Cadila Healthcare LTD India 050319

DEPARTMENT OF HEALTH AND HUMAN SERVI CES
FOOD AND DRUG ADMINISTRATION

D ISTRICT ADDRESS AND PHONE NUMBER DATE(S) OF INSPECTION
1 2 4 20 Parklawn Drive, Room 2032 4/22/2019- 5/3/2019*

Rockville, MD 2085 7 FEJ NUMBER
3002984011
NAME ANO TITLE OF INDIVIDUAL TO WHOM REPORT ISSUED
Umesh Kumar Gupta, Campus Head

F IRM NAME STREET AOORESS
Cadila Healthcare Limited 419 & 4 20 8a Village - Moraiya

C ITY. STATE. Z IP CODE. COUNTRY TYPE ESTABLISHMENT INSPECTED
Ahmedabad, Gujarat, 38221 0 India Drug Manufacturer
This document lists observations made by the FDA representative(s) dtu-ing the inspection of yom· facility. They are inspectional
observations, and do not represent a final Agency detennination regarding your compliance. Ifyou 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) dtumg the inspection or submit this information to FDA at the address above. If you have any
questions, please contact FDA at the phone ntunber and address above.
DURING AN INSPECTION OF YOUR FIRM WE OBSERVED:

OBSERVATION 1
Equipment and utensils are not cleaned an d maintained at appropriate intervals to prevent contamination
that would alter the safety, identity, strength, quality or purity of the diug product.
1. Residues were observed on surfaces of cleaned n.ir equipment. Cleaning procedures do not
include provisions for routine cleaning or inspection of the (6} C41 duct area.
a. Non-dedicated b>C4> equipment CH/TS/013 had residues in the b>C4> duct an d on the
back of the C6H > on April 24, 2019. The equipment was identified as clean . This
tfi' - (.iP
,, ' equipment has been used in the manufacture of tablets with
b)l('f
""in_g_1-·e-d-ie-nts including DfC'I
(b) (4)
. Tablet batches of b) <4> .....
b)(4) ___________
_.
, and
----- manufactured on this equipment have been distributed to the US market.
b. Non-dedicated 6><4> equipment CH/MC/TAB/1999/19 had residues in the lb) ('f) duct
and on the back of the (bf('f) on April 24, 2019. QC testing detected the presence of
the following APis in the residue: (b) C> 6H4> , bf('f (' 6)1..f)
{6f(i11 {6f(i11 b) (4) b) (4) b) ( ) --
(b) (4) (4)
EMPLOYEE($) SIGNATURE DATE lSSUEO
SEE REVERSE Justin A Bo yd, Investigator - Dedicated 5/3 /2019

OF THIS PAGE Drug Cadre
Thomas J Arista, National Exp ert x
=91' --DnJg
A8'1AEIC¥':
~.:..,~ .......
Rita K Kab aso, Office of International
Programs Employee
FORM FDA 483 (09/08) PREVIOUS EDmON OBSOLETE INSPECTIONAL OBSERVATIONS PAGE 1 of 23 PAGES
DEPARTMENT OF HEALTH AND HUMAN SERVICES

FEJ NUMBER
Rockville, MD 2085 7
3002984011

Cadila Healthcare Limited 41 9 & 4 20 8a Village - Moraiya

c. Non-dedicated 6><4> equipment CH/MC/TAB/2009/333 had >(.iJ) residues on

the back of the bH 4> of the )(.iJ) duct on April 24, 2019. Additionally, bf(.iJ
paiiicles were observed on the front side of the ><4 > and on surfaces in the (b) <4>
. The equipment had been cleaned and the previous product manufactured was
(b) <4> tablets, a {fif(.iJ) product. This tbT(.il) equipment has been used to
manufacture tablet products for the US mai·ket including, but not limited to: bf(.iJ
----
t6f<.i11 and (bf(.iJ
d. Non-dedicated 6><4>
'
---
equipment CH/PM/013 had white colored residues in the b)(.iJ)

ductm on April 24, 2019. The equipment had been cleaned. This f<.iJ equipment has
been used to manufacture tablet products for the US mai·ket including, but not limited to:
I6f<.i11 bf(.iJ and >(.iJ)
------- -------' -------
e. Fmiher investigation conducted by the quality unit identified visible
traces/stains/smear/powder in the bf(.iJ duct or 16)1.iJ) on cleaned 6f<'I
equipment CH/MC/TAB/1999/27, CH/MC/TAB/2004/176, CH/MC/TAB/1999/11,
CH/TT/005, CH/TF/004, CH/TE/071 , CH/PP/082, and CH/PG/014. These pieces of
----
equipment were non-dedicated and used to manufacture tablet products for the US market.
2. stopper bowls used on parenteral filling line~> were observed to have unsmooth
,_ __. stopper contact surfaces, including scratches and dents. Both stopper bowls were tagged
as clean and wrapped for entry into the aseptic processing ai·ea on April 29, 2019. Each
contained black residues that could be removed with fmiher wiping.

OF THIS PAGE Drug Cadre JU6t'IABoyd
~or - Dedlca1edDn.IJ
Thomas J Arista, National Expert x gy:o,,:r..,~ .......

