| Public Health Service |
| Rockville, MD 20857 |
Departmentof Health and Human ServicesWarningLetter
| Via Certified andRegistered Mail | WL:320-04-03 |
FEB 10, 2004
Ding You Xin
Factory Director
Shanghai Medical Ltd.,
No. 15 Pharmaceutical Factory
1440 Bei Di Road
Shanghai, China
Dear Mr. Ding:
We have completed our reviewof the inspection of your pharmaceutical manufacturing facility in Shanghai,China, by Investigator Robert C. Horan, Ph.D. and Chemist Susan W. Ting, duringthe period of 27-31 October 2003. The inspection revealed significant deviationsfrom U.S. current Good Manufacturing Practice (cGMP) in the manufacture of activepharmaceutical ingredients (APIs). The deviations were presented to you on anInspectional Observations (FDA-483) Form, at the close of the inspection. ThesecGMP deviations cause your APls to be adulterated within the meaning of section501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act.
We have reviewed your November7, 20 and December 22, 2003, responses to the FDA 483 Inspectional Observationssent through [redacted] Group Vice President, of [redacted] These responsesdo not sufficiently address the deviations observed during the aforementionedinspection.
Specific areas of concerninclude, but are not limited to:
1. Qualifications ofthose working in the Quality Assurance (QA) and Quality Control (QC) unitshave not been demonstrated to be adequate.
In your response datedNovember 20,2003, you state that, “Our parent company has transferredtwo qualified QC supervisors” and that, “The interim head of QChas been replaced with a qualified individual.” In the organization chartthat you provided as Appendix 3, two of these individuals are identified ashaving Bachelor of Science degrees in engineering and one as being a LicensedPharmacist having graduated from a Secondary Technical School. Further, no oneon the organizational chart, including supervisors in QA and QC, are identifiedas having academic or other suitable training in chemistry or microbiology.This is of particular concern because all of the items listed on the FDA 483related to the chemistry and microbiology deviations in the quality controlunit. The investigative team also stated that analysts could not always answertheir questions about testing. For example, a supervisor and QC manager couldnot explain how the calculation was done for the [redacted] assay determinationfor [redacted] and [redacted] In addition, the analyst performing this assaywas unaware that it is necessary to enter the [redacted] in order for the resultto be calculated properly. Lastly, the two microbiologists interviewed wereunable to accurately answer questions about growth promotion and the identificationof microorganisms.
In your recent correspondenceyou offered to provide our office a copy of the internal audit that resultedfrom this inspection. We would like to see your audit findings.
2. One of the discussionpoints with management concerned missing data for the analysis of [redacted]and [redacted] by [redacted] There were six entries in the [redacted] logbookthat could not be found in the correlating computer files.
In your response, you statethat these were samples tested for training purposes and their [redacted] weresubsequently discarded. We fail to see how this could be accurate since theanalyst conducting the test on 2/13/03 conducted 24 other acceptable tests beforethis. In addition, the analyst conducting the tests on 2/21/03, 2/23/03, 2/25/03,2/27/03, and 3/01/03 conducted analyses on 2/20/03, 2/24/03, 2/26/03, and 2/28/03.These test results were entered as acceptable prior to completion of what youare telling us is training. We are concerned about this discrepancy.
3. The microbiologicaltest records all appear to be recently written in spite of the fact that somedate back as far as two years.
You state that the documentsmay appear new because they are kept in plastic folders away from heat and light.The investigative team says they never observed any of the documents they requestedfrom the microbiological laboratory being removed from plastic folders, nordid they observe this practice anywhere else in the firm. In addition, the investigativeteam expressed concerns that the records having one entry per day appeared tohave multiple entries in the same handwriting written at a single time. Also,entries identified as being performed by a single person appeared to be writtenin more than one person’s handwriting. They observed this with virtuallyall of the documents they reviewed in the microbiological laboratory, includingsuch documents as equipment usage logs, logs for record receipt of materials,and for transfer of cultures. You failed to address this in your responses.
