Hyphen BioMed 9/5/12
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Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
| ||10903 New Hampshire Avenue|
Silver Spring, MD 20993
September 5, 2013
VIA UNITED PARCEL SERVICE
Dr. Jean J. Amiral
Scientific and Research Director/President
155, rue d’Eragny
Neuville Sur Oise, France
Dear Dr. Amiral:
During an inspection of your firm located in Neuville Sur Oise, France, on June 18, 2012, through June 20, 2012, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures multiple Class II biological reagents for hemostasis and thrombosis, including Heparin Assay. 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 you dated July 9, 2012, concerning our investigator’s observations noted on the Form FDA 483 (FDA 483), List of Inspectional 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 establish and maintain adequate procedures for implementing corrective and preventive action (CAPA), as required by 21 CFR 820.100(a)(1).
For example, the firm’s Processing Defects, Corrective and Preventive Actions procedure (P.830.01 Rev 12, effective 10/20/2010) and the newly updated Corrective Actions and Preventive Actions procedure (P830-04, Rev 1, effective 6/12/2012), fail to include the requirement for analysis of quality data to identify existing or potential causes of nonconforming product or other quality problems, using appropriate statistical methodology, where necessary. To date, the firm has not analyzed the sources of quality data for existing or potential cause of nonconforming product or other quality problems.
The adequacy of your firm’s response cannot be determined at this time. Your firm’s response does not include the outcome of the retrospective review of all non-conformances and complaint records since January 2011, and your firm did not explain why it will only review information of non-conformances and complaint records up to January, 2011.
2. Failure to establish and maintain adequate procedures that define the responsibility for review and the authority for the disposition of nonconforming product, as required by 21 CFR 820.90(b)(1).
1. For example, your firm's process for controlling nonconforming products (Processing Defects, Corrective and Preventive Actions- P830-01) includes the disposition of "accept as such." However, Defect # 198 does not include a process for documenting the justification for use of nonconforming product (i.e., Elisa plate RK005A, lot #(b)(4)).
2. For example, the Device History Record (DHR) for Biophen UFH Calibrator, Lot #(b)(4), documented a nonconforming result on Calibrator 4; Calibrator 4 was subsequently rejected. However, there is no record of this nonconformance (i.e., (b)(4)) in the firm’s Record of Defects and CAPA.
The adequacy of the response cannot be determined at this time. Your firm’s response does not include the outcome of the retrospective review of database nonconformities, and your firm’s DHR for all lots of 510(k) products distributed in the US, for improperly documented and/or justified non‑conformances.
3. Failure to establish and maintain procedures for rework to include retesting and reevaluation of the nonconforming product after rework to ensure that the product meets its current approved specifications, as required by 21 CFR 820.90(b)(2).
For example, the firm has no procedure to address rework activities. Rework activities were documented by the firm in Defects #147 (labels to be applied to unlabeled vials), #159 (vials to be visually checked for rust particles), #185 (removal of labeling from (b)(4) vials), and #202 (new calibrator had to be manufactured to complete the kit).
The adequacy of the response cannot be determined at this time. Your firm did not provide the outcome of its retrospective review of 510(k) products that were non-expired and that have been waived or reworked, and all lots of 510(k) products distributed in the U.S, for evidence of rework activities.
4. Failure to establish and maintain adequate procedures to ensure that equipment is routinely calibrated, inspected, checked and maintained, as required by 21 CFR 820.72(a)
For example, there is no maintenance procedure specific to the Lyophilizer Serial #(b)(4) (Internal Equipment ID: (b)(4)) used to manufacture multiple types of devices.
The adequacy of your firm’s response cannot be determined at this time. Your firm’s response does not include the outcome of the retrospective review of its maintenance procedures used in the manufacturing process for all equipment or existing service contracts.
5. Failure to establish and maintain adequate procedures to control all documents, as required by 21 CFR 820.40.
For example, the firm's Management of Quality Management System Documentation (P.400.01) requires modifications to documentation to be documented using the "change request form" (F.850.02). However, changes made to the DHF for Hemoclot Quanti V-L were not documented using the change request form. The firm has no documentation regarding modifications to this document throughout the design project prior to its final approval on 12/11/2006. Additionally, the firm was unable to provide change control documentation related to the Table of Managing Equipment (D.630.01, dated 6/14/01). The most recent change request form was dated 6/1/2012; no documentation exists related to the change made 6/14/2012.
The adequacy of your firm’s response cannot be determined at this time. Your firm has not provided the outcome of its systemic reexamination of existing DHF records for IVD products.
6. Failure to establish and maintain adequate procedures for quality audits and conduct such audits to assure that the quality system is in compliance with the established quality system requirements and determine the effectiveness of the quality system, as required by 21 CFR 820.22.
For example, the Quality Manual requires that internal quality audits are to be conducted in order to assure that the company is in compliance with the defined requirements particularly regulatory requirements. However, the Audit plans for (b)(4), (b)(4), and (b)(4) do not reference requirements under the Quality System Regulation (e.g., management reviews, design controls, device master records, device history records).
The adequacy of the response cannot be determined at this time. Your firm did not provide the outcome of the retrospective review of the Quality Manual to assure that 21 CFR 820 requirements are included as applicable, and that adequate procedures are established for each Quality System element.
7. Failure to establish and maintain adequate procedures to ensure that device history records for each batch, lot, or unit are maintained to demonstrate that the device is manufactured in accordance with the Device Master Record, as required by 21 CFR 820.184.
For example, the Device Master Record for Biophen UFH Calibrator includes the lyophilization process parameters in Product Lyophilization (SOP MO.730.33). However the DHRs reviewed for Biophen UFH calibrator sets do not meet the process parameters for lyophilization as documented in the firm’s procedure (Lot # (b)(4), (b)(4), (b)(4), (b)(4), and (b)(4)).
The adequacy of your firm’s response cannot be determined at this time. Your firm did not provide the outcome of the retrospective review of the lyophilization parameters for all 510(k) devices.
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 # 335758 when replying. If you have any questions about the contents of this letter, please contact: Alberto Gutierrez at (301) 796-5453.
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.
Office of In Vitro Diagnostic Device
Evaluation and Safety
Center for Devices and