Dabhel, Daman, Daman & Diu, 396 210 India Specifically ...

DEPARTMENT OF 11.EALTH AND H MAN SERVICES FOOD AND DRUG ADM INISTRATION

OISl RICT AOOO:ESS ANO PHONE NlJMBl:R O•TE(S! OF INSPEC'l"ION

09/09/2019-09/17/2019* ORA OPQO HQ, Room #2032 FEI l'IM.JMSe.R

12420 Parklawn Drive, Rockville, MD 20857 3004086192

0RAPHARMinternational483responses@fda .hhs.gov

I ndusnv Information: www. fda_gov/oc/indus1rv NAM,E ANO lrTLE OF INOIVIDUAl TOWkOM REPORT ISSUED

Mr. Jayant Dwivedy, Executive Director & Chief Operating Officer FIR',4 NAME Sl~EEi ADORl:;SS

osv Private Limited H-13, 16, 16A, 17-21, E-22 , OIDC , Mahatma Gandhi Udyog Nagar,

CJTY, STA'FE, ZIP COOE., COUNTRY J'r'PE ESTMUSI-IMENT INSFECTED

Dabhel, Daman, Daman & Diu, 396 210 Finished Product Manufacturer India

This document lists observations made by the FDA representative(s) during the inspection of your facility . They are inspectional observations, and do nol represent a final Agency determination regarding your compliance. If you have an objection regarding an observation, or have implemented, or plan 10 implement, corrective action in response 10 an observation, you may discuss the objection or action with the FDA representative(s) during the inspection or submit this infom1ation to FDA at the address above. If you have any questions, pleasr: contact FDA at the phone number and address above.

DURING AN INSPECTION OF YOUR FIRM WE OBSERVED:

OBSERVATION 1 There is a failure to thoroughly review any unexplained discrepancy and the fa ilure of a batch or any of its com ponents to meet any of its specifications whether or not the batch has been already distributed.

Specifically, your firm's investigations were found to be deficient in that the Out of Spec ification (OOS) results have been invalidated for various tests without identifying scientifically sound and justifiable root causes. Human errors and instruments errors have been attributed as potential root causes and passing retest results have been reported . Our review of your OOS Investigations during the period beginning January 2017 until September 20 I 9 revealed the follow ing for U.S. marketed products:

Category Tota! 00S Total lnvalided % Invalidated ..

Raw Material 49 39 80%

In-Process 25 25 100%

Microbiology I I 100%

Process Validation JO 25 83%

Finished Product Testing 19 17 89%

FP Stabili ty (before expiry)* 48 48 100%

FP Stability (after expiry) 18 0 0%

*includes only marketed batches, ••rounded to ihc nearest decimal

-E'.MPLOYEE{Sj SIGNA JURE .- l_~'-...L;:, DATE ISSUED

SEE REVERSE Jogy George, Investigator ~ A 09/17/2019 OF THIS PAGE Tamil Arasu, Investigator I \1\1-....I 'Y' ~

' FORM FDA <8l (09/08) l"HFVrous l-:W110N OU.~1.:.TI-: INSPECTIONAL OBSERVATIONS PAGE I OF 9 PAGES

DEPARTME/Vl' Of HEALTH ,\ND HUMAN SERVICES FOOD AND DRUG ADMINISTRATION

OISfRICT "00RESSANO PHONE.NUMBeR ~TE(SJ Of"INSf!cCTK>N

09/09/2019 - 09/17/2019* ORA O?QO HQ , Roo.rn #2032 F£1NJMSeP

12420 Parklawn Drive , Rockville , MD 20857 3004086192

ORAPHARMinternational483responses@fda .hhs.gov

lndustrv In fo m1ation: www. fdae.ov/o c/industrv NAMEANIHITlf Ot- lNOl\llC>!JAL TOW>IOM Rl;PORl ISSUED

Mr. Jayant Dwivedy , Executive Director & Chief Operating Officer FRM NAME STREET AOORESS

osv Private Limited H- 13, 16 , 16A , 17 - 21, E- 22 , OJDC, Mahatma Gandhi Udyog Nagar ,

