DEPARTMENT OF HEALTH AND HUMAN SERVICES FOOD AND DR0G AOMINISTRATION. Jayuya, PR Manufacturer of Terminally-sterilized LVP & SVP

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1 f' DSTRCT ADDRESS AND PHONE NUMBER DEPARTMENT OF HEALTH AND HUMAN SERVCES FOOD AND DR0G AOMNSTRATON 466 Fernandez Juncos Ave..(787) Fax,(787) ndustry nformaton: NAME AND TTLE OF NDVDUAL TO WHOM REPORT SSUED FRM NAME Mr. End.que Perez Sanchez, Plant Manager Baxter Healthcare Corporaton -Road #144, #250 CTY, STATE, ZP CODE. COUNTRY TYPEESTABLSRMEN.T _NSPECTED DA TE(S) OF NSPECTON 04/06/ /01/2015 FENUMBER Jayuya, PR Manufacturer of Termnally-sterlzed, Ths document lsts obsetvatons made by the FDA representatve(s) durng the nspecton of your faclty. They are nspectonal observatons, and do not represent a fnal Agency determnaton regardng your complance. 1 f you have an objecton regardng an observaton, or have mplemented, or plan to mplement, correctve acton n response to an observaton, you may dscuss the objecton or acton wth the FDA representatve(s) durng the nspecton or submt ths nformaton to FDA at the address above. lfyou have any queston$, please contact FDA at the phone number and address above. DUR.NG AN NSPECTON OF YOU~ FRM OBSERVE.D: U~LTY SYSTEM. OBSERVATON 1 The responsbltes and procedures applcable to the qualty control unt are not fully followed. There are no adequate procedures ot revew mechansm n place to ensure _that routne laboratory actvtes are consstently evaluated by the Qualty Unt. Specfcally, on 09/18/14, your Qualty Control laboratory reported an Out-of-Lmt (OOL) result fot the ntal Heparn testng of Heparn Sodu d 0.9 % Sodum Chlorde njecton; Lot #N The OOL assay result obtaned.,w.jj.wtal sample wa~ The esta~lshed specfcaton lmts s 1? to 2.06 u~ts/ml. nvestgaton' ~R -was generated m or er to eva uate potental sources that may be respons1b the OOL result obtamed. As part of the ntal nvestgaton, a re~test was perfonned. The result obtaned was whch confrmed the orgnal OOL result. The results of ths re-test ctvely. Jn addton, the unreleased Lot ned, your Qualty Unt performed a root cause analyss and dentfed the potency of the raw materal Lo a potental root cause. Three (3) addtonal released Lots (#N003079, #N0~3087 & #N003061) Were found that used the same raw materal lot number. On 09/26/2014, your Qual eld Alert Report (FAR) to nform a.bout the confrmed OOL results for the two (2) unreleased Lot l!jld. also tom ted product Lots #N003079, #N & #N were manufoctured wth the-affected raw materal Lot On 10/02/2014, your Qualty Con dentfed released lots. Lots OF THS PAGE EMPLOYEE(S) SGNATURE Jose E. Melendez, nvestgator DATE SSUED.. FORM ~DA 48~ (09/08) P~VfOUS EDTON OSSO~~ J'lSPECTONAL OBSE8VA TONS PAGE OF 7 PAGES

2 DSTRCT ADDRESS AND PHONE NUMBER DEPARTMENT OF HEAL TH AND HUMAN SERVCES FOOD ANO DRUG AOM:NJSTRA TON DA TE(S) OF NSPECTON 466 Fernandez Juncos Aye; 04/06/ /01/2015 FENUMBER (787) Fax,(787) ndustry nformaton: _www.fda.gov/oc/ndustry NAME AND nn..e OF NDVDUAL TO.V/HOM RJ:PORnssuep FRM NAME Mr. Enrque Perez Sanchez, Plant Manager B&xter l{ealthcare Corporaton Road #144, #250 CTY. STATE, ZP CODE. COUNTRY TYPE ESTABLSHMENT NSPECTED Jayuya, PR Manufacturer of Tert)'lnally-sterl:zed s ectvely. The establshed specfcaton s 1.80 to 2.20 U/mL. n addton, Lot On 10/22/2014, your Qualty Unt ssued a second FAR to nform about the decson of rejectng Heparn Sodum 2 U/mL n 0.9 % Sodum Chlorde njecton; Lots #N & #N and to voluntarly recall released Lots #N003079, #N00:3087 & #N However, none oftlw nvestgaton fndngs such as the aforementoned number of devatons to analytcal procedure and nadequate h1boratory practces were