Dr. Reddy's Gets FDA Warning Letter Over Mexico Site
SILVER SPRING, Md., June 14, 2011 - The FDA today posted on its website a warning letter sent to Dr. Dr. Reddy's Laboratories Limited regarding conditions at its Dr. Reddy’s Mexico site. The letter is below.
Warning Letter
VIA UPS MAIL
WL: 320-11-014
June 3, 2011
Mr. G.V. Prasad, CEO
Dr. Reddy's Laboratories Limited
7-1-27 Ameerpet
Hyderabad 500 016
Andra Pradesh India
Dear Mr. Prasad:
During our November 8-11, 2010 inspection of your active
pharmaceutical ingredient (API) manufacturing facility, Industrias
Quimicas Falcon de Mexico, S.A. de C.V. (also known as Dr.
Reddy’s Mexico) located at Km. 4.5 Carretera Federal
Cuernavaca-Cuautla, 62578 Jiutepec, Morelos Mexico, an investigator
from the Food and Drug Administration (FDA) identified significant
deviations from Current Good Manufacturing Practice (CGMP) for the
manufacture of APIs. These deviations cause your 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 December 1, 2010,
and note that it lacks sufficient corrective actions.
Specific deviations observed during the inspection include, but are
not limited, to the following:
1. Your firm did not validate analytical methods used to test
APIs.
For example, the inspection revealed that your firm had not
validated the HPLC method for assay and related substances of
(b)(4) (finished API (b)(4) for human use). This is just one
example of numerous methods used by your firm that had not been
validated according to approved procedures.
Your response states that of the (b)(4) APIs manufactured at your
facility, (b)(4)% are compendial products. The remaining roughly
(b)(4) non-compendial APIs had no method validation. You committed
to complete these method validations by April 30, 2011. However,
this does not address product currently on the market, or product
that will enter the market tested with an unvalidated method. Your
proposal to verify “key parameters” for the first API
batch produced does not provide the same level of assurance as
method validation.
In your response to this letter, provide us with a plan that
details a greater level of assurance that adulterated API will not
reach the U.S. market. Additionally, advise what you will do with
adulterated API on the U.S. market that has been tested with
methods that are not validated (for non-compendial products). In
your response of December 1, 2010, you commit to verify all methods
(for compendial products) by June 30, 2011. Include in your
response to this letter the actions taken to ensure that all
products tested with methods that have not been verified are in
conformance to established quality and/purity standards.
Please also clarify if your test methods are stability
indicating.
2. Your firm's cleaning validation was incomplete for non-dedicated
manufacturing equipment.
For example, during the inspection the investigator observed a
chart, dated November 11, 2010, showing your firm's cleaning
validation progress by area that indicated the manufacturing
equipment in Bay 2 (containing non-dedicated equipment) had no
documented cleaning validation. This is just one example of several
areas lacking cleaning validation for manufacturing
equipment.
Your response states that you commit to start cleaning validation
activities once a validated analytical method is available. We are
concerned about the impact that the lack of cleaning validation has
on marketed product. Provide us your action plan to determine that
cleaning procedures are effective, and ensure that marketed product
is not cross-contaminated.
3. Your firm's out-of-specification (OOS) investigations did not
include analysis of all available data.
For example, the inspection revealed that your firm rejected three
consecutive lots of (b)(4) (an intermediate used in the manufacture
of an API for the product "(b)(4)") on February 26, 2010, for
appearance problems. The deviation investigation into the cause of
the failure did not include an analysis of all available data
including batches manufactured prior to the failures.
The inspection also found many deficiencies regarding handling OOS
investigations. These include the timeliness of closing
investigations, notification of the quality unit (including four to
eight-month delays for reporting failing stability batches), and
failure to follow written procedures. Although some of your
proposed corrections to these individual items appear to be
adequate, we remain concerned that a thorough evaluation of your
investigation approach has not been conducted. Please include in
your response a corrective and preventive action plan regarding
handling investigations.
4. Your firm's quality unit did not exercise its responsibility to
ensure the APIs manufactured were in compliance with CGMP, and met
intended specifications for quality and purity.
As evidenced by the previous deviations, your quality unit has not
overseen the controls required under CGMP to properly produce APIs.
Your December 1 response stated that you will assess your
firm’s quality needs by April 30, 2011. A quality unit is a
basic requirement to ensure that quality APIs are produced at your
facility. Please provide a detailed current assessment of this
deficiency.
The deviations detailed in this letter are not intended to be an
all-inclusive statement of deviations that exist at your facility.
You are responsible for investigating and determining the causes of
the deviations identified above and for preventing their recurrence
and the occurrence of other deviations. If you wish to continue to
ship APIs to 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.
Until all corrections have been completed and FDA has confirmed
corrections of the deviations and your firm’s compliance with
CGMP, FDA may withhold approval of any new applications or
supplements listing your firm as an API manufacturer. In addition,
failure to correct these deviations may result in FDA refusing
admission of articles manufactured at Industrias Quimicas Falcon de
Mexico, S.A. de C.V. (also known as Dr. Reddy’s Mexico) 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)].
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 deviations. Include an explanation of each step
being taken to prevent the recurrence of deviations 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. Please
identify your response with FEI #3002808297.
If you have questions or concerns regarding this letter, contact
Karen Takahashi, 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) 796-3191
Fax: (301) 847-8741
Sincerely,
/S/
Carmelo Rosa on behalf of Richard L. Friedman
Richard L. Friedman
Director
Division of Manufacturing and Product Quality
Office of Compliance
Center for Drug Evaluation and Research
/S/
Eric Nelson
Acting Director
Division of Compliance
Center for Veterinary Medicine
Cc:
Mr. Francisco Casillas, Site Manager
Industrias Quimicas Falcon de Mexico, S.A. de C.V.
(also known as Dr. Reddy's Mexico)
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Posted: June 2011
