Inspections, Compliance, Enforcement, and Criminal Investigations
RTI Biologics, Inc. 10/19/12
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
555 Winderley Place, Suite 200
Maitland, Florida 32751
RETURN RECEIPT REQUESTED
October 19, 2012
RTI Biologics, Inc.
11621 Research Circle
Alachua, FL 32615
Dear Mr. Hutchison:
The Food and Drug Administration conducted an inspection of RTI Biologics, Inc., located at 11621 Research Circle, Alachua, Florida, from June 25 to July 11, 2012. During the inspection, FDA Investigators found significant deviations from the regulations for human cells, tissues, and cellular and tissue-based products (HCT/Ps), set forth in Title 21, Code of Federal Regulations, Part 1271 (21 CFR 1271), and issued under the authority of Section 361 of the Public Health Service Act (42 USC 264).
The deviations documented on a Form FDA 483, Inspectional Observations, were presented to and discussed with Ms. Caroline Hartill, Executive Vice President/Chief Scientific Officer, at the conclusion of the inspection. The items of concern include, but are not limited to the following:
1. Failure to recover, process, store, label, package, and distribute HCT/Ps, and screen and test cell and tissue donors, in a way that prevents the introduction, transmission, or spread of communicable diseases [21 CFR 1271.145]. For example:
a. From January 1, 2011 to June 30, 2012, the finished product packaging swab cultures of your Sports Medicine products detected Pseudomonas species on 70 separate occasions, including one incident of the pathogenic species of Pseudomonas aeruginosa. Within the same time period, Pseudomonas species was also detected in 24 D-test (destructive sterility release testing) cultures of your Sports Medicine products. The packaging for Sports Medicine/soft tissue products was performed primarily in rooms (b)(4) of the (b)(4) area (a Class 5 processing/packaging area consisting of rooms numbered (b)(4)) through (b)(4). You processed and distributed in excess of 33,000 tendons between 2011 and 2012.
Additional organisms detected in finished product packaging swab cultures and destructive testing cultures, during the same time period, include gram negative rods such as Serratia liquefaciens, (21 occasions), fungus (4 occasions), Bacillus species (28 occasions), and yeast (76 occasions).
b. From December 2011 through June 2012, D-test cultures of your aseptically-processed Bio DBM boats detected the following organisms, including but not limited to: Bacillus species, coagulase negative Staphylococcus, and fungus. You processed and distributed in excess of 10,000 Bio DBM boats in 2011 and 2012.
c. The 4th quarter 2011 BioCleanse bioburden monitoring samples, collected during Deval/soft tissue processing, had elevated Colony Forming Unit (CFU) counts for the aerobes and fungi tests on samples from two different donors. The contaminating aerobic organism was identified as Pseudomonas fluorescens. Repeat testing was performed on a sample from one of the donors and produced the same results. Your review of records for both donors found that Pseudomonas fluorescens was not identified on the pre-processing cultures performed on either donor ((b)(6) and (b)(6)).
2. Failure to adequately control environmental conditions and provide proper conditions for operations, where environmental conditions could reasonably be expected to cause contamination or cross-contamination of HCT/Ps or equipment, or accidental exposure of HCT/Ps to communicable disease agents [21 CFR 1271.195(a)]. For example:
a. Gram negative organisms and fungus were recovered during environmental monitoring of your (b)(4) area (Class 5 processing/packaging area) on the following dates:
- January 6, 2011 – 160 CFUs identified as gram negative rods, in room (b)(4);
- January 26, 2011 – 26 CFUs identified as gram negative rods, in room (b)(4);
- April 11, 2011 – 4 CFUs (alert level) identified as fungus, in room (b)(4);
- May 4, 2011 – 3 CFUs (alert level) identified as fungus, gram negative rods, and Micrococcus species, in room (b)(4);
- May 31, 2011 – 20 CFUs identified as fungus, gram negative rods, and Micrococcus species, in room (b)(4);
- June 28, 2011 – 32 CFUs identified as gram negative rods, in room (b)(4);
- June 30, 2011 – 128 CFUs identified as gram negative rods, in room (b)(4); and
- September 27, 2011 and October 2, 2011 –40 CFUs, 48 CFUs, and 8 CFUs identified as gram negative rods and coagulase negative Staphylococcus, in room (b)(4).
