Insert...........................................................................................................99
B. Environmental Assessment Or Claim Of Categorical Exclusion...................................................99
Signature Page.............................................................................................................................100
 CHEMISTRY REVIEW
Chemistry Review Data Sheet

Chemistry Review Data Sheet

1. NDA: 205636

2. REVIEW #: 1

3. REVIEW DATE: 1/22/2015

4. REVIEWER: Yong Hu, Ph.D.

5. PREVIOUS DOCUMENTS:
N/A

6. SUBMISSION(S) BEING REVIEWED:

Submission(s) Reviewed Document Date

Response to information request 1/20/2015

Amendment (Labeling) 11/19/2014
Amendments 8/29/2014
Response to information request 8/8/2014
Amendment (Labeling) 7/28/2014
Response to information request 6/12/2014
Response to Information Request 5/23/2014
Original NDA 5/5/2014

7. NAME & ADDRESS OF APPLICANT:

Name: Teva Branded Pharmaceutical Products R&D, Inc.

Address: 74 NW 176th Street, Miami, FL 33169
Representative: William Kiddell

Telephone: 305-575-6284

8. DRUG PRODUCT NAME/CODE/TYPE:

Page 3 of 100
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Chemistry Review Data Sheet

a) Proprietary Name: Proair RespiClick

b) Non-Proprietary Name (USAN): Albuterol sulfate
c) Code Name/# (ONDC only): N/A
d) Chem. Type/Submission Priority (ONDC only):
 Chem. Type: 3
 Submission Priority: S

9. LEGAL BASIS FOR SUBMISSION:

505 (b)(2);

10. PHARMACOL. CATEGORY:

Beta2-adrenergic agonist

11. DOSAGE FORM:

Inhalation powder (Dry powder inhaler)

12. STRENGTH/POTENCY:
97 μg (metered dose); 90 μg (delivered dose)

13. ROUTE OF ADMINISTRATION:

Oral inhalation

14. Rx/OTC DISPENSED: _x Rx OTC

15. SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):

SPOTS product – Form Completed

x Not a SPOTS product

16. CHEMICAL NAME, STRUCTURAL FORMULA,

MOLECULAR FORMULA, MOLECULAR WEIGHT:
Bis[(1RS)-2-[(1,1-dimethylethyl)amino]-1-[4-hydroxy-3
(hydroxymethyl)phenyl]ethanol]sulphate
or
1,3-benzenedimethanol,alpha1-[[1,1-dimethylethyl)amino]methyl]-4-hydroxy-, sulfate (2:1)
salt
or
alpha1-[(tert-Butylamino)methyl]-4-hydroxy-m-xylene-alpha, alpha1 –diol sulfate (2:1) salt
 CHEMISTRY REVIEW
Chemistry Review Data Sheet

Molecular Formula: (C13H21NO3)2.H2SO4

Molecular weight: 576.7

17. RELATED/SUPPORTING DOCUMENTS:

A. DMFs:

DATE
DMF ITEM
TYPE HOLDER CODE1 STATUS2 REVIEW COMMENTS
# REFERENCED
COMPLETED
(b) (4 )
(b) (4)
II 1 Adequate 12/29/2014

III 4 N/A

IV 4 N/A

IV 4 N/A

IV 4 N/A

1
Action codes for DMF Table:
1 – DMF Reviewed.
Other codes indicate why the DMF was not reviewed, as follows:
2 –Type 1 DMF
3 – Reviewed previously and no revision since last review
4 – Sufficient information in application
5 – Authority to reference not granted
6 – DMF not available
7 – Other (explain under "Comments")
 CHEMISTRY REVIEW
Chemistry Review Data Sheet
2
Adequate, Inadequate, or N/A (There is enough data in the application, therefore the DMF did
not need to be reviewed)

B. Other Documents:

DOCUMENT APPLICATION NUMBER DESCRIPTION

IND 104532 This was the IND supporting the
NDA.

18. STATUS:

ONDC:
CONSULTS/ CMC
RELATED RECOMMENDATION DATE REVIEWER
REVIEWS
Biometrics Not requested.
EES Pending.
Pharm/Tox The impurity Email communications with the
specifications are reviewer Dr. Nikunj Patel
acceptable.
Biopharm Not requested.
LNC Not requested.
Methods Validation Not requested.
Commonly-used
analytical methods for
this type of product.
OPDRA Not requested.
EA Categorical exclusion See this review Dr. Yong Hu
Microbiology Not requested.
 CHEMISTRY REVIEW
Executive Summary Section

The Chemistry Review for NDA 202450

The Executive Summary
I. Recommendations
A. Recommendation and Conclusion on Approvability

The NDA is recommended for approval pending the Office of Compliance’s “Acceptable”
recommendation for the manufacturing and testing facilities.

B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or

Risk Management Steps, if Approvable

N/A.

II. Summary of Chemistry Assessments

A. Description of the Drug Product(s) and Drug Substance(s)
(b) (4) (b) (4)
The drug substance is albuterol sulfate, manufactured by
(b) (4) (b) (4)
under DMF and It is the same drug
substance sourced for the approved product ProAir HFA (albuterol MDI) marketed by the same
(b) (4)
applicant. The drug substance specification is
Particle size
distribution, amorphous content, identification, assay, related substances, heavy metals, residual
solvents, water content, and microbial limits are among the critical attributes to be controlled in
the drug substance specification.

The product is a device-metered, inspiratory-flow driven, multi-dose dry powder inhaler (so-
called Albuterol MDPI). The inhalation powder product contains a formulation mixture of
albuterol sulfate and lactose monohydrate in its reservoir (hopper). The device meters 97 μg and
delivers 90 μg of albuterol free base from the inhaler mouthpiece at each actuation. The product
contains a minimum of 200 doses and has an integrated dose counter which displays the number
of doses remaining. The inhaler is over-wrapped with a heat sealed aluminum foil pouch.

The device operates in three distinct steps: open the mouthpiece cover to meter a specific dose of
medicine, inhale the dose, and close the mouthpiece cover to re-set the device ready for the next
dose. This dry powder inhaler (DPI) product is intended to overcome the difficulty in patient’s
coordinating the “press and breathe” steps in the use of the albuterol MDIs (such as ProAir
HFA). This DPI product was developed to match the in-vivo performance of the ProAir HFA, 90
μg.
 CHEMISTRY REVIEW
Executive Summary Section

The device evolved from the variant to the (b) (4) variant (to-be-marketed) after the first
(b) (4)

pivotal clinical trial ABS-AS-306 and the manufacture of the first three registration stability
batches. All subsequent clinical trials and stability batches were manufactured using the to-be-
(b) (4)
marketed device. The improvements seem to be minor changes, which did not impact dose
metering and dose delivery.
(b) (4)
The device components and sub-assemblies are manufactured by and
the final drug product by Teve Pharmaceutical Industries, Ltd., Israel. All pivotal clinical trial
supplies and registration stability batches were manufactured using the final to-be-marketed
(b) (4)
powder formulation at the proposed commercial scale The drug product manufacturing
(b) (4)
process involves

(b) (4)

The applicant presented two Comparability Protocols in the Pharmaceutical Development

(b) (4) (b) (4)
section. They are to support an material of the
device and a second manufacturing site for the device components. Both protocols are
deemed acceptable for future CBE-30 supplements.

The critical quality attributes of the drug product include delivered dose uniformity (DDU),
aerodynamic particle size distribution (APSD), related substances, assay (total drug content per
inhaler), identification, microbial limits, dose counter reading, and foreign particulates. All these
attributes are controlled in the product specification. The critical material attributes for the sole
excipient, lactose monohydrate, include particle size and amorphous content. Amorphous content
in the lactose has been shown to be undetectable (limit of detection: (b)(4) %) in all batches used so
far, thus will not be routinely analyzed.

The drug product stability program consists of the following nine batches:
(b) (4) (b) (4)
• Three stability batches using the device variant and
one of which was used in the Phase 3 clinical program. 36 months long-term stability data
were provided.
(b) (4)
• Three additional stability batches using the device variant (commercial device) and
(b) (4)
one of which was used in the Phase 3 clinical program. 12
months long-term stability data were provided.
 CHEMISTRY REVIEW
Executive Summary Section
(b) (4) (b) (4)
• Three additional stability batches using device variant and
Six months long-term stability data were provided.
(b) (4)
Teva proposes a month expiration dating period for the drug product, with the inhaler stored
within its protect packaging, either in the upright or inverted orientation. The proposal is
based on an analysis of real time accelerated stability data generated at 6 months and controlled
(b) (4)
room temperature stability data generated at 36 months for drug product batches.
(b) (4)
However, since the available real-time 12-month data for the batches only predict 24
(b) (4)
months shelf life so far, with the supporting 36 months data for the batches, this
reviewer recommends an expiration dating period of 36 months for the NDA approval.

B. Description of How the Drug Product is Intended to be Used

The product is for oral inhalation only.

The inhaler is operated by the patient as follows: The patient holds the device in an upright
position. The patient opens the mouthpiece cover fully, exhales, places the mouthpiece between
the lips, inhales forcefully and deeply, and removes the inhaler from his/her mouth. The patient
then holds his/her breath for ten seconds, or as long as comfortably possible. The patient finally
breathes out slowly and then closes the mouthpiece cover.

The inhaler does not require priming and routine cleaning. The inhaler should not be used with a
spacer.

The product should be stored under controlled room temperature within protective foil
packaging. Once the foil packaging has been removed, the product should be used within 13
months when stored at controlled room temperature .

C. Basis for Approvability or Not-Approval Recommendation

The NDA has provided adequate information to assure the identify, purity, strength, and quality
of the proposed product.

The risk mitigation is acceptable as shown in the table below.

