Warning Letters > Baxter Healthcare Corporation 1/20/11 Page 1 of 2

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Baxter Healthcare Corporation 1/20/11

Public Health Service

Department of Health and Human Services Food and Drug Administration
San Juan District
466 Fernandez Juncos Avenue
San Juan Puerto Rico 00901-3223
Telephone: 787-474-9500
FAX: 787-729-6851

WARNING LETTER
11-SJN-WL-04
CERTIFIED MAIL
RETURN RECEIPT REQUESTED
January 20, 2011

Mr. Robert L. Parkinson

Chairman, President, and CEO
Baxter Healthcare Corporation
One Baxter Parkway
Deerfield, IL 60015-4633
Dear Mr. Parkinson:
During our July 14 to August 26, 2010 inspection of your pharmaceutical manufacturing facility, Baxter Healthcare Corporation, located at No. 250
Road No. 144 Jayuya, Puerto Rico, investigators from the Food and Drug Administration (FDA) 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 product(s) to be adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the 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.
The inspection at Jayuya, Puerto Rico, also identified that your products are misbranded under section 502(f)(1) of the Act [21 U.S.C. § 352(f)(1)].
In addition, the inspection at Jayuya, Puerto Rico, and our September 21 - 30, 2010 inspection at the Baxter Healthcare Corporation, located at
Route No. 3 KM 142.5 Guayama, Puerto Rico, identified your firm's failure to submit NDA Field Alert Reports (FARs) to the FDA as required by 21
C.F.R. § 314.81(b)(1)(i) and (ii), and section 505(k) of the Act [21 U.S.C. § 355(k)].
We have reviewed your firm's response of September 15, 2010, and October 20, 2010, and note that they lack sufficient corrective actions.
Specific violations observed during the inspection include, but are not limited, to the following:

1. The Jayuya Facility (Puerto Rico)

A. CGMP Violations

1. Your firm has not thoroughly investigated the failure of a batch or any of its components to meet its specifications whether or not the
batch has already been distributed [21 C.F.R. § 211.192].
For example, investigations, (b)(4) and (b)(4) identified an equipment malfunction as the root cause of discolored product. These investigations
did not address the possibility of carryover of solution due to the equipment malfunction. Additionally, the investigations did not extend to other lots
manufactured on the non-dedicated filling line. Subsequently, your firm released 17 lots of product that were at risk of cross contamination to the
market.
Furthermore, your firm failed to thoroughly investigate and correlate consumer complaints for discolored drug product distributed by your firm. On
September 7, 2010, your firm initiated a recall of 17 lots of drug product associated with the equipment failure but only after our inspection
identified deficiencies in your investigation and management of consumer complaints. Your firm identified the root cause of the discoloration that
occurred on October 30, 2009, approximately one year prior to initiating a recall.
Lastly, your investigation concluded that the administering health care professionals (i.e., pharmacist, nurse, or physician) would identify any
discoloration and prevent the usage of the drug product. It is unacceptable to rely upon the health care professional to fulfill your Quality Control
Unit responsibilities.
This is a repeat observation from the March 2008 inspection.
2. Your firm failed to ensure your container closure system provided adequate protection against foreseeable external factors in storage and
use that can cause deterioration or contamination of the drug product [21 C.F.R. § 211.94(b)].
For example, your firm identified 542 incidences through consumer complaints of product defects such as, leaks, bursts, and premature activation
during the period of January 2008 to August 2010. These are critical defects that can impact sterility and stability of your product. Your firm
identified that the probable cause was the result of defective materials used in the manufacture of the container closure system.
Your response is not adequate since the sampling plans described are not based on appropriate statistical criteria to sufficiently identify these
known potential defects, especially given the history of the supplier for this container closure system.
Furthermore, your final product inspection procedure and use of a (b)(4) does not appear to be effective in preventing shipments of product with
critical defects to the marketplace. Additionally, our data indicates there may be other cases of foreign substances in products manufactured at your
facility such as an insect found in the intravenous solution of Sodium Chloride and dirt reported inside of (b)(4) and the (b)(4) of Travasol®.
Please provide an evaluation of the suitability of any of these potentially affected lots.

B. Misbranding
Besides the approved labeling of your products, you developed and distributed a color chart to provide instructions to the end user when to use or
not to use your products based on the discoloration of the solution. During the inspection, our investigator requested information provided to the

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Warning Letters > Baxter Healthcare Corporation 1/20/11 Page 2 of 2

