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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Lydall Warning Letter Response

June 24, 2005

Ms. Serene Ackall

Compliance Officer

Food and Drug Administration – Atlanta District

60 Eighth Street

Atlanta, GA 30309

RE: Warning Letter (05-ATL-17)

Dear Ms. Ackall:

Charter Medical, Ltd. has provided a comprehensive response to the above referenced Warning Letter and takes FDA’s concerns very seriously. Although we were disappointed to receive the Warning Letter, we appreciate FDA’s conclusion that our 483 responses were satisfactory, excepting one part pertaining to qualification activities for the differential pressure recorder. The attached response to the Warning Letter provides the information requested by the agency and summarizes the original 483 responses.

Charter Medical is committed to rectifying any compliance-related issues and establishing a first-class FDA compliant operation. We have used this opportunity to take a detailed look at our entire quality system and the oversight of that system by the management team. 

The parent corporation, Lydall, Inc. has implemented an organizational change to include reporting responsibility of Charter Medical’s Quality Assurance/Regulatory Affairs Manager to Lydall’s Vice President and General Counsel to ensure timely communication to the corporate level. As indicated in our meeting with the Atlanta District in March, we have also enlisted the assistance of an outside GMP specialist to perform a gap analysis of the quality system and to provide subsequent GMP audits. The initial gap analysis was conducted in June. The analysis identified additional areas for improvements. Perhaps the most substantial of those areas is environmental controls. Charter Medical plans to utilize a consultant with clean room expertise to formulate a comprehensive plan to review and revise, as appropriate, its environmental controls. Charter Medical will be assigning resources to address all of the opportunities identified in the gap analysis over the coming days. Additional audits from our GMP consultant are planned for October and December/January.

Charter Medical is also pursuing quality and regulatory training for the entire management team. This training will include all aspects of regulatory compliance, such as, quality system regulations, marketing and labeling regulations, corrections and removals, medical device reporting and 510(k) clearances. We anticipate completion of this training activity by October 1, 2005. Documented training is also being performed for all relevant personnel on all new and revised quality system procedures.

Charter Medical grants permission to post our response to the Warning Letter on FDA’s website. However, all attachments to the response are identified as confidential and should not be posted. Charter Medical will continue to provide monthly progress reports to the Atlanta District outlining our progress with each of the 483 observations. 

We look forward to our next inspection, as we believe it will provide an opportunity to validate our commitment to implementing improvements to the quality system. Lydall, Inc. stands behind Charter in full support of the challenges ahead and the successes to follow. We are confident that Charter will achieve its regulatory goals within a reasonable time and believe that the agency will be fully satisfied with the results.

Regards,

David Freeman

President and CEO

Lydall, Inc.

COMMENT 1

Failure to validate with a high degree of assurance and to approve according to established procedures, the results of a process that cannot be fully verified by subsequent inspection and test, as required by 21 CFR 820.75(a), (b). (FDA 483 #1). Specifically,

a. Ethylene Oxide (EtO) sterilization

I. Your original 1993 EtO sterilization validation had product sterility failures, positive biological indicator (BI) spore strips, and inoculated product failures. Although these failures were attributed to laboratory contaminants, laboratory reports were not available for the investigation of these failures.

II. Your 2001 EtO revalidation does not include evidence that the validation results were reviewed and no validation summary was available.

III. Your most recent EtO revalidation conducted in February of 2003 in [redacted] had 5 external positive BI’s and 13 internal positive BI’s during the half-cycle run. Your firm did not review or investigate those positive BI’s, and therefore, did not validate the sterilization procedure with a high degree of assurance. Furthermore, your own SOP, “Validation Protocol EtO. 0592, Rev. C,” requires your firm to make a technical judgment to accept or reject the validation study with input from the [redacted] and [redacted] technical staffs, which your firm did not do. Therefore, Charter Medical failed to approve the sterilization validation according to established procedures.

b. Gamma Sterilization

I. Your 1997 gamma validation package is incomplete in that it consists of a single protocol and no other documentation.

II. Quarterly dose audits for gamma sterilization were not performed between February 2003 and January 2005, even though your procedure, Gamma Sterilization (Document No.: QS-235), states that quarterly dose audits are required.

RESPONSE: Below we address the lack of documentation supporting the validation of the EtO and gamma irradiation processes. We are completing or have instituted new procedures and controls to ensure adequate validation of sterilization processes and documentation thereof, and are working to qualify or have qualified new contract sterilizers for each of these processes. We believe that when complete our validation of these new suppliers and procedures are completed that we will meet all FDA Quality System and sterility requirements to assure our products meet a SAL of 10-6.. 

