Ben Venue Laboratories Inc. B

DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMJNISTRAilON
DISTRICT OFFICE ADDRESS AND PHONE NUMBER DATE(S) OF INSPECTION

6751 Steger Drive
Cincinnati, Ohio 4523 7 FEI NUMBER
1519257
NAME AND TITLE OF INDIVIDUAL TO WHOM REPORT IS ISSUED
.
l_:_:~=:=.~=l-~-~-~-u-~-N-~-~-:_z~-~ ~6-~a~:-;~ =·e_"_s_~·-· I_.-n~c~.=~- ~·-~=·~-~-"'-~~--~-~- ·_. _·_·-·_·- _-.-.~·--··-[i];~~~~=~;•o --~-=~~- -~·- -_
TO: Thomas J. Murphy, President & CEO
.
DURING AN INSPECTrON OF YOUR FIRM {I) (liVE} OBSERVED:
This document lists observations made by the FDA representative{s) durjng the inspection. ofyour facility. They are
inspectiona1 observations, and do not represent a final Agency detem1ination regarding your compliance. If you have an
objection regarding an observation, or have implemented, or plan to implement, corrective action in response to an
observation~ you may discuss the objection or ac.,iion with the FDA representative(s) during the inspection or submit this
information to FDA at the address above. If you have any questions, please contact FDA at the telephone number and
address above, During an Inspection ofyour facility we observed.
1. The "Quality Manual", document #030-SOP-OP-01340, dated 28 Feb 2011,
'~describes the pharmaceutical quality system (PQS) as implemented at BVL. The Quality
Manual identifies the elements of the PQS and the sequences, linkages, and
interdependencies of related processes, and the responsibilities of Management to ensure
effective implementation." The ..Quality Manual includes the principles and responsibilities
for implementation of BVL's PQS and pertains to all BVL departments involved in
performing and/or supporting the development, manufacturing, testing, holding,
distribUtion, and marketing of phannaceutical products." However, the following
observations document a lack of adequate oversight by the Quality Unit to approve or
reject the products manufactured and processed, as well as, approve or reject the
established procedures and/or specifications impacting the quality of the drug product.
2. Failure to identify the root cause of foreign material, identified as stainless steel particles
in two products, (b) (4) and (b) (4) which are contract manufactured by your firm.
These products were all manufactured in the BVL south complex. All of the rots were
released and distributed. Your firm has received 9 complaints from 08/16/06 to 02/09110.
In 7 of the 9 c9mplaints, the foreign material was analyzed by a third party laboratory that
identified the particles as stainless steel or elementally consistent with stainless steel. In
the two other complaints, TRK 46061, the third party analysis identified that the particle
appeared to be metallic and TRK 87006, the third party analysis identified the particle to
be an iron particle, probably rust
Neither a definitive root cause nor a corrective/preventative action has been identified or
implemented to address the foreign particle issue. Also, for each of the complaints there
I v;:~r r
are no samples retained to evaluate the foreign particle issue.
received - Prod~ct(s) L BVLiot # Analyt. ica.fresults

oali~ (b) (4) T0o77:po~9o2o~~3,_,__._I_391J comeJaiQL'!.~ide~
·;;:;A,.~<-- A
DEPARTMENT OF HEALTH AND HUMAN - •• ·~-:
FOOD AND DRUG ADMINISTRATION
~---------~---~--------·~··~~W.--~-·
M-
6751 Steger Drive 5/2-25/11
Cincinnati, Ohio 45237 FE! NUMBER
(513) 679-2700 1519257
!---'-~----------·~~-~--~-------.,--•••••--'"'"-'" ''""'"""'"""''_.,.,.,,.,..,.,,,,"'""''w"•--·"'"""·~·w-
TO:
•Fl
Thomas J. Murphy, President & CEO
..
~------- -·--~--~·"------·------ ......,_•.... ....,... ~,,...
~--~""'" __ ............,,
STREET ADDRESS
·-"~-~----~
Ben Venue Laboratories, Inc. 300 Northfield Road

