DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

DISTRICT ADDRESS ANO PHONE NUMBER DATE(S) OF INSPECTION

12420 Parklawn Drive, Room 2032 4/15/2024 - 4/23/2024*

Rockville, MD 2085 7 FEJ NUMBER

3013712903

NAME ANO Tm E OF INDIVIDUAL TO WHOM REPORT lSSUEO

Rajesh Dessai, Chief - Manufacturing

F IRM NAME STREET AOORESS

Zydus Lifesciences Limited Survey No . 434 /6/B & 434 /1/K, Vadodara -
Halol Highway
CITY. STATE. ZIP CODE. COUNTRY TYPE ESTABLISHMENT INSPECTED

Village - Jaro d, Taluka - Waghodia , Finished Drug Manufacturer

Gujarat, 391510 India

This document lists observations made by the FDA representative(s) dtu-ing the inspection ofyotu· facility. They are inspectional
observations, and do not represent a final Agency detel'lllination regarding yotu· compliance. Ifyou have an objection regarding an
observation, or have in1plemented, or plan to implement, corrective action in response to an observation, you may discuss the objection or
action with the FDA representative{s) dm-ing the inspection or submit this information to FDA at the adch·ess 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
There is a failure to thoroughly review any unexplained discrepancy and the failure of a batch or any of
its components to meet any of its specifications whether or not the batch has been akeady distributed.

1. Investigations for cross contamination due to inadequate cleaning after l (bTC4l

Injection batches were not thorough in evaluating all impacted batches. Tliefoilowmg 6atclies
4
were reiected due to unknown impurity OOS/OOT resulttf : Ctirc Ll!!,jection batches
I t"rr1 (OOS) - (bn"l (OOT), and (b>1"j Injection
batch l lUJl'tl ( OOT).

The investigations identified the root cause for these batch rejections to be cross contamination
with the product I t1,rr, Injection, which had not been adequatelr clea, ed from
surfaces of shared eauioJ!lent including manufacturing vessels, holding vessel, (b)l tank, filling
pumps, and! (bT'i The impact on the following other batches was not thoroughly
investigated:

a. Analysis ofl wci Injection batches detected the presence of an unknown

.implm•ty peak consistent
• •hi
wit (b)l4l •
J cross contammat10n. • These b ateh es
1141
that were below the (b % lirmt unspecitiea""im~unty limit for OOT were released to the
•h • .fy.mg th e presence of'I . (b>141 • •
Us mark et wit out JUSb cross contammahon.
The batches included:

EMPLOYEE($) SIGNATURE DATE lSSUE0

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OF THIS PAGE Anastasia M Shields, Investigator ..ld'!Aecr
2000358686
: 04-23--202A
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 DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
D ISTRICT ADDRESS ANO PHONE NUMBER DATE(S) OF INSPECTION

1 2 4 2 0 Parklawn Drive, Room 2 032 4/ 1 5/2024 - 4/23/2024*

FEJ NUMBER
Rockville, MD 20857
3013 71 2903

NAME ANO TmE OF INDIVIDUAL TO WHOM REPORT lSSUEO

Rajesh Dessai, Chief - Manufacturing

F IRM NAME STREET AOORESS

Zydus Lifesciences Limited Survey No . 434/6/B & 434/1/K, Vadodara -

Halol Highway
C ITY. STATE. Z IP CODE. COUNTRY TYPE ESTABLISHMENT INSPECTED

Village - Jarod, Taluka - Wagho dia, Finished Drug Manufacturer

Gujarat, 391510 India

• I (b)14lo/c ak . •h
j o pe consistent wit 1
(b11 cross
contammat10n.
(bT(.!llo/c ak consistent
. .h (bTC, cross
• I ·1 o pe wit
contammat10n.
(b)14lo/c ak . •h (b111 cross
• I j o pe consistent wit
contammat10n.
(bT(.!llo/c ak consistent
. .h (bTC, cross
• I ·1 o pe wit
contammat10n.

Each of these batches was released to the US market with anl (bY{ilj expiration date
I
(bTC.!ll·1 or.,(6)-(~) I expiration date I
W(l,

b. Following manufacturing of batches (bT~ andl (b111

l (bm~ofl (bY{ilj on shared line c4j equipment, the following batches were
manufactured:

I6>l-t1 (b)11otl (bT~ OT for an

• I 1-1
impurity related to cross contamination with I 1
(b11 Batch was
rejected.
I6J l-t1 - (b)1-0otl
• (bT"'} impurity related to
Icommercialized. (b)(4
cross contamination was detected. Batch was not

t6)-(<l1
• - (b)(4 (bTC.!llofl wc1 impurity related to
I
commercialized.
cross contamination was detected. Batch was not

EMPLOYEE($) SIGNATURE DATE lSSUEO

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2000358686
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FORM FDA 483 (09/08) PREVIOUS EDmON OBSOlEJE INSPECTIONAL OBSERVATIONS PAGE2of18PAGES
 DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
DISTRICT ADDRESS ANO PHONE NUMBER DATE(S) OF INSPECTION

1 2420 Parklawn Drive, Room 2032 4/ 1 5/2024 - 4/23/2024*

Rockville, MD 20857 FEJ NUMBER

301371 2903

NAME ANO TmE OF INDIVIDUAL TO WHOM REPORT lSSUEO

Rajesh Dessai, Chief - Manufacturing

F IRM NAME STREET AOORESS

Zydus Lifesciences Limited Survey No . 434/6/B & 434/ 1 /K, Vadodara -

Halol Highway
CITY. STATE. ZIP CODE. COUNTRY TYPE ESTABLISHMENT INSPECTED

Village - Jarod, Taluka - Waghod ia, Finished Drug Manufacturer

Gujarat, 391 51 0 India

{6f(.ol) - - (bn"ltrials
•
• fb) (4) - 1
(b11 ofl (b1141 Injection. Batch was released to the
US market with an expiration date ofl l
(bJ(44 wh en testmg
• d.d1 not d etect
I (b)\.J
1(b) (4 ) (bf(4}·1ofb (b)1ililn.J~tlon • - OOT Dor an nnpur1ty
• • re1ated
• -
4
to cross contamination with (b>1 jBatch was rejected.