4. Individuals responsiblefor overseeing testing, other management, [redacted] technical managers, andthe individual hired by [redacted] as a cGMP consultant were not forthcomingwith testing documents for [redacted] testing by [redacted]
The investigative teamwas together during the interaction with the above mentioned individuals regardingthe test records for [redacted] testing. Both give the same account of whathappened. They have documented a detailed description of who they spoke withand what responses they received. None of the responses from the above mentionedindividuals was accurate until the investigative team found the test resultson the [redacted]computer. All of the above mentioned individuals initiallydenied that the firm has ever tested [redacted] for [redacted] by [redacted]Then, the QC manager said that they had done the test once a long time ago,but did not have record of the test. Later, when the investigative team lookedat the [redacted] computer files, they found that [redacted] testing for [redacted]was routinely performed. In addition, the QC Manager denied having a writtentest method for [redacted] testing for [redacted] by [redacted] but the writtentest method was later found locked in her office desk. Lastly, when asked whythe testing was performed, both the QC Manager and the Assistant Plant Managerboth stated that the test was done for no reason. When the investigative teamspoke with you and your management team the following day (10/30/2003) theysay that you told them the testing was done at a customer’s request. Theinvestigative team also said that you admitted that your firm had been untruthfulabout the testing. As the investigative team expressed to you that they didnot have confidence in the integrity of your test data as a result of this incident,so we also express our concern that your test records may be unreliable.
Another related observation statedthat one [redacted] test result represented as many as five and eight lots offinished [redacted] and [redacted] API, respectively. Although you have respondedto this observation, it nonetheless adds to our concerns about the reliabilityof the records at your firm.
5. Compendial and secondaryreference standards were not properly stored.
The investigative team found thecompendial and secondary reference standards stored in the controlled room temperaturestability room. We do not have assurance that these reference standards usedto test the finished APIs have not degraded as a result of being subjected tothe temperature and humidity conditions in the stability room. In your response,before installing a ceiling fan, you state that the temperature was [redacted]at the outlet of the heater. The observation indicates that this air was blowingdirectly on the reference standards. Reference standards that are not storedunder appropriate conditions could result in false test values. Product thatis out of specification could test within specification. This draws into questionyour test results for product shipped to the United States.
6. Microbiological testingwas inadequate in that the [redacted] samples was not neutralized prior toperforming the [redacted] testing.
In your response you expressed concernthat if the [redacted] in the sample was neutralized, you would not be testingthe [redacted] "as is". It is necessary to neutralize the [redacted] becauseit interferes with microbiological testing. Without the neutralization step,the [redacted] test will likely show a lower number of bacteria than is actuallypresent in the sample.
The procedure you submitted withyour response indicates that you will add a neutralizing agent, [redacted] tothe sampling container prior to [redacted] Please submit to data or scientificrational that the [redacted] does not alter the effectiveness of the neutralizingagent. In addition, the procedure should require swabbing the sample port andrunning [redacted] for five minutes if this is how you draw the [redacted] beforeadding it in the manufacturing process.
The cGMP deviations identifiedabove or on the FDA-483 issued to your firm are not to be considered an all-inclusivelist of the deficiencies at your facility. FDA inspections are audits, whichare not intended to determine all deviations from cGMP that exist at a film.It is the responsibility of your firm to assure compliance with all U.S. standardsfor current Good Manufacturing Practice.
Due to the significance of thesedeficiencies the FDA will deny entry of drugs manufactured by your firm intothe United States. The articles will be subject to refusal of admission pursuantto Section 801(a)(3) of the Act in that the methods and controls used in theirmanufacture do not appear to conform to current Good Manufacturing Practicewithin the meaning of Section 501(a)(2)(b) of the Act.
Until FDA can confirm compliancewith cGMP and correction to the most recent inspection deficiencies, this officewill recommend disapproval of any new applications listing your firm as themanufacturer of active pharmaceutical ingredients.
Please contact Karen K. Moksnes,Compliance Officer, at the address and telephone number shown below if you haveany questions related to human drugs.
U.S. Food & Drug Administration
Center for Drug Evaluation and Research
Foreign Inspection Team, HFD-325
11919 Rockville Pike, 4th Floor
Rockville, MD 20852
Tel: (301) 827-9008; FAX (301) 827-8909
Or, contact Jorge F. Christian,Compliance Officer at the address and telephone number shown below if you haveany questions related to veterinary drugs.
U.S. Food & Drug Administration
Center for Veterinary Medicine
Division of Compliance, HFV-232
7500 Standish Place
Rockville, MD 20855
Tel: (301) 827-0152; FAX (301) 827-1498
Sincerely,
/s/
Nicholas Buhay for
Joseph C. Famulare Director
Division of Manufacturing and Product Quality
Center for Drug Evaluation and Research
/s/
Gloria Dunnavan
Director
Division of Compliance
Office of Surveillance and Compliance
Center for Veterinary Medicine
cc: [redacted]
Group Vice-President
[redacted]