CITY, Si ATE, ZIP COOE COUtfTRV rYPE t:sT ABl.tSHMENT JNSPECTED

Dabhel, Dama n , Dama n & Diu , 396 210 Finished Product Manufacturer I ndia

Examples include, but are not limited to, the following investigations:

(A) The OOS investigation D/OOS-19-077 was initiated on 7/20/2019 for (b) {4)

{b) (4) Tablels USf(b) (4) mg (Lot~(b) (4) I and ~b) (4) I) due to failure of Re a1ed Substance test results of ' any other secondary impurity' for the finished produc«b) (4) I The test results were

1[ ~~ % and (~~ % against the testing specification value ofNMT (~~ %. The investigation attributed 1he initial OOS result to a potential human error caused by the use of an unclean mortar and pestle by the analyst. The initial results were invalidated, and passing results obtained from retesting were reported. The investigation report also erroneously concluded that this was an isolated incident and no such unclean mortar and pestle event was id entified during January 2016 to June 2019 and no CAPA was initiated. However, we discovered that in an earlier event, the same root cause of the use of unclean mortar and pestle by U1e analyst was also attributed for the product (b) (4) Tablets USP for invalidating the OOS resul ts in November 2017 (Reference OOS Number D/OOS-17-034 Lot #s ,(b) (4) I and ~) (4) I

(B) Since April 20 I 8, your firm has inval idated initial results pertaining to approximately 12 OOS investigations attributing the root cause to HPLC instrument pressure fluctuations during sample runs. However, the underlying root cause of pressure fluctuations purportedly causing the test failures were never identified. Your firm has failed to address this issue effectively even after several repeated occurrences. You have also not studied the impact of this unexpected pressure fluctuation that may have resulted in obtaining inaccurate but passing test results that may have otherwise failed during routine analysis.

(C) Two (2) independent 00 investigations i11 2017 for (b) (4) J Tablets USP under OOS umbers OOS-17-042 (March 2017) and D/OOS-17-056 (December 2017) during Related Substances testing of several batches were attributed to incorrect pH of Mobi le Phase. Details are summarized below:

EU~LO'VEE{CI &IGNAT~li @) DATE.1SSUEO

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FORM n -. 4U (0,.08) l'kJ:VIOO,q ~ I ION Ol).'wOl..tII~ INSPEC rlONAL OBSERVATIONS PACE 2 OF 9 PACES

DEPARTMENT OF IJEALTI~ AND HUMAN SERVICES FOOD AND DRUG ADMINISTRATION

U'~TRIC ~~f~S ~'10 F'l-tONIS NUM13f;R OA~5tOF INSFe.CTION

09/09/2019 - 09/17/2D19~ ORA OPQO HO , Room #2032 FE.IMJMBcR

12420 Parklawn Drive , Rockville , MD 20857 300 4 086192

ORAPHARNJnternationaH 83responses@fda . hhs .gov

lnduiiry Jnformalion. www.fda gov/oc/induslrv NMCE .mo TITLE CJF mOI\/TDC,rAL TOV'.l'HOM REPOA'i ~SI.ED

Mr . Jayant Dwivedy, Executive Director b Chief Operati ng Officer flRMNI\ME S1REeT .-.r.,cmUS,

USV Private Limited H- 13, 16 , 16A , 17-21, E-22 , OIDC , Mahatma Gandhi CJdyog Nagar ,

crrv, ST A re ZIP CODE COUNTRY TYF)E. EST ABt.JSj,IMf.NT L\ISPECTEO

Dabhel , Daman, Daman & Diu , 396 210 finished Product Manufacturer lndia

UR- 17-042 D/OOS-17-056, \(b) (4) Tablets USP ~b) g lb) (4) Tablets USP~~~ g

(Initiated: March I!. 2017\ Al ., <Initiated: December 22, 2017) Batch No. Max. Unknown lmn <RRTl(6J (4) Batch No. Max. Unknown Imp (RRT[~b} I

(b) (4) % (b) (4) I¾ --- }lo i'/4 - :¾ >,t.

