Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
|New England District|
One Montvale Avenue
Stoneham, Massachusetts 02180
FAX: (781) 596-7896
VIA UPS Next Day Air
September 15, 2010
Mr. Rice Powell
Chief Executive Office
Fresenius Medical Care Holdings, Inc.
920 Winter Street
Waltham, MA 02451-1521
Dear Mr. Powell:
During an inspection of your firm located in Waltham, MA on June 15 through August 6, 2010, investigator(s) from the United States Food and Drug Administration (FDA) determined that your firm manufactures kidney dialysis products, including Optiflux Dialyzers and Liberty Cycler Sets. 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 Mr. Joseph P. Winslow, Vice President of Quality Systems, dated August 27, 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 the noted violations. These violations include, but are not limited to, the following:
1. Failure to establish and maintain adequate procedures for implementing corrective and preventive actions, as required by 21 CFR 820.100(a).
Your firm failed to follow your health hazard assessment procedure in that you failed to identify any actions to reduce the risk of Liberty Cassettes in commercial distribution. Your firm investigated 118 complaints from January 2001 thru October 2009 of cassette leaks during patient hemodialysis treatments which included 6 MDRs and two confirmed cases of peritonitis. Your firm indentified a root cause, initiated shipping holds on existing inventory and ordered a product rework in November, 2009, but failed to identify an action to address units in commercial distribution.
Your documented health hazard assessment, conducted according to your procedure, determined the "level of concern" (hazard) to be critical (i.e. death or serious injury) and the "likelihood of occurrence" to be remote which produced a risk acceptability result of "undesirable". For this risk acceptability category your procedure requires that risk be reduced to as low as reasonably practical in order to continue operations. Actions were only identified for existing inventory. No actions were identified to reduce the risk of product in the field. During the inspection your firm indicated that a calculated turn over rate of (b)(4) weeks for the Liberty cassettes addressed the concern of product in the market, however the Agency disagrees that a turn over rate is an action to reduce known risk to patients.
2. Failure to establish procedures for investigating the cause of the nonconformities, as required by 21 CFR 820.100(a)(2).
Naturalyte Acid Concentrate products:
Fresenius complaint, PIR200701295, received in 2007 reported a patient suffered "symptomatic hypocalcemia with parethesias and tetani" after having used the wrong concentration of Naturalyte Acid Concentrate product which was delivered to their residence. The complaint documented the difficulty discerning between different concentrates of calcium values for this product and using it in error. The complaint also noted that this was the second instance in which the incorrect concentration of a Naturalyte Acid Concentrate product had been delivered to the patient. No investigation into product labeling was initiated.
An investigation into to the root cause of product mix ups by the delivery and end user was not initiated for this PIR200701295. A review of complaints from January 2007 thru July 2010 revealed additional complaints regarding difficulty differentiating product by labeling. The additional complaints included, but are not limited to one stating the user facility had nearly used the wrong product (2010), and one stating the wrong product had been used in the past (2008). We did not observe an actual CAPA for this event.
3. Failure to establish and maintain an adequate corrective and preventive action procedure which ensures identification of actions needed to correct and prevent the recurrence of non-conforming product and other quality problems, as required by 21 CFR 820.100(a)(3).
Your procedure for determining and identifying appropriate actions for product in commercial distribution is inadequate and lead to the failure to identify actions to address the risk of product in commercial distribution. The Product Assessment Report (PAR) documented that a field action was not required because the likelihood of occurrence was remote and the "severity" was determined to be "minor". Neither the term "severity" or "minor" are defined in either your "Health Hazard Assessment" procedure or your "Determining the Need for Remedial Product Action Level II" procedure used by your Product Assessment Committee to make this decision. Yet the decision against implementing a field action relied on the conclusion of a severity level of minor as documented in section 9.1 of the Product Assessment Report.
4. Failure to establish and maintain procedures for verifying or validating your corrective and preventive actions, to ensure that such action is effective and does not adversely affect the finished device, as required by 21 CFR 820.100(a)(4).
Your firm failed to verify that the corrections, implemented to existing inventory to address leaks in the Liberty cassettes, were effective in addressing the nonconformity. After determining no field action was necessary for Liberty cassettes in commercial distribution your firm received 42 additional complaints, which included 2 MDRs with confirmed cases of peritonitis related to identified lots in commercial distribution.
Naturalyte Acid Concentrate products:
Your firm has not verified that labeling revisions to the Naturalyte Acid Concentrate product line have addressed the potential for product mix ups by the end user. No formal CAPA was opened for this issue, however your firm stated during the inspection that the changes were made to some labeling to address mixups such as in PIR200701295.
We have received your response to the FDA 483 dated August 27, 2010 which did contain proposed corrective actions to your CAPA system, and find it to be inadequate. We understand that on August 26, 2010, Fresenius initiated a voluntary recall of the 98 lots of Liberty Cassettes described above. We also acknowledge your plan to perform a thorough review of your CAPA and risk assessment procedures and to perform a retrospective review of all CAPA's.