Programs Employee
1 2 4 20 Parklawn Drive, Room 2032 4/22/20 1 9- 5/3/201 9*

Rockville, MD 20857 FEJ NUMBER
3002984011

Cadila Healthcare Limited 41 9 & 4 20 8a Village-Moraiya

Ahmedabad, Gujarat, 38221 0 I ndia Drug Manufacturer
3. Thef1»<4> I chute that is used during the manual transfer of the sterile b) <4> I
stoppers during the aseptic filling process appears to have some f01m of visible scoring on the~)
surface, there are several dents on the~ body and the chute's inlet and outlet po1ts have rough
and uneven edges that are not smooth, cleanable surfaces.
4. Manufacturing equipment includingr» <4> I were observed to contain visible dents on

the exterior and interior surfaces of the equipment. A mallet is used on the exterior surface of the
f6H~1 I to remove diug product adhered inside the flif<'IJ I.
OBSERVATION 2
Procedures designed to prevent microbiological contamination of diug products purpo1ting to be sterile
are not established and followed.
1. Procedure 0301-SOP-MFG-00506 "Guidelines for Working in Aseptic Area" requiring operators

to not lean over sterilized containers or closures and not to obstmct laminar air flow was not
followed:
a. During stopper addition for J6><4> I injection batchp>n'fr - i on

April 22, 2019, the operator passed their hands over the opened bag of sterile stoppers
during bag flif<'n! and handling. When the stoppers were poured into the stopper chute,
the operator's hands were over the sterile stopper chute.
b. During filling of~t>f('f)

1
~iction batch bf('f
interventions to remove a fallen vial at the ~(b) < > vial~(b) < >
4 4
there were six
. During the
intervention, the operator used the restricted access baiTier system (RABS) fb>('f)l to
reach over open, sterile vials at the via1p>f<'lJ 1- These vials were not cleared. The
SEE REVERSE Justin A Boyd, Investigator - Dedicated 5/3/201 9

OF THIS PA GE Drug Cadre JU6t'IABoyd
Thomas J Arista, National Expert x ~~~9 104056

Rita K Kabaso, Off ice of I n ternational
Programs Employee
1 2 4 20 Parklawn Drive, Room 20 3 2 4/22/20 1 9- 5/3/201 9*

300298 40 11
Umesh Kumar Gupt a, Campus Head

Cadila Healt hcare Limit ed 419 & 4 20 8a Village - Moraiya

Ahmedabad, Gujarat , 38 22 1 0 I ndia Drug Manufact urer
Non t>H4 > Quality Assurance Deputy General Manager confamed the iCt>H4 > I are not
sterile an d operators are pe1mitted to use thern.ir>l above empty sterile vials without
requiring the need to clear the vials.
2. During the aseptic filling operations perfo1med in Fill Line~ , we observed personnel enter into
and out of the Grade A area via the r ><4> Iglass vial conveyor that is positioned subsequent
the glass vial stoppering process (Note: there is a similar glass vial conveyor system for Fill Line
~ & ). We observed this activity on numerous occasions with the 6}{'1) RABs access f6f<"11
remaining open for approximately 3 to 4 Ininutes at a time. There is no SOP an d/or language in
the manufacturing batch record to describe and establish the manner of how personnel access an d
personnel activities are to be perfo1med while in the Grade A conveyor area.
OBSERVATION 3
Procedures designed to prevent microbiological containination of diug products purpo1ting to be sterile
did not include adequate validation of the aseptic process.
Regarding th~ a_§~Qtic 12rocessing simulation of the b) <4 > I process, not all media filled vials are
4
subject to the f6l < > ·---, steps in that the media filled vials that are exposed during the fill room
operators' manual interventions are removed from the batch of the media filled vials. In addition;
1. The media filled vials that are removed during the manual interventions and culled from the
media filled batch and are not subject to the routine aseptic filling process. For example, media
fill batch numberf6Jrt> I dated Januaiy 16, 201 9 documents the removal of 1,328 media
filled vials. The production operator and Senior Executive explained that the 1,328 media filled
via_ls were placed on a _collection{~) under LAF conditions, which is the location where the
)l
f6>14 stoppers are ~6>l41 f, manually, on the glass vials. Following the manual process of
SEE REVERSE J u stin A Bo yd, Investigato r - Dedicated 5/3 / 20 1 9

OF THIS PAGE Dr u g Cadre JU6t'IABoyd
Thomas J Arist a, Nat ional Expert x ~~~9 104056

Rita K Kab aso, Off ice of I n t ernat ional
Pr o grams Employee
12 420 Parklawn Drive, Room 2032 4/22/20 1 9- 5/3/201 9*

FEJ NUMBER
Rockville, MD 20857
3002984011

Cadila Healthcare Limited 419 & 420 8a Village - Moraiya

Ahmedabad, Gujarat, 382210 India Drug Manufacturer
(b) <4> the (b) <4 > stoppers on to the media filled vials, they are trnnsfen ed to an
4
(b) < > that feeds into the vial 6 ><4 > station. The aforementioned manual
operations and processing steps are not prut of the routine aseptic filling process for lb) (..f)~-
finished chu g products;
2. The above ractice is commonly perfo1med for all media fill simulations perfo1med in
16>141 Facility~ e.g.
Batch number #o culled units

6f('I 881
6f('I 1354
6f('I 652
6f('I
737
6f('I
1292
b)(4)
1262
1332
OBSERVATION 4
Aseptic processing areas ru·e deficient regarding air supply that is filtered through high-efficiency
pruticulate air filters under positive pressure.


Rita K Kabaso, Office of International
Programs Employee
D ISTRICT ADDR ESS AND PHONE NUMBER DATE(S) OF INSPECTION

