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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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International Brachytherapy s.a. 11-Oct-06

Department of Health and Human Services' logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration

 

2098 Gaither Road
Rockville, MD 20850




October 11, 2006

WARNING LETTER

VIA FEDERAL EXPRESS

Mr. Francois Blondel
Managing Director
International Brachytherapy s.a.
Zone Industrielle C
7180 Seneffe, Belgium

Dear Mr. Blondel:

During an inspection of your firm located in Seneffe, Belgium on July 3 through July 6, 2006, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures iodine 125 and palladium radioisotope brachytherapy device(s). 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 (QS) regulation found at Title 21, Code of Federal Regulations (C.F.R.), Part 820. We received a response from Sylviane Berger, Management Representative dated July 31, 2006 concerning our investigator's observations noted on the Form FDA 483, List of Inspectional Observations that was issued to you. 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 ensure that where the results of a process cannot be fully verified by subsequent inspection and test, that the process be validated with a high degree of assurance and approved according to established procedures. The validation activities and results including the date and signature of the individual(s) approving the validation must be documented. (21 CFR 820.75(a))

For Example:

(a) Protocol [redacted] titled [redacted] Welding Machine Process Qualification-Molded Half Bodies, dated March 28, 2006, does not have approval signatures or dates. The protocol includes a provision for "Tensile test for dummy seeds". The Protocol Report [redacted] dated[redacted] also does not have approval signature or dates. There is no reference to tensile test results.

b. Protocol [redacted] dated [redacted] titled [redacted] Welding Machine Operational Qualification-Molded Half Bodies also includes a provision for "Tensile test for dummy seeds". The corresponding report dated [redacted] does not reference any test results for this requirement. The report includes operating limits for the [redacted] such as an energy range of between [redacted] to [redacted] and a Trigger value of between [redacted] and [redacted]. The report does not include or specifically reference the data that supports these limits.

c. To verify the effectiveness of the ultrasonic welding process, [redacted] Opti-Seed half bodies from lot number [redacted] were welded on [redacted] that did not conform to the "trop grand" ID requirement [redacted] were rejected due to excessive melting in the welding area. No acceptance criteria were established before this testing was initiated.

We have reviewed your response and have concluded that it is inadequate because you did not provide training documentation that assures that managers were trained as stipulated in your letter, provide finalized Sops, and provide evidence of implementation. Additionally, you did not provide the acceptable parameters for the welding process, along with evidence of implementation as well as the test results for the Sops, Weld Visual Inspection of Opti-Seed Seeds, SOP [redacted] and Seed Cleaning and Sealed Source Testing: Opti-Seed [redacted] SOP [redacted].

2. Failure to ensure that design validation is performed under defined operating conditions on initial production units, lots, or batches, or their equivalents. (21 CFR 820.30(g))

For example, the majority of design verification/validation testing was done using Opti-Seed implants manufactured with [redacted] half bodies. However, the production units are manufactured using [redacted] half bodies. The design history file does not document that these materials are equivalent.

We have reviewed your response and have concluded that it is inadequate because you did not provide the revised change control SOP and associated form for review.

3. Failure to ensure that corrective and preventive actions are implemented to correct and prevent identified quality problems. (21 CFR 820.100(a)(5))

For example, after the CAPA investigation CAPA MFG [redacted] the following documents were drafted: Post Acceptance Seed Evaluation Protocol, Document ID [redacted] dated [redacted] and Seed Cleaning and Sealed Source Testing: OptiSeed [redacted], Document [redacted], dated [redacted]. Neither document has been implemented nor does the CAPA file (MFG- [redacted]) include any reference to these documents.

We have reviewed your response and have concluded that it is inadequate because you did not provide any evidence of implementation of the corrective measure taken and the training documentation.

4. Failure to establish and maintain adequate corrective and preventive procedures that identify the action(s) needed to correct and prevent recurrence of nonconforming product and other quality problems. (21 CFR 820.100(a)(3))

For example:

(a) There is no documentation that IBt, Inc., Norcross, Georgia was notified about a non-conforming lot. Specifically, the CAPA MFG-[redacted] concluded that due to an incorrectly set [redacted] detector two Opti-Seed lots were released that may not have met the release criteria of no more than [redacted] of removal activity. Lot [redacted] had about [redacted] of release activity. About [redacted] seeds from this lot were shipped to IBt, Inc., Norcross, Georgia.

We have reviewed your response and have concluded that it is inadequate because you did not provide a copy of your revised CAPA SOP and associated forms, a copy of the training documentation and evidence of implementation.

(b) The Corrective and Preventive Action SOP [redacted] states that "usually a time limit of [redacted] is given to write the action plan." However, no action plan has been prepared for the following Corrective and Preventive Actions:

(1) MFG-[redacted] initiated on [redacted], relating to nonconformance of the OptiSeed Body "trop grand" diameter requirement of [redacted].

