2015 Observations

DEPARTMENf OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMlNISTRA T10"N

DISTRICT AOO~S AND P110Hf NUMBER DATE;(S) OF INSPeCTION
555 Winderley Place, Suite 200 07/20/2015 - 08/14/2015*

fl:l NIINBE:R
Maitland, FL 32751
(407) 475-4700 Fax: (407) 475-4768 1000114235
Indust r y Information: www.fda.gov/oc/indus try
NAME AND TITLE OF INOIVIOUAL TO WHOM REPORT ISSUED
TO: Lou W. Kennedy , CEO and President

FIRM NAME STREET ADDRESS
Nephro n Pharmaceuticals Cor p . 4121 sw 34th St

CITY, STATE, ZIP CODE, COUNTRY TYPE ESTABUstiMEIH INSPECTED
Orlando, FL 32811-6475 Sterile Inhalation Drug and Device

Manufacturer
This document llsts observations made by the FDA representative(s) during the inspection of your fac ility. They are inspectional
observations, and do not represent a final Agency determination regarding your compliance. Jfyou have an objection regarding an
observation, or have implemented or plan 10 implement, correcti ve action in response to an observation, yo u may discuss the objection or
action with the FDA reprcscntatjve(s) during the inspection or submit th is infonnation to FDA at the address above. If you have any
questions, please contact FDA at the phone number and address above.
The observations noted in this Form FDA-483 are not an exhaustive listing ofobjectionable conditions. Under the law, your
firm is responsible for conducting internal self-audits to identify and co"ect any and all violations ofthe quality system
requirements.
DURING AN INSPECTION OF YOUR FIRM WE OBSERVED:
STERILE INHALATION DRUGS
QUALITY SYSTEM
OBSERVATION 1
Drug products failing to meet established standards, specifications, and quality control criteria are not rejected.
SpecificaHy your Quality Unit failed to reject two (2) batches (lot# D4C21A and D4E20A) of(b) (4)
(Albuterol Sulfate/Ipratropium Bromide) Inhalation Solution that were contaminated with(b) (4)
(b) (4) (b) (4) (b) (4) (b) (4)
(b) (4) (b) (4)
on 4/14/14 and 4/29/14, respectively. The following investigations
demonstrate this failure:
A. According to NCR 14-062 investigation (dated 4114/14), black stains were observed around the
necks of vials (pallet# (b) (4) of(b) (4) lot# D4C21A as they exited the (b) (4)
The stains were caused by excessive industrial lubricant (b) (4)
. QA inspected vials in
pallets#(b) (4) and found an unknown number of similar defects and these pallets
were rejected; however, pallets # (b) (4) were not inspected. The investigation did not describe if
the stains could be removed/wiped off or were embedded onto the plastic vial. After the excess
....
EMPLDYEE(S)SIGNAT\JRJ: ~ ,.:- ~ .P'~ DATEISOOEO
Je••ica L Pre••ley , lnve• tigator ~

..._
Melanie M. Walke r, Mi c robiolog~ ~
SEE REVERSE Ivis L. Negron Torres, Chemist ..-...:.. · ~ ~- ~
CAPT Ileana Barreto-Pettit, Investigator ~ 08/14 / 20 1 5
OF THIS PAGE
LCDR Michael H. Tallon, Investigator
FORM FDA 483 (09108) PREVIOUS EDITION OBSOLETE INSPECTIONAL O.DSERVA TIONS PAGE I OF24PAGES
DEPARTMENT OF HEALTH AND IWMAN SERVICES
FOOD AND DJ.tUG ADMINlSTRATION
DISTRICT ADORE~ AND PHONE NUMBER OATE(S) OF INSPECTION

FEI NUMBER
Maitland, FL 32751
(407) 475-4700 Fax: (407) 475-4768 1000114235
Industry Information: www.fda.gov/oc/indust r y
NAME AND Tm.E OF INDIVIDUAL TO WHOM REPORT ISSUED
TO: Lo u W. Kennedy , CEO and President

Nephron Pharmaceuticals Corp . 4121 SW 34th St

CITY. STATE, 2JP CODE. COUNTRY T'IJ'E ESTAilUSHMENT INSPECTED

Manufacturer
lubricant was removed from the (b) (4) molds by engineering, filling continued for the batch.
During secondary packaging operations on 4/20/14, (b) (4)
. The remaining (b) (4) pallets (out of (b) (4) were
packaged and released by the Quality Unit.
B. Similarly, two weeks later on 4/29/14, another batch of(b) (4) , lot# D4E20A, manufactured
in a different (b) (4) was found with similar black stains around the neck
of the vials towards the end of filling (Pallet# (b) (4) and NCR# 14-068 investigation was initiated.
QA inspected the last two trays and similar stain defects were found; all product back to the last
acceptable attribute visual inspection (pallet# (b) (4) was rejected and the excess grease was
removed from the BPS molds before resuming filling operations. The (b) (4) pallets were not
inspected during the investigatio~ but were packaged and released as stains were not observed
during packaging inspections.
The above investigations were not adequate for the following reasons:
a. Your Quality Unit failed to fully evaluate the impact of this unexpected and random
contamination of sterile inhalation drug products with a non-sterile, industrial grade lubricant.
The investigations revealed that the (b) (4) machines
(Lines (b) (4) was excessive during the typical(b) (4) filling runs causing random dripping ofthe
lubricant onto the molds during operation. However, the contamination appeared to be treated as
a cosmetic defect that would not impact the safety, purity, and quality of the drug product as it
would be detected during visual inspections and impacted product would be removed.
b. The investigations did not describe the extent of the contamination and its impact to the sterility,
quality and composition of the other drug products manufactured in the (b) (4)
lines: Albuterol Sulfate 0.083%, Ipratropium Bromide, and Budesonide.
c. The investigations did not reveal that the lubricant was (b) (4) (not (b) (4)
and therefore its impact to product quality and safety was not assessed. The inadequacy
of the lubricants was identified during the FDA inspection.
d. The remaining (b) (4) were not inspected at the time of the investigations
to determine the level of excess lubricant on the bushings and gears of the mold chain to assess
potential cross-contamination of other drug batches.
EMPI.OYEE(S) SIGNATURE DATE ISSUED
Jessica L Pressley, Investigator ~

Melanie M. Walker, Microbiologist
SEE REVERSE Ivis L. Negron Torres, Chernis~
CAPT Ileana Barreto-Pettit, Investigator
08/14/2015
OF THIS PAGE
LCDR Michael H. Tollon, Investigator
FORM FDA 483 (Q9/U8) PREVIOUS EDIDON OBSOLE'IE INSPECTIONAL OBSERVATIONS PAGE 2 OF 24 PAGES
DEPARTMENT OF BEALm AND rmMAN SERVICES
FOOD AND DRUG ADMlNISTRATION
DISTRICT ADDRESS AND PHONE NUMBER OATE(S) OF INSPECTION

FEI NUIIIIER
Maitland, FL 32751
(407) 475-4700 Fax: (407) 475-4768 1000114235
Industry Information: www.fda. gov/oc/indust r y
NAME AND TITl£ OF INDIVIDUAL TO WHOM REPORT ISSUEO

