Inspections, Compliance, Enforcement, and Criminal Investigations
Diagnostics Biochem Canada, Inc. 12/20/11
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
10903 New Hampshire Avenue
DEC 20, 2011
VIA UNITED PARCEL SERVICE
Marie "Manon" Hogue
Owner and Chief Executive Officer
Diagnostics Biochem Canada, Inc.
11-1020 Hargrieve Road
Canada N6E 1P5
Dear Ms. Hogue:
During an inspection of your firm located in London, Ontario, Canada, on 9/6/2011 through 9/9/2011, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures Aldosterone ELISA kit, Free Testosterone ELISA kit, and Dihydrotestosterone ELISA kit. 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 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 your response dated September 22, 2011, concerning our investigator's observations noted on the Form FDA 483 (FDA 483), lnspectional Observations, that 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 adequately establish and maintain procedures for validating device design, as required by 21 CFR 820.30(g). For example, your firm's validation protocol procedure entitled WP 4 General Protocol for R&D of ELISA Systems, File Name: WP 4-v2.doc, Version 2.0, Effective January 8, 2010, was not implemented to ensure that a validation protocol for the firm's PRA ELISA test kit design project was documented and approved with defined methods, statistical rationales, and acceptance criteria prior to the start of the testing as part of the validation of the assay system.
We reviewed your firm's response and conclude that it is not adequate. Your firm has stated that it realizes that the WP 4 General Protocol for R&D of ELISA Systems was not followed in this instance and that it opened a corrective action (CAR#19-2011) to address this. Additionally, your firm opened a corrective action (CAR#13-2011) to implement changes in the General Protocol for R&D of ELISA Systems to outline procedures for including defined methods and acceptance criteria based upon an established statistical rationale to all development validation protocols. Your firm's response also indicated that all research personnel will be trained to the new procedure and that this process will be audited internally every quarter to ensure compliance as part of PAR #1-2011. These corrective actions were to be completed by 11/15/2011. To date, your firm has not completed the corrective actions and has not provided evidence of implementation of all of the corrective actions indicated in the response.
2. Failure to adequately establish and maintain procedures to ensure that the device design is correctly translated into production specifications, as required by 21 CFR 820.30(h). For example, no design transfer procedures were available for review and no mention of design transfer activities was documented in your firm's available design control procedures.
We reviewed your firm's response and conclude that it is not adequate. Your firm has stated that it will include design transfer activities as part of its current processes under CAR #12-211. This corrective action will include drafting a new standard operating procedure outlining the design transfer process and its documentation to ensure compliance with 820.30. Your firm's response also indicated that personnel will be trained on these new procedures and that management will closely monitor the implementation and continued compliance through regular quarterly internal auditing practices as part of PAR#1-2011. These corrective actions were to be completed by 11/15/2011. To date, your firm has not completed the corrective actions and has not provided evidence of implementation of all of your corrective actions indicated in the response.
3. Failure to adequately establish and maintain procedures for acceptance activities including inspections, tests, or other verification activities, as required by 21 CFR 820.80(a). For example, the document WP 5 QC Procedures for ELISA & CLIA Kits and Components Version 3.0 does not ensure that new lots of kit components are routinely tested against qualified kits and released for use prior to use in new kits. Your firm has no defined acceptance test requirements for new components of kits prior to final release testing.
We reviewed your firm's response and conclude that its adequacy cannot be determined at this time. Your firm states that it is initiating a new process to assess each new lot of a kit component in relation to the previous component and established test acceptance standards for each component. These changes will be included in the revision of WP 5 QC Procedures for ELISA & CLIA Kits and Components as part of CARR#16-2011. Your firm's response also indicated that personnel will be trained on these new procedures and that management will closely monitor the implementation and continued compliance through regular quarterly internal auditing practices as part of PAR#1 -2011 These corrective actions are scheduled to be completed by 12/15/2011.