--···-~·•·•m•.w~w.. " -··=··~·'"=·•·•=m•.'•'·"'"·"'mm.•.-·•--"'~"·---+-------··•••• ,,.~•••·•--·~··----~~'"'"
CITY, STATE AND ZIP CODE TYPE OF ESTAI3USHME:NT INSPECTED
Bedford, Ohio 44146 Pharmaceutical Manufacturer
DURING AN INSPECTION OF YOUR FIRM (I) {WE} OBSERVED:
This document lists observations made by the FDA representative(s) during the inspection of your facility. They are
inspectional observations, and do not represent a final Agency detennination regarding your compliance. Ifyou have an
observation, you may discuss the objection or action with the FDA representative(s) during the inspection or submit this
information to FDA at the address above. Ifyou have any questions, please contact FDA at the telephone number and
addre ~rove.-t>\cmin g-atHtlspeetieJ t-ef..yew"-faeiJi.ty we--ebservecl. r--------1 ~~~~ces-
Investigation
Report (QIR)
30887
~~~~-)7~·~-+-0-9/-06-/0_6_'"'1,_....(b) (4) ~:-~-~:....,.~--~i-:-~-=-::-,---+-~::--~-::=-~:-----l--:::~~i~:~~;-
0229-00-604280, 5093J
#3885J indicates
0077-00-902093, the particle 3911 J
0077-00-87 4585, 3888J
characteristics
0077-00-604240, suggest metal 3839J
0230-40-715940 5584J
flakes I stainless
(b) (4) steel
. . 36169-----·--04/1B/07-- · · 0229-00-1000847 510~ 3ra. party
1
c______ analytical report,
05/9/07 lists
metallic flakes I
stainless steel
(b) (4) variety
46061 03/07/oa I
-
0077-00-1007259 3920 3rd. party
analytical report,
02/06/08,
identifies, main
body of the
particle appears
-482"5"1'~~~-J""'~o-5712toif~" (b) (4) r to be metallic.
-~·~ -"622s":oa:·1acfo847=~rs1"o4'""'-'"~·· -3rd. party
analytical report,
I - 04/07/08,
DATE ISSUED
S/2r/u
FORM FDA 483 (8/00) PRt;VIOUS EDITION OBSOLETE PAGE 2. OF']J PAGES
DISTRICT OFFICE ADDRESS AND PHONE NUMBER

6751 Steger Drive
Cincinnati, Ohio 45237
679-2700
WHOM REPORT IS ISSUED

FIRM NAM•r---~--~--------~ -- ---~---·-·---··-rsmEErADoREss--- ----·---··----------- ~-----,.-----·----w~--~---"--··------~-
Ben Venue Laboratories, Inc.

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300 Northfield Road
- -... . . . . - . - - •.. •--•••••"••••••••....,....,...~"·""-''·-~···w,·,·,·, ,'''•"''''...,.,.,.....,.,._ _ _ _ ,_..........,.,.
CITY, STATE AND ZIP CODE TYPE OF ESTABUSHMENT INSPECTED

---··-·
DURING AN INSPECTION OF YOUR FIRM {I) (WE) OBSERVED:
--·-·----~---~-----·------ ·--·-----····-----~--! .
This document lists observations made by the FDA representative(s) during the inspection ofyour facility. They are
inspectional observations, and do not represent a final Agency detennination regarding your compliance. If you have an
information to FDA at the address above. If you have any questions) please contact FDA at the telephone number and
adare~&i~ev~~~~tJfff\~a~rtasp,~tlem~ye,irt.~1t~~ve~~~~~d~----~r----,-~·---G-~~-----~-~---·,
indicates particle
is likely a form of
(b) (4) stainless steel
87006 09/01/09 0077~00 ..1715034 3989 party analysis
performed on or
about 08/27/09
identifies the
particle to be an
iron particle,
rust.
94475 01/28/10 (b) (4) 0229-00-1739828 5123 . party
95173 02/10/10 0229-00-1739828 5123 analytical report,
01/27/10,
indicates the
particle was a
piece of stainless
steel most
(b) (4)
95083 02/09/10 0077-00-1793765 3996
(b) (4)
0229-00-1739828 5123
(b)(4)
steel,
elementally
ent with
(b) (4) d party
cal report,
02/05/10
FOOD AND DRUG ADMINISTRAiiON
DISTRICT OFFICE ADDRESS AND PHONE NUMBER OF INSPECTION

Cincinnati, Ohio 45237 FEI NUMBER
(5132 679-2700 1519257
NAME AND TFfLE OF INDIVIDUAL TO WHOM REPORT IS ISSUED
TO~ Thomas J. Murphy, President & CEO

'FIRM NAME__,,._..w,--,··-···-·-···--·-·-·--·"''.......- ...-...........-·--···--..- ........----····-·--..····--·-··--"·M·STREETADDRE·ss··.. . . . . . . . --.----,.. ------,--.w--···---..·----.w-,-~ . . . ., ___,
- · - - · . _ . . . , ,......__,.,,..,..,••w ....•_.,,,,,,,,,,,,,,_._,..,,..,.....,.,..,,,,.,,,,....._.,_.,,,,_.,,,,,,,,,,,,_,,_,,,__,.......,...,_....,,.,.,.,.,..,,,., .. ,,.....,.......,.,.,..........,..,.,.• . . . . . , . , - ,.. ,,,,.,._.......,""---..,,.......,
300 Northfield Road
_ _ ,.....,._,.._ _ _,..,,,.....,.,..,.,,.,,.. ,., .............._ _ ,........_.,__..,,.,·.·,·,·.•J• .....
...,.........-..•.,.,,,,,_,.....,.._.~""'......,..,__ ....,~.,.~, .......,.
CITY, STATE AND ZIP CODE lYPE OF ESTA8USHMeNT INSPECTED

Bedford, Ohio 44146
~_,...,_~,, .. -•· ' . ... . ' '"'"' • . . "' • . ' .
Pharmaceutical Manufacturer
. """ •·w.·.·'~"""~-- _ _,._...~.~
DURING AN INSPECTION OF YOUR FIRM (I) (WE) OBSERVED:
This document lists obsetVations made by the FDA representative(s) during the inspection ofyour facility. They are
inspectional observations, and do not represent a final Agency determination regarding your compliance. If you have an
infonnation to FDA at the address above. Ifyou have any questions, please contact FDA at the telephone number and
indicates particle
from fot#3996
predominantly a
piece of stainless
steel most li
of (b) (4)
(b)(4)
In addition,
a. Complaint Report TRK # 95083, date received 02/09/10, contains two, third party
analyticallabs, dated 4/9/10 and 4/15/10 which identify stainless steel (b) (4)
particles in two lots {3996 and 40061). Lot 3996 was identified in complaint
report TRK#95 ver, per your Supervisor, Quality System, there was no
complaint investigation conducted for the stainless steel particles found in lot 40061.
b. We observed the metal access doors {e.g., 9-10 doors in buildi (b)(4) used to transfer
various pi~ces of equipment, and/or production related materials, into and out of the
manufacturing areas. The metal access doors and door window frames appear to be
severely dented with deep scratches/scoring on the metal surface areas. The
damaged door conditions provide a source for metal particle contamination within the
manufacturing areas;
c. On 5/6/11, we observed tray racks (b) (4)

which were located behind your facility. Your Supervisor Equipment and Component
Prep, South Facility stated that these tray racks had been (b) (4)e south
facility to this area that morning. The underside of tray rac ained an area
that appeared to be rust-like material. We obsetved appare tches on two sides
of the f ( he bottom shelf and on the outside face of two legs of rack
num (b) (4)
SEE EMPJ.OYEE{S} SIGNATURE

Rl:iVERSE
OF THIS
PAGE
FORM FDA 463 (8/00)
----------~~------


6751 Steger Drive
679k2700 1519257
1,__.;,'--~~~~~------------~-~----------------'--~--------------------
NAME AND TITLE OF INDIVIDUAL TO REPORT IS ISSUED

FIRM NAME
~-4+o~M.~'.WHNH.'............'A~'•~">NMW.".'•W·'·"••<«<v<oo#< .......... <•<••""'''-•••oo<o•--"''"..''''"'..,.."''''".Y.w 0•0'""''''''' 0 W'-H
CITY, STATE AND ZIP CODE

Bedford, Ohio 44146
DURING AN INSPECTION OF YOUR FJRM (I} (WE) OBSERVED:
inspedional observations, and do not represent a final Agency detennination regarding your compliance. If you have an
infonnation to FDA at the address above. If you have any questions, please contact FDA at the telephone number and
address above. During an Inspection of your facility we observed.
d. On 5/11/11, we observed glass tray carts, GTC-2006 and GTC-2008 stored in a

hallway of the factlity. These carts were identified as retrofitted tray racks returned
from the vendor for use in the South facility. We observed what appeared to rust~
like material on the underside of carts GTC-2006 and GTC-2008.
3. The uMedia Fill Program Parameters and Specifications" document #030-SOP-029, and
the "Outlining Test Parameters and Specifications Required For Process Simulations"
document #030-SOP-D-29, effective dates 06 Apr 2011 and 01 Jun 2010, respectively
"outline the test parameters and test specifications required for media fillsu and
establishes the media fill acceptance criteria. A Regulatory Deviation Report TRK
#11 0926, dated 1/4/11 d ument that "During manufacture of lot 1012-60-2017296 on
12/31/10 in filling suite
(b)
(4)
the minimum count requirement was not satisfied." The #
manufacturing batch record document the media fill consisted of filli(b) (4) _ vials and the
deviation report documents ·'The batch size for these products is less than the (b) (4)
minimum requirement outlined in the validation protocol. This media is recommended for
acceptance." Despite the written procedures established in the aforementioned standard
operating pro~dures the media fill was passed and deemed acceptable. In addition;
a. The uMedia Fill Validation Master Plan'' document #VMP33709M, dated 9/20/2010,
establish the media fill test requirements, which references the ~~rationale for the media
fill size" is documented in the llProcess Validation Process Simulation Testing
Rationale for the Establishment of a Representative PST Size", document
#RAT23509M, dated 06/11/09. The PST rationale establishes "a maximum media fill
size on compendia! guidance, PDA recommendations and industry baseline
information.ll However, the aforementioned procedures do not contain language or
establish provisions with respect to having less (e.g., (b) (4) , than the requisite media
filled vials (i.e., (b) (4) established by the media fill protocols;
SEE EMP!.OYEE(S) TITLE (Print orType) DATE ISSUED ,

REVERSE
OFTHIS
'\N\ ¥- 5"'/' 2 I II
L
.J
,____
PA__G_E··--~-----------~-----------··------·~·-~~~·-~.=/;~·~,--~D~;I~~~i~~~~~ r~n~~-if~~~~~~\,__~------~--~ 4
FORM FDA 483 (S/00) PR!;VIOUS EDITION OBSOLETE i~PEC Al OBSERVA'riONS PAGE : ; OF jJ PAGES
FOOD AND DRUG ADMINISTRAIION

6751 Steger Drive
679-2700

FIRM
., ,.-..-..,. ,.. .,......._. _,,........._,__ ~·••m-•"•••••. ••--"•~WN#cm--·«-•-~-~·~:;;;;·;;-;;;:;;-;;'77.;;;:;;~;:;:;~;:;·;•;:;;;;;;;::-.;;;:~=•· . m••r••~•~•~~~--~·~
CITY, STATE ANOZIP CODE TYPE OF ESTABUSHMENT
----------------~--- ---~·
DURING AN INSPECTfON OF YOUR FIRM (I) (WE) OBSERVED:
address abg:e·n~~f~ll¥tf~r{,~Rft8WtfJn8tlhl~Wi[fu'tll1gbm~~ Operations in the Aseptic Processing Area
(APA)", document #030-SOP-D-01155, define intervention as 'lan aseptic manipulation
or activity that occurs at a critical area." The media fill records lists the manual
interventions that are required to be performed by the specified individuals (i.e., job
functions). However, the media fill records do not document that the interventions are
performed by all of the individuals listed in the manufacturing batch record (MBR).
Rather, the Senior Manager North Facility confirmed that the requisite manual
interventions are successfully completed if one of the listed individuals (in the media
fill MBRj performs the intervention;
c. A Regulatory Deviation Report TRK #114581 was initiated due to an operator err
which occurred during the 3/8/11 Media Fill lot #1 038,.71-2036542 in filling suite (b)(4)
The documentation for Intervention #14, "Reconfiguration of Trays", was not
#
performed as required in the Master Productton Record "Routine Interventions"
section RINT1 OOA, which requires the operator to record the identification number of
the "Reconfigure Trays" on the lyophilization chamber shelves after loading said
chamber. Concurrently, the original and relocation of the trays were not documented
on the Chamber Loading Data Sheet MPR 66L by the operator. The Senior Manager
North Faciiity could not confirm that the operator performed the requisite manual
intervention as described in the Master Batch Production Record.
d. A 1/20/2010 CAPA, T(b) (4) 93875, was implemented to address execution of varied
manual interventions pecifically defined interventions) performed during aseptic
./
filling operations. Ho r, not all of the personnel that are currently engaged in the
manufacture of finished products have completed the CAPA's requisite tra-·nin . The
number of employees and manual interventions range, for example, from(b) (4)
employees performing "stopper bowl change out" and "use trayer plastic ,
respectively (Note: aforementioned examples are not intended to be an all inclusive
lists of the number of employees and manual interventions to be accomplished);
SEE EMPI..OYEE(S) SIGNATURE

REVERSE
OF THIS
PAGE
·~-'----·
FORM FDA 483 (8/00)

DISTRICT OFFICE ADClREE>S NUMBER

6751 Steger Drive
Cincinnati, Ohio 4523 7
679-2700
REPORT IS ISSUED
--·-=--
~~e L:oratories, Inc.. ~·~ ·-·-._--·----··--------1$~~~~~~ R:~~------- -----~---
cl;d~~~~~~~:~4~~~E ~-········ ··-~--~···-~----~~~~-,,~h":~~;~~~=:ro --.~

inspectional observatisms, and do not represent a final Agency detennination regarding your compliance. If you have an
address above._Du~n JJ..ection_Qf..¥our facilitv w~ observed. .
e. The (b) (4) t-'roaua \5peclffc meata fill manufactunng batch record #1105-08-2125730,
dated 9/19/10, document process simulations with manual interventions of the
lyophilization pre-chilled vial steps, which is performed prior to the aseptic filling
process. However, the media fill process failed to include the requisite manual
interventions established by the Media Fill Validation Master Plan" (VMP), document
II
#VMP22709M dated 8/30/10, "Media Fill Program Parameters and Specifications"

document #030-SOP-D-29, effective date 01 Jun 2010, and the 9/19/2008(b) (4)
assessment document #RA31208M. The observation is applicable for all
product specific media fill processes; ·
f. The media fill manufacturing batch records do not accurately account for the number
of vials that are filled and there is no reconciliation to assure that all media filled vials
are accounted for. The CAPA TRK #107148, dated 10/15/10 provides Regulatory (b)
Devg~
(b) (4)