FDA in relation to the subject color chart. No analytical data was provided in support of the color chart development, nor was this labeling submitted
as part of the New Drug Application (NDA) or Abbreviated New Drug Application (ANDA) process as a supplement. The failure to do renders your
product(s) misbranded under section 502(f)(1) of the Act [21 U.S.C. § 352(f)(1)], because the approved labeling fails to bear adequate directions
for use. The end user should not be expected to make a determination of product safety and effectiveness based on a color chart that was not
reviewed and approved by the Agency. It is your responsibility to ensure that your products comply with their predetermined specifications to
ensure their quality, safety, and effectiveness.
II. The Jayuya and Guayama Facilities (Puerto Rico)
A. Post Marketing Reports
1. Your firm failed to submit NDA Field Alert Reports (FARs) within three (3) working days of receipt of information concerning a product
defect. This includes any bacteriological contamination, any significant chemical, physical, or other change, any deterioration in the
distributed drug product, or any failure of one or more distributed batches of drug product to meet the specifications established for it in the
application [21 C.F.R. §314.81(b)(1)(ii)]. For example:
Since February 2010, your Jayuya facility has received approximately 43 incidences of consumer complaints related to discoloration in your product
15% Clinisol Sulfite Free (Amino Acid) Injection, 500 ml, lot # P244269. The complaint reports document variability in color intensity of the product
from dark yellow to dark brown. Although an internal investigation confirmed a correlation between the broken damper and the discolored amino
acid samples solutions, no FAR was submitted to the Agency as required under the regulations.
In 2001, your Guayama facility became aware of a product defect with its inhalation anesthesia Suprane: discoloration and particulate matter. Your
firm began receiving complaints in 2004 and has received at least 199 complaints since then.
Beginning in 2008, your firm has received at least 39 complaints regarding particulate matter in the product prompting a Health Hazard Assessment
for these problems in 2009. Again, no FAR was submitted to the Agency as required under the regulations.
The violations cited in this letter are not intended to be an all-inclusive statement of violations that exist at your facilities. You are responsible for
investigating and determining the causes of the violations identified above and for preventing their recurrence and the occurrence of other
violations. It is your responsibility to assure compliance with all requirements of federal law and FDA regulations within your corporation.
You should take prompt action to correct the violations cited in this letter. Failure to promptly correct these violations may result in legal action
without further notice including, without limitation, seizure and injunction. Other federal agencies may take this Warning Letter into account when
considering the award of contracts. Additionally, FDA may withhold approval of requests for export certificates, or approval of pending drug
applications listing your facility, until the above violations are corrected. FDA may re-inspect to verify corrective actions have been completed.
Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct violations.
Include an explanation of each step being taken to prevent the recurrence of violations and copies of supporting documentation. If you cannot
complete corrective action within fifteen working days, state the reason for the delay and the date by which you will have completed the correction.
Your reply should be sent to the following address: Food and Drug Administration, Attention: Carlos A. Medina, Compliance Officer, 466 Fernandez
Juncos Avenue, San Juan, Puerto Rico 00901-3223.

Sincerely,
/S/
Maridalia Torres
San Juan District Director

cc:
Mr. Eladio Alvarez, Plant General Manager
Baxter Healthcare SA
PO Box 518
Jayuya PR 00664

Mr. Eidiol Ghigliotty, General Manager

Route No.3 Km. 142.5
PO Box 1290
Guayama, PR 00785

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Warning Letters > Claris Lifesciences Limited Page 1 of 5

Home > Inspections, Compliance, Enforcement, and Criminal Investigations > Enforcement Actions > Warning Letters

Inspections, Compliance, Enforcement, and Criminal Investigations

Claris Lifesciences Limited

Public Health Service

Department of Health and Human Services Food and Drug Administration
Silver Spring, MD 20993

Warning Letter

VIA UPS
WL: 320-11-003
November 1, 2010

Mr. Arjun S. Handa

Chief Executive Officer & Managing Director
Claris Lifesciences Limited
Chacharwadi - Vasana
Ahmedabad, Gujurat 382 213
India
Dear Mr. Handa,
The U.S. Food and Drug Administration (FDA or Agency), conducted inspections of Claris Lifesciences Limited, located at Chacharwadi - Vasana,
Ahmedabad, India, and Claris Lifesciences, Inc. (a wholly-owned subsidiary of Claris Lifesciences Limited), located at 1445 US Route 130, North
Brunswick, New Jersey 08902-3100 (hereinafter collectively referred to as “Claris”). The inspection of Claris Lifesciences Limited (hereinafter
referred to as “Claris India”), took place during June 5-16, 2010 (June 2010 inspection). The inspections of Claris Lifesciences, Inc. (hereinafter
referred to as “Claris U.S.”), took place during July 1-13, 2009 (July 2009 inspection), and January 22 to February 2, 2010 (January/February 2010
inspection).
During our June 2010 inspection of Claris India, FDA investigators 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 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.
The June 2010 inspection also revealed that Claris failed to submit NDA Field Alert Reports (FARs), to FDA in compliance with section 314.81(b)(1)
of FDA’s regulations [21 C.F.R. § 314.81(b)(1)(ii)], as required by section 505(k) of the Act [21 U.S.C. § 355(k)]. An applicant is required to
submit, within three working days of receipt, information concerning any bacteriological contamination, or any significant chemical, physical, or
other change or deterioration in the distributed drug product, or any failure of one or more distributed batches of drug product to meet the
specifications established for it in the application.
In addition, based on our review of the labeling for your Sodium Bicarbonate Injection drug product, manufactured by Claris India and distributed
by and through Claris U.S., and information collected during the inspections of Claris U.S. in July 2009 and January/February 2010, we conclude
that Claris has marketed an unapproved new drug without an approved application. The introduction or delivery for introduction into interstate
commerce of the product is a violation of sections 301(d) and 505(a) of the Act [21 U.S.C. §§ 331(d) and 355(a)]. The unapproved new drug
product is also misbranded under section 502(f)(1) of the Act [21 U.S.C. § 352(f)(1)], and therefore, the introduction or delivery for introduction of
the drug into interstate commerce is also a violation of section 301(a) of the Act [21 U.S.C. § 331(a)].
We have reviewed responses from Claris dated August 12, 2009, October 7, 13, and 30, 2009, February 24, 2010, and July 3, 2010, but conclude
that they lack sufficient corrective actions as discussed below.
CGMP VIOLATIONS
Specific violations observed during the June 2010 inspection conducted at Claris India include, but are not limited, to the following:
1. Your firm has failed to thoroughly investigate the failure of a batch or any of its components to meet its specifications whether or not the batch
has already been distributed [21 C.F.R. § 211.192].
a. The complaint investigation discussed in the undated report submitted with Claris India’s July 2010 response to the FDA Form 483 and
titled, “Complaint Investigation Report Metronidazole Injection USP Ondansetron In 5% Dextrose Injection” (Complaint Investigation Report),
is inadequate. It lacks sufficient evaluation of several complaints of intravenous (IV) bag contamination, and does not provide scientific
justification and supporting evidence regarding the root cause identified. For example:

