Inspections, Compliance, Enforcement, and Criminal Investigations
Syntron Bioresearch Inc. 5/24/10
Department of Health and Human Services
|Public Health Service
Food and Drug Administration
|Los Angeles District
Irvine, CA 92612-2506
RETURN RECEIPT REQUESTED
May 24, 2010
Dr. James P. Lee, President/CEO
Syntron Bioresearch Inc.
2774 Loker Ave W
Carlsbad, CA 92010
Dear Dr. Lee:
During an inspection of your film located in Carlsbad, California on January 11 through January 21, 2010, investigators from the United States Food and Drug Administration (FDA) determined that your film manufactures drugs of abuse test kits. Under section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 321(h), these products are devices because they are intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease, or are intended to affect the structure or function of the body.
This inspection revealed that these devices are adulterated within the meaning of section 501(h) of the Federal Food, Drug and Cosmetic Act [21 U.S.C. 351(h)], in that the methods used in, or the facilities or controls used for, their manufacture, packing, storage, or installation are not in conformity with the Good Manufacturing Practice (CGMP) requirements of the Quality System (QS) regulation found at Title 21, Code of Federal Regulations (CFR), Part 820.
These violations include, but are not limited to, the following:
1. Failure to establish and maintain adequate procedures for monitoring and control of process parameters for validated processes to ensure that the specified requirements continue to be met, as required by 21 CFR 820.75(b). For example, the process validation reports for both the VirTis Lyophilizer and the Hull Lyophilizer failed to identify the process parameters (i.e. chamber pressure and ramp rate) used for validating the lyophilization process used in manufacturing of test devices.
We have reviewed your response and concluded that it is not adequate because you did not provide any documentation of the corrective action. You stated that the Lyophilizers will be revalidated with stated process parameters, but did not provide documentation of the process parameters. In order to address this observation, you should submit process validation procedures that state the lyophilization process parameters.
2. Failure to review, evaluate, and investigate complaints involving the possible failure of a device, labeling, or packaging to meet any of its specifications, unless such investigation has already been performed for a similar complaint and another investigation is not necessary, as required by 21 CFR 820.198(c). For example:
a. Customer complaint record #08-004 was initiated for two complaints received on QuikPac 2 HCG product lot number 608138. The complaints pointed out that the wrong pipette was included in the test kits and that the foil pouch that contained the kits had ink spots on them. You verified that the wrong pipettes were included in the kit, but did not perform any follow up investigation to determine why the wrong pipettes were packaged or if the problem could be more widespread. The complaint for the ink spots also stated that a different lot number was visible under the printed lot number and that the bags appear to have been relabeled but were not thoroughly cleaned. None of these issues were further investigated.
b. Customer complaint record # 08-006 was initiated when a customer complained that the urine sample did not migrate up the sample strip in the THC and Cocaine test panels for the QuikScreen 10+3 product. Your investigation verified that, in some of the test panels, urine did not migrate up the sample strip, but you did not investigate what caused the failure or how widespread the potential failure was.
c. Customer complaint record #09-001 indicated that the urine sample did not migrate up the test strip of the Dip Drug Scan product. The complaint record does not clarify whether testing was performed to verify that the sample did not migrate up the test strip. The complaint file also indicates that the package insert that instructs the users how to perform the test stated incorrect read times. You acknowledged the issue and corrected it, but did not investigate why the wrong instructions were included.
d. Customer complaint record #09-002 indicated slow sample migration in the Dip Drug Scan 10. The complaint record indicates that QC testing confirmed the slow migration of this product lot, but the film did not investigate the cause of the slow migration with this lot compared to other lots.
We have reviewed your response and concluded that it is partially not adequate. You stated that you corrected the issue with the package inserts for the Dip Drug Scan product; however, you did not provide a copy of the revised package insert for the FDA to review. Your response is partially adequate in that you investigated retain lots for the QuikPac 2 HCG product lot number 608138 and identified the cause of the wrong pipettes. Additionally, the printing on the pouches was legible. You also investigated the lots of the THC and Cocaine test panels for the QuikScreen 10+3 product and determined the root cause of the failure of the sample to migrate. You investigated the lots of the Drip Drug Scan 10 product and identified the root cause of the slow migration.
3. Failure to establish and maintain adequate procedures to control product that does not conform to specified requirements. The procedures shall address the identification, documentation, evaluation, segregation, and disposition of nonconforming product, as required by 21 CFR 820.90(a). This is a repeat observation from the previous FDA 483 issued on 11/20/07.