Reports, for example TRK #1 05923, dated 7/6/10 describes, "During th(4)
a y reads it was discovered the documented amount of units received for
incubation varied from the amount actually incubated. There is currently no
specification for accountability of media filled units." The TRK chronology of event
document a similar concern occurred f(b) (4)(b)(4 dia fills dated from 5/27/1 0 to
)
8/20/10. In addition, the aforementione~ accountability for media filled vials
applies to the following media fill lots;
(b) (4) (b) (4)
i. 12/31/10- #1012-60-2017196, <
(b) (4) (b) (4)
ii. 03/08/11-#1038-71-2036541, <
g. "Media Fill Program Parameters and Specifications" document #030-SOP-0-29,

effective date 06 Apr 2011, establish "the test parameters and test specifications
required for media fills" and "Each intervention should be documented such that
growth positive test results may be appropriately correlated to a designated tray of
media filled units.n However, after performing the requisite manual interventions the
media filled vials are discarded and not included with the incubated vials. Discarding
DEPARTMENT OF HEAlTH AND HUMAN SERVICES
FOOO ANO DRUG ADMINISTRATION

'""~~-----.w~-~~------------"~~~~-~~~---.--~~~•·.~-~-.··••··-~w~~-·.·-·.~·r.<•"""·~--.--·.w--"~-·--••··•·•·•••-~••·--
NAME STREET ADDRESS
Ben........................................
Venue Laboratories, Inc.
.,••...,._,.,.,......
·~·--= ~h................,.• • ,.
300 Northfield Road
TYPE OF ESTABLISHMENT INSPECTED
DURING AN INSPECTrON OF YOUR FJRM (I) (WE) OBSERVED:
This document lists obsexvations made by the FDA representative(s) during the inspection ofyour facility. They are
address above. During an I~pection pfyour fadlitvN{e observed. . .
tne mea1a nnea v1a1s fJrec1uaes tne company from adequately assess1ng and assunng
that the manual interventions do not create or provide adverse conditions that result in
positive media fill vials. (Note: refer to the air flow pattern evaluations and upward
movement of air in Observation #7);
h. The 11 Media Fill Validation Master Plan" (VMP), document #VMP22709M dated
8/30/1 0 establish, uthe general approach for developing the media fill schedule and is
designed to meet the requirements set forth in procedure 030-SOP-D-29, Media
Program Specifications and Parameters." The procedure establishes the media fill
acceptance criteria, for example,
(b) (4)
i.
"When filling fewer th its, no contaminated units should be detected.
One (1) contaminated unit is considered cause for revalidation, following an
investigation."
(b) (4)
ii. ~~when filling from itst One (1) contaminated unit should result
in an investigation, including consideration of a supplemental media fill. Two (2)
contaminated units are considered cause for revalidation, following an
investigation And, .JJ
iii. ~~when filling more t h(b) (4) units, One (1) contaminated unit should result in an
investigation. Two (2) contaminated units are considered cause for revalidation,
following an investigation."
However, the preceding objectionable conditions precludes the company from having
/
the supporting data to document that they can meet the acceptance criteria
established by the standard operating procedure and the VMP Statement of
Commitment, "that the aseptic manufacturing process consistently produces product
meeting an acceptable level of sterility assurance. 11
4. The VMP and the Corporate Procedure uSimulation of Aseptic Processes", document
#OCP~074, dated 01 Jul2006, establish the frequency for "each aseptic filling
DATE ISSUED
s-; zs/ t 1
FORM FDA 4a3 (8/00) PREVIOUS EDITION PAGE 8 OF 33 PAGES
FOOD AND DRUG AOMlNISTRATION
DISTRICT OFFICE ADDRESS AND PHONE NUMBJ::R

6751 Steger Drive
(Sl3) 679-2700

W,,_ _........_ ..........,,.........,._.,.....,,,,,...,,,,o"'"<<'<<<'•..•___,.,,,...._,....,....... """"''''""''''''-....~•\W'N0NN,'NVN.M.W..~ .... ,,.,,...........,,.,.,,_......,~-· ............ ,,O. . .<"O--<<"""'... ""...,._ ... , _.. _ .......... _.._._,,~<-<<<<''"'''''''"'' ..............."""""'"' <'~__,., ....................._ .......,_.,..""""-..-.,-""'..•"'"·'•'.>.'H,<<'<•-'NN-".W,WN,<"'-'M"' ......- ' ' ' '...' ' _ _ ,.., ....................., , _ , _ _ . .,.....,......._,
FIRM NAME STREET ADDRESS
Ben Venu~--~~~.?..!ato:!_~~:. .~~·--w. -·~. .~. . . . . . . . ______.. . . --····..· --· 300 ~-~~eld-~~~~ ·-·--··········-··--···---···--·-··-'"
I
address above. During an In~p~ction of :.wu,5 faci (b) (4)bser (b) (4)
configuranon wm oe qua rr1eu 1 eve1 n tn month)u a~¥. th
o(b) (4) e approme (4) t
(b) (4)
d'
fill validation is a process simulation performe a east eve 11
onths (th)",
respect.. However, regarding the CP-4055 Product Specific media fills pe a
fill line i(b) (4) edia fills #1102-57-2147195, #1102-57-2147196 & #1102.. 57~2187181,
dated 3/09/11, 3/12/11 & 3/14/11, respectively, were performed almost one year after the
3/13/10 media fill.
(b) (4)
5. The "Clearance Procedure for Filling Interventions in Buildi cument
#030-SOP-D-80, effective date 22 Mar 2011, "outlines the steps to be followed for line
clearances performed after interventions in sterile filling", which are also performed during
aseptic media fill processing. The procedure defines the specified zones (4 to 5 each)
within the aseptic filling areas and for example requires zone clearances, "When possible,
remove all filled vials from the line prior to performing an intervention". The Senior
Manager North Facility confirmed that they did not have the rationale or data to support
the establishment of the specified zones.
(b) (4)
6. The design of the aseptic filling room - layout of the fill room equipment and the
plastic airflow 9urtains within the Ctass 100 do not prevent the ingress of objectionable
microorganisms and non~vi~articles. For example, dependent on the production
activities, there can be up t(b)(4) Production I Quality personnel that are needed to
perfonn the aseptic filling operations, which include access into the aseptic fill Class 100
areas via the plastic barrier curtains. The personnel entry and exit activities performed via
the plastic barrier curtains promote the ingress of objectionable microorganisms and non-
viable particles within the Class 100 filling areas. In addition;
a. The "Aseptic Technique Guideline for Personnel Working in the Aseptic Processing
Area" document #030-SOP-D-132, effective date 21 Jan 2011, "provides the
.. - I I"'!-" c
1 • •
(b) (4)
(b) (4)
•
- ' • I
FOOD AND DRUG ADMJNISTRAiiON
1----~-
-~-----------------~-------.-----------~-·-··--·~·~··
DATE(S) OF INSPECTION
-
6751 Steger Drive 1
679-2700 1519257
STREET ADDRESS
..........._........... .,..,....,_,_,..,~,,N.'""'"""""'·'·'·'·'·'""""'.,_,.. ~··t"
300 Northfield Road
·"·-------------·--··----------..--·~-·---~
CITY, STATE AND ZIP CODE TYPE OF ESTABLISHMENT INSPECTED
·-----·......!, - · · - - · - - - - - - ·..·--·~
DURING AN INSPECTtON OF YOUR FIRM (I} (WE) OBSERVED:
address above IJ •· I • • I • • .. . . • I • • - • • • • • - - - A
(b) (4)
area can pose a risk to product sterility." We observed sle o filling

(b) (4)
d personnel activities for fill line (b)(4)
nd # (b) (4) ,--
We observed personnel manually transf lled

vials fro the aseptic fill line to the lyophilizers and the personnel movements were
not consistent with the aforementioned established procedure.
7. The ~~Dynamic and Static Air Flow Pattern Test Procedure for Grade A, Class 100 and
Surrounding Areasll document #03o ..sOP-J..230, effective dated 31 October 2008
describes "the test procedure and acceptance criteria utilized to verify the presence of
unidirectional air flow patterns with Grade A, Class 100, and Grade 8 active areas under
dynamic and static test conditions for qualification." The air flow pattern evaluation failed
to include and assessment of the routine manual transfer process of partially stoppered
vials from the aseptic fill area to the lyophilizer and fail to include an the
(b) (4)
transfer from the stoppered vi l f o t e aseptic fill area (fill room the
inner seal production room (b) (4) - respectively. In addition;
(b) (4)
l;l}!~fE
PAGE
EMPLOYEE(S) SIGNATURE ~.M·~.LO~(S) NAME AND TITLE.-.
'"- -! 1 ~
C'TM <jJ;':J'.;:I V'l) f'J tt..t.."- "''1 '1· r
ri.n.t orType)---r~~s;.~ ~--
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DISTRICT OFFICE ADDRESS AND PHONE

6751 Steger Drive
679-2700 1519257
NAME AND TfTLE OF INDIVIDUAL TO WHOM REPORT IS ISSUED

r-----------"--''""''''''-'"'''"-"'""'~-·--"'"' _ _ _ _ _ _w,.,,,..~~~-.•--•~-·
... . .
PIRM STREET ADDRESS
.. ... ~
~.~~-----''·''''"'"·"'''"'~'-~~-,=··~'·''•'·"~·-"·'·~'''·~-~--~--.·~ ... ~.
infonnation to FDA at the address above. If you have any qqestions, please contact FDA at the telephone number and
address abgve.-.During_~ Ins.n.ection of your facl'litv we.ob&eryed. .
. The arr rrow pattern tests fai ea to JncJuae an assessment of the a1r flow patterns when
manually transferring (i.e., routine dynamic operations) production equipment and/or
monitoring equipment when opening and closing the entry door ways;
c. The air flow patte for the aseptic fill rooms were captured on video. The
videos for fill lines (b) (4) in an upward direction during
manual interventions (b) (4) And, there were no air flow pattern
evaluations over the manual operations performed for interventions (b) (4)
(b) (4) (Please note: the personnel manual operations simulated by the
manual interventions are designed to demonstrate that the personnel manual
operations do not promote the ingress of viable microorganisms and non-viable
particles, as well as, non-disruption of the unidirectional air flow);
d. The 10/13/1 o air flow pattern video document a number of dynamic personnel
activities and manual operations (e.g., placement of EM sampling equipment, entry (b) (4)
ar).Q.exit
(b) (4)
of barrier curtains & access panels of the fill equipment) for aseptic fill line •
However, the air flow pattern evaluations do not include an assessment (smoke
study) of the locations where the specific manual operations/personnel activities take
place (e.g., work surfaces).
e. The 8/17/09 Laminar Flow Verification was perfonned via Study document #8411 09M,
"to verify that laminar air flow exists within the (b) (4) cart.JJ The air flow pattern
evaluations did not include an assessment of the air flow of the interior of the (b) (4)
Transfer Cart with the nonnal configuration of the partially stoppered vials. In addition;
i. The air flow pattern evaluations failed to include an assessment to determine that
the laminar flow of air is not negatively affected during the manual transfer of the
partially stoppered vials into the lyophilizers from the (b) (4)Transfer Cart.
SE£ SIGNATURE
REVERSE
OFTHI.S
PAGE
FORM FDA 483 {8/00)
FOOO AND DRUG ADMINISTRATION

6751 Steger Drive
(513) 679-2700

-'-""-"''""~'.w.·,,W,WNN"'•''•'"'•'•''•••'"'"''"'''"-''•''•'"'• •'•'•'•'•'·'•'•W''•'•'•'·W·'<<·W<W<,W<<@WC.,u'NN-'NN.'•W<C.u",'u',UN<uu,mN<'•"•""""'"--"''"''"~-- -----··'-""'"'''"'""--·----"'"""""·--··WU-~~--·-·--•-•w

DURING AN INSPECTION OF YOUR FIRM (l) (WE) OBSERVED:
·-----------------··-"-·----·-'"--·.. ·-·-~· -----------1
address abf.ve....DUring an Inspectiau of your facilitv ~ obse~~d. . .
. The JJJrector or MlcrOOIOiogy com~rmea tnat the a1r flow pattern evaluations have not
been reviewed by the microbiology department and the air flow pattern studies have
not been evaluated with respect to microbiology e.g., unidirectional air flow patterns,
dynamic operations, personnel activtties, Environmental Monitoring (EM) Program
sampling site locations in support of the aseptic filling processes.
a. The J'Environmental Monitoring Site Selection Rationale" dated 1/31/11, provides ..the
rationale for environmental monitoring site locations at Ben Venue Laboratories aseptic
manufacturing facilities, and to provide a tool to formally document and justify the
Environmental Monitoring location selections." However, the site selection process did not
include, from a microbiological perspective, an assessment of the air flow pattern studies.
In addition;
a. The above mentioned EM site selection rationale consisted of an evaluation of the

historical, previously existing, EM sampling locations. The 1/31/11 site selection
rationale does not document, for example, the evaluation of the air flow patterns and
their affect on the dynamic operations with the varied aseptic personnel activities
and/or when opening and closing the multiple entry ways and their collective impact
upon the aseptic filling process;
9. The sterility failure found on 01/20/1,0 associated wtth (b) (4) lot# 2378-44-1157184
{TRK #93890) identified Paenibifcl1/us(b)woosongensisas
(4)
as the contaminant. This lot was
manufactured on 01/25/08 in Jill ro n the North facility. The environmental .
monitoring program, from dates 1211 through 07/17/oX? identified the recovery ~~;~JII
of Paenibacillus from Class 100 personnel monitoring and from Class 10,000 area and it
was not recovered from the sterility tests isolator. The Senior Microbiologist explained
that they believe that the microbial contaminant was due to concerns with the sterility test
isolator. The aforementioned locations were not considered as a source for the microbial
contamination.
SEE EMPI.OYEE(S) SIGNATURE .;M~~EE(S} NAME AND TITLE (Prl~t-~;:r;;;;)'"'"··~l o;;~SSUE~ ----
RE=VERSE
~~~ :tf"-1~-:· t:rfl1. 7/rl..t/ rn 'P.r' \A.\.\.. I