Initial processing of donor tissue was conducted in the (b)(4) area. After initial processing and BioCleanse sterilization, the tissue was returned to the (b)(4) area (rooms (b)(4) through (b)(4)) for final aseptic packaging, without terminal sterilization. The aseptic processing and packaging of the osteocondral (OC) allografts was also performed in the (b)(4) area.
b. Pseudomonas species was detected in your (b)(4) water system, located in the RTI West facility, during 2011 and 2012, but did not always reach alert or action limits, thus requiring an investigation. The (b)(4) water was used to clean the RTI West facility tissue processing areas and to rinse black sprayers, which were used during cleaning of both RTI West and RTI East facilities. For example:
- June 1, 2011 – 10 CFU/L Pseudomonas fluorescens ((b)(4))
- June 15, 2011 – 50 CFU/L Pseudomonas species ((b)(4))
- June 15, 2011 – 10 CFU/L Pseudomonas species ((b)(4))
- July 7, 2011 – Pseudomonas fluorescens ((b)(4))
- July 12, 2011 –20 CFU/L Pseudomonas fluorescens ((b)(4))
- July 25, 2011 – Pseudomonas fluorescens ((b)(4))
c. Pseudomonas species was detected in your (b)(4) water system, located in the RTI East facility, on at least 16 occasions in 2011 and eight occasions in 2012, but did not always reach alert or action limits, thus requiring an investigation. Three of the positive samples from 2011 were too numerous to count (TNTC) for Pseudomonas fluorescens. The (b)(4) water was used for cleaning in RTI East.
In April 2012, environmental monitoring results exceeded action levels on two occasions for water port (b)(4) in room (b)(4). The contaminating organism was identified as an oxidase-positive, aerobic fastidious, gram-negative rod. Although water port (b)(4), one of (b)(4) ports located in room (b)(4), was rarely used during processing, it was replaced with an autoclaved valve and received an extended sanitization. On May 1, 2012, Pseudomonas fluorescens was detected in a water sample taken from port (b)(4).
3. Failure of your quality program to ensure that appropriate corrective actions relating to core CGTP requirements, including reaudits of deficiencies, are taken and documented, as necessary. Where appropriate, corrective actions must include both short-term and long-term action to prevent the problem’s recurrence [21 CFR 1271.160(b)(3)]. For example:
a. An investigation was opened in March 2011 due to an increase of D-test culture failures for the Bio DBM boats. After implementing corrective actions, including removing the mouse pads from the packaging area, you continued to have sporadic failures in D-test cultures from December 2011 through June 2012. These failures were not considered problematic, despite the continuing environmental contamination with the facility.
b. Prior to March 2012, you did not identify by speciation positive cultures initially identified as gram negative rods that were isolated from your facility during environmental monitoring. As a result, you failed to identify the connection between the presence of Pseudomonas species in the (b)(4) water system, the (b)(4) water system, the carboys/black sprayers, the elevated environmental monitoring results, and the increase in packaging culture failures.
4. Failure to maintain your facilities used in the manufacture of HCT/Ps in a clean, sanitary, and orderly manner, to prevent the introduction, transmission, or spread of communicable disease [21 CFR 1271.190(b)(1)]. For example:
Your firm uses carboys/black sprayers for facility cleaning in both RTI West and RTI East. The carboys/black sprayers are cleaned and disinfected in RTI West and are then used within RTI West or transported back to RTI East. During facility cleaning, they are filled with cleaning solutions or rinse water ((b)(4) water in RTI West or (b)(4) water in RTI East).
In April 2011, you changed your practice of cleaning the carboys/black sprayers from (b)(4). This practice was again changed one week later (b)(4). While testing the effectiveness of this cleaning practice, you detected Pseudomonas fluorescens in multiple samples from the carboys/black sprayers as early as April 28, 2011. However, some of the carboys/black sprayers, cleaned with (b)(4) and (b)(4) water, were used for facility cleaning in both RTI East and RTI West throughout May and June 2011. On June 2, 2011, you changed from cleaning the carboys/black sprayers with (b)(4) to (b)(4) cleaner and (b)(4) water, as (b)(4) was determined to be ineffective.
In RTI East, the carboys/black sprayers were filled with (b)(4) cleaner or (b)(4) water, for the final rinsing step, and used for cleaning of your manufacturing areas, including the (b)(4) area/Class 5 processing/packaging suites. On June 22, 2011, while investigating the cause of an increase in positive finished product packaging cultures of your Sports Medicine products, you detected Pseudomonas species in samples from the (b)(4) cleaner and (b)(4) water. One sample was positive for Pseudomonas fluorescens, a second was TNTC for Pseudomonas fluorescens, and a third was TNTC for Pseudomonas aeruginosa. Your investigation, dated July 21, 2011, determined that “Pseudomonas fluorescens and Serratia liquefaciens were likely introduced into the packaging episodes during the cleaning episodes.”
We have reviewed your written responses, dated July 31, 2012, August 28, 2012, and September 28, 2012, and acknowledge the corrective actions you have implemented to improve your environmental control, environmental monitoring, and cleaning activities. However, we remain concerned about the conditions that were identified during the most recent inspection and the ongoing contamination issues that appear to be problematic throughout your facility. We also have specific comments regarding your response, as follows:
In your August 28, 2012 response, you state, “East campus Pseudomonas detection has remained relatively constant while corrective actions taken to date have reduced the overall percentage of Pseudomonas identified in the West campus…;” “The overall detection of Pseudomonas in the East campus cleanrooms appears to be relatively constant;” and “….the (b)(4) processing area has been isolated as the primary contributor to the current overall Pseudomonas detection at the East campus.” Despite your increased facility and carboy/black sprayer cleaning and sanitization activities, these statements indicate that the contamination identified during the most recent inspection is ongoing and is still detectable in both RTI East and RTI West facilities, and that you may have additional contributors of contamination that have not been identified.
