Emcure Pharmaceuticals Limited 3/3/16

Department of Health and Human Services

Public Health Service

Food and Drug Administration
Silver Spring, MD 20993

Warning Letter
VIA UPS

WL: 320-16-08

March 3, 2016

Mr. Satish Mehta

Chief Executive Officer
Emcure Pharmaceuticals Ltd.,
Plot No. P-1, IT BT Park Phase II, MIDC, Hinjwadi
Pune 411 057, Maharashtra
India

Dear Mr. Mehta:

From January 27 to February 4, 2015, the U.S. Food and Drug Administration (FDA) inspected your
pharmaceutical manufacturing facility, Emcure Pharmaceuticals Limited, located at Plot No. P-1, IT
BT Park Phase II, MIDC, Hinjwadi, Pune 411 057, Maharashtra, India.
We identified significant violations of current good manufacturing practice (CGMP) regulations for
finished pharmaceuticals, Title 21, Code of Federal Regulations, Parts 210 and 211. These
violations cause your drug products to be adulterated within the meaning of Section 501(a)(2)(B) of
the Federal Food, Drug, and Cosmetic Act (the FD&C Act), 21 U.S.C. 351(a)(2)(B), in that the
methods used in, or the facilities or controls used for, their manufacture, processing, packing, or
holding do not conform to, or are not operated or administered in conformity with, CGMP.

We reviewed your February 25, 2015, response in detail. We acknowledge receipt of subsequent
responses.
Our investigators observed specific violations during the inspection, including, but not limited to, the
following.
1. Your firm failed to establish and follow appropriate written procedures that are designed to
prevent microbiological contamination of drug products purporting to be sterile, and that include
validation of all aseptic and sterilization processes (21 CFR 211.113(b)).
Poor Aseptic Processing Techniques
Our investigators observed poor aseptic processing techniques during the manufacture of (b)
(4) injection USP (aseptically filled for U.S. market) batch (b)(4), and (b)(4) injection (aseptically filled
for U.S. market) batch (b)(4). These poor techniques, which may compromise the sterility of
injectable products, included the following.
a. Your operator placed a (b)(4) cup on the floor of an ISO 7 area (Grade B) to collect water (b)
(4) from a (b)(4) unit. As operators set up ISO 5 (Grade A) filling line, they used the cup contents to
wet the mechanical assembly in the piston drive.
b. Operators crawled on the floor on their hands and knees under the filling line during routine
aseptic filling operation activities.
c.

An operator directed vials to the (b)(4) with his hand located directly above open vials.

d. During set up, an operator moved un-bagged sterilized tools from the ISO 7 to the ISO 5 area,
which he placed in the filling area near the stoppering equipment.
e. During (b)(4) unloading in the ISO 7 area, an operator dropped a sterilized lid from a (b)
(4) container onto the floor, which he then picked up and placed it back on the container.
f. Before performing aseptic filling activities in the filling room during aseptic setup, operators wore
goggles on their foreheads and exposed skin.
g. Operators opened (b)(4) barrier (b)(4) to adjust or remove vials from the line with bare hands,
instead of wearing Restricted Access Barrier Systems (RABS) (b)(4).
h. Operators carried unprotected sterilized RABS (b)(4) from the (b)(4) ISO 5 area, to the ISO 7
area, and then to the mobile Laminar Air Flow (LAF) ISO 5 area.

Your procedure BRD/GEN/011/08, Behavior and Aseptic Practices in Classified Areas, restricts
operators from touching the floor or leaning over opened vials. The above examples show that your
operators engaged in these practices.
Poor Sterilization Practices
Although your Validation Report PRD/PQ/107-04 REP-07 references the RABS (b)(4) loading
pattern that should have been followed, the inspection also documented that operators did not follow
the validated loading pattern configuration for RABS (b)(4) during the (b)(4) cycle. For example, the
RABS (b)(4) were (b)(4) inside a (b)(4)and not properly configured in the (b)(4) to ensure
appropriate sterilization of the (b)(4) surfaces, as described in the procedure.
Facility Design
Your facility design may represent an additional contamination risk to the products you manufacture.
For example, we observed an employee crawling under filling equipment to get to the area where he
performed other critical operations. Collecting (b)(4) water from the bottom of the filling machine to
lubricate equipment, as mentioned above, also raises concerns about the design and qualification of
your equipment.
Your response is inadequate because it is limited to a review of video recordings reviewed by FDA
and referenced on the FDA Form 483. Your response does not include an evaluation of all available
videos to identify all batches that could be affected by poor aseptic practices and associated risks.
In response to this letter, list the batches manufactured from November 2014 to the end of the
inspection. Include your independent third partys evaluation of these recordings, and their findings.
Also include a detailed action plan describing the revisions made to your procedures, the content of
employee training, and how video recordings are evaluated and by whom.
2. Your firm failed to establish laboratory controls that include scientifically sound and appropriate
specifications, standards, sampling plans, and test procedures designed to assure that drug
products conform to appropriate standards of identity, strength, quality, and purity (21 CFR
211.160(b)).
Unreliable Environmental and Personnel Monitoring
Your environmental monitoring (EM) and personnel monitoring (PM) data are not reliable because of
the materials and procedures you use to conduct EM and PM tests. Multiple elements of these
programs are scientifically unsound, including the following.
a. Our investigators observed dried media plates you used for surface and personnel monitoring in
the (b)(4)facility incubators. We documented that 36 of (b)(4) plates inside the Plant (b)(4) incubator
showed signs of dryness and desiccation.