OFTHJS
PAGE
FORM FDA 4a3 (8/00) PRE;VIOUS EDITiON OBSOL!;;TE lfi~EcTrol_$!1\oesERVATIONS · , PAGETi oF 3-:i·PAGEsw_,
Ctc-.U"'I by; I'Sl: Meui:. A~' (}'.11)'14:>-.!.4$1 EF
DISTRICT OFFICE ADDRESS AND PHONE NUMBER 'TE(S) OF INSPECTION

--"'··-''"'"----~~--··-~~·-·-~----~-----
FEI NUMBER
(513) 679-2700 -~~~--~~~~~~~........~......_1_5_19_2~5~7---~~----~--·-~-~


···-••••••-•~-··-·--·~-•~••-~m~••·-·•·•·'·•·••····~-···•••-----·•··--··•••••·-•••••-•••••••·••·•.••••••w•..-•••·-•••< ·--~··-•·•-~•·••••.••••"' --··~w.·.w.w•·---~--~ "'"··-~·-·••·••·••"'"'W""""'-•••••··..-w-

----~----------············-~······---·····'-"---···-----~·······----·----··-----·········---··------·-----~--'"·-··----- ··-----····--····-----~--""'" ·"·--··----~-~-----·····
CITY, STATE AND ZIP CODE TYPE OF ESTABLiSHMENT INSPECTED
!----------·--···---·------·····-----·-~-·· ··-~---·-··-----------~----·-~-----
DURING AN INSPECTrON OF YOUR FIRM (I) (WE) OBSERV(;D:
inspectional observations, and do not represent a :final Agency detennination regarding your compliance. If you have an
a4ffi~ss ab6'~· d@8Hr1W, 1RfgeffrWtl1s0hli~~bbBfdlbtgya&lp&ffrWent detected a sterility failure for the
aseptically filled parenteral drug product\ (b) (4)lot #2205-08-1907417 (TRK #1 04155).
vestigation found that during fill operations for this product, operators were using
(b) (4) gloves. These gloves are neither sterilized, sanitized nor cleaned prior to use and
they are composed of a material that appears to shed fibrous material. It was determined
that the root cause of this sterility failure was most likely a compromised outer steriJe
glove, which led to the exposure of the fill line equipment to the (b) (4) glove material. In
addition;
a. Document 030-SOP-0..55, Aseptic Gowning for Entrance to and Exit from the Aseptic
Processing Area, establishes the instruction with specific procedures for donnjng the
required aseptic gowning. However, the SOP is silent with respect to the use ofl (b) (4)
gloves. The Senior Manager of the North facility and the Quality Assurance Manager
stated that they were unaware that these (b) (4)gloves had historically been used by
operators during certain fill operations.
11. The 01/21/11 sterility failure associated with\(b) (4) lot #2499-49-2055596 (TRK
#111988), identified Propionibacterium acnes as the contaminant. The investigation (TRK
#111988) attributes that the anaerobic contaminant came from the isolator gloves, which
failed the integrity testing after the sterility tests were performed. However, the
environmental monitoring program does not include an assessment for the presence of
anaerobes. In addition, a root cause analysis has not been performed to determine the
source of the anaerobic microorganism.
12. The 2010 and 2011 quarterly environmental monitoring (EM) data document the percent
of microbial identification for gram-positive rods (i.e. spore formers and non-spore
formers} isolated via the EM sampling program for the manufacturing areas (Class 100
and Class 10!000, for example:
I Percent gram-positive rods [a1 2010 l Q2 2010 I Q3 2010 L04 29.,10 [Cf[2"511]
-~---~$~£-£---~, EMPI.OYEE(S) 5·1-GNA-T-UR-E~---------LEMPLOYEE(S) NAME AND TITLE (Print o~Type~~~· DATE ISSUED
Rt=VERSE "\ VV\~ ··-
OF THIS . ;)
PAGE '71 f::~-- if:[~\ fJtt__l:) rnp I ~'t- t-.\. b
,__FO.-R-M-FD_A_48_3~(-6/_0_0_)--PR_E_V_Io_u_s-E~P-IT-IO_N_o_s_so-L-E:T_E_ _ _Jl\j,_§.......:...:.
P~Aic)BSE-RVATIONS PAGE) j OF.:J 3"PAGES
~~-,=~'"""~'""~"·~-''"'"~--' ' ----~~' '-~~~
6751 Steger Drive 1
Cincinnati, Ohio 45237 FEINUMBER
(513) 679-2700 1519257
NAME AND IS ISSUED