The investigation failed to thoroughly assess whether (bT<4 should have been released
' (1>)('41
when batches manufactured before it and after it detected cross
contamination. The investigation did not identify which equipment was causing the cross
contamination.

C. Batches filled following! (b>1ilj in 2021 were not evaluated with analytical
methods that were shown to be capable of detecting I {">14} if it was present.
Only the chromatograms for the existing methods were evaluated for the presence of
atypical impurities. For example, the followin~atches were distributed to the US
market: (6J('1 In.Jecbon
. b ate~ (6r(41
and (bT(-0i In.~ect1on
.
batches (b)1-il

(b)(,
d. The investigation did not consider canyover between batches ofl
since it was the same product. There was no evaluation if residues remaining on
eguiQment could have led to increased impurities in initial vials of subsequent batches.
I (b)1ill is filled into l (b>1ilj vials due to I ttiJT1

2. The following investigations were opened when the number of Paiiiculate Type A-Glass
Paiiicles resulted in yield deviations or exceeded defect catego1y limit for glass pa1iicles during

EMPLOYEE($) SIGNATURE DATE lSSUEO

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2000358686
: 04-23--202A
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 DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
D ISTRICT ADDRESS ANO PHONE NUMBER DATE(S) OF INSPECTION

1 2 4 2 0 Parklawn Drive, Room 2 032 4/ 1 5/2024 - 4/23/2024*

Rockville, MD 20857 FEJ NUMBER
3013 71 2903

NAME ANO TmE OF INDIVIDUAL TO WHOM REPORT lSSUEO

Rajesh Dessai, Chief - Manufacturing

F IRM NAME STREET AOORESS

Zydus Lifesciences Limited Survey No . 434/6/B & 434/1/K, Vadodara -

Halol Highway
C ITY. STATE. Z IP CODE. COUNTRY TYPE ESTABLISHMENT INSPECTED

Village - Jarod, Taluka - Wagho dia , Finished Drug Manufacturer

Gujarat, 391510 India

(bTC<llln• • USP, (bf(il

visual inspection ofl ·1 ~ect1on mcg/mrU;mL.

a. Deviation Investigation PR#531860 dated June 03 2021, for! (b>1ilj Injection

USP, (b>1il mcg/~mL, Batches.hnntL (b)C4l was opened when the
~ercenta e yield was found out oflimit 'u"~(%) against the specification of
r (bfC4 % at the visual inspection stage. The lower yield was found to be a result of
increased rejection rates forglass pa1ti~les during visual inspection, including a~~% 6}
reject rate for batch ! 4
(bfC1 and a lbH > % reject rate for batch ! (bT'4} Your nm's
investigation infen ed that the most probable root cause is glass vial lot to lot variation.

CAPA PR# 624883 was opened in response to this deviation investigation. The CAPA
addressed _increasing the visual inspection time of these vials due to the I 11
(b 1
vial andr:]liquid filled into the vial making it more difficult to visually inspect.

b. Deviation/Common Investigation (PR#s 69! 783, 699104, 708504 - dated July 29, 2022)
was opened for exceeding the action limit(:]%) fcla, s paiticles during manual visual
inspection. Each batch was 100% visually mspecte {6)(' times with the following result:
(bf(il
Lot Number Total Vials

.. -, ..

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2000358686
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FORM FDA 483 (09/08) PREVIOUS EDmON OBSOlEJE INSPECTIONAL OBSERVATIONS PAGE 4 of18 PAGES
 DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
D ISTRICT ADDRESS ANO PHONE NUMBER DATE(S) OF INSPECTION

1 2 4 2 0 Parklawn Drive, Room 2 032 4/ 1 5/2024 - 4/23/2024*

FEJ NUMBER
Rockville, MD 20857
3013 71 2903

NAME ANO TmE OF INDIVIDUAL TO WHOM REPORT lSSUEO

Rajesh Dessai, Chief - Manufacturing

F IRM NAME STREET AOORESS

Zydus Lifesciences Limited Survey No . 434/6/B & 434/1/K, Vadodara -

Halol Highway
C ITY. STATE. Z IP CODE. COUNTRY TYPE ESTABLISHMENT INSPECTED

Village - Jarod, Taluka - Wagho dia, Finished Drug Manufacturer

Gujarat, 391510 India
(bTC4l
Following AQL on the round of 100% visual inspection (VI), the batches were
released to the US marlcet.

As pa1t of the investigation, samples were sent for microscopic analysis at a third-paity
laborato1y. The result dete1mined that the paiticles were glass that is the same type as the
vial and the size of the particles in the provided sample ranged from 51.02 to 187.61
micrometers.