,--- Vo f/4

-- :iYo ,%

- Vo - % Specificat ion NMl](b) % Soecificat ion NMT-](I.>) Yo

pl-I Spccilica.tion for A-\

pH Specilicaticm for (A-\

i(b> (4> I ~b) (,t) l Mobile Phase Mobile Phase pH measured during ~b) (l)7 pH measured during (b)(4) l

lnvesti..:ation lnvestil'ation

In both cases, the investigation concluded that results are sensitive to pH based on forced degradation tudies. The forced degradation studies did not include any evaluation within the ranges of pH measured

during the investigation. Additionally no conclusive data was presented to demonstrate that the pH ranges measured (b) (4J tclb~ during the investigation would yield OOS impurity results commensurate with the levels found during the initial analysis (i.e., (b)(4) to~b)(4) o). Furthermore, the remedial training for LIR-17-042 was found to be ineffective. Quality Control analyst~b) who generated the fai ling results for

IIR\

OOS-17-056 was re-trained on adjustment of pH during mobile phase preparation following remedial training for LIR-17-042.

(D) 00S Investigation umber D/OOS-19-9,44 wa$ initiated on 5 15 019 to investigate the failing dissolution results at the 5-Hr time point for !b) ('I) apsules ~~? mg, batch #

1[{6) (4 Dissolution testing at 6-Month Stability (25 ± 2 °C I 60 ± 5 % RH)}. The dissolution data is summarized below:

-EMf"'L.O'r'EE:!~l SIGNAlL/fC (§) 0A.T'E•6'uE:C>

SEE REVERSE Jogy George , Inves i gator 09/17/2019 OF THIS PAGE Tamil Arasu , InvestJ.gator T A

fo-0RA1 fOA. 433 (U5",'03J rtu;v1uos tJJllllo.N OUSl)Lt1h INSPECJ'IONAL 0BSERVA1'1O1"S r,oe J OF' PAGES

D[PARTME rroF HEALTH ANO HUMAN SERVICES FOOD AND DR UG ADMINISTR.A TIO:-!

D'5TRrcl AOOR.f::S5 ANO PHCNl: NUMBl;R UAft:(Slut 1,,...;.,_c ION

09/09/2019 - D9/17/2019* ORA OPQO HQ, Room #2032 FE!"-'Mlll:R

12420 Parklawn Drive, Rockville , MD 20857 3004086192

0RAPHARMinternational483responses@fda .hhs .gov

lnduslr; lnforma1ion; www. fdaeov/oc/indus1ry NiliME ANO 71TLE OF lmlVIOliAl l'O W.HOM REPORT 1~0

Mr . Jayant Dwivedy , Executive Director & Chief Operating Officer FIR .. NAME STREET ADDRl:.SS

USV Private Limited H- 13, 16 , 15A , 17-21, E- 22 , OlDC, Ma hatma Gandhi Udyog Nagar ,

CITY, 51'A1E :ZIP COOE COUNTRY TVPE EST AOtlSHMENr lNSPECTtO

Dabhel, Daman, Dama n & Diu , 396 210 Finished Product Manufacturer India

I Hr. .1 2 Hr. _ I 5 Hr. .1 12 Hr. Soecification ((b) (4) F Initial I During Investigation I

As-is b)(4)

Re-tilled Re-diluted

Re-Test l(b) (4) I

The initial failing dissolution results were invalidated due to "sample homogenization error". This presumptive conclusion was derived from comparing the variatton in dissolution data between the initial analysis and re-test data. 10 stage testing was considered and the sample homogenization error as the contributory root cau e was not conclusively proven during the investigation.