-........,~---.,"'"<......._A_,_,,,w............,__,,,,,,..,. ••,,,,..,,,.....,.......,,,....,..,_...
wu.·.-..-.wA.y.......,~,.w~.·.•_,.,._,.,,,.w,......._·.•--.ON.""'"""n.·.w."'-'.V.W.....,
300 Northfield Road
_ _ _ ,,.,.._.,_.,....,,..,......_.,....,..,.,.,.,__,_,_..............-_ __. _ _,,,,,,,,,,,,,,.,,,,,_,_ _ _,,._,,,,,,,,,,,,,,,...,,....._...,...,,,_..,..........,....._ _ _,_ _........,,.u......-.
CI1Y, STATE AND ZIP CODE TYPE OF ESTABLISHMENT INSPECTED

DURING AN INSPECTION OF YOUR FIRM (I) (WE} OBSERVED:
inspectional observations, and do not represent a final Agency determination regarding your compliance. Ifyou have an
address a f)~tl~ll-lll:S eetielH1f·yetrf ra'Gi-me-& r;se~/~"~-
ort I ss 108 1 o 0 10% 14% I 33°/o =·=
North Class 10,000 ,....,, ..... "'"'""""'

65°/o 25% 28% 27o/o 30% ._._,NM'M
North Class 100,000 33o/o 49o/o 30o/o 61o/o - 67%
North Personnel 10% 6% 14%) 8o/o 9o/o
Phase IV Class A 17°/o 8o/o 21o/o 33o/o 29o/o
___
=""·'"'""
Phase IV Class S
N'. ................__.,..,_.
23% 15o/o 6o/o 33% 17%

Phase IV Class C 33% .. 33o/o 23% 64o/o 63%
- ··- -61%
·
,
44% 70% ··-

·~---
Phase IV Class D 85% 51%
'
M'
Phase IV Personnel 7o/o 11% 12% 14°/o 11%

.. South Class 100 21°/o 15°/o 7o/o N/A N/A
South Class 10,000 ""=·-=·
21o/o 15% 15°/o N/A N/A
South Class 100,000 24% 24°/o 29°/o N/A N/A
-South Personnel 10% 11% 7% N/A I N/A
~.
--- · """-·~-·.
The EM sampling identifies the locations where the microbial contaminates were
recovered. However, the evaluations fail to identify the source(s) of the microbial
contaminants, for example, the root cause for the recurrent presence of the Bacillus
species contamination. The root cause evaluation(s) in turn assist to address, and
ultimately control, the ingress of objectionable microorganisms.
13. The firm has recovered at least 1,171 microbial contaminants between 01/01/10 and
03/30/11, including 1,047 actions of gram-positive organisms, 108 actions of gram~
negative organisms, and 16 actions of mold organisms from various locations within the
firm's classified areas, including the Class 100 and Class 10,000 manufacturing areas.
However, the firm has not investigated these microbial contaminants to determine the root
cause of the contamination, nor have they initiated any corrective action to address the
contamination.
14. The firm contracted the validation of disinfectants and received the results in November
2009 for a disinfection efficacy study performed by the contactor. However;
·-;P.·~GfE~~E(SJ,~S,,~.~GNA_-,_TURE.-,-·_,''•'·_~~ r~.::(S)NAMEANii-TITLE (Print ;;fl-Y,e) rATE ISS~=;-;--

I - . .. -- ________._1-t~ ·-·?.1q <711:"l.J)l:/:i 1~f?j tl.).,\.. -·------·
33 PAGES
M
FORM FDA 433 (8/00) PR~VIOUS EDITION OBSOLETE ~,~E:CTtONAL OBSERVATIONS PAGE/'-/ OF
Cr«<i<:J by: l':,;t: M<~i" t\rt" (Wi) •t4J-2•1)4 EF
FOOD AND DRUG ADMJNISTRAitON
DISTRICT
6751 Steger Drive
679-2700

------ ...,...------------~~"~·-···--·~--~

DURING AN INSPECTrON OF' YOUR FIRM (I) {WE} OBSERVED:
a. The Quality Control Unit did not review and approve the raw data associated with
the Disinfection Efficacy study. Rathe ewed the Qualification Summary
isinfection Qualification for (b) (4) Ready to Use (RTU),I (b) (4)
,
(b) (4) (b) (4)
rl I (b) (4) (b) (4) - -
L_______ _
(b) (4) _ _ _ _ by the Surface Method," dated 11/20/09;
b. The materials that were tested in the Disinfectant Efficacy study were not
representative of all of the surfaces present in the Asepttc Processing Area. For
example, the firm maintains rubber wall bumpers, carts with wheels, and castors
which appeared to be coated with rust..Jike material. These materials were not
tested in this study. Furthermore, we observed stainless steel walls and doors that
were scratched, dented and gouged. The stainless steel coupon tested did not
represent these damaged surfaces;
c. The firm was unable to provide scientific rationale for the use of the selected
organisms used in the Disinfectant Efficacy study. These organisms were not
repres~ntative of organisms isolated from the facility nor were they representative
of the USP guidelines;
d. According to a Senior Microbiologist, the acceptance criteria for the studies were
established from USP <1 072> as is referenced in the Test Protocol- Disinfection
Protocol, as well as USP <1227>. The USP <1 072> indicates that the surface
being decontaminated should measure 2" X 2Jl square. However, the stainless
steel and plexi-glass coupons the firm used in these studies measured
approximately (b) (4) square. The firm did not provide any scientific rationale
to support this change.
15. The "Validation of the Microbial Effect of Utilizing a Sterilized Hose, for An Extended
Period of Time", study number (b) (4) dated 03/21/08, states that the water ~~hoses are
SeE EMPI.OYEE(S) SIGNATURE EMPLOYEE(S) NAME AND TITLE (Print orType) DATE ISSUED
Rt:VERSE
OFTHJS
'\M'?- >/z~t/n
PAGE fhPJ 'o:.'-Ll
FORM FDA 483 (S/00) PRE;VIOUS EDITION OBSOLETE CTJONAL OBSERVATIONS PAGEl~ OF (J PAGES
DEPARTMENT Of: HEALTH AND HUMAN SERVICES
DISTRICT OFFICE ADDRESS AND PHONE NUMBER IDATE(S) OF II'I!;;.J""I:\..IIUI'I

(513) 679-2700 1519257
--'--------t----------~~~-~--~~-~---~-'-------~"'''-~·-·~--~-~
NAME AND TFfLE OF INDIVIDUAL TO WHOM REPORT IS ISSUED
:1i~~~~¥~~~~=--~~~- -~-~==-=-~~==re5i~~~:~f~~~-=--=-=·· ~-
DURING AN IN$PECHON OF YOUR FIRM (I) (WE) OBSERVED:
inspectional observations, and do not represent a final Agency determination regarding your compliance. Ifyou have an
address above. During an lt}spection ofyour faciUtv we Qbsenr~d. · . .
flung, wnne not m use, to preve~ 1egs for the accumulation of mo1sture.'J The
testing methodology states that (b) (4) e t in length hoses "will be acceptable."
However, we observed two braided stainless steel hoses (Gen Comp Hose 1029/Gen
Comp Hose 1033) connected in-series to the WFI Valve WFI-1-9, totally an approximate
30 feet in length. The Formulation Supervisor and Senior Manager North AM confirmed
that both ends of the hoses were closed and fully charged with stationary water. These
two braided hoses containing stationary water lack the ability to vent and drain, thereby
creating a dead leg. Furthermore, the above-mentioned valida vide
language or establish the use of hoses with a length greater t h (b) (4)e t .
16. Document 030-SOP-K-99,

(b) (4)
itoring of Aseptic Areas with Swabs", Effective
Date: 08/29/07, ~~provides the procedure to perform a qualitative assessment of the viable
aseptic environment on a (b) (4) i s with the use of swabs." However, the Associate
Director of -ualit ControJ Microbiology and Supervisor of Microbiology confirmed that
there is no (b) (4) rending of the microbial contaminants. In addition, Gram stain and
~orp o ogy 1s performed for the microbial contaminants recovered via the
(b) (4) b monitoring program. However, no further identification or characterization
rs performed of the microbial contaminants.
17. The Environmental Action Coordinator is responsible for confi.rming non-viable actions by
comparing results to alert/action levels and is also responsible for entering all product-
related actions or trends into I (b) (4) as established in the Document 030-SOP-K-21,
Responses to Viable and Non Viabl~ Results from Aseptic Areas and Critical Systems.
Th.e 030-SOP-K-01029, Environmental Action Committee (EAC), Effective Date: 10/28/09,
states that the EAC will review trends and all non=viable particulate data, and review
(b) (4) aries of all action and alert excursion data.
However, according to the Supervisor of Physical Monitoring. the EAC nor any other
department/component in the Quality Controf unit does not track, trend or review NVP
alert excursions which are detected through theJ (b) (4)
systemiL (b) (4)
I--R-e~-~-~S-E--""-11r-E-M-PL-O-YE-E-(S-)-61-GNA~TU~R-E~~~~·~-~......-.;-MVV\.,-PL-~-~-E-(5-)~NA-M_E_AN_D_T_IT_L_E-(P-r-in-t-or-TJII-pe-~- - - - -~~"e. ·~s-:-E-D~-;---
OFTH1S
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Dl~;~~~~~:;~~~::eRESS AND PHONE NUMBER
(513) 679-2700
1----'-~--L-----,~------~---------------'--~--,,--,---~-~--~~--~
-"-l~~:~~~:E:TIO:
IFEI NUMBER
1519257
==

Ben Venue Labu1 4Lul"ic;:,, Inc. 300 Northfield Road
CITY, STATE AND ZIP CODE
----------~·-~~-~--'~''
IYPE OF ESTABL!SHMENT INSPECTED
,,,W,'

