Inspections, Compliance, Enforcement, and Criminal Investigations

Spartan Bioscience Inc. 5/15/15

  

Department of Health and Human Services logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration
 10903 New Hampshire Avenue
Silver Spring, MD 20993 

 

WARNING LETTER
MAY 15, 2015 
 
VIA UNITED PARCEL SERVICE
 
Mr. Paul Lem
CEO
Spartan Biosciences, Inc.
6 Gurdwara Drive, Suite 204
Ottawa, Ontario, Canada K2E 8A3
 
Dear Mr. Lem:
 
We are amending the Warning Letter issued to your firm on April 9, 2015. Your response to the FDA Form 483, dated January 12, 2015, was received within fifteen (15) business days from the time the inspection at your facility was closed but not included in the original Warning Letter. The amended Warning Letter contains a review and assessment of your responses to the observations noted on the FDA form 483.
 
During an inspection of your firm located in Ottawa, Canadaon December 15, 2014 through December 18, 2014, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures the Spartan RX CYP2C19.  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 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 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 current good manufacturing practice requirements of the Quality System regulation found at Title 21, Code of Federal Regulations (CFR), Part 820.
 
We received a response from Mr. Paul Lem, CEO dated January 12, 2014 concerning our investigator’s observations noted on the Form FDA 483 (FDA 483), List of Inspectional Observations, which was issued to your firm. We address this response below, in relation to each of the noted violations. These violations include, but are not limited to, the following:
 
1.    Failure to establish and maintain procedures for implementing corrective and preventive action, as required by 21 CFR 820.100(a). For example, your firm identified corrective actions during the design of RXCYP2C19 to address failures during the Reproducibility study in approximately August 2012.  Your firm’s report indicates that failures were due to (b)(4) (Root Cause Report-FRX System miss-calls, Doc No. 01001966, Rev 05).  One of the corrective actions documented pertaining to the (b)(4) was to restrict movement of equipment and personnel between the reagent and (b)(4) (Document No 01001966, Rev 05, page 14 of 16).  However, it was not documented that a procedure was created or changed to include this corrective action or how/if the correction action was implemented.  In addition, your firm opened CAPA 131129002 on November 29, 2013 (closed on January 29, 2014) to address (b)(4) failure that was found and documented to be due to (b)(4) from (b)(4) that were in the reagent manufacturing area.  The corrective action documented was to not allow reagents or equipment to move from (b)(4) to the reagent manufacturing clean room.  However, it was not documented that a procedure was created or changed to include this corrective action or how/if the correction action was implemented.
 
We reviewed your firm’s response and conclude that it is not adequate. Your firm provided CAPA141222001 to document the investigation into this observation. Your firm states that the original CAPA131129003 did not correctly identify the source of the contamination. Your firm states that the source of the contamination was not movement of equipment, but rather reagent movement. Your firm states that as a result of this re-evaluation of the CAPA, reagent restrictions were put into place but were not clearly documented in manufacturing procedures. Your firm states that the proposed action plan is to fully document all control of movement relating to equipment, reagents, consumables, products and people in one centralized document (b)(4) Consumable Production Overview. Additionally, you state that training on updated documents will be required for all manufacturing personnel along with annual retraining. Your firm states that a training course will be created which will be required for all Spartan staff and new employees. Your firm states that 17 documents will be updated to include further instructions for the control of movement between facilities. Your firm states that once the action plan is in place, environmental and (b)(4) QC will be monitored. Three months of continued success of the environmental monitoring and (b)(4) QC will result in closure of the CAPA or if violations are found a new CAPA will ensue. However, your firm has not provided evidence of updated documentation incorporating this change to include instructions detailing the reagent restrictions put in place to minimize contamination nor has it provided training records of staff on the new procedures. Your firm has not provided a rationale for why 3 months of continued success of the environmental monitoring and (b)(4) QC is adequate. Your firm has not provided any documentation indicating that a retrospective review of all CAPA records was completed to determine whether all CAPAs have been completed as required.
 
