DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DR UG ADMINISTRATION

DISTRICT AOORESS AHO PHONE NU"81!R OllTE(SJOf "'SPECTION

12420 Parklawn Drive, Room 2032 01/20/2020-01/28/2020

FEINUM8ER
Rockville , MD 20857 3002949085
ORAPHARMinternational483respo111::>e1::>@fdc1 . hh1::>.yov
NNoE lffJ fillE Of INDMOUAl TO wtlO'A REPORT ISSU6D

Mr . Arun Gupta , Vice President & Location Head

FIRMIWE ST·-··--·-
Dr. Reddy's Laboratories Limited CTO APIIC I ndustrial Estate, Pydibhimavarama
Unit VI (Village)
CITY, STATE. ZP CODE, COUNTRY TYPE ESTA8USHMt Nf IN"""CttO

Srikakulam District , Andhra Pradesh, API Manufacturer

India

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 determination 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 action 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 phone number and address above.

DURING AN INSPECTION OF YOUR FIRM WE OBSERVED:

OBSERVATION 1

Process Validation is not performed adequately for manufactured products at the facility.
11 1
Specifically, your process validation fortti ' • s inadequate because your firm has

(b)<•> Out of Specification (OOS) results from December 26, 2017 - December 9,
2019 for manufacturing of commercial batches. The batches have OOS 's for Residual
Solvents (RS) by Gas Chn:~matography (GC) test for <1>>< >
4
content against the ,
specification limit of NMT1b1141 ppm. The 6 ><4 > batches documented in the<bH'>
• '(6Jl4 ) (b) (4)
OOSs were rejected and of these batches were and are approved
for shipment.tb><4 > batcnes are awaiting to be tb>r•)

Your firm reported a full-scale investigation summary report OOS # 310018090 on

4
November 30, 2019 to investigate the failure batches of<b><4 >
4
content inlbH > I
<b>< > The OOS evaluated an out of specification result for 1b1141 by Gas
Chromatography for batch # ll>HilJ That investigation concluded that a correction
4
with an issue with the (b>< > was rectified and no similar incidents were
reported. Additionally, "no impact on the further batches execution." However, batches

/1
r,,,.,
7J!Z-
EAIPl.OYEE(S} NAME ANO nTtE (Pnnl"' OATEISSUEO

01/28/2020
Dipesh Shah, CSO
Aditi Thakur, Chemist

~.Pt
t 'O RM fllA 483 (U9/08) PREVIOUS EOmON OOSOt.ETE INSPECTI ONAL OBSERVATIONS PAGE I Of 8 MOES
 DEPARTMENT OF HEALTH AND HUMAN SERVI CES
FOOD ANO DRUG ADMI NISTRATION
DISTillCT ~US NIO PHONE N\JMll:R OAff(S)Of 11'1:.Pt.Cfl()N

12420 Parklawn Drive , Room 2032 01/20/2020-01/28/2020

fEll<UM6fR
Rockville , MD 20857 3002949085
ORAPHARMinternational483respo nses@ f da . hhs . gov
NM<EANOT1fl.E()f lllll<ll10l.W. TOWt!OLl~TISSUEO

Mr. Arun Gupta, Vice President & Location Head

flRl.A'<AME STREET it.DDRESS

Dr . Reddy ' s Laboratories Limited CTO APIIC Indus t rial Estate, Pydibhimavarama
Unit VI (Village )
CITY, STATE. ZIP uvuE, COUNTRY IY>'t:tS1A8 llSHMENT IHSPECTl!O

Srikakulam DisLrict , Andhra Pradesh , API Manufacture r

India
'(b) (4)
_Jwere tested and failed against your specification of NMT
(b)(4) of<bH4>
content. Batch results were as follows:
(b)(4)
Notification Date Batch Number I
Number Observed Content (ppm)
- (b)(4) (b)(4) (b)(4)
December 3,
1--1
2019
(b)(4~
December 23, r
2019
'---'

Where a list e_rovided during the inspection states that batch numbersCbH•>
CtiH•> will beCb>l4> Additionally, during the inspection we found that your
finn documented incidents for failed results during process validation. The details are as
follows:
(b)(4J
Notification Initiated Category Batch Number I
Number Date Content
(b)(4) '(b)(4) - -cb~~pm)
October Incident
3,2018 ..._ ,_
H
August oos
13, 2019
- August Incident
,___
I I
,_ 20,2019 lot:::r (b)(4)
I August Incident
(DJ(4)
(b)(4)
and l
20,2019