(2) MFG- [redacted] initiated on [redacted], relating to the Iodine 125 vial test leakage of two seeds due to damage welds from lot [redacted]

(3) CMP-[redacted] initiated on [redacted] relating to the loss of Phi and Assay values from the [redacted] files for Opti-Seeds 855, 856 and 857 for run Pd [redacted]

We have reviewed your response and have concluded that it is inadequate because of the following:

(1) MFG-[redacted]- For this CAPA plan, you did not provide the change control documentation, welding tests results and evidence of implementation.

(2) CMP-[redacted] - For this CAPA plan, you did not provide a copy of the Protocol [redacted] with the test results dated [redacted]. An English translation of this protocol and test results is needed to complete our review. Additionally, a copy of an internal memo, dated [redacted] was also provided; however, an English translation of this memo is needed to complete our review of this documents.

5. Failure to establish and maintain adequate corrective and preventive procedures for investigating the cause of nonconformities relating to product, processes and the quality system. (21 CFR 820.100(a)(2)).

For example, the Corrective and Preventive Action SOP [redacted] states that "usually a time limit of [redacted] is given to write the action plan." However, no investigation has been documented for the following Corrective and Preventive Actions:

(a) MFG-[redacted] initiated on February 5, 2006, relating to nonconformance of the OptiSeed Seed Body "trop grand" diameter requirement of 0.425 mm +/-0.01.

(b) MFG [redacted] initiated on May 8, 2006, relating to the Iodine-125 vial test leakage of two seeds due to damaged welds from lot [redacted]

(c) CMP [redacted] initiated on [redacted], relating to the loss of Phi and Assay values from the [redacted] files for Opti-Seeds 855, 856 and 857 for run Pd [redacted].

We have reviewed your response and have concluded that it is inadequate because you did not provide a copy of the revised CAPA form and provide evidence of implementation of corrective measures taken, including the training documentation of affected employees.

6. Failure to establish and maintain adequate complaint files for assuring that any complaint involving the possible failure of a device to meet any of its specifications be reviewed, evaluated and investigated, unless such investigation has already been performed for a similar complaint and another investigation is not necessary. (21 CFR 820.198(c))

For example, complaint [redacted] reported on [redacted] notes the presence of radioactivity in a patient urine sample. The patient received an [redacted] implant on [redacted]. The complaint follow-up states to "Collect quantitative data on the urine/thyroid activity to decide further actions for the patient." The complaint did not include any additional information concerning patient risk assessment.

We have reviewed your response and have concluded that it is inadequate because you did not submit the finalized SOPs, and associated forms, provide the training documentation and provide evidence of implementation.

7. Failure to establish and maintain adequate procedures to ensure that the results of a design review, including identification of the design, the date, and the individual(s) performing the review, shall be documented in the design history file (the DHF). (21 CFR 820.30(e))

For example, the identity (lot traceability) of the OptiSeed implants used to perform the dose distribution studies are not documented in the design history file.

We have reviewed your response and have concluded that it is inadequate because you did not submit the revised Design Control Process, SOP and associated forms, along with evidence of implementation.

8. Failure to ensure that when changes or process deviations occur, that the process is reviewed and evaluated, a revalidation is performed where appropriate and the results are documented. (21 CFR 820.75(c))

For example:

(a) The cleaning process specified in SOP [redacted], for the cleaning of vials, caps and rubber stoppers was not evaluated for revalidation when the process was changed in [redacted]. The change eliminated the requirement to heat (maximal temperature) during the minimum [redacted] cleaning phase.

(b) The cleaning procedures used in [redacted] for the Opti-Seed samples sent for chemical and biologic testing have been modified as stipulated in procedures [redacted] draft dated [redacted] and [redacted] dated [redacted]. Specifically, the requirement to rinse the Opti-Seeds in [redacted] was changed.

We have reviewed your response and have concluded that it is inadequate because you did not provide a copy of the revised documents (SOPs and associated forms), provide training documentation and evidence of implementation.

9. 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 to determine the effectiveness of the quality. (21 CFR 820.22)

For example, the Internal Quality Process SOP [redacted] states that Manufacturing departments are to be audited at least [redacted]. No audit has been done in 2005 or 2006 for the [redacted] an [redacted] departments.

Your response to this observation appears to be adequate.

10. Failure to establish adequate procedures for identifying training needs and ensuring that all personnel are trained to adequately perform their assigned responsibilities. (21 CFR 820.25(b))

For example:

(a) On [redacted], the operator responsible for the InterStrand suture straightening operation, Work Order [redacted], did not record the straightening time and temperature. The lot had been removed from the oven and was observed cooling next to the oven. There was no documentation on the work order that the lot was being processed on both [redacted] and [redacted].