1) On April 15, 2010, your firm received a complaint from a U.S. distributor (Sagent Pharmaceuticals) informing you that
Metronidazole Injection USP IV bags (lot A090744) were contaminated with a swirling mass, which the complainant identified as the
fungus Cladosporium species. There is no information in the Complaint Investigation Report to show that Claris initiated an
investigation to determine the root cause and extent of the problem until April 26, 2010, when Claris received this contaminated large
volume parenteral and examined it.

On May 5, 2010 the same customer (Sagent Pharmaceuticals) reported that another lot of Metronidazole Injection USP bags
(A090742) was contaminated with fungi (Mucor species).

The Complaint Investigation Report does not adequately address either of this complainant’s contamination findings, or the root cause
of the problems. For example, your customer’s test results confirmed the presence of visual contaminants without discovering any
leaks in the intravenous (IV) bags. You have claimed that the uniqueness of your firm’s method to detect leaks supersedes the
customer’s methods. Accordingly, you disregarded their findings regarding the integrity of the IV bag because their test was not
performed or supervised by your own laboratory. This does not address the presence of fungi. For instance, the investigation
conducted by Sagent involving Metronidazole Injection USP bags (lot A090744) did not detect a leak on the IV bag tested (dye
penetration by injection), even though fungi (Cladosporium species) were found inside the IV bag.

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Furthermore, your firm’s conclusions were based solely on the returned bags examined, and do not take into account the overall
implications, extent, or root cause of the detected contamination.

In your response to this letter, include your final investigation, assessment, rational and the corrective actions implemented
addressing your failure to initiate the complaint investigation promptly. Also, explain if the Dye Ingress method (Container Closure
Integrity) is still used to release your IV bags to the market, or if a different method was developed as part of the investigation to
detect leakage in the bags.

2) On May 6, 2010, your firm received a complaint from the (b)(4) indicating a problem when they opened a case that contained six
Metronidazole Injection USP IV bags (lot A090460). The technician from the pharmacy observed that fungi were in the IV bag (as well
as inside the overwrap). Claris submitted a Field Alert Report (FAR) on June 3, 2010, however, your Complaint Investigation Report
indicates that no leak or contamination was found in the bags received from (b)(4). Please explain this discrepancy in your response
to this letter.

3) On May 31, 2010, your customer (Pfizer) reported that Metronidazole Injection USP IV bags (lot A090722) were contaminated with
fungi (Cladosporium species) and Gram positive bacteria (Brevibacterium casei). Pfizer returned 33 unopened Metronidazole Injection
USP bags, but your Complaint Investigation Report failed to identify the contaminants that Pfizer visually observed in at least 31 of
these bags.

4) Through its investigation your firm identified defective printing stereos, along with packaging, shipping, and handling as the primary
root causes of the contamination. The Complaint Investigation Report, however, failed to explain why a defective printing stereo would
only have affected IV bags that were returned by your customers, and not other lots produced and released for distribution. Moreover,
the Complaint Investigation Report lacks supporting evidence to demonstrate that the packaging, shipping, and handling contributed
to the contamination.

In your response to this letter, address those issues, and also explain why these stereos were being used during the manufacturing
process and how the suppliers of these defective stereos were qualified, and provide a complete explanation of how and when Claris
became aware of the defect(s). In your written response to this letter, provide specific information regarding the requalification of the
printing operation, and any formal study conducted to demonstrate the new printing parameters that the response states your firm
adopted will prevent recurrence of the problem.

5) Claris India acts as a contract manufacturer for IV bag products marketed by other firms, as well as a distributor of some batches
under Claris’s own label. Your responsibility as a contract manufacturer is to inform all of your customers of a significant production
problem or possible product hazard immediately. In fact, Claris India’s Quality Agreements with its customers requires that your firm
notify the other party within (b)(4) business days of any quality issues related to the product. We note that your firm received
worrisome complaints of lost IV bag package integrity and contamination. Yet, the Complaint Investigation Report fails to indicate what
steps Claris took to ascertain whether other customers were affected by this issue, or to notify all customers of the potential for
significant contamination. Please explain how and when Claris identified and informed all customers affected by your IV bag
manufacturing problems. Also include your SOP describing how you keep customers promptly informed of significant occurrences (e.g.,
complaints, OOS, rejections, major deviations or discrepancies, any potential product hazard), concerning the products you
manufacture for them.