communcated to the agency a.t that tme. Moreover, durng the nspecton; observed th~t approxmately-of Heparn Sodum 2 U/mL n 0.9 % Sodum Chlorde njecton were affected by smlar laboratory devatons for the perod from 2013 to Ths tendency of devatons from the establshed control procedures and tranngs denote the lack of supervsory responsbltes to prevent adverse events mpactng the ntegrty of the laboratory operatons a.nd the lack of authorty to exercse the control necessary for assurng t)le accuracy of the analytcal results. Moreove;:r, your Qualty control unt dd not capture ether these events pror to releasng the drug products by ensurng data accuracy and ntegrty. Ths a recurrent observaton from prevous FDA nspectons conducted on & OBSERVATON 2 Contaner closure systems do not provde a.dequate protecton aganst foreseeable external factors n storage and use that can cause deteroraton or contamnaton of the drug product. Specfcally, yout Qualty Unt faled to mplement adequate and relable process controls for ensurng that dstrbuted soluton bags correspondng to (15 % CLNJSOL, O% TRA VASOL, O% PREMASOL, 20 % PROSOL) drug products always comply wth-the attrbutes that they represent to possess for ther ntended use. From January 2015 to Match 2015, your fnn has dentfed al ncrease n the number of customer complants receved due to mssng or loose blue tp port protector for dfferent soluton bag products. hs crtcal defect was acknowledged n each OF THS-PAGE EMPLOYEE($) SGN.A TURE AMENDMENT 1 Jose E. Mel.endez, nvestgator DATE SSUED.! FORM FDA 483 (09/0"8) PRE VlOUS EDmON OBSO.ElE NSPECflONAL OBSERV "'TON_S PAQ_E 2 OF 7.PAQ!;S

3 ==-=====-=========a DEPARTMENT OF HEALTH AND HUMAN SERVCES 1 FOOD AND.DRUG ADM!NSTE,ATQN DSTRCT ADDRESS ANO PHONE NUMBER Fernandez Juncos Ave. 'QA TE(S) OF NSPECTON (787) Fax: (787) ndustry nformaton: NAME AND TrrLE OF NDVDUAL TO WHOM ~EPORT SSUED 04/06/ /01/2015 FENUMBER Mr. Enrque Perez Sanchez, Plant Manager ' -,,=:,"""'.-~~~~~~~~~~~~~~~~~~,...,--===~===--~~~~~~~~~"--,~~~~~~~--. FRM NAME STREET ADDR.ESS Baxter Healthcare Corporaton. Road #44, #250 CTY; STATE. ZP coo.e: COUNTRY TYPE ESTABLSHMENT NSPECTED Jayuya, PR Manufacturer of Termnally-sterlzed of the approxmately fve (5) complants reported correspondng to 15 % CLNSOL 500 ml njecton, Lot P326975; 10 % PREMASOL 500 ml njecton, Lot P327080; 20 % PROSOL 2000 tnl njecton, Lot P327502; l O % TRA V ASOL 2000 ml njecton, Lots P & P323394,. Feld Alert Reports (F ARs) were ssued for each of the events. old) followng the requrements of control procedure Doc 1111blJttled n that, f approxmately fve (5) complants are receved for a sngle lot regardng m1ss1hg blue tp, actons need to be mplemented, Therefore, up to now no acton has been taken aganst aforementoned dstrbuted drug products based on the referenced acton lmt.. Nonetheless, your raton.ale fals to consder.that ths crtcal defect may ncrease the possbltes of exposng the patent to product contamnated at pont of use. After ths ssue was brought to your attenton durng current nspecton, your qualty unt determned not to follow the approach of the acton lmt. Your frm stll has not dentfed an exact source that may be responsble for cal!sng the referenced defects. Ths a recurrent.observaton from WL 13-ATL-17 dated and WL l l-sjn-wls04 dated MATERAL SYSTEM OBSERVATON 3 Each lot of components and closures s not wthheld from use untl the lot has been sampled, tested, examned, and released by the qualty control unt Your Qualty Control Unt faled to mplement adequate and relable procedures to ensure that crtcal components receved from your sster stes are approprate for ther ntended use and meet wth the requrements of safety