The lot of glass vials used to fill the product was found to be common between the three
batches, the investigation dete1mined !hat the most Qrobable root cause was lot to lot
variation between the vial with the (b)C4lof th~ (bY{4} also a contributing
factor. Your investigation failed to assess other potential sources of glass oa1t icle
generation. For example: product fo1mulation, constru ction of the vial! (bT(4
r (bY{,4l storage conditions of the vial containing the finished diug product, etc.
C. Deviation/Common Investigation (731813, 735565, 740156, 744450 - dated September
30, 2022) was opened when the rejection rate for glass paiticles exceeded the ale1t or
action limit for the following batches:
CbT(4

Lot Number Total Vials

EMPLOYEE($) SIGNATURE DATE lSSUEO

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2000358686
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 DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
D ISTRICT ADDRESS ANO PHONE NUMBER DATE(S) OF INSPECTION

1 2 4 20 Parkl a wn Drive, Room 2032 4/1 5 /2024 - 4/23/2024*

FEJ NUMBER
Rockvi lle, MD 2085 7
3013 712903

NAME ANO Tm E OF INDIVIDUAL TO WHOM REPORT lSSUEO

Raje sh De ssai, Chief - Manuf actur ing

F IRM NAME STREET AOORESS

Zydus Life science s Li mited Survey No . 4 3 4 /6/B & 4 3 4 /1/K, Vado dara -
Ha lol Hi ghway
C ITY. STATE. Z IP CODE. COUNTRY TYPE ESTABLISHMENT IN SPECTED

Vi lla g e - Jaro d, Taluka - Waghodia , Fin i shed Dr ug Ma nufac t u rer

Gu jarat, 391510 I n dia
(bT(l

4
Following AQL on the1 (bY{ ~round of 100% visual inspection (VI), the batches were
released to the US market.
(bY{4
Your investigation identified a lot of vials which was common among the batches
vials of each batch under investigation were sent for characterization and pru.ticle size
detennination. Per your investigation the analysis confnmed the pa1ticles were glass
with a vru.·iation in size ranging from 33.55 micrometers to 312 micrometers. It was
dete1mined that the pru.ticles were attributed to the specific lot of vials used for these
batches. The root cause was dete1mined to be "material" .

After the release of these four batches, DEV/0317/2023/0034 (PR#853661) (batch

I t"ff1 mcg/mL uslf~mL, manufactured May 29, 2023, US
market) was opened when vials purchased from an alternative vendor and used in
production also resulted in a batch that exceeded the action limit for Pru.ticulate Type A-
Glass Pa1t icles.

ILot Number ITotal Vials

:~
Per your deviation investigation "In earlier investigations, the root cause was identified as
lot-to-lot vru.·iation in glass vials", "However, higher% glass pru.ticle rejections were
found out of limit after changing the glass vial manufacturer." Based on that, your
investigation infen ed that lot to lot vru.·iation in the vials alone may not be the only

EMPLOYEE($) SIGNATURE DATE lSSUEO

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OF THIS PAGE Anastasia M Shie lds , Inve stigator ..ld'!A ecr
2000358686
: 04-23--202A
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FORM FDA 483 (09/08) PREVIOUS EDmON OBSOlEJE INSPECTIONAL OBSERVATIONS PAGE 6 of18 PAGES
 DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
D ISTRICT ADDRESS ANO PHONE NUMBER DATE(S) OF INSPECTION

1 2420 Parklawn Drive, Room 2032 4/ 1 5/2024 - 4/23/2024*

Rockville, MD 20857 FEJ NUMBER
301371 2903

NAME ANO TmE OF INDIVIDUAL TO WHOM REPORT lSSUEO

Rajesh Dessai, Chief - Manufacturing

F IRM NAME STREET AOORESS

Zydus Lifesciences Limited Survey No . 434/6/B & 434/ 1 /K, Vadodara -

Halol Highway
C ITY. STATE. Z IP CODE. COUNTRY TYPE ESTABLISHMENT INSPECTED

Village - Jarod, Taluka - Waghod ia, Finished Drug Manufacturer

Gujarat, 391 51 0 India

contributing factor.

Subsequent investigation inchc1ded a study executed in Febrnarv 2024 where

I (b)l1 Inj . USP :::)mcg/mL was filled into I (bY{4j vials instead of glass
vials and identified a significant reduction in the rejection rate due to glass pa1t icles.

I Lot Number
I~:~
(b114l

Based on this finding, the investigation infen ed the probable cause for glass paiticles in
4
the previous batches is use o( (bY{ j vial and an interaction between the product
and the vial.

Following this study, your fnm made the decision to reject batch1 Ctifc based on the l
4

number of vials found to have glass particles exceeding the limit and for the
dete1mination that the source of the glass pa1ticles was most probably related to
incompatibility/interaction between the vial and the dmg. Your fnm also made the
decision to cease manufacturing of this product packaged in thJ~~mL vial due to the
source of the glass paiticles being undete1mined. However, previous batches released to
the market with siinilar out of limit glass paiticle defect rates, filled into the same type
and size of glass vial, were pe1mitted to remain on the market.