6) The Complaint Investigation Report also reflects a number of other shortcomings in the investigation. For example, the Complaint
Investigation Report fails, among other things, to:

(a) Identify when the problems that lead to the damaged IV bags and contamination of the product started.

(b) Provide a thorough evaluation and supporting evidence regarding the origin of the contamination that extended to at least
eight batches of two products - Metronidazole Injection USP bags and Ondansetron Injection USP in 5% Dextrose Injection
bags. The contamination was reported through at least five complaints.

(c) Provide a rationale why other products filled in the same packaging line, with the same bags and printing process, were not
affected or contaminated. Similar complaints of contamination extended to batches distributed outside the United States, but
the Complaint Investigation Report provides no details of when the complaints were received, or whether an investigation was
conducted.

(d) Include an evaluation of the time that elapsed between the manufacturing/filling and printing process of the different
batches, and the time the contamination was detected and reported by Claris India. The investigation also lacks details
regarding the number of examined lots on hand, tests performed, and the sampling plan used.

(e) Supply an evaluation of the set up process, as well as the number and type of damaged bags generated during the set up.
We are concerned with your proposed identification of root causes, because it fails to explain how the sharp edges and stereos
only affected the bags that complainants identified, and not any of the bags remaining under your control, or other released
batches.

Your firm’s response dated July 3, 2010 (July 2010 response), does not provide sufficient information regarding the aforementioned
issues. Please include in your response to this letter information regarding each of the issues noted above, and include the nature and
origin of contamination or leakage complaints received for lots of the same products that may have been distributed outside of the
United States. In addition, please provide a summary of your shipping and handling validation studies under stress conditions.

b. Your investigation into an incident involving IV bag filling rooms and Laminar Air Flow (LAFs) losing positive pressure is inadequate. For
example,

During the production of Metronidazole Injection USP bags (lot A000241) the bag filling room and LAFs – intended to provide a constant flow
of clean air out of the work area to prevent potentially contaminated air from entering – lost positive pressure. Your July 2010 response
indicated that your firm rejected only the bags filled after 9:30 a.m. until the line was stopped, despite the fact that in the same response,
your firm indicated that the last acceptable positive pressure was at 9:21 a.m. The deviation report, however, failed to provide an adequate
rationale for not rejecting all the bags at risk. Specifically, the July 2010 response indicates that the reason for not rejecting the bags filled
after 9:21 a.m., which potentially could have been affected, was because the microbial environmental monitoring results were within
acceptable limits. This approach, however, is unacceptable because the loss in pressure may also have affected the accuracy or reliability of
the environmental monitoring results; there is, thus, no assurance that all bags filled after 9:21 a.m. were unaffected by the loss of positive
pressure, and therefore free of microbial contamination.

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Your written procedures related to bag filling and environmental monitoring should be revised. They should ensure that all units of drug
products filled between the time the last acceptable differential pressure reading was obtained, and the time the room returns to acceptable
conditions, be rejected.

As noted above, we are concerned about the inadequate investigation into the contamination of your IV drug products, process deviation, and the
inappropriate documentation practices cited during this inspection. Please provide a corrective action plan that describes your revised procedures,
corrective and preventive actions, and controls to ensure product quality.

This plan should include a comprehensive retrospective review of your root cause analysis and the effectiveness of your corrective/preventive
actions of the contamination in your drug products, raw material suppliers, equipment adequacy, sterilization cycles, and cleaning and maintenance
procedures implemented to ensure that all products produced and released by your quality unit meet specifications. It should also include an
evaluation of the independence, authority, and effectiveness of your firm’s quality unit to rapidly address significant manufacturing issues. A robust
quality unit will be essential for your firm to address any emerging or ongoing manufacturing issue in the future, and prevent the distribution of
adulterated product.

2. Your firm does not have adequate written procedures for production and process control designed to assure that the drug products you
manufacture have the identity, strength, quality, and purity they purport or are represented to possess [21 C.F.R. § 211.100(a)]. For example:

The inspection revealed that your firm fails to have a procedure or process in place to evaluate in-process units that are rejected due to defects
during the filling of Metronidazole Injection USP bags. In fact, the investigators documented that for Metronidazole Injection USP bags (lot
A000247), 48 rejections occurred during the filling process No deviation was documented and no investigation was conducted, and you have not
documented whether or not the rejected units were caused by a significant process deviation that directly affects the integrity of the other IV bags
in the production lot.

Your July 2010 response is inadequate because it fails to include your rationale for releasing production lots with unexplained deviations, on the
basis that the filling yield was found within limits.

Please provide a retrospective analysis of the in-process and finished units of Metronidazole Injection USP bags, Ciprofloxin Injection USP bags, and
Ondansetron Injection USP bags that were rejected due to defects found during your filling, printing, and packaging operations. Include the amount
of defective units in this analysis. We also recommend that an adequate timeframe be considered for this study to enable you to establish trends
regarding the amount and type of defect, and amount of rejected units per batch. Provide information on the type of defects identified, and the
corrective and preventive actions implemented.

