| Public Health Service Food and Drug Administration |
| 10903 New Hampshire Avenue Silver Spring, MD 20993 |
Department of Health and Human ServicesDEC 1, 2010
WARNING LETTER
VIA UPS EXPRESS
Dr. Greogory J. Roger
Chief Executive Officer
Advanced Surgical Design & Manufacture, Ltd.
Unit 2 12 Frederick Street
St. Leonards, NSW 2065
Australia
Dear Dr. Roger:
During an inspection of your firm located in St. Leonards, Australia on June 28, 2010 through July 1, 2010, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures the cemented Active Total Knee System and the associated loaned surgical tools. 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 Ms. Manoja Ranawake, QA & RA Manager dated July 20, 2010 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 establish and maintain procedures for implementing corrective and preventive action, as required by 21 CFR 820.100(a).
For example, your firm’s Corrective and Preventive Action Procedure QAD-SOP-4 does not define how quality data will be analyzed to identify existing and potential causes of nonconforming product or other quality problems. Your firm’s quality data sources include Non-conformances, Customer Complaints, Clinical Observations and Feedback, Internal/External/Regulatory Audit Non-conformances and Observations, and Incident Reports. Your firm’s CAPA related procedures do not define how data from these data sources will be analyzed. The procedure Analysis of Data QAD-SOP-23 also does not define how quality data will be analyzed. This procedure only defines the available (b)(4) and how to perform them in (b)(4).
We have reviewed your response and have concluded that it is inadequate. According to your firm’s response, an electronic data management system (b)(4) was validated and implemented on February 2, 2010 and is used to capture new data. Additionally, older paper records have been transferred into (b)(4). Your firm has been conducting base level analysis on a (b)(4) basis since adopting the (b)(4) system, but has not analyzed more specific categorization of non-conformances from a broader field to include (b)(4). Your firm’s short-term plan of action is to analyze and categorize this data to develop, for example, (b)(4). This information will then be added to the CAPA procedure to form the basis for future data analysis. A retrospective analysis of CAPA data will be conducted once the review parameters have been defined. Data analysis will also be completed for all other sources, including, but not limited to Change Control and Customer Complaints. Your firm’s response is not adequate because you failed to submit documentation that includes evidence of implementation of correction and proposed corrective action. Your firm’s response is incomplete as the development of methods for trending and failure mode analyses to a product and process level have yet to be undertaken. Your firm’s response also does not include a discussion of the cause of the nonconformity.
2. Failure to adequately 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, no design validation was scheduled, performed, or documented for your firm’s (b)(4) Active Knee Femoral Implant design project. The new product with (b)(4) intended for the (b)(4) for the (b)(4) Active Knee Femoral Implant was never validated to assure the design met its intended use. Design validation was not defined in your firm’s design plan for the project and there is no documentation of any design validation being conducted. According to your firm’s design manager, no design validation study was conducted to assure the design met its intended use was conducted.
We have reviewed your response and have concluded that it is inadequate. According to your firm’s response, selected surgeons in the presence of your representatives conducted the specific design validation of the (b)(4) Femoral Implant and no anomalies were identified during the initial trials. Your firm plans a retrospective study to address the insufficient documentation. Your firm’s response is not adequate because you failed to submit documentation that includes a description and evidence of implementation of correction and proposed corrective action. Your firm’s response contradicts the statement made during the inspection by your firm’s design manager that no design validation took place. Your firm’s response also does not include a discussion of the cause of the nonconformity.
3. Failure to adequately ensure that when the results of a process cannot be fully verified by subsequent inspection and test that the process is validated with a high degree of assurance and approved according to established procedures, as required by 21 CFR 820.75(a).
For example, the cleaning and packaging processes for your firm’s Meniscal Insert Products have not been adequately validated. The only documented validation study your firm has performed for the cleaning and packaging processes was dated November 13, 2004, Validation of Cleaning Procedures For Surgical Implant Manufactured By (b)(4). This document contains test results for cleaning and processing residues from three separate batches of product, but does not contain or reference the cleaning procedures for the process being validated, the qualification of cleaning equipment and maintenance schedule, and development of process monitoring and control activities.
We have reviewed your response and have concluded that it is inadequate. According to your firm’s response, the packaging validation and elements of the cleaning “qualification” have been completed. Your firm’s response also commits to a documented review of all processes pertinent to cleaning, transfer and final packaging prior to final completion of the validation of these processes. According to your firm’s response, specific elements of the qualification, will include, but not be limited to the following; residuals testing on implants prior to packaging and effects of temperature of implants on packaging. Your firm’s response is not adequate because you failed to submit documentation that includes evidence of implementation of correction and proposed corrective action. Your firm’s response also does not include a discussion of the cause of the nonconformity.
4. Failure to ensure that all inspection, measuring, and test equipment, including mechanical, automated, or electronic inspection and test equipment, is suitable for its intended purposes and is capable of producing valid results, as required by 21 CFR 820.72(a).
For example, the (b)(4) used to monitor the output of your firm’s (b)(4) machining processes has not been demonstrated to be capable of producing valid results. The (b)(4) is the only full dimensional verification performed on implant products (e.g. Meniscal Inserts) fabricated in-house using (b)(4) machining processes.