flRNI NAME STREET ADDRESS
Nephro n Pharmaceuticals Corp. 4121 SW 34th St

CITY, STATE. ZJP CODE, COUNTIIY TYPE ESTABUSHI.IEINT INSPECTED

Manufacturer
OBSERVATION 2
There is a failure to thoroughly review any unexplained discrepancy and the failure of a batch or any of its components to
meet any of its specifications whether or not the batch has been already distributed.
Specifically,
A. On 10/7/14, S2 Racepinephrine Inhalation Solution 2.25%, lot R4033A (annual lot) failed color and
clarity at (b) (4) R.H.) which was confirmed by the laboratory on
10/7/14 in LIR 14-017. Your QU initiated NCR 14-127 on 10/9114 and identified that the (b) (4) API
(RM # (b) (4) used within the finished product for Lot# R4033A was also used in Lot# R4031A
and Lot# R4032A and the (b) (4) API (RM # (b) (4) was also used in Lot# R4026A, Lot# R4027A
and Lot# 4034A. On 6/22/15, S2 Racepinephrine Inhalation Solution 2.25%, lot R4033A, also
failed color and clarity at(b) (4) R.H.) which was confirmed by the
laboratory on 6/22/15 in LIR 15-015. Your QU failed to conduct a manufacturing investigation for
this failure and evaluate that RM # (b) (4) (containing (b) (4) adrenolone) and RM # (b) (4)
(containing (b) (4) adrenolone) were used within the following lots that are currently on the market:
Lot# R4031A (Exp. 11115), Lot # R4032A (Exp. 11115), Lot# R4026A (Exp.I0/15), Lot #R4027A
(Exp. 10/15) and Lot # 4034A (E:xp.l1/15). Your firm has received a high rate of 20 complaints for
Lot# R4034A and 6 complaint~ for Lot# R4027A for discoloration.
B. On 7114/15, an OOS for color and clarity results were detected for Asthmanefrin Racepinephrine
Inhalation Solution 2.25%, (b) (4) sample ((b) (4) .) for Lot# R4002A which
was confirmed by the laboratory in LIR 15-016. Your QU submitted aFAR on 7/17/15 but failed to
conduct a manufacturing investigation. Your QU has identified the (b) (4) API (small scale batches) to
contain higher levels ofadrenolone as illustrated in CAPA 2014-033 which was closed on 5/8/15.
We observed that the (b) (4) API (RM # (b) (4) used to manufacture the finished product Lot#
R4002A was also used to manufacture Lot# R4030A and Lot R403 1A which are currently on the
market with an expiration date of 11/15. Your QU has failed to evaluate the lots currently on the
market that shared the RM # (b) (4) which had been observed to exhibit elevated levels of
adrenolone (b) (4) leading to a possible failure for color and clarity according to your firm's
documentation.
EJ.IPI.DYEE(S) SIGAATURE OATE ISSUED
Jessica L Pressle y, I nvesti gat or 5)~

Melanie M. Walker , lticrobio logist
SEE REVERSE Ivis L. Negron To rres , Chemis ~
CAPT Ileana Barret o - Pet t i t , I nves t i g ato r ~ 08/14/2015
OF THIS PAGE
LCDR Michael H. Tollon, I nvestigator
FORM FDA 483 (09/08) PR.IWJOUS EDITION OllSOum! INSPECOONAL OBSERVATIONS PAGE 3 OF 24 PAGES
DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINlSTRAllON

Maitland, FL 32751
(407) 475-4700 Fax: (407) 475-4768 1000114235
Industry Information: www.fda.gov/oc/industry
NAME AND TITlE OF INDIVIDUAL TO WHOM REPQRT ISSUED
TO : Lou W. Kennedy , CEO and President

FIRM NAME SlREET ADDRESS

CITY, STATE, ZIP CODE. COUNTRY TYPE ESTABUSH.IENT INSPEC1Bl

Manufacturer
C. On 3/12/15, your QU identified that the (b) (4) API (small scale batches) contained higher levels of
adrenolone as illustrated in CAPA 2014-033 which was closed on 5/8/15. Your QU determined that
elevated levels of adrenolone (b) (4) have led to potential color and clarity failures. Therefore,
your QU failed to evaluate all batches on the market that were manufactured with Racepinephrine
API known to have (b) (4) levels of adrenolone.
D. The two nonconformance reports (NCR) that we reviewed since the last inspection, we observed
that investigations are not in depth investigations to clearly determine the root cause and/or
implement effective corrective actions.
1. Product cross-contamination involving improper cleaning of mixing tanks is evident
within the following:
a) NCR #14-058- Ipratropium Bromide Inhalation Solution 0.2%, Lot #P4409A, was
contaminated with Racepinephrine based on improper cleaning practices.
b) NCR#15-009- Ipratropium Bromide 0.5 mg and Albuterol Sulfate 3 mg, Lot
#0484 7A, was contaminated with Racepinephrine based on improper cleaning
practices.
***This is a repeated observation from the previous FDA Form 483 issued to your flrm on
2/21/14.
OBSERVATION 3
Drug product containers or closures are additive so as to alter the safety, identity, strength, quality, and purity of the drug
beyond the official or established requirements.
Specifically, on 1/8/13, your Quality Unit detected an unknown impurity (RRT (b) (4) ) above the
specification level ofNMT (b) (4) (results: (b) (4) ) at (b) (4) (b) (4) R.H.) in
Ipratropium Bromide Inhalation Solution 0.02% validation batches (b) (4) and (b) (4)
manufactured from 1119/10 thru 12/13/10; however, a root cause was not identified during the original
investigation (NCR 13-004). On 2/2/15, as part of an expanded investigation (NCR 14-050 opened on
3/12/14) your R&D department identified this impurity as a leachable originating from the (b) (4)
ink imprinted on the secondary packaging pouches of vials. However,
A. Your Quality Unit failed to implement corrective and preventive action to ensure finished drug
EMPLOYEE(S) SIGNATURE DATE ISSUED

Melanie M. Walker, Microbiolo~is~
SEE REVERSE Ivis L. Negron Torres, Chemis~
OF THIS PAGE CAPT Ileana Barreto-Pettit, Investigator ~ 08/14/2015
FORM FDA 483 (09108) PREVIOUS EDmON OBSOLETE INSPECTIONAL OBSERVATIONS PAGE 4 OF 24 PAGES
DEPARTMENT OF llEALm AND HUMAN SERVICES
FOOD AND DRUG ADMJNISTRATION
DISlRlCT ADDRESS AND PHONE NUMBER OATE(S) OF INSPECTION

FEIN\JMBER
Maitland, FL 32751
(407) 475-4700 Fax: (407) 475-4768 1000114235
NAME AND TITlE OF INOMDUAL TO WHOM REPORT ISSUED

FlRMNAME STREET ADDRESS

CITY, STATE, ZIP CODE. COUmRY TYPE ESTABUSHMENT INSPECTED

Manufacturer
product vials are not contaminated with this leachable impurity as your firm continues to use the
same ink in the packaging of this drug product. The R&D report (14·021.00-RDR) which
identified the impurity was just filed with NCR 14-050 by the Director of Quality Operations on
5112/15 without taking any further action as the leachable contaminant was deemed as safe for
patients. lpratropium Bromide Inhalation Solution is a bronchodilator for the maintenance
treatment of bronchospasm associated with chronic obstructive pulmonary disease.
B. As part ofthe NCR 14-050 investigation, your Quality Unit failed to determine the level ofthis
leachable impurity in distributed batches.
C. Your Quality Unit failed to submit a Field Alert Report (FAR) to notify the FDA about the
potential leachable in the distributed batches ofthis approved drug product (ANDA 07-5562)
once the impurity was identified in February 2015.
D. Previously on 6/4/13, your firm submitted a CBE-30 to (b) (4)

specifications for unidentified impurities from (b) (4) The rationale for the
change was documented in the CBE-30 as "(b) (4)
There was no mention in this CBE-30 of the newly

detected unidentified impurity@ (b) (4) that (b) (4)
(LIR 13-002 closed on 2/25/13). The supplement was denied by
the FDA due to insufficient justification and subsequently withdrawn by your firm. However, no
further communication was made with the Agency once the impurity was identified as a
leachable.
E. Your finn failed to investigate Ipratropium Bromide Solution 0.02% batches released using the
(b) (4) , "(b) (4) Leachable Testing oflpratropium Bromide Inhalation
Solutions" (PR # 883269, dated Oct. 17, 2014) after identifying a more suitable test method
((b) (4) "(b) (4) Testing of Albuterol Sulfate and lpratropium Bromide in
Albuterol Sulfate and lpratropium Bromide Raw Materials and Inhalation Solutions", PR #
963820, dated Apr. 1, 2015) capable of identifying leachables on your finished drug product
during the laboratory investigations (LIR 13-002 and LIR 13-004).
EMPI.OYEE(S) SIGNATURE DATE ISSUED
Jessica L Pressley, Inve stigator ~

SEE REVERSE !vis L. Negron Torres, Chemis~
CAPT Ileana Barreto-Pettit, Investig ator
08/14/2015
OF THIS PAGE
FORM FDA 483 (09/08) I'RIIVIOUS ED.m DN OBSOLETE JNSPECTIONAL OBSERVATIONS PAGES OF 24 PAGES
DEPARTMENT OF HEALm AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
DISTRICT ADDRESS AND P>10NE NUMBER DATE(S) OF INSPEOTION

I'EINUMI!ER
Maitland, FL 32751
(407) 475-4700 Fax: (407) 475-4768 1000114235
Industry Information: www.fda. gov/oc/industry
NAME AND TITlE OF I NOt VIDUAl TO 'MIOM REPORT ISSUED.
TO: Lou W. Kennedy, CEO and President