ETO—Background Charter Medical is a subsidiary of Lydall, Inc. In 1998, Lydall bought an existing medical device manufacturer, CharterMed, Inc. and formed a new company Charter Medical, Ltd. Charter Medical, Ltd. operated two manufacturing facilities: one in New Jersey and one in Winston-Salem, NC. In April 2003, the New Jersey facility was closed and all manufacturing operations were moved to North Carolina. The sterilization process remained with the same contract sterilization facility in New Jersey after the move.

The original EtO sterilization validation was performed and documented by CharterMed, Inc. in 1993. When Charter Medical, Ltd. was formed in 1998, the company believed that the existing EtO sterilization validation was appropriate. The 1998, 1999, 2000, 2001 and 2003 half-cycle validations were performed at the Charter Medical New Jersey facility before device manufacturing was transferred to North Carolina. Charter Medical adopted the sterilization validation documentation from New Jersey, which it believed was complete.

(a)(i) the 1993 validation
The original 1993 validation contained deviations which were documented within the summary report, including positive growth. The summary indicates that the documented positive growth was identified as contamination and not the indicator organism, although the lab reports to substantiate this claim were not included in the formal report and are not in the possession of Charter Medical. Even with the absence of the lab reports, we have no reason to believe the data was falsified. We believe the conclusions of the summary report are accurate and consider that the cycle was successfully validated.

(a)(ii) the 2001 validation
As stated previously, when closing the New Jersey facility and moving the manufacturing operations to North Carolina, Charter Medical did not review the 2001 sterilization validation documents. Charter Medical has been unable to definitively determine whether the summary and associated approvals of the 2001 revalidation were not generated or were misfiled or lost before or during the plant move. Although we don’t expect another physical relocation, to the extent that it might happen, and to the extent that we make changes internally that will affect processes, we will review the basis for validations and validate as necessary.

(a)(iii) the 2003 validation
In investigating the 2003 half-cycle revalidation, we determined from interviewing our former quality manager that the individual who initiated the half-cycle revalidation did so independently and did not communicate to management that the validation had occurred or that there were failing results. Nor did this individual follow up with an investigation of the failures. In fact we are now informed by the testing laboratory that the individual specifically declined a follow-up investigation. Although the procedure required half cycle revalidation approximately annually, management was unaware that these specific half cycle revalidation activities were initiated. Therefore, a final report and acceptance/rejection of the sterilization revalidation were not documented. While we believe that this breakdown in the quality system is related to the actions of one employee who is no longer with the company, we will institute training on our new procedures discussed below to ensure validation activities are scheduled and completed in a timely fashion, that anomalies are investigated and resolved, and that management is made immediately aware of problems with validation activities. Also, we contacted the New Jersey test lab to request an investigation. Unfortunately, the test lab informed us that an investigation cannot be performed retrospectively. We have reviewed the sterilization cycle reports since the 2003 half-cycle revalidation and no anomalies were noted.

Moving forward, Charter Medical has ceased using the sterilization cycle identified in these observations. We initiated a new validation with a new contract sterilization service, [redacted]. This validation protocol meets requirements for [redacted] and [redacted] , including the cycle development fractional studies and relative resistance studies. Cycle development resulted in completely new sterilization parameters. The relative resistance study has substantiated our selection of process challenge device/external monitoring system. Validation activities are on-going and we believe that upon successful completion, our new sterilization process and associated validation documents will meet all regulatory requirements.

Additional corrective actions include creation of a new SOP to govern all aspects of EtO sterilization such as validation, requirements for the assessment of revalidation, control of load configuration, and definition of the process challenge device. Implementation of the SOP will occur after successful completion of the validation, because some of the information required to create this SOP can not be determined until validation is complete.

We have also implemented methods to better control validation documents. Validation documentation, including sterilization validation, will be housed in the document control department as a centralized location. The document control department will be responsible for issuing a protocol number at protocol initiation. They will also be responsible for monitoring the log of protocols to ensure that after a protocol is initiated a summary report is generated to close the project. Thereby ensuring that each protocol initiated is summarized and either accepted or rejected. We believe this procedure will ensure that validations are adequately reviewed and approved in a timely fashion.