Your response indicated that you initiated a study to assess the signs of desiccation in (b)(4) plates.
You committed to switch to outsourcing (b)(4) and (b)(4) plate supplies. However, your use of
dried (b)(4) plates in prior testing was not scientifically sound, and compromised your results.
In response to this letter, indicate steps you have taken to determine whether products made under
these conditions meet limits. Also explain how you will improve laboratory controls to prevent use of
unsuitable media in the future.
b. Your EM data for the filling areas did not specify the sampling location of the RABS (b)(4) used
during filling and (b)(4) operations. SOP QCD/MIC/034-10 Procedure of Surface Monitoring by
Swab does not require sampling from predetermined (b)(4) locations identified as critical risk points
of your filling and (b)(4) operations. Instead, the procedure permits individual operators to determine
the location to be sampled. Additionally, you only collected a (b)(4) swab sample from (b)(4), and
failed to sample other (b)(4) used in daily aseptic operations.
According to your response, you will increase the sampling frequency for your RABS (b)(4) tests.
However, you failed to specify whether you will ensure sampling of (b)(4) used in daily aseptic
operations.
In response to this letter, specify (b)(4) locations in the RABS and your improved sampling
procedures.
c. Your firm lacked personnel monitoring data for aseptic operations on line (b)(4). Documents
generated in the laboratory for personnel monitoring did not identify specific employees involved in
filling operations.
According to your response, it was difficult to accurately locate plates corresponding to specific
operators, because the plates were not uniquely identified. You indicated that operators were trained
in aseptic practices; practices we observed were deviations that you considered serious lapses by
the facility management. Furthermore, you acknowledged serious gaps especially with respect to
the suspected data integrity and falsification in data generated in your environmental monitoring
program.

Your response is inadequate. Despite your claim that your operators were appropriately trained,
video recordings of your manufacturing operations clearly showed that your employees were not
following proper aseptic techniques.
These violations posed a significant risk to the sterility of your products. You may wish to review
FDAs
guidancewww.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm07
2171.htm to help you improve your manufacturing of sterile products. You are responsible for

ensuring that your quality and production management organizations oversee critical operations in
your facility. We acknowledge your decision to cease production during the FDA inspection and (b)
(4).
Inadequate Visual Inspection Program
In addition to the inadequacies of your EM and PM programs, our inspection documented that your
visual inspection program is unreliable. Your qualification and re-qualification of operators did not
include determining the operators ability to detect and identify known product defects for (b)
(4) products or products filled in amber vials.
For example, one inspector failed to correctly identify major defects as defined in your SOP
PRD/VAL/003 -05 Qualification of Visual Inspection Operators. Your inspector incorrectly identified
three of (b)(4) vials containing fiber material, one of (b)(4) vials containing particles, and one of (b)
(4) vials that had the incorrect volume from the Kit (b)(4) challenge set. A second inspector also
failed to correctly identify two of (b)(4) units containing fiber, 2 of (b)(4) units containing particles, and
one of (b)(4) units that had the incorrect fill volume from the (b)(4) Kit (b)(4) challenge set.
Your SOP PRD/OPN/065-09 Visual Inspection of Vials permits inspectors to classify defects such as
fragmented glass subjectively, as critical or major. Your SOP has no objective criteria for these
classification decisions.
According to your response, you will revise the qualification procedure for visual inspections and
requalify your inspectors. However, you did not include the revised SOP or your schedule for
completing re-qualification.
In your response to this letter, provide a detailed summary of improvements you have made to your
visual inspection qualification program. Include training you have provided and will continue to
provide to your visual inspectors. Also indicate how you will determine the effectiveness of your
visual inspection training program, how you will improve your defect classification, and what you will
do if visual inspectors are unable to correctly discriminate between critical and major defects.
In addition to details on the training and re-qualification of your visual inspectors, indicate how you
will ensure that no batches with critical defects were released to the market, given that your visual
inspection program relied on subjective determinations of criticality by visual inspectors who were
unable to correctly classify defects during the inspection. Conduct and provide the results of a risk
assessment of products that were visually inspected by unqualified employees and released for
distribution. Indicate steps you have taken to ensure that patients have not been, or will not be,
exposed to products with critical defects.
3. Your firm failed to ensure that laboratory records included complete data derived from all tests
necessary to assure compliance with established specifications and standards (21 CFR 211.194(a)).