and effectveness of the fnal drug products. Specfcally, your frm's current practce tor the recept of n-comng materals from your sster stes (to nclude packagng components n drect contact wth fnshed product and ntended to assure fnshed product sterlty) does not provde for a test-and/or'physcal evaluaton n order to approve them and determne that they are sutable for usng nto successve manufacturng actvtes. After ths ssue was broug nted control proceduremul!.ttled. that descrbes n detals _the procedure, for samplng, testng, evaluatng and releasng of the n-comng materals recept from sster stes. Ths s a recyrrent observaton from prevfous FDA nspectons conducted n 02/11/2014. LABO RA TORY CONTROL SYSTEM EMP~OYEE(S) SGNATURE Jose E. Melendez, nve~tgator OF THS PAGE FORM FDA 483 (09/08) ~REVOUS EDrrlON OBSOLETE NSPECTONAL OBSERVATONS DATE SSUED P~GE 3 OF 7 PAGES

4 .l.--~~~~~~~~~==~===~~=======-==~~~~~==~=t 01STRCT ADDRESS AND PHONE NUMBER DEPARTMENT OF HEAL TH AND HUMAN SERVCES FOOD AN:D DRUG ADMNSTRATON DATE(S) O' NSPECTON 466 Fernandez Juncos Ave. 04/06/ /01/2015 FENUMBER (787) Fax: (787) ndustry nformaton: NAME ANO TTLE OF NDVDUAL TO vyhom REPORT.1$SUEO FRM NAME Mr. Enrque Perez Sanchez, Plant Manager Baxter Healthcare Corporaton Road #144, #250 CTY, STATE, ZP CODE. COUNTRY TYPE ESTABLSHMENT NSPECTED Jayuya; PR Manu:l;acturer of Termnally-sterlzed OBSERVATON 4 There s a falure to thoroughly revew any unexplaned dscrepancy and the falure of a batch or any of ts components to meet.any of ts specfcatons whether or not the batch has bc:-en already d.strbuted. Your fttn faled to conduct a thorough techncal assessment of the data n order to confnn the orgn and characterzed the below Out-of-Alert (OOL) and Out-of-Specfcaton (OOS) results that have been seen on Heparn Sodum 2U/mL and 0.9 % Sodum Chlorde njecton assay testng. Specfcally, between the month of January and March 2015, your frm has been reported. ether OOS or OOL results for?t!al or fn~l assayj~!\n_:~~~m 2U/mL ~nd 0.9 % Sodu~ ~hlorde _njecton. Thee blshed alert ntal hm1ts range 1s from~.tfllj~ The estabhshed alert fnal hm1ts range 1s fro The establshed product specfcatons range s.from 1.80 to 2.20 U/mL. The Heparn Sodum Lots 1mpacte tendeney n the fnal assay testng are: N003483; N003475; N & N For example, Lot N showed results n the range from 1.79 to 1.86 U/mL (Recommended for rejecton) Lot N showed results n the range from 1.75 to 1.94 U/mL (Recommended for rejecton) Lot N showed results n the range from 1.87 to 1.95 U/mL (Recommended for releasng) Lot N showed results 1n the range from 1.88 to 1.96 UmL (Recom.rnendecl for releasng) On 01/16/2015, your QC L,aboratory ntated nvestgaton PR lots. Ths nvest aton was also extended to the manufacturng process. correspondng to Heparn Sodum were evaluated. No assgnable cause for the OOL and OOS Your frm concluded that the root cause for these results are related to the varablty among analyts, method varablty and not approprate establshed lmts, snce those lmts do not take n account the method varablty wthn the ntal and pro9uct alert lmt. However, your analytcal method valdaton report datecl r t/2009, does not show sµch ~nalyst and method varabltes. Moreover, the establ.shecl lmts durng the valdaton actvtes ~e the current lmts that have been usng for releasng or rejectng commercal lots of Heparn Sodum. Up to now, your frm has faled to establsh scentfcally sound evdence n order to dentfy a defntve root cause and prevent teocurrence. nvestgaton PR s stll n progress. see REVERSE OF THS PAGE EMPLOYEE($) SGNATURE Jose E. Melendez' nvestgator DATE SSUED FORM FDA 483 (09/08) PREVlOUS EDTON OBSOLElE NSPECTON AL OBSERVATONS PAGE 4 OF 7 PAGES