 CHEMISTRY REVIEW
Executive Summary Section

Initial Quality Assessment

Current Review Assessment
Life-cycle
CQAs Factors affecting CQAs Risk ranking
Risk mitigation approach Risk evaluation conside rations/comme nts
Particle size of lactose is controlled in the specification
Amorphous content of lactose is undetectable (below
(b) (4)%
Inhomogeneity or low formulation ) The amorphous content of API is controlled in the
(b)
assay of albuterol sulfate/lactose API specification to be below (4)% The blend uniformity is
blend (e g , from manufacturing; assured by the process param rs established using DOE Teve committed to revisit the
studies and the in-process test (b) (4)
Delivered result of shipping); Lower than target acceptance criterion for the
dose fill of reservoir; Failure of protective API amorphous content once
uniformity packaging (moisture ingress); 8 Acceptable data from 15 batches of drug
(DDU) Amorphous content of substance is available or one
API; Device malfunction; Particle year after the product is
size/amorphous content of lactose; The launched
Static charge of
packaged inhalers are 100% checked for foil seal integrity
formulation
The DDU throughout inhaler life is tested for product
release and stability The device appears robust based on
the characterization studies

Particle size of lactose is controlled in the specification

Amorphous content of lactose is undetectable (below
Inhomogeneity or low assay of (b) (4)
%) The amorphous content of API is controlled in the
albuterol (b)
API specification to be below The blend uniformity is
%
sulfate/lactose blend; Lower than
target fill of reservoir; Failure of assured by the process parameters(4) established using DOE

protective studies and the in-process test (b) (4)

Aerodynami packaging; Particle size
c particle
distribution of API; Amorphous
size 8 Acceptable
content of API; Device malfunction;
distribution
Particle size/amorphous content of
(APSD)
lactose; Composition of device air
The
flow path
packaged inhalers are 100% checked for foil seal integrity
components; Device flow resistance
The APSD is tested for product release and stability The
variation; Static charge of
device appears robust based on the characterization studies
formulation
For example, the APSD is not affected when (b) (4)

The input API and lactose have suitable specifications for

impurity control The degradants are also controlled by the
Purity Degradation of API as formulated; product specification The product is protected by aluminum
(impurities/d Input purity of API; Input purity of 4 foil and stored at controlled room temperature Extensive Acceptable
egradants) lactose stabiltiy data show that degradation is not a significant issue
for this product, even when the inhalers were stored
unwrapped at 30 C/65% RH for 24 months
 CHEMISTRY REVIEW TEMPLATE
Chemistry Assessment Section

Chemistry
Assessment

I. Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2:

Body Of Data
(b) (4)
S DRUG SUBSTANCE [Albuterol sulfate, ]

Adequate.
(b) (4)
The drug substance information is provided in DMF , which has been deemed adequate.
The following information from the NDA is reviewed.

The nomenclature of the drug substance is shown below.

The structure formula, molecular formula, molecular weight are presented below.
 CHEMISTRY REVIEW TEMPLATE
Chemistry Assessment Section

Albuterol sulfate is manufactured by (b) (4)

under DMF (b) (4)
and
#
is the same drug substance as that used for the marketed ProAir HFA (albuterol
(b) (4)
sulfate) Inhalation Aerosol (NDA 21-457).

(b) (4)

(b) (4)

(b) (4(b) (4)

DMF (b) (4) has provided adequate manufacturing process information and process controls for
(b) (4)
albuterol sulfate
(b) (4)
 CHEMISTRY REVIEW TEMPLATE
Chemistry Assessment Section
(b) (4)

The (b) (4)

drug substance specification (see below) meets the requirements in the USP
(b) (4)
monograph for albuterol sulfate .
 CHEMISTRY REVIEW TEMPLATE
Chemistry Assessment Section

(b) (4)

(b) (4)

(b) (4)

(b) (4) (b) (4)

(b)
(4)

(b) (4)

(b) (4)

(b) (4)
 CHEMISTRY REVIEW TEMPLATE
Chemistry Assessment Section

(b) (4) (b)

(4)
(b)
(4)
(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4 )

(b)
(4)
(b) (4)

(b) (4)

(b) (4) (b) (4)

(b) (4)

(b) (4)

(b) (4)

(b)
(4)

(b) (4) (b) (4) (b) (4)

(b)
(4)

(b) (4)
 CHEMISTRY REVIEW TEMPLATE
Chemistry Assessment Section
(b) (4)
The amorphous content of the drug substance is measured by the
The method appears suitable for the determination of amorphous content in albuterol
sulfate as the results of the linear regression indicated(b) good linear correlation suitable for
quantitative analysis of amorphous content down to (4)%.

Table 1 below contains a list of all batch data generated on the amorphous content. The results
show that the amorphous content of the albuterol batches was in the range (b) (4)
of %. The
(b)
mean content was about (4)% and the standard deviation (b)
(4)
%. The applicant proposes an
(b) (4)
acceptance criterion of Not More Than (NMT) % and states that the acceptance criterion will
be revisited once data from 15 batches of drug substance is available or one year after the
product is launched on the market, whichever is sooner. This proposal is acceptable given the
limited data at this stage.

(b) (4)
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Chemistry Assessment Section

P DRUG PRODUCT [Albuterol, Inhalation Powder]

P.1 Description and Composition of the Drug Product [Albuterol, Inhalation
Powder]

Adequate.

The product is a device-metered, breath-actuated, multi-dose dry powder inhaler (so-called

Albuterol MDPI). The inhalation powder product contains a mixture of albuterol sulfate and
lactose monohydrate, delivering 90 µg of albuterol free base from the inhaler mouthpiece at each
actuation. The metered dose is 97 µg of albuterol free base. For dry powder inhalers (DPIs), the
strength of the product is expressed as the metered dose, as opposed to delivered dose for
metered dose inhalers (MDIs). Therefore, the strength of the product is 97 µg (albuterol base).

The product contains a minimum of 200 doses and has an integrated dose counter which displays
the number of doses remaining. The inhaler is over-wrapped with a heat sealed aluminum foil
pouch.

The quantitative composition of the product is shown below.

(b) (4)

(b) (4) (b) (4)

(b) (4)

(b) (4)

(b) (4)

The Albuterol MDPI device consists of an assembly of a (b) (4)

and the following
subassemblies: (b) (4)
 CHEMISTRY REVIEW TEMPLATE
Chemistry Assessment Section

The schematic showing of the sub-assemblies can be found below. Details of the device
component parts are described in Section 3.2.P.7.1 Description.

(b) (4)

The inhaler is operated by the patient as follows: The patient holds the device in an upright
position. The patient opens the mouthpiece cover fully, exhales, places the mouthpiece between
the lips, inhales forcefully and deeply, and removes the inhaler from his/her mouth. The patient
then holds his/her breath for ten seconds, or as long as comfortably possible. The patient finally
breathes out slowly and then closes the mouthpiece cover.

P.2 Pharmaceutical Development [Albuterol, Inhalation Powder]

P.2.1 Components of the Drug Product

The product is comprised of a hard plastic case, within which a reservoir (or hopper) contains a
drug powder formulation consisting of albuterol sulfate drug substance and lactose monohydrate
as the only excipient. The device has an internal mechanism governing the metering of
individual doses, a mouthpiece through which the dose is inhaled, and an attached mouthpiece
 CHEMISTRY REVIEW TEMPLATE
Chemistry Assessment Section

cover. The product contains a minimum of 200 doses and has an integrated dose counter which
displays the number of doses remaining. The inhaler is over-wrapped with a heat sealed
aluminum foil pouch.

P.2.1.1 Drug Substance

Particle size:

The representative particle size distribution (PSD) data for the drug substance prior to
(b) (4)
is shown below.
(b) (4)

(b) (4)

(b) (4)

(b) (4)

The particle size distribution of (b) (4)

albuterol sulfate is a critical material attribute (CMA)
in determining the aerodynamic particle size of the final drug product. The development of the
(b) (4)
particle size of the drug substance (b) (4)

for the Albuterol MDPI program. Different lots of (b) (4)

albuterol sulfate batches were employed in the development of Albuterol MDPI as reflected in
(b) (4)
Table 2 below. The PSD method was based on
(b) (4)

(b) (4)

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 CHEMISTRY REVIEW TEMPLATE
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(b) (4)

P.2.2 Drug Product

There are three albuterol sulfate press-and-breathe metered dose inhaler (MDI) products
(ProAir® HFA, Proventil HFA and Ventolin HFA) marketed in the United States. The applicant
states that it is well known that many asthma patients do not use their MDIs correctly and find
difficulty in coordinating the “press and breathe” instruction. The applicant has thus intended to
develop a proprietary Multi-dose Dry Powder Inhaler (MDPI) to overcome these co-ordination
issues; the patient’s own inspiratory effort is directly linked to the delivery of a dose of
medication.

Albuterol MDPI product also intends to remove the need for inhaler priming before use and
requires no periodic cleaning to prevent blocking, as is the case with the marketed MDI products.

Teva’s MDPI is designed to fit within the palm of a patient’s hand and have a minimum number
of operating steps (open the mouthpiece cover to meter the dose; inhale the dose; close the
mouthpiece cover to reset the device).
(b) (4)
Albuterol MDPI was developed performance of ProAir® HFA (albuterol
sulfate inhalation aerosol, 90 mcg) marketed in the United States (NDA-21-457) by the
applicant.