In your July 31, 2012 response, you indicate that you performed an extended (from one hour to six hours) sanitization of your (b)(4) water system. Your SOP, “Functional Description of the (b)(4)” states the system is maintained at a temperature of (b)(4) during continuous operation and the loops are sterilized at a temperature of (b)(4). However, during the inspection, the investigator observed that the hot loop temperature was maintained at 33oC at that time. We continue to be concerned about the potential development of a biofilm in your water system(s), as the ideal temperature for Pseudomonas species growth is between 30oC and 35oC.
We are concerned about your practice of collecting (b)(4) water samples for environmental monitoring after the water passes through a filter. We note that during 2011 and 2012, you detected Pseudomonas species and gram negative rods in filtered and unfiltered samples taken from your (b)(4) and (b)(4) water systems. While point of use filters may be used for a specific purpose, they can mask the level of microbiological contamination in a water system. Therefore, samples taken after filtration and used for microbiological testing may not give a true representation of the status of your water system.
In your July 31, 2012 response, you state, “…environmental monitoring trends in the Surgical/Dental packaging area are more favorable. Therefore, BioCleanse soft tissue packaging has been moved from the (b)(4) to the packaging area in the (b)(4) effective 7/30/2012. Furthermore, in order to limit potential contamination of the OC tissue grafts, processing and packaging of OC has been dedicated to Rooms (b)(4) & (b)(4) in the (b)(4)…” In your August 28, 2012 response, you state, “…Sports Medicine Packaging was moved from the (b)(4) into a General Packaging area. Second, in an attempt to localize OC processing and reduce environmental variation, the OC Processing suites are now dedicated to processing only OC grafts.” Due to the ongoing detection of Pseudomonas throughout your facility, it appears as though you have performed multiple relocations of product packaging and/or processing. However, based on our review of the updated RTI East Core Floor Plan provided with your July 31, 2012 response, along with the additional changes described in your August 28, 2012 response, we are unable to determine where each product line is processed and packaged and the rationale for the relocations.
We are concerned about the corrective actions taken after the failed BioCleanse bioburden audits in 2011 and 2012. You opened an investigation (CAR-00107-ISS) on January 5, 2012 to address the elevated 3Q11 and 4Q11 BioCleanse bioburden audits, due to the presence of Pseudomonas fluorescens. It was not until March 1, 2012 that you held a meeting to “lay out a plan to conduct the investigation for the elevated bioburden results….documented in CAR-00107.” Investigations, sampling, and process changes took place from mid-March 2012 through May 2012 and as of the close of the inspection (July 11, 2012), the investigation CAR-00107-ISS remained open. You also generated an Interoffice Memorandum, dated March 19, 2012 to justify the continued use of product after receiving the failed bioburden audit results for 3Q11 and 4Q11. That memo stated, “(b)(4).”
In April 2012, you received the results of the 1Q12 BioCleanse Bioburden audit, which also had elevated bioburden results on multiple samples, again for Pseudomonas fluorescens. Instead of recognizing the significance of the failed BioCleanse bioburden audit for another consecutive quarter, and for the same contaminating organism, you simply combined these audit results with the investigation and corrective actions for CAR-00107.
From January 2011 to June 2012, there was an increase in finished product packaging cultures and D-test culture failures; positive environmental monitoring samples in your (b)(4) and (b)(4) water systems and processing/packaging areas; and failed BioCleanse Bioburden audit results for three consecutive quarters. Pseudomonas species was identified during each of these activities. Instead of recognizing a trend in your environmental monitoring data, indicative of contamination throughout your facility, you continued to justify the distribution of final product based on negative final packaging culture and D-test results for individual donors. In addition, as of your August 28, 2012 response letter, you reported that you are currently detecting Pseudomonas species in your facility, yet you continue to distribute tissue products.
The above identified violations are not intended to be an all-inclusive list of deficiencies at your facility. It is your responsibility to ensure that your establishment complies with all applicable requirements of federal regulations. You are responsible for reviewing your firm’s operations to assure you are in compliance with all applicable FDA regulatory requirements. You should take prompt action to correct these deviations and prevent their recurrence. Failure to do so may result in additional regulatory action. Such action may include, but is not limited to, an order to retain, recall, destroy, or cease manufacture of HCT/Ps.
We request that you notify this office in writing, within fifteen working days of receipt of this letter, with further details of the specific steps you have taken to correct the noted violations and prevent their recurrence. If corrective action cannot be completed within fifteen working days, state the reason for the delay and the time frame within which the corrections will be completed.
Your response should be sent to the Food and Drug Administration, Florida District Office, 555 Winderley Place, Suite 200, Maitland, Florida, 32751, to the attention of Andrea H. Norwood, Compliance Officer. Should you have any questions concerning this letter you can contact Ms. Norwood at (407) 475-4724.
Emma R. Singleton
Director, Florida District