(E) OOS Investigation number D/00S/ 18-154~b)(4) Capsules, usp(fi) <4>mg Proces Validation batch b)(4) l(Mfg Date: Oct-20 I 8, Exp Date: 1(b)(4) ) was initiated on December IO 2018. This batch failed dissolution testin at the 4 Hr. time point with a result of(b) o for capsule# 4 against a specification limited ofNLT(b o. The result was invalidated based on ,._discovery that the disso lution vessel (#4) temperature wiif(b) <4) C against a specification requirement ot1lb) <4> :1:. ~b~ °C. However vessel II 2 yielded passing result(~~? oat 4 Hr.) despite being at the same temperature o (bH4>0 c. Thet> C marginal difference from the lower end of specification limit (i.e. '(b) <4>0 q was not conclusively prtten in the investigation documents as the contributing root cause for the ~> o dissolution result for capsule# 4 at the 4 Hr. rime point

On September 7 2019, an additional OOS investigation (D/OOS/19-095) for the same batch ((b)(4) J for dissolution failure was initiated durin stability testing at the 3M tirne point (25 ± 2°C I 60 ± 5 % RH). The initial reported results were~~~ ~~~ :-1(b) 1/o at the 4 Hr. time point. Thi investigarion was pending

I h . f . . tlA) c osure at t e time o current inspection.

EMf!ILOVE:~S)Siet""-TU't!!. @ OAirE1seveo

SEE REVERSE Jogy George , Inves i ga cor 09/17/2019 OF THIS PAGE Tamil Arasu, Investigator 'TA

FORM fOA 481 (09,1111) 1,tJ;\IK.)lhWITH:tfOl tSf..lUJlt: I.NSPECTIONAL O8SERYATIO,._S P°'Gt! ◄ OF f PA(JF.5

DEPARTMENT Of' IIEALTB AND HUMA. SERVICES FOOD ANO DRUG ADMINISTRATION

US I "!' IC I nuu"Rt:>$ ANO PHONE Nl,JM.BI;~ DATets, or IN:5'Pf;'.CTt0,N

09/09/2019 - 09/17/2019~ ORA OPQO HQ , Room ft2032 F-EJNJ)..416~

12420 Parkl awn Drive , Rockville , MD 20857 3OD4086192

ORAPHARNinter:na tional4 83r:esponses@fda . hhs . gov

Jndustrv Information: www.fda.eov/oc/111d(1Slry N,1,_p,df N'l0 TJTL£0F 100\flOVJ\L TOvvMl.lM REPQR:r ISSl,,EO

Mr . Jayant Dwivedy, Executive Director; Chief Operating Officer f=IRJ.tNAME STRID ,-coRS'SS

USV Private Limited H-13 , 16 , 16A , 17 - 21 , E- 22 , OIDC , Maha trna Gandhi Udyog Nagar ,

crrv. STATE ZIPCQOe COUNT~ fVPE EST A8LtSHMEftlJ Jti/SPECTE0

Dabhel, Daman, Daman & Diu , 396 210 Finished Product Manufacturer 1ndia

otably, batch # (<6><4) lis the 3rd PV batch in a revi.sed process validation campaign after the 151 and 2nd PY batches were rejected (See OBSERVATION# 2). Several process changes were incorporated during the revi ed PV campaign of 3 batches that included batch # {b) (4) I Despite the complexities involved in batch manufacturing process, no effort was made by the investigat ive team to understand if the repeated lower dissolution value during release (O/OOS/ 18-154) and stability (D/OOS/19-095) has any correlation to the manufacturing process.

OBSERVATION 2

Control procedures are not established which of th ose manufactu ring processes that may be responsible for ca using , •ariability in the characteristics of in -r>rocess material and the drug product.

Specifica lly

(A) The current manufacturing process utilized for F 4>

Capsules, u sp(b) <4> g. (b) <41ng, and~~~ mg is not robust to consistently manufacture products that meet I the predetermined specrficatton limits. Notably, adequate controls are not established to ensure that the (b)"(4) steps consistently yield product lots that meet the in-process[{b <4>

(DJ l4l J limits and the finished product dissolution limits. The fo llowing is a summary of batches manufactured since the process validation campaign for the products:

Stren2lh Batches Batch Disposition Remarks (b) 'Ilg (fi) rt} Reiected for~~~ failure Initial Validation Batch IA \

{ejected due to 1.i PY batch fai lure Init ial Validation Batch Released and disoatche<l I " Validation batch Released and disoatched 2nd Validation balch

l eleased and di patched 3rd Validation batch (i n est igated for Di solulion failure :!urine. release 1estin2.. and stabilitv testing)