3. Your firm failed to assure that equipment used in the manufacture, processing, packing, or holding of a drug product is of appropriate design for
its intended use [21 C.F.R. § 211.63]. For example:

The calibration of thermocouples (TCs) used during the validation of your terminal steam sterilizers is not performed before or after the autoclave
cycles. Your response failed to provide data to support that the TCs used during the validation runs are within acceptable calibration range. The
calibration of these TCs provides assurance of an accurate reading of the temperature in the sterilizer. Please provide your sterilization cycle
summary for all the terminal sterilizers and cycles used by your facility, with the appropriate parameters and conclusion of the data generated.

4. Your firm has not established appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be
sterile [21 C.F.R. § 211.113(b)]. For example:

The written procedures related to the production simulations – “media fills” - conducted to validate your capability to aseptically produce small
volume parenteral (SVP) were found to be inadequate. The media fills for this line did not represent actual operations used in the aseptic production
of ampoules and vials. For instance, the media fill performed by your firm in October 2009 failed to simulate the interventions performed in actual,
routine production. For example, a routine production of a (b)(4) Injection vials lot would take approximately (b)(4) hours to be filled. Your
written procedures (reflected in production protocols and batch record forms) for routine production require that an intervention take place every
(b)(4) minutes for fill-weight verification measurements. Our review found, however, written procedures for the media fill simulation (reflected in
media fill protocol), require performance of this fill-weight verification measurement only (b)(4) times throughout the media fill process. In your
response to this letter, provide the finalized protocol and the summary report including all data generated during the execution of this media fill.

5. Your firm does not clean and maintain equipment at appropriate intervals to prevent contamination that would alter the safety, identity, strength,
quality, or purity of the drug product [21 C.F.R. § 211.67(a)].

During the inspection the investigators observed three dispensing vessels used in the step prior to terminal sterilization that were labeled clean,
however, the vessels had liquid residue inside. Your response indicated that this liquid is from final cleaning with (b)(4) rinse. The presence of
liquid residue in a vessel (labeled as clean) that is later used to manufacture sterile drug products is unacceptable. In your response to this letter,
provide the production lot numbers that included use of these vessels. Additionally, provide documentation to support that your firm’s cleaning
procedures and practices are adequate to prevent contamination of your products. Lastly, provide the investigation report with your findings
including the cleaning methods performed, as well as the corrective and preventive actions for all of your other equipment.

6. Batch production and control records prepared for each batch of drug product produced do not include complete information relating to the
production and control of each batch [21 C.F.R. § 211.188]. For example:

Your firm failed to exercise adequate control over issuance of production batch records. The inspection revealed that not all pages of the batch
record used in the production area are stamped and dated when issued. The purpose of this requirement is to ensure that the correct master
production record is used to produce the batch record. There should be procedures and controls in place to maintain the batch record during the
manufacturing of your drug product. In your response, provide your established procedures regarding issuance of batch records to provide
assurance that appropriate controls are implemented, and that all the accurate pages of the issued batch records and other records are used.
FIELD ALERT REPORTING VIOLATIONS
FDA “Field Alert” reporting requirements require applicants to submit certain information about distributed drug products, including information
concerning bacteriological contamination, any significant chemical, physical, or other change or deterioration product, or any failure of a distributed
batch to meet the specifications established for it, to the appropriate FDA district office within three working days of receipt by the applicant [21
C.F.R. § 314.81(b)(1)]. The regulation helps establish an “early warning system” by requiring that applicants bring significant problems to the
Agency’s attention promptly in order to prevent potential safety hazards from drug products already in distribution and also to prevent potential
safety hazards with drug products manufactured in the future.

Based on the observations and information obtained during the inspection, Claris failed to submit Field Alert reports as required by 21 C.F.R. §
314.81(b)(1)(ii). For example:

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a. Your firm received visibly contaminated Metronidazole Injection USP bags (lot A090744) on April 15, 2010. The field alert report submitted
to FDA was dated May 6, 2010.

b. Your firm received a contaminated sample of Metronidazole Injection USP bags (lot A090460) on May 6, 2010, but the field alert report
was sent to FDA on June 3, 2010.

c. Your customer ((b)(4)) found three instances of a leaking bag with possible microbial growth of Metronidazole Injection Solution Bag and
reported this to Claris India on May 20, 2009 (lot A080758), November 10, 2009 (lot A080784), and May 4, 2010 (lot A080765). None of
these complaints were sent to FDA.
UNAPPROVED NEW DRUGS VIOLATIONS
Observations and information obtained during the July 2009 and January/February 2010 inspections, and review of labeling, further indicate that
Claris, including by and through its wholly-owned subsidiary Claris U.S., has marketed an unapproved new drug in violation of the Act. Specifically,
information obtained during those inspections indicates your firm has marketed the following prescription drug:

• Sodium Bicarbonate Injection (8.4% w/v; 250 mL and 500 mL glass vials)

As labeled, the above product is a drug within the meaning of section 201(g)(1)(B) and (C) of the Act [21 U.S.C. § 321(g)(1)(B) and (C)], because
it is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease and it is intended to affect the structure of function of
the body. Further, this drug product, as marketed by your firm, is a “new drug” within the meaning of section 201(p) of the Act [21 U.S.C. § 321
(p)], because it is not generally recognized as safe and effective for its labeled uses. Under sections 301(d) and 505(a) of the Act [21 U.S.C. §§ 331
(d) and 355(a)], a new drug may not be introduced or delivered for introduction into interstate commerce unless an application approved by FDA
under either section 505(b) or (j) of the Act [21 U.S.C. § 355(b) or (j)], is in effect for the product. Based upon our information, there is no FDA-
approved application on file for the above product. The marketing of this product without an approved application constitutes a violation of these
provisions of the Act.