P.2.2.1 Formulation Development

All the pivotal clinical and(b)

stability batches are summarized in Table 29. The final to-be-
marketed formulation ( % w/w blend) was used in all batches for pivotal clinical trials and
(4)
(b) (4)
stability study. The batches were manufactured at the commercial scale

Page 24 of 100
 CHEMISTRY REVIEW TEMPLATE
Chemistry Assessment Section

(b) (4)

Some notable changes occurred during the timeframe in which clinical and stability batches were
(b) (4)
manufactured: a change in device iteration as highlighted in Section
(b) (4)
3.2.P.2.4 and additional supplier of
was introduced as outlined in Section 3.2.P.2.3.
(b) (4)
The device variant was updated from to (b) (4) in order to address potential device failure
from mis-use (repeatedly opening and closing the mouthpiece cover without taking a dose) and
observations made during pre-verification testing. The final commercial product will be
(b) (4)
manufactured using

P.2.2.2 Overages

Albuterol MDPI was developed to ensure each individual inhaler contains a minimum quantity
of powder blend to ensure delivery beyond the nominal label claim of 200 doses (even when the
device is used off the vertical orientation). The fill weight of powder blend target per inhaler and
the proposed range for the commercial filling process is outlined in Table 30.
 CHEMISTRY REVIEW TEMPLATE
Chemistry Assessment Section

(b) (4)

P.2.2.3 Physicochemical and Biological Properties

One of the most critical properties of the product is aerodynamic particle size distribution
(APSD). Figure 10 compares the APSD profiles of pivotal clinical/stability drug product batches
and it is clear that the profiles are comparable.
 CHEMISTRY REVIEW TEMPLATE
Chemistry Assessment Section

(b) (4)

P.2.3 Manufacturing Process Development

(b) (4)
The development of the manufacturing process encompassing
is described in Figure 1.

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following this page.
 CHEMISTRY REVIEW TEMPLATE
Chemistry Assessment Section
(b) (4)

P.2.4 Container Closure System

The Albuterol MDPI product is a reservoir type, inspiratory flow driven, multi-dose dry powder
(b) (4)
inhaler. The design is based on and operates in three distinct steps:
open the mouthpiece cover to meter a specific dose of medicine, inhale the dose, and close the
mouthpiece cover to re-set the device ready for the next dose. A dose counter decrements each
time a dose is taken.
(b) (4)
The inhaler consists of

These sub-assemblies combine to enable the Albuterol MDPI device to operate as follows:
• As the patient opens the mouthpiece cover, the device dispenses a metered dose of
(b) (4)
the drug and then transfers this metered dose to the
inhalation position.
• The patient inhales through the mouthpiece and receives the metered dose of medicine.
• As the patient closes the mouthpiece cover, the metering mechanism is reset and the
counter mechanism decrements by one count.

The materials selected for drug-product contact and user contact components of the device are
(b) (4)
The secondary packaging used is a heat-sealed aluminum foil laminate.

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following this page.
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Evaluation of Clinical Trial Complaint Samples and Due Diligence Samples from Phase 3
Clinical Trials ABS-AS-301, ABS-AS-302, ABS-AS-304, ABSAS- 307 and ABS-AS-308
for
Albuterol MDPI

There were 5652 devices in total used across the five Phase 3 clinical studies for Albuterol
MDPI. A total of twenty-seven complaint samples and seven due diligence samples were
thoroughly investigated from these clinical studies. The thirty four devices that were investigated
accounted for 0.6% of the total number of devices used by patients across the five Phase 3
clinical studies for Albuterol MDPI:
 Eight clinical complaint samples were reported to contain broken/dislocated mouthpiece
covers.
 Nine clinical samples were reported that the patient did not feel delivery of medication.
 Four clinical samples were reported to cause patient discomfort (plastic component
touching the lips of the patient when inhaling a dose).
 One clinical sample was reported that the dose counter mechanism was not working as
intended.
 Seven due diligence samples were identified for investigation from the ABS-AS-308
study; one device was identified during the conduct of the study and six devices were
identified after data analysis. The data showed that the dose counter readings in these
devices were outliers compared to patient diary entries.
 Five clinical samples were reported that the device did not work after being submerged in
water.

The investigation results are summarized below.

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 CHEMISTRY REVIEW TEMPLATE
Chemistry Assessment Section

The complaint devices functioned as intended; where exceptions applied, the device was
misused, subject to conditions beyond normal use, or not operated as instructed.

Container closure system – extractables and leachables

Dry Powder Inhalers (DPIs) in general pose a lower risk for leachables than typical Metered
Dose Inhalers (FDA May, 1999 - Guidance for Industry, Container Closure Systems for
Packaging Human Drugs and Biologics) where solvents facilitate leaching from the container
closure system. Albuterol MDPI Inhalation Powder product contains a dry powder formulation
(b) (4)
and correspondingly has a low potential for container closure interaction. In addition,
are used in the devices, further supporting the low risk for leachables.

Whilst packaging interaction is likely to be low, the applicant assessed the critical components,
i.e. those in contact with the formulation or patient’s mucosa, for extractables. The applicant also
carried out a leachables study for three batches of product in upright and inverted orientations
under 25 ºC/60% RH and 40 ºC/75% RH. Recommendations proposed by the Product Quality
Research Institute (PQRI) document – Safety Thresholds and Best Practices for Extractables and
 CHEMISTRY REVIEW TEMPLATE
Chemistry Assessment Section

Leachables in Orally Inhaled and Nasal Drug Products (8 September 2006) were followed in the
studies.

No extractable or leachable compound has been identified at a level that would pose a risk to the
patient.

Container Closure System Manufacturing

(b) (4)

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(b) (4)

P.2.5 Microbiological Attributes

(b) (4)
The dry powder drug substance is expected to have a and on this basis it
does not present a matrix congruent for microbial proliferation. Nonetheless, the drug substance
is tested for estimation of the number of viable aerobic microorganisms present and for absence
of designated microbial species. The excipient lactose monohydrate is also tested according to these
criteria. The device components are manufactured under GMP conditions in clean room
environments. The microbial specification is in place for the drug product.

Examination of stability samples for Albuterol MDPI pivotal and exhibit batches stored for up to
36 months demonstrated the absence of detectable levels of microorganisms. No microbial
growth was detected when returned clinical inhalers from the long term safety study ABS-AS-
307 were tested.

Page 57 of 100
 CHEMISTRY REVIEW TEMPLATE
Chemistry Assessment Section

P.3 Manufacture [Albuterol, Inhalation Powder]

P.3.1 Manufacturers

Evaluation: Pending.

The name and address of the manufacturer responsible for manufacture, packaging, release and
stability testing of commercial product is:

Teva Pharmaceutical Industries, Ltd.

2 Hamarpe Street
Jerusalem 9777402
Israel
FEI: 3003414719
DUNS: 533065822
(b) (4)
Release and stability examination for foreign particulate testing will be conducted at
or at Teva Pharmaceutical Industries, Ltd. (2 Hamarpe Street,
Jerusalem).
(b) (4)

Manufacturer of(b)device
(4)
parts (Listed on Form 356h):

Extractables and Leachables testing (Listed on Form 356h):

(b) (4)

P.3.2 Batch Formula

Adequate.
(b) (4)
Table 1 below outlines the quantities of active ingredient and excipient per batch ( (b) (4)
inhalers), which is the planned commercial batch size. The batch formula is consistent with the
phase 3 formulation.
 CHEMISTRY REVIEW TEMPLATE
Chemistry Assessment Section
(b) (4)

(b) (4)

(b) (4) (b) (4)

(b) (4)

(b) (4

(b) (4)

P.3.3 Description of Manufacturing Process and Process Controls

Adequate.
(b) (4)
Table 1 below lists the procedures for the product.
The proposed manufacturing process is represented in the flow chart shown in Figure 1.

The master batch record is provided in this section. The master batch record and the process are
consistent with those for the manufacture of the registration batches, thus acceptable. Note the
clinical batches and stability batches were manufactured at the final commercial scale. The
process development information in the Pharmaceutical Development section also supports the
proposed process.

Each filled device contains a minimum of approximately (b)

(4) % overage of the formulation to

ensure each device always delivers the claimed number of doses.

3 Pages have been Withheld in Full as b4 (CCI/TS) immediately

following this page.
 CHEMISTRY REVIEW TEMPLATE
Chemistry Assessment Section
(b) (4)

P.3.5 Process Validation and/or Evaluation

Adequate.

The applicant states that process validation will be performed prior to product launch. Full scale
process validation of the manufacturing process will be performed on three batches of Albuterol
MDPI at the commercial scale and on the manufacturing line intended for commercial
manufacture.

P.4 Control of Excipients [Albuterol, Inhalation Powder]

P.4.1 Specifications [Albuterol, Inhalation Powder]

Adequate.
(b) (4)
The only excipient used in the product is (Lactose Monohydrate, NF)
(b) (4)
manufactured by

The excipient complies with the USP/NF monograph for lactose monohydrate. Additional tests
are also performed on the excipient. The specification is shown below.

Page 63 of 100
 CHEMISTRY REVIEW TEMPLATE
Chemistry Assessment Section

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)
(b) (4)

Additional tests and acceptance criteria:

PARTICLE SIZE DISTRIBUTION by the method QEX0007504:

(b) (4)
d10 = µm
 CHEMISTRY REVIEW TEMPLATE
Chemistry Assessment Section

d50 = (b) (4) µm

d90 = (b) (4) µm
%< (b) (4) = (b) (4) %

DETERMINATION (b)OF ANOMERIC PURITY BY GC (method QEX0007519):

(b) (4)
: NMT (4)%

SPECIFIC AND QUANTITATIVE PROTEIN CONTENT (method QEX0007521):

Protein concentration: NMT (b) (4) ppm

DETERMINATION OF PARTICLE SHAPE AND MORPHOLOGY (method QEX0007516)

(b) (4)
An homogenous size distribution is observed. The crystalline particles are

ASSAY (method (b) (4)

QEX0007515): %

RELATED SUBSTANCES FOR LACTOSE MONOHYDRATE (Method QEX0011872):

(b) (4)
NMT (b)
(4) %
(b) (b) (4)
NMT (4) %

MICROBIOLOGICAL EXAMINATION (Method QEX0006202)

(b)
Total combined yeasts/molds count (TYMC): NMT (4) CFU/1 g
(b) (4)
Total aerobic microbial count (TAMC): NMT CFU/1 g
Escherichia coli – Absent/g
Pseudomonas aeruginosa - Absent/g
Staphylococus aureus - Absent/g
Bile tolerant gram negative bacteria - Absent/g

BACTERIAL ENDOTOXIN (QEX0006210):

(b)
Bacterial Endotoxins NMT (4) EU/g

Amorphous content is not routinely analyzed. See justification in P4.4

P.4.2 Analytical Procedures

Adequate.

