Sumitomo Chemical Co., Ltd.

Department of Health and Human Services	Public Health Service Food and Drug Administration
	CENTER FOR DRUG EVALUATION AND RESEARCH Division of Manufacturing and Product Quality International Compliance Branch While Oak. Building 51 10903 New Hampshire Avenue Silver Spring, MD 20993

Warning Letter

VIA FEDERAL EXPRESS MAIL

WL: 320- 09-11

August 24, 2009


Mr. Shinji Kawamura

General Manager, Gifu Plant

Sumitomo Chemical Company Limited

3750 Juhachicho

Maid, Anpachi-Cho, Anpachi-Gun

Gifu Prefecture, Japan 503-0125
Dear Mr. Kawamura:
This is regarding an April 6-9, 2009, inspection of your active pharmaceutical ingredient

(API) manufacturing facility, Sumitomo Chemical Company Limited, located at 3750

Juhachicho, Maid, Anpachi-Cho, Anpachi-Gun, Gifu Prefecture, Japan, conducted by

Investigator, Jose R. Hernandez and Chemist, Javier O. Vega. The inspection revealed

significant violations from U.S. current good manufacturing practice (CGMP) in the

manufacture of APls. The CGMP violations were listed on an Inspectional Observations

(FDA-483) form issued to you at the close of the inspection.
These violations cause the APls manufactured by your firm to be adulterated within the

meaning of Section 50 I(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act)

[21 USC § 351(a)(2)(B)]. Section 501 (a)(2)(B) of the Act requires that all drugs, as

defined in the Act, be manufactured, processed, packed, and held according to CGMP.
We have received your firm's responses of May 14 and August 12,2009, and note that

they lack sufficient corrective actions.
Specific violations observed during the inspection include, but are not limited, to:

1. Your firm does not assure that suitable processing (b)(4) is used for the (b)(4) step of the Hydralazine HCI manufacturing process. This API is

intended for use in parenteral drug products. Your firm currently uses (b)(4)

and does not test this (b)(4) for endotoxins and total microbial

count. [FDA-483 Observation 8]

Your written response states that you do not intend to conduct endotoxin testing for

(b)(4) or sanitize your (b)(4) system. It is essential that non-sterile APls intended for use

in parenteral drug products are manufactured using (b)(4) that is suitable for the process

stage and that routine monitoring is performed to ensure ongoing (b)(4) system control.

Our inspection found that your firm uses (b)(4) at the (b)(4) and

(b)(4) stage, and failed to test for total microbial count and endotoxins.

Please refer to ICH Q7A Guidance for Industry for guidance regarding" quality of

active pharmaceutical ingredients intended for use in parenteral drug products.

2. Your firm's (b)(4) system is not designed to minimize the risk of microbial

contamination. [FDA-483 Observation 8]

Your written response states that you are in the process of re lacin the distribution

pipes, connections, and flexible hoses. However, your (b)(4) tank #(b)(4)

cannot be drained and has been in use since 1990. Your (b)(4), approximately 100-

meter, distribution pipe contains numerous threaded connectors, at least two flexible

hoses, and has no mechanism for (b)(4). This design is not conducive for

controlling the (b)(4) system's microbial and endotoxin levels. We continue to have

serious concerns about the impact of your (b)(4) system's design on endotoxin and

microbial load.

Please provide us with a corrective action plan for how you will address these concerns.

3. The new method validation for bicalutamide API did not include sensitivity

(limit of quantitation), linearity, accuracy, or an appropriate precision

determination. [FDA-483 Observation 1]

The establishment inspection report indicates that the new method has not been validated

for the aforementioned validation elements, and the precision was conducted with only

three injections. Your response states that you have revised your method validation

protocol, but does not indicate whether your protocol includes the elements, or if you

have performed the method validation. Please provide us with your revised stability and

method validation protocols, and method validation report.
Please note that an analytical method should be adequate for its intended use. The extent

of the analytical method validation studies will depend on the purpose of the analysis and

the complexity of the manufacturing process. Adequate analytical performance elements

should be considered in the validation to establish that the method meets proper standards

of accuracy and reliability, as well as the requirements for the intended analytical

procedures. For example, the validation of the assay method of a component may include

performance elements such as accuracy, precision, specificity, linearity, and range. For a

method used to determine impurities, additional elements such as quantitation limit and

detection limit will be required.



The violations cited above, or on the FDA-483 issued to your firm, are not an all inclusive

list of the CGMP violations that may exist at your facility. FDA inspections

are audits that are not intended to address all deficiencies from CGMP, or violations

that may exist at a firm. 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

violations, and your firm's compliance with CGMPs, this office may recommend

withholding approval of any new applications or supplements listing your firm as an API

manufacturer. In addition, failure to correct these violations may result in FDA denying

entry of articles manufactured at Sumitomo Chemical Company Limited, Gifu Prefecture,

Japan, into the United States. The articles could be 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)].
Please respond to this letter within thirty days of receipt and identify your response

with FEI #3002808125. 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, RM 4244

10903 New Hampshire Ave

Silver Spring, MD 20993

Tel: (301) 796-3191

Fax: (301) 847-8741

Sincerely,

/S/
Richard L. Friedman

Director

Division of Manufacturing and Product

Quality

Office of Compliance

Center for Drug Evaluation and Research

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