During our inspection, we observed multiple examples of incomplete, inaccurate, or falsified

laboratory records.
a. EM records for active air monitoring of the aseptic filling area reported samples as being
collected when they were not actually collected, and some records documented purported EM
results of zero colony forming units (CFU) even when the samples for which those results were
reported were not actually collected. Contemporaneous video recordings that FDA reviewed during
the inspection showed that such EM samples had not been collected, even though your laboratory
records reported results for those samples. Our investigators observed your firms practice of
falsifying EM results for samples that were not collected for multiple drugs, including (b)(4) injection
USP lot (b)(4) and (b)(4) injection lot (b)(4).
Although your laboratory records for these products and lots indicated that you collected active air
samples, the video we reviewed during the inspection demonstrated that operators did not actually
collect the samples. During the inspection, your microbiologist confirmed that these EM samples
were never collected. Additionally, two microbiologists informed the investigator that media plates
were labeled and submitted for incubation as though they had been exposed to the environment.
However, these media plates were never actually exposed to the environment. Your microbiologist
indicated that this practice was routine and due to work pressure. Because the EM results for
samples were falsely reported as having been collected and/or as having produced no CFU growth,
you lack assurance that the injectable drugs your firm produced in this area were sterile at the end of
the aseptic filling process.
b. Our review of EM records from January 2014 through September 2014 found that no samples
had exceeded the action levels for any of the (b)(4) filling lines in your (b)(4) plant, or for the filling
line in Plant (b)(4). However, we observed 12 microbiological plates in the incubator showing EM
results that required further action during our inspection of your laboratory.
These EM records provide critical data on environmental trends and whether environmental control
is maintained during aseptic filling of a batch. Environmental monitoring should promptly identify
potential routes of contamination, allowing for implementation of corrections before product
contamination occurs.
In your response, you stated there have been serious gaps in the management, oversight and
execution of the environmental monitoring program, especially with respect to the suspected data
integrity and falsification of data concerns. Your response also indicated that you revised
procedures, provided training, and reviewed documents from March 2013 to January 2015. Your
investigation confirmed that EM samples were not collected and the data was fraudulent. You
acknowledged these problems in your response and took some corrective actions. However, your
response is inadequate because you have not demonstrated how you can ensure that EM records
generated before the inspection were reliable and accurate, or how the falsification of some of your
reported EM data may have affected the quality of your products.

We acknowledge your (b)(4) after the inspection, your management changes, and your engagement
with consultants. However, your investigation was not extended to all systems and areas that may
have been affected by your questionable practices. You have not provided data sufficient to
demonstrate that all products released for distribution were manufactured with the appropriate
environmental controls in place during aseptic filling operations.
Furthermore, data falsification and manipulation, and your reliance on incomplete records to release
product to the market, are repeat violations. A February 2014 inspection of solid (b)(4) dosage
operations at this same facility also reported data manipulation and falsification of test results
generated by your firm, along with other deficient laboratory practices that also resulted in products
being recalled from the U.S. market.
In your 2014 response, you made a similar commitment to hire a third party auditor to conduct a
comprehensive audit of all laboratory electronic and hard copy data for tests conducted for all
release and stability finished product. Our 2015 inspection found continuing practices of data
falsification and manipulation at your facility, indicating that previous corrections were ineffective.
c. Our investigators observed poor documentation practices during production and in-process
testing.
i. Media fill batch (b)(4) documented a check by operation performed by an operator who was not
present at the facility. This operator signed checked by for 63 out of (b)(4) individual (b)(4). In
addition, during this media fill, a Quality Assurance (QA) individual signed checked by for observing
the intervention (b)(4) of conveyor belt from (b)(4) to (b)(4) on December 2, 2014, but the QA
individual was not present in the filling room when this intervention was performed, and did not view
it.
Your response admitted that the individual signing the QA checked by column was not present
during that portion of the media fill (b)(4) to (b)(4) on December 2, 2014.
ii. Disinfection of the filling machine was not completed before filling of (b)(4) injection USP
batch (b)(4)(aseptically filled, (b)(4), and distributed to the U.S. market). Records were made for
cleaning on November 13, 2014, from (b)(4) to (b)(4), but review of videos show that cleaning did not
match records.
Your response confirms that the cleaning and disinfection did not occur on November 13, 2014.
iii. On January 29, 2015, an operator performed in-process weight checks for (b)(4) during the
filling operation performed at 13:30. This activity was not documented until 14:15. In addition,
another weight check operation performed at (b)(4) had not been documented on the record when
reviewed at (b)(4) by the inspector.

