Released by FDA: 6/28/01.  Posted by FDA:  7/26/01

Mr. Fang Yu Lee 
President
Yung Shin Pharm. Inc. Col, Ltd. 
1191, Sec. 1, Chung Shan Road 
Tachia, Taichung
Taiwan, R.O.C.

Dear Mr. Yu Lee:

This is regarding an inspection of your active pharmaceutical ingredient (API) manufacturing facility in Tachia, Taiwan by the United States Food and Drug Administration during May 4 - 8, 2001.   The inspection revealed significant deviations from U.S. good manufacturing practice in the manufacture of bulk [confidential, deleted by FDA] that resulted in the issuance of a twelve-item FDA Form 483 at the completion of the inspection.

These deviations cause this API to be adulterated within the meaning of Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act.  Section 501(a)(2)(B) of the Act requires that all drugs be manufactured, processed, packed, and held according to current good manufacturing practice (CGMP).  No distinction is made between active pharmaceutical ingredients and finished pharmaceuticals, and failure of either to comply with CGMP constitutes a failure to comply with the requirements of the Act.

We have reviewed the May 31, 2001 response to the FD-483 observations submitted by your US Agent [confidential, deleted by FDA] on June 1, 2001.  We conclude that this response lacks sufficient details, explanations, or documentation to adequately address all of the deviations observed during the May 2001 inspection.  Our comments regarding the most significant observations are shown below:

1. Well water and city water used in the manufacture of APIs has not been demonstrated to be suitable for its intended use.  In addition, your firm lacked a written procedure for the routine monitoring of both sources of water and the actual monitoring of both waters for chemical and microbial attributes is very limited.

Our inspection disclosed that well water is used for the initial rinsing of manufacturing equipment and as a component for preparing [confidential, deleted by FDA].  The well water is processed through [confidential, deleted by FDA].  In addition, city water taken directly from the spigot without further treatment, is used for the final rinsing of equipment.  Both water sources have not been qualified to demonstrate suitability for use in manufacturing of APIs.

Furthermore, your firm lacked a written procedure for routine monitoring of water for chemical and microbial attributes and monitoring of the water was very limited.  Well water is tested  [confidential, deleted by FDA] a month from only one of three points of use on a rotating basis and after the [confidential, deleted by FDA] filter [confidential, deleted by FDA] months.   City water is tested [confidential, deleted by FDA] a month from only one of three points of use on a rotating basis.

Your written response reports that a new validation protocol for the water systems was approved on May 25, 2001, equipment installation and operational qualification was completed on May 31, and you have initiated performance qualification on June 4.   The latter will be completed by July 5, 2002.

Our review of the Document No. [confidential, deleted by FDA] Performance Qualification Protocol of the [confidential, deleted by FDA] Water an Tap Water" (Attachment 3), disclosed that the latter refers to a microbial alert limit of [confidential, deleted by FDA] and an action limit of [confidential, deleted by FDA] for [confidential, deleted by FDA] filtered water and city tap water.   These alert and action limits are excessive.   The United States Pharmacopeia (USP 24) recommends a microbial action limit of 500 CFU/ml for potable (drinking) water.

Furthermore, our review disclosed that you plan to continue to use city water directly from the spigot without further treatment or chlorination.   Since the quality of municipal water often varies significantly from day to day and throughout the seasons, we recommend that tap water be collected in a storage tank and subjected to further treatment (i.e., filtration and/or chlorination) and testing for chemical and microbial attributes before its use in the manufacture of APIs.

Please address these concerns in your written response and provide results of chemical and microbial testing of [confidential, deleted by FDA] filtered and tap water obtained to date to show that the water is suitable for use in manufacturing APIs.

2. The sterilization cycle of the [confidential, deleted by FDA]  and the [confidential, deleted by FDA] have not been validated.

Your response reports that protocols for validating the sterilization cycles for both [confidential, deleted by FDA] were approved on May 15, 2001.   These protocols provide for [confidential, deleted by FDA].  You indicate that the validation process for [confidential, deleted by FDA] was initiated on May 15, 2001 and will not be completed until September 30, 2001.

Your time frame for completing validation of the sterilization cycles seems excessive. Please explain why it will take 4 1/2 months to complete this validation.   Also your response does not indicate whether production of continue during this validation phase. Please address these issues in your response to this letter.

3. The laminar flow hood in the micro lab and [confidential, deleted by FDA] filters in the Class 100,000 production area had not been certified.

Your response acknowledges that you have inadequately certified the [confidential, deleted by FDA] filters in the Class 100,000 production areas and laminar flow hood in the microbiology laboratory.   You report that the validation protocol for the HVAC system of the [confidential, deleted by FDA] plant and laminar flow hood were revised to include tests for air flow and air changes, [confidential, deleted by FDA] filter [confidential, deleted by FDA] integrity testing, and sampling of the air for viable particulates.  This qualification was initiated on June 5 and will be completed by June 20, 2001.

However, our review of the protocol for integrity testing of [confidential, deleted by FDA] filters disclosed two deficiencies.  First, the SOP does not address sampling of the [confidential, deleted by FDA] filters to calibrate the [confidential, deleted by FDA].  Second, it does not provide for [confidential, deleted by FDA].  Please address these issues in your response.

The above deficiencies are not to be considered as an all-inclusive list of the deficiencies at your plant. FDA inspections are not intended to uncover all CGMP deviations that exist at a firm.   We recommend that you conduct a complete evaluation of your facility for CGMP compliance.  If you wish to ship APIs to the United States, your firm is responsible for assuring compliance with U.S. standards of good manufacturing practice for active pharmaceutical ingredients manufacturers.

Until the FDA reinspects your facility and confirms that these deficiencies have been corrected, this office will recommend disapproval of all applications listing your firm as a supplier of bulk [confidential, deleted by FDA].   We may also recommend that all APIs you manufacture for U.S. clients be denied entry into the United States.   These articles may be subject to refusal of admission pursuant to Section 801(a)(3) of the Act because 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).

In your response please submit English translations of supporting documents, procedures or other information detailing corrective actions that you plan to take or have taken to bring your API facility into compliance.   If you have questions or concerns regarding this letter, please contact Edwin Rivera Martinez, Compliance Officer, at the address and telephone numbers shown below:

Foreign Inspection Team, HFD-322 
Food and Drug Administration
Center for Drug Evaluation and Research 
7520 Standish Place
Rockville, Maryland 20855-2737

Telephone: (301) 594-0095
FAX: (301) 594-1033

Please reference Central File Number 9612854 in all correspondence to this office.

To schedule a reinspection of your facility after corrections have been completed, contact the Director of FDA's International Programs and Technical Support Branch (HFD-134), Division of Field Investigations, 5600 Fishers Lane, Rockville, Maryland, 20857.   You can also contact this office at (301) 443-1855 or by FAX at (301) 4436919.

Sincerely,

Joseph C. Famulare
Director, Division of Manufacturing and 
  Product Quality, HFD-320

cc:  [confidential, deleted by FDA]