EJJPl..OVEEJ~JNAME OATE IS SUEO

~o~
A.NO nTt.E (Pr'"' ot t yp.J

01/28/2020
Dipash Shah, cso
Aditi Thakur, Chemist

~ ~J_M
FORM tl>A OJ (09/08) PREVIOUS EDITION OBSOLETE INSPECTIONAL OBSERVATIONS PAGE~ OF 8 PAGES
 DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADM INISTRATlON
DISTRICT DRESS AND PHONE NUMBER 1DATE(SJ OF 1rlSPECTfON

12420 Parklawn Drive, Room 2032 01/20/2020 - 01/28/2020

FEINUMBER
Roc kv ille, MD 20857
3002949085
ORAPHARMint e rnational483responses@fda.hhs.gov
NAf.\EAND nne OF lllOIVIOUAL TOWHOM REPOllT ISSUED

Mr. Arun Gu pta , Vice Presiden t & Location Head

ARM NAME STREET ADDRESS

Dr . Reddy's Laboratories Li mi ted CTO APIIC Industrial Es tate , Pydi bhimavarama

Un it VI (Village)
Cl"IY STATE. ZIP CODE.. COUNTRY TYPE ESTABLISHMCNT INSPECTED

Srikakulam Dis trict, Andh ra Pradesh, AP! Manufacturer

India
4
Your firm continues to have recurrent failures fo tt>>< > residual solvent intended for
process validation batches and commercial batches without have a scientifically justified root
cause analysis.

OBSERVATION 2
Investigations are inadequate in that they do not evaluate all potential root causes.

Specifically,

A. Investigations for the following Out of Specifications (OOS) and Incidents were not performed
adequately. For example,
4
1. For OOS # 310018104 and Incident # 200338632 the initial investigation for"b>< > batch
4
H > with re ort date December 01, 2019 and December 09, 2019 resulted in an in-
- - -1b)(4l (b)(4)
grocess
(bl\4l fie res amp e passe wttli <4> an the root r) fo
cause iSdetermined to e y madvertent uman error documented in Incident# 200338632.
The batch was then moved for further production, however, during release testing an OOS #
310018104 was observed. The batch failed for Solubility testing on December 09, 2019 and
4
failed for residual solvent <b><4> content lbll4> ppm with release specification 0£<b>< >
ppm) on December 23, 2019. During the final release investigation, the most probable cause
was identified that the original test results for the in-process r n4> was accurate
4
which was initially identified to be'<b>< > % initially identified tobettie samp e. The resampled
results were discarded with documented justification.
2. OOS # 310017867 with . report date October 17, 2019 for MW batch # -~ an
4
OOS result was reported forFH > content by LCMS teste at contract laboratory identified
lb)(4) (b)(4) . . . '(b)(4) .
as The OOS was for mpunty which was reported as ppm against the
4
specification limit oflb>< > ppm. Your firm only performed a laboratory investigation. The
documented most probaole root cause was determined to be cross contamination of the

EMPLQYEE(S) NAME AND nTl.E (Prinl 01 Typo) DATE ISSUED

01/28/2020
Dipesh Shah, CSO
Aditi Thakur, Chemist

FORM FDA 483 (09/081 PREVIOUS EDITION OBSOLETE INSPECTIONAL OBSERVATIONS PAGE 3 OF 8 PAGES
 DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
DISTRICT ADDRESS J'.NO PHONE NU'111ER l>ATE(S) OF INSPECTION

12420 Parklawn Drive, Room 2032 01/20/2020 - 01/28/2020

FEI NUMBER
Rockville, MD 20857
30 02949085
ORAPHARMi nternational 483respo nses@fda . hhs .gov
NAME ANI) TlTI.E OF INDIVIDUAi. TO WHOM REPORT ISSUED

Mr. Arun Gupta, Vice Pres ident & Location Head

FIRM NAME STREET AOORESS

Dr. Reddy ' s Laboratories Limited CTO APIIC Industrial Estate , Pydibhimavarama
Uni t VI (Village)
CITY, STATE. ZIP CODE, COUNTRY TYPE E TABUSHMEN"l INSPECTED