The non-compendial methods are briefly described below.

Particle size:
(b) (4)
Measured using Particle size Analyzer for the dry powder.

Determination of anomeric purity:

Gas chromatograph with (b) (4) , autoinjector.
 CHEMISTRY REVIEW TEMPLATE
Chemistry Assessment Section

Protein content:
Measured by spectrophotometer to determine the proteins’ reaction with (b) (4)
.

Particle shape and morphology:

(b) (4)
Determined by using microscope.

Assay and related substances:

Determined by HPLC.

Microbiological examination:
The Method complies with USP<61> and USP<62>.

Bacterial endotoxin:
The method complies with USP <85>.

P.4.3 Validation of Analytical Procedures

Adequate.

The method for determination of particle size distribution has been validated by demonstrating
method suitability, ruggedness and robustness.

The method for assay has been validated by demonstrating acceptable specificity, accuracy and
precision, ruggedness, robustness and linearity.

The method for related substances has been validated by demonstrating acceptable specificity,
accuracy and precision, ruggedness, robustness and limit of detection.

The method for the determination of protein has been validated by demonstrating method
suitability and ruggedness.

The method for the determination of the anomeric purity has been validated by demonstrating
acceptable specificity, linearity, ruggedness, accuracy and precision, limit of detection and limit
of quantitation.

P.4.4 Justification of Specifications

Adequate.

Lactose Monohydrate is a USP NF compendial excipient. The specifications for identification

(Fourier Transform Infra Red Spectroscopy and Thin Layer Chromatography); water
determination; clarity and color of solution; acidity and alkalinity; specific optical rotation;
protein and light absorbing impurities; heavy metals; residue on ignition; and loss on drying are
taken from the USP monograph.
 CHEMISTRY REVIEW TEMPLATE
Chemistry Assessment Section

In addition to the USP monograph, the specification includes tests for assay; particle shape
and morphology; specific and quantitative protein content; morphic form; anomeric purity;
impurities and degradants; endotoxins; particle size distribution; and microbial tests.
(b) (4)
The assay acceptance criterion is justified by the release data
) of ten batches of lactose monohydrate used in the manufacturing of the clinical and
registration drug product batches.

The acceptance criterion for the particle size is also justified by the data (see Table 12 below) for
the ten lactose batches (also see evaluation in Pharmaceutical Development Section).

(b)
(4)
(b) (4)

The acceptance criteria for shape, protein content, anomeric purity, endotoxin, and related
substances are also justified by the batch data of the ten lactose batches.

The tests and acceptance criteria for microbial examination are consistent with the
recommendations in USP <1111> and the lactose monohydrate USP monograph.

The amorphous content of 16 batches of lactose was measured by DSC method. The limit of
quantification (LOQ) of this method is (b)
(4) %. There was no detectable amorphous content above

LOQ therefore the applicant proposes not to analyze the amorphous content as part of the routine
release testing. However, should the manufacturer change the process, the first 3 batches will be
tested for amorphous content (acceptance criteria NMT (b)(4) %). This proposal is reasonable.

P.4.5 Excipients of Human or Animal Origin

Adequate.

The excipient (lactose monohydrate) (b) (4) . The TSE/ BSE statement for
lactose monohydrate is provided. Based on OPS policy, lactose carries low risk of BSE/TSE
contamination.

P.4.6 Novel Excipients

 CHEMISTRY REVIEW TEMPLATE
Chemistry Assessment Section

Not applicable.

P.5 Control of Drug Product [Albuterol, Inhalation Powder]

P.5.1 Specification(s)

Adequate.

The originally proposed specification is as follows.

(b) (4)

1 Page has been Withheld in Full as b4 (CCI/TS) immediately

following this page.
 CHEMISTRY REVIEW TEMPLATE
Chemistry Assessment Section
(b) (4)

After evaluation of the product data, the CMC team sent the following comments to the
applicant. The applicant provided responses via an email to the project manager, Leila Hann.

1. Revise the drug product specification as follows:

(b) (4)

Page 70 of 100
2 Pages have been Withheld in Full as b4 (CCI/TS) immediately following this page.
 CHEMISTRY REVIEW TEMPLATE
Chemistry Assessment Section
(b) (4)

The applicant has provided the revised specification as follows.

(b) (4)

(b) (4)

(b)
(4)

(b) (4)

Page 73 of 100
CHEMISTRY REVIEW TEMPLATE
Chemistry Assessment Section

(b) (4)

(b) (4) (b)

(4)

(b) (4)

(b) (4)

(b) (4)
(b) (4)

(b) (4)

(b) (4)

(b) (4) (b) (4)

(b) (4)
 CHEMISTRY REVIEW TEMPLATE
Chemistry Assessment Section

(b) (4)

(b) (4)

(b) (4)
(b) (4)
(b) (4)

(b) (4)

(b)
(4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)
(b) (4)

R – Release; S – Stability.

P.5.2 Analytical Procedures

Adequate.

Page 75 of 100
15 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
 CHEMISTRY REVIEW TEMPLATE
Chemistry Assessment Section
(b) (4)

Expiration Period:

Teva is proposing a (b) (4) month expiration dating period for drug product, with the inhaler
stored within its protective packaging, either in the upright or inverted orientation. The request
is based on an analysis of real time accelerated stability data generated at 6 months and
(b) (4)
controlled room temperature stability data generated at 36 months for drug product batches.
(b) (4)
However, since the available real-time data from the batches only predict 24 months
shelf life so far, with the supporting 36 months data(b) (4)
from the batches, this reviewer
considers a shelf life of 36 months more reasonable for the NDA approval.

The applicant is proposing an in-use period of 13 months. Based on an analysis of in-use stability
data from 0 through 24 months storage, an expiry dating period of 13 months is supported, when
the inhaler is stored horizontally without protective packaging (i.e. unwrapped).

Proposed Storage:

The drug product should be stored under controlled room temperature within protective foil
packaging.

Once the foil packaging has been removed, the product is considered to be stable for 13 months
when stored at room temperature (59°F to 77°F), avoiding extreme heat or cold.

Device orientation on storage has no pharmaceutically significant effect on product performance.

The applicant proposes that the drug product will be packaged and transported in the inverted
orientation in accordance with recommendations from study on the Effect of Simulated Shipping
on Albuterol MDPI (see review under 3.2.P.2.4), which is acceptable.

Page 92 of 100
6 Pages have been Withheld in Full as b4 (CCI/TS) immediately following this page.
 CHEMISTRY REVIEW TEMPLATE
Chemistry Assessment Section
(b) (4)

R REGIONAL INFORMATION
R1 Executed Batch Records

The executed batches records for the nine stability batches MD2001, 2003, 2004, AB 1001,
1002, 1004, 4001, 4002, and 4003 are provided. The batch records support the proposed
commercial manufacturing process.

II. Review Of Common Technical Document-Quality (Ctd-Q) Module 1

A. Labeling & Package Insert

The product name and strength should be revised to “Albuterol inhalation powder” and “97 µg.”

B. Environmental Assessment Or Claim Of Categorical Exclusion

Adequate.

Teva requests a categorical exclusion pursuant to 21 CFR Section 25.31(b), as the FDA’s
approval of this application will increase the use of the active moiety, but the estimated increase
in the concentration of the substance at its highest level in the next 5 years at the point of entry
into the aquatic environment will be below 1 part per billion.

Page 99 of 100
 CHEMISTRY REVIEW TEMPLATE
Chemistry Assessment Section

Signature Page

Reviewer: Yong Hu, Ph.D., Office of New Drug Quality Assessment

Electronic Signature:

Digitally signed by Yong Hu -S

Yong Hu -S
DN: c=US, o=U.S. Government, ou=HHS,
ou=FDA, ou=People, cn=Yong Hu -S,
0.9.2342.19200300.100.1.1=2000336960
Date: 2015.01.22 16:40:05 -05'00'

Supervisor: Julia Pinto, Ph.D., Branch Chief, Office of New Drug Quality Assessment

Electronic Signature:

Digitally signed by Julia C. Pinto -A

Julia C. Pinto DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, ou=People,

cn=Julia C. Pinto -A, 0.9.2342.19200300.100.1.1=1300366849
Date: 2015.01.27 10:05:55 -05'00'

-A
 NEW DRUG APPLICATION OMPQ REVIEW

Initial Manufacturing (CGMP/Facilities)

Assessment (IMA) and Filing Review for
Pre- Marketing Applications (Original)
I. Review Cover Sheet
II. Application Detail
III. Filing Checklist
IV. Manufacturing Summary
V. Overall Conclusions and Recommendations

I. Review Cover Sheet

1. OMPQ Reviewer: Linda Ng, Ph.D.

2. NDA/BLA Number: 205-636

Submission Date: May 5, 2014
21st C. Review Goal Date: January 15, 2015
PDUFA Goal Date: March 15, 2015

3. PRODUCT PROPERTIES:

Trade or Proprietary Name: ProAir RespiClick

Established or Non-Proprietary
Albuterol Multi-Dose Dry Powder Inhaler
Name (USAN) and strength:
Dosage Form: Dry powder inhaler

4. SUBMISSION PROPERTIES:

Review Priority : STANDARD

Applicant Name: Teva Pharmaceutical
Responsible Organization
DPARP
(OND Division):

Page 1 of 9

Reference ID: 3530283

 OMPQ Initial Manufacturing (CGMP/Facilities) Assessment and Filing Review
For Pre-Marking Applications

II. Application Detail

INDICATION: Treatment or prevention of bronchospasm with reversible obstructive

airway disease and for the prevention of exercise induced bronchospasm.