EMPLOYEE($) SIGNATURE DATE lSSUEO

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OF THIS PAGE Anastasia M Shield s, Investigator ..ld'!Aecr
2000358686
: 04-23--202A
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FORM FDA 483 (09/08) PREVIOUS EDmON OBSOlEJE INSPECTIONAL OBSERVATIONS PAGE 7 of18 PAGES
 DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
DISTRICT ADDRESS ANO PHONE NUMBER DATE(S) OF INSPECTION

12420 Parklawn Drive, Room 2032 4/15/2024 - 4/23/2024*

Rockville, MD 20857 FEJ NUMBER
3013712903

NAME ANO TmE OF INDIVIDUAL TO WHOM REPORT lSSUEO

Rajesh Dessai, Chief - Manufacturing

F IRM NAME STREET AOORESS

Zydus Lifesciences Limited Survey No . 434/6/B & 434/1/K, Vadodara -

Halol Highway
CITY. STATE. ZIP CODE. COUNTRY TYPE ESTABLISHMENT INSPECTED

Village - Jarod, Taluka - Waghodia , Finished Drug Manufacturer

Gujarat, 391510 India

The following batches were manufactured, released and pennitted to remain on the U.S.
market without reevaluating the original root cause for exceeding glass pa1ticle liinits as
discussed in the aforementioned investigations:
(b)14j CbTC4l ·cliJ(4

(Finished/Packaged Batch Expiration

(Finished/Packaged Batch Expiration
(Finished/Packaged Batch Expiration
,(Finished/Packaged Batch Expiration

OBSERVATION 2
Established sampling plans and test procedures are not followed.

1. Procedures 03 l 7-SOP-QC-00193 "Sampling and Testing procedure of l Cb>1"j and

03 l 7-SOP-QC-00118 "Quality monitoring of( ~ System" were not followed for
collecting (bfj samples. Scheduled samples for specified sample points were not collected.
However, analytical records were made to document the samples were collected and used for
testing, even though QC microbiology personnel confnmed samples were not collected.

From April 4, 2024-April 13, 2024, there were r Cl2personnel that paiticipated in CbTC4l sampling.
Each individual on one or more occasion during t is time period paiticipated in coilecting or
documenting (b1141 samples that were not collected from the specified sampling point. For
example:

a. On A~ril 12, 2024, an employee collected CbTC4l extra bioburden Cb>1"jsamples from p_oint
- · H4 • (tif(41
These extra samples were represented as pomts
(b)(4 . . (b)(4}
which were not sampled. The documented samples for pornts I
(b)(4
Cb)l1 were repo1ted to have all been collected from use pointl

EMPLOYEE($) SIGNATURE DATE lSSUEO

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2000358686
: 04-23--202A
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 DEPARTMENT OF HEALTH AND HUMAN SERVI CES
FOOD AND DRUG ADMINISTRATION
D ISTRICT ADDRESS ANO PHONE NUMBER DATE(S) OF INSPECTION

1 2420 Parklawn Drive, Room 2032 4/15/2024 - 4/23/2024*

Rockville, MD 20857 FEJ NUMBER
3013712903

NAME ANO TmE OF INDIVIDUAL TO WHOM REPORT lSSUEO

Rajesh Dessai, Chief - Manufacturing

F IRM NAME STREET AOORESS

Zydus Lifesciences Limited Survey No . 434/6/B & 434/ 1 /K, Vadodara -

Halol Highway
CITY. STATE. ZIP CODE. COUNTRY TYPE ESTABLISHMENT INSPECTED

Village - Jarod, Taluka - Wagho d ia, Finished Drug Manufacturer

Gujarat, 391 51 0 India

There were~ (bJj samples for Bacterial Endotoxin Testing (BET) documented to be
collected from (bH4ldifferent points s,n April 12, 2024. (b1141 of these were collected from a
4
single point, (bH1 The other (bH samples were poured into the BET test tubes in the
4
microbiology laborato1y with excess sample collected from l (bY{ ~ so they could be
submitted for testing.

The emr <btir that collected the samples was a fixed te1m employee not qualified to
collect ~(l samples, enter the production area, or make GMP records. The signed

sampling records indicated a second employee had been the sampler, even though that
employee confnmed that they had not collected any samples and had instructed the fixed
te1m employee to collect the samples without sampling from each point. These analytical
records contained sampling staii and end times that did not con elate to actual activities.
The sampler in the records was awai·e the samples they signed for were not collected

-
from the actual locations and identified this was a practice that had been occmTing on
occasion for the past four months.

b. On Apnl• 6, 2024, an employee collected exti·a samples from sample porn• ~ ..J
and represented these as other points that were scheduled for sampling, but not actuaily
(b111Additionally, no sample was collected from, (b j
11
sampled, including!

The employee that collected the samples was still lmder qualification and had been
directed by a qualified analyst to sample this way to avoid more difficult to sample
points. The qualified analyst filled out the analytical records as the sampler, awai·e that
they had not collected samples and the samples were not from the documented location.
The qualified analyst confnmed failing to sample from specified locations was not an
isolated incident.

EMPLOYEE($) SIGNATURE DATE lSSUEO

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OF THIS PAGE Anastasia M Shields, Investigator

FORM FDA 483 (09/08) PREVIOUS EDmON OBSOlEJE INSPECTIONAL OBSERVATIONS PAGE 9 of18 PAGES
 DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
DISTRICT ADDRESS ANO PHONE NUMBER DATE(S) OF INSPECTION

1 2 4 2 0 Parkl a wn Drive, Room 2 032 4/ 1 5 /2024 - 4/23/2024*

Rockvi lle, MD 2085 7 FEJ NUMBER
3013 71 2903

NAME ANO Tm E OF INDIVIDUAL TO WHOM REPORT lSSUEO

Raje sh De ssai, Chief - Manuf actur ing

F IRM NAME STREET AOORESS

Zydus Life science s Li mited Survey No . 4 3 4 /6/B & 4 3 4 / 1 / K, Vado dara -

Ha lol Hi ghway
CITY. STATE. ZIP CODE. COUNTRY TYPE ESTABLISHMENT IN SPECTED

Vi lla g e - Jaro d, Taluka - Wagho d ia , Fin i shed Dr ug Ma nufac t u rer

Gu jarat, 391 51 0 I ndia

On the same day, the analyst under qualification was documented to have collected
separate samples for the pmpose of analyst qualification from I ~ The
samples were not observed to be collected. A qualified analyst signed the qualification
documentation documenting they had witnessed the sampling for the pmpose of analyst
qualification.

