|Issuer:||Center for Devices and Radiological Health|
|Issued:||Dec. 18, 2006||Closed:||
Department of Health and Human Services
Public Health Service
9200 Corporate Boulevard
DEC 18, 2006
VIA FEDERAL EXPRESS
Senior Vice President and Director of Operations
Medeon Science Park, SE-205 12
Dear Mr. Johansson:
During an inspection of your firm located in Malmo, Sweden on October 23 through October 26, 2006, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures dental bone grafting materials. 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 tile 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 Christian Johansson, Sr. VP, Operations and Plant Manager, dated November 9, 2006, concerning our investigator's observations noted on the Form FDA 483. Inspectional Observations that was issued to you. We will address your responses in a separate letter. These violations include, but are not limited to, the following:
1. Failure to establish and maintain adequate procedures for defining and documenting design output in terms that allow an adequate evaluation of conformance to design input requirements, as required by 21 CFR 820.30(d).
For example, the OEM agreement with [redacted] for the material specification of porous [redacted] , states that trace elements will conform to ASTM F1088 and F1185, based on raw materials. ASTM F1185-03 for [redacted] for surgical implants includes thc following. "4.3.1-The analysis of other trace elements may be required, based on the conditions, apparatus, or environments specific to the manufacturing techniques and raw materials." The design history file does not include any documentation relating to this ASTM section.
2. Failure to establish and maintain adequate procedures to ensure that formal documented reviews of the design results are planned and conducted at appropriate stages of the device's design development. The procedures shall ensure that participants at each design review include representatives of all functions concerned with the design stage being reviewed and an individual(s) who does not have direct responsibility for the design stage being reviewed, as well as any specialists needed. 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), as required by 21 CFR 820.30(e). For example:
There is no documentation indicating the [redacted] acceptance test had been reviewed prior to product commercialization for the Straumann Bone Ceramic project plan.
The Straumann Bone Ceramic Design [redacted] review checklist dated February 22, 2005, has a "No" response regarding if a report on the clinical acceptance study/post market surveillance had been received. Page 4 of the review states, "measures must be taken for all unfulfilled points of the checklists." There is no justification for approving the device for [redacted] acceptance test" without the completion of tile clinical acceptance study.
3. Failure to establish and maintain adequate procedures for validating the device design. Design validation shall be performed under defined operating conditions on initial production units, lots, or batches, or their equivalents. Design validation shall ensure that devices conform to defined user needs and intended uses and shall include testing of production units under actual or simulated use conditions. Design validation shall include software validation and risk analysis, where appropriate, as required by 21 CFR 820.20(g). For example:
The Risk Analysis Failure Mode and Effects Analysis-FMEA [redacted] states the risk management files will be reviewed at least annually. Your annual review for the Straumann Bone Ceramic has not been conducted since the initial risk analysis in February 2005.
The hazard of ineffective bone formation was not included in the Risk Analysis for [redacted] Regeneration granules (February 28, 2005).
4. Failure to establish and maintain an adequate DHF for each type of device, as required by 21 CFR 820.200(j).
For example, the design history file (DHF) did not include documentation that reviews were completed before launching the device in the U.S. and Europe. The Strauniann Bone Ceramic Design Review [redacted] Review states the next reviews were to be conducted before launch in the U.S., before pre-announcement in Europe, and before launching in Europe.
5. Failure to establish and maintain adequate procedures to develop, conduct, control, and monitor production processes to ensure that a device conforms to its specifications. Where deviations from device specifications could occur as a result of the manufacturing process, the manufacturer shall establish and maintain process control procedures that describe any process controls necessary to ensure conformance to specifications. Where process controls are needed they shall include: Documented instructions, standard operating procedures (SOPs'), and methods that define and control the manner of production, as required by 21 CFR 820.70(a)(I).
For example, employees in the Emdogain syringe inspection area were using cotton tipped swabs to clean the inside of the upper portion of the syringe barrel after removal of the plunger. The SOP for this operation [redacted] did not reference using a cotton swab to clean the syringes.
6. Failure to establish and maintain adequate procedures for investigating the cause of nonconformities relating to product, processes, and the quality system, as required by CFR 820.100(a)(2).
For example, your firm failed to initiate or document a CAPA investigation for the decrease pH results for the Emdogain Stability Report (August 23, 2006) on batches [redacted] and [redacted]
7. Failure to establish and maintain adequate procedures for implementing corrective and preventive action. The procedures shall include requirements for; Identifying the actions needed to correct and prevent recurrence of nonconforming product and other quality problems; as required by 21 CFR 820.100(a)(3). For example:
Your firm's Risk Management SOP [redacted] does not specify when, how, and what risk analysis process will be used regarding CAPA investigations.