Additionally, because the above product is intended for conditions that are not amenable to self-diagnosis and treatment by individuals who are not
medical practitioners, adequate directions cannot be written for it so that a layman can use this product safely for its intended uses. Consequently,
its labeling fails to bear adequate directions for its intended uses, causing it to be misbranded under section 502(f)(l) of the Act [21 U.S.C. § 352(f)
(1)]. Because your product lacks a required approved application, it is not exempt under 21 C.F.R. § 201.115 from the requirements of section 502
(f)(1) of the Act. The introduction or delivery for introduction into interstate commerce of this product therefore also violates sections 301(a) of the
Act [21 U.S.C. § 331(a)].

We acknowledge Claris’s assertions of “grandfather” status and have responded to that claim in a letter to Arun Menon, President-North America,
Claris U.S., dated May 27, 2010. In summary, materials submitted did not demonstrate that Claris’s sodium bicarbonate injection, USP 8.4% as
marketed today has the same formulation, strength, dosage form, route of administration, indication, intended patient populations, and other
conditions of use as a pre-1938 product.

There was no evidence indicating your product is identical to a product, bearing labeling containing identical representations concerning the
conditions of its use, that was introduced prior enactment of the Act in 1938.

The introduction or delivery for introduction into interstate commerce of misbranded products without approved new drug applications violates, inter
alia, sections 301(a) and 301(d) of the Act [21 U.S.C. §§ 331(a), 331(d)]. Therefore, Claris should discontinue distributing this unapproved new
drug immediately. In addition, new drugs without an approved application as required may not be lawfully imported into the United States.
Therefore, new drugs without an approved application are subject to refusal of admission pursuant to section 801(a)(3) of the Act [21 U.S.C. § 381
(a)(3)].

We request that you outline the action Claris is taking to discontinue the marketing of this unapproved new drug product. Also please note that if
you are no longer marketing this product, you must update the drug listing files in accordance with 21 C.F.R. § 207.30(a)(2).
ADVERSE DRUG EXPERIENCE REPORTS
Section 505(k)(1) of the Act [21 U.S.C. § 355(k)(1)], and 21 C.F.R. §§ 314.80 and 314.981, require an applicant to establish and maintain records
and make reports to FDA of adverse drug experiences, along with certain other data or information. Failure to comply with section 505(k) of the Act
is a prohibited act under section 301(e) of the Act [21 U.S.C. § 331(e)]. In addition, section 310.305 of FDA’s regulations, [21 C.F.R. § 310.305],
requires manufacturers, packers, and distributors who market prescription drug products that are not the subject of approved drug applications, to
establish and maintain records and make reports to FDA of serious, unexpected adverse drug experiences associated with the use of their drug
products.
During our July 2009 and January/February 2010 inspections of Claris U.S., FDA investigators identified violations of post-marketing adverse drug
experience reporting regulations of Title 21, Code of Federal Regulations Parts 310 and 314, and section 505(k)(1) of the Act [21 U.S.C. § 355(k)
(1)]. We acknowledge the responses, dated August 12, 2009, October 7, 13, and 30, 2009, and February 24, 2010, from Arun Menon, President of
Claris U.S., to the FDA Form 483s issued following the inspections, and Claris’s stated commitment to developing and implementing adequate
written procedures, including a number of promised additions and changes to Claris India procedures (SOPs) for handling ADE reporting. Indeed,
information obtained from the inspections and the Claris responses also indicates that Claris India and Claris U.S. have shared responsibility for
activities involved in meeting their ADE reporting obligations under FDA regulations. Claris also indicated certain activities have been transferred to
an independent contractor, (b)(4). We note, however, that Claris has not provided all of the SOPs noted in its correspondence and, hence, the
revised procedures for certain ADE reporting activities remain unclear. We request that Claris meet with FDA staff to discuss a resolution to this
situation.
CONCLUSION
The violations cited in this letter are not intended to be an all-inclusive statement of violations that exist at your facility. You are responsible for
investigating and determining the causes of the violations identified above and for preventing their recurrence and the occurrence of other
violations. If you wish to ship your products to and distribute them in the United States, it is the responsibility of your firm to ensure compliance
with all U.S. standards for CGMP and all applicable U.S. laws and regulations.
You should take prompt action to correct the violations cited in this letter. Until all corrections have been completed and FDA has confirmed
corrections of the violations and your firm’s compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your
firm as a drug product manufacturer. In addition, until such time as your manufacturing practices are verified to comply with CGMPs, your firm will
remain under FDA Import Alert, and FDA will continue to refuse admission of all articles manufactured at Claris India, Chacharwadi - Vasana,
Ahmedabad, India into the United States. The articles are subject to refusal of admission pursuant to section 801(a)(3) of the Act [21 U.S.C. § 381
(a)(3)], in that, the methods and controls used in their manufacture do not appear to conform to Current Good Manufacturing Practice within the
meaning of section 501(a)(2)(B) of the Act [21 U.S.C. § 351(a)(2)(B)]. Failure to promptly correct violations affecting your products that are being
marketed within United States commerce may also result in legal action without further notice, including, without limitation, seizure and injunction.
Other federal agencies may take this Warning Letter into account when considering the award of contracts.
Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct violations.
Include an explanation of each step being taken to prevent the recurrence of violations and copies of supporting documentation. If you cannot
complete corrective action within fifteen working days, state the reason for the delay and the date by which you will have completed the correction.