DURING AN INSPECTION OF YOUR FIRM (l) (WE} OBSERVED;
information to FDA at the address above. If you have any questionS, please contact FDA at the telephone number and
address abqve. Du;:ing an Insnection of_~our facility :we..Qbseyved. . .
aunng me- manuracture or aseptically mrea products. Furthermore, the firm fatled to rev1ew
the year-to-year trends of the viable and nonviable particles taken via the Environmental
Monitoring (EM) program.
18. According to the Supervisor of Physica ring, the firm has defined the limits of non-
viable particulates to be not more that (b) (4) micron and not more than (b) (4) micron
particulates in 1 cubic meter of air, as defined in Annex 1 and ISO 14644. However,
between 09/01/10 and 01/31/11, the firm detected 112 events during which these NVP
limits were exceeded during the manufacture of aseptically filled products. The firm did not
initiate investigations to determine the root causes of these excursions, nor did they take
corrective action to address the excursions.
19. There is no record to document that the air pressure readings (inches per water column)
for the aseptic filling areas (Class 100 and 10,000} and the surrounding manufacturing
areas are reviewed by the Physical Monitoring Department and/or the Quality Unit. In
addition;
a. The Physical Monitoring Department an Quality Unit perform verifications that the
(b) (4)
air pressure monitoring records and th ssure Reversal Alarm Reports are
complete and accurate. The alarm rep ument the air pressure monitoring
location, alarm start and end time as well as the alarm duration. However, the records
do not document the actual air pressure measurements (inches of water column);
b. The Quality Compliance Manager and the Supervisor of Physical Monitoring

confirmed that the differential air pressure alarm measurements and non-viable
particle (NVP) alarm conditions are not periodically reviewed. And, they confirmed,
that the alarms are not trended to assure that the aberrant events and/or conditions
that created the alarms do not present a state of control that is inconsistent with the
requisite NVP and air pressure specifications.
~;;;a;T,EMPL.OYEE(s) siGNATURE·~cc=--------..E-1-~-Lo-~-~-E(_s_>NA_M_~:;_AN_D_T_JT_L_E-<P-rin_t_o_r_rYI-Pe_)_ _ ,.-o:/":s/-- - 1
11
PAGE '~l ·1'11;-"f f::~{fl l.j)!J~b'/ f1"J;tj h~\.,L
~FOO-M-~-A-m~~-O-O_)_ _P_R-~-~-U-S_E_D_IT_~_N_O_B_OO_L_~-E--~~~N~OB~R~~-N-S-~-p-~~E-/_7_0_F_:~U-P_m_E_S~
Crc-.ld b)'' P!lC Mocfi• A tis tWO 44J·1A54 £F

6751 Steger Drive
679-2700
NAME AND TITLE OF INDIVIDUAL TO WHOM RE;:PORT IS ISSUED
TO! Thomas J. Murphy, President & CEO

--~-
1..2B~~e:~n_V~~~e~~nu:~e~~~:~~,~:~~~~~.~~!.."In~.~c:·~·=····-"·-·==~~-~~.-~~---J-~30~0~N~o~r:~~fi-el~~~~-~- ·=·~m~-.,..·~~·····~-----·-····-·····--·
CITY, STATE AND ZIP CODE: TYPE OF ESTABLISHMENT INSPECTED
address ab.o.ve. Durin~ illl In~em.ion..of YCJu.r.-facilitv Wx obsery,ed. f h c t'
20. uocument u~o-~ut-'-1'\.-011 o6, uany upera11on o t e an mucus Non-v·ta ble p arttcu . Iate
Monitoring System, states that if an NVP Action level is detected using the continuous
monitoring system, then the operators must halt production and notify the QA auditor. QA
will determine how to proceed with remediation prior to restarting fill operations. The
established written procedure is silent with respect to providing directions on haw the QA
auditor should determine appropriate remediation. In addition;
a. Between 03/16/10 and 11/24/10, 16 reports were reviewed which investigated one or
more NVP Action levels which took place during filling operations of aseptically filled
finished drug products. In these reports, 14 of these Action levels were remediated by
(b) (4)
halting production and air washing the fill line for at lea utes. Operators and QA
did not include clearing and sanitizing the lines during the remediation of the14
separate events.
21. The "Environmental Monitoring (EM} Program" Clean Room Characterization, 028-0CG-
00021, Effective Date: 08/01/03, establishes the baseline requirements reflecting current
regulatory ruling and industry thinking rather than to identify the highest expectation from
the existing St~ndards and Guides. Specific regulatory situations may require higher clean
room conditions than described here. With respect to the EM Program the following
standard operating procedures (SOP) are used;
a. 03Q..SOP-D-84, Viable Monitoring with the Use of Settling Plates, Effective Date:
03/07/11;
b. 030-SOP-D-15, Sampling of Surface-Derived Viable Particulates, Effective Date:
09/01/10;
c. 030-SOP-D (b) (4)
toring of Aseptic Areas with Swabs, Effective Date:
08/29/07;
d. 030-LST-00127, Viable Monitoring Sites in Building No. 20 Aseptic Complex,
Effective Date: 04/19/1 0;
~-~•·•-·--•• ...... ~--~~·••w''""""1"w"~"·-"~""-------··~------~·-----·~"""'""·-···-------~-·""-"""""".."'"''""'""-''~·--~---·-"•""''""""""'"'""J--·""''"""'' ........,.,,_ _,.._
SEE SIGNATURE EMPLOYEE(S) NAME AND TITLE (Print orType) DATE ISSUED
Rl3V£RSE
0FTH/S
' \ ~ \4!..- s-;z j
PAGE ''Jk;t:f'c..(.._ . @1 c;}(/.,(j (\') pJ l.t..t,'i_.
,3 --PAGES
FORM FDA_48_3..~..(8/_0_0_)--P-R~-V-IO-US_E_O-IT-IO_N_O.B_S_O_LE_T_E_ _.....~..lf'f-.i!....:.P...:_E_CV-'tf-::l{JJ:PN~A-l_O;;;_B_S_E...~,R::.:::.V..;::A:_.T_IO-N-S-~-P-A-LGE-/-.ffOF~-?
Cn::.tetl by; I'St: M<ili;, Arh (3\IJ) 443-24$4 !::F

DISTRICT
6751 Steger Drive
679-2700
NAME AND TITLE OF INDIVIDUAL TO WHOM REPORT lS ISSUED
CITY, STATE AND ZIP CODE OF INSPECTED

address above. Dmil)g,a:p l:n.ID8c:tion..Pfs.ou.r facilitv we qbsel)l..ed. . 'ld' N M' .
e. u;.ru-LST~ 0U~~, VlaDie MOnttonng ~1tes In 8 Ul 1ng 0. 24 ICrOblology
1
Laboratories, Effective Date: 01/31/11;

f. 030-LST-00126, Viable Monitoring Sites in Building No. 19 Aseptic Complex,
Effective Date: 03/19/11;
g. 030-LST-00128, Viable Monitoring Sites in the Building No. 22 Aseptic Complex,
Effective Date: 02/08/11
However, the aforementioned standard procedures fail to contain EM sampling

maps/diagrams to document the EM sampling locations for either work suliaces, settle
plates or for the active air sampling. In addition, the Associate Director of Quality Control
Microbiology and Manager Quality Assurance confirmed that there has been no
evaluation performed to determine the validity of the EM sampling locations.
22. Document 030-SOP-J-204, Dynamic and Static Environmental Monitoring Using Portable
Non-Viable Particulate Counters, states that NVP monitoring during dynamic filling
operations will be performed according to 030-LST-00033, Dynamic Non-Viable
Particulate Sampling Locations. However, this list does not clearly define the locations of
where the portable NVP machines are to be placed within the room classified areas. In
addition;
a. The Supervisor of Physical Monitoring explained that the Environmental Control {EC)
technicians are verbally instructed to place the NVP machines randomly inside the
classified areas. However, the SOP does not address the verbal instructions nor does
the firm have any controls in place to ensure that the EC technician is objectively
placing the NVP-machines in the appropriate location.
23. We observed that three tools maintained in aseptic fill room 4165 of the Phase IV facility
had rust-like material inside th(b) (4)ockets. These tools are used during the set-up and
interventions of aseptic filllin md come into contact with the fill line equipment. These
tools are not sterilized prior to use. And,
EMPLOYEE(S) SIGNATURE
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EMPLOYEE(S) NAME AND TITLE (Print orType) I

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Cr".Udhy: f'St: Mdb A~-' !.301) •f4J..2~5'l EF


