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RESPONSE LETTER

Hyphen BioMed Mar 04, 2016

Hyphen BioMed - 335758 - 03/04/2016


Company:
Hyphen BioMed

   

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 

MAR 4, 2016

Ms. Anne-Marie Vissac
President
Hyphen BioMed
155, Rue D’ Eragny
Neuville Sur Oise, 95000, France
 
 
DearMs. Vissac:
 
The United States Food and Drug Administration (FDA) completed an evaluation of  your firm’s corrections and corrective actions in response to our Warning Letter CMS Case # 335758 dated September 05, 2012. We address your 10/20/2015, 10/26/2015 and 12/28/2015 responses below, in relation to each of the noted violations. These violations previously cited 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:
 
a.    Corrective actions identified for CAPA #239 opened on January 10, 2013, to address non-conformances identified and complaints received for packaging and labeling deficiencies in 2012 were not verified and/or validated prior to implementation. The corrective action documented in CAPA #239, to recruit and hire new packaging department manager, to date, has not been verified and/or validated to demonstrate whether the actions implemented are effective and do not adversely affect the devices. The firm has continued to receive complaints of packaging/labeling deficiencies and CAPA # 239 has not yet been closed.  Additionally, on 01/07/2014, during a retrospective review of complaints and non- conformances, the firm identified at least 4 processing/packaging related non-conformances between January 2010 and the time of analysis.
 
b.    The firm’s procedure “Actions Correctives et Actions Preventives” (Rev 5, Effective 08/27/2013) does not specify that corrective and preventive actions will be verified and/or validated prior to implementation to ensure that such actions are both effective and do not adversely affect the finished device.
 
c.    The firm’s procedure “Actions Correctives et Actions Preventives” (Rev 5, Effective 08/27/2013) includes the requirement for analysis of data sources including, but not limited to complaints. The firm’s analysis of complaints includes only “confirmed” complaints and omits “non- confirmed” complaints. Ms. Diane Agnangii-Belei, the firm’s Quality Assurance Manager, stated that the analysis of data sources required by the CAPA subsystem only included confirmed complaints and does not include non-confirmed complaints as required by the firm’s CAPA procedure.
 
Your firm’s response to our Warning Letter appears to be adequate.
 
2.    Failure to validate computer software for its intended use according to an established protocol when computer or automated data processing systems are used as part of production or the quality system, as required by 21 CFR
820.70(i). For example the firm has not performed software validation according to established protocols for the software in the production lyophilizers (ML091 and ML197) which are automated software-driven. Ms. Anne Marie Vissac, the firm’s President/Technical Director, and Mr. Damien Lehuede, the firm’s Manufacturing Manager, verbally confirmed to the investigator that there was no evidence of software validation and/or protocol available during the inspection for the software contained in the ML091 and ML197 production lyophilizers.
 
Your firm’s response to our Warning Letter appears to be adequate.
 
3.    Failure to establish and maintain procedures to ensure that equipment is routinely calibrated, inspected, checked, and maintained, as required by 21 CFR 820.72(a). For example, the firm does not have procedures for routine calibration of the temperature probe indicators, pressure gauge indicators, and timers used in the lyophilizers (ML091 and ML197) used in production. Mr. Damien Lehuede, the firm’s Manufacturing Manager, stated that calibration of the temperature probe, pressure gauge, and timers was done upon installation and is done upon their replacement once they are changed (which is when they break). The temperature probe, pressure gauge, and timers have not been changed.
 
Your firm’s response to our Warning Letter appears to be adequate.
 
4.    Failure to review and evaluate the process and perform revalidation where appropriate when changes or process deviations occur, as required by 21 CFR 820.75(c). For example, the firm re-lyophilized 641 vials out of a batch of 2552 vials (lot 31801-1) in ML091 to address a nonconformance with Fibriphen-5 coagulation assay; however, this re-lyophilization process is not included as a part of the firm’s process validation for ML091 lyophilizer. Mr. Damien Lehuede, the firm’s Manufacturing Manager, and Ms. Anne Marie Vissac, the firm’s President/Technical Director, stated that re-processing/re-lyophilization was not done as part of the validation process and that validation was done for single cycles only.
 
Your firm’s response to our Warning Letter appears to be adequate.
 
5.    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, the firm’s procedure “Audits Qualite” (Quality Audits, Rev 3, Effective Date 07/25/2013) does not include minimum criteria to be covered during internal audits including relevant portions of the Quality System Regulation to ensure the effectiveness of the firm’s quality system.
 
Your firm’s response to our Warning Letter appears to be adequate.
 
Please be advised that it is your firm’s responsibility to assure compliance with the Federal Food, Drug, and Cosmetic Act and its implementing regulations or with other relevant legal authority.
 
A Warning Letter close-out letter will not be issued until an FDA follow-up inspection has been conducted to verify that corrections and/or corrective actions (which must address systemic problems) have been implemented by your firm.  An FDA staff member will contact you to arrange a mutually convenient date for conducting a follow-up inspection.
 
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.
 
If you have any questions about the contents of this letter, please contact: Kennita Riddick at 301-796-3717.
 
 
Sincerely yours,
/S/ 
James L. Woods
Deputy Director
Patient Safety and Product Quality
Office of InVitro Diagnostics and Radiological Health
Center for Devices and Radiological Health