Inspections, Compliance, Enforcement, and Criminal Investigations

Ortho Clinical Diagnostics Gmbh 9/3/15

  

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

Public Health Service
Food and Drug Administration
 Silver Spring, MD  20993 

 

WARNING LETTER
SEP 3, 2015
 
VIA UNITED PARCEL SERVICE
 
Ms. Gundula Twieling
Managing Director for Germany, Austria, Switzerland (DACH)
Ortho-Clinical Diagnostics GmbH
Karl-Landsteiner-Strasse 1
Neckargemund, 69151, Germany 
 
Dear Ms. Twieling:
 
During an inspection of your firm located in Neckargemund, Germany on 02/09/2015 through 02/12/2015, an investigator from the United States Food and Drug Administration (FDA) determined that your firm is a refurbishment facility for Class II Clinical Chemistry and Immunodiagnostics equipment such as Vitros 250, Vitros 5.1, Vitros5600, Vitros 3600, Vitros Eci, and Pro Vue.  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 Jennifer Paine, Executive Vice President WW Quality, Regulatory and Compliance, dated March 4, 2015 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, the Ortho-Clinical Diagnostics CAPA procedure for EMEA Refurbishment Center (OCD-ERC) ((b)(4), current Rev. 2 and previous Rev.2) and the global Ortho-Clinical Diagnostics CAPA procedure ((b)(4), Rev. 30, effective date 01/05/2015) describe the review of data, origination of CAPA, failure investigation, and implementation and effectiveness monitoring stages of CAPA. As per these procedures, the CAPA record is recorded on form 53206. The firm’s CAPA records have fields to record details pertaining to the effectiveness monitoring plan and if the effectiveness check is required (form 53206 states the effectiveness monitoring is only required for corrective CAPAs). However, there were 4 CAPAs ( CAPA 2013-003, CAPA 2013-002, CAPA 2013-001, and CAPA 2013-005) (of which the firm had 10 documented CAPAs: 7 for 2013 and 3 for 2014) from the past 2 years in which the firm failed to adequately document the effectiveness check of corrective and preventive actions. Specifically:
 
A.  CAPA 2013-001 was initiated to address out (b)(4). In the CAPA action plan field on Form 53206, the CAPA correction ((b)(4)) was completed on 09/18/2013. The fields titled “Effectiveness Monitoring Plan” and “Proposed effectiveness monitoring due date” in the CAPA report are checked as “not required” and the rationale states that the effectivity will be assessed via compliance audit. The date of the audit is also not documented and the “CAPA status Effective/Ineffective” field is stated as “N/A”. Furthermore, the form did not document what acceptance criteria and evidence that the effectiveness monitoring at each time point was assessed, as required (b)(4). This CAPA was approved to close on 09/18/2013, which would have been prior to the CAPA origin from an internal audit, IA-001281 (conducted from 11/26/2013-11/28/2013).
 
B.  CAPA 2013-002 was initiated to address out (b)(4). In the CAPA action plan field on Form 53206, the CAPA correction ((b)(4)) was completed on 07/26/2013. The field titled “Effectiveness Monitoring Plan” in the CAPA report is checked as “not required” and the rationale states that the effectivity will be assessed via internal audit. The date of the audit is also not documented and the “CAPA status Effective/Ineffective” field is stated as “N/A”. There was no documentation regarding initiation of the CAPA based on internal audit results and the acceptance criteria and evidence of the effectiveness monitoring at each time point was not recorded on the form, as required (b)(4). This CAPA was signed approved to close on 07/26/2013, which would have been prior to its origin from an internal audit, IA-001281 (conducted from 11/26/2013-11/28/2013).
 
C. CAPA 2013-005 was initiated to address various measuring instruments that were not recorded (b)(4). In the CAPA action plan field on Form 53206, the CAPA correction ((b)(4)) is dated as due on February 2014, however no completion date is stated. The implementation evidence states that (b)(4) went effective on 02/27/2014 (implemented under DCO-38732). The field titled “Effectiveness Monitoring Plan” in the CAPA report is checked as “not required” and the rationale states that the effectivity will be assessed via internal audit of calibration by compliance. There was no documentation regarding initiation of the CAPA based on internal audit results and the acceptance criteria and evidence of the effectiveness monitoring at each time point was not recorded on the form, as required (b)(4). The date of the audit is also not documented and effectiveness check results were not documented, as confirmed by OCD-ERC.
 