DOS for:~b) (4) I Under lnves ti!'.!,ation

E~LOYl!EI-DJS~"'-~ @ C>A~ ISS-UW

SEE REVERSE Jogy George , Invest i gator 09/17/2019 OF THIS PAGE Tamil Acasu , Investigator ,A

..-OKJ'\I t'OA 441 (O,JOJI) l'tU•,YQt/:,. JJ)l llOrl (1115U1. l. lli INSPECTIONAL OBSERVATIONS fA.GE $ OF, PAGES

D[PARTMENT OF l-lEAI_Tl-1 AND HUMAN SERVICES FOOD AND DRUG ADMINIS1RA TION

t HSTRl:;T A®lilf:S.S ""'-'DP~ NUM 8fR DA Tl;[SJ Of tNSf'ECT ,or-,

09/09/2019 - 09 / 17/2019* ORA OPQO JiQ , Room #2032 fE• NJMBER

12420 Parklawn Drive , Rockville , MD 20857 .3004 0861 92

ORAPHARl1Internat i onal4B3 r esponses@fda . hhs .gov

lndusu-v lnfonnation: www. fdac.ov/oclinduslry NAME ANO TITLE OF INOIVIOOAL TO\oVHOM REPOff:11ssue.o

Mr . Jayant Dwi1redy , Executive Director & Chief Ope r ati ng Of fi c er Fl~M NAME Sl REET ADDRESS

USV Pri vate Limi ted H- 13 , 16, 16A , 17 - 21 , E- 22 , OIDC , Ma ha tma Gandhi Udyog Nagar ,

CITY. SJ>.TE, ZIP COOE.COUtl fRY rvPe ESTJ.BU.&IMENT mSPE.CTEO

Dabhel, Daman, Daman & Diu, 396 210 fin i shed Product Manufacturer I ndia

(b)_Jn~(b) (~) \Released and djsoatched I" Validation batch (4\ !Released and dispatched 2nd Validation batch

JRelcased and dispatched :3 •• Validation batch pas ro11Cb) C4> I Under Investigation Released (b) ln Warehouse Released (4) in Warehouse !Released in WareJiouse ~eleased ln Warehouse

(~LJmg Released and dispatched P' Validation batch LA

Released and dispatched 2"d Validation batch investigated for dissolution failure)

1Released and dispatched 3rd Validation batch

(B) The sample quantities used for establishing b) (4) hold time studies for U.S. marketed products do not represent the respective commercial batch sizes. For example, the ~6) <4> ,sample quantity used for establishing the hold time fo~(b) (4) ablels SP is as follows :

Strene.th Batch Size Satnolc OllaotilY Hold Time ~b) 'mg l(b) (4) I 1<b)(4) I ~b) (4) I X4) )i i:\ I I I I I I

Approximately two (2) batches in 2019 fo~~~6) 41 USP~b) (4) ablets g (batches [(b) (4) and [(b) (4) were held for~b) (:if) at the (b) (4) tage.

OBSERVATION 3

Procedures designed to prevent microbiological contamination of drug products purporting to be terile are not followed.

ENJ>I..OV El St SIGNA. TIJJ,E: ~ DATE fSSUf.O

SEE REVERSE Jogy George , Invest i gat or 09/17/2019 OF THIS PAGE Tami l Arasu , In ve st igator ,I\

• ORM F"DA ,tJ 109!"-') J'R,EV1t.)IJS .ll)IT10 N OI·~ HIT INSP[CTJONAL OBS!:RVATIONS PAGE 60F S PAGES

D[PARTMENT OF HEALTH AND H MAN SERVICE:S FOOD ANO DRUG ADMINISTRATION

ION

09/09/2019-09/17/2019* ORA OPQO HQ , Room #2032 12420 Parklawn Drive , Rockville , MD 20857 [email protected]

lndum-y lnfonnation; www.fi:la, NAME -',N.0 lr'TU; OF INDtVICXJAl TO~ E

FEJ Ml'MOER

3004086192

Mr . Jayant Dwivedy , Executive Director & Chief Operating Officer ARM W.M€ STREET ADDRESS