4. Failure to adequately establish and maintain procedures for identifying valid statistical techniques required for establishing, controlling, and verifying the acceptability of process capability and product characteristics, as required by 21 CFR 820.250(a). For example:
a) Your firm provided WP 5 QC Procedures for ELISA & CLIA Kits and Components Version 3.0, which requires (b)(4) for final acceptance testing for kit release. The determination of (b)(4) was not based on a statistical rationale.
b) The (b)(4) is also described in WP 5 QC Procedures for ELISA & CLIA Kits and Components Version 3.0 and it is not based on statistical rationale.
c) The design project for the PRA test kits (7.3.6 Design and Development Validation File Name: 7.3.6-v2.doc Version 2.0 Effective: 1/8/2010 and WP 4 General Protocol for R&D of ELISA systems File Name: WP 4-v2.doc Version 2.0 Effective: 1/8/2010) did not include a statistical rationale for the verification and validation testing by the firm.
We reviewed your firm's response and conclude that it is not adequate. Your firm has stated that procedures used to establish, control, and verify both process capability and product characteristics, including final acceptance testing for kit release, required (b)(4) and were based on historical practices rather than a valid statistical rationale according to WP 5 QC Procedures for ELISA & CLIA Kits and Components Version 3.0 Systems. Additionally, the (b)(4) was based on historical precedence and not a coherently valid statistical rationale. Your firm has indicated that it will develop a sampling plan that is in compliance with ASQ Z1.4 using an appropriately justified Acceptance Quality Limit under general inspection level II with a normal type of inspection for the next 6 months. At the end of the 6 month period, your firm has committed to investigate the use of a reduced sampling plan and statistically justify such a sampling plan based upon the results of the previous 6 months. This will be done under corrective action (CAR#14-2011) and personnel will be trained to these new procedures. In addition, the process will be audited internally every quarter to ensure compliance as part of PAR #1-2011. Your firm has committed to completing these corrective actions by 12/30/2011.
Additionally your firm acknowledges the lack of a statistical rationale contained in the validation and verification testing documents for the PRA ELISA test kits. WP 4 General Protocol for R&D of ELISA Systems will be modified under CAR#15-2011 to require inclusion of the statistical rationale in development of a verification and validation protocol, as well as inclusion of these explanations within the final verification and validation reports. The procedure will be modified to state that all statistical rationales must be based upon an Acceptance Quality Limit for the individual product being developed and that statistical analysis must clearly demonstrate that verification and validation both exceed a 95% confidence level. The corrective action also includes the revision of the verification and validation reports for the PRA ELISA test kits to include a statistical rationale based on these new requirements and the appropriate statistical analysis. Personnel will be trained to these new procedures and the process will be audited internally every quarter to ensure compliance as part of PAR #1-2011. Your firm has committed to completing these corrective actions by 12/30/2011.
5. Failure to adequately control labeling and packaging operations to prevent labeling mixups, as required by 21 CFR 820.120(d). For example:
a) No labeling procedures were available and no controls were in place to prevent labeling mix-ups.
b) None of the labels and labeling used for each finished lot were documented in the Device History Records (DHR).
We reviewed your firm's response and conclude that it is not adequate. Your firm states that it is developing a procedure to include a new form that identifies the numbers of labels required, printed, destroyed, and applied to ensure accounting of all labels in the labeling control process. As part of this new procedure, your firm will include attachment of the device label for each finished lot to the Device History Record and personnel will be trained to the new procedures. This new process will be internally audited quarterly under PAR#1-2011 for compliance. This corrective action was scheduled to be completed by 11/15/2011. To date, your firm has not completed the corrective actions and it has not provided evidence of implementation of all corrective actions indicated in the response.
A follow up inspection will be required to assure that corrections and/or corrective actions are adequate.
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. 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 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 (including any systemic corrective actions) 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.
Your firm's response should be sent to: Food and Drug Administration, Center for Devices and Radiological Health, Office of Compliance, Field Operations Branch, White Oak Building 66, Rm 2609, 10903 New Hampshire Ave., Silver Spring, MD 20993. Refer to CMS case #251194 when replying. If you have any questions about the contents of this letter, please contact: 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 lnspectional 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.
Office of In Vitro Diagnostic Device
Evaluation and Safety
Center for Devices and