(bY{4l
C. On April 4, 2024, samples were not observed to be collected from~
(b)(4 .
The analyst responsible for sampling stated samples were taken from ·i mstead,
because it is an easier point to access. The analyst acknowledged creatmg records for
4
(tif( samples that were not collected and confnmed this was not an isolated incident.

d. On Apn•l 5, 2024, samples were not observed to be collected froIIL -' t H4i The
analyst responsible for making the analytical records stated the samples were col ected
from a different room. The analyst acknowledged creating records for j (bH"isamples that
were not collected and confnmed this was not an isolated incident.
4
During interviews with employees responsible for CbH sampling on April 15-16, 2024,
employees provided inaccurate statements or refused to answer questions.

2. Procedure 0317-SOP-QC-00240 "Operation and Calibration of High Perfo1mance of High

Perfo1mance Liquid Chromatography (HPLC)" requires documented authorization to use
different processing methods within a sequence. The documentation made lacks specific details
of what was reviewed and what was found to be inappropriate that justified different processing
methods that include addition of manually entered timed integration events into the processing
method.

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2000358686
: 04-23--202A
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FORM FDA 483 (09/08) PREVIOUS EDmON OBSOlEJE INSPECTIONAL OBSERVATIONS PAGE 10 ofl8 PAGES
 DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
DISTRICT ADDRESS ANO P HONE NUMBER DATE(S) OF INSPECTION

1 2 4 2 0 Parklawn Drive, Room 2 032 4/ 1 5/2024 - 4/23/2024*

Rockville, MD 20857 FEJ NUMBER

3013 71 2903

NAME ANO TmE OF INDIVIDUAL TO WHOM REPORT lSSUEO

Rajesh Dessai, Chief - Manufacturing

F IRM NAME STREET AOORESS

Zydus Lifesciences Limited Survey No . 434/6/B & 434/1/K, Vadodara -

Halol Highway
C ITY. STATE. ZIP CODE. COUNTRY TYPE ESTABLISHMENT INSPECTED

Village - Jarod, Taluka - Wagho dia , Finished Drug Manufacturer

Gujarat, 391510 India

OBSERVATION 3
Procedures designed to prevent microbiological contamination of mug products pmpo1ting to be sterile
did not include adequate validation of the aseptic process.

The airflow visualization study conducted on Lin~ ~ Protocol Document CHL-QUA-00315-00,

effectiv~ June 05, 2021, under dynami~ conditions did not demonstrate unidirectional airflow during
I 1
(b)C, interventions. When the (b)C4l to the RABs was1 (b11 the airflow (smoke) was observed
flowing out of the RABs and into the air intake duct located near the I
4
11
(b line. Air 1
flow on the line was not visible when the (bTCl was1 (bH ) and thus was not able to be evaluated for
unidirectional airflow.
,)14)
Lins~ was observed to have the same design with air intakes located directly j (liH"j where RABS
~ '

OBSERVATION 4
Procedures designed to prevent microbiological contamination of mug products pmpo1ting to be sterile
are not followed.

Procedure 0317-SOP-MFG-00039 "Clean room and aseptic behaviour" was not followed to ensure
sterilized components are only contacted with sterile forceps and aseptic manipulations are perfo1med
from the side, so as not to dismpt the laminar air flow. For example:

I .During an intervention to adjust the stopper bowl alignment during asec ic filling of (br(41
batch L _ (bTC4l (US market batch), the operator allowed thej RABS (b~l)l4l to contact sterile
stoppers. Tliese stoppers were subsequently returned to the stopper bow .

2.During observation of aseptic filling activities forl (b)l1 batch ! (bT'i (US market batch),

EMPLOYEE($) SIGNATURE DATE lSSUEO

SEE REVERSE Justin A Boyd, Investigator 4/23/2024

OF THIS PAGE Anastasia M Shields, Investigato r ..ld'!Aecr
2000358686
: 04-23--202A
X ~US::' 1

FORM FDA 483 (09/08) PREVIOUS EDmON OBSOlEJE INSPECTIONAL OBSERVATIONS PAGE 11 of l8 PAGES
 DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
DISTRICT ADDRESS ANO P HONE NUMBER DATE(S) OF INSPECTION

1 2420 Parklawn Drive, Room 2032 4/ 1 5/2024 - 4/23/2024*

Rockville, MD 20857 FEJ NUMBER

301371 2903

NAME ANO TmE OF INDIVIDUAL TO WHOM REPORT lSSUEO

Rajesh Dessai, Chief - Manufacturing

F IRM NAME STREET AOORESS

Zydus Lifesciences Limited Survey No . 434/6/B & 434/ 1 /K, Vadodara -

Halol Highway
C ITY. STATE. ZIP CODE. COUNTRY TYPE ESTABLISHMENT INSPECTED

Village - Jarod, Taluka - Waghod ia, Finished Drug Manufacturer

Gujarat, 391 51 0 India

(b>1 j the ~RABS

4
media fill L _ (bTC4land media fill( (bTC4l were observed to pass over the
stopper bowlauri.ng assembly, over the stopper bo~ and stoppers during change of
environmental monitoring plates, and over open vials during removal of fa llen vials in the
incoming vial area.