(b) SOP [redacted] (Straightening InterStrand Suture) states that the heating temperature should be at [redacted] degrees C; however, the temperature control dial on the oven next to the sutures being cooled was set at about [redacted] degrees C. Procedure Deviation [redacted] dated [redacted] was issued allowing for a reduced temperature of [redacted] degrees C. This change did not reference SOP [redacted]; therefore, this SOP had not been revised with the reduced temperature. The test report justifying a change in temperature is not signed or dated and it is not evident if it was approved by designated management representatives.

We have reviewed your response and have concluded that it is inadequate because you did not provide the completed training documentation, the modified Change Control SOP and associated forms and evidence of implementation.

11. Failure to ensure that documents established to meet the requirements of this part be available at all locations for which they are designated, used, or otherwise necessary, and all obsolete documents be promptly removed from all points of use or otherwise prevented from unintended use. (21 CFR 820.40(a))

For example, the procedures [redacted] (Cleaning of vials, caps, and rubber stoppers) dated [redacted] and [redacted] (Cleaning Stainless Steel Tubes and Caps for InterStrand and Mick Cartridges) dated [redacted] were present in the Cold Cleaning Department although both procedures had been superseded by draft revisions cleared for use via Procedure Deviation Request Form no. [redacted]dated [redacted].

We have reviewed your response and have concluded that it is inadequate because you did not provide copies of the revised/finalized SOPs, (Document Control Procedure SOP [redacted], Procedure and Equipment Deviation Procedure [redacted], Cleaning of vials, caps, and rubber stoppers, SOP [redacted]). Your response did not address SOP [redacted] (Cleaning Stainless Steel Tubes and Caps for [redacted and [redacted] Cartridges) dated nor, was a copy of the finalized SOP provided for review. Finally, you should provide evidence of implementation.

Our inspection also revealed that your InterStrand 125 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 C.F.R. Part 803 - Medical Device Reporting (MDR) regulation. Significant deviations include, but are not limited to, the following:

1. Failure to develop, maintain and implement adequate MDR procedures for internal systems that provide for timely and effective identification, communication and evaluation of events that may be subject to MDR requirements. (21 CFR 803.17(a)(1))

For example, the evaluation criteria for determining if an event is reportable are not included in the MDR procedure. There is no documented justification for concluding that complaint [redacted] (urine was reported as radioactive in a patient implanted with [redacted]) is not a reportable event.

We have reviewed your response and have concluded that it is inadequate because your response is in draft which make its difficult to assess how well its new, proposed corrective actions address the deficiencies noted in the MDR related observations ; and/or what the final procedures will contain. You will have to submit your final procedures before a definitive review can be made. In addition, you should provide the training documentation and provide evidence of implementation.

2. Failure to ensure that information is in your possession or references to information related to the adverse event, including all documentation of your deliberations and decision making processes used to determine if a device-related death, serious injury, or malfunction was or was not reportable. (21 CFR 803.18(b)(i))

For example, the firm did not have documented justification for concluding that [redacted] (urine was reported as radioactive in a patient implanted with [redacted]) is not a reportable MDR event and the firm failed to comply with its Written MDR procedures. Specifically, Section [redacted]., i.e. "IBt will maintain MDR event files that are identified as such and filed to facilitate timely access. The file must contain:

[redacted] Information in the possession of the reporting entity or references to information related to the adverse event, including all information on deliberation and decision making processes used to determine whether the event was reportable - Italics added

We have reviewed your response and have concluded that it is inadequate because you have not submitted the revised documentation to FDA that pertains to your reevaluation of complaint [redacted], including your documented findings, and implementation of a corrective action, if appropriate.

Given the serious nature of the violation(s) of the Act, the radioisotope brachytherapy device(s) manufactured by your firm are subject to refusal of admission under section 801(a) of the Act, 21 U.S.C. § 381(a), in that they appear to be adulterated. As a result, FDA may take steps to refuse these products, known as "detention without physical examination," until these violations are corrected. In order to remove the devices from detention, you should provide a written response to this Warning Letter as described below and correct the violation(s) described in this letter. We will notify you if your response is adequate, and we may need to re-inspect your facility to verify that the appropriate corrections have been made.

Also, 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. 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 (15) 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(s), or similar violation(s), 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 15 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: Mr. Emil Wang, Food and Drug Administration, Center for Devices and Radiological Health, Office of Compliance, Division of Enforcement B, Radiology Devices Group, HFZ-340, 2098 Gaither Road, Rockville, Maryland 20850 USA. If you have any questions about the content of this letter please contact: Mr. Emil Wang at (240)-276-0160 or FAX (240) 276-0129.

Finally, you should know that this letter is not intended to be an all-inclusive list of the violation(s) at your facility. It is your responsibility to ensure compliance with applicable laws and regulations administered by FDA. The specific violation(s) noted in this letter and in the Inspectional Observations, Form FDA 483 (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(s), and take prompt actions to correct the violation(s) and to bring your products into compliance.

Sincerely yours,

/S/

Timothy A. Ulatowski
Director
Office of Compliance
Center for Devices and
Radiological Health