5 DSTRCT ADDRESS A~D PHONE NUMBER DEPARTMENT OF HEAL TH AND HUMAN SERVCES FOOD AND DRUG ADMNSTRATON DA TE(S) OF NSPECTON 466 Fernan.dez Juncos Ave. 04/06/ /01/2015 FENUMBER (787) Fax: (787) ndustry nformaton: NAME AND TTLE OF NDVDUAL TO \NHOM REPORT SSUED FRM NAME Mr. Enrque Perez Sanchez, Plant Manager Baxter Healthcare Corporaton Road #144, #250 CTY, STATE. ZP.CODE. COUNTRY TYPE'ESTA.BllSHMENT NSPECTED Jayuya, PR Manufacturer'of Termnally-sterlzed PRODUCTON SYSTEM OBSERVATON 5 Control procedures are not establshed whch montor the output and valdate the performance of those manufacturng processes that may be responsble for causng varablty n the characterfatcs of n-process materal and the dtug product. There s no assurance that your ftm has accurately dentfed the source that may be responsble for causng crtcal defects for dfferent parenteral dtug products. From March 2014 to March 2015, your frm has receved approxmately eleven ( ) customer complants due to mssng, fall off or loose blue tp port protector for 5 % CLNSOL, 10 % TRA V ASOL, O % PREMASOL, 20 % PR OSOL drug products. n all the events, there were no nonconformtes, falures, rework or devatons documented n the batch records that could have contrbuted to the reported crhcal defects. The n-process testng were verfed and also found wthn establshed specfcatons.. ~~.20".lllrnn dentfed a number of correctve actons lbm, to mprove the manufacturng process Of the reterencf:d n,orpntp r<> mplementaton of such actons, your frm contnued recevng customer complants for the same crtcal defects. For example, 03/18/2015, your fnn receved a consumer complant whch descrbes that the blue seal was not coverng the bag spke port. The complanant also mentoned that the tp 'wl!,s stuck to the sde of the bag. The soluton bag corresponds to 15 % Clnsol Sulfte-Free njecton 500 ml; Lot P32697S; Exp. Date 12/2015. Accordng to the complant nvestgaton; ths lot was manufactured on 12/02/2014. The product was manufactured at Fllng Lnelland packed at Packagng 1,..ne No devatons were reported conc.emng to the manufacture and packagng of ths lot. A retan sample evalµaton was performed and was found to be acceptable. The complant sample was vsually nspected and the reported defect was confrmed. The nvestgaton s stll n progress. 03/ l/2015, your frm receved a consumer complant descrbes that the blue seal was not observed on the port of the soluton contaner, but was observed attached to the back panel of the soluton contaner. The soluton bag corresponds to 10 % Premaso_l njecton 500 ml; Lot P327080; Exp. Date 12/2016. Accordng to the complant nvestgaton, ths lot was manufactureq on 12/04/20 4, The product was manufactured at Fllng Lne!land packed at Packagng Lne t{lljno devatons were reported concernng to the manufaoture and OF THS PAGE EMPLOYEE(S) SGNATURE Jose E. Melendez, nvestgator DATE SSUED FORM FDA 483 (09/08) PREVOUS EDTON OBSOLETE NSP[CTONAL OBSERVATONS PAGE 5 OF 7 PAGES

6 DSTRCT ADDRESS AND PHONE NUMBER DEPARTMENT OF HEALTH AND HUMAN SERVCES FOOD AND DRUG _ADMNSTRATON DATE(S) OF NSPECTON 466 Fernandez Juncos Ave. 04/06/ /01/2015 San Juan, PR (787) Fax:(787) ndustry nformaton: www. fda. gov oc/ ndustry NAME AND TT:!, OFN_DVOUAL TO WHO!,fREPORT SSUED FRM NAME Mr. Enrque Perez Sanchez, Plant Mana_ger FENUMBER Baxter Healthcare Corporaton Road #144, #250 CTY. STATE. ZP CODE. COUNTRY TYPE ESTABLSHMENTNSPECTED Jayuya, PR Manufacturer of Termnally-sterlzed packagng of ths lot. A retan sample evaluaton-was performed and was found to be acceptable. The complant sample was vsually nspected and the reported defect was confrmed. A Correctve and Preventve Acton (CAPA) nvestgatons was not ntated as the result of ths complant. Accordng to the complant nvestgaton, only one ncdence was reported for!lclbject lot; therefore, an accurate falure rate ca.m:ot be calculated to compare the threshold. As a result, no other nvestgaton wll be ntated. 