Your response indicated that activities that occurred on January 29, 2015, are deviations.
iv. Cleaning of the (b)(4) and parts of the filling machine was not completed before filling (b)
(4) injection USP batch (b)(4) (aseptically filled, (b)(4), and distributed to the U.S. market). Records
were made for cleaning on November 26, 2014, from 08:57 to 09:26, but videos show that cleaning
did not match records.
Your response indicates that the cleaning and sanitization of the conveyor (b)(4) was missed on one
side.
Your investigation into this issue is inadequate because it did not consider other in-process tests, or
whether the operator(s) have been involved in the same poor documentation practices for others
batches. Your response lacks an assessment of your documentation practices to determine the
extent of the problem in your facility.
Conclusion
Violations cited in this letter are not intended to be an all-inclusive list. You are responsible for
investigating and determining the causes of the violations identified above, for preventing their
recurrence, and preventing other violations.
If, as a result of receiving this warning letter or for other reasons, you are considering a decision that
could reduce the number of finished drug products produced by your manufacturing facility, FDA
requests that you contact CDER's Drug Shortages Staff immediately, as you begin your internal
discussions, at [email protected] so that we can work with you on the most effective way
to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also
allows you to meet any obligations you may have to report discontinuances in the manufacture of
your drug under 21 U.S.C. 356C(a)(1), and allows FDA to consider, as soon as possible, what
actions, if any, may be needed to avoid shortages and protect the health of patients who depend on
your products. In appropriate cases, you may be able to take corrective action without interrupting
supply, or to shorten any interruption, thereby avoiding or limiting drug shortages.
Until all corrections have been completed and FDA has confirmed corrections of the violations and
your firms compliance with CGMP, FDA may withhold approval of any new applications or
supplements listing your firm as a drug product manufacturer. In addition, your failure to correct these
violations may result in FDA continuing to refuse admission of articles manufactured at Emcure
Pharmaceuticals Limited, Plot No. P-1, IT BT Park Phase II, MIDC, Hinjwadi, Pune 411 057,
Maharashtra, India, into the United States. Under Section 801(a)(3) of the FD&C Act, 21 U.S.C.
381(a)(3), articles may be refused admission because manufacturing methods and controls do not
appear to conform to CGMP within the meaning of Section 501(a)(2)(B) of the FD&C Act, 21 U.S.C.
351(a)(2)(B).

Within 15 working days of receipt of this letter, please notify this office in writing of the specific steps
that you have taken to correct and prevent the recurrence of violations. In addition to the specific
requests noted above, supporting documentation should include your third party assessment of the
following.
1. A comprehensive evaluation of the extent of the inaccuracy of your recorded and reported data.
Include a detailed action plan to fully investigate the extent of your deficient documentation and data
management practices.
2. A risk assessment of the potential effects of observed failures on the quality of your drug
products, including the effects of deficient documentation and data management practices, aseptic
processing breaches, and inadequate environmental monitoring program. Determine the effects of
your failures on the quality of drug products released for distribution and the data supporting all
associated submissions.
3. A management strategy for your firm that includes the details of your corrective action and
preventive action plan. Describe the actions you will take, such as contacting your customers,
recalling drugs, conducting additional testing and/or adding lots to your stability programs, or other
steps to assure the quality of your drugs manufactured under the deficient conditions discussed
above. Also indicate measures you will take, such as revising procedures, implementing new
controls, training or re-training personnel, or other actions to prevent the recurrence of CGMP
violations, including breaches of data integrity.
Provide copies of supporting documentation. If you cannot complete corrective actions within 15
working days, state the reason for the delay and the date by which you will have completed the
corrections. Additionally, if you no longer manufacture or distribute the drug products at issue,
provide the date(s) and reason(s) you ceased production. Send your reply to:
Maan Abduldayem
Compliance Officer

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Compliance Actions and Activities

Warning Letters
2015

Sun Pharmaceutical Industries Ltd. 12/17/15

Department of Health and Human Services

Public Health Service

Food and Drug
Administration
Silver Spring, MD 20993

WARNING LETTER

VIA UPS
WL: 320-16-04

December 17, 2015

Mr. Avinash Joshi

Quality Head SPIL Halol
Sun Pharmaceuticals Industries Ltd.
Halol-Baroda Highway, Halol,
Gujarat, 389 350, India

Dear Mr. Joshi:

From September 8-19, 2014, investigators from the U.S. Food and Drug Administration
(FDA) inspected your pharmaceutical manufacturing facility, Sun Pharmaceutical Industries Ltd.,
Halol-Baroda Highway, Halol, Gujarat.

We identified significant violations of current good manufacturing practice (CGMP) regulations for
finished pharmaceuticals, Title 21, CFR, Parts 210 and 211. These violations cause your drug
products to be adulterated within the meaning of Section 501(a)(2)(B) of the Federal Food, Drug, and
Cosmetic Act (the FD&C Act), 21 U.S.C. 351(a)(2)(B). The methods used in, or the facilities or
controls used for, their manufacture, processing, packing, or holding do not conform to, or are not
operated or administered in conformity with, CGMP.