Srikakulam Di s trict , Andhra Pradesh , API Manu fact urer

Ind ia

weighing balance or the micropipette during laboratory analysis without an investigation in the
manufacturing area.
4
3. OOS# 310016984 with report date April 05, 2019 for '<b>< >
[(ll 4l
bl1 . (b)(4) ~b)(4)
with an OOS result was reported for Assay analysis. %,
c4i::fb><4> % . According to sr.ecification # S-08-IJ-USP/08 states that the specification._s_ar _ e ....
4 4
NLT: <b>< > % and NMT: '<b>< > %. The investigation revealed to be instrumentation failure. A
re-analysis was condµcte on April 05, 2019 in which results were found not meeting
specifications '<b><4> <b><4> %,'(b><4>- T(b><4> %. Inadequate sci en ti fie justification was
provided for the failing reanalysis resuft stating the hypothesis that there is a chance of
r~~ from the already used injected vials. '(b)(4l roduct is approved for the
mted States market.
4
B. During the inspection we observed that your firm did not initiate investigations for '<b>< >
batch # ~b>< > 4
for unknown peaks in residual solvents. According to sectio_n_6___1._2_o_f..
your firm s SOP SOP-GLOB-QC-0018, titled 'Handlin of Extraneous Peaks ' criteria for
4
.
mvestt . .
at1ons ior res1.duaI so Ivents states (b>< >
.c
WW (bl(4l
consistently". Batcnffl as
~h
determmea to . ave <b><4> - a--·--·- .- d d Th .
n no mvest1gat1on was con ucte . e mvesttgatton states t at . . h
these unknown pea s appear to be isomers o ~b>< >
4
nd no investigation was conducted.
4
C. Risk Assessments titled 'Assessment of'!bll > and (b><4> in ~b><4> A Pis Manufactured at
CTO-VI Dr. Reddy's Laboratories Limited' with approved date of March 25, 2019 conducted
to assess the potential resence o{<b><4>
lbll4> and othertb><4> ; mpurity in <b><4> PJ's. Only a theoretical evaluation of
the ey Starting Material (KSM) was evaluated and no KSM was tested b u our firm.
Additionallu our firm doesn't test fo ~b>< >
4

4
lbll > tOr\JiliteaState bound pro ucts. our firm has
shipped multiple Datches o .<b>< > 4 A.Pl's to United States and it appears that your costumers
were not notified.

EMPl.OYEE(S) NAME ANO mu (Prlol « Typo) DATE ISSUED

01/2 8/2020
Dipesh Shah, CSO
Aditi Thakur, Chemist

FORM rnA 483 IMIU8) l'REVIO\-S WITIOs 06SOLnE INSPECTIONAL OBSERVATIONS PAGE~ OF 8 PAGES
 DEPARTMENT Of HEALTH ANO H UMAN SERVI CES
FOOD AND DRUG ADMINISTRATION
OATE(SJOf' INOf'ECTlON

12 420 Parklawn Drive , Room 20 32 0 1 /20/2020-01/28/2020

FEJH\MER
Rockvi lle , MD 20857 3002949085
ORAPHARMinternational483responses@fda.hhs. gov
NAME /HJ TITlE OF INOIVIOUo\I. TO WHOM ~T ISSUEO

Mr. Arun Gupta , Vice Pres ident & Location Head

FIRMIW.'E STREET AOOR£SS

Or . Reddy' s Laboratories Limited CTO APIIC Industrial Estate, Pydibhimavarama

Unit VI (Village)
CITY, sr..re. ZP COO£. COUNTIIY fYPt; t$1 "Ill. ~MtNl IN:>PtCTtoD

Srikakulam District , Andhr a Prades h, API Manufacturer

India

OBS ERVATI ON 3
Your firm 's cleaning processes for equipment have not been adequately established and
validated.

