Inspections, Compliance, Enforcement, and Criminal Investigations
ESKA Implants GmbH & Co 16-May-06
Department of Health and Human Services
Public Health Service
2098 Gaither Road
May 16, 2006
VIA FEDERAL EXPRESS
Dr. Hans Grundei
President and Owner
ESKA Implants GmbH & Co.
Dear Dr. Grundei :
During the inspection of your firm located in Lubeck, Germany on November 14 through November 17, 2005, the United States Food and Drug Administration (FDA) investigator determined that your firm manufactures total hip replacement prostheses. These products are devices within the meaning of section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. § 321(h)).
The inspection revealed that the devices manufactured at the Lubeck facility appear to be 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 (CFR), Part 820 . The devices your firm manufactures are also misbranded within the meaning of Section 502(t)(2) of the Act (21 U.S.C. § 352(t)(2)) because your firm failed to provide information required by Section 519 of the Act (21 U.S.C. § 360i) and the Medical Device Reporting (MDR) regulation (21 C.F.R. Part 803)
The FDA investigator observed significant violations including, but are not limited to, the following:
Quality System Regulation
1. Failure to establish and maintain adequate procedures for implementing corrective and preventive actions, as required by 21 CFR 820.100(a). For example, the corrective and action procedures contained in your quality manual do not contain sufficient detail to meet the requirements for:
a. Analyzing processes, work operations, concessions, quality audit reports, quality records, service records, complaints, returned product, and other sources of quality data to identify existing and potential causes of nonconforming product, or other problems. (21 CFR 820.100(a)(1))
b. Investigating the cause of nonconformities relating to product, processes, and the quality system. (21 CFR 820.100(a)(2))
c. Identifying the actions needed to correct and prevent recurrence of nonconforming product and other quality problems. (21 CFR 820.100 (a)(3))
d. Verifying or validating the corrective and preventive action to ensure that such action is effective and does not adversely affect the finished device. (21 CFR 820.100(a)(4))
e. Implementing and recording changes in methods and procedures needed to correct and prevent identified quality problems. (21 CFR 820.100(a)(5))
f. Ensuring that information related to quality problems or nonconforming product is disseminated to those directly responsible for assuring the quality of such product or the preventing of such problems. (21 CFR 820.100(a)(6))
g. Submitting relevant information on identified quality problems, as well as corrective and preventive actions, for management review. (21 CFR 820.100(a)(7))
2. Failure to adequately 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 the design change [redacted] PE Inserts, [redacted], lacks documentation of the design change requirements, per the engineering change notice [redacted].This design change also lacks evidence that the change was validated, or if appropriate, only verified.
3 . Failure to adequately establish and maintain procedures for defining and documenting design outputs in terms that allow for an adequate evaluation of conformance to design input requirements, as required by 21 CFR 820.30(d): For example, the device master record (DMR) acceptance specifications for the cast cobalt chromium-molybdenum alloy used to manufacture cementless femoral stems required conformance to the consensus standards ASTM F75 and ISO 5821. However, review of the requirements in ASTM F75 standard, identified numerous specification differences between the DMR and the standard which have not been addressed. More specifically:
a. The chemical composition requirements for chromium, molybdenum, nickel, and iron in the DMR have acceptable ranges outside those defined in the ASTM standard.
The standard ASTM [redacted] includes composition limits for tungsten, sulfur, nitrogen, aluminum, titanium and boron. These elements are not included in the DMR acceptance specification nor are these elements included in the certificate of analysis [redacted] for sales order [redacted].
b. The standard ASTM defines both chemical composition requirements and mechanical properties for the cast cobalt-chromium alloy material. The ASTM standard requires an 8% minimum reduction in area. The DMR does not require a minimum reduction in area.
c. The liquid penetrant examination in ASTM [redacted] specifies supplier/purchaser agreed upon sampling plans and acceptance criteria based upon examination using either ASTM Practice [redacted] or Test Method [redacted]. However, there is no agreed upon sampling plan or acceptance criteria in the DMT and the alloy supplier is currently using the [redacted] est method.
d. The radiographic examination in ASTM [redacted] specifics a supplier/purchaser aged upon sampling plan or acceptance criteria based on examination in accordance with ASTM Practice [redacted]. There is no agreed upon sampling plan or acceptance criteria in the DMR and the alloy supplier is using ASTM.
e. The metallography requirement in ASTM [redacted] consists of a supplier/purchaser agreement regarding microstructural requirements and frequency of examination with specimen preparation conforming to ASTM practices [redacted].The DMR contains no specified metallographic requirements.
f. ASTM [redacted] provides for information only hardness values. Hardness testing information is not being provided by the supplier, nor does the DMR address why hardness information is not supplied.
4. Failure to adequately ensure that when the results of a process cannot be fully verified by subsequent inspection and test that the process shall be validated with a high degree of assurance and approved according to established procedure, as required by 21 CFR 820.75(a). For example:
a. Cleaning process [redacted] was validated for cleaning polymer (PE) devices. This cleaning program was used to clean polymer devices mixed with Femoral stems, a metallic device, on August 24, 2004 [redacted]; There is no documentation that this cleaning program is validated for mixed loads of both metallic and polymer devices.
b. Chemical residual acceptance levels for the cleaning processes, [redacted] is have not been established.