For example, the current Nonconforming Product Procedure, Q22-P08, Revision 05, described non conforming product as any material purchased or manufactured by Syntron that does not conform to specified requirements. The procedure stated that upon discovery of any nonconformance, the nonconforming product was to be segregated, labeled with a red "Reject" label, stored in the Quality Reject Area, and a nonconforming product report (NCFR) initiated. Syntron's Raw Material Inspection and Testing Procedure also stated that if materials failed to meet inspection and testing criteria they were to be placed in the Quality Reject Area. In your receiving material inspection log there were three lots of raw materials (PUP-117 - Lot#(b)(4) PUP-116 - Lot# (b)(4) PLW-036 - Lot#(b)(4) that were rejected by the QC inspector. The raw material inspection records for these materials each indicated that 32 samples were tested and all 32 samples were defective. Each lot's raw material inspection record indicated that the lot was rejected, but each lot was still released to the warehouse. NCFRs were not initiated for any of these lot rejections. Since the rejected materials were released to the warehouse and NCFRs were not initiated, Syntron failed to follow its own Nonconforming Product Procedure and its Raw Material Inspection and Testing Procedure.
We have reviewed your response and concluded that it is not adequate because you did not submit documentation verifying your correction for this observation. You claimed that the inspector who failed the QC lots without initiating nonconforming product records for each lot of rejected material was retrained to the proper documentation of nonconforming materials, but did not provide supporting documents such as the employee's training records.
4. Failure to adequately document acceptance activities to include the results, as required by 21 CFR 820.80(e)(3). For example:
a. Packaging Specification Sheets for a Foil Pouch (POU-055 - D03-ES123 - Revision 03) and the Raw Material Specification Sheet for Temperature Indicator (TEM-001 - D03-DS182 - Revision 04) listed the acceptable dimensions and functional testing requirements, however, the receiving inspection records did not include the measurements taken or the results of the functional testing performed on these materials by the QC inspector.
b. Raw Material Specification Sheet for a Urine Cup (UCP-009 - D03-DS78 - Revision 02) listed acceptable dimensions for the cup, but the receiving inspection records did not include the measurements taken to demonstrate that the incoming cup met the documented raw material specifications.
c. Specialty Chemical Specification Sheet for a Methadone BSAJBTG Antigen Conjugate (9MAD-01 - D03-BS074 - Revision 02)) required that the material had a minimum purity of (b)(4) but the raw material inspection records did not contain any evidence that this purity was met.
We have reviewed your response and concluded that it is not adequate because you did not provide any documentation of the corrective action. You stated that specifications on raw materials needed to be reviewed and updated to reflect actual testing performed and new documents will be created to record the results. You stated that the process, and presumably, the documents will be completed by 2/28/10.
5. Failure to establish and maintain procedures for acceptance of incoming product. Incoming product shall be inspected, tested, or otherwise verified as conforming to specified requirements. Acceptance or rejection shall be documented, as required by 21 CFR 820.80(b). For example, you do not have a procedure in place to test the purity of Methadone BSAJBTG Antigen Conjugate and the specification sheet provided by the vendor does not specify the purity level of the material.
We have reviewed your response and concluded that is not adequate because you did not provide a procedure for testing the purity of the Methadone BSA/BTG Antigen Conjugate.
6. Failure to establish and maintain adequate procedures to ensure that sampling methods based on a valid statistical rationale are adequate for their intended use and to ensure that when changes occur the sampling plans are reviewed, as required by 21 CFR 820.250(b). This is a repeat observation from the previous FDA 483 issued on 11/20/07. For example:
a. The current Statistical Quality Sampling Plan and Raw Material Specification Sheet require that for inspection of a urine cup part (UCP-009), the correct sample size for a lot of 23,520 is (b)(4) samples. However, 23,520 cups of UCP-009 - Raw Material Lot#(b)(4) were received on 10/12/09, and only 32 samples were tested.
b. The sampling plan established in the Raw Material Specification for Nitrocellulose Membrane requires a sample size of (b)(4) of the membrane roll stock. The following sample sizes for nitrocellulose membrane were tested:
a) Raw material lot (b)(4) received on 2/23/09: 1 foot was sampled for visual inspection and 10 feet were sampled for functional inspection. The correct sample size was (b)(4) feet.
b) Raw material lot (b)(4) received on 7/27/09: 10 feet were sampled for functional testing. The correct sample size was (b)(4) feet.
c) Raw material lot (b)(4) received on 9/24/09: 10 feet were sampled for functional testing. The correct sample size was (b)(4) feet.
d) Raw material lot (b)(4) received on 11/10/09: 10 feet were sampled for functional testing. The correct sample size was (b)(4) feet.
c. Production personnel perform in process testing of the Lyophilized Colloidal Gold-Antibody Conjugate Coated Fiberglass. When this testing was performed on lot number (b)(4) of an Ab/Ag-coated THC membrane, 10 samples were tested at each THC concentration level defined in the test procedure. However, there was no written procedure that defines the sampling plan to be used by production in this testing.