1. ROUTE OF ADMINISTRATION: Inhalation

2. STRENGTH/POTENCY: 90 mcg/dose, 200 doses

3. Rx/OTC DISPENSED: X Rx OTC

4. ELECTRONIC SUBMISSION (yes/no)? Yes

5. PRIORITY CONSIDERATIONS: No

Parameter Yes No Unk Comment

1. NME / PDUFA V X
Breakthrough Therapy
2. X
Designation
Orphan Drug
3. X
Designation
4. Unapproved New Drug X
Medically Necessary
5. X
Determination
Potential Shortage
Issues [either alleviating
6. X
or non-approval may
cause a shortage]
7. Rolling Submission X
Drug/device
8. combination product X
with consult
9. Complex manufacturing X Manufacture of Dry Powder Inhalers
Other (e.g., expedited
10. X
for an unlisted reason)

Page 2 of 9
Reference ID: 3530283
 III. FILING CHECKLIST
The following parameters are necessary in order to initiate a full review (i.e., the application is complete
enough to start review but may have deficiencies). On initial review of the NDA application:

A. COMPLETENESS OF FACILITY INFORMATION

Parameter Yes No Comment
Is all site information complete
11. (e.g., contact information, X
responsibilities, address)?
Do all sites indicate they are
12. ready to be inspected (on X
356h)?
Is a single comprehensive list
of all involved facilities
13. X
available in one location in the
application?
For testing labs, is complete
information provided
14. regarding which specific test is X
performed at each facility and
what stage of manufacturing?
Additional notes (non-filing
issue) X
1. Are all sites
registered or have FEI
#?
15.
2. Do comments in EES X
indicate a request to
participate on
inspection(s)? X
3. Is this first
application by the
applicant?
*If any information regarding the facilities is missing/omitted, communicate to OPS/ONDQA
regarding missing information and copy EESQuestions. Notify OMPQ management if
problems are not resolved within 3 days and it can be a potential filing issue.
 B. DRUG SUBSTANCE (DS) / DRUG PRODUCT (DP)
Parameter Yes No Comment
Have any Comparability
16. X
Protocols been requested?

IMA CONCLUSION
Parameter Yes No Comment
Does this application fit one of the
17. X New dosage form
EES Product Specific Categories?
Have EERs been cross referenced
against the 356h and product (b) (4)
specific profile for accuracy and
18. X has not been
completion?
added
Have all EERs been updated with
final PAI recommendation?
From a CGMP/facilities
perspective, is the application
fileable?
19. X
If the NDA is not fileable from a
product quality perspective, state the
reasons and provide filing comments
to be sent to the Applicant.
IV. Manufacturing Summary:
Critical Issues and Complexities

Does the submission contain any of the following elements?

Nanotechnology RTRT Proposal PAT Drug/Device Combo

PET Design Space Continuous Mfg Naturally derived API

Other (explain):

Manufacturing Highlights
1. Drug Substance

Parameter Yes No Comment

Is manufacturing process
considered complex (e.g.,
unusual unit operations,
X
innovative manufacturing
technology, unusual control
strategy)?

Include process flow chart/diagram (see eCTD Section 2.3.S.1)

2. Drug Product

Parameter Yes No Comment

Is manufacturing process
considered complex (e.g.,
unusual unit operations,
X
innovative manufacturing
technology, unusual control
strategy)?

Include process flow chart/diagram (see eCTD Section 2.3.P.1)

 (b) (4)

3. Facility-Related Risks (e.g., expected in-process testing not being performed,

questionable development, unexplained stability failures, data integrity issues, etc.).
Describe any potential 21CFR 211 compliance issues. Nothing obvious
 4. Drug Product Facility Inspectional History that could impact the manufacturing
of this product.

The drug product manufacturing facility has never been inspected as an ADM
facility. It is currently a testing facility CTL. See the Table for the rest of the
facilities.

Additional information not covered above. None

Page 7 of 9
Reference ID: 3530283
 OMPQ Initial Manufacturing (CGMP/Facilities) Assessment and Filing Review
For Pre-Marking Applications

Manufacturing Facilities Chart (generated from 602A DARRTS report and OMPQ macro):
NDA: 205636 Albuterol Sulfate Multi-Dose Dry Powder Inhaler
Sponsor: TEVA BRANDED PHARMACEUTICAL PRODUCTS R AND D INC
Indication: Treatment or prevention of bronchospasm with reversible obstructive airway disease and for the prevention of exercise induced bronchospasm
PDUFA: 3/5/2015 under STANDARD Review
Responsible Organiz CDER/ODEII/DPARP
EERS Submitted By: LIU, YOUBANG: CDER/ONDQA
Chart Generated On: 6/11/2014
Overall OC Recomendation: PENDING entered into EES on 5/27/2014 2:08:09 PM
Reevaluation date:
Most Recent
EER Inspection Facts
District Country Profile Firm Profiles - Most Recent EER
Establishment Name Creation FEI Num Responsibilities History, Dates, Assignment
Short Code Code Current Status Classifications Id Milestone Compliance
Date
Final manufacture, http://intranetapps.f
TEVA PHARMACEUTICAL packaging, release da gov/scripts/mpq AC as CTL, inspected ASSIGNED
5/27/2014 3003414719 ROW ISR ADM 9459237 PN
INDUSTRIES LTD. and stability testing a/profile.cfm?FEI=3 10/10/2013 INSPECTION TO IB
of commercial 003414719
product
(b) (4)

(b) (4)

http://intranetapps.f
AC as ADM hat
TEVA PHARMACEUTICALS Amorphous Content da gov/scripts/mpq OC
5/27/2014 3002807777 WEU IRL CTL includes tes ing, AC
IRELAND Tes ing a/profile.cfm?FEI=3 RECOMMENDATION
inspected 9/12/2013
002807777

Test and release

http://intranetapps.f
active ingredient, AC for capsules and
TEVA PHARMACEUTICAL da gov/scripts/mpq OC
5/27/2014 3005202697 ROW ISR inactive ingredient, CTL tablets, inspected AC
INDUSTRIES a/profile.cfm?FEI=3 RECOMMENDATION
and 10/17/2013
container/closure 005202697

For each EER, indicate PAI recommendation on the Manufacturing Facilities Chart above (e.g., PS, GMP, 10 Day, AC based on file
review). This is the recommendation that will be entered into EES. For PAI, include the reason for the PAI (i.e. PAI Trigger) in
the comment section of the facilities chart.

Page 8 of 9

Reference ID: 3530283

 OMPQ Initial Manufacturing (CGMP/Facilities) Assessment and Filing Review
For Pre-Marking Applications

V. Overall Conclusions and Recommendations

Is the application fileable? (yes/no, Yes to questions 11-12) Yes

Based on Section IV, is a KTM warranted for any PAI? yes. If yes, please identify
the sites in the above chart. Recommend KTM for Teva Pharmaceutical, Israel which
has never been inspected as an ADM facility.

Are there comments/issues to be included in the 74 day letter, including

appropriate identification of facilities? (yes/no) No
Comments for 74 Day Letter
1.
2.
3.

REVIEW AND APPROVAL

(DARRTS)

Page 9 of 9
Reference ID: 3530283
 ---------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
---------------------------------------------------------------------------------------------------------
/s/
----------------------------------------------------
LINDA L NG
06/23/2014

VIPULCHANDRA N DHOLAKIA
06/23/2014

Reference ID: 3530283

 ONDQA Initial Quality Assessment (IQA) ADDENDUM
For Pre-Marking Applications

IQA ADDENDUM
1. NEW DRUG APPLICATION NUMBER: N205636
2. DATES AND GOALS:
Letter Date: 05-MAY-2014 Submission Received Date : 05-MAY-
2014
PDUFA Goal Date: 05-MAR-2015

3. PRODUCT PROPERTIES:
Trade or Proprietary Name: ProAir® RespiClick®1
Established or Non-Proprietary
Albuterol
Name (USAN):
Dosage Form: Inhalation powder
Route of Administration Oral inhalation
Undeclared2/device delivers 108 mcg of albuterol sulfate from
Strength/Potency
the mouthpiece (equivalent to 90 mcg of albuterol base)
Rx/OTC Dispensed: Rx X OTC

4. INDICATION: For 1) treatment/prevention of bronchospasm in patients 12 years of age

and older with reversible obstructive airway disease (asthma); 2) for the prevention of
exercise-induced bronchospasm in patients 12 years of age or older. Albuterol sulfate is a
short-acting β2-agonist bronchodilator already approved in other forms for the treatment of
asthma.

5. NAME OF APPLICANT (as indicated on Form 356h): Teva Branded

Pharmaceuticals R&D, Inc.

6. DRUG SUBSTANCE STRUCTURAL FORMULA/DRUG PRODUCT:

1 The device had previously been referred to as “ (b) (4)

” but the Agency did not agree with this proprietary
device name.
2 See correspondence of 06-MAY-2010.