With regards to distributed products that were sterilized under our prior EtO process, we have not received any complaints or adverse event reports related to compromised sterility (with the exception of unrelated reports related to package integrity1)). Routine processing loads were seeded with 18 biological indicator spore strips populated to 106. Loads were not and are not released without verification that all of the indicators were negative. The sterilization results of each load are reviewed by Quality Assurance prior to release. We have had no positive indicators during routine processing since 2001. We also retain sample products from each sterilization load. We have tested [redacted] pieces of retained product for sterility. Laboratory data indicate that all of the retains tested were sterile. Although we do not have any data to suggest that products were compromised by the validation inadequacies, Charter Medical recognizes that according to validation guidelines, we do not have the documentation to ensure that the sterility assurance level of 10-6 and therefore initiated a voluntary recall of these devices to err on the side of caution. Notification was sent to the agency of the recall on January 24, 2005.

GAMMA (b) (i) the 1997 validation
As mentioned previously, documents were transferred from New Jersey to North Carolina in 2003 and the sterilization documents were not adequately reviewed and inventoried at that time. As with the EtO sterilization documentation, it is unknown whether the summary and associated approvals of the 1997 validation were not generated or were misfiled or lost before or during the plant move. Moving forward we will be utilizing the document control department to log and monitor validation documents. This will ensure that protocols, reports and summaries reside in a central location and that data does not get separated. 

(b)(ii) quarterly dose audits
Charter Medical acknowledges that quarterly dose audits for the gamma process have not occurred since February 2003, although we must respectfully disagree that the failure to do those audits was contrary to our procedures, to the extent that the procedures in place from 2003 – January 2005 did not include a requirement for quarterly dose auditing. However, the company acknowledges that it is normal and good practice to conduct quarterly dose audits for gamma sterilization 

After transfer of the manufacturing processes to the North Carolina site, the Quality Assurance /Regulatory Affairs Manager did not perform dose audits. Because it was the custom to perform quarterly dose audits prior to the move, we believe, through our investigation of records, that the person charged with the responsibility of quarterly dose audits did not understand the requirements for sterilization (although she represented that she did). This individual is no longer employed by Charter Medical. 

Charter Medical completed a full validation of a new gamma sterilization service in January 2005 (see Attachment B to 483 response). Upon completion of this validation, the gamma sterilization procedure (QS-235) was revised and a requirement was added to the procedure to specify that dose audits are to be performed on a quarterly basis and that the Quality Assurance/Regulatory Affairs Manager is responsible for initiating and documenting those dose audits (see Attachment A to 483 response). The dose audit has been added to the preventive maintenance program to provide a mechanism for producing automated reminders and for ensuring that completion is recorded. In addition, our contract sterilization service provides reminders on a regular basis of upcoming due dates for dose audits. Our first dose audit was completed in April 2005 with no failures. (Attachment 1 )

Status:

ETO: Validation report signed on June 24, 2005; complete validation package expected by July 15, 2005

GAMMA: Complete in May date 2005; on-going quarterly dose audits

1 Complaints referenced are not issues with seal integrity, but rather tears in packaging.

COMMENT 2

Failure to review and evaluate a process and perform revalidations where appropriate when changes or process deviations occur, as required by 21 CFR 820.75 (c). (FDA 483 item #2)
Specifically,

a) When your manufacturing process relocated to North Carolina, the EtO sterilization process was not revalidated. (FDA 483 item #1.c).

b) There was no documentation or formal review of the sterilization process when a new contractor was hired to perform gamma sterilization.

Response:
EtO
FDA 483 item #1. c. specifically stated “The EtO sterilization process has not been revalidated since February 2003” , which relates to this warning letter comment. Charter Medical’s interpretation of this comment from the 483 was that the required annual revalidation assessments and associated half cycle revalidations were not completed as scheduled. The reference in the Warning Letter provides a clearer meaning to the observation. As such, the initial response to the 483 may not have adequately addressed this observation.

When Charter Medical transferred the manufacturing process to the North Carolina facility, the EtO contract sterilizer and the EtO sterilization cycle were not changed. Charter Medical should have performed a complete environmental assessment of the impact of the move on the sterilization cycle and performed a revalidation, if necessary. At the time of the move, Charter Medical did document a comparison of bioburden data, but the document did not draw explicit conclusions regarding the need to revalidate the sterilization process.

For corrective action, Charter Medical has since ceased using the sterilization cycle used in 2003 and has initiated a validation of a new contract sterilizer and a new EtO sterilization cycle (see Comment 1).