2.    Failure to establish and maintain process control procedures that describe any process controls necessary to ensure conformance to specifications where deviations from device specification could occur as a result of the manufacturing process, as required by 21 CFR 820.70(a).  For example
 
a.    The manufacturing record for the (b)(4) External Control (b)(4) lot #0912304831-089814 shows that the quantities of the (b)(4) and (b)(4) were derived due to initial failure to follow the Procedure for (b)(4) (Doc ID: 01001742, Rev 19).  Specifically, section 9.4.4 on page 12 instructs the employee to record the concentrations of the (b)(4) dilutions in the table provided in the procedure (b)(4). However, the originally calculated values shown in Doc No. 01005069, Rev 10 for Oligo Part# (b)(4) and (b)(4) manufacturing record, does not identify the correction or deviations made to the calculations that were applied to arrive at the manufacturing quantity indicated in Doc 01001742, Rev 19, sections 9.4.4 and 9.5.1, respectively on page 14.  Additionally, (b)(4) (Doc No 01001838, date 01/28/2014) does not describe manufacturing procedures for batch adjustment of the quantities of (b)(4).
 
b.    The manufacturing of (b)(4) Lot#0914205031-0870814 failed QC testing 4 times before passing on the fifth test (Doc No. 01005102_EPC_QC_08 (1).xlsm Rev 8).  The tests were repeated 4 times with failures identified each time.  The fifth result identified a Pass result and the lot was passed.  No modifications were made, only the test was repeated according to the VP of Diagnostics, Mr. Chris Harder.
 
We reviewed your firm’s response and conclude that it is not adequate. Your firm provided CAPA141219001 to document the investigation into this observation for Lot #09123049831-089814 and Lot # 0914205031-0870814. Your firm provided manufacturing records for (b)(4) Lot 0912304831-089814 which indicates how the corrected quantities used for manufacturing the (b)(4) were determined. Your firm states the manufacturing record for (b)(4) indicating the correction applied to arrive at the quantity included in Document 01001724, Revision 19 was not readily available during the inspection although included in Section 9.4.4 on page 12 of Document 01001742, Revision 19. Your firm further states that these values were obtained as instructed in the procedures for failed results as outlined in the procedure for FRX External control (b)(4), Section 9.1.6, which states “(b)(4).  Your firm also provided clarification of the information noted in the observation for Lot # 0914205031-0870814. Your firm states that (b)(4) Lot # 0914205031-0870814 test was repeated 3 times and passed on the fourth attempt contrary to the language in the observation. Your firm states that the reason that multiple re-tests are allowed is that the (b)(4). Your firm determined that the root causes of the multiple repeats are the variable spec results and (b)(4). Your firms’ proposed action is to alter (b)(4).  Additionally, your firm’s plan includes changing the process of spec’ing to reduce the risk of (b)(4) rather than (b)(4) simultaneously.  Your firm states this change will be verified and validated. Your firm states that staff will be trained on the new procedure and training will be documented. Your firm states that Document 01001838 will be updated to clarify that any QC failure must be recorded through the NCR process.  Your firm states that the NCRs will be monitored and trends in modes of failure will be addressed through the CAPA process to ensure that no further incidents occur.  Your firm states that all staff will be retrained on the NCR process and training will be documented. Document 01001838 will also be updated to require clear record keeping within the batch records to indicate how a QC result was obtained; specifically, if the batch was a first attempt pass, or a remade batch after an NCR.  Your firm states that all actions will be verified and validated March 2015. Additionally, your firm states that after implementation of these corrections and corrective actions, the (b)(4)  QC process will be monitored for the next (b)(4) batches.  However, your firm has not provided updated procedures with clarified instructions defining how many repeats are allowed or the process of when reagents should be remade versus retested included. Your firm has not provided evidence that it implemented a correction to include the recalculation of the quantity for the external control (b)(4) using the appropriate calculations per the procedure provided. Your firm has not provided evidence that a correction has been implemented for (b)(4) repeat QC after restarting the procedure as per the procedure.  Your firm has not provided a rationale as to why monitoring the process for (b)(4) batches is sufficient. Additionally, your firm has not provided evidence that a retrospective review of all batch records has been conducted to ensure that adequate procedures were followed and documented to address failures in QC products. Your firm has also not provided evidence that the staff have been trained on the new processes and procedures.
 
3.    Failure to establish and maintain procedures to ensure that Device History Records (DHRs) for each batch, lot, or unit are maintained to demonstrate that the device is manufactured in accordance with the DMR and the requirements of this part (21 CFR 820), as required by 21 CFR 820.184.  Specifically, the DHR for the manufacture of the Spartan RX CYP2C19 platform for Units (b)(4) and (b)(4) include observed failures on the Spartan (b)(4).  There was no observed nonconformance identified and the product was released based on a technical decision. In addition, the DHRs for the manufacture of the Spartan RX CYP2C19 platform do not include a representation of the product label.
 