D.  CAPA 2013-003 was initiated to address lack of adequate personal protection during handling of controls and reference material during final QC release testing of refurbished devices. In the CAPA action plan field on Form 53206, the CAPA correction ((b)(4)) was completed on 07/26/2013. The field titled “Effectiveness Monitoring Plan” in the CAPA report is checked as “not required” and the rationale states that the effectivity will be assessed via internal audit. There was no documentation regarding initiation of the CAPA based on internal audit results and the acceptance criteria and evidence of the effectiveness monitoring at each time point was not recorded on the form, as (b)(4). The date of the audit is also not documented.
 
We reviewed your firm’s response and conclude that it is not adequate. Your firm stated that effectiveness check details were lacking form CAPA 2013-003, CAPA 2013-002, CAPA 2013-001 and CAPA 2013-005 in part due to the use of local paper processes and local language requirements. Your firm provided the following corrective actions: 
  • Updated CAPA record details for CAPA 2013-003, CAPA 2013-002, CAPA 2013-001 and CAPA 2013-005 to include effectiveness check information.
  • Retrospective review of CAPAs from January 2013 to February 2015 regarding effectiveness checks and release of nonconforming product.
  • Documentation of all records that were processed according to the paper based system in the global electronic system according to the procedures (b)(4), to be completed by 03/26/15.
  • Review (b)(4) to determine if additional modifications are required for implementation at OCD Germany, to be completed by 04/23/15.
Your response is not adequate because your firm did not provide any corrective action regarding the local paper processes and local language requirements and improved effectiveness check documentation. In addition, the effectiveness assessment information on the updated form for CAPA 2013-005 (b)(4) devices were picked at random and their calibration status reviewed, however no rationale is provided with regard to the sampling procedure (b)(4) devices, as required per (b)(4). In addition, the response is not adequate because your firm did not provide a justification for why a retrospective analysis was performed for CAPA records (b)(4) period and not all CAPA records to ensure that all effectiveness check details were documented as required. Your firm did not provide a retrospective review of all CAPAs to ensure all aspects of CAPA requirements were completed as required. Your firm has not provided a revised procedure regarding effectiveness documentation (b)(4) of global procedures outlined in (b)(4). Furthermore, your firm has not provided training records for any updated procedures.
 
2.    Failure to establish and maintain procedures to control product that does not conform to specified requirements, as required by 21 CFR 820.90(a). Specifically:
 
A.  Your firm failed to adequately evaluate/investigate nonconformance event #337393. The (b)(4) of the refrigerator that housed reagents (b)(4) an investigation result stated that this device was defective. Ms. Janette Morris, your firm’s Quality Operations Director, stated that nonconformances are handled through OCD global procedure, Ortho Clinical Diagnostics Nonconforming Procedure, (b)(4) and OCD- ERC local procedure, Nonconformance procedure for EMEA Refurbishment Center, (b)(4). The OCD-ERC local procedure (Nonconformance procedure for EMEA Refurbishment Center, (b)(4)) states that the investigation includes an identification of potentially affected product(s) and documentation of the investigation in the nonconformance records. However, your firm failed to document details on the nonconformance record form (or provide evidence of documentation in their electronic record) for event #337393 in the fields pertaining to potentially affected chemicals (names, lot numbers, quantities) located inside of the refrigerator. The investigator also asked Mr. Matthew Witcome, the Quality Engineering Manager, about the identification of the possibly affected chemicals and he stated that this information had not been recorded.
 
B.  Your firm failed to document objective evidence of product disposition for nonconformance event # 2013-022b and record investigation details. Chemicals for release testing of refurbished devices were stored in a functioning freezer that was not being monitored and were subsequently moved to another freezer. However, your firm failed to adequately document identification of affected product(s) (product codes, lot number and quantities) and document evidence of disposition implementation, as required by (b)(4), on Form 53171. The product correction/disposition field on Form 53171 only states that the “(b)(4)” and the disposition plan field states that “(b)(4)”. Mr. Matthew Witcome, your firm’s Quality Engineering Manager, had also stated that the detailed information on affected products by nonconformance should have been documented.
 
We reviewed your firm’s response and conclude that it is not adequate. Your firm provided the following corrections and corrective actions:
  • Update nonconformance events #337393 and #2013-022b to include more investigation details.
  • Conduct a retrospective review of nonconformances from January 2013 to February 2015.
  • Record all paper-based nonconformances in the global electronic system, to be completed by 03/26/2015.
  • Review (b)(4) (Ortho-Clinical Diagnostics Nonconformance Procedure) to determine if additional modifications are required for implementation at OCD Germany, to be completed by 04/23/15.
Your firm’s response is not adequate because the additional information that is stated for the nonconformance record for event #33793 only contains additional information pertaining to (b)(4) still does not contain any further details regarding the chemicals that were stored in the affected refrigerator. For the updated nonconformance record for event #2013-022b, no details regarding the chemicals that were stored in the unmonitored freezer are provided. Your firm also did not provide copies of any relevant updated electronic records that may also contain any updated information for the nonconformance records. Your firm also did not conduct a retrospective review to determine if any nonconforming products were linked to the use of the potentially nonconforming reagents that were the subject of nonconformance events #337393 and #2013-022b. Furthermore, the updated record states that training was given to workshop staff, including the requirement to (b)(4) of status equipment and to check calibration status before use (b)(4) has not been provided. Additionally, your firm has not stated that training was given to perform adequate investigations of nonconformances and document all information pertaining to potentially affected products and reagents. In addition, the response is not adequate because your firm did not provide a justification for why a retrospective analysis was performed for nonconformance events (b)(4) period instead of a review of all nonconformances. Your firm has not provided a revised procedure regarding effectiveness documentation for (b)(4), nor has your firm provided training records for any updated procedures.
 