3002984011

Cadila Healt hcare Limited 41 9 & 4 20 8a Village - Moraiya

1. The Airflow Visualization Test Protocol cum Repo1ts (aka smoke studies) acceptance criteria
includes '~) turbulence should be observed. Laminar visible smoke I air flow should be
maintained inside the LAF. The visible smoke I air should move from the working zone to
,ol_!tside area ." J\nd, ~·qing the acceptance criteria. dring-Je material transfer from the
ft>J C4)I zone to f6>141 I,ft>J C'frl to filling room and (6} <4> zone to filling room, is as follows.
The visible smoke I air should move from more critical area to less critical areas immediately
while opening the 16>141. However, there are a number of instances where either the personnel
activities and/or production related equipment block the ability to view the laminar air flow, for
,e~am~he video does not capture when personnel are removing the stoppered vials out of the
ft>J <41 1, the personnel activities impact upon the laminar air flow, or the impact on the
laminar air flow when moving equipment. In addition:
a. The air flow pattern evaluations for line~ demonstrnted air flowing~~) the stopper addition
l
chute and creating turbulence where the laminar flow p>> <4 > the stopper addition air meets
with the air flowing~~ of the stopper chute.
b. The air flow pattern evaluations did not include an assessment of the air flow when manually
transfening the f6><4> I media filled glass vials from the fill line to ~6>141 I 2.
c. There is no air flow pattern evaluation perfo1med to dete1mine the ~!!!pact upon t_he laminar
airflow during the movement of the mobile transfer unit from them_J zone to ft>J<4>j.
d. There is no air flow pattern evaluation pe1fo1med to ensure that the movement of HEP A
filtered air from the Grade B does not enter into the Grade A fb)('l) I area.
e. There is no air flow pattern evaluation for the routine intervention of removing fallen vials at
the vial flif<"J I using the RABS f6>1")1 .
SEE REVERSE Justin A Bo yd , Investigator - Dedicated 5/3 /2019


Rita K Kab aso, Office of I n ternational
Pr ograms Employee
1 2 4 20 Parklawn Drive, Room 20 3 2 4/22/20 1 9- 5/3/201 9*

FEJ NUMBER
300298 40 11
Umesh Kumar Gupt a, Campus Head

Cadila Healt hcare Limit ed 419 & 4 20 8a Village - Moraiya

Ahmedabad, Gujarat , 38 22 1 0 I ndia Drug Manufact urer
2. The air pressure differential readings are obtained i(b) <4 > during the fb) <4 > I I
manufacturing bf< ~ . For examp~roduction 012erator exolained the air pressure readings are
4
taken at the p>><4 > However, there are no air I.

pressure measurements taken during a dynamic state of manufacturing operations. In addition;
a. Analog i(b) <4 > I gauges are used to measure/monitor the air pressure differentials between
the controlled an d classified manufacturing areas. The individua1p>f<4 J Igauges are not
connected (e.g., computer based system) in a manner to collectively monitor all of the air
pressure differences in a dynamic state of operation. The manner of monitoring real time air
pressure differentials via the use of the analog f6H~1 I gauges during routine
manufacturing operations in the controlled and classified manufacturing areas is not cmTent
good manufacturing practice technology.
b. There is no record to document the mm of water column air pressure differentials are
maintained durino routine aseptic filling operations to demonstrate that the requisite air
pressures (e.g., ~(6)C~)I positive air pressure to less positive or negative air pressures) are
appropriately sustained.
c. There are ~Al trnnsfer~t>f('fr-i used to move ml!.terial into and/or out of the controlled and
,cl~ssified manufactur1~~as. The trnnsfer~6) <">! without an air flow unit (aka static
)1
f6J <4 and do not f6f<"1 ) do not have an air pressure monitoring device (e.g.,
analog/digital gauge) and there is no record to document that the appropriate air pressures are
maintained i.e., the lesser quality of air (non-classified) does not ingress into the controlled
and classified manufacturing areas.
3. On filling line ~~ , the stoppered filled glass vials are conveyed under Grade A conditions
following the aseptic filling as they trnvel to the vial capping station located in room 11,t6J ('f)J
(Grade C). As the stoppered vials enter the capping station the they are no longer in a Grade A
environment. Rather, the Senior Man ager Quality Assuran ce explained that the air is intended to
SEE REVERSE J u stin A Bo yd, Investigato r - Dedicated 5/3 / 2 01 9

OF THIS PAGE Dr u g Cadre JU6t'IABoyd
Thomas J Arist a, Nat i o nal Exp ert x ~~~9 104056

Rita K Kab aso , Off ice o f I n t ernat i o nal
Pr o grams Emp l o yee

FEJ NUMBER
3002984011


be unidirectional with no specific classification of the air;
There is no scientific rationale to suppo1t not maintaining the stoppered glass vials under Grade
A conditions prior to the capping process.
OBSERVATION 5
Aseptic processing areas are deficient regarding the system for monitoring environmental conditions.
f. The EM b'end data documents recmTing microbial contamination via the personnel monitoring
program. The EM data reveal ce1tain individuals who appear to be a somce for the Bacillus and
Pseudomonas microbial contamination in the Grade B and Grade A manufactming areas. The
data shows the Grade B conidor used to access fill lines ~ and~~) may be a route of
contamination to the Grade A areas. Effective actions have not been taken to address these
recmTences.
g. Thorough assessments to establish rationale for viable environmental monitoring limits,

frequencies, and locations have not been documented. For example, the assessments lack
documented rationale for the following:
a. The personnel working with their body 6} {'J) inside of the Grade A stopper addition area
aseptically open bags of sterile stoppers and add sterile stoppers via a sterilized chute.
The operator is held to Grade B limits dming personnel monitoring. This allows for~
CFU on the operators hands without requiring any additional action.
b. There is no viable air monitoring via settle plates or active air sampling of the Line b)
Grade A conveyor areaf6l {'J)I the stoppering station and the capping room. A smface