Office of New Drug Quality Assessment (ONDQA) Internal Quality Procedure 5106 Record A
Effective Date: 09/01/2013 Page 1 of 5

Reference ID: 3524170

The application is submitted in support of an albuterol sulfate inhalation powder drug product for
the treatment of asthma. Note that while there are multiple single ingredient albuterol sulfate
inhalation aerosols approved, there are no inhalation powder drug products (i.e., a new dosage
form for albuterol). The device for this combination product is a reservoir type (device-metered)
of inhalation product. The formulation in the reservoir is composed mainly of lactose
(b) (4)
monohydrate with (b) (4) of albuterol sulfate. A schematic drawing of the device is
reproduced below from the application:

Start of Applicant Material

(b) (4)

End of Applicant Material

Note that this addendum has been written to provide a more formal risk assessment to the
reviewer regarding the drug product, which had not been required at the time the original IQA
was written. The table below captures the associated risk analysis for each drug product CQA
and is meant to help focus the reviewer on the higher risk aspects of the application during
review.
 ONDQA Initial Quality Assessment (IQA) ADDENDUM
For Pre-Marking Applications

DP attribute/ Factors that can impact the O4 S4, 5 D4 FMECA Comment & considerations
CQA CQA3 RPN #
Delivered Dose  Inhomogeneity or low 2 2 2 8  DDU tested at release and for routine stability; small sample
Uniformity formulation assay of size
(DDU) albuterol sulfate/lactose (b) (4)

blend (e.g., from  Net content fill weight test; small sample size
manufacturing; result  DP characterization study for exhaustion provided to assure
of shipping) sufficient reservoir overfill (b) (4) + 100%
 Lower than target fill of check weigh of filled inhalers
reservoir (b) (4)
 Failure of protective 
packaging (moisture
 100% overwrap integrity IPC test
ingress)
 100% inhaler functionality test for first 3 actuations
 Amorphous content of
 API tested for amorphous content at release
API
 30°C/65%RH equilibration period to address
 Device malfunction
triboelectrification prior to overwrapping
 Particle
 Reference P.2.1 re: potential for amorphous lactose
size/amorphous content
of lactose  PSD of lactose specified
 Static charge of
formulation
Aerodynamic  Inhomogeneity or low 2 2 2 8  APSD tested at release/stability; small sample size
Particle Size assay of albuterol (b) (4)

Distribution sulfate/lactose blend  Net content fill weight test; small sample size
(APSD)  Lower than target fill of  DP characterization study for exhaustion provided to assure
reservoir sufficient reservoir overfill + 100% check weigh of filled
 Failure of inhalers
protective (b) (4)
packaging 
 Particle size  (b) (4)
as per approved ProAir HFA® MDI of
distribution of API N21457
 Amorphous content of  100% overwrap integrity IPC test
API  100% inhaler functionality test for first 3 actuations
 Device malfunction  Device flow resistance is specified
 Particle  API tested for amorphous content/PSD at release
size/amorphous content
of lactose

3
Based on underlying assumption that patients use the device as intended (human factors beyond scope of CMC evaluation).
4O = Probability of Occurrence; S = Severity of Effect; D = Detectability
Office of New Drug Quality Assessment (ONDQA) Internal Quality Procedure 5106 Record A
Effective Date: 09/01/2013 Page 4 of 5

Reference ID: 3524170

 ONDQA Initial Quality Assessment (IQA) ADDENDUM
5
For Pre-Marking Applications
Severity of effect can only be estimated; input from clinical or pharmacology/toxicology team would be necessary for more accurate assessment of clinical impact of failures of
product CQAs.

Office of New Drug Quality Assessment (ONDQA) Internal Quality Procedure 5106 Record A
Effective Date: 09/01/2013 Page 5 of 5

Reference ID: 3524170

  Composition of device  30°C/65%RH equilibration period to address
air flow path triboelectrification prior to overwrapping
components  Reference P.2.1 re: potential for amorphous lactose
 Device flow  PSD of lactose specified
resistance variation (b) (4)

 Static charge of
formulation
Purity  degradation of API as 1 2 2 4  Dry powder less susceptible to degradation than liquid based
(impurities/degrad formulated formulations
ants)  input purity of API  API compatibility with lactose and device reservoir
 input purity of lactose component can be evaluated based on drug product stability
data (total impurities slightly trend with time)
 API already approved for use for inhalation product of
N21457
 (b) (4)
lactose grade not evaluated, but supplier approved for
other grades for inhalation products

This document will be sequentially signed in DARRTS by all of the following who authored or reviewed this assessment:

See appended electronic signature page}

Craig M. Bertha, PhD
Acting CMC-Lead
Division III
Office of New Drug Quality Assessment

{See appended electronic signature page}

Eric Duffy, PhD
Acting Branch Chief/Division Director
Division III
Office of New Drug Quality Assessment

Office of New Drug Quality Assessment (ONDQA) Internal Quality Procedure 5106 Record A
Effective Date: 09/01/2013 Page 5 of 5

Reference ID: 3524170

 ---------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
---------------------------------------------------------------------------------------------------------
/s/
----------------------------------------------------
CRAIG M BERTHA
06/13/2014

ERIC P DUFFY
06/13/2014

Reference ID: 3524170

 ONDQA Initial Quality Assessment (IQA) and Filing Review
For Pre-Marking Applications

IQA and Filing Review Cover Sheet

1. NEW DRUG APPLICATION NUMBER: N205636
2. DATES AND GOALS:
Letter Date: 05-MAY-2014 Submission Received Date : 05-MAY-
2014
PDUFA Goal Date: 05-MAR-2015

3. PRODUCT PROPERTIES:
Trade or Proprietary Name: ProAir® RespiClick®1
Established or Non-Proprietary
Albuterol
Name (USAN):
Dosage Form: Inhalation powder
Route of Administration Oral inhalation
Undeclared2/device delivers 108 mcg of albuterol sulfate from
Strength/Potency
the mouthpiece (equivalent to 90 mcg of albuterol base)
Rx/OTC Dispensed: Rx X OTC

4. INDICATION: For 1) treatment/prevention of bronchospasm in patients 12 years of age

and older with reversible obstructive airway disease (asthma); 2) for the prevention of
exercise-induced bronchospasm in patients 12 years of age or older. Albuterol sulfate is a
short-acting β2-agonist bronchodilator already approved in other forms for the treatment of
asthma.

5. DRUG SUBSTANCE STRUCTURAL FORMULA:

1 The device had previously been referred to as (b) (4)

” but the Agency did not agree with this proprietary
device name.
2 Note that the applicant was informed in the correspondence of 06-MAY-2010, that:

(b) (4)
“The strength of the product will need to correspond to the metered dose,
. Thus reference to ‘Label Claim’ technically refers to the metered target dose for
inhalation powder drug products. Revise the various acceptance criteria that involve reference to the
emitted dose target such that ‘Label Claim’ is substituted with a more appropriate term (e.g., Label Claim
Emitted Dose or LCED).” The absence of a defined “metered dose” may result in labeling discrepancies
versus other similar drug products.

Office of New Drug Quality Assessment (ONDQA) Internal Quality Procedure 5106 Record A
Effective Date: 09/01/2013 Page 1 of 19

Reference ID: 3519160

6. NAME OF APPLICANT (as indicated on Form 356h): Teva Branded
Pharmaceuticals R&D, Inc.

7. SUBMISSION PROPERTIES:
Review Priority: Standard Priority
Submission Classification
(Chemical Classification Based on draft MaPP 7500.3, Type 3: New Dosage Form
Code):
Application Type: 505(b)(2)

Breakthrough Therapy Yes No X

Responsible Organization
DPARP
(Clinical Division):

8. CONSULTS:
CONSULT YES NO COMMENTS: (list date of request if already sent)
Drug product expiration dating period is based on
real time stability data; Although not an NME,
reviewer should consider the principles outlined in
Biometrics X
ICH Q1E when evaluating the applicant’s
proposed expiration dating period and stability
data.
Clinical Pharmacology X
Establishment Evaluation The ONDQA PM entered the EER in EES on 27-
X
Request (EER) MAY-2014
 CONSULT YES NO COMMENTS: (list date of request if already sent)
It is unlikely that a consult to the
pharmacology/toxicology group will be necessary
as the albuterol sulfate (DMF (b) (4) ) is already
found acceptable for use in inhalation drug
products and the lactose (b) (4) is being
sourced from a supplier that has been used by
other applicants for approved inhalation powder
drug products, albeit, under other master files.

However, it is noted that we “encouraged” the

Pharmacology/Toxicology X sponsor at the CMC EOP2 meeting and at the 05-
OCT-2010, EOP2 meeting to reduce the allowance
of the levels of the (b) (4) impurity
and referred them to the draft guidance on
genotoxic and carcinogenic impurities. Currently
the limit for (b) (4) in the drug
product is not more than (b) % (with 12 actuations
this (4)
would equate to a maximum of (b) (4)
mcg of
(b) (4) per day. Consult with the
pharm/tox team regarding the acceptability of this
limit.
It will be left to the reviewer to decide if it is
warranted to send any methods for assessment by
Methods Validation the Agency laboratory, based on evaluation of the
method and the associated validation data
provided.
The applicant claims categorical exclusion as per
21 CFR 25.31(b). The reviewer can consult with
Environmental Assessment the OPS EA expert (R. Bloom, PhD) if the
calculations related to the expected introduction
concentration are determined to be questionable.
The DPARP PM has sent a consult to CDRH
dated 28-MAY-2014, regarding the human factors
study report included in P.2 of the application.
From a purely CMC-perspective, it is not
CDRH necessary at this point to request CDRH to
evaluate any of the quality-related information for
the device, however, this may change once a
detailed evaluation is performed by the reviewer
(if NDA is filed).
Other N/A
 Overall Filing Conclusions and Recommendations
CMC:
Is the Product Quality Section of the application fileable from a CMC perspective?
Yes X No
CMC Filing Issues:
Currently the application does not include a letter of authorization from the device
manufacture to allow our review of a DMF that contains pertinent CMC information for the
device. It appears that the device manufacturer (b) (4) had a DMF
(b) (4)
(b) (4)
1
for the inhaler, but that due to inactivity, the file was closed in 2013. An
information request regarding this filing issue was sent to the firm on 03-JUN-2014.
However, the applicant has indicated that they own the device and all of the associated
technology such that any questions regarding the CMC information for the device can be
directed to the applicant directly.
Are there potential CMC review issues to be forwarded to the Applicant with the 74-Day
letter?
Yes X No
CMC Comments for 74-Day Letter (assuming filing):
1. Provide data to support the label claim strength of the drug product for the label/labeling.
We remind you of our communication dated May 6, 2010, where we had informed you that
the strength of the product should correspond to the metered dose, not the amount of drug
emitted from the mouthpiece.