We have reviewed your response and have concluded that it is inadequate. According to your firm’s response, several elements of the installation qualification (IQ) for the (b)(4), including calibration, program checks, maintenance schedules and others have been completed. Your firm plans a retrospective study of the (b)(4) under simulated production conditions including worst-case scenarios and tests and trials, replicated sufficiently to ensure the reliable performance of the (b)(4) in routine production. Your firm’s response is not adequate because you failed to submit documentation that includes evidence of implementation of correction and proposed corrective action. Your firm’s response also does not include a discussion of the cause of the nonconformity.
5. Failure to validate computer software for its intended use according to an established protocol (when computers or automated processing systems are used as part of production or the quality system), as required by 21 CFR 820.70(i).
For example, the program used to control (b)(4) milling machines during production of Meniscal Inserts has not been validated for its intended use according to an established protocol.
We have reviewed your response and have concluded that it is inadequate. Your firm’s response includes no discussions of corrections or corrective actions associated with (b)(4) machining processes.
6. Failure to establish and maintain adequate procedures to control environmental conditions, as required by 21 CFR 820.70(c).
For example, procedures for the control of environmental conditions affecting the (b)(4) do not address conditions defined in the operation manual or installation specifications. Your firm is monitoring and documenting temperature and relative humidity of the quality control room containing the (b)(4) in accordance with procedure PRD-SOP-9 (b)(4) Operation Procedures (WI-063). This procedure does not ensure the control of airflow, air quality, or other environmental conditions as specified by the (b)(4) operation manual or the (b)(4) manufacturer’s installation specifications.
We have reviewed your response and have concluded that it is inadequate. According to your firm’s response, the plan of action is to revise existing procedures to include the monitoring of incoming air pressure, temperature, and humidity during the start-up and shutdown of the (b)(4). In cases where the temperature, humidity or line pressure is noted as being out of specification, the entire batch shall be re-measured when these parameters are within specification. Air quality in the room will be monitored on a (b)(4) basis to account for seasonal changes and to establish a baseline. Your firm’s response is not adequate because you failed to submit documentation that includes evidence of implementation of correction and proposed corrective action. Your firm’s response also does not include a discussion of the cause of the nonconformity.
7. Failure to establish and maintain adequate schedules for the adjustment, cleaning, and other maintenance of equipment, as required by 21 CFR 820.70(g)(1).
For example, there are no established maintenance procedures and records for the ultrasonic bath and drying oven in the cleaning and packaging clean room which are used for the final cleaning of implants prior to packaging. The procedures regarding the ultrasonic cleaners and drying oven in, PRD-SOP-17 Operations of Ultrasonic Cleaners and incomplete draft of, PRD-SOP-XX Operation and Maintenance of Drying Oven (Cleanroom), do not define how maintenance will be performed and documented.
We have reviewed your response and have concluded that it is inadequate. According to your firm’s response, the issue of a lack of maintenance procedures for several processes and some equipment has been noted during an internal audit of the facility. At the time of the inspection, the documentation of maintenance procedures for the specific equipment mentioned in the observation had not been completed. Maintenance procedures for all other equipment are currently being written. Your firm’s response is not adequate because you failed to submit documentation that includes evidence of implementation of correction and proposed corrective action. Your firm’s response also does not include a discussion of the cause of the nonconformity.
8. Failure to use a valid statistical rationale for sampling plans, as required by 21 CFR 820.250(b).
For example, the sampling defined in PRD-WI-21 In Process Dye Penetration Testing is not based on any documented statistical rationale and is not being implemented due to insufficient lot sizes; instead, sampling is being done across multiple lots without a sampling plan. Neither the sampling defined in the procedure nor your current sampling method is based on any recognized statistical rationale.
We have reviewed your response and have concluded that it is inadequate. According to your firm’s response, the toluidine-blue dye penetrant test is used to check the integrity of the packaging seals, where leaks are present in the seal when the dye is able to pass through. Your firm states the use of this test in routine production is not regarded as essential, but an unsystematic check to confirm seal integrity. The continued use of this test and/or visual inspection of the seal in production are currently under review, together with a statistically relevant sampling plan based on historical data. Your firm’s response is not adequate because you failed to submit documentation that includes evidence of implementation of correction and proposed corrective action. Your firm’s response also does not include a discussion of the cause of the nonconformity.
9. Failure to maintain adequate device history records (DHR), as required by 21 CFR 820.184.
For example, a review of (b)(4) Meniscal Insert DHRs found one DHR did not contain documentation of monitoring activities specified for the environment containing the (b)(4); and one DHR contained an inaccurate date (b)(4).
We have reviewed your response and have concluded that it is inadequate. According to your firm’s response, an investigation revealed that the procedure does not stipulate the frequency for the monitoring of environmental conditions. The current practice is to record the conditions for each batch of product. According to your firm’s response, environmental data, which is currently on a separate log, will be transferred to the DHR for sign off by the process operator, and then to QA for final review and sign off. Your firm’s response is not adequate because you failed to submit documentation that includes evidence of implementation of correction and proposed corrective action. Your firm’s response also does not include a discussion of the cause of the nonconformity.
Given the serious nature of the violations of the Act, the cemented Active Total Knee System and the associated loaned surgical tools 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: Matthew Krueger, 10903 New Hampshire Ave, Building 66/Room 3676, Silver Spring, MD 20993. If you have any questions about the content of this letter please contact: Kenneth Chen at (301) 796-5595 or (301) 847-8438.
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.
Sincerely yours,
/S/
Steven D. Silverman
Director
Office of Compliance
Center for Devices and Radiological Health
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