DEPARTMENT OF HEALTH AND HUMAN SERVICES FOOD AND … · Dr. Reddy's Laboratories Limited CTO APIIC...

DEPARTMENT OF HEALTH AND HUMAN SERVICES FOOD AND DRUG ADMINISTRATION

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

12420 Parklawn Drive, Room 2032 01/20/2020-01/28/2020 Rockville , MD 20857 FEINUM8ER

ORAPHARMinternational483respo111::>e1::>@fdc1 . hh1::>.yov 3002949085

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 EST A8USHMt 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.

Specifically, your process validation fortti11

'1

• 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) and are approved OOSs were rejected and of these batches were

for shipment.tb><4> batcnes are awaiting to be tb>r•)

Your firm reported a full-scale investigation summary report OOS # 310018090 on November 30, 2019 to investigate the failure batches of<4> content inlbH4

> I <

4> The OOS evaluated an out of specification result for1b1141 by Gas

Chromatography for batch # ll>HilJ That investigation concluded that a correction with an issue with the (b><

4> was rectified and no similar incidents were

reported. Additionally, "no impact on the further batches execution." However, batches

/1

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

01/28/2020 Dipesh Shah, CSO

~.Pt Aditi Thakur, Chemist

t 'ORM fllA 483 (U9/08) PREVIOUS EOmON OOSOt.ETE INSPECTIONAL OBSERVATIONS PAGE I Of 8 MOES

DEPARTMENT OF HEALTH AND HUMAN SERVICES 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 Rockville , MD 20857 fEll<UM6fR

ORAPHARMinternational483respo nses@ f da . hhs . gov 3002949085

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:

Notification Date Batch Number (b)(4) I

Number Observed Content (ppm) - (b)(4)

December 3, (b)(4) (b)(4)

1--1 2019 December 23, r

(b)(4~

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:

Notification Initiated Category Batch Number (b)(4J

I Number Date Content

- -cb~~pm) (b)(4) October Incident

'(b)(4)

H 3,2018 ..._ ,_ August oos

- 13, 2019

I ,___

August Incident I ,_ 20,2019 lot::: r

I August Incident (DJ(4) l (b)(4)

and 20,2019

(b)(4)

~o~ EJJPl..OVEEJ~JNAME A.NO nTt.E (Pr'"' ot t yp.J OATE ISSUEO

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

DISTRICT DRESS AND PHONE NUMBER

DEPARTMENT OF HEALTH AND HUMAN SERVICES FOOD AND DRUG ADM INISTRA TlON

1DATE(SJ OF 1rlSPECTfON

12420 Parklawn Drive, Room 2032 01/20/2020 - 01/28/2020 Roc kville, MD 20857 ORAPHARMint e [email protected] NAf.\EAND nne OF lllOIVIOUAL TOWHOM REPOllT ISSUED

Mr. Arun Gupta , Vice Presiden t & Location Head ARM NAME STREET ADDRESS

FEINUMBER

3002949085

Dr . Reddy's Laboratories Li mi ted CTO Unit VI

APIIC Industrial Es tate , Pydi bhimavarama (Village)

Cl"IY STATE. ZIP CODE.. COUNTRY

Srikakulam District, Andhra Pradesh, India

TYPE ESTABLISHMCNT INSPECTED

AP! Manufacturer

Your firm continues to have recurrent failures fo tt>><4

> 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,

1. For OOS # 310018104 and Incident # 200338632 the initial investigation for"b><4> batch

H4

> 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 r) <4> fo an the root 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 failed for residual solvent <4> content lbll4> ppm with release specification 0£<4>

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 which was initially identified to be'<4> % initially identified tobettie samp e. The resampled results were discarded with documented justification.