OBSERVATION 5
Your fnm failed to establish adequate written procedures for production and process controls designed
to assure that the diug products have the identity, strength, purity, and quality that they are purported or
represented to possess.

I .Process validation studies fo1: (b)1l ~roducts that have been distributed to the US market
4
including! {"ff1 InJecbo°;~ {"ff1 Injection, and I (b>1 } Injection have
not evaluated whether prope~ lti 1is achieved and maintained after stoppering throughout the
batch. There has been no desbuctive 9r non-desbuctive testing for any of the products to show
the presence of an appropriate1 (bT'1

There have been six US market complaint investigations (694519, 710383, 749188, 753359,
783672, 832994) for difficulty in administeringl. (b)l4l Injection because they were not
able to di·aw the full contents of the vial when ad.m1mstenng [ e product. None of these
investigations evaluated whether the vials had an appropriate h (b)ll There was no evaluation
of retains or data collected from validation or commercial bate es to emonstrate the vials had
(tif~ l and were stoppered completely at the ,)""(4) of·1
4 (tif~4l
appropn•ate r to prevent
ingress of environmental air.

2.Process validation studies do not establish statistical sampling plans that allow for evaluation of
inter-batch and intt·a-batch variability. No acceptance criteria to evaluate intra-batch or inter-
batch variability are established. For example:

EMPLOYEE($) SIGNATURE DATE lSSUEO

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OF THIS PAGE Anastasia M Shields, Investigator ..ld'!Aecr
2000358686
: 04-23--202A
X ~US::'1

FORM FDA 483 (09/08) PREVIOUS EDmON OBSOlEJE INSPECTIONAL OBSERVATIONS PAGE 12 of18 PAGES
 DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
D ISTRICT ADDRESS ANO PHONE NUMBER DATE(S) OF INSPECTION

1 2420 Parklawn Drive, Room 2032 4/15/2024 - 4/23/2024*

Rockville, MD 20857 FEJ NUMBER
3013712903

NAME ANO TmE OF INDIVIDUAL TO WHOM REPORT lSSUEO

Rajesh Dessai, Chief - Manufacturing

F IRM NAME STREET AOORESS

Zydus Lifesciences Limited Survey No . 434/6/B & 434/ 1 /K, Vadodara -

Halol Highway
C ITY. STATE. Z IP CODE. COUNTRY TYPE ESTABLISHMENT INSPECTED

Village - Jarod, Taluka - Wagho d ia, Finished Drug Manufacturer

Gujarat, 391 51 0 India

{l,)14
a.During process validation studies for
------- Inj ection:
i.The sam les to evaluate the product after.-----. (b)1l f~r assay of {tiJT]
assay of (b)14 im urities, and pH were (b)C4l from vials coilected
from ~> different b) < and only a single result was generated for each
proces~ validation batch.

iii. There were no acceptance criteria for intra-batch or inter-batch variabili for the
4
W(l content or for variability between the different {bTC
4
(bH The results were only compared to the finished product specification of
,_n_o_t -m o-re than rTcj % without determining what amount of variation was
acceptable.

For exam~ e, dw·ing 2020 process validation batch "'"!from .,,.

(b>14 the (bT1j·anged from the (bH4 sample at (bH4l%
,_w..,h,...,i""le- the ,;;n"i sample was Hj %. This is inconsistent with an
additiona tErocess val1dafioti batch (b)(4) m 2021, where the W(l
4
from i{ 1ranged from (b)"l4l%.

EMPLOYEE($) SIGNATURE DATE lSSUEO

SEE REVERSE Justin A Boyd, Investigator 4/23/2024

OF THIS PAGE Anastasia M Shields, Investigator ..ld'!Aecr
~~2000358686
8:'l"~ : 04-23--202A
X US::'1

FORM FDA 483 (09/08) PREVIOUS EDmON OBSOlEJE INSPECTIONAL OBSERVATIONS PAGE 13 ofl8 PAGES
 DEPARTMENT OF HEALTH AND HUMAN SERVI CES
FOOD AND DRUG ADMINISTRATION
D ISTRICT ADDRESS ANO PHONE NUMBER DATE(S) OF INSPECTION

12420 Parklawn Drive, Room 2032 4/15/2024 - 4/23/2024*

Rockville, MD 20857 FEJ NUMBER
3013712903

NAME ANO TmE OF INDIVIDUAL TO WHOM REPORT lSSUEO

Rajesh Dessai, Chief - Manufacturing

F IRM NAME STREET AOORESS

Zydus Lifesciences Limited Survey No . 434/6/B & 434/1/K, Vadodara -

Halol Highway
C ITY. STATE. Z IP CODE. COUNTRY TYPE ESTABLISHMENT INSPECTED

Village - Jarod, Taluka - Waghodia , Finished Drug Manufacturer

Gujarat, 391510 India

b.Process perfo1mance qualification studies for the US market I_ (b~<"

Injection USP W(l mg/ Vial, do not include an evaluation of mtra-batch or mter- atch
variability nor do they include acceptance criteria for variability. The process
perfo1mance qualification was approved without evaluating potential som ces of
variability or addressing variability of results. For example:

Test for Unifo1mity of Dosage Units produced the following results for the process
validation batches:

Batch Result
{6f(.ol)- ·r -
(b) (4) )
fb)(4) )
~)_
Test for Total lmpmities produced the following results:

Batch Result
.- -
{6f(.ol)-
?%
(b) (4) )%
\
fb)(4) ))_ o/c0
~

The following process validation batches ofl (bT<, Injection

(bY{<I mg/Vial were released for distribution to the U.S. market:

(b,{il
Finished/Packaged Batch
Finished/Packaged Batch
(b)14l . . .I
Exp~rat~o5
1Expirabo
~1
EMPLOYEE($) SIGNATURE DATE lSSUEO

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OF THIS PAGE Anastasia M Shields, Investigator ..ld'!Aecr
2000358686
: 04-23--202A
X ~US::' 1

FORM FDA 483 (09/08) PREVIOUS EDmON OBSOlEJE INSPECTIONAL OBSERVATIONS PAGE14of18PAGES
 DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
DISTRICT ADDRESS ANO PHONE NUMBER DATE(S) OF INSPECTION

1 2 4 20 Parklawn Drive, Room 20 32 4/ 1 5/2024 - 4/23/2024*

Rockville, MD 20857 FEJ NUMBER
3013 71290 3

NAME ANO TmE OF INDIVIDUAL TO WHOM REPORT lSSUEO

Rajesh Dessai, Chief - Manufacturi ng

F IRM NAME STREET AOORESS

Zydus Lifesciences Limited Survey No . 434 /6/B & 434 /1/K, Vadodara -
Halol Highway
CITY. STATE. ZIP CODE. COUNTRY TYPE ESTABLISHMENT INSPECTED

Village - Jarod, Taluka - Wagho dia, Finished Drug Manufact u rer

Gu jarat, 391510 I ndia

OBSERVATION 6
Aseptic processing areas are deficient regarding the system for monitoring environmental conditions.
1141
Review of the non-viable o~iicle count (NVPC) continuous monitoring from the ~ (b , which is used
to transpo1i I (bT'i vials from the filling line to the (bT, show ·equent I
communication enors. These occur when the unit fails to have an adequate WIFI signal or power to the
NVPC is lost, leaving gaps in the ability to repo1i NVPC data. These communication enors were first
documented in a maintenance notification, July 23, 2020, but no effective actions have been taken to
ensure NVPC data is available continuously during batch production activities. For example, during line
4
set-up, filling, andl (bH lloading:

(bH4l
I.For batch ibatch l (b)14) •
·i on Janua1y 19-20, 2024, there were 49 commun1cat10n •
~
en ors totaling 1 hour and 30 minutes oftime. This included communication enors from1 (bT'1
I (b)l4l on Janua1y 19, 2024, when l (b)l1 vials were being
loaded into the I
\UJ\"9

4
2.For batch (bH ibatc~ (b)l1 on April 7-8, 2024, there were 45 communication enors
totaling 2 hours and 3 minutes of time. One communication en or lasted 41 minutes and 46
seconds.

3.For batch (b'H-41 batch I (b)l1 on April 1-2, 2024, there were 54 communication enors
totaling 58 minutes of time.

The procedure 0317-SOP-MFG-00037 requires a breakdown notification if the enors continue during
the batch, but provides no specific instructions describing the threshold that would reguire a notification.
No breakdown notification was generated for batches I (bJ{,

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2000358686
: 04-23--202A
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FORM FDA 483 (09/08) PREVIOUS EDmON OBSOlEJE INSPECTIONAL OBSERVATIONS PAGE 15 of l8 PAGES
 DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
DISTRICT ADDRESS ANO PHONE NUMBER DATE(S) OF INSPECTION

1 2 4 2 0 Parklawn Drive, Room 2 032 4/ 1 5/2024 - 4/23/2024*

Rockville, MD 20857 FEJ NUMBER

3013 71 2903

NAME ANO TmE OF INDIVIDUAL TO WHOM REPORT lSSUEO

Rajesh Dessai, Chief - Manufactur ing

F IRM NAME STREET AOORESS

Zydus Lifesciences Limited Survey No . 4 3 4 /6/B & 4 3 4 / 1 /K, Vadodara -

Halol Highway
CITY. STATE. ZIP CODE. COUNTRY TYPE ESTABLISHMENT INSPECTED

Village - Jarod, Taluka - Wagho d ia , Finished Dr ug Manufact u rer

Gu jarat, 391 51 0 I ndia

Additionally, the alanns are not being acknowledged in a timelx manner with comments entered to
1 4
describe the activity occmTing. For example, durint = atc: : ] (b,{ } communication eITors on April 2,
4
2024, a! (b111(8 minutes 43 seconds duration), (b>< (8 minute 56 seconds duration)__, and
I (bJ ~1(8 minute 42 seconds duration) were not acknowledged in the system until L . (bH" on April
2, 2024. The comment was written as "NA" and did not assess the impact of the loss ofNVPC data prior
. ;I
to 1oadmg (b,{44j via
. 1s mto
. th e , ~(b1141i

OBSERVATION 7
Equipment and utensils are not cleaned and maintained at appropriate intervals to prevent contamination
that would alter the safety, identity, strength, quality or purity of the diug product.

1~ (bY{ill on line [ffiwere observed to have scratches, rough surfaces, and small
pieces that were not fully attached during aseptic filling ofl
6 4
crc j bate
11
lb on April 1
19, 2024.

2 tt>f(.il) on the inside ofth~ RA~ S (bY{ilj were observed to have a 1 (1,J(1 residue during aseptic
filling ofl
6 4
crc ) batch
4
(b><j on April 19, 2024.
OBSERVATION 8
Employees engaged in the manufacture of a di11g product lack the training required to perfo1m their
assigned functions.