We reviewed your October 10, 2014, response in detail. It lacks sufficient corrective actions. We
acknowledge receipt of your additional correspondence of December 12, 2014; February 10, 2015;
and May 5, 2015.

Our investigators observed specific violations during the inspection, including, but not limited to the
following.

1.

Your firm failed to establish and follow appropriate written procedures that are designed to

prevent microbiological contamination of drug products purporting to be sterile, and that include
validation of all aseptic and sterilization processes (21 CFR 211.113(b)).

a.

You failed to perform adequate unidirectional airflow studies (smoke studies) under dynamic

conditions to determine how the movement of air and personnel during aseptic operations could
pose risks to product sterility. In addition, the studies indicate that your aseptic processing equipment
is not properly designed. For example, an audit of your smoke studies found:

Significant airflow turbulence, including air moving in an (b)(4) direction, in the laminar airflow
(LAF) unit in which aseptic (b)(4) and tubing connections are made for the (b)(4) process. Also,
the studies lacked dynamic simulation of this critical intervention.

No dynamic smoke studies to demonstrate unidirectional airflow during the manual aseptic
transfer of (b)(4)units into the (b)(4) used for transport to the (b)(4).

Inadequate evaluation of airflow patterns in your stopper (b)(4) area, and turbulence around
the stopper (b)(4).

Lack of smoke studies during aseptic filling line setup activities.

Operators (b)(4) open filled vials when adjusting the stopper (b)(4), which is a hazard to
sterility assurance.
Without smoke study data to demonstrate unidirectional airflows over all aseptic operations and

processing steps, you cannot show that your processes are designed to prevent microbiological
contamination or provide adequate assurance of product sterility.

In your response to the FDA-483, you acknowledged the need for design improvements and new
airflow studies. You also proposed to revise your smoke study protocol (b)(4) to cover all aseptic
interventions and material movement, and to conduct smoke studies by November 15, 2014. Your
firm has submitted neither a revised smoke test (b)(4), nor a satisfactory new smoke study.

In response to this letter, perform and send a video of new dynamic smoke studies that fully evaluate
unidirectional airflow during your aseptic manufacturing operations, and a copy of your revised
smoke test (b)(4). Also explain how your firm will be comprehensively evaluating the design of your

aseptic processing operation, and describe any major equipment and facility upgrades that are
planned.

b.

You rejected vials during media fills without written justification or explanation.

Your media fill reconciliation records failed to include a specific description of the reason why your
firm rejected vials from each batch. Although a significant number of media-filled units were rejected
with no written justification, you found the media fill runs in the following table acceptable.

Table 1. Media Fill Runs & Total Rejected Vials

Batch

Manufacturing
Date (dd/mm/yy)

Number of
Filled Units

Number of Filled
Units Rejected

(b)(4) Products
(b)(4)

08/07/14

(b)(4)

(b)(4)

25/06/14

(b)(4)

(b)(4)

24/12/13

(b)(4)

(b)(4) Products
(b)(4)

03/08/13

(b)(4)

(b)(4)

09/07/13

(b)(4)

(b)(4)

15/03/13

(b)(4)

Your media fill batch records did not include further rationale for rejecting these vials, although your
Process Simulation Using Media Fill SOP PAR-095/09 states that the types of rejected vials must
be identified before incubation. During the inspection, your deputy general manager and your Quality
Assurance (QA) manager confirmed that the rejected vials were discarded during the media fill
process without assignable causes recorded or documented.

Your media fill batch record also failed to adequately document non-routine interventions performed
to simulate the aseptic manufacturing operation for (b)(4)(injection USP) (b)(4) mg/mL, (b)(4) mL,
and (b)(4) mL. In addition, you failed to define and justify the most challenging conditions for each
media fill performed (e.g., fill volume, container size, maximum hold times, personnel present during
aseptic filling, (b)(4) operations, routine and non-routine intervention, assuring routine use of (b)
(4) rather than (b)(4)) as required in your Process Simulation Using Media Fill SOP PAR-095/09.

Your response is inadequate for reasons including, but not limited to, the following.

Your response appropriately committed to remove no more units than that specified in
production SOPs regarding local line clearances. However, you still allowed for removal of units in
media fills based on a subjective normal practice judgment. Local clearances are appropriate in
media fills only if production SOPs clearly specified the number of units to clear and the type of
intervention.

You failed to include adequate improvements to your media fill procedure to ensure that you
account for each filled and rejected vial in future media fills more specifically and quantitatively.

The current standard for maintenance clearances was open-ended (e.g., at least (b)
(4) units are cleared). The type of maintenance clearances and associated clearance
requirements should be better defined.

Units with minor defects to a (b)(4) were classified as non-integral.

You failed to explain how your reliance on non-specific information on types of interventions
and reasons for vial rejections affected the conclusions of your media fill studies. You did not
show how you can rely on the results of your media fills to conclude that your aseptic process
operation for(b)(4) (injection USP) (b)(4)mg/mL, (b)(4) mL, and (b)(4) mL was in a state of
control.

