Inspections, Compliance, Enforcement, and Criminal Investigations

Greiner Bio One Brasil Produtos Medicos Hospitalares Ltda. 8/8/14

  

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
AUG 8, 2014 
 
VIA UNITED PARCEL SERVICE
 
Mr. Haroldo Graci
General Manager
Greiner Bio One Brasil Produtos
Medicos Hospitalares Ltda.
Av. Affonso Pansan, 1967
Americana, SP, Brazil 
 
 
Dear Mr. Haroldo Graci:
 
During an inspection of your firm located in Americana, Brazilon January 13, 2014 through January 16, 2014, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures Vacuette blood collection tubes.  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 Haroldo F. Graci, General Manager dated February 4, 2014 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, procedures for design change have not been adequately established. Specifically, review of a labeling change, #25/2013, (dated 2013, Lot number 25) for Vacuette Erythrocyte Sedimentation Rate Tubes revealed that your firm does not have a formal procedure specifying change activities, or verification and documentation of the completion of these activities. Change #25/2013 did not appear to document required change activities. Available procedures including the change control procedure, change control form, and change log form do not address timing of change implementation or effect on existing stock. Applicable design changes are currently managed and documented using informal meetings and documented using uncontrolled meeting notes. Mr. Marcelo Saura, your firm’s Quality Manager, indicated that your firm’s local procedure covering design change control activities, (b)(4), does not specify local methods for tracking or documenting required change implementation activities. to add instructions and timelines for validation and approval of product modifications by January 31, 2014.
 
Your firm’s response dated February 4, 2014 is not adequate. Your firm opened a CAPA for this observation that provided the following planned corrective action (b)(4) to add instructions and timelines for validation and approval of product modifications by January 31, 2014.
 
Your firm only addressed design changes for the Erythrocyte Sedimentation Rate Tubes and the documentation provided was not written in English. The response is not adequate because your firm did not provide evidence that a correction was implemented to include documenting change activities for the labeling change of the Vacuette Erythrocyte Sedimentation Rate Tubes. In addition, your firm did not provide evidence that a systemic corrective action was considered that included a retrospective review of all design changes conducted to ensure they were completed as required. In addition your firm did not provide evidence that its employees were trained on the revised procedure, (b)(4).
 
2.    Failure to establish and maintain procedures for validating the device design, as required by 21 CFR 820.30(g). For example, the Vacuette collection tubes have specific requirements contained in the product labeling for shelf-life and maximum trace element content. However, review of batch records revealed that your firm has not performed continuing testing in support of shelf life stability requirements or maximum permissible trace element content. Specifically:
a.    Testing to confirm that requirements for maximum trace element content quoted in the product labeling for trace element tubes is not performed.
b.    Testing to confirm that Vacuette collection tubes continue to meet shelf life stability requirements (as quoted in specifications and product labeling) is not performed.
 
The firm’s response dated February 4, 2014 is not adequate. Your firm opened a CAPA for this observation that provided the following planned corrective actions:
a.    Requalify raw materials and inputs by May 30, 2014.
b.    Create addendum to the (b)(4) to include the production of (b)(4), annual trace element testing, and annual revalidation of the (b)(4) by February 28, 2014.
c.    Implement trace elements testing on tubes and (b)(4) by March 31, 2014.
d.    Modify customer complaint management to include follow-up investigations for all complaints involving trace elements by February 28, 2014.
e.    Request blood collection tube stability study protocols from alternate site and review study design to ensure adequacy and viability by November 30, 2013.
f.     Implement stability testing by November 30, 2015.
 
Your firm has provided the above planned corrections and corrective actions for the trace element testing and stability testing for the Vacuette collection tubes. However, your firm did not provide evidence that the corrections and corrective actions provided were implemented. In addition, your firm did not provide documentation that a systemic corrective action was considered to include a retrospective review of device design validation to ensure validations were completed and documented as required. Your firm did not provide evidence that employees were trained on the addendum created to the Validation Master Plan.
 
3.    Failure to establish and maintain procedures for acceptance of incoming product, as required by 21 CFR 820.80(b). For example, inspection requirements for receiving rubber stoppers were not documented. Specifically, incoming acceptance documentation does not contain the presence of data or certificate of conformance demonstrating the performance of your firm’s required acceptance testing protocol.
 
Your firm’s response dated February 4, 2014 is not adequate. Your firm opened a CAPA for this observation that provided the following planned corrections:
a.    Document statistical methods used for acceptance activities by January 31, 2014.
b.    Revise list of material for receipt including the relevant analysis of the Certificate of Analysis issued by the supplier of stoppers by January 31, 2014.
c.    Revise procedure of incoming receipt based on globally recognized techniques by February 28, 2014.
 
The response is not adequate because your firm did not provide evidence that corrections were implemented to include conducting and documenting receiving acceptance activities for receipt of the rubber stoppers. In addition, your firm did not provide evidence that a systemic corrective action was considered to include a retrospective review of all acceptance activities to ensure receiving acceptance activities were completed and documented as required. Your firm did not provide evidence that employees were trained on the revised procedures.
 
4.    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, procedures for quality audits have not been adequately established. Specifically, the internal audit criteria do not identify any requirements from the Quality System Regulation (21 CFR 820, Medical Device Reporting Regulation (21 CFR 803), and the Medical Devices: Reports of Corrections and Removals Regulation (21 CFR 806) or other applicable FDA regulations in the applicable internal audit procedures or internal audit plans. Mr. Haroldo Graci, General Manger, and Mr. Manfred Abel, Quality Systems and Regulatory Affairs for Monroe, NC, acknowledged that the 2013 quality audit plan had not explicitly required auditing against any FDA requirements.
 
Your firm’s response dated February 4, 2014, is not adequate. Your firm opened a CAPA for this observation that provided the following planned corrective actions:
a.    Revise the (b)(4) to cover ISO 9001, ISO 13485, RDC 16:2013, and FDA quality system regulations by November 29, 2013.
b.    Train new internal auditors on the FDA requirements by July 31, 2014.
c.    Train existing internal auditors on ISO 9001, ISO 13485, RDC 16:2013 and CFR21 by February 28, 2014.
d.    Create (b)(4) and ensure compliance with regulatory standards by February 28, 2014.
 
Your firm’s response is not adequate because your firm did not provide evidence that corrections were implemented to include evidence that an internal audit was completed to assure that your firm’s quality system was in compliance with the quality system requirements. Your firm did not provide evidence of implementation of the corrective action including requiring that your firm’s procedures include auditing your firm’s quality system to ensure it is in compliance with other FDA required regulations in addition to the Quality System regulation. Your firm did not provide evidence that a systemic corrective action was considered to include a retrospective review of management controls to ensure they were completed as required.
 
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 #423198 when replying. If you have any questions about the contents of this letter, please contact: Ileana Elder at 301-796-6143or 301-847-8514.
 
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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