Specifically, your firm's Quality Unit failed to do the following:

A. According to section 5.13.l of your firm 's Standard Operating Procedure SOP-GLOB-QA-
0048, Cleaning Validation Program for Drug Substance states, "Validation of cleaning
Jirocess involves successful completion of minimum <DH•> cleaning runs either
141 115/001 ,
'. However, your cleaning validation report, CVP/<DH•>
titled ·Report on ~ment cleaning validation during product change over from(bH•>
(b1f4> of>H4> any other Pro_d.,,..u_c_t_,.i-n
<DH•> date February l /,20f7 was performed with onllH•> ::leaning run.
According to the cleaning validation report section VIII states, "As there is no current
Ciroduction plan and no visibility of future plan for (bl 141 of(b><•> roduct i 'tti><">
><•1 facility, the cleanin,g validation study forlbll•> of<b><4> s closed with the
4
execution of <b>< > A new cleaning validation study shall be initiated with the current
approach of cleaning validation, if warranted." The Head of Quality Assurance also stated
that the firm did not manufacture~ b>< > during the cleaning validation done in February
4

17, 2017. He further stated the'<DH > batch ofi1b1141

4
hat the firm manufactured was on
~atches of<b>< > in 2018, lb><4>
4
September l 0, 2018. The firm manufactured <b><4 >
4
<b>< in 2019 and ~t>n•> batches in 2020 without conducting a cleaning
vauaanon wnn<b><4> runs as requiredby SO'P-GLOB-QA-0048.
B. During our review of the surface area of each equipment documented in the cleaning
validation, we asked for the raw data for the surface calculations for each equipment.
According to the Team Member Process Engineer and Head Quality Assurance, there is no
raw data for the surface area calculation for each manufacturing equipment. Because there is
no raw data, there is no evidence that swab samples were actually analyzed. He further stated
that they do not have raw data calculations for all the cleaning validations of all equipment.

EMl'l.OYEE(S/ NAME ANO nTl.E tpufl °' T-/ O"TEISSUEO

01/28/2020
Dipesh Shah, CSO
Aditi Thakur, Chemist

FORM FDA 48l (0910S) PREVIOUS EDITION OOSOlfTE INSPECTIONAL OBSERVATIONS PAGES OF~ PAGr.S
 DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADM INI STRATION
DISTRICT ADDRESS AND PHONE NUM8ER DATE(S) Of •"lSPECTlDN

12420 Parklawn Drive , Room 2032 01/20/2020 - 01/28/2020

Fel NUMBER
Rockvi l le, MD 20857
3002949085
ORAPHARMinternational483responses@fda . hhs.gov
NAME ANO TITLE OF INDIVIDUAi. TO WHOM RePORT 1ssueo

Mr. Arun Gupta, Vice Pres i den t & Location Head

FIRM NAME STREeT ADDRESS

Dr . Reddy's Labo r atories Limited CTO APIIC Industrial Estate, Pydibh imavarama
Unit VI (Village)
CITY, $ f ATE. ZIP COOE. COUNTRY TYPE ESTA8USH~i..ENT INSPECTED

Srikakulam District, Andhra Pradesh, API Manufacturer

I ndia

C. According to the Team Member Quality Assurance the Quality Unit's choice of sampling
point locations for swab samples of product contact surfaces during cleaning validation were
based on "experience" and not scientific justification.
D . Dunng . our review
. 1t . was o bserved that th e fi1rm h astbH4l nknown peaks related to tbJ 141
1
41 41
'<bH jDbserved in the analysis o :ci>n JAPI

tb)(4)

41
In add.1tton,
. the fi1rm h as recordedlbH ~nknown peaks in other manufactured AP Is
such asjr f(4J hich are pending applications in United
States.

OBSERVATION 4
Trend Analysis of manufactured APl's are not conducted.

-~-~
EMPLOYEE(SJ NAME AND Tl 11.£ (Pt111I 01 Type) OATEISSUEO

01/28/ 2 020
Dipesh Shah, cso
Aditi Thakur, Chemist

V"\
I
rrf~
FOR~I FOA 48J (09108) l'RlMOVS EDITION OBSOLETE INSPECTIONAL OBSERVATIONS PAGE 6 OFS PAGES
 DEPARTMENT OF HEALTH ANO HUMAN SERVICES
FOOD AND DRUG ADM INISTRAT ION
DISTRICT ADDRESS AND PHONE NUMBER DATE(S) Of INsPECTION

