DEPARTMENT OF HEAL TH AND HUMAN SERVICES FOOD AND DRUG ADMI NISTRATION

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

Detroi_t District Office t06/23f20 Is -07/09/2015* 300 T~1ver Place Dr., Suite 5900 =:l Detroit, Mf 48207 FEfrJUMiiER--~------·--------···---· --3 13-393-8100

l ,, r t· . fi" I cf" d l81()189 nuustry n ormat1on: www.ua.gov o m IL'>1ry NAMEANO TITLE OF iNDMOUACfO°"WHoM REPORT IS ISSUED------------··-·-- -- ·- --·-------·---·-------·-----·-

.. TO: Robeit l Be!Zig, Interim Site: 1.eader ""F-IR_M_N_A_M_E ______ . __ .,, _______ , ____ ., ________ ~S-.rR-EE0T ADDRESS-··- --------,.------ ---- ---····--

. Pharmacia & Upjohn Company LLC 7000 Portage Rd.

crrY, STATE AND ZIP CODE 1YPE OF ESTABUSHMOO 1NSPECTEO ----·

Kalama:r,,oo, MI 4900 I I Manufacturer -'-···-··-·-,~-··-·-·---·------.. ----.. - ·--·--------- ---L - .. -----·· .. ·----.. -----···-----··-.. ------.. ···-···--·-···- "·-·--· THIS DOCUMENT LISTS OSSERVATIONS MADE BY THE FDA REPRESENT AT!VE(S) .WRING THE .l~SP.ECTION. ()!:. YOUR FAClU:r:Y.- THE¥ .. ARE· INSPE6'FIONAL· '·

· ·oasi:R11A'lroNS·;-AlilO'O'Cl'"Nor·Ra>REseNY .. i«.F'iNiil .i\'GeriicvornRt:A1r-iAT10N FiE:GARb1Nc3 YouR coMPUANCE. IF You HAve AN oaJEcnoN REGARDING AN OSSERVATlON, OR HAVE IMPLEMENTED. OR Pl.AN TO IMP'...EMENT CORRECTIVE ACTION lN RESPONSE TO AN OBSERVATION, YOU MAY DISCUSS THE OBJECTION OR ACTION WITH THE FDA REPRESENTATIVE($) DllRING THE INSPECTION OR SUBMIT THIS INFORMATION TO FDA AT 11-lE ADDRESS ABOVE. IF YOU HA VE ANY QUESTIONS, PLEASE CONT ACT FDA AT THE PHONE NUMBER AND ADDRESS ABOVE.

DURING AN INSPECTION OF YOUR FIRM (I) {WE) OBSERVED:

QUALi.TY SYSTEM

OBSERVATION #I

Documented investigations into discrepancies and out-of-specification results are not fully investigated .

. Specifically,

A. Non-confirmed OOS investigations do not include documentation to support that an adequate investigation has been performed prior to batch rel.ease. In certain instances, the UR record andWJIQJlot result records do not include a summary of the aspects of the manufacturing process that may have caused the problem as weU as the re.suits of a documentation review from this perspective. For example, UR I 089785 documents a non-confirmed OOS release result for methylprednisolone in Solu-Mcdrol lot L57022 with a result of 86.6%. The investigationa1 measurements protocol revealed no defiri itive laboratory error. A forth.er analysis protocol consisting o£m retesting did not confirm the original result and the average of the retests was reported in tmlUJ TheW>IU)ot result record does not adequately document an appropriate manufacturing investigation as part of the iot release process. Additional examples include a non-confirmed OOL release result for free hyd.tocortisone in Solu-Cort.ef lot IA 1543 documented in LJR !055593 and a non-confirmed OOS release resu.lt for pH in Depo-Med.rol lot H28452 documented in UR 70602 l .

OBSERVATION #2

Annual product reviews do not include a review of all appropriate data to evaluate qualily characteristics indicative of potential trends.

Speci flcally,

>-------~--·--------------·----·- --- ----------- - - -----..- - -,-----1 EMP~OY~ES) G,~~TU~. EMPLOYEE($) NAME AND TITI..E (Pnnt or Type) DATE ISSUED

SEE REVERSE OF THIS

PAGE

a>.. . Jelli"ey D. Meng, lnvestigator ., J (] . . ..-·-- . Andrew J. ldr.ior, Investigator /2 ,_. ? ') Rebecca G. Dombi:owsld, Supervisory Jnvestigaior 07/09 015