We reviewed your firm’s response and conclude that it is not adequate. Your firm provided CAPA141222003 to document the investigation into the observation of product being released on a technical decision.  Your firm states that 5 documents were identified with the following language included, “consult engineering for a corrective course of action.” Your firm states that these documents will be modified so that the technician or user of the document initiates a NCR upon failure of the test. Your firm provided CAPA141222004 to document the investigation regarding the device not being manufactured in accordance with the device master record.  Your firm indicates that the root cause of this deficiency was failure to update documentation when a new QC test was added.  Your firm states that the new metric was added as a separate analysis tool in December 2013.  Your firm states that the old metric was obsoleted in practice but not in documentation.  Your firm states that it will review for other instances of this failure mode use of old metrics, initiate a change order and ECO to remove the areas of obsolescence in the calibration software, verify and validate the changes and train manufacturing staff on new procedures. Your firm states that it did not understand that keeping a representation of the product label with the Device History Records was required and therefore the manufacturing procedure (b)(4) did not require a representation of the product label to be stored with the DHR.  Your firm states that procedure (b)(4) will be updated to require a duplicate of the product label to be stored with the DHR. However, your firm has not provided evidence that the 5 documents identified with the following language included, “consult engineering for a corrective course of action.” have been updated to include instructions to the user of when to initiate a NCR.  Your firm has also not provided training records indicating that staff has been trained on these new documents and procedures. Your firm has not provided evidence that a review for other instances of this failure mode, initiation of a change order and ECO to remove the areas of obsolescence in the calibration software, verification and validation of the changes and training of manufacturing staff on the new procedures have been implemented.  Your firm has not provided evidence that a nonconformance report was opened for the Spartan (b)(4) and all failures documented in the DHR and a retrospective review of all unit/batch records was conducted to determine if all batch records were adequately maintained to demonstrate that the device is manufactured in accordance with the DMR as required. Your firm has not provided evidence that the primary identification label of the Spartan RX CYP2C19 platform has been included in the DHR as required.  Your firm has also not indicated that a retrospective review of all DHRs for all devices has been conducted to ensure a primary identification label was included.
 
4.    Failure to establish procedures for quality audits and conduct such audits to assure that the quality system is in compliance with the established quality system requirements and to determine the effectiveness of the quality system, as required by 21 CFR 820.22.  Specifically, your firms’ Internal Audit procedure (Doc No. 01001178 Rev. 05) does not include audit planning to ensure that all areas of the quality system will be audited and in what frequency.  Audits of the quality system show that the audit of the quality management system was made in 2013 but not in 2014.
 
We reviewed your firm’s response and conclude that it is not adequate in that it did not address this observation. 
  
U.S. federal agencies may be advised of the issuance of 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 III devices to which the Quality System regulation deviations are reasonably related will not be approved until the violations have been corrected. 
 
Please notify this office in writing within fifteen business days from the date you receive this letter of the specific steps your firm has taken to correct the noted violations, including an explanation of how your firm plans to prevent these violations, or similar violations, from occurring again.  Include documentation of the corrections and/or corrective action (which must address systemic problems) that your firm has taken.  If your firm’s planned corrections and/or corrective actions will occur over time, please include a timetable for implementation of those activities.  If corrections and/or corrective actions cannot be completed within fifteen business days, state the reason for the delay and the time within which these activities will be completed.  Please provide a translation of documentation not in English to facilitate our review. We will notify you regarding the adequacy of your firm’s response(s) and the need to re-inspect your firm’s facility to verify that the appropriate corrections and/or corrective actions have been made.
 
Your firm’s response should be sent to: Food and Drug Administration, Center for Devices and Radiological Health, Office of Compliance, Field Inspections Support Branch, White Oak Building 66, Rm 2622, 10903 New Hampshire Ave., Silver Spring, MD 20993. Refer to CMS case #452036 when replying. If you have any questions about the contents of this letter, please contact: Mr. James Woods at 301-796-6225.
 
Finally, you should know that this letter is not intended to be an all-inclusive list of the violations at your firm’s facility.  It is your firm’s responsibility to ensure compliance with applicable laws and regulations administered by FDA.  The specific violations noted in this letter and in the Inspectional Observations, FDA 483, issued at the close of the inspection may be symptomatic of serious problems in your firm’s manufacturing and quality management systems.  Your firm should investigate and determine the causes of the violations, and take prompt actions to correct the violations and bring the products into compliance. 
 
 
Sincerely yours,
/S/                                                           
Alberto Gutierrez
Director
Office of In Vitro Diagnostics and
     Radiological Health
Center for Devices and
      Radiological Health
 

Page Last Updated: 04/22/2016
Note: If you need help accessing information in different file formats, see Instructions for Downloading Viewers and Players.
Language Assistance Available: Español | 繁體中文 | Tiếng Việt | 한국어 | Tagalog | Русский | العربية | Kreyòl Ayisyen | Français | Polski | Português | Italiano | Deutsch | 日本語 | فارسی | English