Pr ograms Employee

3002984011


monitoring sample is taken in this area (b) <4> per (b) <4> , although filling can occur up to
16)1"11 a 16)1"11 . Personnel move through this area with their >("I) body in the Grade A
area and the banier 6}1"11 were observed to remain open to the Grade B areas for
approximately 3-4 minutes.
c. Monitoring of sterilized tools including the (b) <4> used for aseptically opening stopper
bags, the sterile rod for removing stuck stoppers, and the sterile forceps for removing
fallen or jammed stoppers and vials are only conductedJCfif('f) per 6}-C4> . Batches could be
filled up to ~Al times per 6) {'I) . Additionally, there are~ forceps located in the Grade A
filling banier and the personnel perfonning monitoring chooses one forceps at random.
They do not document which forceps is chosen for sampling.
d. Viable air monitoring in the Grade A bf('f zone where the fi) <4> is unloaded and
4
filling machine paiis are stored is Grade A is only conducted Cb) < > per C6}l"11 .
e. Procedures and environmental monitoring records lack descriptions of the locations to be

sampled. For example, the Grade A (bf('f in the stopper addition is to be
monitored, but the location is chosen at random. Sampling of Grade B floors and walls is
done at random. The location chosen is not documented.
h. Non-viable paiiicle (NVP) measurements are taken in the Line~ Grade A glass vial conveyor
area 6)141 the stoppering station and the capping room. However, the NVP probe is located
16)1"11 (approximately f('f ) away from the personnel access ai·ea and the NVP data does
not accurately reflect the NVP levels when personnel enter and/or exit the Grade A glass vial
conveyor ai·ea.
i. NVP measurements ai·e taken during routine aseptic filling process of the bf('f mug


Pr ograms Employee
12420 Parklawn Drive, Room 2032 4/22/20 1 9- 5/3/201 9*

3002984011


Ahmedabad, Gujarat, 382210 I ndia Drug Manufacturer
products via the use of stationaiy and mobile po1table NVP monitoring equipment. During the
loading of the 6 ><4 > glass vials into the >(.iJ) the NVP measurements are
4 4
obtained (i.e., d bH > batch (b)( ) per )(.iJJ during the loading" of the lb)(.iJ) ) via the use of
po1table mobile NVP monitoring equipment. However, the batch manufacturing records (BMR)
do not document the time (as confamed by Manager Quality Assurance) when the NVP
measurements ai·e taken during the loading of the th> <4> glass vials into ~><"'4""
> --
to conoborate and ensure that the (bf(.iJ open vials are maintained in a Grade A
environment. In addition:
a. The "Monitoring of Non Viable Paiiicles Count" document # SOP MFG-01153 instrncts
to "Take the particle count under the HEPA filter and are at operational height ... ".
However, the SOP is silent with respect to establishing the manner of how the NVP probe
should be positioned; and,
b. The SOP is deficient with regards to establishing what specifically constitutes an

"operational height" and there is no specific description of where exactly the NVP
monitoring should take place in the 6>rt Grade A ai·ea .
J. In l6 f<.i11 the {fif(.iJ) aseptically filled glass vials are manually transfened
from the filling equipment to the (b) <4> via the use of a b) <4> Semi-Automatic
~ Loading Trolle . The NVP isokinetic probe ~> (.iJ ) is pos1honeo approximately b) <4 >
(approximately ><4 > ) from the mobile trolley's HEPA filter face. The NVP probe is not
positioned or located near the work surface. Rather, the isokinetic 12robe is positioned such that
the toQ of the 6f(.il is approximately (bf<4
---- vials;
(approximately 6f( ) away from the 6f(.il
---


Rita K Kabaso, Office of I n ternational
Programs Employee
DE PARTMENT OF HEALTH AND HUMAN SERVI CES
1 2 4 20 Parklawn Drive, Room 20 3 2 4/22/2019- 5/3/2019*

FEJ NUMBER
300298 40 11


During the qualification of the semi-automatic loading trolley, the Senior Manager Quality
Assurance, explained that the NVP measurements were obtained via the use of a mobile paiiicle
counter. However, the location an d/or placement of the isokinetic probe is unknown.
OBSERVATION 6
The production ai·ea air supply lacks an appropriate air filtrntion system.
The Vice President Projects & Engineering described the "As Built" diagrams for HVAC reflect all
changes made in the specification an d working diagrams during th e constrnction process, which include
the exact dimensions, geometry an d location of all elements of the work. However, there are no "As
Built" engineering diagrams for the air handling units that supply air into Fill Lines ~ ('l~ an d
f6>l41 I manufacturing facilities that are used to manufacture aseptically fil ea1ims ed chug
commodities. In addition;
4. There are approximately ~l air handling units in the a~froximate lif< square meter building
that contain the aseptic fi lmg lines in the parenteral an d t>) <4 > manufacturing facilities.
The building also houses, for example, the manufacturing operations for the tablet, aerosol,~~)
andr» <4 > I,c~Rsules (b) <4> and fb> <4> I OJ)erations. Notwithstan ding the aseptically
filled sterile and ft>J <4J injectables, there are (bf<4> l Rhaimaceutical collllllodities that
are manufactured in tablet facility~~ , tablet facility <~~J, and~b) <"> I. The ft>J <4> I
6 4
chugs and f >l J I are summarized as follows;
M edicinal Products I ~<b> <4> L
lif('l)


Rita K Kab aso, Off ice of I n ternational
Pro grams Employee
FORM FDA 483 (09/08) PREVIOUS EDmON OBSOLETE INSPEC TIONAL OBSER VATIONS PAGE 11 of 23 PAGES

3002984011


bf('l)
There are no "As Built" engineering dia&!·ams to ensure that the return air from the production
areas that are used to manufacture the >('l) _j diugs do not enter an d/or connect to the air
a
ducts for the air handling unit used for tlie aseptic filling processes;
5. There is an "As Built" engineering diagram for the fbf<'l> air ducts, that is, diagram
4
#TTT-DRG-0506-46-03 dated 11.02.06. The Head of Non (b) < > Quality Assurance Deputy
General Manager confomed that the individuals that reviewed an d approved the "As Built"
diagram no longer work at the company and the cun ent ~ali!Y Unit has not reviewed and
approved the 11.02.06 dated "As Built" diagram for thep>> ('l Ioperations.
OBSERVATION 7
Failure to maintain a backup file of data entered into the computer or related system.
Regarding the 6fC'IJ I

process the SCADA (Supervisory Contrnl and Data Acquisition) computer
system monitors ano controls the f6l ~ I processing parameters an d should there be abe1rnnt
events (e.g., process failure, PC failure, instrument failure, device failure, device state failure and/or
utility failure) the computer based systems electronically captures the alaimed events. The fb)('l) I
operator explained that the data that is captured by the SCADA is retained for approximately 6-months