You did not perform a comprehensive evaluation to determine whether you increased
customer risk by accepting units in commercial batches that would have been removed in a
media fill.

Your revised SOP PAR-095/09 and your revised media fill batch records did not specify limits
and adequate descriptions for rejects, nor did they indicate what you do if the number of rejects
exceeded your acceptance limit.
In response to this letter, include a risk assessment regarding your practice of rejecting media fill

vials without a written justification and acceptance limits. Also provide your revised SOP on media
fills, specifically addressing the changes you have made related to rejection and investigation of nonintegral vials. Include specific data from all media fills conducted following your revised SOP to
demonstrate its effectiveness.

For our current thinking on this topic and others relating to aseptic processing of sterile drugs, see
our guidance for industry, Sterile Drug Products Produced by Aseptic Processing-Current Good
manufacturing Practice, at http://www.fda.gov/downloads/Drugs/.../Guidances/ucm070342.pdf.

2.

Your firm failed to maintain floors, walls, and ceilings of smooth, hard surfaces that are easily

cleanable in aseptic processing areas (21 C.F.R. 211.42(c)(10)(iv) and (i).

The floors, walls, and ceilings in your aseptic processing area were not maintained as smooth, hard
surfaces that were easily cleaned. Our investigator documented the presence of leaks in the form of
water stains and ceiling damage in the parenteral manufacturing area personnel corridor. The FDA
investigator observed buckets with water collected from ceiling leaks and other leaks in this
manufacturing area.

During the inspection, we noted that your Engineering Department investigated the leaks. However,
you failed to address environmental control in the parenteral manufacturing area during the period of
concern, or to determine how leaks in this area could compromise the quality of your aseptically-filled
products.

In your response of October 10, 2014, you committed to conduct an overall assessment regarding
the potential for rain water leakage by October 30, 2014, and to revise the Engineering Procedure
for Building Maintenance SOP ENG-033. You also proposed revising QA Reporting & Compliance
of (b)(4) Observations SOP QA-078 to include (b)(4) QA monitoring of the facilities. We
acknowledge receipt of these revised procedures. However, your response is inadequate because it
did not include a retrospective assessment of your environmental control (including but not limited to
environmental monitoring data) in the affected areas.

In response to this letter, provide a summary of your environmental data and other facility
maintenance since the inspection. Address the impact on environmental control from the start of the
leakage and for the subsequent six months. Include all instances in which fungi or bacterial
sporeformers were identified, and also explain to what extent microbial identifications were done in
these areas. Provide all microbial results from the affected area and its immediately adjacent rooms,
and describe any adverse trends or results at or above action levels. Explain the potential effects on
quality of the drug products manufactured during this period and include a summary of your risk
assessment.

3.

Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch

or any of its components to meet any of its specifications whether or not the batch has already been
distributed (21 CFR 211.192).

a.

Your July 6, 2010, Out-of-Specification (OOS) report 141/2010 documented other unknown

impurities in a 6-month accelerated stability test of (b)(4) mg/(b)(4) mL (b)(4) Injection manufactured
for the European market, exhibit batches (b)(4). Under (b)(4), you also manufactured this drug for
distribution in the U.S. market.

You attributed the failures to product degradation from your (b)(4) process, but you failed to identify
the specific impurities or their root causes. You did not extend your investigation to batches
distributed in the United States. You also failed to notify the FDA of these stability failures.

Further, the unknown peaks were not thoroughly investigated. According to your response, you
conducted your investigation at your Sun Research & Development facility (the R&D facility), a
separate facility in (b)(4).

Your response is inadequate because it did not include a comprehensive assessment of the
informal investigations of drug quality test data generated by your R&D facility.

Decisions to retest samples should be based on a strong scientific rationale and predetermined
testing objectives. Any retesting plan should also include the maximum number of retests. These
rationales and criteria should be specified in advance, in a written investigative protocol. For more
information about handling OOS results, refer to FDAs Guidance for Industry: Investigating Out-ofSpecification (OOS) Test Result for Pharmaceutical Production, October 2006.

In your October 2014 response, you also stated that you tested (b)(4) exhibit batches of (b)(4) mg/
(b)(4) mL (b)(4) Injection from lots (b)(4) for the U.S. market as your impurity investigation
progressed. According to your summary, all test results were within specification.

The fact the impurity levels were within specification for these exhibit batches does not justify the
failure to conduct a thorough investigation into the significance of the peaks and to identify all
affected batches, including those intended for the U.S. market. Your investigation did not identify a
root cause or source of the impurities. You provided no justification to support your assertion that the
impurities are from the (b)(4) process, and proposed to reduce (b)(4) assurance by ceasing (b)
(4) without first determining whether the impurities pose any meaningful toxicological risk.

