| Public Health Service Food and Drug Administration |
| 10903 New Hampshire Avenue Silver Spring, MD 20993 |
Department of Health and Human ServicesJuly 26, 2011
WARNING LETTER
VIA UNITED PARCEL SERVICE
Ludwig Georg Braun
President and CEO
B. Braun Melsungen AG
Europagebaude, Industriegebiet Pfieffewiesen
34212 Melsungen, Germany
Dear Mr. Braun:
During an inspection of your firm, Laboratorios B. Braun S.A. located in Sau Goncalo, Brazil on February 21, 2011, through February 24, 2011, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures intravascular extension sets and liquid medication dispensers.
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 (CGMP) requirements of the Quality System regulation found at Title 21, Code of Federal Regulations (CFR), Part 820.
We received a response from Neidi Kawabata, Director Quality and Management Representative dated March 14, 2011, 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 procedures to control product that does not conform to specified requirements. The procedures shall address the identification, documentation, evaluation, segregation, and disposition of nonconforming product, as required by 21 CFR 820.90(a). For example, your firm’s (b)(4) Procedure, Doc. No. I-UIDM-0072- Rev. 8 requires non-conformities to be documented in Form F-0005-UIDM. Your firm’s procedure addressed identification, rejection and segregation the non-conforming products during assembly and packaging. The rejected products were later documented but the documentation was discarded once the disposition of the non-conforming products was determined. In addition, the rejected products and the documentation were discarded without any evaluation or investigation regarding the cause of the non-conformance.
Your firm’s response to this observation appears to be adequate. Your firm has revised (b)(4) procedure, Doc. No. I-UIDM-0072, to include a completed form F-UIDM-0005, as part of the Device History Record (DHR). Since the form F-UIDM-0005, was not originally included as a required element of the DHR, its inclusion prompted necessary changes in two of your firm’s procedures related to the contents and the release of the DHR. According to your firm, you conducted a review of the DHR requirements listed in the checklist P-0161-01, against the requirements stated in 21 CFR 820.184, to ensure that no further gaps existed. Your firm stated that there were no additional gaps identified after the review.
2. Failure to adequately establish and maintain procedures for receiving, reviewing, and evaluating complaints by a formally designated unit, as required by 21 CFR 820.198. For example, your firm’s Treatment of Product Complaints Procedure, P-0006- Rev. 16, does not have a requirement for complaints to be evaluated to determine whether the complaint represents an event which is required to be reported and submitted as a Medical Device Report (MDR) to the U.S. Food and Drug Administration (FDA).
Your firm’s response to this observation appears to be adequate in conjunction with FDA’s response to your request for an exemption to 21 CFR 803.19(b). Your firm is a contract manufacturer and is required to have established procedures addressing the evaluation of complaints and filing of MDRs. Your firm admitted that at the time of the inspection, your procedure, P-0006 - Procedure Product Complaint Handling, did not require complaints to be evaluated to determine if the complaint should be filed as an MDR to FDA. Your firm continues to assert that based on the Quality Agreement between Laboratorios B. Braun (LBB) and B. Braun Medical US (BBMUS), the responsibility for evaluating complaints and filing of MDRs belongs to BBMUS. On March 9, 2011, you filed a request for exemption to 21 CFR 803.19(b), allowing BBMUS to submit a single MDR involving devices manufactured by LBB, to meet MDR reporting requirements for both entities. FDA’s Office of Surveillance and Biometrics granted your firm’s request for an exemption in a letter dated March 25, 2011. The exemption allows BBMUS to submit a single MDR to FDA for events in which both LBB and BBMUS have a reporting obligation to the Agency.
Concurrently, a revision of procedures P-0006 Procedure Product Complaint Handling and P-0157- Procedure (b)(4) has been conducted to include a more robust description of the requirements and responsibilities regarding the regulatory reporting of MDRs. According to your response, the training and implementation of these revised procedures were completed on March 14, 2011.
3. Failure to establish and maintain procedures to ensure that DHRs for each batch, lot, or unit are maintained to demonstrate that the device is manufactured in accordance with the Device Medical Record and the requirements of this part, as required by 21 CFR 820.184. For example, your firm’s Final Inspection Medical Procedure, Doc. No. P-0057- Rev, 12, has not been adequately established because it failed to include the provisions to document the final quantity released as a requirement of the Device History Record (DHR). Eleven of the DHRs for the ATE116- extension sets were reviewed and none of the DHRs included the documentation of the quantity released. The lack of documentation in the DHR is an indication that a discrepancy between the quantities packaged and the final quantities released may exist.