03/06/2015, your fnn receved a consumer complant The customer reported that the port coverng on one Ptosol soluton bag was loose and drop off. The customer also reported that ths event has been occurrng more frequently wth-ths product. n addton, mentoned that they have h<)d about 2 bags wth ths ssue (03/06/2015). Accordng to the complajnt nvestgaton, the c1.1.stomer reported that they contnued to use the bags. All affected bags are from the same lot number. The customer reported that there were other bags that had lo?se caps as well over the past few weeks. The soluton bags correspond to 20 % Prosol njecton 2000 ml; Lot P327502; Exp. Date 12/2015. Accordng to the complant nvestgaton, ths lot was manufactured ol 12/12/2014. The product was manufactured at Fllng Lne and packed at Packagng Lne No devatons were reported concernng to the manufacture and packagng of ths lot A retan Sl:,lmple evaluaton was performed and was found to be acceptable. The complant sample was vsually nspected and the reported defect was confrmed. The event wll be dscussed wth the manufacturng operators. The nvestgaton s stll n progress. The examples above dscussed confrm that the approved n-process controls are not capable of detectng defects durng the manufacturng process that could be changng the characterstcs of the parenteral solutons; therefore, producng fnshed drug products that do not always meet wth the establshed specfcatons. Ths s a recurrent observaton from prevous FDA nspectons conducted on l l/201 land 02/11/2014. OBSERVATON 6 An NDA-Feld Ale~ Report was not submttecl wthn three workng days of recept of nformaton concernng sgnfcant chemcal, physcal, or other change or deteroraton n l:.l dstrbuted drug product, Accord~g to control procedure-ttled "Global Feld Alert Procedure" a FeldA/ert Report must be flled wth the Food and Drug Admnstraton (FDA) wthn 3 workng days from the recept the nformaton. Nonetheless, a revew of NOA-Feld Alert Reports (FARs) ntated by your fnn snce March 2014 to Aprl 17, 2015, dsclosed a total often (10) F ARs not beng submtted by your Corporate Product Survellance team wthn three (3) workng days. All the F ARs are related to Jayuya manufacturng process. These nclude ssues related to seve nt sterle drug products sµch as labelng ssues, leaks, damaged component and partcle matter. nvestgaton was generated; however not a.j the OF THS PAGE FORM FDA 483 (09/08) EMPLOYEE(S) SGNATURE Jose E. Melendez, nvestgator N,SPECTOl\!A,., OBSE;RV,4.'HONS DATE SSUED PAGE60F 7 PAGES [

7 DSTRCT ADDRESS AND PHONE NUMBER DEPARTMENT OF HEALTH AND H{JMAN SERVctS FOOD AND DR.UG AQMNSTRA TQN 466 Fernandez Juncos.Ave. (787) Fax:(j87) ndustry nformaton: NAME AND TTLE OF NDVDUAL TO WHOM REPORT SSUED FRM NAME Mr. Enrque Perez Sanchez, Plant Manager Baxter Healthcare Corporaton, CTY, STATE, ZP CODE. COUNTRY Jayuya, PR 00664~1503 Road #144, #250 TYPE ESTABLSHMENT NSPECTED DA TE(S) OF NSPECTON 04/06/ /01/2015 FE/NUMBER Manufacturer of Termnally-sterlzed n the referenced nvestgaton even though these wete devatons to the subject control procedure Ths s a recurrent observaton from WL 13-A TL- 7 dated 05-31s2013, WL l-sjn-wl-.o4 dated O l ~20-20 and prevous FDA nspectons conducted n 08/20 0, 04/20 l 3 & 02/2014. OF THS PAGE FORM FDA 483 (09/08 J EMPLOYEE(S) SGNATURE AMENDMENT 1 Jose E. Melendez; :trtvestgator PREv1ous EDmON OBSOLETE NSPECTONAL OBSERVATONS PAGE 7 OF 1 PAGES