In response to this letter, please provide a progress report on your efforts to identify the noted
unknown peaks.

b.

You failed to initiate an investigation for an extraneous peak identified during the analysis of (b)

(4) residue in your cleaning validation report for (b)(4) tablets, (b)(4) mg, lot (b)(4) (dated August 20,
2011). Your cleaning validation report concluded that the extraneous peak was caused from
contamination while handling the sample. You have not provided a scientific rationale or evidence to
support this conclusion.

You did not initiate an investigation to determine the root cause for this extraneous peak at the time
of the event. You stated that you began an informal investigation at the time of the event and later
incorporated the informal findings in a formal investigation. However, you did not provide evidence of
the informal testing you conducted, nor did you indicate whether the results were included as part of
your later documented investigation. You did not document a deviation regarding informal testing of
the solutions.

In response to this letter, provide your formal investigation, including quantitative results obtained and
copies of all raw data (e.g., laboratory notebooks; other records) from both the informal and formal
investigations.

4.

Your firm failed to establish and document the accuracy, sensitivity, specificity and reproducibility

of test methods employed by the firm (21 C.F.R. 211.165(e)).

Analytical method validation demonstrates that a testing procedure is suitable for its intended use.
The outcomes of method validation are important to assess the quality, reliability and consistency of
analytical results.

a.

You did not evaluate the accuracy of your dissolution test method for (b)(4) tablets, (b)(4) mg by

UV during method validation in your January 10, 2009 analytical method validation report
#MJ/ANAR/597 Determination of Dissolution of (b)(4) in (b)(4) tablets, (b)(4) mg by UV Method.

In your response, you stated that you based your method validation on a May 12, 2007 method
validation master plan that did not require accuracy studies. However, both the Sun Corporate
Validation of analytical methods used for the evaluation of drug products SOP CALS-034/03 (March
3, 2011) and your site Validation of analytical methods used for the evaluation of drug products
SOP QCS-074/01 (May 30, 2013) require accuracy studies. We acknowledge your response that you
completed the supplemental validation for (b)(4)tablets, (b)(4) mg and your plan to review the
completeness of validation (e.g., UV methods) for other products made at your site. We will evaluate
the analytical raw data and associated chromatograms, and your more comprehensive remediation,
during our follow-up inspection.

b.

Your November 21, 2007 method validation failed to evaluate the capacity to separate unknown

late-eluting peaks for (b)(4) mg/(b)(4) mL, (b)(4) Injection, high performance liquid chromatography
(HPLC) Related Substance Method II, (STP #0011409) MJ/ANAR/467.

In your October 2014 response, you stated that your revised method, including a (b)
(4) chromatographic run time to detect unknown late eluting peaks, was approved by FDA on
February 25, 2014.

Your response is inadequate in that you asserted that the analytical method was properly validated.
Our investigators documented repeated revisions to this method that suggested that your method
was not promptly and adequately improved after first detecting and investigating the impurities in
2010 and continuing after the revised method was approved. Recent events include the following.

Between January 2013 and September 2014, you repeated the analysis of 42 samples
because of improper peak shape and merged peaks.

On March 22, 2014, you again revised the method to ensure proper separation between late
eluting peaks and adjacent blank peaks.

In your response of October 10, 2014, you referenced late-eluting peak resolution issues
found in a lot of (b)(4) finished product.

In your response of October 10, 2014, you reported that you revised your method again on
September 19, 2014, to address resolution of the late eluting peaks.
These repeated revisions to your analytical method STP #0011409 indicate that (b)(4) method may

not have been properly validated and was not promptly improved. In your response to this letter,
discuss how your firms quality system oversees test method adequacy and assures needed
improvements.

c.

During a walkthrough of your microbiology laboratory on September 8, 2014, the investigator

observed that sterile gloves intended for use in the manufacture of sterile products were partially
immersed in (b)(4) medium. The investigator found that the fingers of the gloves were not immersed;
the Testing Procedure for Sterile (b)(4)Gloves SOP lacked a requirement for full immersion of
gloves in sterility test media; and the test method was not validated.

In your response to this letter, provide your revised test procedure and validation report.

5.

Your firm failed to routinely calibrate, inspect, or check according to a written program designed

to assure proper performance and to maintain adequate written records of calibration checks and
inspections of automatic, mechanical, or electronic equipment, including computers, used in the
manufacture, processing, packing, and holding of a drug product (21 C.F.R 211.68(a)).

Since 2005, you have been using an un-validated and unqualified Agilent data acquisition unit (DAU)
to monitor the temperature of the microbiological incubation rooms for media filled vials. During our
inspection, your quality engineer officer and QA manager stated that the DAU has not been qualified,
and that you have not used a preventative maintenance schedule for this equipment during the nine
years that it has been in use.

Your October 10, 2014 response confirmed that you have no records documenting qualification of
the DAU. Because this equipment was never qualified or validated, it is unclear whether it accurately
monitored the temperature in your incubation rooms. You indicated that you would requalify the DAU.
We acknowledge the corrective actions and will verify them upon re-inspection.