FIRM NAME STReET ADDRESS

CITY, STATE. ZIP CODE. COUNTRY TYPE ESTABUSHMENT INSPECTED

Manufacturer
OBSERVATION 4
Procedures describing the handling of all written and oral complaints regarding a drug product are not followed.
Specifically,
A. Your firm's SOP Drug Product Quality Complaint Handling (SOP 7.1.8, PR # 975342, dated May 07,
2015) is ina~equate as it states in Section D-Drug Product Quality Complaint Investigation to review
the drug quality complaint logs to determine if similar complaints have been received within two
years but it does not provide instructions to trend and evaluate when repeated occurrences are
observed. Furthermore, your finn has received a high rate of 20 complaints for discoloration for
Racepinephrine Inhalation Solution, 2.25%, 0.5 mL, Lot# R4034A, Exp. 11/15 and a high rate of 6
complaints (your finn typically receives only 1 or 2 complaints if any) for discoloration for
Racepinephrine Inhalation Solution, 2.25%, 0.5 mL, Lot# R4027A, Exp. 10/15. Your QU stated the
root cause to be that Racepinephrine Inhalation Solution, 2.25% exhibits a known color change over
time and that a potential link has been observed with the (b) (4) (supplier) API and premature
discoloration but your QU failed to identify the root cause behind the high level of complaints
received for the two particular lots.
B. Your firm's SOP Drug Product Quality Complaint Handling (SOP 7.1.8, PR # 975342, dated May
07, 2015) is inadequate as it states in Section (b) (4)
This is evident by the following

examples:
1. Your firm received Complaint No. QR 14-02702 on 12/22/14 (approximately 6 months

into the shelf life ofthe product) and Complaint No. QR 15-00078 on 2/3/15
(approximately 8 months into the shelf life of the product) for discoloration of Lot#
R4034A, Exp: 11/15. The complainant returned (b) (4) unopened pouches ((b) (4) vials).
Your QU made the determination to (b) (4) vials
returned for color and clarity (which passed) without any justification as to why all return
samples were not examined.
EMPLOYEE($) SIGNATURE DATE ISSUED

SEE REVERSE Ivis L. Negron Torres, Chemis~~
CAPT Ileana Barreto-Pettit , Inv estigator
08/14/2015
OF THIS PAGE
FORM FDA 483 (09/08) PRI!VlOUS EDmON OUSOLE'JE JNSPECTJONAL OBSERVA TIONS PAGE 6 OF 24 PAGES
DE PARTMENT OF HEALTH AND HUMAN SERVlCES
DISTRICT ADDRESS /'J'IO PHONE NUMBER OATE(S) 01' INSPEC00/'1

FEINUUBER
Maitland, FL 32751
(407) 475-4700 Fax: (407) 475-4768 1000114235
Industry Information: www.fda. gov/oc/industry
NAME AND TITlE. 01" INOIVID\IAL TO WHOM REPORT lSSUEO

ARM NAME STREET ADORESS

CITY, STATE, ZIP CODE. COUNTRY TYPE E"STI\BUSHMENT INSPECTEl

Manufacturer
2. Your ftrm received Complaint No. QR 15-00213 on 3/5/15 (approximately 9 months into
the shelflife of the product) for discoloration of Lot# R4034A, Exp: 11115 (13th
complaint for this lot). The complainant returned 72 vials (67 vials contained in sealed
pouches and 5 vials which had been removed from the pouches). Your QU failed to have
the returned samples tested for color and clarity and stated within the complaint
investigation that a (b) (4) vials are required for color and clarity testing and
since only 16 vials were returned, testing could not be conducted. During the current
FDA inspection, this statement was obse:rved within a previous complaint investigation
report, QR 15-00148. Also, your QU again made the determination not to test retain
samples since they w~re previously tested in a previous complaint dated 12/5/14 (QR 14-
02658). Your QU failed to consider that the previous retains were tested within the fust
complaint for this lot and only approximately 6 months into the shelflife of the product
rather than the current complaint which is approximately 9 months into the shelf life of
the product.
3. Your frrm received Complaint No. QR 15-00733 on 6/30115 (approximately 12 months

into the shelf life of the product) for discoloration of Lot# R4034A, Exp: 11115 (16th
complaint for this lot). The complainant returned 12 vials which by your ftrm is not
considered enough to conduct color and clarity testing therefore your QU visually
inspected the 12 vials and stated that they would most likely fail. Your QU made the
determination not to test retains at this particular time point since retains were tested in a
previous complaint dated 12/5/14 (QR 14-02658) and passed. However, your QU failed
to consider that the previous retains were tested approximately 6 months into the shelf
life of the product rather than the current complaint which is approximately 12 months
into the shelf life of the product.
4. Your ftrm received Complaint No. QR 15-00481 on 5/4/15 (approximately 12 months into
the shelflife ofthe product) for discoloration of Lot# R4027A, Exp: 10115 (6th complaint
for this lot). Your quality unit stated that no return product was required because it
would not provide any added value to the investigation since this lot was previously
associated with discoloration.
EM!'\.OYEE(S) SIGNA'IURE DATE ISSUED

Melanie M. Walker, Microb i ologis~~
SEE REVERSE !vis L. Negron Torres, Chemist~
CAPT Ileana Barreto-Pettit, I nvestigator 08/14/2015
OF THIS PAGE
FORM FDA 483 (09108) PRIMo us romaN OIISOIEI'E lNSPECI'IONAL OBSERVATIONS PAGE 7 OF 24 PAGES
DEPART MENT OF HF.J\LUI AND HUMAN SERVICES
DISTR ICT ADDRESS AND PHONE NUMBER DAl£{5) OF INSPECTION
555 Winderley Place , Suite 200 07/20/2015 - 08/14/2015*

FEINUMBCR
Maitland, FL 32751
(407) 475 - 4700 Fax : (407) 475 -47 68 1000114235
Industry Information: www.fda. gov /oc/indust ry
NAME AND TTTU: OF 1NOIVIOU.Al TO WHOM REPORT ISSUED

FIRMNIIME SffiEEr ADDRESS

CITY, STATE. ZlP CODE. COUNTRY 1YPE ESTABI.ISHMENT INSPECTED

Manufacturer
a. Your QU failed to require return samples to be sent back to conduct at a minimum

a visual assessment for the complaint samples.
b. Your QU failed to test retains at this time point with the justification that one
carton was previously visually examined within complaint report, QR 15-00453
(approximately 11 months into the shelflife of the product) and retains were
tested for color and clarity and passed testing within complaint report, QR 15-
00140 (approximately 9 months into the shelflife ofthe product).
c. Your QU failed to consider that the previous retains were tested at only
approximately 9 months into the shelf life of the product rather than the current
complaint which is a~oxim ately 12 months into the shelflife of the product.
OBSERVATION 5
Employees engaged in the manufacture, processing, packing, and holding of a drug product lack the education, training, and
experience required to perform their assigned functions.
Specifically,
A. Your firm's training program, "Nephron University" is not adequate in that it only consists of
"reading and understanding" electronic versions of hundreds of SOPs without effective controls
to ensure adequate training of the employee prior to the performance of duties. For example,
1. The training curriculum for a Material Handler consists of reading and understanding
approximately 347 SOPs within a 10-day timeframe. On 8/10115, it was observed that a
Material Handler ((b) (6) ) completed her training curriculum consisting of347 SOPs within 4
days.
2. On 8/10/15, it was observed that a Material Handler ((b) (6) ) completed her training curriculum
consisting of 345 SOPs within 2 days.
3. On 8110115, a mock demonstration was conducted for a new employee and the training
curriculum was designed for a QA (on-line sampler for secondary packaging) within
Nephron University. The training curriculum for a QA employee consists of reading and
understanding approximately 932 SOPs within a 10-day timeframe.
EMPLOYEE($) SIGNATURE DATE ISSUED

SEE REVERSE Ivis L. Negron Torres, Chemist~
CAPT Ileana Barreto-Pettit, rn-~;tigator
08/14/2015
OF THIS PAGE
FORM FDA 483 (09/08) PREVIOUS lll)ffiON OBSOU!'lll INSPECTIONAL OBSERVATIONS PAGE 8 OF 24 PAGES
DEPARTMENT OF HEALm AND 'DUMAN SERVICES
DISTRICT ADORESSAND PHONE NUMBER DATE(S) OF INSPECTION