Charter Medical has incorporated a mechanism within our validation process and change control procedures to ensure that changes in materials, place of manufacture (internal and external), significant processes (e.g.: sterilization) or suppliers receive proper documented assessments of the need to validate or revalidate. This mechanism is tied to the change control process, in the form of a checklist. The checklist is routed with the request for change and is reviewed with the change packet by the appropriate approvers. (Attachment 2 and 3)

Gamma
When the manufacturing was moved from New Jersey to North Carolina in June 2003, the gamma sterilization service was moved from [redacted] to [redacted] for efficiency. There was no documented review of the change in service provider and the impact on the sterilization validation. Charter Medical agrees that for a change of this nature documentation of the evaluation of the need for revalidation should be maintained, and documented.

Charter Medical has since ceased use of the [redacted] gamma sterilization facility. A new gamma contract sterilizer was validated in January 2005. All validation activities are complete and documented appropriately, including supplier qualification activities. (see attachment B to 483 response)

As stated previously, Charter Medical has implemented new mechanisms within the change control process and the validation procedures to ensure that changes of this nature are evaluated for the need for revalidation. A checklist has been added to the change control procedure that guides the initiator of a change to consider all relevant factors when initiating changes including validation, regulatory requirements, risk analysis, etc. The new procedure providing guidance on validation activities specifies that change in location for a process (both internal and external) requires a documented assessment of the need for revalidation. (Attachment 2 and 3)

Status:
EtO: Validation report signed on June 24, 2005; complete validation package expected by July 15, 2005
Validation procedure revisions: Complete

Gamma: Complete

COMMENT 3

Failure of management with executive responsibility to establish its policy and objectives for, and commitment to, quality and to ensure that quality policy is understood, implemented, and maintained at all levels of the organization, as required by 21 CFR 820.20 (FDA 483 item #3) Specifically,

a) Your firm’s management has not ensured effective routine sterilization of neonatal syringe sets, blood administration sets, plasma transfer sets, blood transfer bags and other distributed medical devices.

b) Your firm’s management was unaware that the sterilization processes were not adequately monitored, in that the quarterly dose audits for gamma sterilization were not performed, as required by your procedure, Gamma Sterilization (Document No: QS-235), and the positive BI results in your EtO half cycle revalidation were not investigated.

c) Your firm’s management has not performed formal reviews of the quality processes and procedures, such as procedures for evaluating environmental monitoring data, for product bioburden activities, and for Quality Control equipment calibrations. 21 CFR 820.20 (c).

Response: During conversation with the investigator, we understood this observation to be directed at a lack of oversight by executive management and quality management of validation, monitoring activities and other controls in the quality system. We also understood that the investigator felt that employees may be undertaking actions without appropriate monitoring of their activities, and the data generated by their activities, by management.

Charter Medical recognized the need to improve management performance in 2004. The Quality Assurance/Regulatory Affairs Manager was terminated in 2004 due to performance related issues, such as, a lack of oversight and monitoring in quality related activities, including sterilization, validation and environmental monitoring. The Facilities Manager was also terminated for similar issues. The Quality Assurance/Regulatory Affairs Manager has been replaced with a highly knowledgeable individual in the areas of FDA compliance and sterilization (Attachment 4). The FDA inspector commented that our new Quality Assurance/Regulatory Affairs Manager would be an asset to the company. In addition, the management structure was redefined in 2003 – 2004 to ensure better communications between operations, quality and marketing and the site General Manager. (see attachment F to 483 response) Specifically, a director level of management was created to ensure direct reports in these critical areas have a direct line of communication to executive management. The General Manager meets biweekly with regulatory/quality and conducts weekly staff meetings with regulatory/quality, operations, product development and marketing. This level of management facilitates a higher level, more comprehensive, cross-functional review of activities for the company. In addition, this new structure allows the VP/GM to focus on those areas in the organization requiring extra attention. In addition, the parent corporation, Lydall, Inc. has implemented an organizational change to include reporting responsibility of Charter Medical’s Quality Assurance/Regulatory Affairs Manager to Lydall’s Vice President and General Counsel to ensure timely communication to the corporate level. (Attachment 5)

This new level of management now makes up the Management Steering Committee that is responsible for Management Review. This is the same group that formulates yearly business and strategy plans and identifies and recommends resource requirements necessary for the organization to comply with standards and continuously improve. These plans and strategies are communicated to the corporate level through the site General Manager. In addition to the organizational structure improvements, several other initiatives have been established to ensure that critical areas will not be neglected. For example, the company has established two cross-functional teams, one to review environmental monitoring data, and the other team, a Trend Analysis Team, to be responsible for oversight of critical conditions, trends and deviations and to make recommendations for corrective action. The results of the reviews and data from these teams are a part of the Management Review agenda. In addition, sterilization requirements have also been added to the Management Review agenda. (see attachment E, G and H to 483 response)