3.    Failure to establish and maintain procedures to ensure that DHR's 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, as required by 21 CFR 820.184. For example, the refurbishment records, including release test results and associated raw data, contained within the DHRs for Vitros 5600 (S/N 56000642) and Vitros 5600 (S/N 56001482) had hand written numbers that were documented as the “required range” for each chemistry assay on the test sheets. Mr. Peter Dorr, service engineer, stated that the required range for each assay (b)(4). However, the DHR did not contain the (b)(4) for the required ranges. Furthermore, the online information revealed different range of means and estimates of within-lab SD for both websites for the same product/lot. Your firm could not provide any related information regarding this matter during the inspection since the control assay data sheets are not contained within the DHRs.
 
We reviewed your firm’s response and conclude that it is not adequate. Your firm has provided the checklist (FRM51887) and test sheet (FRM53464; contains information such as name of the chemistry, lot number, required range, current mean and precision, pass/fail result) for the Vitros 5600, which your firm states are representative DHR documentation in OCD Germany. Your firm provided the following corrective actions:
  • Your firm has stated that it will retrospectively review the DHR for the past 2 years for all instruments shipped to the U.S. by 04/29/2015 and it will review the remaining DHR (results will be documented under CAPA 339564).
  • Your firm has also stated that it will evaluate the DHR, acceptance records, and Device Master Record processes to ensure document traceability is in place, which is to be completed by 04/23/2015.
  • Furthermore, your firm states that it will implement process improvements based upon the outcome of the retrospective review, to be completed by 06/12/2015.
Your response is not adequate because your firm provided some parts of the checklist in German and the full checklist should be provided in English. Furthermore, the checklist and test sheet that are provided have blank fields and are not specific to the Vitros 5600 (S/N 56000642) and Vitros 5600 (S/N 56001482). Your firm has also not provided the results of its retrospective review of all DHR records. Furthermore, your firm has not provided any revised procedures (such as (b)(4) pertaining to the checklist in which specific assay QC information is included) regarding improved documentation in the DHR and associated training records.
 
4.    Failure to retain records, required by this part, for a period of time equivalent to the design and expected life of the device, but in no case less than 2 years from the date of release for commercial distribution by the manufacturer, as required by 21 CFR 820.180(b). For example, Mr. Thomas Philippi, Manager of the EMEA Refurbishment Center, stated that all current lot control assay data sheets used to set the reagent/lot specifications for QC release testing, including the Vitros Chemistry Systems assay sheets, are available online at the OCD website. When asked how long are these control sheets available and accessible on the website, Ms. Janette Morris, the Quality Operations Director, stated that they do not keep a hard or electronic copy and they do not know for how long the control sheets are available online.
 
We reviewed your firm’s response and conclude that it is not adequate. Your firm provided the following corrective actions: 
  • Your firm has stated that it will retrospectively review the DHR for the past 2 years for all instruments shipped to the U.S. by 04/29/2015 and it will review the remaining DHR (results will be documented under CAPA 339564).
  • Furthermore, your firm states that it will implement process improvements based upon the outcome of the retrospective review, to be completed by 06/12/2015.
Your response is not adequate because your firm has not provided the results of its retrospective review of all DHR records. Furthermore, your firm has not provided any revised procedures which state that records required by 21 CFR 820 will be maintained a period of time equivalent to the design and expected life of the device, but in no case less than 2 years from the date of release for commercial distribution.
 
Your firm’s response dated April 15, 2015 and May 11, 2015 to the Form FDA 483 (FDA 483) was not reviewed because it was not received within fifteen business days of issuance of the FDA 483. The response will be evaluated along with any other written material provided in response to the violations cited in this Warning Letter. 
 
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 actions (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.
 
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 #457877 when replying. If you have any questions about the contents of this letter, please contact: James L. Woods, at 301-796-6225 or fax 301-847-8513.
 
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
 

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