USV Private Limited A- 13, 16, 16A, 17 - 21 , E-22, OlDC , Mahatma Gandhi udyog Nagar ,

CITY srAT£. ZIPCOOE.COUN1R'f

Dabhel, Daman, Daman & Diu, 396 21 0 I ndia

TYPEEsr,a.1s1-!Me.NftNSPeCTEO

Finished Prod~ct Manufacturer

Specifically, the process simulation studies (media fills) conducted to evaluate the sterility confidence of the process are inadequate in representing the commercial production. For example, the most recent four (4) process simulation studies (medial fills) conducted on the vial filling line did not ade~uately represent the production process of (b)(4) Injection.~~! nl batch number (b)(4) intended for the U.S. market. These process sim lation studies included an <l>J<4> micron filter in the filling room whereas the filling 12rocess of(b 4> lnjection.~~!·nl does aot use an <b) {'J) filter in the filling room. The(b) (4) icron filter is used in addition to th f!i~~~ icron filter located in the filtration room. The filling act1v1ty for batch numbe (b) f4> as observed during the current inspection.

OBSERVATION 4

The responsibilities and procedures applicable to the quality control unit are not fully followed.

Specifically

(t\) An incorrect HPLC instrument method was used for testing o (b) (.il) for the drug product (b) {'J) and the lb) r4> was released (on 07/ 11 /2018) for the manufacturing of finished product (batch fl b)(4) . This HPLC instrument method b)(4)~AS)~1 was created by a QC Supervisor with incorrect test parameters (column temperature and wavelength), verified and signed by another QC Senior Officer and the sample was tested by a 3rc1 QC Analyst. After completion of the test, the electronic raw data, including audit trail and work sheets were reviewed and signed by a 4th QC Executive. Despite purportedly signed/reviewed by four QC personnel the use of the incorrect inS1rument method remained unidentified and the (bH4) as released thus raising concerns about the ability of your quality unit's review process. The finishe product COA for (b) (4) ablets USP t~) mg batch # (b)(4) was approved on 07/29/2018.

(B) The Raw Material test records for approvedl6) {'J) USP with AR Number DMRMJ 90000436 was found with mis ing "Reviewed By" signature for the~b) (4) analysi conducted on 04/29/2019. The associated A Pl lo (b) (4) was released for commercial use on 05/04/2019.

SEE REVERSE OF THIS PAGE

FORA! FDA ..U (09fOI)

EAlPl.OYEEfSl SlGhA f~E:

Jogy George , Investigator

Tamil Arasu, Investigator

fliU.i.V:0 \JS U)l'nON OU!.Qi.K J INSPE:CTIO AL OB ERVATIONS

CATE ,ssue.o 09/17/2019

DEPARTMENTOFHEAl.TA ANDHUMAIII SF.RVICES FOOD AND DRUG AOM INIS1' RA TION

D ISTA'ICf AODAE:SS mo l!'I-IONE NUM8Eff O,Vl!ISIOf' INs.PECTiQllt

09/09/2019 - 09/17/20 19* ORA OPQO HQ, Room ff2032 'BNU~ BE i:i

12420 Parklawn Drive , Rockville , MD 20857 3004086192

ORAPHARMinternationa l483responses @fda -hhs -gov

lndustrv Information: www.fda.gov/odi11duslTy NAME ANO l llU. OF INDMDUAL TO WHOM RIEPORT lSSUEO

Mr . Jayant Dwi vedy, E:xecutive Director & Chie f Operating Officer ~!~MNArME S f~EET ~OllflESS

usv Priva te Li mi ~ed H-13 , 1 6 , 16A , 17-2 1, E- 22, OIOC , Mahacma Gandhi Udyog Nagar,

ClTY STAlE, ZIP COCE. CO'..INTRY TYPE: esrABUS~MENT INSPECTE.O

Dabhel, Dama n, Daman & Diu, 396 210 Fini shed Product Manufacturer India

OBSERVATIO 5

Equipment and utensils are 1101 clea11ed at appropriate intervals to prevent contamination that would alter the safety, identity, strength, quality or purity of the drug product.