FE! NUMBER
Maitland, FL 32751
(407) 475-4700 Fax: (407) 475-4768 1000114235
NAME ANO TITlE OF INOIVIOUAL TO v.tiOiol REPORT ISSUED

Nephron Pharmaceuticals Corp. 4121 SW 34th St

CITY, STATE, ZIP C00E. COUNlRY TYPE ESTABUSHMENT INSPECTED

Manufacturer
B. Your firm's Form 8.136 (b) (4) Material Handler (Production) On The Job Training Certification
is not adequate as it does not provide supporting documentation to show that the trainee observed
the tasks conducted by the trainer for two performances as well as the fmal task conducted by the
trainee to qualify the individual for their particular job function. In addition, your employees'
on-the-job training (OJT) certifications are not being reviewed or followed by the department
managers and employees are allowed to independently conduct their job function, sign off in the
batch record as well as verify tasks during operations without being adequately trained.
1. On 8/11115, a Material Handler ((b) (6) ) hired on 3/16/15 was interviewed and stated that she
has been working independently for approximately 1.5 months, but according to the batch
record for lot# D5819A, dated 4/13/15 your employee has been independently working for
approximately 4 months. In addition, her OJT Certification has not been completed as of
8/13/15 as required by your firm's Form 8.136. Furthermore, there is no supporting
documentation (other than an initial and date) to confirm that your firm's employee has
conducted any OJT functions.
a. During the interview, SOP 5.36.1 "Work in Progress (WIP) Stock Scanning Procedure
for Tray Unloaders was provided to (b) (6) . She stated that she had seen this SOP before
but had never conducted any operations for the start and end of the lot on the (b) (4)
but her Form 8.136 (on the job training certification) stated that she had
observed a trainer for the start of the lot on the (b) (4) on 5/21/15 and 6/22/15 and
then independently conducted the task on 7/15/15. She had observed a trainer for the end
ofthe lot on the (b) (4) on 6/10115 and 6/15/15 and then independently conducted
the task on 7115/15. Form 8.136 stated that she had observed a trainer for the start and
end of the lot on a (b) (4) on 7114/15. Your management stated that these particular
tasks could not be located in the batch record as completed by the trainer or the trainee
for the dates listed on the employees certification form.
2. On 8/11115, it was observed that a Form 8.i36 (b) (4) Material Handler (Production) On The
Job Training Certification was never conducted for Material Handler (b) (6) that was hired on
3/30/15. Your firm's employee has been independently working during operations as evident
by batch record P5421A, dated 4/21115 without being certified to conduct her job function as
EMPLOYEE(S) SIGNATURE

Melanie M. Walker, Microbiologis~~
SEE REVERSE Ivis L. Negron Torres, Chernis~~
CAPT Ileana Barreto-Pettit, Investigator ~~ 08/14/2015
OF THIS PAGE
FORM FDA 483 (0 ~108) PREVIOUS EDmON OBSOLEIE INSPECTIONAL OBSERVATIONS PAGE 9 OF 24 PAGES
FOOD AND DRUG ADMfNISTRATION

FEINUMBER
Maitland, FL 32751
(407) 475-4700 Fax: (407) 475-4768 1000114235
twiiE ANO TITlE OF INOl\IIOUAL10 WHOM REPORT ISSUED

Ne phr on Pharmaceuticals Corp . 4121 SW 34th St

CllY, STATE. ZIP COOE, COuNTRY 1YPE !;:STASUSHMEHT INSPEcTED

Manufacturer
stated in Form 8.136.
OBSERVATION 6
Records are not maintained so that data therein can be reviewed at least annually to evaluate the quality standards of each
drug product to detennine the need for changes in specifications or manufacturing or control procedures.
Specifically, your Quality Unit failed to follow SOP Conducting Product Trend Analysis (PTA) (SOP
7.8.3, PR # 906271, dated Dec 15, 2014) Section A. General Requirements# 1. i. in that the complaints
captured in the 2015 Product Trend Analysis for Racepinephrine fuhalation Solution, 2.25%, 0.5 mL
(January 1, 2015-June 30, 2015) were not adequately evaluated to identify trends such as discoloration
by lot number (12 complaints for discoloration for Lot# R4034A during the review period and a total of
20 complaints for this lot as of 7/24/15) that may indicate a need to change product specifications or
controls. In addition, your firm's SOP for the review of Product Trend Analysis is inadequate as it states
that the (b) (4)
FACILITIES & EQUIPMENT SYSTEM
OBSERVATION 7
Substances required for equipment operations such as lubricants and coolants come in contact with components, drug product
containers, closures, in-process materials, and drug product so as to alter the safety, identity, strength, quality or purity of the
drug product beyond tbe official or other established requirements.
Specifically, your firm lacked written procedures and acceptance criteria for the receipt and approval of
lubricants used in the Blow/Fill/Seal (BFS) machines used in the manufacturing of your sterile
inhalation drug products: Albuterol Sulfate, Ipratropium Bromide, Duo-dose (Albuterol
sulfate/Ipratropium Bromide), and Racepinephrine. As a result, (b) (4)
such as(b) (4) , and(b) (4) were used in close
proximity to the (b) (4) and (b) (4) machine molds where vials are formed and filled. On
4/14/14 and 4/29/14, (b) (4) batches of(b) (4) Inhalation Solution (lot #s: D4C21A and D4E20A) were
contaminated with (b) (4) during vial formation/filling in
EMPlOYEE($) SIGNATURE DATE ISSUED

08/14/2015
OF THIS PAGE
FORM FDA 483 (091l)8) PREVIOUS EDmON OBSOLETE INSPECTIONAL OBSERVATIONS PAGE 10 OF 24 PACES
DEPARTMENT OF HEAL1H AND HUMAN SERVICES
fOOD AND DRUG ADMINISTRATION
DISTRlCT ADDRESS AND PHONE NUMBER OATE(S) OF INSPECTION

FEINUMllER
Maitland, FL 32751
(407) 475-4700 Fax: (407) 475-4768 1000114235
NAME AND 1111.E Of' INDIVIDUAL TO IMiOM REPORT ISSUED

Ne phron Pharmaceuticals Corp . 4121 SW 34th St

CITY. STA'TE, ZIP CODE, CO\INTRY TYPE ESTABUSHMENT INSPECTED

Manufacturer
(b) (4) machines in (b) (4) respectively, as a result of excessive lubricant that
dripped onto the molds.
OBSERVATION 8
Buildings used in the manufacture, processing, packing, or holding of a drug product do not have the suitable construction
and location to facilitate cleaning, maintenance, and proper operations.
Specifically, your firm's HQ Warehouse used to conduct secondary packaging operations (pouching and
cartoning of sterile vials) for the combination drug product, lpratropium Bromide 0.5mg and Albuterol
Sulfate 3mg, is deficient based on the following observations:
A. The interior walls of the warehouse are not finished and contain exposed insulation.
B. On 7/29/15 two large fans were observed at opposite ends ofthe packaging warehouse blowing
dust during the packaging operations of Lot # D5C23A.
C. We could not verify that all packaging and storage areas for the drug product, lpratropium
Bromide 0.5mg and Albuterol Sulfate 3mg, are maintained within the labeled storage conditions
(b) (4)
PRODUCTION SYSTEM
OBSERVATION 9
Records of the inspections of automatic, mechanical or electronic equipment, including computers or related systems are not
maintained.
Specifically, proper controls have not been placed on your (b) (4) and (b) (4) tanks
to prevent operators from manipulating their respective (b) (4) ) displays. On
08/13/15, it was observed that operators could manually adjust the time and date to back date print-outs,
which are used to verify tank weights during production. Therefore, data accuracy from these
dispensary scales could not be verified.
EMPLOYEE(S) SIGNATURE DA'TE ISSUED

Melanie M. Walker, Microbiologis~
SEE REVERSE Ivis L. Negron Torres, Chemist~ ft~-~
CAPT Ileana Barreto-Pettit, Investigator Jrf7' 08/14/2015
OF THIS PAGE
FORM FDA 483 (09/08) PREVIOUS EDmON OBSOLE'I'E INSPECTIONAL OBSERVATIONS PAGE II OF24PAGES
DEPARTMENT OF HEALTH AND HUMAN SERVl CF..S
FOOD AND DRUG ADMINISTRA TIO.N
DISTRICT AODRESS AND PHONE NUMBER DATE(S) OF INSPECTlON