We have reviewed your response and concluded that it is not adequate. You stated that the sampling plan procedure will be reviewed and edited to define requirements such as units of measurement and sample size. However you did not provide documentation of the revised procedure and did not state how it will ve1ify the correct implementation of the procedure.
7. Failure to establish and maintain adequate procedures to ensure that equipment is routinely calibrated, inspected, checked, and maintained to include provisions for handling, preservation, and storage of equipment, so that its accuracy and fitness for use are maintained, as required by 21 CFR 820.72(a). This is a repeat observation from FDA 483 issued on 11/20/07. For example:
a. The Lyophilizer Maintenance and Calibration Procedure (Q56-P14, Revision 02) specified that lyophilizers are to undergo quarterly preventative maintenance by a licensed contractor. However, quarterly preventive maintenance has not been executed for the VirTis and Hull Lyophilizers. Additionally, the firm admitted that quarterly maintenance procedures have not been performed by a licensed contractor.
b. A product technician at the firm admitted that the chart recorder used on the VirTis Lyophilizer to document lyophilization parameters has not been functioning since mid December 2009. No service work order had been initiated to repair the broken recorder.
c. The digital caliper (Equipment ill # (b)(4) used in receiving inspection activities is overdue for annual calibration. Last calibration was performed in 10/30/08.
We have reviewed your response and concluded that it is not adequate. You stated that you completed a review of your maintenance schedule and reminders have been entered into Outlook. However, you did not state if the lyophilizers and calipers would be immediately calibrated. Also, you stated that the VirTis operator was retrained but did not provide documentation of the training.
8. Failure to establish and maintain adequate procedures to prevent contamination of equipment or product by substances that could reasonably be expected to have an adverse effect on product quality, as required by 21 CFR 820.70(e). This is a repeat observation from the previous FDA 483 issued on 11/20/07. For example, your procedure for cleaning and maintenance of the manufacturing areas (Q53-P03, Revision 02) did not identify a schedule for routine cleaning of air vents in the dry room areas where product is assembled. During the inspection on 1/13/10 the vents were covered in dust and debris in Dry Room#(b)(4)
We have reviewed your response and concluded that it is not adequate because although you stated that a procedure was written to define and schedule air vent cleaning, you did not state if the air vents would be immediately cleaned or provided the written procedure for FDA's review.
9. Failure to establish and maintain adequate procedures that describe the methods for authorizing receipt from and dispatch to storage areas and stock rooms, as required by 21 CFR 820.150(b). Specifically, you have no procedure in place to specify who is authorized to retrieve mini-batches of product found in Room (b)(4).
We have reviewed your response and concluded that it is not adequate because although you stated that you will create a procedure for controlling in-process materials in Room. you did not provide a copy of the procedure for FDA's review.
10. Failure to establish and maintain adequate procedures for the control of storage areas and stock rooms for product to prevent mixups, damage, deterioration, contamination, or other adverse
effects pending use or distribution and to ensure that no obsolete, rejected, or deteriorated product is used or distributed, as required by 21 CFR 150(a). For example, the mini-batch materials (optimized gold/membrane combinations) stored in Room (b)(4) are labeled "quarantine"; however, these materials are used to manufacture product.
Your response to this observation appears to be adequate.
11. Failure to establish and maintain procedures to adequately control environmental conditions that could reasonably be expected to have an adverse effect on product quality, as required by CFR 21 820.70(c). This is a repeat observation from FDA 483 issued on 11/20/2007. For example, the firm does not have temperature and humidity controls in the VirTis Lyophilizer Room, Room &(b)(4) where mini-batch lots are stored and require controlled temperature and humidity conditions.
Your response to this observation appears to be adequate.