Your firm’s response dated March 14, 2011, appears adequate. Your firm admitted that at the time of the inspection, the requirements of the DHR related to the quantity released were not defined. However, your firm clarified that although the DHR was incomplete; the reconciliation of quantities throughout the manufacturing of each lot, up to and including the final lot was maintained by LBB in your validated business operating system called SAP. Your firm also corrected the deficiency in the DHR by revising procedures I-UIDM-0071, with instructions how to complete form F-UIDM-0043, Device History Record-BBMUS and established a new procedure P-0161 specific to BBMUS products. Your firm revised several procedures to address Observation 1 and Observation 4. By implementing the correction such as not discarding the documentation F-UIDM-0005 - Losses Records and doing corrective actions such as revising your DHR related procedures, you have addressed Observations 1 and 4.
Our inspection also revealed that your intravascular extension set devices are misbranded under section 502(t)(2) of the Act, 21 U.S.C. 352(t)(2), in that your firm failed or refused to furnish material or information respecting the device that is required by or under section 519 of the Act, 21 U.S.C. 360i, and 21 CFR Part 803 - Medical Device Reporting (MDR) regulation. Significant violations include, but are not limited to, the following:
4. Failure to develop, maintain, and implement written Medical Device Reporting (MDR) procedures, as required by 21 CFR 803.17. For example, your firm is a manufacturing facility and it does not have any written MDR procedure. Your response stated that you do not have any procedures regarding reporting MDRs because of the Quality Agreement you have with BBMUS in Pennsylvania. The Quality Agreement stipulates that BBMUS has the responsibility for evaluating and submitting MDRs for your facility (LLB). During the inspection, your firm’s representative provided a copy of a Quality Agreement between B. Braun Medical, Inc. (BBMUS) and LBB in which it states that BBMUS is responsible for LBB’s MDR evaluations and submissions. Based on this agreement, your firm believed that you were not required to submit MDRs or to have any MDR procedure in place. However, as a contract manufacturer, your firm (LBB) meets the definition of “manufacturer” as defined in 21 CFR 803.3 and must comply with all of the requirements in 21 CFR Part 803, including Parts 803.17 and 803.18. As an importer, specifications developer and re-labeler/re-packager, BBMUS also has a responsibility to comply with all of the requirements in 21 CFR 803.
We reviewed your firm’s response to Observation 2, dated March 14, 2011, and have concluded that it is not adequate because the procedure included in your response entitled “Procedure Product Complaints Handling”, P-0006, Version 17, does not comply with the requirements of 21 CFR Part 803.17. Specifically,
• The procedure does not address how your firm will submit timely and complete medical device reports to FDA as required by Part 803.17. Specifically, Section 4.4.3 BBMUS line products states, (b)(4). This instruction does not describe how your firm will be able to meet the 30 calendar day or 5 work day timeframes described in 21 CFR Parts 803.50 and 803.53, respectively.
• The procedure also does not describe how your firm will address the documentation and record-keeping requirements. Specifically, the procedure does not address how your firm will allow access to information that facilitates timely follow-up and inspection by FDA; or how your firm will establish and maintain MDR files, as required by 21 CFR Part 803.18.
Additionally, your firm’s MDR procedure is located at the end of your current complaint handling procedure and it is not clearly identified as being related to MDR. We recommend that you separate the MDR reporting requirements into a separate document or into a clearly marked section of an overall reporting document.
To discuss MDR reportability criteria or to schedule further communications, contact the MDR Policy Branch at 301-796-6670 or by email at MDRPolicy@fda.hhs.gov.
A follow up inspection will be required to assure that corrections and/or corrective actions are adequate.
U.S. federal agencies are advised of the issuance of all Warning Letters about devices so that they may take this information into account when considering the award of contracts.
Please notify this office in writing within fifteen working days from the date you receive this letter of the specific steps you have taken to correct the noted violations, including an explanation of how you plan to prevent these violation, or similar violation, from occurring again. Include documentation of the corrective action you have taken. If your planned corrections will occur over time, please include a timetable for implementation of those corrections. If corrective action cannot be completed within fifteen working days, state the reason for the delay and the time within which the corrections will be completed. Please provide a translation of documentation not in English to facilitate our review.
Your response should be sent to: Field Operations Branch/DRMO/OC. Refer to CMS case # 187013 when replying. If you have any questions about the content of this letter please contact: Valerie A. Flournoy, Branch Chief, General Hospital Devices Branch by telephone at 301-796-5770 or by fax at 301-847-8137.
Finally, you should know that this letter is not intended to be an all-inclusive list of the violation at your facility. It is your responsibility to ensure compliance with applicable laws and regulations administered by FDA. The specific violation noted in this letter and in the Inspectional Observations, FDA 483, issued at the closeout of the inspection may be symptomatic of serious problems in your firm’s manufacturing and quality assurance systems. You should investigate and determine the causes of the violation, and take prompt actions to correct the violation and to bring your products into compliance.
Sincerely yours,
/s/
Steven D. Silverman
Director
Office of Compliance
Center for Devices and
Radiological Health
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