FEINUMBER
Maitland, FL 32751
(407) 475-4700 Fax: (407) 475-4768 1000114235
NAME AND TITlE Of INDMOUAL TO WHOM REPORT ISSUED

FIRM NAME STREET AOORESS

CITY. STATE. ~p CODE, COUNTRY TYPE ESTABliSHMENT INSPECTED

Manufacturer
OBSERVATION 10
Control procedures are not established which monitor the output and validate the performance of those manufacturing
processes that may be responsible for causing variability in the characteristics of in-process material and the drug product.
Specifically,
A. Your finn lacks adequate data to demonstrate that the (b) (4) test conducted at (b) (4) Hg pressure
for a (b) (4) (according to SOP 7.11.1 Pouch Testing, PR #954654, dated Feb
03 2015) as an (b) (4) the pending ANDA (b) (4)
((b) (4) and Ipratropium Bromide 0.5mg and Albuterol
Sulfate 3mg is effective in detecting leaks as small as a pinhole. On 7/30/15, a QA Inspector was
observed conducting the (b) (4) test for lpratropium Bromide 0.5mg and Albuterol Sulfate 3mg Lot#
D5C23A at(b) (4) . ofHg pressure for approximately (b) (4) ((b) (4)
) which has not\been qualified and is not in accordance with SOP 7.11.1.
B. On 7/30/15, two Line Inspectors were observed conducting attribute inspections (taken approximately
(b) (4) s) in accordance with SOP 7.14.3 which included:
inspecting vial condition, vial position, pouch condition, lot and expiration date, and seal integrity for
Ipratropium Bromide 0.5mg and Albuterol Sulfate 3mg Lot # D5C23A. During the FDA Inspection,
Line Inspectors were observed documenting attribute inspection times that did not represent when the
actual samples were taken. When questioned, the Line Inspectors stated that (b) (4)
(b) (4) .
Therefore, it cannot be verified when the actual attribute inspections were conducted.
Furthermore, no verification of these attribute inspections are being conducted. It was observed during
the inspection that the second Line Inspector does not verify the attribute inspections being conducted
and instead just checks for completeness and then signs off on the document. In addition, QA stated that
they also just check for completeness of the document anq will sign off rather than conduct any
verifications of the attribute inspections while they are being performed.
EMPLO'I'EEI,Sl SIGNATURE DATE ISSUED
Jessica L Pressley, Investigator ~~

Melanie M. Walke r , Microbiologist
SEE REVERSE !vis L. Negron Torres, Chemist-~
CAPT Ileana Barreto-Pettit, In~lgator
08/14/2015
OF THIS PAGE
FORM FDA 483 (09/08) PREVIOUS EDIDONOBSOLETB INSPECTIONAL OBSERVATIONS PAGE 12 OF 24 PAGES
DEPARTMENf OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINJSTRATlON
DISTRICT ADDRESS AND PHONE NUMBER DATE($) OF INSPEOnDN

FEI NUMBER
Maitland, FL 32751
(407) 475-4700 Fax: (407) 475-4768 1000114235
NAME AND TIT\.E OF INDIIIIDUf<L TO WHOM REPORT ISSUED

Nephron Pharmaceuticals Corp . 4121 sw 34th St

CJTV, STAlE, ZIP CODE. COUNTRY lYPE ESTABUSHMENT INSPEC"TED

Manufacturer
OBSERVATION 11
Actual yield and percentages of theoretical yield are not determined at the conclusion of each appropriate phase of
manufacturing, processing, and packaging of the drug product.
Specifically, your finn's calculation of(b) (4) is inadequate in that (b) (4)
; therefore, this calculation is not
considered representative of the process.
OBSERVATION 12
Procedures prescribing a system for reprocessing batches to insure that the reprocessed batches will conform with all
established standards, specifications, and characteristics are not written and followed.
Specifically, your firm's SOP "De-package, Inspect and Re-package Product" (PR # 742714, dated Nov
18, 2013) is inadequate in that it does not provide a requirement for QA approval prior to re-work during
filling operations. On 8/10/14, your firm re-worked lot # Z4040A, Albuterol Sulfate Inhalation Solution
0.5% (NCR# 14-102) after leaking vials were detected during the monitoring of the line; however,
batch record documentation did not illustrate how many filled vials were inspected, how many defects
were found and which trays were impacted. Therefore, your firm was unable to ensure that all
implicated leaking vials were removed from the line.
LABORATORY CONTROL SYSTEM
OBSERVATION 13
Appropriate controls are not exercised over computers or related systems to assure that changes in master production and
control records or other records are instituted only by authorized personnel. Electronic records are used, but they do not meet
systems documentation control requirements to ensure that they are trustworthy, reliable and generally equivalent to paper
records.
Specifically, your QU lacks the authority to fully investigate altered injections observed during the
inspection of the electronic data records generated by your HPLC's computerized systems. For example,
EMPlOYEE($) SIGNATURE DATE ISSUED
Jessica L Pressley, Investigator ~~~

Melanie M. Walker, Microbiolog~
SEE REVERSE Ivis L. Negron Torres, Chemist
OF THIS PAGE CAPT Ileana Barreto-Pettit, Investigator
P1M' 08/14/2015
FORM FDA 483 (6!1/08) PREVIOUS EDffiON OBSOLE'I'E INSPECTIONAL OUSERVATIONS PAGE 13 OF 24 PAGES
FOOD AND DRUG ADMINIS1RATION
DISTRICT ADDRESS AND PHONE NUMBER DATE(S) OF INSPECTION

Maitland, FL 32751 FEINUMBER
(407) 475-4700 Fax: (407) 475-4768 1000114235

NAME AN~ Tm..E OF INOIVIOVI\l. TO WHOM REPORT ISSUE~

FIRM NI\ME STRSET AO~RESS

CITY, STATE, ZIP CODE, COUNTRY TYPE ESTABUSHMENT INSPECTED

Manufacturer
A. Your QU failed to review computer audit trails in the (b) (4)

as part of the batch release process and provide adequate training to analytical chemists. In
addition, (b) (4)
sample/standard injections
were altered without scientific justification. The inability of your Quality Unit to detect and
prevent poor data integrity practices raises serious concerns about the effectiveness of your
quality system.
B. Your firm failed to establish the controls and procedures to assure authenticity, integrity and
security of all electronic records including data generated in the QC Laboratory. During the
inspection of electronic records generated/handled by the (b) (4)
for the release of raw materials and finished drug product, it was found that the System
Administrator has two accounts (Administrator/QC_R&D Chemist) with different access levels
and privileges that grant him the capability of altering electronic data in the system. In addition,
at least two employees that have already left the company still have active accounts within this
system.
OBSERVATION 14
Laboratory records do not include complete data derived from all tests, examinations and assay necessary to assure
compliance with established specifications and standards.
Specifically, your QC unit lacks appropriate controls over the laboratory notebooks to assure that
changes/modifications are not performed in the raw data contained within the notebooks. It was
observed that dozens of laboratory notebooks were stored in an unlocked/uncontrolled cabinet in the QC
Laboratory.
OBSERVATION 15
Procedures describing the calibration of instruments, apparatus, gauges and recording devices are deficiently written or
followed.
Specifically, your firm failed to conduct a full qualification of the High Performance Liquid
Chromatography (HPLCs) instruments used for the release testing of raw materials and finished drug

Melanie M. Walker, Microbiologis~_..
CAPT Ileana Barreto-Pettit, Investigator 08/14/2015
OF THIS PAGE
FORM FDA 483 (09/08) PREVIOUS EDmON OBSOLElE INSPECTIONAL OBSERVATIONS PAGE 14 OF 24 PAGES
DEPARTME NT OF HEALTH AND HUMAN SERVICES
DISTRICT AOOOESS ANO PHONE- NUMBER OATE(S) OF INSPECTION

FEI f'ruMBER
Maitland, FL 32751
(407) 475-4700 Fax: (407) 475-4768 1000114235
NAME AND TTnE OF INOIVIOUAL TO WHOM REPORT ISSUED
TO: Lou W. Ke nne dy, CEO and President