The Management Review procedure has been revised to formalize the communication between the General Manager and the Quality Assurance/Regulatory Affairs Manager (or Management Representative) in the form of bi-weekly meetings in which critical conditions are discussed. (see attachment E to 483 response)

(b) quarterly dose audit
As stated above (see Comment #1) there was no requirement for quarterly dose audits, however it was the practice at the company. After moving the manufacturing processes to North Carolina in 2003, the Quality Assurance/Regulatory Affairs Manager either did not understand those requirements or chose to ignore those requirements. Charter Medical recognized the gap in dose auditing in late 2004 and revised the gamma sterilization procedure (QS-235) in January 2005 to formalize and document the requirements for completion of quarterly dose audits. (see attachment A to 483 response)

(b) positive BI results
In response to the comments on the failed biological indicator from the half cycle revalidation in 2003, a half cycle validation of the EtO sterilization process was initiated by the Quality Assurance Specialist at the New Jersey location of Charter Medical, Ltd. Half cycle revalidations were typically initiated and reported by the Quality Assurance/Regulatory Affairs Manager. There is no evidence in the firm’s files that the Quality Assurance/Regulatory Affairs Manager initiated this validation or requested that it be initiated. The records and correspondence from the sterilizer and the test laboratory went directly to the Quality Assurance Specialist suggesting that the employee acted independently.

As discussed above in item #1, the employee acted independently and did not make known the positive results or conduct a follow up investigation to verify a true positive result. The New Jersey plant closed one month later. Under these circumstances, the employee had no incentive to inform management and given the timing the company had no mechanism to unearth these unknown facts. In review of the CAPA system and the Management Review minutes at the time, no communication of the validation or the BI failures was found. These were the two main vehicles to ensure management knowledge of key activities affecting the quality system. Both the Quality Assurance/Regulatory Affairs Manager and the Quality Assurance Specialist, at the time, are no longer with the company. As discussed in our response to comment 1, above, Charter Medical will be introducing a new procedure governing the EtO sterilization process upon completion of on-going validation activities. This procedure will give guidance with regards to failure investigations for sterilization validation activities. In addition, sterilization activities, including validation activities, are reviewed regularly during the management review.

(c) quality processes
Regarding the remainder of the observation, the company has procedures for environmental monitoring, product bioburden testing and calibration of equipments. While all of these activities were being conducted as required, there was a lack of oversight on the part of quality management to review monitoring data, trend data and to respond to out of control conditions. As stated previously, personnel responsible for those activities had not fulfilled the requirements of their job descriptions and were terminated as a result. Charter Medical firmly believes that our new management team and management structure will ensure that an observation of this nature does not recur.

Charter Medical is also pursuing quality and regulatory training for the entire management team. This training will include all aspects of regulatory compliance, such as, quality system regulations, marketing and labeling regulations, corrections and removals, medical device reporting and 510(k) clearances with emphasis being on compliance with regulations and internal procedures and the importance of the accountability of the management team for enforcement and compliance with Charter Medical’s quality system.

Status: Restructure of management: complete as per March 2005 progress report
Management Training – expected completion date October 1, 2005

COMMENT 4

Failure to develop, conduct, control, and monitor production processes to ensure that a device conforms to its specifications, as required by 21 CFR 820.70 (a). (FDA 483 item #4)
Specifically,

a) You did not have any data to substantiate the validity of the External Monitoring System (EMS), which are used in routine EtO processing. 

b) The procedure for the preparation of External Monitoring Systems, Preparation of Biological Indicator for EtO Sterilization Work Instructions (Document No.: QS-QI-215), did not reflect the actual method described in the validation protocol. In addition, your procedures governing EtO sterilization were not comprehensive in that they did not address all steps of the process.

c) There is no documentation to show product line extensions have been formally evaluated for approval into the EtO or gamma sterilization processing cycles. Specific instructions, indicating which sterilization method was to be used for each of the various products you manufacture were unclear.

Response: As discussed above in our response to comment 1,Charter Medical is finalizing and will implement a procedure at the SOP level to give overall guidance that comprehensively describes each of the elements in the EtO sterilization process, including validation, requirements for the assessment of revalidation, control of load configuration, and definition of the process challenge device. Charter Medical intends to implement such a procedure upon successful completion of the EtO sterilization validation.