6751 Steger Drive
Cincinnati, Ohio 45237 FE! NUMBER
679-2700 1519257

FIRM NAME
Ben Ven~e~~-abor~!~~.:~;Jnc. ""~"'""~·--". ··-""···----..- -"·..-------- 300 ~~hfield -~~~-~---~·-·. ····--·••+··~·-···--····~..-~.-----"·. . --~-.·
This document lists observations made by the FDA representative($) during the inspection of your facility. They are
objection regarding an observation 7 or have implemented, or plan to impiement 1 corrective action in response to an
address above. During an Inspection ofyour facility we observed.
a. Document 030-SOP-F-2 states that tools are sanitized with before and after
(b) (4)
use, then placed in a toolbox in the room. The firm does not have a procedure in place
to document this sanitization-, nor is there a formal procedure in place in which firm
employees inspect tools for defects such as rust-like material or dents and scratches.
24. Document 03Q..SOP-K-46, Personnel Monitoring Program, states that every employee
who participates in the set up for the active filling portion of the aseptic filting operation is
required to contact Environmental Control (EC) for glove and gown testing. The
Supervisor of Environmental Control explained that the personnel monitoring requirement
includes the EC technicians who take environmental samples during filling operations.
However, the SOP does not address personnel monitoring of the EC technicians.
Furthermore, the Quality Unit cannot assure that the EM monitoring of the EC technicians
is objective, in that, the EC technicians perform the EM gloves and gown monitoring on
themselves.
25. The Manager Quality Assurance and Supervisor Physical Monitoring confirmed (b) (4)
that the
temperature a.nd relative humidity of the sterile storage area in building as not
monitored in response to a rain water leakage from the ceiling on 4/23/11 as required per
SOP "Contingency Plan", Document #030-SQP.. D-48, effective date 05 Jut 2007. The
rainwater that leaked from the roof through the plenum above the HEPA filters ultimately
leaked into the sterile storage area via seams in the curtain tracks. The plastic curtain$
affixed to the tracks serve as a barrier between Class 100 and Class 10,000 areas. This
area is also used to store depyrogenated glass vials.
26. The 11 Facility and Equipment Qualification Master Plan", document #030..SOP-OP-13,
effective date 30 Dec 2009, "applies to all Facilities, Utilities, and Process Equipment
involved in the manufacture, packaging or holding of raw materials or drug products at
BVL. This master plan details the Qualification process for new facilities and systems and
re-qualification of existing facilities and systems." The (b) (4) Closed Circuit
~~~" ....iiMPLDYEEiSJSiGN.iiTURE- - ---- · --- - ·· -T~~~(S) NAM~ AND TITLE(;:;,;;;;;I'I}'p;;/----T~/::SU_'eM6'"·--
PAGE
FoRM FDA 483 (8/00) PREVIOUS EDITION OBSOLE:TE
_ ch .
I
jh--tt 1. ) ;; : C;)J/IJ r; fJJ
CTIONAL OBSERVATIONS
t~.::~~-. L__ _ _ _ _ _ _ _ ~-
PAG!:2 {) OFJ) PAGES
FOOD AND DRUG ADMINISTRAlJON

6751 Steger Drive
679-2700
-rSTREET ADDRESs
300 Northfield Ro_~-~----
TYPE OF ESTABUSHMENT INSPECTED
DURING AN INSPECTION OF YOUR FIRM {I) {WE} OBSERVED:
address ab.o,v~. During AA Jrw;~ction of your Sacilitv ;w~abserved.
1eJevtsrorr \ vv 1v) ~ystem, wv..c:.;uoo cons1sts of
(b) (4)
cameras and new
replacement color monitors. The CCTV is routinely used by Production, Physical
Monitoring and Compliance Departments to observe personnel and production activities
performed in the North, Phase IV and South manufacturing controlled areas (e.g., Class
100, 10,000) and varied personnel entryways/rooms. However, the camera monitoring
system has not been appropriately qualified as per the aforementioned procedure. In
addition;
a. There are no written standard operating procedures that establish and describe the
use of the (b) (4) CCTV Monitoring System;
b. There is no records to document the production and/or personnel activities that are
observed by the above mentioned departments;
c. The CCTV monitor in the Quality Assurance Lab room 209 has the capabilities of
capturing the obse via the DVD recorder that is electro ed to the
CCTV monitor. (b) (4)
(b) (4)
27. A 9/19/2008 a_ssessment (Document #RA31208M) was prepared by a pharmaceutical
consultant company and the assessment is used "To ensure that interventions occurring
during normal production are covered, BVL is performing an assessment to determine if
any other enhancements are needed", which inclu the aseptic operations.
The visual observations were performed via the (b) (4) Closed Circuit
Television and observin via the uction room door windows.
(b) (4)
a. The production room entry doors for fill lines
(b) (4)
ve viewing windows (i.e., 23"
x 29" and 19" x 31u, respectively). However, the windows do not provide for an
unobstructed view of the Class 100 and Class 10,000 production areas.
- - S£E~EMPLOYEE(S) SIGNAT-UR-E-~-"'"-~"--·"------,........,____~"_-:E-M-Pl_O_Y-EE-(S_}_NA_M_E_A-ND-TJ-TL-E-(P-ri-nt-or-TJii-p-e)----. DATE ISSl,JED
REVERSE
OF THIS
'\W\ i?. 5-; 2. :l/fl
PAGE. ·--~----...._'-/.-'-~.=~ 'fl-1--f' en11 '~iJd. mrr t.-..l.<_ -----~
FORM FDA 483 (6/00) PREVIOUS EDITION OBSOLtTE f EC'f(ONAL OBSERVATIONS PAGE 2/ OF J 3 PAGES
I 5/2-25/11
DISTRICT OFFICE ADDRESS AND PHONE NUMBJ.:R DATEI OF INSPECTION
6751 Steger Drive
Cincinnati, Ohio 45237 MBER
__{~}3) 679-2700 9257
------------------1

.FIRM NAME ISTREET ' .....................
Ben Venue Laboratories, Inc. .
300 Northfield Road
......,..,.....,,..._,~,.....,.','·-...-~--~·.·.•.•.· .,-<•·v·.+en"-·-""·""-'"'N,.,.__._,w.~<.WA'•'""W-'~"""""·'·""-""""""'""
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information to FDA at the address above. If you have any questionS, please contact FDA at the telephone number and
address above. D ion ofyour facility we observed.
28. The I
(b) (4)
CCTV System can be used to observe the production and/or
personnel activities, independently or collectively, by the Production, Physical Monitoring
and Compliance Departments. However, the reason(s) for observing the production or
personnel activities via the CCTV and the final conclusions and/or evaluations of the
observed activities are unknown to the Quality Unit.
29. An Operational Q f the North Complex Air Handling System Dehumidifier,

study numberl (b) (4) ) study performed September 1996. The objective of
the OQ is liTo verifv that the "new'' North Complex Air handling system dehumidification
unit (BVL I.D.I (b) (4) operates appropriately", which includes "Velocity Testing
of North Complex (b) (4) ers". The 1996 OQ report documents the filter velocity test
status as "SAT"; the Manager of Quality Assurance Engineering confirmed that there is no
raw data to document the filter velocity test measurements.
30. The written procedure 030-SOP-OP-13 (Version 12.0 da /30/2009), "Facility and
(b) (4)
Equipment Qualification Master Plan" fails to identify th~ system as a qualified
system subject to a routine re·qualification. In addition;
(b) (4)
a. A performance re-evaluation has not been conducted for the systems seNing
the Phase IV Complex to access the I (b) (4) system servicing the lyo corridor, room
1
(b) (4)
4115, subsequent to the extension of the corridor and addition of filters and air
handling units servicing this corridor;
b. The IQ/OQ/PQ forthel
(b) (4)
systems s~ing
(b) (4) e l l as routine
air velocity testing conducted in buildi (b) (4) c k a e errmnation ofthe air
velocity at work surfaces in the class 100 areas of fill s u(b) (4) -
31. The Quality Unit lacks the responsibility and authority to review and approve BVL
Engineering or ContractorNendor CAD drawings. "BVL CAD Standards Revision
$t=£ EMPLOYEE(S) SIGNATURE EMPLOYEE(S) NAME AND TITLE (Print orType) DATE ISSUED
~l~~~E \M~ s-jt.s-ju

PAGE ---~~~~--------,.J;!.'_ _ ,+lf.A~--·:=----·?'1_7;:~-·"-[-._,;C::;:;;.'1i_1'1_1 LJJ!_.}j ('1(1/ t.L\.C. ----
FORM FDA 483 (8100) PR!EVIOUS EDITION OBSOLETE I,~;~ECTIONAL OBSERViTIONS PAGE 2 2. OFj :J PAGES
Ctc·41,dhy: f>SC M,tli:. An-' i}OI) Ml--14:14 EF
DEPARTMENT Of: HEALTH AND HUMAN SERVICES
]~~~~~~:~:;S::?AND PHONE NUMBER -··------ ~--Ji-~-~-1-~"'~~~-~-~-~--TI-:--.-~-----~----•:. -~ -~: -_:_~ - - :_:_~=

NAME AND TrTLE OF INDIVIDUAL TO WHOM REPORT IS ISSUED

••••.. •--•·-•••~"'-·-·••-~"'"~'•·~-----.-------·••••••••~·--~~~M'' ·~--··----1
CITY, STATE ANDZIP CODE IYPE OF ESTABUSHMENT INSPECTED
1---------------··-··------'--------------~----1
DURING AN INSPECTION OF YOUR FIRM (I} (WE) OBSERVED:
information to FDA at the address above. If you have any questions, please co.ntact FDA at the telephone number and
address abp,ve. During anJ:n.so.emioo..of~ow facilitv we obael'}(ed. .
LiOntrol", ~UtJ ffu;:su-"Uf"-1""-26, vers1on ~.u, effect1ve date 11 Jun 2008, "covers both the
generation of new drawings and the subsequent revision to existing drawings" and states
that ''The Project Engineer/Manager (or AMMS requester): Is responsible for the final
approval and sign off of the revised drawing." On 11/12/2010 CAPA TRK #108615 was
opened to revise "BVL CAD Standards Revision. Control", SOP # 030-SOP-P-26, ve(sion
3.0, effective date 11 Jun 2008, to require changes to CAD drawings go through the
Change Control Process. The CAPA also states that the aforementioned SOP-P-26 is to
be revised "Include in the revision the requirement for quality review/approval of changes
to level 1 equipment and drawings that would have a regulatory impact. The Due Date
according to the CAPA was 3/31/2011. The CAPA has yet to be closed. In addition;
a. The Manager Project Engineering confirmed that there is no written procedure at BVL
for CAD drawings which describe the departmental use of BVL Engineering CAD
drawings. The Manager Project Engineering also confirmed that Engineering drawings
are used by Engineering as well as Facility Maintenance when performing
maintenance related activities. However;
i. On 5/3/2011 Work Order #050311 06001 was completed and "removed r

41668 &C" as well as "renamed room 4166A to 4166, from "Building N(b) (4) -
Fiow Diagram Class "An &"8" ACOND-401", drawing #HVACFD401, revision E,
revised date 11/09/2010.
(b) (4)
Rev. E of the aforementioned CAD drawing~ FD401 illustrated proposed
modifications to the air handling system pertaining to a future addition of exit
(b) (4)
airlocks in fill room nd sterile storage.
andl (b) (4) Filters", SOP #030-SOPNJ-212, version

(b) (4)
b. The "Velocity Testing o~
13.0, effective date 01 Jun 2010, establishes that "For each filter tested, record the
velocity test data on an applicable facsimile of an Engineering drawing and the
appropriate tes1 document." The Supervisor Environmental Control confirmed that
FOOO AND DRUG ADMINISTRAiiON
DISTRICT OFFICE ADDRESS AND PHONE NUMBER f DATE(S) OF IN~t't;t.; llUN

6751 Steger Drive 5/2-~5/11
(513) 679-2700 1519257
~---L-----------------------------~----------··--«--~

,FIRM NAME ;sTREET
Ben Venue T ·• Inc. 300 Northfield Road
~--~-~-~~··~""''~~~-~~~·~~-~M'•~~-~-~~~----~---·-N---~-r------------ -·~--------~-~~-~-------~
CITY, STATE AND ZIP CODE IYPE OF ESTABLISHMENT INSPECTED
- Bedford, Ohio 44146

DURING AN INSPECTION OF YOUR FIRM {I) {WE) OBSERVED:
-
-
address above. _Duong an Insp~ction Qfyour facilitvwe observed. . .
Env1ronmema1. Momto(b) (4)ses t:ngtneermg draw1ngs dunng the performance of
(b) (4)
velocity testing at thel and filter face and confirmed that Environmental
Monitoring does not have access to the I (b) (4) database which contains the most
current revision of BVL Engineering CAD drawings.
32. The I
(b) (4)
Hot Air Oven is used to depyrogenate vials and glassware for the
manufacture of finished products. Th(b) (4)pyrogenation processes are controlled via the
equipment automated control system Controller), which contains the password
protected depyrogenation cycle recipes. The Manager- Process Controls Engineering
confirmed there is a password that is used for each of the controller's multiple levels of
access (i.e., Levell, Level II, and Level Ill) for Process Operators, Supervisory Staff and
Administrators, respectively. However, there are no records to document the individuals
(b) (4)
ch) who have access and their respective levels of access for the automated control
system to assure that the depyrogenation recipes that are used for the validated process
are not inadvertently changed and/or modified. In addition;
a. The Hot Air Oven controller maintains a history file of the individual cycles e.g., date,
time, duration of events and any alarm events that occur. The Manager of Quality
Compliance confirmed that the equipment's history file is not reviewed;
b. During routine operations, if there is an alarm event (e.g., time out, high & low
temperature for washing & siliconizing, instrument line failure, jacket ~ failure and
steam header failure) during the wash & depyrogenation process, the (b) (4) Stopper
/
Washer captures the alarm condition via a print out and the data is retained with the
manufacturing batch record. The Quality Compliance Manager confirmed that the
alarmed events are not periodically reviewed or trended to assure that the (b) (4)
stopper washer and/or wash & depyrogenation process is not drifting from~
validated state of control;
.. ......---~--·--··-~·---···--····---.------------ ----·y--"··---..· ---·······----1
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---···----·······-··-·-·-···---~--··--~·-· ~-
SEE EMPL.OYEE(S) SIGNATURE EMPLOYEE(S) NAME AND TITLE (Print orType) DATE ISSI,JED
RF;:VERSE
OF THIS 1 VV\\.tr \,l,1...tL
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,.,;
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FORM FDA 4a3 (8/00) PREVIOUS EDITION OBSOLETE 1
4
· f>ECTIONAL OBSERVATIONS ' PAGE2 Lj OF]~~ PAGES
Crc-..Jcdby: l'~lC M'"Ii" Art' (J\ll.H·l3-24$4 EF
FOOD AND DRUG ADMJNISTRA'TION
1----~·-----·-·----.~----------·-·--------------.----~---------·-~M
DISTRICT OFFICE ADDRESS AND DATE(S) OF INSPECTION
6751 Steger Drive
Cincinnati, Ohio 4523 7 FEINUMBER
679-2700 1519257

FIRM NAME
-·-~·-~···-·-··--·-··~••-••w•-••m•"""'"""'"'"""""''"-"'""'"'"j"'STREETADDREi'3s-"'"'
300 Northfield Road
• ,.,.,..-.•·.~~~-·•••·••·•· ...
····~•••·~··•.•m.·m·.•·•w,y,,,,. ,.,.".'"'-.wm,y-•--~•••,.,.•··•w•····•'·""'m•-m.• --~-~·~--.·~•·Nm-·••w•·-----
CITY, STATE ANOZIP CODE TYPE OF ESTABLISHMENT INSPECTED

. ' . -~-··-·· --···-·-·~~-.-~-··-·- ·------····-·-~-~·"
DURING AN INSPECTfON OF' YOUR FIRM (I} (WE) OBSERVED:
address above ...Du~_an In~ecti,c:m ofyour.facilitv ;w~bserv~d. . . . .
c. 1ne Manager- t="rocess ~omrols t:ng~neenng confirmed there extsts a stmllar
concern, as n e preceding observation, for other automated control systems
(approximately
(b) (4) which are used for the manufacture, process, packaging and
holding finished products. A 4/15/11 CAPA, TRK #115713, describes an action to
completed with the creation of a new procedure, which "will address security access
approval and changes to levels for all pieces of equipment, including lyophilizers.l!;
33. The 1/25/93 ilization/Depyrogenation Cycle Validatio ious Glass Carboys in

document the time (b) (4)
(b) (4)
Hot Air O Study (b) (4) and
temperature ( (b) (4) of the depyrogenation of glass ware. However, there is no
record to document that the device that measure time is calibrated to a reference
standard. In addition;
a. The "Retrieval o
(b) (4)
Solution~~, study~ dated September 23, 2001,
(b) (4)
documents a reduction (i.e., 3-log) of the bacterial endotoxin challenge. However,
there is no raw data to support the results of analysis.
34. Per SOP 030-.SOP-E-1 0 (7.0), "Operating the Exterior Vial Washer", your firm uses a vial
washer on packaging lines (b) (4) n build
(b) (4)
f the south complex, to ensure that
the exterior of vials are clean of any foreign material. The vial washer consists of an
enclosed conveyor line in which water jets pour tap water onto the shoulder of each
individual vial and then each individual vial is dried with compressed air before exiting the
vial washer. There is nothing documented to assure that various temperatures of tap
/
water used in the vial washer have no effect on packaged lyophilized products contained
in crimped and sealed vials which pass through the vial washer.
a. Per SOP 030-SOP-E-10 (7.0), ~~operating the Exterior Vial Washer'', Section Ill, C. 1.
b. identifies that the water temperature is to be controlled by the water valve on each
line and states that for room temperature products~ (b) (4) , room temperature
water is to be used, and for (b) (4) and (b) (4) products, the water valve
r-~-=---~~ ~ ------------~----------------------------r
SEE EMPLOYEE(S) SIGNATURE lMP.LOYEE(S) NAME. AND. TITLE (Prin.torT.ype) DATE ISSUED
REVERSE
~~
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~ ~
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FORM FDA 483 (8/00) PRENIOUS EDITION OBSOLSTE ~PECTJONAL OBSERVATIONS J PAGES

(513) 679-2700 1519257
!-·-'--~~~···'··~·~·~----··------~-----~----.-·-~·-··-----······-···-·-··------·-·~--~---------~-----~---······-··-····~---··---···-"'-

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CITY, STATE AND ZIP CODE TYPE OF ESTAI:3l1SHMENT INSPECTED
---~~~-------------·-----------lL------------~-----~-1
address above. Duri1.1g an Ins__neption of_v_QW fapilinc we obser.ved. . . .
showa oe set to tne cotaes aaJUStment possible. Per your packagtng superv1sor, the
vial washer water tempera monitore(b) (4)ris it recorded for any products that
are run on packaging l (b) (4) buildin fthe south cotnplex. (b
b. The water valve for l i (b) (4) in buildi

(b) (4)
f th_e south complex, each contain
a sticker that reads: "NOi'CALfBRATED" "NOT FOR OFFICIAL USEli. However, per
your packaging supervisor the water valve detennines the water flow and water
temperature of the water supplied to the vial washer.
c. Vial washer ID:I (b) (4) t building

is currently located on packaging line
(b) (4) (b) (4)
o omplex. Work Order Report #12130709003 for vial w stier ID #:

(b) (4)
(b) (4)
I identifies that the vial washer was moved from li (b) (4)
li n.. (b) (4)
12/14/07. There is no qualification for the vial washer since it was~oved to li

There is also n.2.9.ualification for the vial washer for the period ed on
he most recent IQ/OQ/PQ for vial washer (b) (4)
(b) (4)
packaging li was I
performed under study no: IQ/OQ/PQ 00198M in 1998 when the vial washer was on
(b) (4)
li
(b) (4)
The •j (b) (4)
(b) (4)
35. Clean Air Carts Used For Transferring Trays in Building