FIRM NAME
Neph r on Pharmaceuticals Corp . 4121 SW 34th St

CrlY, STAlE, ZIP COOE, COUNTRY TYPE ESTABLISHMENT INSPECTED

Manufacture r
products (Budesonide, Albuterol Sulfate/Ipratropium Bromide, and Racepinephrine, among others) as

well as testing of cleaning samples of major manufacturing equipment for residual contaminants. For
example,
A. The Waters HPLC instruments identified as #'s: 1, 2, 8, 9, 10, 11, and 12 were not qualified for
the following tests: carry over, flow rate accuracy, gradient accuracy (quaternary pump), oven
temperature accuracy, and injector linearity to assure the reliability of these instruments during
sample analysis of raw materials, finished drug products, and cleaning validation samples.
B. The Test Method (b) (4) " is

deficient in that the (b) (4)
C. Your instrument specialist responsible for the qualification ofthese HPLC instruments was not
aware of the necessary tests and operational ranges required for the adequate qualification of
these critical testing systems.
OBSERVATION 16
Laboratory controls do not include the establishment of scientifically sound and appropriate specifications and sampling
plans designed to assure that conform to appropriate standards of identity, strength, quality and purity.
Specifically,
A. Your QU failed to establish appropriate specifications for the API Racepinephrine USP (current
spec. 0.2%) for the degradant adrenalone which your firm had identified as the root cause for the
premature discoloration and increase of complaints for S2 Racepinephrine Inhalation Solution
2.25%. The change in product color can prevent the consumer from getting appropriate respiratory
treatment for bronchial asthma as both labels for S2 and Asthmanefrin state: "Do not use ifproduct
is brown in color or cloudy". Your QU failed to test for adrenalone levels during the re-testing after
long storage periods to ensure that the adrenalone levels remained the same after the API was
opened. For example, RM # (b) (4) had an adrenalone level of(b) (4) (considered elevated by your
firm but still within the current spec of(b) (4) ) at receipt and this raw material was used within the
EMPLOYEE($) SIGNATURE OATE ISSUEO
Jessica L Pressley, Investigator ,9~

Melanie M. Walker, Microbiologis~~
SEE REVERSE Ivis L. Negron Torres, Chemist~r
08/14/2015
OF THIS PAGE
FORM FDA 483 (09108) PREVIOUS EDffiON OBSOLE'IE INSPECTIONAL OBSERVATIONS PAGE 15 OF 24 PAGES
DISTRICT ADDRESS AND PHONE NUMBER DATE(S) OF INSPECTION

FEINUMBER
Maitland, FL 32751
(407) 475-4700 Fax: (407) 475-4768 1000114235
NAME AND TITI.li OF INDIVIDUAL TO WHOM REPORT ISSUED

FIRM NAME SffiEEf ADDRESS

CITY, STATE, ZIP CODE, COUNTRY TYPE ESTABliSHMENT INSPEClED

Manufacturer
finished product Lot# R4002A (stability sample) which failed color and clarity testing at (b) (4)
on 7/14/15. Your firm conducted re-assay testing for RM # (b) (4) on 4/28114
but did not conduct testing on the adrenalone levels. On 6/4114 your firm used RM # (b) (4) within
the finished product Lot# R4030A (2 complaints received for this lot) and on 6/6114 your firm used
RM # (b) (4) within the finished product Lot # R4031A.
B. The sampling plans specified within each production batch record for the testing and release of
finished drug product are not adequate as samples are (b) (4)
. Collection of
samples (b) (4)
OBSERVATION 17
Established test procedures and laboratory control mechanisms are not followed.
Specifically, your firm failed to follow established test procedures within the QC laboratory. During
the review of analytical data generated it was observed that the analyst used expired volumetric solution
for the determination ofthe (b) (4) test in Albuterol Sulfate raw material lot# RM-(b) (4) conducted on
2/24/2015 and used the incorrect sample weight during the analysis ofFerrocyanides in Sodium
Chloride raw material lots; (b) (4) and (b) (4) conducted on 4/23/2014.
NUCROBIOLOGYLABORATORY
OBSERVATION 18
Aseptic processing areas are deficient regarding systems for maintaining any equipment used to control the aseptic
conditions.
Specifically, a review ofPQ-511B, 11 Performance Qualification of the Decontamination Cycle of the

(b) (4) used for release testing of manufactured product

Melanie M. Walker, Microbiologist~
OF THIS PAGE
FORM FDA 483 (09/08) PREVIOUS EDmON OBSOLE'IE INSPECTIONAL OBSERVATIONS PAGE 16 OF 24 PAGES
DEPARTMENT OF HEAL1H AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATJON
DISTRICT I\OORESS ANO PI-lONE NUMBER OATE(S) OF INSPECTION

FEJNUMIIER
Maitland, FL 32751
(407) 475-4700 Fax: (407) 475-4768 1000114235
Indust r y Information: www.fda.gov/oc/industry
NAME AND TlTlE Of INDIVIDUAL TO WHOM REPORT ISSUED

Neph r on Pharmaceuticals Corp . 4121 SW 34th St

CITY. STATE. ZIP CODE, COUNTRY TYPE ESTABliSHMENT INSPECTED

Manufacturer
performed (b) (4) runs. Section 9.6 Acceptance Criteria states (b) (4)
(run #'s (b) (4) ) of
the(b) (4) runs were not within the acceptable range of the (b) (4) population outlined in the protocol
section 8.1 "Maximum Loaded Isolator Inactivation Testing" which states (b) (4)
."
Biological Indicator (BI) (b) (4) lot# H1963 used for (b) (4) runs did
(b) (4)
not meet the acceptable range of the (b) (4) population. Run #'s
did not meet the specified protocol criteria. Therefore, the acceptance criteria of(b) (4)
satisfactory validation runs of maximum load pattern was not met.
***This is a repeated observation from the previous FDA Form 483 issued to your firm on
2/21/14.
MEDICAL DEVICES
OBSERVATION 19
Procedures for design change have not been adequately established.
SpecificaUy, your firm's Design History File (D ) for Asthmanefrin Starter kit (EZ Breathe Atomizer)
does not contain design changes or cleaning instruction revisions for your EZ Breathe Atomizer as
requjred by SOP-HQ-DV-1746 "Design Changes" and SOP-HQ-DV-1747 "Design History File".
In addition~ no validation or verification docum{:ntation was provided to demonstrate that these changes
and revisions are effective and do not adversely affect the device.
A. EZ Breathe cleaning instructions
According to Customer Service representatives and supporting documentation, your firm's
personnel instruct patients to use either (b) (4) dilutions to clean their EZ Breathe
Atomizers. However, citric acid as a cleaning agent is not included in your approved DHF and
no document or change control revisions could be provided showing that this cleaning agent was
approved.
No documentation was provided to demonstrate that using a (b) (4) cleaning solution will
assure the device continues to function as expected after an extended period of time (i.e. months
EMPlO'VEE(S) SIGNI\1\JRE DATE ISSUED

Melanie M. Walker, Microbiologis~
SEE REVERSE Ivis L. Negron Torres, Chemist~('
08/14/2015
OF THIS PAGE
FORM FDA 483 (09108) PREVIOUS EDffiON OBSOLIITE fNSPECTIONAL OBSERVATIONS PAGE 17 OF 24 PAGES
FOOD AND DRUG ADMINlSTRATION
DISTRICT 1\DDRESSAND PliONE NUMBER 01\TE(S) OF INSPECTION

FEJNUMBER
Maitland, FL 32751
(407) 475-4700 Fax: (407) 475-4768 1000114235
Industry Information: www.fda . gov/oc/industry
NII"'E AND TITLE OF lNOIVIOUAL TO WHOM REPORT ISSUED

Ne phron Pharmaceuticals Corp . 4121 SW 34th St

OilY, STATE. ZIP CODE. COUNTRY TYPE ESTI\BUSHMENT INSPECTED

Manufacturer
of use) and/or under worst case conditions (12 uses over a 24 hour period).
B. Electrical circuit ch~ges
According to finn's personnel and documentation, (b) (4) redesigned some of the
electrical components of the EZ Breathe Atomizer to conform with International Electrotechnical
Commission 60601~1 standards. There is no mention of this design change in you DHF and no
documentation was provided demonstrating these changes do not adversely affect the device.
OBSERVATION 20
Procedures to ensure that all purchased or otherwise received product and services conform to specified requirements have
not been adequately established.
Specifically,
A. No scientific rationale or assessment could be provided justifying why (b) (4)