. MW -~ 2. OOS # 310017867 with report date October 17, 2019 for batch # an OOS result was reported forFH4

> 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 specification limit of lb><4> ppm. Your firm only performed a laboratory investigation. The documented most probaole root cause was determined to be cross contamination of the

FORM FDA 483 (09/081 PREVIOUS EDITION OBSOLETE

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

Dipesh Shah, CSO Aditi Thakur, Chemist

INSPECTIONAL OBSERVATIONS

DATE ISSUED

01/28/2020

PAGE 3 OF 8 PAGES

DISTRICT ADDRESS J'.NO PHONE NU'111ER

DEPARTMENT OF HEAL TH AND HUMAN SERVICES FOOD AND DRUG ADMINISTRATION

l>ATE(S) OF INSPECTION

12420 Parklawn Drive, Room 2032 Rockville, MD 20857

01/20/2020- 01/28/2020 FEI NUMBER

ORAPHARMi nternational 483responses@fda . hhs .gov 3002949085

NAME ANI) TlTI.E OF INDIVIDUAi. TO WHOM REPORT ISSUED

Mr. Arun Gupta, Vice President & Location Head FIRM NAME STREET AOORESS

Dr. Reddy ' s Laboratories Limited CTO Uni t VI

APIIC Industrial Estate , Pydibhimavarama (Village)

CITY, STATE. ZIP CODE, COUNTRY

Srikakulam Dis trict , Andhra Pradesh , India

TYPE E TABUSHMEN"l INSPECTED

API Manufact urer

weighing balance or the micropipette during laboratory analysis without an investigation in the manufacturing area.

3. OOS# 310016984 with report date April 05, 2019 for '<4> [(llb l14l . (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 .... NLT: <4> % and NMT: '<4> %. The investigation revealed to be instrumentation failure. A re-analysis was condµcte on April 05, 2019 in which results were found not meeting specifications '<4> <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. B. During the inspection we observed that your firm did not initiate investigations for '<

4>

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 . . . .c .d I I (b><4> mvestt at1ons ior res1 ua so vents states

WW (bl(4l consistently". Batcnffl as d ~h <4> - a--·--· - .- d d Th . . . h etermmea to . ave n no mvest1gat1on was con ucte . e mvesttgatton states t at these unknown pea s appear to be isomers o ~b><4> nd no investigation was conducted.

C. Risk Assessments titled 'Assessment of'!bll4> 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{<4>

lbll4> and othertb><4> ; mpurity in <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>

lbll4> tOr\JiliteaState bound pro ucts. our firm has

shipped multiple Datches o .<4> A.Pl's to United States and it appears that your costumers were not notified.

FORM rnA 483 IMIU8) l'REVIO\-S WITIOs 06SOLnE

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



DATE ISSUED

01/2 8/2020

PAGE~ OF 8 PAGES

DEPARTMENT Of HEALTH ANO HUMAN SERVICES FOOD AND DRUG ADMINISTRATION

OATE(SJOf' INOf'ECTlON

12420 Parklawn Drive , Room 2032 Rockvi lle , MD 20857

01/20/2020-01/28/2020 FEJH\MER

3002949085 [email protected]. gov NAME /HJ TITlE OF INOIVIOUo\I. TO WHOM ~T ISSUEO

Mr. Arun Gupta , Vice President & Location Head FIRMIW.'E STREET AOOR£SS

Or . Reddy' s Laboratories Limited CTO Unit VI

APIIC Industrial Estate, Pydibhimavarama (Village)

CITY, sr .. re. ZP COO£. COUNTIIY

Srikakulam District , Andhr a Pradesh, India

OBS ERV A TI ON 3

fYPt; t$1 "Ill. ~MtNl IN:>PtCTtoD

API Manufacturer

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

'. However, your cleaning validation report, CVP/<DH•> 115/001 , 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<4> s closed with the execution of <

4> 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><

4> during the cleaning validation done in February

17, 2017. He further stated the'<DH4> batch ofi1b1141 hat the firm manufactured was on September l 0, 2018. The firm manufactured <4

> ~atches of<4> in 2018, lb><4>

<4 in 2019 and ~t>n•> batches in 2020 without conducting a cleaning vauaanon wnn<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.