In the response to Comment 1, we indicated that the documentation associated with the sterilization validations was not reviewed for appropriateness when manufacturing operations were moved to the North Carolina location. We have been unable to locate an historical document to substantiate the validity of our EMS. Charter Medical has included a relative resistance study as a part of our EtO sterilization validation. Upon completion of a successful validation, we will have appropriate documentation for our EMS. Preliminary data suggests that the EMS will be changed to a test pack prepared by the contract sterilization provider.

Charter Medical has reviewed and revised the procedure for the preparation of the EMS to remove any errors or inaccuracies. (see attachment I to 483 response) All personnel have been instructed in the importance of accuracy of procedures. In all areas of our operation, we are making revisions to procedures to ensure that the procedure and practice are in alignment.

Charter Medical does not currently utilize a specific procedure for product line extensions; in stead, line extensions are added to manufacturing through documented change control. The product specifications for each catalog number indicate what sterilization method will be used to sterilize the product. We believe that the product specifications are clear with regards to which sterilization method is to be utilized for each product. However, we agree that a documented rationale for the choice of sterilization method for a line extension should be generated, and that the selection of a validated sterilization process should be documented.

To clarify the integration of line extensions, Charter Medical has completed a procedure to govern the process for introducing line extension. This process will be effective by June 30, 2005. (Attachment 6) In addition, we have revised the change control procedure to improve the associated checklist used in revising or introducing new product specifications, including line extensions. (Attachment 3) The revised change control checklist provides guidance on all of the areas of consideration when introducing a new or revised product specification, for example, labeling, intended use, process validation requirements and items specific to sterilization. There is an entire section of the checklist devoted to sterilization considerations, including, product packaging, product density, effect on worst case for EtO residuals, etc. The Quality Assurance/Regulatory Affairs Manager, R&D Engineering and Process Engineering Manager are all required to review and approve the introduction or revision of product specifications, including evaluation of the change control checklist. We believe that this mechanism will enhance our documentation of the assessment of line extensions.

Status: EtO Sterilization SOP – Expected Completion Date 7/15/05
Relative Resistance Study and EtO Sterilization Validation – Expected Completion Date 6/30/05
Revision of EMS Preparation Procedure – Complete
Introduction of Line Extension Procedure – Expected Completion Date 6/30/05
Revision of Change Control Procedure and Checklist - Complete

COMMENT 5

Failure to establish and maintain procedures to adequately control environmental conditions, as required by 21 CFR 820.70 (c). (FDA 483 item #6) Specifically,

a) The new [redacted] Monitoring System was installed in April 2004; however, your firm neither performed installation qualification of the system, nor performed a documented calibration after installation (operation qualification), both of which are necessary to assure that the system was functioning properly and according to specifications. 

b) Environmental action levels for the Air Sampler test for microbes exceeded established action limits, but were not investigated on 6/25/04; 8/20/04; 9/10/04; and 9/20/04. Your firm did not have detailed instructions for addressing alert and action levels in the controlled area.

Response: Charter Medical installed a [redacted] Recorder* in the controlled manufacturing area in April 2004. The equipment consists of a differential pressure sensor and a chart recorder. Charter Medical recognizes now that an installation qualification and post installation calibration (operational qualification) would have been appropriate for this type of equipment. However, at the time, these qualifications were not performed. In addition, Charter Medical failed to explain in response to 483 observation #6 that although a calibration of the equipment was not performed immediately post-installation, the unit was originally added to the calibration schedule in April 2004 that required an annual calibration. The unit was calibrated in February 2005. (attachment 7) At that time the frequency of calibration was assessed and Charter Medical determined it would be prudent to change the frequency requirement to every six months. As per the manufacturer’s user manual, routine preventive maintenance is not required. The legibility of the chart recorder is checked daily by the Quality Assurance department during routine checks in accordance with INS-TI-327, Chart Recorder Work Instructions. (Attachment 8)

Charter Medical did not have an overall procedure governing validation and qualification activities. Charter Medical has since instituted a procedure to provide guidance on the level of validation required for different types of equipment, as well as examples of different scenarios that may require revalidation, such as equipment moves, modifications or repairs. We have also clarified the requirements to ensure that the rationale for level of validation in every situation is documented. (Attachment 2)

With regards to the failure to document an investigation for environmental action limits, Charter Medical attributes the condition to the lack of quality management oversight, as discussed in the response to Comment 3. Although the root cause of the action limits was known to the organization, the Quality Assurance/Regulatory Affairs Manager did not document an investigation, initiate a corrective action or document justification for the disposition of product. The firm became aware of this lack of oversight prior to the FDA inspection in January 2005 and had begun implementation of a corrective action. A cross-functional Environmental Monitoring Team of management personnel was created to review all environmental data on a monthly basis and take actions accordingly. The team reviews all trends and deviations. The team is governed by the Environmental Monitoring Procedure (QS-234) that was implemented on January 17, 2005. (see attachment G to 483 response) Another element of this procedure is that all environmental alert and action limits require completion of an Environmental Action Report. This form requires documentation of disposition of product, immediate actions and corrective/preventive actions.