Your fnm ' s manual vis:µal inspection process requires operators to inspec ~ mL (bY{ilj vials that L
contain I (bT'1Injection, USP for the presence of glass paiiicles. Your guahticat10n procedure
for visual inspectors Annexure_No. 0317-SOP-P 11-00001 -01 , utilizes aJCb>C4> Jwhich include~ mL
1
1 (b <
1 vials of (bJC1Inj . seeded with glass paiiicles. This 6}(4~ ailed to challenge
operators on identification of paiiiculates (glass particles) that are below <:> micrometers in size. Per

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2000358686
: 04-23--202A
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FORM FDA 483 (09/08) PREVIOUS EDmON OBSOlEJE INSPECTIONAL OBSERVATIONS PAGE 16 of l8 PAGES
 DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
DISTRICT ADDRESS ANO PHONE NUMBER DATE(S) OF INSPECTION

1 2 4 20 Parklawn Drive, Room 2032 4/15/2024 - 4/23/2024*

Rockville, MD 20857 FEJ NUMBER
3013712903

NAME ANO TmE OF INDIVIDUAL TO WHOM REPORT lSSUEO

Rajesh Dessai, Chief - Manufacturing

F IRM NAME STREET AOORESS

Zydus Lifesciences Limited Survey No . 434/6/B & 434/ 1 /K, Vadodara -

Halol Highway
CITY. STATE. ZIP CODE. COUNTRY TYPE ESTABLISHMENT INSPECTED

Village - Jarod, Taluka - Wagho d ia, Finished Drug Manufacturer

Gujarat, 391 51 0 India

your out of limit investigations, PR#s 53 1860, 691783, 699104, 708504, 73 1813, 735565, 740156,
744450 and 853661, glass particles, with a measured size as low as 150 micrometers, have been
• th.1s same pro duct, 1
1·denb·fi1ed m (tif~"11n·J. ,)"'(4)1.1qm·d packaged m (b1 mL,r (lirc.. via 1) .
• ~ i·
OBSERVATION 9
Procedures for the cleaning and maintenance of equipment are deficient regarding sufficient detail of the
methods, equipment, and materials used in the cleaning and maintenance operation, and the methods of
disassembly and reassembling equipment as necessa1y to assure proper cleaning and maintenance.

Your fnm 's Equipment Cleaning Validation Master Plan (CVMP), Document ID CVMP/001-07 and
Document LPL-CVAL-003-00, "Cleaning Validation Protocol cum Report", dated May 20, 2020,

. r
incon ectly identified the hardest to clean/most toxic API, manufactured on Lin[ ~~using non-dedicated
eqmpment, as
fully assess
1141
(b ·j De fi1c1enc1es
• • m_t • he finm ' s pro duct n•sk
(b)(4
d 1 b'l'
an c eana 1 1ty
· 1u de £ai·1ure to
lb~-' me
of m
. d'1v1'dua1 \U/\~

manufacturmg_ surfaces. Your cleanmg validation study also fa iled to assess tfie cleanabili[ of t]e APis
on the full ra_!lge of surfaces by excluding 1 <"ff j which is used in the consh11ction of the
4
WCl of the
I (b)<1

The following rejected batches off mished diug product, manufactured on Linej were found to be cross
•
contammate d wit• hi (b)<4l·1

(bY{-4 In' . j)~( ~mL

(6)l4l Inj . USP~ m~ mL

OBSERVATION 10
(b)(

(b)(
4

4
B=
Inj.
Inj.
mL
mL

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OF THIS PAGE Anastasia M Shields, Investigator ..ld'!Aecr
2000358686
: 04-23--202A
X ~US::'1

FORM FDA 483 (09/08) PREVIOUS EDmON OBSOlEJE INSPECTIONAL OBSERVATIONS PAGE 17 of18 PAGES
 DEPARTMENT OF HEALTH AND HUMAN SERVI CES
FOOD AND DRUG ADMINISTRATION
D ISTRICT ADDRESS ANO PHONE NUMBER DATE(S) OF INSPECTION

1 2420 Parklawn Drive, Room 2032 4/ 1 5/2024 - 4/23/2024*

Rockville, MD 20857 FEJ NUMBER
301371 2903

NAME ANO TmE OF INDIVIDUAL TO WHOM REPORT lSSUEO

Rajesh Dessai, Chief - Manufacturing

F IRM NAME STREET AOORESS

Zydus Lifesciences Limited Survey No . 434/6/B & 434/ 1 /K, Vadodara -

Halol Highway
CITY. STATE. ZIP CODE. COUNTRY TYPE ESTABLI SHMENT INSPECTED

Village - Jarod, Taluka - Wagho d ia, Finished Drug Manufacturer

Gujarat, 391 51 0 India

Appropriate controls are not exercised over computers or related systems to assure that changes in
master production and control records or other records are instituted only by authorized personnel.

The ~MODA software svstem is used for microbiology documentation of sampling and testing for the
I CbT'isystem l Cb)l1 and environmental monitoring. The system is intended to be integrated
with a barcode scanner to populate sample locations, sample info1mation, and time and date info1mation.
Analysts are pe1mitted to oveITide the use of the scanner and make manual entries. The software is not
configured with an autosave function, allowing analysts to make changes to entiy before manually
saving without committing the changes to the audit ti·ail.

*DATES OF INSPECTION
4/15/2024(Mon), 4/16/2024(Tue), 4/17/2024(Wed), 4/18/2024(Thu), 4/19/2024(Fri), 4/22/2024(Mon),
4/23/2024(Tue)

X =~
Anastasia MShields
Anastasia M. Shiekjs -S
OateSigned:04--23--2024 18:41:45

EMPLOYEE($) SIGNATURE DATE lSSUEO

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