Thomas J Arista, National Expert x ~~~9 1040 56

Rita K Kab aso, Off ice of International
Programs Employee

FEJ NUMBER
3002984011


(Note: the computer's memo1y capacity is ~? GB). For example, the fl»<4> I operator demonstrated
by displaying all the cmTently retained-~6> <4> I data, which is only as far back as October 28, 2018
to the present (April 29, 2019). In addition:
k. On J anuaiy 5, 2019, deviation DC/2019/014 was initiated due to J6l {'J)

computer monitor and CPU breakdown observed dming f6><4> .of b) <4>
p;r~
Injection m
mg/vial injection batch no. (6f('f
repo1i was Ji,!Ot oeneratedf6f<'lJ and ~b) <4>
. Due to the breakdown the b) <4>
I fod 6><4 CPU has a storage >
1
capacity of~~i1GB which provides six (6) months of original data storage. Original b'ending data
for alaims could not be recovered as the system is not backed-up. Prior to Januaiy 5, 2019, alaim
trending data and system audit trnil data could not be provided for review.
Deviation DC/2019/014 was closed and approved on Febrnaiy 1, 2019 by the Plant Head,
Quality Assmance. Y om Conective and I)eventative Action was to install an external hard
drive. The ( TR external hard drive for ~6} C'fJ"l pmchase order is dated April 15, 2019. This is
approximately 73 days after Deviation DC/2019/014 was closed and 100 days after yom ~fif('f)l
PC data crashed. You could not provide justification for the time-lapse between deviation
occmTence and external drive pmchase.
1. The General Manager Quality Assmance confomed that they do not track or trend the
f6H~1 I process abenant alaim events that are captmed by the SCADA computer based
system.
m. The "Computer System Validation Master Plan" document #CQA/CSVMP/00 dated 01/12/15
" ... provides guidance and typical approach to validate a computerized system. It also serves as a
resomce for development of specific computer system validation project plans." In addition, the
Computer System VMP establishes and provides guidance regai·ding for example, " ... Back-up
and restoration policies are in place and effective for Operating softwai·e, application softwai·e,
configmation settings and data. and are getting backed up on an external or any ce1iified media to


Rita K Kab aso, Off ice of I n ternational
Pr ograms Employee

FEJ NUMBER
3002984011


C ITY. STATE. ZIP CODE. COUNTRY TYPE ESTABLISHMENT INSPECTED
ensure access if on-line records are lost either through accidental deletion or equipment
problems." The f6><4 > I equipment operator, the Senior Executive and Quality Assurance
confirmed that th~ cunently do not have the capacity to back up the electronic data that is
captured by the ~(b (..f) SCADA system. l
n. A f6f<..fJ I process report is printed out subsequent the routine fif<4> ~ess,
which includes orinting out a color coded graphical representation of the fb)< >4
process.
Thep>><•> I equipment operator, the Assistant Manager4 and ~ualty Assurance explained
that they perform a "verification and confirmation" of the fb) < > processing data. As an
example, with the Vice President oflnjectable Operations anoQuahty Assurance it was
calculated that there are approximately 6f<..f data points summarized in the digital print out.
However, there is no specific language in the standard operating procedure (SOP) to establish the
content of the verification and confirmation process (i.e., what specific process data is verified
and confirmed).
0. The "Rights of authorization level" lists the personnel who are allowed access to the fbf<'l) I
computer. Of the~ individuals that are listed as "active", 9 individuals no longer work for the
company or have moved to other departments.
OBSERVATION 8
There is a failure to thoroughly review any unexplained discrepancy whether or not the batch has been
aheady distributed.
1. Investigations into failures during periodic qualification of the terminal sterilization cycles did
not identify assignable root causes for failures to requalify the previously validated cycle
parameters.


Programs Employee

3002984011


a. Investigation DC/2018/381 did not establish an assignable cause for failure during the
periodic requalification of bf(.iJ Injection ml in ml vial. During
periodic qualification of load ~ b ~ (minimum load) it was noted.that the requi_red ~' was
not achieved in fC.iJ number .4\ b) and .4\
b durincre> the cycle and there were _ 4
bfC_ _ __.
fluctuations observed in fC.iJ and~~ . The investigation DC/2018/381 states:

"ba;;e~ on the disc~1ssion with ~FT team~, cycle parameters for LoadM~ was changed
,fo_!16} <41 from (I>) f4 > _for 6} <4 > to {I>) ('I) for 6} {'I) , wl!ich is more efficient for
(6} C > and (b) 4 > time ><4 > the sterilization (I>) ('lJ to have 6} {'I)
and b) <4 > during sterilization cycle
4
because D) l ) have more lD) l )4 time during ll>fC.iJ) phase". However,
the investigation does not identify an assignable cause for why the previously validated
cycle parameters could not be requalified.
b. Investigation DC/2017 /580 did not establish an assignable cause for failure during the
periodic requalification of~bf(.iJ Injection USP~ ml in~ ml vial. During periodic
qualification of load (b) < (minimum load) the required~ was not achieved in ><4 >
4
numbered C ~~) •
c. Investigation DC/20171736 did not establish an assignable cause for failure during the
periodic requalification of~l>f('l) Injectionm ml in~ ml vial. During perio~ic
qualification of load~) (minimum load) the minimum sterilization I>) <4 time of~
lb>l41 was not achieved for I>) <4 > numbered ~~ .
2. ll>)l.111 tablets~!> g process validation was approved on 07/12/2017. After approval, 18

consumer complaints have been documented regarding Organopathy ~bf('l smell). Of_the 18-
consumer complaint documented, 0 retain or complaint return samples were tested for 6} <4 >
(b) <4> . Complaint investigation included opening of the retain lot and smelling the retain lots