FORM FDA 48l (0910S) PREVIOUS EDITION OOSOlfTE

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



O"TEISSUEO

01/28/2020

PAGES OF~ PAGr.S

DEPARTMENT OF HEALTH AND HUMAN SERVICES FOOD AND DRUG ADM INISTRATION

DISTRICT ADDRESS AND PHONE NUM8ER DATE(S) Of •"lSPECTlDN

12420 Parklawn Drive , Room 2032 01/20/2020- 01/28/2020 Rockvi l le, MD 20857 Fel NUMBER

ORAPHARMinternational483responses@fda . hhs.gov 3002949085

NAME ANO TITLE OF INDIVIDUAi. TO WHOM RePORT 1ssueo

Mr. Arun Gupta, Vice Pres i dent & Location Head FIRM NAME STREeT ADDRESS

Dr . Reddy's Labo r atories Limited CTO APIIC Industrial Estate, Pydibhimavarama 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 D . . . b d th h fi h tbH4l nknown peaks related to tbJ 141 . unng our review 1t was o serve at t e 1rm as1

'<bH41 jDbserved in the analysis o :ci>n41 JAPI

tb)(4)

I dd. . h fi h d dlbH41 n a 1tton, t e 1rm as recor e ~nknown peaks in other manufactured AP Is

jr f(4J hich are pending applications in United such as States.

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

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

01/28/2020 Dipesh Shah, cso

rrf~ Aditi Thakur, Chemist

V"\ I

FOR~I FOA 48J (09108) l'RlMOVS EDITION OBSOLETE INSPECTIONAL OBSERVATIONS PAGE 6 OFS PAGES

DEPARTMENT OF HEALTH ANO HUMAN SERVICES FOOD AND DRUG ADMINISTRATION

DISTRICT ADDRESS AND PHONE NUMBER DATE(S) Of INsPECTION

12420 Parklawn Drive , Room 2032 01/20/2020- 01/28/2020 Rockvil le , MD 20857 ORAPHARMinternational483responses@fda . hhs.gov

FEINUMBER

3002949085

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 Unit VI

APIIC Industrial Estate, Pydibhimavarama (Village)

CllY,$TArt;, Z.IP cooe. COVNTRY

Sr ikakulam District, Andhra Pradesh, India

TYPE ESTABUSHMENT INSPECTED

API Manufacturer

Specifically, no trend analysis was conducted on peaks related to rn4> Jin the film's 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.

B- On January 27, 2020, while we were reviewing analytical method transfer from'lbH41l to

your firm, we discovered that the initial method transfer otjb><4> '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> .J USP with specification numbel><

4> 1and found that the system suitabihty criteria

is less than lb><4> % RSD fod b><4> ,USP peak standard injection. However, during review of the Method Validation, Addendum R~£ort Number TDC/ ARD/MV~<bll4> 002 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> I 3-month intermediate stability sample was not available. According to firm's records the sample was not tested.

FORM .-OA 483 t09/08) PREVIO~ EDITION OOSOL£TE

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



DATE ISSUED

01/28/2020

PAGE 7 OF 8 PAGES

OISll'JCT ADOllESS ANO PliONE. NUMBER

DEPART MENT OF HEALTH ANO HUMAN SERVICES FOOD AND DRUG ADM INISTRATION

OATE(S)OF INSPECTION

12420 Parklawn Drive , Room 2032 01/20/2020-0 1/28/2020 Roc kville , MD 20 857 ORAPHARMinter nat ional483r e sponses@fda . hhs. gov l-1aANDllTl.C OF IKOIVIOUM. TOWHOt.1 REPORT ISSUED

Mr. Arun Gupta , Vice President & Loca tion Head FIRMNAMc STREET ADDRESS

FEI NUMoER

3002949085

Dr . Reddy ' s La b oratories Limited CTO Unit VI

APIIC I ndustrial Estate , Pydibhimavarama (Village)

Cl1Y STATE" ZIP COOi'. COUNTRY

Srikakul am Di str i ct, Andhra Pradesh, Indi a

Dates of Inspection:

lYPE EST ABUSHMENT INSPECTED

API Manufacturer

January 20, 2020; January 21, 2020; January 22, 2020; January 23, 2020; January 24, 2020; January 25, 2020; January 27, 2020; January 28, 2020

FORM FDA 483 (09/08) PREVIOUS EOmON OBSOLETE

EJ,fPLOYEli(S) NAME AND T111.E {Poor or T Yi»!

Dipesh Shah , CSO Aditi Thakur, Chemist

INSPECTJONAL OBSERVATIONS

DATE ISSUED

01/28/2020

PAGE 8 OF 3 PAGES

DEPARTMENT OF HEALTH AND HUMAN SERVICES FOOD AND … · Dr. Reddy's Laboratories Limited CTO APIIC...

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