Your firm failed to document the foreign particle contamination analysis (trace metal concentrations or unexpected impurities) on the Straumann Bone Ceramic material for the [redacted] meeting on [redacted] The Patient Safety Analysis stated the material contained no impurities and substances and did not affect patient safety or efficacy of the product.
Your firm failed to document Complaint [redacted] dated [redacted] whether the presence of black thread like particles found in the product is chemically identical to the foreign particles in the [redacted] Complaint.
Your firm failed to evaluate and determine the causes of osteointegration failures, premature re-entry augmentation, or unexpected radiographic appearance. Additionally, your firm did not evaluate if clinicians submitting complaints were informed "a minimum healing period of 6 months is recommended in order to allow bone to form and mature at sites augmented using bone ceramic."
U.S. Complaints [redacted] and [redacted] dated July 8, 2005, indicated the use of bone ceramic without sufficient bone formation after three months, while the customer based bone formation on experience with [redacted] (another product).
U.S. Complaint [redacted] dated February 17, 2006, state there was no bone re-growth upon re-entry of the augmentation sites in [redacted] different subjects. An e-mail dated March 16, 2006, to the customer discusses the handling of the complaint and contention that the "patients were being used for clinical trials on Straumann Bone Ceramic." This email states the customer was informed about "the importance of waiting six months before reentering the site." The email requests that the customer provided the previously requested information, however, the complaint file does not indicate if this information was received.
Complaint [redacted] dated August 9, 2006, from [redacted] indicated that after four months of healing a Strauniann implant was placed and analysis determined that no new bone was present but fibrous tissue.
8. Failure to establish and maintain adequate procedures for verifying or validating the corrective and preventive action to ensure that such action is effective and does not adversely affect the finished device, as required by 21 CFR 820.100(a)(4). For example:
Your firm's Change Request, Approval, and Implementation number, [redacted] did not have a documented justification for the Straumann Bone Ceramic instructions adding the statement, "In order to allow bone to form and mature at sites augmented using Strauniann Bone Ceramic, a minimum healing period of 6 months is recommended." The healing time is patient and site dependent and is determined by a clinician.
[redacted] relates to the repackaging/resterilization of bone ceramic lots [redacted] and [redacted] due to commingling with non-sterile units. A decision was made to repackage the inner blister into new outer packages and to resterilize these [redacted] lots. The risk analysis states that a [redacted] is unlikely to cause leakage in the [redacted] lid, but will influence the seal strength ...A lower seal strength might lead to a shorter shelf life, that is leakage before the end of the expiry date. The inner blister will, however, be re-packaged in an outer blister which will only be [redacted] higher seal strength might lead to the need of stronger force to remove the lid, that is, granules lost due to spillage. But the inlay in the inner blister will prevent this scenario." No product testing has been conducted to confirm whether the foregoing assessment is valid. Moreover, there is no source documentation confirming that chemical and physical properties of the bone ceramic will not be altered by the second irradiation.
9. Failure to review and evaluate adequately that all complaints are processed in a uniform and timely manner, as required by 21 CFR 820.198(a)(I). For example:
A biopsy sample was sent for histological analysis on [redacted] but to date no results have been received for US Complain [redacted] dated [redacted] which reported the bone ceramic failure after six months.
Your firm's SOP "Reporting Product Complaints and Adverse Reactions", [redacted] does not include timeliness requirements for investigation of complaints.
Your firm failed to obtain results or additional information to complete the investigation of Complaint [redacted] This complaint was reported to [redacted] by a customer a letter, dated [redacted] discussing the use of bone ceramic on a patient in [redacted]
Complaint [redacted] dated [redacted] was reported to [redacted] in [redacted] A Histologic Histomorphometric Analyses of Four Human Osseous Biopsies [redacted] states the biopsies were received on [redacted] and the study completed on [redacted]
Complaint [redacted] was reported on [redacted] regarding the use of bone ceramic or [redacted] in a 63 year old male patient (initials and a lack of implant stability on [redacted] A report titled Histologic and Histomorphometric Analyses of Four Human Osseous Biopsies" dated [redacted] indicated that [redacted] biopsies were received on [redacted] and the study was completed on [redacted] The report states that the biopsy for patient [redacted] showed "fibrous encapsulation of the granules without bone formation."
Complain [redacted] dated [redacted] relates to the use of bone ceramic in July 2005 on a patient and the implant placement biopsy did not occur until November 3, 2005.
10. Failure to review and evaluate adequately all complaints to determine whether ail investigation is necessary. When no investigation is made, the manufacturer shall maintain a record that includes the reason no investigation was made and the name of the individual responsible for the decision not to investigate, as required by 21 CFR 820.198(b). For example:
U.S. Complaint [redacted] dated [redacted] states that [redacted] patients ( [redacted] % of total) who had been treated with bone ceramic developed serious infections and after 6 - 7 months, the particles were "still sitting loosely" and had "not been incorporated by the body." The Straumann notification of damage/complaint states, "Three written requests sent to clinician - do not anticipate additional information." However, another complaint form stated, "The clinician no longer had the products. He will ask his office staff to gather as much information as they can. He wants to know if there are other clinicians who have had this issue."