Biopharmaceutics:
Is the Product Quality Section of the application fileable from a Biopharmaceutics
perspective?
Yes X No
Biopharmaceutics Filing Issues:
1.

Are there potential Biopharmaceutics review issues to be forwarded to the Applicant with
the 74-Day letter?
Yes No X
Biopharmaceutics Comments for 74-Day Letter:
1.

Microbiology:
Is the Product Quality Section of the application fileable from a Microbiology perspective?
Yes X No
Microbiology Filing Issues:
See memorandum dated 29-MAY-2014 from Bryan S. Riley, PhD. The microbiology
team recommends that the application be approved (and presumably filed).
 Summary of Initial Quality Assessment
Does the submission contain any of the following elements?
Nanotechnology QbD Elements PET Other, please explain
No No No N/A

Is a team review recommended? Yes No X

Suggested expertise for team:

Summary of Critical Issues and Complexities: See the summary list below at the beginning
of the IQA review.
 INITIAL QUALITY ASSESSMENT
The application is submitted in support of an albuterol sulfate inhalation powder drug product for
the treatment of asthma. Note that while there are multiple single ingredient albuterol sulfate
inhalation aerosols approved, there are no inhalation powder drug products (i.e., a new dosage
form for albuterol). The device for this combination product is a reservoir type (device-metered)
of inhalation product. The formulation in the reservoir is composed mainly of lactose
(b) (4)
monohydrate wit (b)
(4) mg of albuterol sulfate. A schematic drawing of the device is
h
reproduced below from the application:

Start of Applicant Material

(b) (4)

End of Applicant Material

In addition to the lack of information regarding the manufacturing of the (b) (4) device as
noted above, below are a list of critical issues and complexities that have been noted during
development (under IND 104532) or observed in the cursory IQA/filing review that should be
taken into consideration during the evaluation of the application, assuming it is filed:
 As noted above, there does not appear to be any data supporting the label claim strength
of the drug product in the application (see filing letter comment above).

 We had requested that the applicant include a test for amorphous content for the lactose
excipient. They indicate in P.4.4, that amorphous content will not be tested for the
lactose, and they have provided data to support a justification that will need to be
evaluated.

 Routine extractables controls for device components are described in P.7 and will need to
be evaluated to assure they serve the purpose intended.

 The Agency had requested that the applicant include appropriate tests with acceptance
criteria for those dimensions of the device that would be critical to the reproducible
metering and delivery of the drug product formulation. The specifications for the various
device components appear to be limited in terms of dimensional requirements (and there
is no associated DMF from the device manufacturer). An evaluation of the adequacy of
the specifications should consider assurance of dosing reproducibility during the shelf life
of the drug product.

 The proposed acceptance criterion for the fine particles of drug collected on stages 3-5 of
(b) (4) (b) (4)
the impactor for APSD individual determinations is mcg. This
(b) (b)
range of (4) fold is somewhat larger than the “rule-of-thumb” limit of (4) fold that the
Agency has typically recommended for similar drug products. The reviewer may need to
seek input from the clinical team regarding the acceptability of these limits if the data do
not support tightening of the criterion. Note that the applicant is testing n = 5 inhalers at
beginning and end and mass balance criterion for each determination is in line with
Agency recommendations ( (b) (4) % of label claim emitted dose).

 As indicated above, it does not appear that the applicant has characterized the metered
dose of the drug product, which also relates to potential dose hold-up or build-up. In the
drug product characterization section it is claimed that no cleaning is necessary during
patient use.

 The applicant appears to have provided drug product characterization data supporting the
ruggedness (effect of dropping, shaking, simulated shipping, etc.) and impact of use in
different orientations, as was addressed at the 27-MAR-2009, meeting during
development.

 The applicant has provided in-use data (after overwrap removed and under intermediate
storage conditions of 30°C/65%RH) as requested by the Agency during development.
And, as also requested due to the unique design, the applicant has provided data
characterizing drug product performance with the mouthpiece left open both prior to dose
delivery and after dose delivery. These studies are in the P.2 section of the application.

 The sponsor was sent responses to multiple CMC-related questions posed at end-of-phase
2 (06-MAY-2010, correspondence). The advice and recommendations provided were in
 line with the current policy and practice in place at the time for DPI drug products. As a
result, the sponsor cancelled the CMC EOP2 meeting. A few issues are worth noting:

o The sponsor was informed that they should incorporate counter accuracy and
reliability assessment during any “through life” performance testing that takes
place at release, for stability samples, for drug product characterization studies, or
for drug product returned from the clinical site (both complaint devices and
routine returns). It is important that the dose counter have sufficient accuracy and
reliability to meet the clinical expectations. The reviewer may need to discuss the
counter-related data with the clinical reviewer if it appears to be marginally
acceptable or otherwise problematic.

o Note that the applicant currently has a single set of APSD acceptance criteria for
(b) (4)
the Impactor testing of the drug product at the beginning and end
of inhaler life (through life). We had indicated that if there were a significant
beginning-to-end trend in APSD, separate acceptance criteria may be necessary
for the two life stages. The reviewer should keep in mind this advice we gave to
the sponsor at the EOP2 when evaluating the APSD through life data.

o The Office provided the sponsor with comments on their approach to the handling
of APSD mass balance failures. Refer to the Agency comments when reviewing
the current proposed protocol.

o We reminded the sponsor that they would need to characterize the stability of the
drug product with-out the protective packaging for a length of time twice that of
the proposed in-use period. This should be considered when evaluating the in-use
stability data. Also, at the subsequent pre-NDA meeting held on 19-NOV-2013,
we asked that the applicant also consider potential pro re nata usage of the drug
product when conducting their in-use studies. This is important considering that
some patients do not use albuterol regularly or daily.

o The sponsor was asked to also examine simulated use that would mimic dose
emission from the device if the patient were in the supine position. This had not
been included in the proposed protocol presented at EOP2. Such data will be
important to support the patient instructions for use.

o The Agency questioned the proposals for the justification of the reservoir fill
weight. The reviewer should assure that the extremes of the allowed fill weight
range are justified with data.

 In 2012 the Division became aware that the sponsor had observed a patient mis-use issue
in the clinical studies, and as a result they made several device modifications to address
such mis-use. Refer to the CMC review dated 04-MAR-2013, prior to review of the
application, for details and evaluation.
  At the 19-NOV-2013, meeting, we agreed to accept updated stability data for 3 batches of
(b) (4)
the drug product manufactured at
the commercial site, which would be in addition to other stability data from that site for
(b) (4)
product from the

 The applicant has submitted comparability protocols in P.2.4, as outlined in the cover
(b) (4)
letter of the NDA, regarding changes to drug device components and site
changes for device manufacturing. We had agreed to accept and evaluate these protocols
at the 19-NOV-2013, pre-NDA meeting.

 Drug product characterization studies are included in section P.2.4 of the application,
along with detailed information pertaining to the device. These should be evaluated to
support labeling and patient instructions.

BIOPHARMACEUTICS INITIAL ASSESSMENT

Biopharmaceutics Summary
Albuterol Multi-dose Dry Powder Inhaler (Albuterol MDPI) Inhalation Powder product contains
a formulation of albuterol sulfate and lactose monohydrate, delivering 90 mcg of albuterol base
from the inhaler mouthpiece at each actuation. It is proposed to be used for the treatment or
prevention of bronchospasm with reversible obstructive airway disease and for the prevention of
exercise-induced bronchospasm.

The clinical program consisted of 8 clinical studies: a cumulative dose Phase 1 study, a 5-way
single-dose Phase 2 dose-ranging study and 5 Phase 3 studies that included 3 pivotal efficacy
studies.

A Chemistry, Manufacturing and Controls (CMC) program has been conducted for the product
including a stability program on nine exhibit batches. Based on the testing at various orientations
(b) (4)
and conditions, as well as in- and out-of-package testing, the Applicant is proposing months
expiry for the packaged product and 13 months expiry for the out-of- package product. Full
details are in 3.2.P.8.1 Stability Summary and Conclusions. Key CMC reports are in Section
3.2.P.2 Pharmaceutical Development:

 Report on the Results of Human Factors Testing (Section 3.2.P.2.4, Container Closure
System – Human Factors Study Report)

 A total of 15 Drug Product Characterization Studies, including a Spacer Study, as

recommended by the Agency (Section 3.2.P.2.4, Container Closure System – Drug
Product Characterization)

 Two comparability protocols: the first for (b) (4) for one of the
components; the other for an alternate site of manufacture of the device (Section
3.2.P.2.4, Container Closure System).

The two comparability protocols are summarized below.

 (b) (4)
1.

The Applicant has been notified that commercial supply of (b)

(4)
is being discontinued. It is therefore proposed to replace the (b) (4)
with an alternative (b) (4) The
alternative material will be chosen to have similar characteristics and performance to the existing
material.

The change to an alternative material grade has been risk assessed as low risk. The alternative
material will undergo a (b) (4) qualification program. Albuterol MDPI
devices will be manufactured using (b) (4)
These
will undergo full batch release testing of sub-assemblies, they will be filled with drug
formulation and will undergo full finished product release testing.

Upon prior agreement with FDA, the material change will be communicated to FDA through a
CBE-30 Supplement with a comparability report based on original and new material batch
release testing and finished product release testing.

A detailed comparability protocol for this material change is in Section 3.2.P.2.4 (b)
(4)

2. Second Device Manufacturing Site

The exhibit and clinical batches of Albuterol MDPI used devices manufactured from sub-
assemblies that had been (b) (4) at (b) (4)
To meet the anticipated volume demands for Albuterol MDPI, a second manufacturing site for
the device sub-assemblies is being developed at (b) (4)
This site will carry out comparable (b) (4) test and release activities to those currently
undertaken at the
(b) (4) site. It is proposed that devices manufactured at the new site and subsequently
filled with drug formulation will undergo finished product release testing and be placed on a
stability program.