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Warning Letters > Claris Lifesciences Limited Page 5 of 5

Additionally, your response should state if you no longer manufacture or distribute Ciprofloxacin, Metronidazole, Ondansetron, Fluconazole,
Levofloxacin, (b)(4), and provide the dates and reasons you ceased production. Please identify your response with FEI # 3004610460.
We also recommend that you contact Paul Balcer at [Link]@[Link], or 301-796-3525, within five days of receipt of this letter to schedule
a regulatory meeting with Claris U.S. and Claris India. If you have questions or concerns regarding this letter, contact Maan Abduldayem,
Compliance Officer, at the below address and telephone number.

U.S. Food and Drug Administration

Center for Drug Evaluation and Research
Division of Manufacturing and Product Quality
International Compliance Branch
White Oak, Building 51
10903 New Hampshire Ave
Silver Spring, MD 20993
Tel: (301) 796-3916
Fax: (301) 847-8741

Sincerely,
/S/
Deborah M. Autor
Director
Office of Compliance
Center for Drug Evaluation and Research

cc: A Menon, President – North America, Claris Lifesciences, Inc.

___________________________________________________________________________________
1 Section 314.98 of the regulations requires applicants holding an approved abbreviated new drug application (ANDA) to comply with certain
reporting and recordkeeping requirements of 21 CFR § 314.80.

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Warning Letters > Lonza Biologics, Inc. 9/1/2011 Page 1 of 2

Home > Inspections, Compliance, Enforcement, and Criminal Investigations > Enforcement Actions > Warning Letters

Inspections, Compliance, Enforcement, and Criminal Investigations

Lonza Biologics, Inc. 9/1/2011

Public Health Service

Department of Health and Human Services Food and Drug Administration
New England District
One Montvale Avenue
Stoneham, Massachusetts 02180
(781) 587-7700
FAX: (781) 587-7556

NWE-27-11W

VIA UNITED PARCEL SERVICE

OVERNIGHT DELIVERY

September 1, 2011

Stephan Kutzer
Chief Operating Officer
Lonza Biologics, Inc.
101 International Drive
Portsmouth, NH 03801

Dear Mr. Kutzer:

During our April 4, 2011 to May 6, 2011 inspection of your pharmaceutical and active pharmaceutical ingredient (API) manufacturing facility, Lonza Biologics, Inc.,
located at 97 South Street, Hopkinton, MA, investigator(s) from the Food and Drug Administration (FDA) identified significant violations of Current Good
Manufacturing Practice (CGMP) regulations for Finished Pharmaceuticals, Title 21, Code of Federal Regulations, Parts 210 and 211, and from CGMP for the
manufacture of APIs. These violations cause your drug product(s) and APIs to be adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug,
and Cosmetic Act (the 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 have reviewed your firm’s response of May 26, 2011, and note that it lacks sufficient corrective actions.

Specific violations observed during the inspection include, but are not limited, to the following:

CGMP Violations of Drug Products and Components:

1. Your firm has not thoroughly investigated the failure of a batch or any of its components to meet its specifications whether or not the batch has already been
distributed [21 C.F.R. § 211.192].

For example, your firm failed to conduct an investigation for ONTAK (b)(4) after an unidentified peak was observed co-eluting with the primary product peak at the
(b)(4) and (b)(4) month stability time point (b)(4) analyses.

In your response, your firm states that you did not conduct an investigation for this lot because the same co-eluting peak is routinely observed in both the sample
and reference chromatograms. Your firm indicates that the occurrence of co-eluting peaks in the (b)(4) method has been investigated and established that the
method resolution observed was “sufficient to a varying degree.” Your response, however, fails to provide an adequate scientific rationale to describe the reason
why the co-eluting peak is significantly larger in this lot (as compared to the reference chromatogram), address the impact of the overlap of larger peaks, and
evaluate how the method can be refined to prevent overlapping peaks.

CGMP Violations of Active Pharmaceutical Ingredients:

1. Inadequate or lack of an investigation of critical deviations or a failure of a batch to meet its specifications or quality standards.

For example, your firm failed to conduct an investigation after a number of ONTAK Drug Substance Lots (b)(4) failed to meet release specifications for residual (b)
(4).

In your response, your firm states that the lots described above were manufactured in 2009 after (b)(4) had suspended DNA testing due to on-going DNA method
investigations. Your firm also states that (b)(4) did not communicate to you their commitments to the FDA until May 2010 in which, (b)(4) planned to conduct a
minimum of (b)(4) independent tests for residual DNA until the assay variability was resolved. Thus, your firm initiated and documented a planned deviation, and
began testing batches from the 2009 campaign in June 2010 with results received in December 2010 and January 2011. Your response, however, is inadequate
because your firm has yet to address the failure to investigate the Out-of-Specification (OOS) results and identify a root cause.

2. Failure to validate analytical test methods used for API for potency testing.

For example, your firm failed to validate the ONTAK (b)(4) to quantify Peak A for potency and robustness. For example, only (b)(4) chromatographic columns
were able to adequately separate (b)(4) and (b)(4). Your firm has been unable to determine why the chromatographic columns of the same make and model had
variability and could not provide adequate separation.