Your firm failed to document complaint [redacted] dated [redacted] why additional information was not requested from the clinician to allow for an appropriate investigation to determine the reason the product did not perform well in comparison to other bone grafting products.
Lack of osteointegration at the time of re-entry obtained from histology reports relating to the bone ceramic for complaints and [redacted] and [redacted] were not evaluated to determine if additional investigations were required.
Complaint Analysis Report for complaint [redacted] indicated that no response was received after additional information was requested relating to the age of a patient, use of collaplug and Straumann Bone Ceramic (SBC). The complaint file did not indicate if the customer failed to provide the additional information or whether the firm did not request or provide the information.
11. Failure to establish and maintain adequate procedures for any complaint involving the possible failure of a device, labeling, or packaging to meet any of its specifications shall be reviewed, evaluated, and investigated, unless such investigation has already been performed for a similar complaint and another investigation is not necessary, as required by 21 CFR 820.198(c). For example:
U.S. Complain [redacted] indicates that [redacted ] customer reported "a lot of soft tissue and unresorbed graft particles" after six months while [redacted] other customers reported similar problems after four months.
U.S. Complaint [redacted] states there was inadequate healing of the extraction socket four months after bone ceramic was used in August 9, 2005. Implant surgery was scheduled four months after the bone ceramic while the training materials provided to the U.S. sales representatives state a 6-9 month post augmentation interval and in some cases the interval will be 12-18 months.
Complaint [redacted] fails to discuss the reason a customer was unaware of the time required for complete resorption of biphasic calcium phosphate after having radiograph and noticing a "huge mass of material". The customer questioned if the mass was normal, because he expected to see the same consistency similar to the remaining bone.
12. Failure to establish adequately any complaint that represents in event which must be reported to FDA under part 803 of this chapter shall be promptly reviewed, evaluated, and investigated by a designated Individual(s) and shall be maintained in a separate portion of the complaint files or otherwise clearly identified. In addition to the information required by 820.198(e), records of investigation under this paragraph shall include a determination of the relationship, if any, of the device to the reported incident or adverse event, as required by 21 CFR 920.198(d)(3).
For example, there was no documentation for complaint [redacted] on whether the patient's hematologist was contacted to determine if the cause of thrombocylopenia had been identified.
13. Failure to establish and maintain adequate procedures for Management with executive responsibility to review the suitability and effectiveness of the quality system at defined intervals and with sufficient frequency according to established procedures to ensure that the quality system satisfies the requirements of this part and the manufacturer's established quality policy and objectives. The dates and results of quality system reviews shall be documented, as required by 21 CFR 820.20(c).
For example, the Analysis of Data-Trending SOP [redacted] states that quality and operational performance data trends are reported to the management team for decision-making and planning within the framework of management review. The management review procedure requires at least annual reviews (recently the firm has been scheduling biannual reviews), which may not be sufficient to detect unresolved quality problems or to initiate further corrective actions in a timely fashion.
14. Failure to establish 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 system, as required by 21 CFR 820.22.
For example, the last audit of the QA system including CAPA investigation was conducted in February 2005 and the design control processes were not audited in 2005 or 2006. Your firm's SOP for internal audits requires annual audits.
Our inspection also revealed that your 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 deviations include, but are not limited to, thc following:
15. Failure to report to FDA no later than 30 calendar days after the day that you receive or otherwise become aware or information, from any source, that reasonably suggests that a device that you market: may have caused or contributed to a death or serious injury, as required by 21 CFR 803.50(a)(1).
For example, your firm failed to submit an MDR for a reported case of thrombocytopenia and enlarged spleen associated with the use of Emdogain 0.3 mL which required treatment.
Given the serious nature of the violations of the Act, dental bone grafting materials 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 violations 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 violations, or similar violations, 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: Ronald L. Swann, Chief, Dental, Ear, Nose, Throat & Ophthalmic Devices Branch, 9200 Corporate Boulevard, Rockville, Maryland 20850. If you have any questions about the content of this letter please contact: Ronald L. Swann at 240-276-0115 or fax 240-276-0114.
Finally, you should know that this letter is not intended to be an all-inclusive list of the violations at your facility. It is your responsibility to ensure compliance with applicable laws and regulations administered by FDA. The specific violations 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 violations, and take prompt actions to correct the violations and to bring your products into compliance.
Timothy A. Ulatowski
Office of Compliance
Center for Devices and