- RX South DBA RX3 Compounding Pharmacy LLC
DATE: November 12, 2014
Ernest F. Bizjak
FDA Baltimore District Office
U.S. Food & Drug Administration
6000 Metro Drive, Suite 101
Re: Rx3 Pharmacy's Response to FDA Warning Letter
FEI Number 3008723337
Dear Mr. Bizjak:
In response to the FDA's October 23, 2014 Warning Letter, I am writing on behalf of Rx3 Compounding Pharmacy (Rx3), a retail compounding pharmacy located in Chester, Virginia that I founded with my father, C.F. Sonny Currin, Jr., R.Ph. in 1995. Together we have over 50 years of pharmacy experience serving the Richmond, Virginia area. Please be aware that Rx3 takes its commitment to quality and patient safety very seriously. Rx3 strives to maintain high standards of practice and works diligently to ensure that our practice is evolving with the current USP compounding industry standards. Furthermore, Rx3 was the first, and remains one of only a few compounding pharmacies in Virginia to enjoy accreditation by the Pharmacy Compounding Accreditation Board.
As an initial matter, it is important to note that the Warning Letter was triggered by a complaint regarding suspected particulate matter contamination of an Rx3 sterile compounded product that was ultimately determined to have been caused by the cold temperatures the product was exposed to during shipping. Indeed, consistent with the high-quality sterile compounding practices in place at Rx3, there was no microbial contamination. Specifically, the hydroxyprogesterone caproate solution in question passed the FDA's own independent testing in that it was found to be negative for microorganisms, and all tubes and MEA plates showed no growth. (Exhibit A). Furthermore, prior to dispensing, in compliance with USP <797>, an appropriate quantity of the medication was submitted for USP<71> sterility testing, endotoxin, and potency testing at an independent testing facility with ISO 17025:2005 laboratory accreditation, that is also FDA as well as DEA registered. (Exhibit B). Consequently, it appears that the particulate matter was due to a factor outside of Rx3's control. Specifically, severe cold temperatures experienced in January 2014 during delivery to patients caused some of the hydroxyprogesterone caproate solution to develop crystals, which upon rewarming readily dissolved. Thus, there was no contamination.
Furthermore, notwithstanding the fact that Rx3 only compounded hydroxyprogesterone caproate solution based on patient-specific prescriptions, all of which identified allergy risks that necessitated the use of a (b)(4) effective January 31, 2014, Rx3 is no longer compounding any quantities of hydroxyprogesterone caproate solution.
Aside from these high-level issues, Rx3 has a comprehensive set of policies and procedures in place to ensure that all compounded products are prepared, packed, and held in sanitary conditions. The two specific areas identified by the inspector in the Warning Letter are addressed in our Standard Operating Procedures, which were in place before this incident occurred. The first of which is in 1.40 "Compounding Area Requirements (Sterile). "(Exhibit C) All appropriate staff members have received re-training regarding the appropriate and routine cleaning of materials during the transfer into the cleanroom (Exhibit D). Additionally, routine observational audits are being conducted (b)(4) to ensure compliance. (Exhibit E). Secondly, Rx3 contracts the certification of our cleanrooms, to include our ISO 5 areas, to a qualified service provider, and in compliance with USP <797>, undergoes recertification every (b)(4) as is noted in Policy and Procedures Section. 2.16 "Hood." (Exhibit F). To ensure compliance, effective January 2015, all contractors involved in the certification process will be required to review applicable sections of our standard operating procedures and document compliance prior to performing testing. (Exhibit G). Furthermore, we have re-educated our staff on our SOPs, and we have implemented additional computer tracking systems to ensure appropriate preparation, packaging, and storage of all drug products at Rx3. We will continue to monitor SOP compliance and will make additional revisions as needed in the future.
Rx3 Is and Has Been Engaged Only in Traditional Compounding
Rx3 understands the FDA's position on compounding is evolving based on recent events. Nevertheless, Rx3 believes it has maintained compliance with FDA guidance to the extent it is available, as well as applicable Virginia law. Specifically, Rx3 believes it has always complied with 21 USC § 353a, regarding pharmacy compounding, by only compounding drug product pursuant to individual prescriptions or physician orders or by producing limited quantities before the receipt of a valid order, with those quantities, based on a knowledge of the history of previous orders generated from our relationships with these individual physicians, as permitted by Virginia law. To be sure, the November 27, 2013 revisions to 21 USC § 353a did not change the relevant provisions in subsection (a), as it relates to applicability. Ultimately, Rx3 does not believe it is now or has ever been a "manufacturer" under the FDCA.