Status: Complete

*Note: The Warning Letter and 483 inaccurately identified this equipment as a [redacted] Monitoring System. Charter Medical has verified that proper identification of the equipment is [redacted] Recorder.

COMMENT 6

Failure to conduct quality 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 (FDA 483 item #7). Specifically, ten of twenty-four internal audits one the 2004 audit schedule were not completed.

Response: Charter Medical performed extensive training for all internal auditors in June 2004. The firm had elected not to establish a 2004 internal audit schedule and delayed 2004 audits until completion of the training program. The net result was that because the internal audits for 2004 did not begin until June, the 2004 internal audit schedule could not be implemented fully if competent and thorough internal audit was the goal. 

Charter Medical aggressively pursued attempting to complete the 2004 schedule. The internal audit procedure at the time required that all nonconformances resulted in generation of corrective actions. Therefore, numerous corrective actions were being initiated as a result of this aggressive pursuit of the audit schedule. Upon realization that the schedule could not be met and that resources were being spread too thin in attempting to implement corrective actions while continuing to generate more audit observations, the management team elected to suspend the internal audit program while improvements and corrective actions were being implemented. In parallel, the management team contracted with a consultant to perform a gap analysis of the entire quality system. This external audit was intended to cover any gaps in the 2004 audit schedule and identify all areas for improvement.

The 2005 Internal Audit Schedule has been reviewed and implemented and is both effective and achievable in that the Internal Audits are now spread throughout the year. A conscious effort was made to ensure that those Internal Audits not conducted in 2004 were completed within the first two months of 2005, in the context of a twelve-month review of the system. Seven qualified Internal Auditors have been chosen to ensure that staffing is sufficient. To date, we are on target with the 2005 schedule. (attachment 9)

The internal audit procedure has been revised to remove the mandatory requirement for corrective action of each and every finding. The new procedure requires that the Trend Analysis Team reviews internal audit observations for determination of which observations require initiation of a formal corrective action. (see attachment P of 483 response) This approach has helped to ensure that the CAPA system is meaningful and effective and has prevented overburdening the system with repetitive or trivial observations.

Status: Complete

COMMENT 7

Failure to establish and maintain procedures to ensure that the device design is correctly translated into production, as required by 21 CFR 820.30 (h). (FDA 483 item #19) Specifically, your Design Control Procedure (Document No.: DES-500) did not address design transfer.

Response: Charter Medical’s design control procedure addresses design transfer but we agree there is a need for additional detail on transferring a design into production.

Charter Medical is confident that our design outputs have been appropriately transferred to manufacturing through the change control process. However, we agree that a stand alone procedure for design transfer would be appropriate. We believe that our design control activities are and have been adequate. Nonetheless, we are reviewing the entire design control process to ensure all elements are vigorously addressed.

In March 2005, Charter Medical hired a new Technical Director with GMP experience to oversee all development activities including design control. In June 2005, Charter Medical completed a GMP compliance gap analysis with an external consultant. One element of the analysis was the design control process. Charter Medical will be utilizing this gap analysis in conjunction with the expertise of our new Technical Director to develop a new design control process, including a stand alone design transfer procedure.

Status: Expected completion date – October 2005

COMMENT 8

Failure to perform risk analysis, where appropriate, as required by 21 CFR 820.30 (g). (FDA 483 item #20) Specifically, risk analysis was not performed for design project, [redacted] “Bonding to Drip Chamber”.

Response: Based on conversations with the investigator, the observation was based on an incomplete risk assessment that was included in the design control file specifically, an assessment of the risks associated with the intended use of the product was included, but a risk assessment of the change in the process from solvent to [redacted] bonding was not.

Charter Medical has re-evaluated our initial response to this observation and has determined that corrective actions beyond those listed in the 483 response are necessary. Charter Medical has implemented revisions to the change control procedure to enhance the documentation of rationale and justification for changes and to enhance the checklist utilized in specification revisions. The new checklist gives improved guidance on additional considerations to review when making changes. The revised checklist points to specific areas where a design review or risk analysis would be appropriate. However, these are primarily pointing to product design risk analyses. After further review, a requirement for process risk analysis is not specified directly through a process risk analysis procedure or indirectly through process validation or the change control checklist. Although our procedures defined a product risk analysis, they failed to define a process risk analysis.

