Inspections, Compliance, Enforcement, and Criminal Investigations
Delta Synthetic Co., Ltd 05-Jan-04
Department of Health and Human Services
Public Health Service
Rockville, MD 20852
January 5, 2004
Mr. Y.C. Chen
Delta Synthetic Co., Ltd
15 Min-Shen Street
Tu Chen City, Taipei Hsien 23607
Taiwan, Republic of China
Dear Mr. Chen:
We have completed our review of the inspection of your Active Pharmaceutical Ingredient (API) manufacturing facility in Taiwan, Republic of China, by Investigator George J. Flynn and Chemist Richard Needham, during the period of October 27-29, 2003. The inspection revealed significant deviations from U.S. Current Good Manufacturing Practices (CGMP) in the manufacture of Active Pharmaceutical Ingredients (APIs). The deviations were presented to you on an Inspectional Observations (FDA-483) form, at the close of the inspection. These CGMP deviations cause your APIs to be adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. section 351(a)(2)(B).
Our review also included your companys response letter dated November
26, 2003 to the FDA-483 observations. We note that many corrections have been
completed, or will soon be implemented. There are however, issues which need
more comprehensive corrections. We have, concluded that this response lacks
sufficient details, explanations or documentation to adequately address all
of the significant deviations observed during the inspection. Specific areas
of concern include, but are not limited to:
LABORATORY CONTROLS SYSTEMS:
1) Appropriate laboratory tests to determine conformance to specifications have not been performed on each batch of [redacted]
The laboratory did not have an adequate impurity profile for [redacted] that
identifies organic, inorganic and solvent impurities to monitor unidentified
and apparent impurities in the API to ensure that they are appropriately controlled.
For example: an unidentified [redacted] which has not been characterized was
seen at about the [redacted], level in all [redacted] of [redacted] reviewed
during the inspection.
Your response indicates that you have started to monitor this unidentified land will attempt to identity its structures You also indicate that you have established an impurity
profile for [redacted] except for the unidentified impurity. However your response fails to adequately address the unidentified impurity within the impurity profile. Please provide documentary evidence that a complete impurity profile has been compared to the impurity profile in the regulatory submission and to historical data, so that your firm can detect changes to the API manufacturing process.
An impurity profile describing the identified and unidentified impurities present
in a typical batch produced by the specific controlled production process should
be established for each API. The impurity profile should include the identity
or some qualitative analytical designation, the range of each impurity observed,
and classification of each identified impurity. The impurity profile should
be compared at appropriate intervals against the impurity profile in the regulatory
submission or compared against historical data to detect changes to the API
resulting from modifications in raw materials, equipment, operating parameters,
or the production process.
Stability-indicating methods were not used in the stability testing program for [redacted]
Your response indicates that you will use stability indicating methods in the future stability testing of [redacted]. However, it fails to indicate whether you are currently using stability indicating methods in your stability program and did not provide a timeframe for beginning the use of stability indicating methods.
The test procedures used in stability testing should be validated and be stability
indicating. Please provide documentary evidence that you are currently using
stability indicating methods for all stability testing of [redacted], and any
other API manufactured for the US market.
The inspection of the microbiological laboratory fails to document the lot
number and expiry date of the [redacted] used to prepare the media [redacted]
of the media in the [redacted] such as [redacted]. Additionally, the [redacted]
was not calibrated.
Your response did not address the [redacted]
It should be noted that laboratory controls such as testing should be documented
at the time of performance and records should include complete data derived
from all tests conducted to ensure compliance with established specifications
and standards including examinations and assays.
2) Sampling and Testing of incoming [redacted] used in the manufacture of [redacted] were inadequate.
At least one test to verify the identity of the incoming material was not conducted.
The reliability of the suppliers certificate of analysis (COA) was not established in that a complete analysis was not performed and compared with the COA at the appropriate intervals.
Your response indicates that you have initiated a testing procedure for incoming. However, your response did not provide any documentary evidence of corrective actions.
At least one test to verify the identity of each batch of materials should
be conducted. Furthermore, supplier approval should include an evaluation that
provides adequate evidence that the manufacturer can consistently provide material
meeting specifications. At a minimum a complete analysis should be performed
at appropriate intervals and compared with the COA Reliability of the COA should
be checked at regular intervals. Please provide documentary evidence that corrective
actions have been completed.
3) Procedures for the recovery of solvents were inadequate.
Procedures for solvent recovery had not been established to ensure that solvents are controlled and monitored to assure that they meet appropriate standards before reuse or commingling with other approved materials.
There were no specifications established or testing performed for the reuse of redistilled [redacted]
There were no procedures established for determining the number of [redacted] cycles required for the [redacted] recovery process.
Your response indicates that you have initiated a testing procedure for recovered
[redacted] and established specifications and testing methods for controlling
[redacted] used in the manufacture of [redacted]. However, your response did
not provide any documentary evidence of these corrective actions.
Solvents can be recovered and reused in the same processes or in different
processes, provided that recovery procedures are controlled and monitored to
ensure that solvents meet appropriate standards before reuse or commingling
with other approved materials. Fresh and recovered solvents can be combined
if adequate testing has shown their suitability for all manufacturing processes
in which they may be used. The use of recovered solvents should be adequately
documented. Please provide documentary evidence that corrective actions have
PACKAGING AND LABELING SYSTEM
4) Failure to have written procedures describing the receipt, identification, quarantine, sampling, release, and handling of labeling material. Furthermore, incoming labels received from the vendor are not proofed against the master label.
Your response indicates that you have created a new procedure [redacted] to incorporate all of the corrective actions. However, you did not provide a copy of this SOP or evidence that these corrective actions have been completed.
The CGMP deviations identified above or on the FDA483 issued to your firm are not to be considered an all-inclusive list of the deficiencies at your facility. FDA inspections are audits, which are not intended to determine all deviations from CGMPs that exist at a firm. If you wish to continue to ship your products to the United States, it is the responsibility of your firm to assure that all APIs manufactured by your firm are in compliance with all U.S. standards for Current Good Manufacturing Practices.
Failure to correct these deficiencies may result in FDA denying entry of articles manufactured by your firm into the United States. The articles could be subject to refusal of admission pursuant to Section 801(a)(3) of the Act in that the methods and controls used in their manufacture do not appear to conform to Current Good Manufacturing Practices within the meaning of Section 501(a)(2)(B) of the Act.
Please respond to this letter within 30 days of receipt. Your response should
include data collected in your correction of the deficiencies cited as well
as copies of procedures not already submitted. Please identify your response
with FEI: 1545. Until FDA can confirm compliance with CGMPs and correction
to the most recent inspection deficiencies, this office will recommend disapproval
of any new applications listing your firm as the manufacturer of Active Pharmaceutical
Please contact Marybet Lopez., Compliance Officer, at the address and telephone numbers shown below, if you have any questions, written response or concerns regarding these decisions.
U.S. Food & Drug Administration
11919 RockvilIe Pike, Montrose Metro II
Rockville, MD 20852
Tel: (301) 827-9055; FAX (301) 827-8909
To schedule a re-inspection of your facility, after corrections have been completed and your firm is in compliance with CGMP requirements send your request to: Director, Division of Field Investigations, HFC-130, 5600 Fishers Lane, Rockville, MD, 20857. You can also contact that office by telephone at (301) 827-3777 or by fax at (301) 443- 6919.
Joseph C. Famulare
Division of Manufacturing and Product Quality
Center for Drug Evaluation and Research