Programs Employee

3002984011


for (b) <4> smell. Per your findings, b) <4 > smell was observed in retain and complaint returned
samples. However no analytical testing was conducted. Additionally, you failed to verify
whether 6><4 > used in the fo1mulation con!aining complaint batches was used in
other diu g products which resulted in Organ opathy l6} C4 > smell).
You dete1mined Organ opathy ~fif('f) smell) is due to the bottle headspace area. You did not
conduct a risk assessment to dete1mine whether other products having Organopathy lfifC4
smell) complaints have the same/similar headspace range.
OBSERVATION 9
There are no written procedures for production and process controls designed to assure that the diug
products have the identity, strength, quality, an d purity they purpo1t or are represented to possess.
p. tfif(.il) Tablet~~ g f6H.il1 i lij {'J) variabiliJY has not been

assesseOwitlim a batch and between batclies. CmTently (b) < > batch ofCbfC4
4 Tablet
1(~) g is (b) <4> an d b) <4 > for b) <4 > at our fixed b) <4 > range.
~er your Sr. Vice Pres1Clent Corporate Quality Assurance, ui l 41 testmg lias been
,e~emQted from routine testin_g_based on process validation batches. Your esta~li~hed >(.if)
1
~l <41 parameter is NMT (lij l4 ) m. Refer to the table below for examples of lij C4 >
ata o tained during 6fC'I process validation: ------
f6fC.il) (6f('f)
I batch
~(6f(.il)
J~b) (4)
J~b) (4)
J~b) (4)
I


Programs Employee

3002984011


Data demonstrating that your cunent f('l proces_s effectively and consistently lb) ('l)
from different locatioJ!.s _of the bf{4 was not included in process
validation studies. According to your (lij ('l) consll_!ller complaint~~C-0301-2018-0002
initiated on Januaiy 10, 2018 regarding Organo).)ath l6} <4 > smell our investigation
indicated that the most probable cause for the (b) <4 > smell in b) <4 > is due to the use of
l6fl41 in your formulation.
q. l6>l'l1 Tabled~~ g validated hold time st!_Idies are not representative of your cmTent
manu actmmcr process. ff old time validation for (lij ('l) was conducted by dispensing bf<4>
4
(b) < > 4
batch (b) < > 4
in (b) < > containers with net weight varying between b) <4 >
to b) < > . b~ g was obtained from each container using a 6><4 > and placed in a bf{4 and
4
16} <4 > container. Hold time study was conducted from the b) ~~ample over lb) <4 > period.
There is no scienriflc ·usti(ic~tion demonstrnting that product Cb > in them g study sample is
4
equivalent to the (lij <4 > or (lij <41 storage container. In addition, your samplmg plan for lij <4 >
does not evaluate variabili within a batch or between batches. The followincr arameters were
tested for 6>l'l1 : f('l
ll)H'l1 Tablet~~ g validation for hold time study for compression is not representative
Of the manufacturing process. l6f<4 > tablets were obtained from b}l'l tablet batch size for
6
compression hold time. Sam12les were kept over ( fl'lfl_eeriod after com ression and evaluated
for lb>l41 . Your cmTent
sampling plan does not evaluate for variability within a batch. Total hold time from
manufactming to packaging has been established for no more than b}l'l .
r. Production personnel are permitted to set the compaction force reject limits outside of the limits
established in the batch records without requiring a documented justification or evaluating the
impact on the validated process. Tablet compaction force reject ranges are established during
process validation batches and the subsequent~) commercial batches. The compaction force can


Programs Employee

3002984011


CITY. STATE. ZIP CODE. COUNTRY TYPE ESTABLISHMENT INSPECTED
4
be impacted based on variability on the b} < > prope1ties.
tablet batch 6} ('f) was
KN, but the actual range
OBSERVATION 10
The responsibilities and procedures applicable to the quality control unit are not fully followed.
1. Closed Circuit Television Cameras CCTV), DVR & Monitoring Screens were installed for the
parenteral facility Fill Lines {fif('f) and tfif<.il) Facility~ . As described in the
change control documents CC/ 15/EG/044 dated April, 27, 2015 and CC/ 15/EG/066 dated
August 10, 2015, the reason/justification for change is "To keep close watch on production
practices and upgrading the facility" . The installation and~erational qualifications (I/OQ) for
lines 6f(.il were perfo1med on August 2015; for lines bf('f.:J in September 2015 and for the
tfif<.il) Facility~ the CCTV I/OQ was perfo1meo on May 2015. Some of the key
functional checks perfo1med during the I/OQ include but not limited to Staitup of the DVR,
Shutdown of the DVR, Locking the DVR, and Status Checking of the DVR. Despite the
installation and operation of a digital video recorder, the Head of Non lb) ('f) Quality Assurance
Deputy General Manager explained that they do not record the production operations. In
addition:
a. The Head of Non lfiH4> Quality Assurance Deputy General Manager explained that they
video record all aseptic processing simulations (aka media fills) via the use of a small
video camera and b'ipod positioned and located outside of the fill rooms; the video
EMPLOYEE(S) SIGNATURE DATE lSSUEO