Upon prior agreement with FDA, the supply of commercial devices from the new site will be
communicated to FDA through a CBE-30 supplement with a comparability report based on
original and new manufacturing site batch release testing, finished product release testing and
results from a minimum of six months stability testing.

A detailed comparability protocol for this second manufacturing site is in Section 3.2.P.2.4
‘Comparability Protocol for Second Device Manufacturing Site’.
Critical Review Issues
Critical review issues identified during filing are as follows.
 The suitability of the comparability protocol for the proposed changes.
Comments for Day 74-Letter
None
 FILING REVIEW CHECKLIST
The following parameters are necessary in order to initiate a full review, i.e., complete enough to
review but may have deficiencies. On initial overview of the NDA application for filing:

A. GENERAL
Parameter Yes No Comment
Is the CMC section organized
1. X
adequately?
Is the CMC section indexed and
2. paginated (including all PDF X
files) adequately?
Are all the pages in the CMC For the pages that were examined for this IQA
3. X
section legible? review.
Has all information requested See details outlined above.
during the IND phase, and at the
4. X
pre-NDA meetings been
included?

B. FACILITIES*
* If any information regarding the facilities is omitted, this should be addressed ASAP with the
applicant and can be a potential filing issue or a potential review issue.
Parameter Yes No Comment
Is a single, comprehensive list of
5. all involved facilities available in X
one location in the application?
For a naturally-derived API only, NA
are the facilities responsible for
critical intermediate or crude API
manufacturing, or performing
upstream steps, specified in the
6.
application? If not, has a
justification been provided for
this omission? This question is
not applicable for synthesized
API.
 Parameter Yes No Comment
Are drug substance manufacturing
sites identified on FDA Form 356h or
associated continuation sheet? For
each site, does the application list:
 Name of facility,
 Full address of facility including
street, city, state, country
7.  FEI number for facility (if X (b) (4)
previously registered with FDA) DMF
 Full name and title, telephone, fax
number and email for on-site contact
person.
 Is the manufacturing responsibility
and function identified for each
facility?, and
 DMF number (if applicable)
Are drug product manufacturing sites
identified on FDA Form 356h or
associated continuation sheet. For
each site, does the application list:
 Name of facility,
 Full address of facility including
street, city, state, country
8.  FEI number for facility (if X
previously registered with FDA)
 Full name and title, telephone, fax
number and email for on-site contact
person.
 Is the manufacturing responsibility
and function identified for each
facility?, and
 DMF number (if applicable)
 Parameter Yes No Comment
Are additional manufacturing,
packaging and control/testing
laboratory sites identified on FDA
Form 356h or associated
continuation sheet. For each site,
does the application list:
 Name of facility,
 Full address of facility
9. including street, city, state, X
country
 FEI number for facility (if
previously registered with
FDA)
 Full name and title, telephone,
fax number and email for on-site
contact person.
 Is the manufacturing
responsibility and function
identified for each facility?,
and
 DMF number (if applicable)
Is a statement provided that all
facilities are ready for GMP
10. X
inspection at the time of
submission?

C. ENVIRONMENTAL ASSESMENT
Parameter Yes No Comment
Has an environmental assessment A categorical exclusion is requested as per 21
11. or claim of categorical exclusion X CFR 25.31(b).
been provided?
 D. DRUG SUBSTANCE/ACTIVE PHARMACEUTICAL INGREDIENT (DS/API)
Parameter Yes No Comment
Does the section contain a
12. description of the DS Reference is made to DMF (b) (4)
manufacturing process?
Does the section contain
identification and controls of
13. Reference is made to DMF (b) (4)
critical steps and intermediates of
the DS?
Does the section contain
14. information regarding the Reference is made to DMF (b) (4)
characterization of the DS?
Does the section contain controls
15. Reference is made to DMF (b) (4)
for the DS?
Has stability data and analysis
16. been provided for the drug Reference is made to DMF (b) (4)
substance?
Does the application contain
17. Quality by Design (QbD) Reference is made to DMF (b) (4)
information regarding the DS?
Does the application contain
Process Analytical Technology
18. Reference is made to DMF (b) (4)
(PAT) information regarding the
DS?
 E. DRUG PRODUCT (DP)
Parameter Yes No Comment
Is there a description of
manufacturing process and
methods for DP production
19. X
through finishing, including
formulation, filling, labeling and
packaging?
Does the section contain
identification and controls of
critical steps and intermediates of
20. the DP, including analytical X
procedures and method
validation reports for assay and
related substances if applicable?
Is there a batch production record
21. and a proposed master batch X
record?
Has an investigational
formulations section been
provided? Is there adequate
22. X See P.2
linkage between the
investigational product and the
proposed marketed product?
Have any biowaivers been
23. X
requested?
Does the section contain (b) (4)
Note that the final device is the and that an
description of to-be-marketed (b) (4)
24. X earlier version was (supportive stability
container/closure system and
presentations? data are provided with the latter device).
Does the section contain controls
25. X
of the final drug product?
Has stability data and analysis
26. been provided to support the X
requested expiration date?
Although the applicant uses some QbD related
terminology and has performed some DoE
Does the application contain
experiments to support some of their
27. Quality by Design (QbD)
manufacturing processes, none of this information
information regarding the DP?
appears to be used for revising the drug product
control strategy for “regulatory relief.”
Does the application contain
Process Analytical Technology
28. X
(PAT) information regarding the
DP?
 F. METHODS VALIDATION (MV)
Parameter Yes No Comment
If the reviewer determines that it is prudent to
send one or more methods to the Agency lab for
Is there a methods assessment, a request for sample information can
29. X
validation package? be made of the applicant. Other pertinent
information typically provided in a MV package
are found in various locations within the NDA.

G. MICROBIOLOGY
Parameter Yes No Comment
If appropriate, is a separate
microbiological section
30. X
included assuring sterility of the
drug
product

H. MASTER FILES (DMF/MAF)

Parameter Yes No Comment
There is no DMF letter of authorization
allowing review of information on the
manufacture of the (b) (4) device (now
referred to as “RespiClick”) by (b)
Is information for critical DMF (4)
references (i.e., for drug (DMF (b) (4) ). It appears that
substance and important this DMF was inactive and has subsequently
31. X
packaging components for been closed. However, in an electronic mail
non- solid-oral drug products) message from the applicant dated 04-JUN-
complete?
2014, they indicate that they own the device
and all associated technology. Thus, any
requests for additional device-related
information or data can be made directly to
the applicant.

DMF # TYPE HOLDER ITEM REFERENCEDLOA DATE COMMENTS

(b) (4) (b) (4)
2 Found adequate 16-APR-2013
to support an inhalation solution drug product 17-MA
submitted subsequently

(b) (4)
4 02-MAY-2013

3 21-JAN-2014
Unclear from DARRTS if reviewed for this particular

(b) (4)
 (b) (4) (b) (4)
3 20-JUL-2013 Unclear from
DARRTS if reviewed
for this particular
(b) (4)

3 26-APR-2013 DMF not reviewed

I. LABELING
Parameter Yes No Comment
Has the draft package insert been
32. X
provided?
Have the immediate container
33. X
and carton labels been provided?
The following parameters for the ONDQA’s Product Quality-Biopharmaceutics filing checklist
are necessary in order to initiate a full biopharmaceutics review (i.e., complete enough to review
but may have deficiencies).

ONDQA-BIOPHARMACEUTICS
A. INITIAL OVERVIEW OF THE NDA APPLICATION FOR FILING

PARAMETER YES NO COMMENT

Does the application contain
34. X NA
dissolution data?
Is the dissolution test part of the
35. X
DP specifications?
Does the application contain the
36. dissolution method development X
report?
Is there a validation package for
37. the analytical method and X
dissolution methodology?
Does the application include a
38. X
biowaiver request?
Does the application include an
39. X
IVIVC model?
Is information such as BCS
40. classification mentioned, and X
supportive data provided?
Is information on mixing the
41. product with foods or liquids X
included?
A Phase 1 study with accumulative dose
Is there any in vivo BA or BE
42. X was conducted. The study will be reviewed
information in the submission?
by OCP.
Is there a modified-release claim?
X
If yes, address the following:
a.) Is there information
submitted to support the
claim in accordance with
43.
320.25(f)?

b.) Is there information on the

potential for alcohol-induced
dose dumping?
 B. FILING CONCLUSION

Parameter Yes No Comment

IS THE BIOPHARMACEUTICS
44. SECTIONS OF THE X
APPLICATION FILEABLE?
If the NDA is not fileable from the
product quality-biopharmaceutics
45. perspective, state the reasons and Not applicable.
provide filing comments to be
sent to the Applicant.
Are there any potential review
46. issues to be forwarded to the X
Applicant for the 74-day letter?

This document will be sequentially signed in DARRTS by all of the following who authored or
reviewed this assessment:

See appended electronic signature page}

Craig M. Bertha, PhD
Acting CMC-Lead
Division III
Office of New Drug Quality Assessment

{See appended electronic signature

page} John Duan, PhD
Biopharmaceutics Reviewer
Office of New Drug Quality Assessment

{See appended electronic signature page}

Tapash Ghosh, PhD
Biopharmaceutics Team Leader
Office of New Drug Quality Assessment

{See appended electronic signature page}

Eric Duffy, PhD
Acting Branch Chief/Division Director
Division III
Office of New Drug Quality Assessment

Office of New Drug Quality Assessment (ONDQA) Internal Quality Procedure 5106 Record A
Effective Date: 09/01/2013 Page 19 of 19

Reference ID: 3519160

 ---------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
---------------------------------------------------------------------------------------------------------
/s/
----------------------------------------------------
CRAIG M BERTHA
06/05/2014

JOHN Z DUAN
06/05/2014

TAPASH K GHOSH
06/05/2014

ERIC P DUFFY
06/05/2014

Reference ID: 3519160