Specifically during inspectional walkthrough of the!l:i)(il) Facility Phase~b n 09/09/2019, a ~6) (4) i (Equipment ID No. D/PRDl~~! l 02) that was documented as major cleaned on 09/07/2019 and subsequently Re-cleaned on 09/09/2019 was found with visible powder residue near product contact surface areas. Notably, the powder residue was found around the perimeter of the;(b) (4)

that separates the fb) (.if)

The associated equipment 1ogbooK 1nd1cares that tlie cleaning acuv1ty was venl1ea 6y rwo tZ) personner (i.e .. a manufacturing operator and a supervisor), and the subsequent line clearance was carried out by \b) <4> personnel (b) {'I) I

. he pertinent 0 ' l4 ) '·quipment is validated for use during routine commercial production of severa I U.S. marketed products.

OBSERVATION 6

Backup data is not assured as exact, complete, secure from alteration, erasure or loss through keeping ha rd copy or alternate systems.

Specifically the audit trail tiles on your JCP-MS instrument (Instrument o: O/QCD/ICP O I) used in the quality control laboratory were not available in a verifiable format during the inspection. Due to multiple software hanging issues, the audit trail files on th is instrument were recorded as corrupted and subsequently the impacted audit trail files were converted into "hash codes" and only viewable a obscure codes comprising of several thousand lines through internet explorer. During the inspection, events from the original instrument qualification activities were not traceable in the hash codes. For example, an

£MPt.OYEE~J StGNATuRE. (Q!!) CATE ISSUED

SEE REVERSE Jogy George , Invest i gator 09/17/2019 OF THIS PAGE Tami l Arasu , I nvestigator \t\.

FORM mA ~II.I 1091081 l'MJ•VU"tlB j;;J)I nn,., on..c:ot PTF INSPECTIONAL OBSERVATIONS PAGE 8 OF 9 PAGFS

DEPARTMENT Of' HEALTH AND H MAN SERVIC ES FOOD At--D DRUG ADM INISTRATI ON

0 1ST RlCT AIJORESS AND PHOM; NUMBEIQ OATE:!S) OF" INSPECTtON

09/09/2019 - 09/17/2019* ORA OPQO HQ , Room "2032 FE.I NUMBER

12420 Parklawn Drive , Rockville , MD 20857 3004086192

ORAPHARMinternational483responses @fda.hhs . gov

lndus1rv Informal ion: www. fda AOV/oc/indus1rv NAM.E AND 'lfTtE OF INDtVlDfJAL IOWtJOM REPORT lSSUED

Mr. Jayan t Dwivedy , Executive Director & Chief Operating Officer Fl~M r«ME SMEET AOORESS

USV Private Limited H- 13, 16 , 16A, 17-21, E- 22 , OIDC, Mahatma Gandhi Udyog Nagar ,

CITY, Sl A TE. ZP CODE. COUNTRY TYPE: E-STABLISHMem IN$PECTffi

Dabhel , Da ma n, Da ma n & Di u , 396 2 1 0 Fin.shed Product Manufacturer Ind ia

electronic signature events during the initial qualification event could not be located among the hash codes. Additionally, the qualification of the instrument was also found deficient. In particu lar, the Clear Resull option under the administrator user level was not challenged during the initial qualification. You have not conducted any retrospective risk assessment or evaluation to detenn ine your aud it trail backup fi les are complete, accurate, and reliable for the ICP-MS instrument.

*DATES OF INSPECTION 9/9/20 I 9(Mon), 9/ 10/2019(Tuc), 9/l l /2019(Wed), 9/12/20 I 9(Thu), 9/1 3/20 I 9(Fri ), 9/ 14/20 I 9(Sat), 9/ 16/20 I 9(Mon). 9/ l 7/2019(Tue)

EMPI.OYee1s1 SIGNATURE c::~.l ; DATE ISSUED

SEE REVERSE Jogy George , Investigator . - -=- 09/17/2019

OF THIS PAGE Tamil Arasu , Investigator ' A "f'4..~

FORM FDA 483 (09/0II) 11u-:v1ous imr not,1 oosou.11t INSPECTIONAL OBSE RVATIONS PAGE 9 OF 9 PAGES