/h!Jl'z,.-rr:#:.£{V~ Thomas J. Cosgrove, Director, CDER, OMQ

FORM FDA 483 (9/08) PREVIOUS EDITION OBSOLETE INSPECTIONAL OBSERVATIONS Page 1of5

DISTRICT OFFICE ADDRESS ANO PHONE NUMBER

Detroit District Office

DEPARTMENT OF HEALTH ANO HUMAN SERVICES FOOD ANO DRUG AOMINISTRA TION

DATE(S) OF INSPECTION

06123/20 15 - 07/09/2015'* 300 River Place Dr., Suite 5900 Detroil, Mf 48207 'FEfNUMBER ----------·----- -

3 13-393-8 l 00 18101 89

Industry fnfom1ation: www.fdn.gov/nc/industry NF.ME ANOTITLE0 0FINOIV1buALto \/llHOM REPORT IS ISSUED

__ __,,_ _________________ _.

The 2015 Annual Product Review for Cleocin Ovule Suppository l 00 mg with review period ending 2/18/l 5 did not include an evaluation of content uniformity data on a[tiJJQMasis as part of the Trend Review Summary .section to ensure the detection of potential adverse trends.

FACILITIES & EQUIPMENT SYSTEM

.OBSERVATION #3

Equipment used in the manufacture, processing, packing, or holding of drug products is not of appropriate design to facilitate operations for its intended use, cleaning, and maintenance.

Speci fie.ally ,

A. During filling of lot ~13447 on 6/29/l 5,mPradetmJnonitoring probes were observed near the north and south trayers of li.na,vhere vial. hartia!Jy seated stoppers are transported via belt and manual tray loading occurs. Theselllcontinuou • ' 10oitoring probes were observed approxjmately 2 feet above the working surface and do not appear to represent potential product exposure to the environment.

B . A slight residue on a HEPA filter grate determined to be rouging was observed on 6/23/15 within theWJIUI boundary of the Gradeilt-rea in Roomll Activities within this area i.nclude the aseptic addition and blending of sterile API for suspension formulation, induding Depo~Medrol lot L80068 on 6/17/15.

C. On 6/23/15, an autoclave cart i.n the autoclave prep a:rea was observed with apparent surface discoloring and roughening due to rouging. These autoclave carts are used to load material into the autoclaves and then exit the autoclave into the Grade- septic storeroom area.

D. Exposed sprinkler heads observed on filling lineand linlln the Gradellpaces were observed to consist of an older design w ith surfaces that are not easily cleanable .

--·----~E-M_Pl_O_YEE(~-~-S-IGN~A-TI.J._R_E~------~~! EM_PL_O_YE~~-S)-NAM~E-A_N_O_T_ITL_E_(_Pd_n_l~-Type-j·-~---~0-A_TE_ISSUE_~-D--~

.4#/<'~t;'-- I Jeffrey D. Meng, TnvesLigator SEE REVERSE OF THIS

PAGE

/ ~,i..-\-- Andrew J, ldzior, Investigator I Rebecca E. Dombrowski, Supervisory fnvestigator i Thomas J. Cosgrove, Director. CDER, OMQ

FORM FDA 483 (9!08) PREVIOUS EDITION OBSOLETE lNSPECTIONAL OBSERVATIONS

07/09/201.S

Page2 of 5

DISTRICT OFF'IC!: ADDRESS AND PHOl\'E NUMBER

Detroit District Ofticc 300 River Place Dr., Suile 5900 Detroit, Ml 48207 313-393-8100

DEPARTMENT OF HEAL TH AMO HUMAN SER'tllCES FOOD ANO DRUG ADMINISTRATION

DATE(S) OF INSPECTION

06/23/20 l.5 - ()7 /09120 l 5*

l 1810 l &9 . Industry information: www.fdagov/oc/iodustry . . NAME AND TITLE OF itiDIVlDUAL TO \MioM REPORT =1s~is'""s~UED~-. -. - -------. -. -. -. - - -'---.. - - .- .- ----·--. -. -.. --.· .----.-.•

TO: Robert J. Betzig, Interim Site Leader ·-·--- ··-·-- ----·-.... .... .......-.... .. --- __ ,_.._ __ ·--··------ .. --..... ---··-··---·-··,.~·-· ··"~ ........ ·--··----·-·--·-----FIRM NAME STREEI ADDRESS

Pharmacia & Upjohn Company LLC 7000 Portage Rd.