Programs Employee

FEJ NUMBER
3002984011


recording is taken from a viewin~window (approximately fb) <4 > I x p»<4 > I) in the
personnel coITidor. Regardingp>J <1' fill line, there are a number of objects
that prevent from having an unobstmcted view of the aseptic processing simulations. For
example, the fill equipment, the fill equipmentr> ('l~' the size an d movement of the
mobile transfer trolley, as well as, the personne achv1hes perfo1med in the Grade A and
Grade B areas, present limitation with regards to observing the aseptic process, which is
fwther hindered by the location of the video camera and physical limitation of the
viewing window;
b. There is a CCTV system with a video camera that provides the ability to observe the
Grade A and Grade B areas in front of~ 2 without the aforementioned
obstrnctions. However, the Head of Non b) <4 > Quality Assuran ce Deputy General
Manager explained that they do not use the CCTV to record the aseptic media filling
process; and,
c. The CCTV system has a video camera to observe various aseptic filling operations in Fill
L.
Line However, one of the cameras is positioned in a manner such that the strncture of
the fifling equipment obstm cts the ability to observe the aseptic filling operations.
2. The protocol and repo1t regarding the personnel "Aseptic Area/Clean Room Gaim ents
Qualification Study After Maximum Sterilization Cycle (Sta1t From Washing, D1ying,
Sterilization and Usage) document# OSNP/610 dated March 08, 2016 is used to suppo1ts an d
" ... recommends the use of personnel gaiments up to~) washing, diy ing and sterilization cycle
and usage for routine commercial purpose." Evaluations an d dete1minations of the gaiments are
perfo1med via a Geiman company vendor. For example, dete1minations of the following i.e.,
• I6>l'l1 LI(6f('l) ~
• ~UI l'll b) (4) : I6>l'l1 I)·
• baITier ability against airborne paiticles ~b) -method; fb> <4>
I);

Thomas J Arista, National Exp ert x ~~~9 1040 56

Programs Employee

FEJ NUMBER
3002984011


• pore size ~(b) <4>

• ]Jaiiiculate contaminant by fbl <4 > ~; 0>l
Method{~ -method according to ~fi) <4> I
~6} ) · an d
•
(! ' ' c. ))--1
paiiiculate contaminant by f15 <4 I qC6f('f) I).
Despite the establishment of stan dai·d operating procedures regarding vendor qualification for
excipients and qualification for API, a similai· consideration was not perfo1med for the Geiman
contract vendor. In addition:
a. There is a cunent "Qualification of Service Provider" document #SOP-CQ-00058 dated

Januaiy 09, 2018. Corporate Quality Assuran ce confomed that the company has not
retrospectively perfo1med a vendor audit of the contractor noted above;
b. The biological indicators (BI) used in suppo1i of the (bfC'l>~.J sterilization process ai·e
purchased from an outside vendor. However, Corporate Quality Assurance confomed that
they have not perfo1med a vendor audit of their BI supplier.
3. The fom uses a Building Management System (BMS) to monitor the temperature, percent
relative humidity an d air pressure differences between the Class D glass washing room and the
Grade B aseptic filling suites. The BMS installation and qualification (I/OQ) is dated December
17, 2008. The Head of Non l6fC" Quality Assurance Deputy General Manager confomed that the
individuals that reviewed an d approved the I/OQ documents no longer work at the fom and the
cun ent Quality Unit has not reviewed and approved the 2008 I/OQ documents.
OBSERVATION 11
Laborato1y contrnls do not include the establishment of scientifically sound an d appropriate test
procedures designed to assure that diu g products confo1m to appropriate stan dai·ds of identity, strength,
quality an d purity.


Programs Employee
1 2420 Parklawn Drive, Room 2032 4/22/20 1 9- 5/3/201 9*

3002984011


1. SOP-QC-00055 "Investigation of Extraneous Peaks Observed Dming Chromatographic

Analysis" is not applied to raw materials received from vendors. The chromatograms have not
been evaluated for extran eous unknown peaks. For example, during residual solvent testing of
fb) (4) I #~b> <4> there was a peak at approximatelyr» <4> I that
was not fwther evaluated.
2. Method QC/STP/I/2252-03 was not followed in analysis of~b}l.iJ) I tablets for~Ct>H~r1

tt>f(.il)
4
r.
by gas chromatography. The method requires the standards be prepared
with (b) < > . During the preparation of stan dards for sequence QC863VENI 606A, the
standards were prepared with both b>l4> and >(.iJ)7 ' so the same stan dards could be
used to evaluatep>fC.iJJ I tablets for b)(4) t>>C4> laild
tablets for~ . The~ and
f fl
6 4
)1
peaks co-elute, potentially reducing the accuracy of the stan dard area count compared to
the approved method.
3. Per your "Operation, Calibration an d Data Acquisition of Online Data Logger" SOP 0301 -SOP-
QC-00240, incidents will be generated for investigation for incubator temperature excursions of
fl>fC.il)I or more. No sound justification was provided for the ~Ct>fC.illl limit as it is not
representative of your incubator historical temperature excursions.
OBSERVATION 12
In-process specifications are not detennined by the application of suitable statistical procedures where
appropriate.


Programs Employee

3002984011


There is no documented rationale to explain how the critical, major, and minor limits for rejected
parenteral vials during visual inspection are established. Sources of commonly observed major defects
have not been fmther investigated, including high volume vials, low volume vials, or vials with fibers.
OBSERVATION 13
Aseptic processing areas are deficient regarding the system for cleaning and disinfecting the room and
equipment to produce aseptic conditions.
Sterile wipes used during cleaning of equipment in the IS05 and IS07 aseptic filling lines, intended to
remove paiticles from equipment surfaces, were observed to contain loose fibrous threads.
OBSERVATION 14
Master production and control records lack complete manufacturing and control instrnctions.
The 6f<'I process for Fill Line~, during routine aseptic filling and the aseptic process simulation, the
fbl <4> ; J - l crobial growth media is transfeITed to a sterilizedr>™ I holding
vessel in roomf0 ' l 41 (Grade B). A production room operator confirmed there is no written standai·d
operating procedure, and/or in the BMR, that specifically describes and establishes that the fb>(•f )l
tubing is to be manually transfeITed from the Grade B ai·ea into the Grade D room.
*DATES OF INSPECTION
4/22/2019(Mon), 4/23/2019(Tue), 4/24/2019(Wed), 4/25/2019(Thu), 4/26/2019(Fri), 4/29/2019(Mon),
4/30/2019(Tue), 5/0l/2019(Wed), 5/02/2019(Thu), 5/03/2019(Fri)


