- Cantrell Drug Company - Company
February 10, 2015
Mr. Jeff R. Wooley, Compliance Officer
FDA Dallas District Office
U.S. Food and Drug Administration
4040 N. Central Expressway,
Dallas, TX 75204-3158
Subject: FDA Warning Letter - January 21, 2014
Dear Mr. Wooley:
A CGMP inspection was conducted at Cantrell Drug Company ("Cantrell") located at 7321 Cantrell Road, Little Rock, AR 72207-4144, between October 15th, 2013 and November 4th, 2013. At the conclusion of the inspection on November 4th, 2013, a Form FDA-483 ("483") was issued with twelve (12) observations. FDA issued a warning letter to Cantrell on January 21st, 2015. Cantrell does not believe it has put patients at risk, nor does it believe the production environment at the time of the inspection posed a significant risk of contamination. Cantrell took very seriously the observations made by the investigators and has taken significant corrective action during the intervening period between the inspection and issuance of the warning letter to eliminate the potential risk of contamination.
A. Cantrell History
Since its inception, Cantrell has strived to operate beyond the industry standard and continues today to stay actively engaged in complying with all applicable FDA draft guidelines. Through its commitment to quality and safety, Cantrell has become a national leader in customized pharmacy sterile compounding.
Cantrell has a long history of compliance with CGMP regulations to the extent and degree it deemed applicable to the small batch operations of an outsourcing facility, even before an outsourcing facility became an official designation under the Drug Quality and Security Act ("DQSA"). Since 2009, Cantrell has sought out and hired pharmaceutical professionals having significant experience with CGMP and national regulatory requirements to design and implement controls for insuring quality. In 2010, Cantrell voluntarily registered with the FDA as an Outsource Human Drug Compounder for which there were few, if any, regulations governing the designation. It was the first compounder to list its labels with the FDA using the web site fda.labels.gov where the entries were clearly designated as unapproved drugs.
Upon receipt of the 483, Cantrell began taking certain corrective action as reflected in its response to the 483 submitted to the FDA on November 21, 2013, and continued to make improvements beyond what was initially included in our response. Although the warning letter notes that certain corrective actions were insufficient, Cantrell implemented policies and procedures to address those deficiencies well before the issuance of the warning letter, and a detailed plan of action will be sent to you under separate cover.
Shortly after the passage of the Drug Quality and Security Act ("DQSA"), Cantrell became the fourth establishment to register with the FDA as a 503B Outsourcing Facility. A long-time proponent of increased FDA oversight, Cantrell welcomed the passage of the DQSA, which for the first time clarified the regulations under which outsourcing facilities operate and the FDA's authority to enforce those regulations. We believe that Cantrell was a forerunner in compliance with many of the regulations found in the legislation before it was passed. Cantrell is also pleased that the FDA has published the draft Guidance for Industry Good Manufacturing Practice - Interim Guidance for Human Drug Outsourcing Facilities Under Section 503B of the FD&C Act which we believe were foreshadowed by the conditions under which Cantrell operated. A project to revise all Cantrell's labels to be compliant with Section 503B (a)(10)(A) of the FD&C Act is nearly complete.
Since the passage of the DQSA and Cantrell's registration as an outsourcing facility, Cantrell has been audited eight times by client institutions (hospital systems or their contracted auditor) and two state boards of pharmacy doing their due diligence. These on-site auditors included consultants with CGMP experience specializing in aseptic processing and microbiology. In all cases, the hospital systems have chosen to outsource from Cantrell. State auditors have stated that Cantrell is much more advanced in quality systems compared to other companies they have audited. Even so, Cantrell has strived to continuously improve upon its operations based not only on the observations noted by the FDA investigators and the comments of the client auditors, but on FDA draft guidance, ISPE publications, PDA publications, and other similar industry standards.
B. CGMP Violations Observed during FDA's Inspection
With regard to the specific observations noted in the January 21, 2014 warning letter, please note that Cantrell has had procedures and programs which address such observations in effect for well over a year. Those procedures and programs are applied to all of Cantrell's drug products and are as follows:
1. Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)).
• Cantrell has revised written procedures observed to be insufficient to prevent microbiological contamination of drug products purporting to be sterile. We have instituted an extensive training program under direction of a full time trainer to ensure that all clean room technicians know the procedures and are capable of following them.
• Cantrell has undertaken a program of validating its aseptic processes and sterilization processes to comply with 21 CFR 211.113(b).
