Inspections, Compliance, Enforcement, and Criminal Investigations
Cyclotron Center of NE Florida 1/28/09
Department of Health and Human Services
|Public Health Service
Food and Drug Administration
|555 Winderley Pl., Ste. 200
Maitland, Fl 32751
RETURN RECEIPT REQUESTED
January 28, 2009
Dr. Shyam Paryani, CEO
Cyclotron Center of NE Florida
1895 Kingsley Avenue, Ste. 600
Orange Park, FL 32073-4414
Dear Dr. Paryani:
The U.S. Food and Drug Administration (FDA) conducted an inspection at your facility located at 1895 Kingsley Ave., Ste. 600, Orange Park, Florida on July 31, 2008 through August 7, 2008. The inspection documented serious deviations from the United States Pharmacopoeia (USP) compounding standards and official monograph for Positron Emission Tomography (PET) drugs in the manufacturing of Fludeoxyglucose (FDG) F18 for injection.
These deviations were listed on an Inspectional Observations (FDA-483) form issued to you at the close of the inspection. These deviations cause your drug products to be adulterated within the meaning of Section 501(a)(2)(C) [21 U.S.C. § 351(a)(2)(C)] of the Federal Food, Drug, and Cosmetic Act (the Act).
The deviations observed during the inspection include, but are not limited to the following:
1) Your firm failed to establish, document, perform sterilization activities and appropriate QC tests to assure that the finished drug product is sterile. This is a repeat violation from the 2005 inspection. Specifically,
a) Your procedures are deficient in that:
(1) Aseptic techniques used to make sterile products and operator qualification have not been evaluated through a process simulation (i.e., media fill).
(2) The safety hood used for aseptic processing has not been certified as having an air cleanliness rating of [(b)(4)].
(3) There is no documentation of cleaning performed within the aseptic processing safety cabinet.
b) The sterility test performed for end-product testing is inadequate in that:
(1) No growth promotion testing is done to verify suitability of the media used for drug product sterility testing.
(2) Positive controls are not included with each sterility test performed.
(3) Sterility samples are to be incubated at [(b)(4)] for FTM tubes and [(b)(4)] for TSB tubes. However, incubator temperatures were found to be elevated between [(b)(4)] without any justification or action taken.
2) Your firm's procedure for conducting bacterial endotoxin testing of finished drug products is inadequate in that the SOP, no. Q104A Bacterial Endotoxins - [(b)(4)] Test, that describes the [(b)(4)] automated testing equipment currently in use was never completed and approved; although this test has been in use since late 2005. There is no assurance that your endotoxin test results are accurate and reliable. Specifically:
a) There is no documentation that this piece of equipment was qualified when put into use.
b) In addition, one Operator interviewed stated that she had not been trained to evaluate the endotoxin values on the printout and had only been trained on the use of the equipment by the manufacturer's representative who emphasized the spike recovery value which indicates if the test was valid (but this training also was not documented).
3) Your firm's incoming materials and supplies are not subjected to quality control examination prior to storage and use, but are merely logged into an Inventory Tracking Log. Specifically,
a) There is no documentation to show the evaluation of incoming materials prior to acceptance and use. In addition, there are no supplier evaluations performed.
b) The components and supplies used for the compounding of PET drug are not stored in controlled storage conditions. For example, the refrigerator that contains the media and [(b)(4)] cartridges is not monitored for storage temperature.
4) Your firm failed to investigate any unplanned deviations or unexpected" results of, verified compounding procedures or processes and failed to document the outcome of such investigations. Specifically, Lot no. 080709B1 was rejected for low pH but the majority of the documentation for this batch was discarded and this incident was not investigated.
5) Your firm failed to designate a qualified and trained person to be responsible for ensuring that the production activities are carried out properly. Specifically, management failed to:
a) Review and update written procedures on a regularly scheduled basis to ensure they reflect correct and current practices.
b) Ensure that verification studies of the compounding procedure are conducted on an annual basis, and there is no SOP addressing verification studies.
c) Ensure production activities are carried out by qualified and trained personnel. Specifically, an operator did not have training records, although she has performed drug production and quality control tasks since the summer or 2006.
d) Ensure that written production records for each batch are maintained properly. For example, an operator-in-training admitted to performing work to batch # 080718B1, but there were no entries on the batch record dated 7/18/08, that indicated the operator performed a task.
6) Your firm failed to conduct equipment maintenance as necessary to assure that it operates properly. Specifically, the [(b)(4)] maintenance was not completed as required and the [(b)(4)] and [(b)(4)] maintenance records do not identify the person who performed the work. Also maintenance records are not reviewed.
The violations cited in this letter are not intended to be an all-inclusive statement of violations that exist at your facility. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence or the occurrence of other violations. It is your responsibility to assure that your firm complies with all requirements of federal law and FDA regulations.
You should take prompt action to correct the violations cited in this letter. Failure to promptly correct these violations may result in legal action without further notice, including, without limitation, injunction. Other federal agencies may take this Warning Letter into account when considering the award of contracts. Additionally, FDA may withhold approval of requests for export certificates, or approval of pending new drug applications listing your facility as a manufacturer until the above violations are corrected. A re-inspection may be necessary.
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 violations. Include an explanation of each step being taken to prevent the recurrence of violations, as well as copies of related documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the time within which you will complete the correction. We will review and evaluate the implementation and adequacy of your corrective actions during our follow-up inspection of your firm.
Please send your reply to the U.S. Food and Drug Administration, Attention: Winston R. Alejo, Compliance Officer, 555 Winderley Place, Suite 200, Maitland, Florida, 32751. If you have questions regarding any issues in this letter, please contact Mr. Alejo at (407) 475-4731.
Emma R. Singleton
Director, Florida District