In your response, your firm states that the same RPLC column type has been used for 15 years for the (b)(4) method. In the last 2 years, there has been a
change in the resolution (i.e., column-to-column variability outside the previously observed range). (b)(4) out of (b)(4) columns of the same model number,
produced by the same vendor used in this analytical methodology, provided adequate resolution of (b)(4) from (b)(4). Your firm states further that (b)(4) is
making significant progress with both the (b)(4) and the (b)(4) column approaches, which may address both the (b)(4) peak issues. (b)(4) Your response,
however, is inadequate because there is no assurance that the current columns are providing acceptable separation.

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Warning Letters > Lonza Biologics, Inc. 9/1/2011 Page 2 of 2

3. Failure of your quality unit to exercise its responsibility to ensure that APIs manufactured are in compliance with CGMP, including meeting established
specifications for quality and purity. For example:

a. Your firm’s quality control unit (QCU) failed to ensure that all released lots and any lots still in inventory of ONTAK API meet revised specifications for the
level of (b)(4) (lot #(b)(4)), a chemical used during the (b)(4) step in the API manufacturing process. Specifically, your firm released a lot of ONTAK API to the
sponsor’s site in December 2010 with a concentration level of (b)(4), although your firm had already implemented the required change to the (b)(4) release
specification (implemented on March 16, 2010).

In your response, your firm has committed to providing an adequate Standard Operating Procedure (SOP) that requires generating interim Certificates of Analysis,
comparing the interim Certificate of Analysis to the current approved specification, and keeping lots in quarantine until you have confirmed that specifications are
met. Your response, however, is inadequate because it is unclear whether you will evaluate all lots of ONTAK API to ensure that the lots meet required
specifications.

b. Your firm failed to reanalyze five production lots of ONTAK (b)(4) originally analyzed using a general DNA (b)(4) method not specifically validated for
ONTAK, although a more specific validated DNA (b)(4) Method was approved.

In your response, your firm states that you had implemented the use of the general (b)(4) method per client request. Your firm tested and released product using
this method prior to any communication from the FDA to the license holder requesting further validation of the more specific (b)(4) method. Your response is
inadequate because there is no assurance from your firm or the license holder that the initial DNA analytical results were valid.

c. Your firm issued an outdated Certificate of Analysis for ONTAK (Lot #(b)(4)) that was manufactured on September 4, 2009, after receiving the DNA test
results on March 3, 2011. The outdated Certificate of Analysis did not include a revised purity specification for the (b)(4) as required by the BLA.

In your response, your firm states that you agree that there was a failure to check the amended Certificate of Analysis against the current specification as required
by your disposition procedure, (b)(4). This failure was due to human error and your firm will retrain appropriate staff on this aspect of the procedure. Your
response, however, is inadequate because there is no assurance that other staff did not use the outdated Certificate of Analysis.

The violations cited in this letter are not intended to be an all-inclusive statement of violations that exist at your facility. You are responsible for investigating and
determining the causes of the violations identified above and for preventing their recurrence and the occurrence of other violations. It is your responsibility to assure
compliance with all requirements of federal law and FDA regulations.

You should take prompt action to correct the violations cited in this letter. Failure to promptly correct these violations may result in legal action without further
notice including, without limitation, seizure and injunction. It is our expectation that the corrections implemented to address the violations are sustainable and that
these corrections are applied to all products currently manufactured and any products marketed in the future (e.g., Increlex). Other federal agencies may take this
Warning Letter into account when considering the award of contracts. Additionally, FDA may withhold approval of requests for export certificates, or approval of
pending drug applications listing your facility, until the above violations are corrected. FDA may re-inspect to verify corrective actions have been completed.

Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct violations. Include an
explanation of each step being taken to prevent the recurrence of violations and copies of supporting documentation. If you cannot complete corrective action within
fifteen working days, state the reason for the delay and the date by which you will have completed the correction. Additionally, your response should state if you no
longer manufacture or distribute the drug product(s) manufactured at this facility, and provide the date(s) and reason(s) you ceased production.

If, as a result of receiving this Warning Letter or in general, you are considering making a decision that will result in a decreased number of finished drug products
or bulk drug substances produced by your manufacturing facility, FDA requests that you contact CDER's Drug Shortages Program immediately, as you begin your
internal discussions, at drugshortages@[Link] in order to ensure that your action(s) does not adversely affect the public health.

Your response should be sent to: Lori A. Holmquist, Compliance Officer, Food and Drug Administration, 330 Civic Center Drive, Suite 1, Box 4, Augusta, ME 04330.
If you have any questions about the content of this letter please contact: Lori A. Holmquist at (207) 622-8268 x 13.

Sincerely yours,
/S/
Mutahar S. Shamsi
District Director
New England District

Cc: Ian Elvins

Executive Vice President, Lonza Global Quality
Lonza Biologics, Inc.
101 International Drive
Portsmouth, NH 03801

Michael J. Cicio
Vice President Operations and Site Manager
Lonza Biologics, Inc.
101 International Drive
Portsmouth, NH 03801

Mr. Stefan Borgas

Chief Executive Officer
Lonza Group Ltd.
Muenchensteinerstrasse 38
CH-4002
Basel Switzerland

(b)(4)

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