document #030-SOP-D-131, effective date 07 Feb 2007, establishes that the clean air
carts are 'used by the Production Department to maintain an air quality environment of
''Class A" during transfer of filled and stopped vials to the ..Class A" environment located in
front of the freeze drier chambers.' The written procedure requires to ~~Periodically check
thel (b) (4) gauge on the clean air chart when the unit is plugged in and unplugged.
The gauge must be within the high I(b) (4)inches of water column) and low (b) (4)inches
of water column) validated alarm s~ ns." However, the Quality Co
Manager confirmed that there is no record to document that the requisite! (b) (4)
alarm specification check is achieved.

6751 Steger Drive
(513) 679-2700 1519257
STREET ADDRESS
~
..........,-.•.,..,.,.,....-... ..
~......,....., ,w,•-.,...,,,,,,,,,,..,~...,......,~,,J.-.·-"v·'·""'""'~W'-W-"""''·'·'·W·'·''''"'"'""-•"""""'...........,.,.'.,. ...,.........,.._...,. _ _ _..,........_.,,.,,;.;;<<<;<"'-•.. _-1'............ <
300 Northfield Road
' " ' ' " " " ' " ' ' " ' ' _ ,_ _ _ , _ ....-...,,,.,,,,,,..,,.,...........,_...................,.,.,_., _ _~.---.~,""'''''

~------·-----
address aboy~. During an .Inspection ofyour facilitv we ob~e;:v~d. .. . .
3o. we observed namerous ~approximately ~u~40+) cerhng panels (1.e., "wet-formed mln~n:;)l.....
fiber" with "factory-applied latex paint") within the personnel corridors [contrglled-nbn:·
classtfied (CNC)area] that lead into the controlled manufacturing areas (Class 10,000 and
Class 100) that appeared to be slightly opened and not seated securely on the ceiling
panel supports. The Quality Compliance Manager confirmed that the ceiling panels are
not sealed or secured on the ceiling panel supports. The unsecured and unsealed panels
propagate the ingress of non-viable particles and/or viable microorganisms from the
uncontrolled environment above the ceiling panels and into the manufacturing areas.
37. We observed various mobile carts that are used to transfer material or equipment into the
Class 10,000 manufacturing fill rooms with what appears to be rust-like, non-smooth,
uncleanable surfaces on the wheel supports.
(b) (4)
38. spray bottles lab d as , and water were observed on packaging lines
(b) (4) 6 located in buildi(b) (4)-f the South complex. There is no SOP for preparing the
solution and there are no records regarding the preparation of the solution. Your monthly
packaging line cleaning record identifies that (b) (4) and water is used for cleaning
packaging line equipment including the interior
(b) (4)
of the I (b) (4) vial washer and conveyors.
ere is no documentation to justify the day expiration date assigned to the
(b) (4) and water.
As outlined in Appendix 002 of the written procedure, "Freeze Dryer Chamber

Cleaning/Condenser Defrost fori(b) (4) Remediated Freeze Dryers", document #030-
SOP-CC-20, version 6.0~ effecti~28 Feb 2011, a squeegee is used to remove WFI
... _. rinse water from the shelves of the freeze dryer chambers in the North Facility and ·"PtTa5e ~c~·~TV- 1
Po"'Facility Complex (Chamber # ' (b) (4) • • • • • • • • · · - · · · ·
The manufacturers specifications state that the blue colored squeegee is constructed of
"reinforced PP and rubber! suitable for "sweeping wet and smooth floors to remove large
amounts of dirt". However;
·-~-------~~--~--------------------

FOOD AND DRUG ADMINISTRAilON

6751 Steger Drive
(513) 679-2700 1519257
f-2--~~--------~---~-·~··---~---------------~--------------··~~---~

t"'''"'"---·----------·~·-~--~~~-~~,.----·~~.-.,~~·w~.w.•••owmw--"<••--~~---~"'-''·'""'-----•--•-•
r----·-·"·-·---~·····-"'·'"'''-"-"'""~
CITY, STATE ANOZIP CODE:
........................................_,... _,_....,..._,_~..· - - - - - - · - - - --+-------~-····-··~---~·"'"''--'"-----------·
TYPE OF ESTABLISHMENT INSPECTED
. -. .
DURING AN INSPECTrON OF YOUR FIRM (I) (WE) OBSERVED:
------------------
objection regarding an observation) or have implemented, or plan to implement, corrective action in response to an
addreSS above _DuripLUIJl. Jnsr 1t; f~ciJitv .,:lV~ O.b.aerved
a. ·The Ml-'K fo (b) (4) 101 #21 ~u88b was· found to contain 4 copies of the Start~Up
Check Sheet, document number 03(b) (4) SOP-CC-20 GFRM 001, for the sterilizat (b) (4)
checks performed on Freeze Dryer located in the class 100 area of fill su
dated 4/26/2011, 5/3/2011 (0340 hr), 5/3/2011 (1826 hr) 5/11/2011. The
Production Manager of th(b) (4)orth Complex confirmed that operators performed several
cleanings of Freeze Dr ue to blue specs found in the chamber after the initial
cleaning performed on 4/26/2011;
b. Although a deviation was not initiated, the Production Manager North Facility
attributed the blue specs found in the lyopholizer cham(b) (4)to the use of the blue
colored squeegee during the cleaning of Freeze Drye and, (b) (4)
c. A study has not been performed to qualify the use of the blue colored squeegee
during the cleaning p he6 (b) (4) Remediated Freeze Dryers in the aseptic
core of both building (b) (4) " ... t \
lW\~- 5 1~<; 1
40. The
(b) (4)
Sterility Test Isolators were qualified and validated on 3/26/07 and 4/2/07. The
following document a number of concerns with the data to support the validation and
current use of the Sterility Test Isolators;
a. According to TRK #93890 and #94127, the (b) (4)ated concentration of I

(b) (4) is (b) (4) However, the firm used
L concentration of (b) (4) - ---
(b) (4)
which is inconsistent e validated concentration, to decontaminate theL__
(b) (4) (b) (4)
Isolators and from 11/01/09 to 02/04/10. The firm detected three lots
which failed sterility testing during this time period, including lot #2378-44-1157184
discovered on 01/20/10, lot #2080-10-1859569 discovered on 01/23/10 and lot #2413-
12-1925943 discovered on 01/23/10;
b. A Senior Microbiologist confirmed that the initial validation of the isolators was
perfonned by the manufacturer (i.e. (b) (4) , which consisted of using multiple (i.e.,
AND PHONE NUMBER
FEI NUMBER
1519257

- , •• ~.,...,.,..-~.~~~.~-··""""·~~-~-.....-......
.. """·-~······~,..._.._..~_.........,._...,... ....w.w................. •.•.••·••~-···.W••••N>A"""""'"""'"'-'"'-"'' ..•.. •••"'"....,.~''-''~--.............,,
~
.......,......... ~.·~""""'"'~''........... ""'"'·'"'"''~-""'"'...,"""''""·'Hv............,."'-''''''""""""'"w"'...........,..."""'"'""'"'""""''''"'"............,.""'""""'......._....,.._, _ _ _ "'''..,"'"'..'"..'_.,.,._..,.,,,
300 Northfield Road
_,,.._,_.._._...,_ _ _w...,.~wc.v,·,._.,,.,w,w...w•u.· .........,w,w<•'•W·""....,........,...,..,......_.,_ _ _ ..,,..._.,,.,.,..,.,......~.

DURING AN INSPECTION OF YOUR FJRM (I) (WE) OBSERVED:
objection regarding an observatio~ or have implemented, or plan to implement, corrective action in response to an
address above During an Inspe~ti nh«P.rued_
·four) aoses oT (b) (4)
litu UIP
However, the 09/01/09 01/26/10

and 05/14/10 revalidations consisted of using two doses of ~-
(b) (4) -------
c. A Senior Microbiology confirmed tha.t low-pressure alarms and high city

were ignored during the decontamination cycle of isolators (b) (4) and
(b) (4)
Microbiology employees were instructed to disregard these alarms if the
dosing of (b) (4) was performed correctly. According to the Senior
Microbiologist, the firm does not have written instructions to"define when it is
appropriate to clear isolator alarms and proceed with testing;
d. The Quality Control Unit does not review the charts which reco(b) (4) e temp e,
(b) (4)
humidity, air velocity and differential pressure of the isolators and,__ _
(Note: Temperature and humidity impact upon the decontamination cycle. Air velocity
and differential pressure impact the site selection for Biological Indicator challenges.);
e. The firm did not review the raw data to support initial validation of the Chemical
I or and Biological Indicator testing performed by the isolator manufacturer
(b) (4)
f. The firm did not perform smoke evaluation or air flow pattern testing on the isolator.
These studies are used to evaluate the Chemical Indicator (CI) placement to support
the Biological Indicator (81) challenge, which is used to validate the decontamination
process; and,
g. According to the Senior Microbiologist, the firm did not perform any qualification
after maintenance on air dampners was performed on isolators (b) (4) and
(b) (4) on 02/16/2010. Furthermore, the investigation did not include corrective action
to address the cleaning of the Isolator for metal and plastic debris.

6751 Steger Drive
679-2700

''"'=·r~"-~'''"'"~···'·'·"' W<-••·----·
"-"'·W·Wm~.~---n.• -·-·--~-~-~--»--•·······-~---·
CITY, STATE AND ZIP COOE TYPE OF ESTAI3USHMENT INSPECTED
--------·---------------
DURING AN INSPECTtON OF YOUR FJRM (I) (WE) OBSERVED:
add)'ess ab.Qve. During a.u.In!Weru.on..ofJtour f~ciHtv we observ~d.. E d t · Ut'l' · th
41 . uo jO-::sUJJ-"'-7s, uetecuon or Bactena1 n o ox1ns 11zmg e
~
(b) (4) System, states that precautions are to be taken in handling all
--~~
samples to be tested to minimize contamination. However, the firm cannot ensure that all
utensils used in the testing of finished parenteral drug products are from endotoxin.
On 05/17/11, a microbiologist was observed performing endotoxin testing as part of the
release testing for 2 finished parenteral drug products. In addition;
a. In order to remove the metal outer seal on the 6 glass vials containing the drug
product samples, the microbiologist used a wrench that appeared to be coated with a
rust-like material;
b. The microbiologists performing endotoxin testing do not use barrier pipette tips to
mitigate the risk of contaminating the barrels of the pipettors with solutions containing
high levels of endotoxin. For example, one microbiologist used the 1OO~L pipettor to
prepare the endotoxin standard control solutions. Immediately following this, another
microbiologist used the same pipettor to aliquot water samples for endotoxin testing
without cleaning or sanitizing the barrel of the pipettor;
c. On 11/06/09, a microbiologist obtained out of spe rforming

~ otoxin testing on (b) (4) lot (b) (4) n g method
(b) (4) u e date 12/15/00. This method requires removal of the stoppers
from the vials containing the drug product followed with water bath sonication for (b) (4)
minutes. This OOS result was attributed to the water bath sonicator, which apparently
poses a risk of contamination to the samples because the water is not free from
endotoxin. 3/05 0,-gist perfo - c t endotoxin
testing on (b) (4) l o(b) (4) s i n g method (b) (4) d again
obtained out of specification results. Despite the OOS results the firm has not modified
this method to minimize the risk of endotoxin contamination from the sonicator.
- ---~~~-~~E'M'Pi.ovee(s) slGNATuR:Ir~~-----·-----------.-e-M_P_Lo-v-ee-(s_>_NA_M_e_A_N_orliL_e_(_Pr,-int~rry;;;r·-- --·-----DA_T_E iss-uE_o .

REVERSE ·~ VV\'f-
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FORM FDA 483 (8/00) PREVIOUS EDITION OBSOU!TE ECTIONAL OBSERVATIONS PAGE,~() 0f;_j) ...PAGES
DISTRICT OFFICE ADDRESS AND PHONE NUMBE:R

6751 Steger Drive
679-2700
STREET ADDRESS
~~---··•--••••••w··~·'·'"""--·.-~.-.-·•·••·•••~•·••••~••-•••••••••·••·••·•••-·•······•·w••• ·~-.~-~....-.·-·~~--••M•-+---·
CITY, STATE ANDZIP CODE TYPE OF ESTABLISHMeNT INSPECTED
--------·-----·---
DURING AN INSPECTrON OF' YOUR FIRM (WE) OBSERVED: (I)
un 05/1 r11, we observea a batcn o (b) (4)
address abgye. DuriBg ap Inspection of your facilitvw{ ~ •
42. med1a #LB031811, prepared on
03/18/11, which was labeled "at risk." Document 030-SOP-K-11 states that media may be
used at risk if it is needed prior to qualification. However, this media must pass
qualification prior to the product being released. If qualification testing is not acceptable,
then a deviation must be initiated.
(b) (4)
This media was used during the release testing of finished drug produ lot #0553-
52-2053109, which was authorized by Quality Assurance on 04/06/11 to be shipped to the
customer in quarantine status. A Senior Microbiol ined that microbiology
department management was unaware that this (b) (4) batch had not passed
growth promotion testing. Document 030-SOP-K-11, Media and Rinse Qualification,
states that if nonconforming results are detected, then one retest may be performed with
Supervisory authorization. The microbiologists performing this growth promotion study did
not obtain supervisory approval before repeating a portion of the growth promotion testing
with a different organism. Furthermore, these microbiologists did not initiate a deviation to
address the unacceptable qualification testing results.
43. Document SOP 030~SOP-K-85, Atypical Endotoxin Results, when Out of Specification
(OOS) endotoxin results are obtained while testin finished product, the second repeat
+t!io~iH ....... consists of ana · (b) (4) uct. However,
(b) (4) (b) (4)
the second repeat
(b) (4) According to a Senior
Microbiologist, the ale for determining how many
retests are required to determine that initial OOS results can be attributed to laboratory
error.
(b) (4) (b) (4)
44. On 08/08/10, the parenteral finished drug product l - failed
sterility testing, which was determined to be caused by the us (b) (4)
sed
during the transfer of pre-chilled glass vials from the lyophilizer to the infeed fill table. The
Senior Manager of the North Facility and Quality Assurance Manager confirmed that the
, SE~, ...~·-cEMPLOYE.E(sf'siGNATURE EMPLOYE.E(S} NAME AND TITLE (Print orType) DATE ISSUED
REVERSE 'l\N\,\L-
OFTHIS \ S/L5/ii
~..!.~_GE·~·-- - . -~,-,---~-·---JV1t~f e_1M '\11)1 mp5 tt..\..t
FORM FDA 483 (aJOO) PRE;VIOUS EDITION OBSOLETE lf,tri~ .ECTIONAl OBSeRVATIONS PAGE 5I OF J!f PAGES
DISTRICT OFFICE ADDRESS

6751 Steger Drive
(513) 679-2700
~=:~ ~~·--~~--=----
DURING AN INSPECTrON OF YOUR FIRM (I) (WE} OBSERVED;
address above. During an Insnection,ofyour faciljty we ob.s~ed. .
operators, manufactunng supervisor ana uuahty Assurance Audttors were aware of the
use of these gloves. However, they did not intervene in the practice of using the gloves,
the firm did not initiate any retraining of personnel in regards to acceptable aseptic
practices, which will decrease the risk of contaminating product during fill operations.
45. On 04/02/11, an Environmental Control technician collected a water sample from a valve
in the Water for Injection Loop I, which is use in the manufacture of aseptically filled
parenteral drug products. This water sample was tested for endotoxin levels and failed to
meet specifications. During the resulting investigation, it was determined that the sample
had most likely been contaminated during collection, due to the fact that the technician
had dropped the water sample tube onto the ground where a pool of water was located.
The technician had picked up the sample and submitted it to the microbiology laboratory
for processing. The technician was not retrained after this incident on proper aseptic
practices and correct collection techniques.
The investigation into an OOS investigation for a finished product was not initiat a
timely manner. A Laboratory Interview Worksheet was not initiated, nor was a (b) (4) ~~
system regula viation report in at~ days after OOS results were
obtained for (b) (4) Final Product l (b) (4) - According to SOP, #030-
SOP-J-113 (effective 10/30/09), entitled ~~Management and Investigation of Discrepant
Results" the initial labor sessment is to Interview
Worksheet and in the (b) (4) system within (b) (4) r nizing a
(b) (4) Final
discrepant r st ed
Product lot - (b) (4)o~ (b) (4) purity, (b) (4)and% largest
unknown impurity on 3/1912010.
The Regulatory Deviation Report TRK #98292 for this investigation indicates that the
investigative testing was performed on the original samples "approximately 27 day
the initial testing. However, according to Quality Control(b)Analytical Test Method i (b) (4)
(b) (4) u e date 5/19/00), samples are to be run with (4)urs of preparation.
EMP!.OYEE(S) SIGNATURE ~·~ ·~~· "-~l EMPLOYEE(S) NAME AND TITLE (Print orTypeJ~-~ DATE
s/z s-/u
SeE
R~VERSE
OFTHJS
·1 \IV\ \i-
PAGE
----------~.rf~ ft\.-f'f L~,JV\ C.ffj~-"'·,l ~=j~¥1_1°_"_1 - - - ' - - - - : : : - : - - - - - - - J
FORM FDA 483 (8/00) PRE;VIOUS EDITION OBSOLE:TE ,~PECTIONAL OBSERVATIONS PAGEj2 OF 13 PAGES
Crc;tdby: PSC Mdia Ans !)(ll) 44J-.1451 EF
FOOO AND DRUG ADMINISTRATION
,--~,~~~,~~~-~,,·--,,~,'~
DISTRICT OFFICE ADDRESS AND PHONE NUMBER DATE{S) OF INSPECTION

6751 Steger Drive
679-2700 1519257
STREET ADDRESS
300 Northfield Road
TYPE OF ESTA8USHMENT INSPECTED
' ____ ,
-----------~----------------------'~
inspectional observations, and do not represent a final Agency de:tennination regarding your compliance. If you have an
4 7. The Regulatory Deviation Report TRK #98283 indicates that standard preparation error
(i.e. the standard did not dissolve com as the probable root
After Filtration (AF) assay resu1ts for (b) (4) In-Process lot (b) (4)
Despite the probable root cause finding, the QC Chemist used the nnn•n~• &M-~•,11-eal"li
solutions to r~- e rginal AF assay samples using Quality Control Analytical
Test Method (b) (4) (issue date 11/13/02). While the TRK #98283 indicates that
the impact of using the original standards is negligible, it does not provide empirical data
to support this conclusion.
48. According to SOP #030-SOP-J-36 (effective 12/30/08), entitled "Training of Quality Control
Analysts" al sts and technicians in the Quality Control Laboratory must successfulfy
complete (b) (4) e r evaluation of knowledge. However.l
• Docum~oes not exist of the 200(b) (4) wledge check f(b) (4) ity
Control Chemists. (b) (4)
• N (b) (4) edge check was administered in 2010 fo mists who began work
in the laboratory in 2008.
(b) (4)
• f th hnicians working in the Quality Control Laboratory have received a
(b) (4)wledge check since the SOP became effective.
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R13VERSE t..K<;;:{"'f"''•· '{, '/!!h,:/5(:1 r.:?hri;J/~~J.,·:..; T-1<l'Ju)Ju)~ .H··, 'J.;rtv{!'.;/-..).,.4...-·1 -; 2. .
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DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMJNISTRAilON

DISTRICT OFFICE ADDRESS AND PHONE NUMBER DATE(S) OF INSPECTION

received - Prod~ct(s) L BVLiot # Analyt. ica.fresults

Ben Venue Laboratories, Inc. 300 Northfield Road

DISTRICT OFFICE ADDRESS AND PHONE NUMBER

TO: Thomas J. Murphy, President & CEO