12 420 Parklawn Drive , Room 2032 01/20/2020 - 01/28/2020

FEINUMBER
Rockvil le , MD 2085 7
3002949085
ORAPHARMinternational483responses@fda . hhs.gov
NAME ANO mlE OF 1/'i!l1v10t1AL TO WHOM REPORT ISSUED

Mr. Arun Gupta , Vice President & Location Head

FIRM NAME STREET ADDRESS

Dr . Reddy's Labo ratories Limited CTO APIIC Industrial Estate, Pydibhimavarama

Unit VI (Village)
CllY,$TArt;, Z.IP cooe. COVNTRY TYPE ESTABUSHMEN T INSPECTED

Sr ikakulam District, Andhra Pradesh, API Manu facturer

India

Specifically, no trend analysis was conducted on peaks related to 4 > Jin the film 's rn
manufactured AP Is. Your firm has approximately nineteen ( 19) incidences mat were found
during our review of the residual solvent from 2018 - 2019.

OBSERVATIONS
Your Quality Unit lacked oversight of your quality documents.

Specifically,

A- On January 24, 2020, while we were reviewing the issued I retrieval and reconciliation of
documents, we observed that that your firm's booklets for document titled 'Phase 1
Laboratory Investigation' in 2019 three (3) booklets were destroyed, in 2018 two (2) booklets
were destroyed and in 2017 two (2) booklets were destroyed. In one instance the firm was
missing sequence number page 186 of the investigation. These booklets are used to
document yow- film 's OOS investigations.
41
B- On January 27, 2020, while we were reviewing analytical method transfer from 'lbH l to
4
your firm, we discovered that the initial method transfer otjb>< > 'API for residual solvent
was performed on July 1, 2009. That method transfer is incomplete because it lacked
analytical test conclusions, test results, etc.
C- On January 27, 2017, we reviewed Specification and Method of Analysis fortb>< >
4 1
4
.J
USP with specification numbel>< > and found that the system suitabihty criteria
4 4
is less than lb>< > % RSD fod b>< > ,USP peak standard injection. However, during
review of the Method Validation, Addendum R~£ort Number TDC/ ARD/MV~<bll > 002
4

stated that the method is validated for less thanrCbrt-4> % system suitability requirement without
any documented justification.
D- On January 25, 2020, we observed that sample 'lbH4> Jbatch #tb><4> I3-month
intermediate stability sample was not available. According to firm 's records the sample was
not tested.

E"IPLOVEE(S) NAME AND nn.E (hmt or Type) DATE ISSUED

01/28/2020
Dipesh Shah, CSO
Aditi Thakur, Chemist

FORM .-OA 483 t09/08) PREVIO~ EDITION OOSOL£TE I NSPECTIONAL OBSERVATIONS PAGE 7 OF 8 PAGES
 DEPART M ENT OF HEALTH ANO HUMAN SERVICES
FOOD AND DRUG ADM INISTRATION
OISll'JCT ADOllESS ANO PliONE. NUMBER OATE(S)OF INSPECTION

12420 Parklawn Drive , Roo m 2032 01/20/2020-0 1 /28/2020

FEI NUMoER
Roc kville , MD 20 857 30029 4 9085
ORAPHARMinter nat ional483 r e spon ses@fda . hhs. gov
l-1aAND llTl.C OF IKOIVIOUM. TOWHOt.1 REPORT ISSUED

Mr. Arun Gupta , Vice President & Loca tio n Head

FIRMNAMc STREET ADDRESS

Dr . Reddy ' s La b oratories Limited CTO APIIC I ndustrial Estate , Pydibhimavarama

Unit VI (Vill age)
Cl1Y STATE" ZIP COOi'. COUNTRY lYPE ESTABUSHMENT INSPECTED

Srikakul am Di str i ct, Andhra Prades h, API Manufacturer

Indi a

Dates of Inspection:
January 20, 2020; January 21, 2020; January 22, 2020; January 23, 2020; January 24, 2020;
January 25, 2020; January 27, 2020; January 28, 2020

EJ,fPLOYEli(S) NAME AND T111.E {Poor or TYi»! DATE ISSUED

01/28/2020
Dipesh Shah , CSO
Aditi Thakur, Chemist

FORM FDA 483 (09/08) PREVIOUS EOmON OBSOLETE INSPECTJONAL OBSERVATIONS PAGE 8 OF 3 PAGES