Programs Employee
12 4 20 Parklawn Drive, Room 2032 4/22/20 1 9- 5/3/201 9*

FEJ NUMBER
Rockville, MD 20857
3002984011

Cadila Healt hcare Limited 419 & 4 20 8a Village - Moraiya

Ahmedabad, Gujarat, 382210 I ndia Drug Manufacturer
Thomas J AMtl Rna K KaDa&O
x ~:O:t'e~rnas J. Arista -S
OateSipd: 05-03-2019 10:41:25 x ~~~~~;,~9 1041 56
omoe 01 lntemaUona1P'.J'Ograms Et11>1oyee

Thomas J Arista, National Expert x ~,,:r..,~ .......

Pr ograms Employee

Cadila Healthcare LTD India 050319

Uploaded by

Copyright:

Available Formats

Cadila Healthcare LTD India 050319

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Cadila Healthcare LTD India 050319

Uploaded by

Copyright:

Available Formats

DEPARTMENT OF HEALTH AND HUMAN SERVI CES

FOOD AND DRUG ADMINISTRATION

1 2 4 20 Parklawn Drive, Room 2032 4/22/2019- 5/3/2019*

NAME ANO TITLE OF INDIVIDUAL TO WHOM REPORT ISSUED

Umesh Kumar Gupta, Campus Head

Cadila Healthcare Limited 419 & 4 20 8a Village - Moraiya

Ahmedabad, Gujarat, 38221 0 India Drug Manufacturer

DURING AN INSPECTION OF YOUR FIRM WE OBSERVED:

""in_g_1-·e-d-ie-nts including DfC'I

----- manufactured on this equipment have been distributed to the US market.

EMPLOYEE($) SIGNATURE DATE lSSUEO

SEE REVERSE Justin A Bo yd, Investigator - Dedicated 5/3 /2019

1 2 4 20 Parklawn Drive, Room 2032 4/22/2019- 5/3/2019*

NAME ANO TITLE OF INDIVIDUAL TO WHOM REPORT ISSUED

Umesh Kumar Gupta, Campus Head

Cadila Healthcare Limited 41 9 & 4 20 8a Village - Moraiya

Ahmedabad, Gujarat, 38221 0 India Drug Manufacturer

c. Non-dedicated 6><4> equipment CH/MC/TAB/2009/333 had >(.iJ) residues on

equipment CH/PM/013 had white colored residues in the b)(.iJ)

EMPLOYEE($) SIGNATURE DATE lSSUEO

SEE REVERSE Justin A Bo yd, Investigator - Dedicated 5/3 /2019

Thomas J Arista, National Expert x gy:o,,:r..,~ .......

1 2 4 20 Parklawn Drive, Room 2032 4/22/20 1 9- 5/3/201 9*

NAME ANO TITLE OF INDIVIDUAL TO WHOM REPORT ISSUED

Umesh Kumar Gupta, Campus Head

Cadila Healthcare Limited 41 9 & 4 20 8a Village-Moraiya

Ahmedabad, Gujarat, 38221 0 I ndia Drug Manufacturer

4. Manufacturing equipment includingr» <4> I were observed to contain visible dents on

1. Procedure 0301-SOP-MFG-00506 "Guidelines for Working in Aseptic Area" requiring operators

a. During stopper addition for J6><4> I injection batchp>n'fr - i on

b. During filling of~t>f('f)

EMPLOYEE($) SIGNATURE DATE lSSUEO

SEE REVERSE Justin A Boyd, Investigator - Dedicated 5/3/201 9

Thomas J Arista, National Expert x ~~~9 104056

1 2 4 20 Parklawn Drive, Room 20 3 2 4/22/20 1 9- 5/3/201 9*

NAME ANO TITLE OF INDIVIDUAL TO WHOM REPORT ISSUED

Umesh Kumar Gupt a, Campus Head

Cadila Healt hcare Limit ed 419 & 4 20 8a Village - Moraiya

Ahmedabad, Gujarat , 38 22 1 0 I ndia Drug Manufact urer

EMPLOYEE($) SIGNATURE DATE lSSUEO

SEE REVERSE J u stin A Bo yd, Investigato r - Dedicated 5/3 / 20 1 9

Thomas J Arist a, Nat ional Expert x ~~~9 104056

12 420 Parklawn Drive, Room 2032 4/22/20 1 9- 5/3/201 9*

NAME ANO TITLE OF INDIVIDUAL TO WHOM REPORT ISSUED

Umesh Kumar Gupta, Campus Head

Cadila Healthcare Limited 419 & 420 8a Village - Moraiya

Ahmedabad, Gujarat, 382210 India Drug Manufacturer

Batch number #o culled units

EMPLOYEE($) SIGNATURE DATE lSSUEO

SEE REVERSE Justin A Boyd, Investigator - Dedicated 5/3/201 9

Thomas J Arista, National Expert x gy:o,,:r..,~ .......

1 2 4 20 Parklawn Drive, Room 2032 4/22/20 1 9- 5/3/201 9*

NAME ANO TITLE OF INDIVIDUAL TO WHOM REPORT ISSUED

Umesh Kumar Gupta, Campus Head

Cadila Healt hcare Limited 41 9 & 4 20 8a Village - Moraiya

Ahmedabad, Gujarat, 38221 0 I ndia Drug Manufacturer

EMPLOYEE($) SIGNATURE DATE lSSUEO

SEE REVERSE Justin A Bo yd , Investigator - Dedicated 5/3 /2019

Thomas J Arista, National Expert x gy:o,,:r..,~ .......