, manufacturer of your EZ Breathe Atomizer and medication cups, is currently listed as an
approved Type 1 (Direct Impact, High Risk) supplier. The following was observed during my
review of your finn's supplier program procedures, supplier evaluation forms, and third party on-site
audits that were provided during this inspection:
1. Nephron's Supplier Performance Evaluation Form (8.258), evaluation date 5/20/13 and
signed on 6/4113:
(b) (4)
a. Documentation states that &L was deemed "Not Acceptable" based on a product
recall and a supplier audit was required.
b. Documentation states that a third party, on-site audit (7/17/13, 7/18/13, 7/19/13 and
7/22113) demonstrated that (b) (4) performance was unsatisfactory and that they will
be placed on probation.
c. Documentation states that no material purchases or receipts will be approved until
another audit (or other means) confirms that the identified deficiencies have been
addressed appropriately and remedial actions have occurred and are proven to be
effective.
2. Third party on-site audit report for (b) (4) - assessment dates 7/17/13, 7/18/13, 7/19/13 and
EMPI.OYEE(S) SIGNIIT\JRE OATEISSUED
Jessica L Press~ey, Investigator ~

Me~anie M. wa~ker, Microbio~og~'st
CAPT Ileana Barreto-Pettit, Inve tigator
08/14/2015
OF THIS PAGE
LCDR Michael H. Tol~on, Investigator
FORM FDA 483 {09/0S) 1'1\F.VIOUS EOO'ION OBSOLE1E INSPECTIONAL OBSERVATIONS PAGE 18 OF 24 PAGES
FOOD AND DRUG ADMJNISTRATION
DISTRICT ADOR6SS AND PHONE t-{UMSEn DATE(S) OF INSPECTlON

FEI NUMIIER
Maitland, FL 32751
(407) 475-4700 Fax: (407) 475-4768 1000114235
NAME AND l1TLE OF INDIVIDUAL TO WHOM REPORT ISSUED

FIRM NAt.~£ STREET ADDRESS

CITY. STATE. ZIP CODE, COUNTRY TYPE ESTABLISHMENT INSPECTED

Manufacturer
7/22/13:
a. Documentation states that the on-site auditor found that (b) (4) s change control system
does not capture all changes since the device launch and their CAP A system is not
established.
b. Documentation states further follow up audits are strongly recommended and (b) (4)
employees need QSR training to better understand their existing system.
3. Nephron's 21 CFR 820 Medical Device Supplier Quality System/GMP Questionnaire

(8.307), evaluation date 10/9/14:
a. (b) (4) completed the questionnaire and documented a self-assessment if their
procedures were adequate.
b. No documentation was provided showing your firm's assessment for adequacy for any
document/procedure that (b) (4) listed and/or provided.
4. Nephron's Supplier Performance Evaluation Form (8.258), evaluation date 10/1/14 and
signed on 5/21/15:
a. Documentation states that (b) (4) was deemed "Average" and that they remain on
probation. No documentation was provided explaining why (b) (4) was no longer "Not
Acceptable".
b. No documentation was provided verifying or validating that the remedial actions that
were implemented based on the identified deficiencies found during the July 2013 on-
site audit had been proven to be effective.
c. Documentation states that no on-site audit is scheduled at this time.
B. For each incoming shipment ofEZ Breathe Atomizers and medication cups, firm personnel states
they use (b) (4) Certificate of Conformance (CoC) value for mass median aerodynamic diameter
(MMAD) when confirming ifthe device/component meets specifications (b) (4) ). However, your
firm has not verified that (b) (4) CoC test results are reliable. Firm's personnel stated that the
MMAD represents the median particle size of the aerosol when using the device.
EMPLOYEE(S) SIGNA1\.IRE DATE ISSUED

SEE REVERSE Ivis L. Negron Torres, Chemis~~
OF THIS PAGE
FORM FDA 483 (0~108) PREVIOUS EDmON OBSOLETE INSPECTIONAL OBSERVATIONS PAGE 19 OF 24 PAGES
DISTRICT AO!lRESSAND PHONE NUMBER DATE($) OF INSPECTION

fEJNUMBER
Maitland, FL 32751
(407) 475-4700 Fax: (407) 475-4768 1000114235
Industry Information: www.fda . gov/oc/industry
N.o.ME AND TITlE OF INDIVIDUAL TO WHOM REf'O!IT ISSUED

CITY, STATE, ZIP CODE, COUNTRY TYPE ESTABLISHMEN T INSPECTED

Manufacturer
2/21/14.
OBSERVATION 21
Documentation of rework and reevaluation activities does not include a detennination of whether there has been any adverse
effect from rework upon the product.
Specifically, your fum received EZ Breathe Atomizers (Lot #130401) on approximately 6/3/13 that h~d
medication cups with rusty hinges. The atomizers were returned to your supplier/manufacturer (b) (4)
for rework and the same Lot was shipped back to Nephron on approximately 9/9/14 based on
documentation that was provided during the current FDA inspection.
The following documentation could not be provided during this FDA inspection:
A. Documentation stating what rework was conducted.
B. Documentation to verify or validate that the rework was effective.
C. Investigation documentation detailing the root cause analysis for why rusty hinges were
occurnng.
D. An SOP for accepting reworked materials and what reevaluation activities shall take place
before accepting reworked materials.
OBSERVATION 22
Procedures for corrective and preventive action have not been adequately established.
Specifically,
A. Your fum's Corrective and Preventive Action (CAPA) SOP 7.7.5, dated 7118/14, lacks the
requirement to verify or validate a CAPA's effectiveness prior to closing the CAPA. Three (3)
medical device CAPAs were reviewed and it was observed that the CAPAs were closed with no
verification or validation documentation demonstrating them as effective.
1. CAPA 2014-010- Perform a gap analysis ofNephron's Quality System and implement
changes so that it meets 21 CFR 820 requirements.
Jessica L Pressley, Investigator ~~

Melanie M. Walker, Microbiologist~-
SEE REVERSE Ivis L. Negron Torres, Chemist~£
OF THIS PAGE
FORM FDA 483 (09/08) PREVIOUS EDmON OBSOLETE INSPECTIONAL OBSE RVAT IONS PAGE 20 OF 24 PAGES
FOOD AND DRUG ADMJNJS'IRATION
DISTRICT ADDRESS AND PHONE NVMSER DATE(&) OF INSPECTION

FEI NVMB€R
Maitland, FL 32751
(407) 475-4700 Fax: (407) 475-4768 1000114235
NAMe AND Tf1l.E OF lNDMOUJ\L TO WHOM REPORT ISSUEP


CITY, STATE, ZIP CODE, COUNTRY TVf'E ESTABUSHMENTIHSPECTED

Manufacturer
2. CAPA 2014-012- Develop Design History File for Asthmanefrin Starter kit (EZ Breathe
Atomizer).
3. CAPA 2014-014- Implement acceptance activities and incoming specification checks for EZ
Breathe Atomizer.
B. For customer complaints received for your EZ Breathe Atomizer between January 2014 and the start
of this FDA inspection, approximately 92% are based on "no aerosol production". Your firm has
identified potential root causes and stated that corrective actions have been implemented for these
root causes. However, no verification or validation documentation was provided demonstrating that
these corrective actions are effective. Examples of potential root causes include the following:
1. Firm's personnel stated that a silicone ring within the medication cup was being improperly
installed, which allowed moisture into the system causing no aerosol production. Firm's
personnel could not provide any acceptance criteria checks or data demonstrating that the
silicone ring is now properly installed.
2. Firm's personnel stated that a washer within the medication cup was being improperly
soldered, which can cause the washer to block the mesh, resulting in reduced or no aerosol
production. Finn's personnel could not provide any acceptance criteria checks or data
demonstrating.that the washer is now properly soldered.
2/21114.
OBSERVATION 23
Procedures for receiving, reviewing, and evaluating complaints by a formally designated unit have not been adequately
established.
Specifically, your finn's SOP 6.11.1 11 Medical Device Complaint Handling" and SOP 6.15.1
"Instructions for Drug Adverse Events and Medical Device Reports Processing and Reporting" do not
adequately capture potential root causes during complaint investigations.
A. Potential root causes your finn has identified that can result in the EZ Breathe Atomizer producing
reduced or no aerosol are not tracked or trended based on an actual root cause (e.g., silicone 0-ring
EMPlOYEE($) SIGNATVRE DATE ISSUED