Cirv~STATEAi'io ZIP CODE

Kalamazoo, MI 4900 J

, ____ . _ _____ ,,, _ _,_..,.._ ..... ___ ., __ L--------·-··-- - .. ---.... -.---- ·--·-· ....... _...._...._..._ ____ _ lYPE OF ESTl'.BLISHMENT INSPECTED

Manufactur<.~

~;::::::.:::.:::~":".7"::::::-.-:::--: .. ........ --·- __ _____ :.. ...... . .... _ -······ -· -·- -·----.. - .·.---.. -----.--·.--.-~:.·=----~-=-·- ··-. -------------·-------........... - - ... .-----OBSERVATION #4

Individual logs for D'lajor equipment do not include written records of cleaning.

Specifically,

Equipment logs for major equipment such asaDmm-do not include written records of within campaign deanings.

MATERIALS SYSTEM

OBSERVATION #5

Written procedures are not foll.owed for identification, handling, and storage of components.

Specifically,

Containers of material that were tom, leaking, and associated witti an investigation of a rodent infestation were not taped off, placed in an area identified for rejected materials, and labeled or marked a<> rejected material according to written procedures. These materials included approximately • bags of soy flour. bags of granulated sucrose. bags of material ID ROOOJ 80340, and- ags of material ID ROOOl30405. Additionally, containers of lllBuffer stored with material containers approved for use in cold storage were not identified with uniqueill labels according to written procedures.

PRODUCTION SYSTEM

OBSERVA TJON #6

Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not - -------,------------- - ·- -------------------------·-.-- ---- ·--·-

EMPLOYEE{S) SlGNA T'URE I EMPLOYEE{S) NAME AND TITLE (Print or Type) I DATE ;ssuro SEE

REVERSE OF THIS PAGE

;.j-10.A,___ 1

Jeffrey D. Meng, lnvcstigafOI" 'l11n Andrew J. ldzior, Investigator 10.:. ..V Rebecca E. Dombrowski, Suplwisory lnvcst.igator

Thoma~ J. Cosgrove, Director, CDER, OMQ

FORM FDA -483 (9/08) PREVIOUS EDITION OBSOLETE INSPECTIONAl OBSERVATIONS

07/09/2015

Page 3 of 5

DEPARTMENT OF HEAL TH ANO HUMAN SERVICES FOOD AND DRUG ADMINISTRATION

DISTRICT OFFICE ADDRESS AND PHONE NUMBER

Detroit District Office 300 River Place Dr., Suite 5900 Detroit, Ml 48207 313-393-8 100

Jndustry Jnfom1ation: www.fda.gov/oc/industry . NA.ME ANO T.rtl.E OF' !1'101\llDUAL T.O WHOM REPORT IS ISSUED

TO: Robeit J. Betzig, lnterim Site Leader

DATE{S) OF INSPECTION

06/23/20 15 -07/0912015"

\ 1810189 . ... ..__._ .......... ~-- ... -· ..... ------·-·-·-----_L__ __ ..,_..,_·~·--------·--

::~~~::=-~on~~~~~ u.~-----~-==-P:,::::..~d ------. --.. ---·-··---··-··-·-·· .. -~ CITY, STATE AND ZIP CODE TYPE OF ESTABLISHMENT INSPECTED

Kalama.mo, MI 49001 j' Manufactu rer ·-·--.-. ~"'"-~.~~~.·:o;.~~.~!'.~$.'"7,--1TN $ .,,, •• , ••••• :-C,==·"'"·~==::,~-:r·..,. · ~~,..-,.,...,..-_..............----. - . -·-------·- .. - ·- '"·--·-•__. ....... ._,.,..,_._ _ _.._

written and followed.

Speci:fically,

A. The rationale for the selection of representative processes for demonstration during media fill simulations within SOP 10554, Media Fill Program, does not include an assessment of the risks associated with various filling line speeds to capture worst case scenarios for aseptic processing lines In addition, tilling line speed during media fill s are not specified or recorded for evaluation at the time of fill. For example:

Media Fill tot W417J was fi lled on lin. simuiatindlmLmmJlllvials. The line speed limits in the batch record ar~ontainers per minute (cpm) with no specified setting stated or recorded. Data puiled from the automated. line historian indicates the line was running at approximatelylli:cpm) for most of the batch.

Media Fill lot W41 JF was filJed on lin.imulating.mL~ials. The line speeds limits in the batch record ar~pm with no specified setting stated or recorded. Line speed data for this lot was not available from the historian.

B. The program for managing aseptic processing personnel participation in media fills does not ensure that a person's participation is representative of their routine responsibilities. For example, a "technician" is responsible for the majority of critical filling line setup tasks and typical! ' erforms th.e majority of the major interventions required during routine processing. However, technicians id not participate in setup activities or per form major interventions in any media fi lls since F'or examplc,. edia fill parti.cipation history consisted primarily of manipulating vials with forceps.