2. Your firm failed to ensure that manufacturing personnel wear clothing appropriate to protect drug product from contamination (21 CFR 211.28(a)
• Cantrell has enhanced sterile garbing to CGMP levels and utilizes sterile garb supplied by a third party well respected in the pharmaceutical industry.
• The sterile garb includes hoods, googles, coveralls, and boots.
• Standard operating garbing procedures have been written for the new garb.
• Personnel entering the clean rooms have been trained on donning the garb and qualified by successfully meeting pre-determined personnel monitoring microbiological criteria.
3. Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv)).
Cantrell has revised environmental monitoring procedures from USP 797 standards to the following:
• Daily air sampling in clean rooms and anterooms- bacterial and fungal
• Daily contact plate testing - hoods
• Daily settle plate testing - hoods
• Daily personnel monitoring once each shift
• Weekly contact plate testing for incidentals in ISO-7 cleanrooms - e.g. pumps, computer mouse, trash cans
4. Your firm failed to establish an adequate system for cleaning and disinfecting the room and equipment to produce aseptic conditions (21 CFR 211.42(c)(10)(v)).
Specifically this observation dealt with the use of nonwoven wipers and sterile isopropyl alcohol and their appropriate use. Cantrell immediately took action as follows:
• Cantrell now purchases and uses sterile non-shedding wipes
• Procedures have been revised on the proper use of the wipes within the ISO-5 area.
C. Corrective Actions
Cantrell notes that the Warning Letter dated January 21, 2014, states that several of the proposed corrective actions appear adequate. For those deemed deficient we have undertaken programs to remedy those deficiencies. Specifically:
• Process Simulations (Media Fills)
a. Cantrell has increased the number of test units for its semi-annual process simulation for each operator
b. We attended two PDA Training and Research Institute courses to supplement our understanding of process simulation design:
i. Process Simulation Testing for Aseptically Filled Products
ii. Recommended Practices for Manual Aseptic Processes
c. Media fill testing procedures have been revised to include the appropriate number of test units, which units to be tested, and the duration of the testing period needed to satisfy CGMP media fill guidelines.
• Validation of autoclave sterilization processes.
a. Cantrell employed a contract firm to validate the autoclave sterilization processes. The validations were completed and demonstrated a theoretical 12-log reduction in the indicator organisms. However, the bioindicator used only contained a mean population (cfu) of Geobacillus stearothermophilus of greater than 105 microoranisms. Cantrell will use only bioindicators containing a mean population (cfu) of Geobacillus stearothermophilus of greater than 106 microorganisms in their autoclave sterilization cycles.
• Alternative Sterility Test Methods
• Cantrell enlisted the services of a well-known consultant to assist in designing a validation protocol for the ScanRDI rapid sterility test method.
• Subsequently, BioMerieux Industry submitted DMF No. 14621 to the FDA demonstrating that the ScanRDI instrument used by Cantrell is capable of producing test results equivalent to the USP <71> Sterility Test method including data for over 1000 strains of microorganisms.
• Independently, Dynalabs LLC published a White Paper also demonstrating the equivalency of ScanRDI test results to those of the USP <71> Sterility Test.
• BioMerieux Industry personnel have completed the on-site Installation Qualification and Operation Qualification for the ScanRDI instrument used by Cantrell for sterility testing.
• Therefore, we have undertaken only product suitability testing for product families using scientifically sound and appropriate methodology under the direction of Cantrell's microbiologist.
We trust that the actions described in this response convey our commitment to addressing the 483 and its associated warning letter in a comprehensive manner. Cantrell's Senior Management team, consisting of the CEO, President, Vice-President of Quality Assurance and Regulatory Affairs, and the Pharmacist in Charge, is committed to quality and addressing all items noted in the warning letter. Changes to policies and procedures have been coupled with the implementation of an extensive training program of all relevant personnel effected by the updates. An updated version of our corrective actions will be supplied to you separately within fifteen (15) working days of our receipt of the warning letter.
We look forward to meeting with the FDA Dallas District at your first opportunity to discuss our response to the warning letter as well as timelines and appropriate documentation.
We also request that the FDA post our Warning Letter response on the FDA website. Please accept this letter as authorization to post on the US FDA Internet website Cantrell Drug Company's unredacted February 10, 2015 response to the Warning Letter issued to Cantrell Drug Company on January 21, 2015.
James L. McCarley Jr., CEO Mike Pierce, President