Melanie M. Walker, Microbiologist~
08/14/2015
OF THIS PAGE
FORM FDA 483 (09108) PREVIOUS EDIDON OBSOLETE INSPECTIONAL OBSERVATIONS PAGE 21 OF 24 PAGES
DISTRICT ADDRESS ANO PHONE NVMS!OR OATE(S) OF INSPECTION

FEI NIJMBER
Maitland, FL 32751
(407) 475-4700 Fax: (407) 475-4768 1000114235
Industry Informa t ion: www .fd a.gov/oc/indust ry
NAME AND TITLE OF INDIVIDUAl.TO WHOM REPORT ISSUED

FIRM NAME STREET JIDDRESS

CrtY, STATE, ZIP CODE. COUNTRY OYPE ESTASUSHMENT INSPECTED

Manufacturer
improperly installed). For 9 out of 9 complaints reviewed for "no aerosol production", complaint
investigations are not comprehensive and assigned root causes lacked scientific rationale.
B. Firm's personnel stated that complaint investigations are used for tracking the effectiveness of
implemented corrective actions. However, the necessary information (e.g., medication cup revision)
to assess a corrective action is not captured in your current complaint handling procedures and
forms. Firm's personnel could not demonstrate during the current FDA inspection how corrective
actions are verified or validated as effective for your EZ Breathe Atomizer units and medication
cups.
2/21/14.
OBSERVATION 24
Acceptance or rejection of incoming product was not documented.
Specifically, no acceptance criteria documentation for AC-14-003 (replacement medication cups) could
be provided demonstrating if these components met specifications. These (b) (4) medication cups were
distributed to patients via your Customer Service Center as replacement medication cups for their EZ
Breathe Atomizers.

Melanie M. Walker, Microbiologist~~
SEE REVERSE Ivis L. Negron Torres, Chemist~ nA~
CAPT Ileana Barreto-Pettit, Investigator ~)?
08/14/2015
OF THIS PAGE
FORM FDA 483 (09108) PREVIOUS EDffiON OBSOLETE INSPECTIONAL OBSERVATIONS PAGE 22 OF 24 PAGES
DEPARTMENT OF HEALm AND HUMAN SERVICES
DISIRICT ADDRESS AND PKONE NUMBER DATE(S) OF INSPECTION

FEINUMBER
Maitland, FL 32751
(407) 475-4700 Fax: (407) 475-4768 1000114235
NAME AND TITlE OF INDiVIDUAl TO 'M10M REPORT ISSUED

ARM NAME STREET ADDRESS

CITY, STATE, ZIP CODE, COUNTRY TYPE ESTABliSHMENT INSPECTED

Manufacturer
Observation Annotations
Observations intentionally left blank.
EMPlOYEE(S) SIGNATURE DATE ISSUED

Melanie M. Walker, Microbiologi~t
CAPT Ileana Barreto-Pettit, Inve tigator ~
08/14/2015
OF THIS PAGE
FORM FDA 483 (09/08) PREVIOUS EDmON OBSOLE'IE INSPECTIONAL OBSERVATIONS PAGE 23 OF 24 PAGES
DEPARTMENT OF HEALffi AND RUMAN SERVICES
1'000 AND DRUG ADMlNTSTRA'I'lON
DISTRICT ADDRESS AND PHONE NUloiiiER DAlE(S) OF INSPECTlON

FE! NUMBER
Maitland, FL 32751
(407) 475-4700 Fax: (407) 475-4768 1000114235
NAME ANDimE OF INOMDUI\1. "TO~ F1EP0RT IS1WED


CITY, STATE, ZIP CODE, COUKTRY TYPE ESTl\BLISHMENT INSPECTED

Manufacturer
* DATES OF INSPECTION:
07/20/2015(Mon), 07/21/2015(Tue), 07/22/2015(Wed), 07/23/2015(Thu), 07/24/2015(Fri), 07/27/2015(Mon), 07/28/2015(Tue),
07/29/2015(Wed), 08/I0/2015(Mon), 08/11/2015(Tue), 08/12/2015(Wed), 08/13/2015(Thu), 08/14/2015(Fri)
EMPLOYEE(S) SIGNAllJRE ~ ~ u. Ll~ DAlE ISSUED
Jessica L Pressley, Investigator ~~ \·

Melanie M. Walker, Microbiologist; ~ ~ .
SEE REVERSE Ivis L. Negron Torres, Chemist ~- ~22 .::;;;.·~-----
CAPT Ileana Barreto-Pettit, Investigator / ~~
08/14/2015
OF THIS PAGE
FORM FDA 483(0'1108) PREVIOUS EDUlON OIISOLim! INSPECriONAL OBSERVATIONS PAGE 24 OF 24 PAGES

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DEPARTMENf OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMlNISTRA T10"N

555 Winderley Place, Suite 200 07/20/2015 - 08/14/2015*

TO: Lou W. Kennedy , CEO and President

Nephro n Pharmaceuticals Cor p . 4121 sw 34th St

Orlando, FL 32811-6475 Sterile Inhalation Drug and Device

DURING AN INSPECTION OF YOUR FIRM WE OBSERVED:

STERILE INHALATION DRUGS

Je••ica L Pre••ley , lnve• tigator ~

555 Winderley Place, Suite 200 07/20/2015 - 08/14/2015*

TO: Lo u W. Kennedy , CEO and President

Nephron Pharmaceuticals Corp . 4121 SW 34th St

Orlando, FL 32811-6475 Sterile Inhalation Drug and Device

EMPI.OYEE(S) SIGNATURE DATE ISSUED

Jessica L Pressley, Investigator ~

555 Winderley Place, Suite 200 07/20/2015 - 08/14/2015*

TO: Lou W. Kennedy , CEO and President

Nephro n Pharmaceuticals Corp. 4121 SW 34th St

Orlando, FL 32811-6475 Sterile Inhalation Drug and Device

EJ.IPI.DYEE(S) SIGAATURE OATE ISSUED

Jessica L Pressle y, I nvesti gat or 5)~

555 Winderley Place, Suite 200 07/20/2015 - 08/14/2015*

TO : Lou W. Kennedy , CEO and President

Nephron Pharmaceuticals Corp . 4121 SW 34th St

Orlando, FL 32811-6475 Sterile Inhalation Drug and Device

Jessica L Pressley, Investigator ~

555 Winderley Place, Suite 200 07/20/2015 - 08/14/2015*

TO: Lou W. Kennedy , CEO and President

Nephron Pharmaceuticals Corp . 4121 SW 34th St

Orlando, FL 32811-6475 Sterile Inhalation Drug and Device

D. Previously on 6/4/13, your firm submitted a CBE-30 to (b) (4)

There was no mention in this CBE-30 of the newly

Jessica L Pressley, Inve stigator ~

555 Winderley Place, Suite 200 07/20/2015 - 08/14/2015*

TO: Lou W. Kennedy, CEO and President

Nephron Pharmaceuticals Corp . 4121 SW 34th St

Orlando, FL 32811-6475 Sterile Inhalation Drug and Device

This is evident by the following

1. Your firm received Complaint No. QR 14-02702 on 12/22/14 (approximately 6 months

Jessica L Pressley, Investigator ~

555 Winderley Place, Suite 200 07/20/2015 - 08/14/2015*

TO: Lou W. Kennedy , CEO and President

Nephron Pharmaceuticals Corp . 4121 SW 34th St

Orlando, FL 32811-6475 Sterile Inhalation Drug and Device

3. Your frrm received Complaint No. QR 15-00733 on 6/30115 (approximately 12 months

EM!'\.OYEE(S) SIGNA'IURE DATE ISSUED

Jessica L Pressley, Investigator ~

555 Winderley Place , Suite 200 07/20/2015 - 08/14/2015*

TO: Lou W. Kennedy, CEO and President

Nephron Pharmaceuticals Corp . 4121 SW 34th St

Orlando, FL 32811-6475 Sterile Inhalation Drug and Device

a. Your QU failed to require return samples to be sent back to conduct at a minimum

Jessica L Pressley, Investigator ~

555 Winderley Place, Suite 200 07/20/2015 - 08/14/2015*

TO: Lou W. Kennedy, CEO and President

Nephron Pharmaceuticals Corp. 4121 SW 34th St

Orlando, FL 32811-6475 Sterile Inhalation Drug and Device

Jessica L Pressley, Investigator ~

555 Winderley Place, Suite 200 07/20/2015 - 08/14/2015*