LABORATORY SYSTEM

OBSERVATION #7

Acceptance criteria for the sampling and testing conducted by the quality control unit is· not adequate to assure that batches of drug product meet appropriate statistic.al quality control criteria as a condition for their approval and release. ---·~E-M_PL_O_Y-EE_(_S)-s--,G-N-AT_u_R_E __ ,,_. ___ , _____ .. _-.--E_M_PL_o_YE __ E-<S-> NAME AND TITLE (Print ·~r-rYP.,J

SEE RE.VERSE OF THIS PAGE

.~J;.~~ Jeffrey D. Meng, Investigator / /}j ~ Andrew J . ld:zior, Inveb'tigator r.r.· , Rebecca E. Dombrowski, Supervisory Investigator

Tltom11s J. Cosgrove, Director, CDER, OMQ

FORM FDA 433 {9/GS) PREVIOUS EDITION OBSOLETE INSPECTIONAL OBSERVATIONS Page 4 of S

DISTRICT OFFICE AOORESS ANO PHONE NUMBER Detroit Dislrict Office

DEPARTMENT OF HEAi.. TH AND HUMAN SERVICES FOOD AND DRUG ADMINISTRATION

I DA TE(S) OF INSPECTION

I 061231201 s - 0110912u1s· 300 River Place Dr., Suite 5900 Detroit, MI 48207 313-393-8100

-·----~--·-----------FEINUMBER

Industry lnfonnation: wv.iw.taa.gov/oc/industry L8l01S9

~N~.A=M=~~AN=o~n=TL=-=-E =oF~INOM~=-=ou~AL,.,...,T=o=WH==oM~REP==o=RT=~=. =iss=UED==,--------~-----~------------------

TO: Robert J. Betzig. fnterim Site Leader ----------------·----------.. -------~-----·----·------·---·-----·--------·-·--------..-··-FIRr.A NAME STREET ADDRESS

Pharmacia & UP.john Company !LC 7000 Portage Rd. __ C_ITY_ , ST- AT_E_A_N_O_Zl_P_C_OD_E _____ ·--·----------------+. -TY_P_E_O_F -EST-ABL,...,.,.IS'""'HM"'"'E"'"lll~T IN"""'sp,..e~--CT--E-D'"·--------------·- -· .. ··-··-

Kalamaz.oo, MI 49001 I Manufacturer ., :-:: .... , ........ '7."777'-----··-···---.·-.. ·-.. ·-... -.... -... - .. -... -.... -... ·- . -. ,·,- .·.-·-. -.... ·-,.-.... -.. · .-.. , .·.-.. , .. :!'!Z:':':"'.~.'::':=-:-:.~::··~"!"!':"'~:":".~.~-~·.~ • .,,~;-.~.~.~'~·'""~"····-:-. .,.,...,,.,. • ..,,.=.··=·==~·-· -· ~,._ ....................... ... .

Spedtically,

An appropriate statistical evaluation of lot release data was not performed to assure tht~ acceptability of individual lots with an appropriate confidence and probability. For example,

Depo-Medrol lot #L39677 with a total of 5 nits tested for content uniformity with a resulting AV otUllllJ average otflDJDlland an RSD offllll

Depo-Medrol lot #H l 5529 with a total o. units tested for content uniformity with a resulting average oill and an RSD ofllilBI)

O.BSERV A'nON #8

Drug products not required to be sterile are not examined to prevent objectionable microbfo!ogical contamination.

Specifically,

API products such as Phenytoin Sodium, Toceranib Phosphate, Tr iazolam are not examined to ensure they are free from objectionable microbiological contamination.

---------------------------- .. --·-------------------- 1 *Dates of fnspection: 06/23/2015 - 06/26/201 5, 06/29/2015 - 07/02/2015, 07/06/2015 - 07/09/201 5

'---RE~-SE---·~E-M·Pl~--~-~~1-__ -.:-)r-:-~~~---A--.---._-------,-EM-Je-~-:-~-D-.(·~--~-g-,~-:-:~-~-:ga-,T-~-:-PM-.,-0-rT_ype_j·~---~1-0A_TE_c_~_S_UEO_~----~ OF THIS . 'z;J~ I Andrew J. Idziol~ Investigator 1

1: 071091201 S

PAGE ~~/ 0 {)/, Rebecca E. Dombrowski, Surcivisory Investigator /P'fii~~ Thomas J. Cosgrove, Director. CDER. OMQ J

FORM FDA 483 (9/08) PREVIOUS eomoN OBSOLETE INSPECTlONAL OBSERVATIONS Page 5 of s