Charter Medical will also review and revise the process validation procedure and the change control checklist to provide guidance on when and how to use process risk analyses.

Status: expected completion date – July 31, 2005

COMMENT 9

Your devices, Albumin IV Administration Set (K791672A), Transfer Pack (BK960043), and Transfer Bags (K802671C and K791673), are misbranded under section 502(o) of the Act. Specifically, you labeled these as Blood Administration Sets, and Platelet Sampling Devices, respectively, without providing FDA with notice or other information regarding the new intended uses of the devices, as required by section 510(k) and 21 CFR 807.81(a)(3)(ii). We remind you that until FDA has evaluated these devices and issued a 510(k) for their new intended uses, you may not distribute these products in interstate commerce labeled as indicated for the new intended uses.

Response: We respectfully disagree with a portion of this warning letter statement. Had our new Quality Assurance/Regulatory Manager been fully familiar with all products and their respective 510(k)’s this would have been made clear to the investigator at the time of the inspection. The investingator’s conclusion that the blood admin set was being marketd as an albumin iv set is incorrect. We hold a 510(k) for an albumin administration set, but do not distribute any product under this 510(k). Likewise, Charter Medical does not distribute any devices under the 510(k)’s K802671C and K791673

Since the time of our March meeting with the Atlanta District, Charter Medical has been diligently working to review documentation of the regulatory status of each product marketed. With regards to each of the products listed in this comment, Charter Medical provides the following information:

Albumin IV Administration Set (K791672A) – Charter Medical no longer distributes this device, nor do we market any devices under this 510(k)

Transfer Pack (BK960043) – Charter Medical currently distributes all of our transfer bags under this 510(k)

Transfer Bags (K802571C and K791673) – Charter Medical no longer distributes these versions of the transfer bags

Blood Administration Sets – Charter Medical distributes blood administration sets as a preamendments device

Platelet Sampling Devices – Charter Medical classifies these devices as blood transfer sets; a 510(k) was submitted on April 5, 2005 for all blood transfer sets, including the Platelet Sampling Device. 

Charter Medical evaluates the regulatory status of each product prior to marketing a new catalog item. One portion of the evaluation is a determination of intended use and a comparison of the proposed intended use with cleared 510(k)’s. As described above, Charter Medical distributes Transfer Packs/Bags under 510(k) BK960043. Charter Medical believed that this 510(k) adequately covered both blood transfer bags and blood transfer sets. The intended uses are significantly similar and the components of the devices are essentially the same. A transfer pack/bag consists of a bag and tubing set with connector (i.e., the tubing set alone with a new connector). The transfer set was created by removing the bag and replacing it with a connector. A platelet sampling device is a specific type of transfer set. We believed BK960043 to adequately cover the transfer set. We submitted 510(k) and chose not to disagree with the agency on this point, because we determined after the inspection, and with advice of counsel, that there is a separate regulation for transfer sets. Nonetheless, it is apparent that the FDA agreed with our prior position that the transfer set is a separate component of the transfer pack and is fully covered by that 510(k). see Haemonetics BK040001 section 6

Therefore, to clarify the regulatory status and in a good faith effort to respond to the agency, Charter Medical prepared and submitted a premarket notification for the transfer sets in April 2005. This submission is currently under review at CBER and a 510(k) has been assigned BK050021.

In regard to the root cause of the observation, decisions regarding the regulatory status of products were not always adequately documented so that new personnel could easily locate and interpret the rationale at the time the decision was made. Additionally, a controlled list of all product offerings and their associated regulatory status has not been utilized at Charter Medical. 

In response to your request in the Warning Letter , a comprehensive list of all product offerings and their regulatory status has been included with this response (Attachment 10). Charter Medical is also reviewing the change history for each product. All historical design changes and line extensions are being comprehensively reviewed for their effect on 510(k) clearance status. Where lacking, modification analyses are being prepared to document the rationale for inclusion under the 510(k) clearance. This process is approximately 30% complete. We anticipate completion by September 15, 2005. This item will be added to the monthly progress reports provided to the Atlanta District Office.

With regards to corrective and preventive actions, Charter Medical will build upon the list provided with this response to include a reference to the location of the modification analysis and 510(k) decision trees for each new product or line extension. Additionally, our procedure governing regulatory activities is being revised to reflect the use of this list. Appropriate personnel will be trained on the new requirements.

Status: Expected Completion Date- September 15, 2005