Inspections, Compliance, Enforcement, and Criminal Investigations

Cepheid Ab 7/23/15

  

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
JUL 23, 2015 
 
VIA UNITED PARCEL SERVICE
 
Ms. Anita E. Herrström Sjöberg
Vice President and Managing Director
Cepheid Ab
Roentgenvaegen 5
Solna, Sweden
 
Dear Ms.Herrström Sjöberg:
 
During an inspection of your firm located in Solna, Swedenon March 30, 2015, through March 31, 2015, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures Xpert® Norovirus. 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 Ms. Anita Herrström Sjöberg, Vice President and Managing Director, dated April 17, 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 the identification, documentation, validation or where appropriate verification, review, and approval of design changes before their implementation, as required by 21 CFR 820.30(i). 
 
For example:
 
a)    Your firm does not define, or establish, the procedures for the identification, documentation, validation or where appropriate verification, review, and approval of pre-production design changes before their implementation for the Xpert® Norovirus design project. Dr. Per Grufman, the firm’s Senior Director R&D, and Ms. Judith Howard, the firm’s Global Vice President Regulatory Compliance & Quality Systems, stated that procedures for pre-production design changes are not defined.
b)    Upon request by the investigator, Ms. Judith Howard, the firm’s Global Vice President Regulatory Compliance & Quality Systems, stated that the firm’s procedure, (b)(4) Rev R “Commercial Production Change Control” dated 10/21/2014, which defines any procedures for implementing design changes to a purchased or commercially released part, does not define the procedures for when to verify post-production design changes before their implementation.
 
We reviewed your firm’s response and conclude that it is not adequate.  1) Your firm did not provide documentation or evidence of the implementation of corrective actions identified in (b)(4), including a revised Design Control procedure to address the identified deficiency. 2) Your firm failed to include a retrospective review of design changes for the Xpert® Norovirus and other products at the site to ensure that design changes were identified, documented, validated or where appropriate verified, reviewed, and approved prior to their implementation as a corrective action for the deficiency. 3) Your firm did not provide evidence that employees were trained on the revised design change procedures as required. 4) Your firm did not provide evidence that a systemic corrective action was considered to include a retrospective review of all design control procedures to ensure that all design control activities were completed as required.
 
2.    Failure to establish and maintain procedures for implementing corrective and preventive action, as required by 21 CFR 820.100(a).
 
For example:
 
a)  Upon request by the investigator, Ms. Anna-Karin Wahlström, the firm’s Director Regulatory & QA, stated that the firm’s CAPA procedure, (b)(4) Rev 4 “Forebyggande och korrigerande atgarder (CAPA)” does not define the requirement for verifying or validating the CAPA to ensure that such action does not have an adverse effect on the finished device.
b)   Upon request by the investigator, Ms. Anna-Karin Wahlström, the firm’s Director Regulatory & QA, stated that the firm’s CAPA procedure, (b)(4) Rev 4 “Forebyggande och korrigerande atgarder (CAPA)”  does not require that information related to quality problems be disseminated to those directly responsible.
 
We reviewed your firm’s response and conclude that it is not adequate. Your firm did not provide documentation or evidence of the implementation of corrective actions to include a retrospective review of all CAPAs to 1) verify or validate that the CAPA was effective and did not adversely affect the finished device; 2) to ensure CAPA information was disseminated to those directly responsible for assuring the quality of such product or the prevention of such problems; and 3) to ensure that all CAPAs were completed as required. In addition, your firm did not identify that training was completed prior to implementation of the updated procedures.
 
3.    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.
 
For example:
 
a)    Upon request and confirmation by the investigator, Ms. Anna-Karin Wahlström, Director Regulatory & QA, stated that your firm’s internal audit procedure, (b)(4) Rev 9, “Internrevision av kvalitetsledningssystemet” dated 03/11/2015, does not include the requirement for conducting a re-audit of deficient matters.
b)    Upon request and confirmation by the investigator, Ms. Anna-Karin Wahlström, Director Regulatory & QA, confirmed that management controls and design controls were not included in the 2013, 2014 and 2015 audit plans, but these activities were being conducted at the facility. In addition, although the procedure, (b)(4) Rev 9, ““Internrevision av kvalitetsledningssystemet” dated 03/11/2015, describes the development of an annual audit plan, the annual audit plan was confirmed by Ms. Wahlström not to be a controlled document.
 
We reviewed your firm’s response and conclude that it is not adequate. Your firm did not provide documentation, or evidence of the implementation of corrective actions, or effectiveness checks to include a retrospective review of previous audits to determine if any re-audits are required based on the revised procedures. In addition, your firm did not identify that training was completed prior to implementation of the updated procedures.
 
4.    Failure to establish and maintain procedures to ensure that all purchased or otherwise received product and services conform to specified requirements, as required by 21 CFR 820.50. 
 
For example:
 
a)    Upon request and confirmation by the investigator, Ms. Ann-Marie Bill, Manager Purchasing and Production Planning, stated that the procedure for purchasing controls, (b)(4) Rev 7 “Leverantorer” (supplier) dated 12/27/2013, only covers purchased parts and services, and does not include within its scope the requirements that must be met by consultants.
b)    Upon request and confirmation by the investigator, Ms. Anita Herrström Sjöberg, the firm’s Vice President and Managing Director, stated that the procedure for purchasing controls, (b)(4) Rev 7 “Leverantorer” (supplier) dated 12/27/2013 does not define removal of poor performing suppliers from the approved supplier list.
 
We reviewed your firm’s response and conclude that it is not adequate. Your firm did not provide documentation or evidence of the implementation of corrective actions or effectiveness checks to include 1) a retrospective review of all approved suppliers to determine if all previously approved suppliers are still approved; and 2) a retrospective review of all consultants that were utilized to determine that they met specified requirements. In addition, your firm did not identify that training was completed prior to implementation of the updated procedures.
 
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 #470862 when replying. If you have any questions about the contents of this letter, please contact: Leroy N. Hwang, Ph.D. at 240-402-6427.
 
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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