5. Failure to adequately establish and maintain procedures for finished device acceptance to ensure that each production run, lot or batch of finished device meets acceptance criteria, as required by 21 CFR 820.80(d). For example, the sterilization process conformance is based on a minimum specification of 25 kGy. The reference dosimeter results received from the sterilization contractor are not calculated based on the correction factor [redacted] obtained during dose mapping studies. In the case o [redacted] the sterilization certificate of analysis dated 1/21/05, reported a reverence dose of 25.1 kGy. No calculation was done to determine if this dose still met the minimum dose specification using the established correction factor of 0.951, prior to release of the finished device.
Medical Device Reporting
The above-stated 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 any material or information required by or under section 519 of the Act, 21 U.S.C. 360i and 21 CFR Part 803 - the MDR regulation. Specifically, an MDR serious injury report has not been submitted concerning complaint number 121 dated September 24, 2002, which related to a fracture requiring explant of a Partial Structured Cementless, Colarless 12/14 Taper, 120 mm GHE Hip Stem.
Previous Response to FDA's Inspectional Observations
We received a faxed response from Mr. Georg Wittler, Quality Management Representative dated December 1, 2005, concerning our investigator's observations noted on the FDA 483. We have reviewed your response and have concluded that it is inadequate for the following reasons:
Your firm's response to observation 1 promised corrections to the DMR, corrections to supplier agreements and addition of documentation of equivalence of test methods, with completion dates ranging from 12/2005 to 3/2006. This response is not adequate. No evidence of the implementation of the corrective action was provided. In response to this letter, please provide evidence of the proposed corrections to the DMR, corrections to supplier agreements and the addition of documentation of equivalence of test methods. Additionally, you should explain whether this DMR is an isolated example or if other DMRs have the same problem of correctly defining and documenting design outputs.
Your firm's response to observation 2 promised to conduct retrospective evaluation of the quoted NCRs for bipolar heads for the reported period according to risk, regarding the effect on stored/marketed products by March 2006. This observation suggests that your firm may not be documenting the required decision to conduct an investigation of each product nonconformity. In your response to this letter, please explain your firms process for making a decision on the need for an investigation into each product nonconformity and how your firm documents that process methodology, and documents the decision itself.
Your firm's response to observation 3 promised to introduce a system for evaluation of root cause and related risks with respect to NCR evaluation, and if required, for initiation of corrective actions, recall or reprocessing of concerned and restored/marketed products by March 2006. The response is not adequate. No evidence of the implementation of the proposed corrective actions has been submitted.
Your firm's response to observation 4 promised to perform retrospective design change control and generate an ECN, as well as, address risk analysis of the change, clinical evaluation of the change, and any biocompatibility issue associated with the change by February 2006. The response is not adequate because no evidence of corrective actions has not been supplied. In response to this letter, please supply evidence that retroactive design change control activities for [redacted] PE Inserts have been performed. Additionally, you should describe how ESKA Implants plans to ensure that any future design changes are appropriately controlled and documented.
Your firm's response to observation 5 promised process validation and surface residual analysis for metal & polymer mixed cleaning loads with [redacted] by February 2006. The response is not adequate. No evidence of the proposed corrective action was provided, such as a process validation protocol, a process validation report, or chemical residual acceptance levels were provided. In the response to this letter please provide the process validation report and the missing residual acceptance levels as evidence of correction of this problem.
Your firm's response to observation 6 promised to provide more details in the final acceptance procedure and perform an analysis of the impact of releasing product that did not meet the 25 kGy minimum dose requirements by December 2005. The response is not adequate. No evidence of the proposed corrective actions was provided. In the response to this letter, please provide the revised final acceptance procedure, the analysis of the impact of product released that did not meet the 25 kGy dose requirement and any correction or removal actions related to the results of the analysis.
Your firm's response to observation 7 promised to file a retroactive MDR with FDA for the complaint by December 2005. The response is not adequate. No evidence of the corrective action, such as a copy of the MDR, was provided in the response. In your response to this letter, please provide a copy of the MDR as evidence of the correction of the item in the observation and explain your firm's plan to ensure that all appropriate MDR events are reported to the FDA in a timely manner.
This letter is not intended to be an all-inclusive list of deficiencies at your facility. It is your responsibility to ensure compliance with the Act and applicable regulations. 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 underlying problems in your firm's manufacturing and quality assurance systems.
You should take prompt action to correct these deviations. Failure to promptly correct these deviations may result in regulatory action, which may include detaining your devices without physical examination upon entry into the United States until the corrections are completed under Section 801(a) of the Act (21 U.S.C. § 381(a)).
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 government contracts.
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 all documentation of the corrective action you have taken. If you plan to make any corrections in the future, include those plans with your response to this letter as well . If the documentation is not in English, please provide a translation to facilitate our review.
Your response should be sent to the Food and Drug Administration, Center for Devices and Radiological Health, Office of Compliance, Division of Enforcement B, Orthopedic, Physical Medicine and Anesthesiology Devices Branch, 2098 Gaither Road, Rockville, Maryland 20850 USA, to the attention of Mr. William MacFarland.
If you need help in understanding the contents of this letter, please contact Mr. William MacFarland at the above address or at (240) 276-0120 or FAX (240) 276-0129.
Timothy A. Ulatowski
Office of Compliance
Center for Devices and Radiological Health