6.

Your firm failed to establish appropriate controls over computers and related systems to assure

that changes in master production and control records or other records are instituted only by
authorized personnel (21 CFR 211. 68(b)).

You lacked audit trails or other sufficient controls to facilitate traceability of the individuals who
access each of the programmable logic controller (PLC) levels or Man-Machine Interface (MMI)
equipment. You had no way to verify that individuals have not changed, adjusted, or modified
equipment operation parameters.

Access to production equipment used in parenteral manufacturing and solid (b)(4) dosage forms
used a password shared by four or five individuals to gain access to each individual piece of
equipment and access level. During our inspection, your Executive Production and QA manager
confirmed that the password was shared. Neither your operators nor your supervisors had individual
passwords.

During our inspection, firm officials also confirmed that you had not established or documented a
control program to describe the roles and responsibilities of production equipment system
administrators. There was also no record documenting the individuals who have access to the
production equipment or the manner in which individual personnel access production equipment.

In your response, you indicated that you have performed a comprehensive review of the PLCs and
manufacturing equipment associated with the production of parenteral and solid (b)(4) dosage forms
to assess your access controls and traceability to individual operators. You suggested that
traceability to the individual operator could be determined through a hybrid system using the batch
manufacturing record and equipment logbook. However, because you used shared login credentials
that did not permit identification of a specific person using the shared login, you have not shown how
your hybrid system could link specific actions to a specific operator.

In your response, you also stated that you will conduct a retrospective risk assessment to evaluate
the effects of your deficient computerized system controls on the quality of the products
manufactured using this automated equipment. However, you did not indicated the timeframe for
your review, your criteria for evaluating the effects of these deficiencies on your products, or any
actions needed for products within expiry.

Finally, in your response, you indicated that you planned to (b)(4). Your response is inadequate
because you did not indicate what controls you will implement in the interim to assure that only
authorized personnel change your production or other records.

In response to the letter, provide your retrospective review and risk assessment of lots manufactured
using equipment with shared passwords. Explain how you will identify which operators or personnel
performed and recorded specific activities, your criteria for evaluating how manufacturing and quality
of your products has been affected by your deficient controls, and any actions needed to assure the
quality, safety, and efficacy of products within expiry.

Conclusion
These examples are serious CGMP violations. Your quality system does not ensure the quality,
safety, and effectiveness of your drug products. It is essential that executive management
systematically improve their oversight of manufacturing quality to ensure sustainable quality
assurance.

We acknowledge your commitment to work with a third party consultant to conduct a comprehensive
assessment of your firms manufacturing, laboratory, and quality operations. However, it is your
responsibility to ensure that the third party audit includes a full evaluation of your systems,
operations, procedures, and documentation practices, and that you implement appropriate changes
in response.

Violations cited in this letter are not intended as an all-inclusive list. You are responsible for
determining causes, for preventing recurrence, and for preventing other violations.

If, as a result of receiving this warning letter or for other reasons, you are considering a decision that
could reduce the number of active pharmaceutical ingredients and/or finished products produced by
your manufacturing facility, FDA requests that you contact CDERs Drug Shortages Staff
immediately, as you begin your internal discussions, at [email protected] so that we can
work with you on the most effective way to bring your operations into compliance with the law.
Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report
discontinuances in your drug manufacture under 21 U.S.C. 356C(a)(1) and allows FDA to consider,
as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health
of patients who depend on your products. In appropriate cases, you may take corrective action
without interrupting supply, or to shorten any interruption, thereby avoiding or limiting drug shortages.

Until you complete all corrections and we have confirmed your compliance with CGMP, we may
withhold approval of any new applications or supplements listing your firm. We may also refuse
admission of articles manufactured at Sun Pharmaceutical Industries Ltd., Halol-Baroda Highway
Halol, Gujarat, into the United States under Section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3).

Articles may be subject to refusal of admission pursuant to Section 801(a)(3) of the FD&C Act, 21
U.S.C. 381(a)(3), in that the methods and controls used in their manufacture do not appear to
conform to CGMP within the meaning of Section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351(a)(2)
(B).

Within 15 working days of receipt of this letter, please notify this office, in writing, of the specific steps
that you have taken to correct and prevent the recurrence of violation. If you cannot complete
corrective actions within 15 working days, state the reasons for the delay and the date by which you
will have completed the corrections. Send your reply to:

Cesar E. Matto
Compliance Officer
U.S. Food and Drug Administration
White Oak, Building 51, Room 4235
10903 New Hampshire Ave
Silver Spring, MD 20993

Please identify your response with FEI #3002809586.

Sincerely,
/S/
Thomas Cosgrove, J.D.
Director
Office of Manufacturing Quality

Office of Compliance
Center for Drug Evaluation and Research

2015

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