In response to this Warning Letter, please provide documentation of your revised procedures to demonstrate that they are capable in preventing these significant failures from recurring. These procedures need to clarify how hazard, likelihood, and final risk acceptability will be used in decision making and contain clear definitions for the terms used throughout your organization.
Also, we would like to review documentation of your CAPA review when complete. We are especially interested in your review of all the HHA's that were performed that resulted in a risk acceptability of "undesirable" to assure the actions identified were appropriate for product remaining on the market.
Your response indicated that Fresenius opened a CAPA 2010012 to document the investigation into labeling revisions. In response to this Warning Letter, please provide additional data on how your film is implementing effective labeling changes to prevent further mix-ups.
5. Failure to establish and maintain procedures for receiving, reviewing, and evaluating complaints by a formally designated unit, as required by 21 CFR 820.198(a).
Naturalyte Acid Concentrate products:
For example, on June 09, 2009, your company received a complaint (PIR 200901506) regarding a possible dialyzer reaction incident that occurred on April 6, 2009 in which a dialysis patient experienced lose of pulse/consciousness and CPR was required. Related complaint, PIR 200901614 was received on June 10, 2010, and referenced a second occurrence of a possible dialyzer reaction on April 20, 2009 in which the patient loss consciousness again, and required CPR a second time. The patient ultimately died on May 08, 2009 due to coronary artery disease, end stage renal failure, and sepsis.
The second complaint was voided, contrary to your own SOP S100006-01, even though two events were clearly reported. The original complaint file was subsequently closed on July 17, 2009 without investigation to determine that the event was not reportable under 21 CFR Part 803. The file did not include any documentation that your devices did not cause the events described in the two separate incidents. We are concerned that you relied on your own internal assessment to make such a decision, without further investigation or contact with the complainant.
Also, your firm received a complaint on June 23, 2008 (PIR 200801118) involving Naturalyte products (08-4017) which indicated that since the labels look the same, "the wrong product actually has been used on one occasion". The complaint did not include any documentation that indicated an attempt was made to follow-up with the complainant to determine whether a patient reaction was involved.
You should take prompt action to correct the violation(s) addressed in this letter. Failure to promptly correct these violation(s) may result in regulatory action being initiated by the Food and Drug Administration without further notice. These actions include, but are not limited to, seizure, injunction, and/or civil money penalties. Also, federal agencies are advised of the issuance of all Warning Letters about devices so that they may take this information into account when considering the award of contracts. Additionally, premarket approval applications for Class III devices to which the Quality System regulation deviations are reasonably related will not be approved until the violations have been corrected. Requests for Certificates to Foreign Governments will not be granted until the violations related to the subject devices have been corrected.
Please notify this office in writing within fifteen (15) working days from the date you receive this letter of the specific steps you have taken to correct the noted violations, including an explanation of how you plan to prevent these violation(s), or similar violation(s), from occurring again. Include documentation of the corrective action you have taken. If your planned corrections will occur over time, please include a timetable for implementation of those corrections. If corrective action cannot be completed within 15 working days, state the reason for the delay and the time within which the corrections will be completed.
Upon further review of the inspectional findings, we are concerned with your firm's oversight of your contract manufacturers, specifically drug manufacturers. We understand that Fresenius has the responsibility for the final approval and release of finished products for distribution,including Phoslo gelcaps which are contract manufactured for Fresenius by (b)(4). On at least two occasions, we observed the release of these above drug products that did not meet quality specifications.
• In one instance your firm was in receipt of OOS stability results for a lot of Phoslo gelcaps (#1308035) at three separate time points, (12, 15 and 18 months). Your investigation into these non-conforming reports concluded that no action to product in the field was necessary because the risk of hazard was "acceptable" and made a number of conclusions that do not appear to be based on sound scientific data. A thorough review of the contractor's investigation into these stability failures was also lacking.
• We also observed the commercial release of Phoslo gelcaps that were found to contain grease. This decision was made after a previous Fresenius PAR report indicated that the three finished lots were to be used by the contractor for stability purposes and would not be released for commercial distribution. This failure in oversight of your release decisions is very concerning. FDA considers contamination of finished drug products with foreign material (e.g., grease) a significant product quality issue.
We understand that you have initiated a recall of two lots of Phoslo gelcaps (#1308035 and #1308039) that had failing stability results. We also note that you have terminated your business with the contract manufacturer of this product. In your response to this item, please address how your firm plans to prevent these types of failures from recurring with other contract manufacturers.
Please direct your response or any questions you may have to Karen Archdeacon, Compliance Officer, Food and Drug Administration, One Montvale Avenue, 4th Floor, Stoneham, Massachusetts 02180. Her telephone number is (781) 596-7707.
Finally, you should know that this letter is not intended to be an all-inclusive list of the violation(s) at your facility. It is your responsibility to ensure compliance with applicable laws and regulations administered by FDA. The specific violation(s) noted in this letter and in the Inspectional Observations, Form FDA 483 (FDA 483), issued at the closeout of the inspection may be symptomatic of serious problems in your firm's manufacturing and quality assurance systems. You should investigate and determine the causes of the violation(s), and take prompt actions to correct the violation(s) and to bring your products into compliance.
Mufahar S. Shamsi
Acting District Director
New England District