12. Failure to establish adequate procedures for identifying training needs and ensure that all personnel are trained to adequately perform their assigned responsibilities and to be made aware of device defects which may occur from the improper performance of their specific jobs, as required in 21 CFR 820.25(b)(1). This is a repeat observation from the previous FDA 483 issued on 11/20/07. Specifically, not all employees have documented training to the job related procedures specific in the Department Specific Training Procedure, Q22-P30, Revision 05. For example:
a. Employee Training Records for two production employees (VT and BL) show that they do not have documented training in the Quality Manual Q01-M01, Revision 11. This training is required for all employees according to the firm's Department Specific Training Procedure document.
b. One Quality Assurance employee (HT) whose training record was reviewed did not have training in the General Manufacturing Area Procedure, Q53-P03, Revision 2. This training is required of all employees entering the production, laboratory, and warehouse areas.
c. Another employee (TH) involved in the lyophilization process does not have documented training in the film's Nonconforming Product Procedure (Q22-P08 - Revision 5) or Out of Tolerance (OOT) Procedure (Q22-P02), Revision 05. This employee is required to be trained in procedures instructing employees on how to handle equipment that is not working properly or performing out of specification.
We have reviewed your response and concluded that it is not adequate because although you stated that you will revise your Department Specific Training Procedure to include Core and job related procedures, you did not provide evidence of training or re-training for employees nor provided a copy of the revised procedure for FDA's review.
Our inspection also revealed that the QuikScreen 5 Plus 4, QuikScreen 9, and QuikScreen 11 Plus 3 drugs of abuse test kit devices are adulterated under section 501(f)(1)(B) of the Act, 21 U.S.C. 351(f)(1)(B), because you do not have an approved application for premarket approval (PMA) in effect pursuant to section 515(a) of the Act, 21 U.S.C. 360e(a), or an approved application for an investigational device exemption (IDE) under section 520(g) of the Act, 21 U.S.C. 360j(g). The devices are also misbranded under section 502(0) the Act, 21 U.S.C. 352(0), because you did not notify the agency of your intent to introduce the devices into commercial distribution, as required by section 510(k) of the Act, 21 U.S.C. 360(k). For a device requiring premarket approval, the notification required by section 510(k) of the Act, 21 U.S.C. 360(k), is deemed satisfied when a PMA is pending before the agency. 21 C.F.R. 807.81(b). The kind of information you need to submit in order to obtain approval or clearance for your devices is described on the Internet at http://www.fda.gov/cdrh/devadvice/3122.html. The FDA will evaluate the information you submit and decide whether your product may be legally marketed.
Under section 801(e)(1) of the Act, 21 U.S.C. 381(e)(1), a device not approved for marketing in the United States may be legally exported provided it meets the requirements of section 801(e)(1) of the Act. Further information about the requirements of section 801(e) of the Act may be found on the internet at http://www.fda.gov/cdrh/devadvice/39.html#procedures. One requirement is that the device is not sold or offered for sale in domestic commerce, under section 801(e)(1)(D). Our inspection revealed that your firm sold unapproved devices to (b)(4) Calabasas, CA and (b)(4) Chatsworth, CA. Even with conditions of exportation, this constitutes a sale in domestic commerce which is a violation of section 801(e)(1).
You should take prompt action to correct the violations addressed in this letter. Failure to promptly correct these violations may result in regulatory action being initiated by the Food and Drug Administration without further notice. These actions include, but are not limited to, seizure, injunction, and/or civil money penalties. Also, federal agencies are advised of the issuance of all Warning Letters about devices so that they may take this information into account when considering the award of contracts. Additionally, premarket approval applications for Class ill devices to which the Quality System regulation deviations are reasonably related will not be approved until the violations have been corrected. Requests for Certificates to Foreign Governments will not be granted until the violations related to the subject devices have been corrected.
Please notify this office in writing within fifteen (15) working days from the date you receive this letter of the specific steps you have taken to Correct the noted violations, including an explanation of how you plan to prevent these violation(s), or similar violation(s), from occurring again. Include documentation of the corrective action you have taken. If your planned corrections will occur over time, please include a timetable for implementation of those corrections. If corrective action cannot be completed within 15 working days, state the reason for the delay and the time within which the corrections will be completed.
Your response should be sent to:
Director, Compliance Branch
Food and Drug Administration
Irvine, CA 92612-2506
If you have any questions about the content of this letter please contact Dr. Raymond W. Brullo, Compliance Officer at (949)608-2918.
Finally, you should know that this letter is not intended to be an all-inclusive list of the violation(s) at your facility. It is your responsibility to ensure compliance with applicable laws and regulations administered by FDA. The specific violation(s) noted in this letter and in the Inspectional Observations, Form FDA 483 (FDA 483), issued at the closeout of the inspection may be symptomatic of serious problems in your film's manufacturing and quality assurance systems. You should investigate and determine the causes of the violation(s), and take prompt actions to correct the violation(s) and to bring your products into compliance.
Alonza E. Cruse