Notwithstanding the above and consistent with the evolving guidance on compounding, effective July 2014, Rx3 no longer engaged in the compounding of any quantity of sterile drugs without first obtaining an individually identifiable, patient-specific prescription from a duly licensed prescriber. Additionally, effective November 1, 2014 this policy now also includes all nonsterile prescriptions for human use.
Even prior to instituting its policies on patient-specific compounding, Rx3 believes that its compounding activities were consistent with the core content in FDA's July 2014 Guidance, "Pharmacy Compounding of Human Drug Products Under Section 503A of the Federal Food, Drug, and Cosmetic Act." Significantly, despite issuance of the July 2014 guidance, the FDA has not defined the "limited quantities" that can be produced, but did provide guidance in a 2002 compliance policy guidance document (2002 Guidance), which listed several ''red flags" practices that the FDA believes related to the scope and nature of a drug manufacturer, rather than a traditional retail compounding pharmacy like Rx3. Rx3 believes it has avoided the "red flag" practices listed in the 2002 Guidance as well as the types of activities of other pharmacies that have been cited in FDA warning letters as crossing the line into drug manufacturing. To be specific, Rx3 does not compound drugs for institutional orders, does not compound drugs for resale, and does not compound copies of FDA-approved drugs. Notwithstanding the above, Rx3 is aware that the 2002 Guidance has been formally withdrawn (78 FR 72841 (Dec. 4, 2013)), which has resulted in Rx3 looking for additional guidance at the state level.
Because the term "limited quantities" (21 USC § 353a(2)) is not expressly defined, Rx3 has relied on Virginia State statutory and regulatory guidance on pharmacy compounding. Specifically, Virginia law provides that:
"Compounding" means the combining of two or more ingredients to fabricate such ingredients into a single preparation and includes the mixing, assembling, packaging, or labeling of a drug or device (i) by a pharmacist, or within a permitted pharmacy, pursuant to a valid prescription issued for a medicinal or therapeutic purpose in the context of a bona fide practitioner-patient-pharmacist relationship, or in expectation of receiving a valid prescription based on observed historical patterns of prescribing and dispensing; (ii) by a practitioner of medicine, osteopathy, podiatry, dentistry, or veterinary medicine as an incident to his administering or dispensing, if authorized to dispense, a controlled substance in the course of his professional practice; or (iii) for the purpose of, or as incident to, research, teaching, or chemical analysis and not for sale or for dispensing. The mixing, diluting, or reconstituting of a manufacturer's product drugs for the purpose of administration to a patient, when performed by a practitioner of medicine or osteopathy licensed under Chapter 29 (§ 54.1-2900 et seq.), a person supervised by such practitioner pursuant to subdivision A 6 or A 19 of § 54.1-2901 , or a person supervised by such practitioner or a licensed nurse practitioner or physician assistant pursuant to subdivision A 4 of § 54.1-2901 shall not be considered compounding. Virginia Code § 54.1-3401
We believe it is clear that the FDCA and Virginia law allow a pharmacy to provide compounded drugs to a physician in-office administration, and further allows for a pharmacy to compound drugs prior to receiving an order based on observed prescribing patterns-this is exactly what Rx3 did prior to July 2014. Now, as stated above and consistent with Rx3's understanding of the FDA's current policy guidance, Rx3 only compounds human use medications in response to a patient-specific prescription.
For the above reasons, Rx3 is a traditional retail and compounding pharmacy that produces compounded drugs in response to individual prescriptions and physician orders. As such, Rx3 believes it has been and remains in good faith compliance with 21 USC § 353a, applicable Virginia Law, and other relevant guidance that has been available to compounding pharmacies. Nevertheless, in response to the items identified in the Warning Letter, please see below.
Compounded Drugs Under the FDCA
Because Rx3 only compounds human use medications in response to valid prescriptions for individually-identifiable patients, it is entitled to the exemptions set forth in 21 U.S.C. § 353a. Most significantly, the requirements for compliance with current good manufacturing practice (cGMP) are not applicable. Nevertheless, Rx3 is in compliance with applicable requirements of USP Chapter <797> and has numerous mechanisms in place to ensure the quality and safety of its products.
Violations of the FDCA
As indicated above, Rx3 believes it was not in violation of the FDCA because it only compounded in a manner allowed under 21 U.S.C. §353a or Virginia pharmacy compounding law. As result, Rx3 was and is not a manufacturer, did not and is not misbranding any drugs, and did not and is not preparing, packing, or holding any sterile drug product under insanitary conditions.
Misbranded Drug Products
Prior to July 2014, the drug products that Rx3 produced without individually-identifiable prescriptions were, instead, compounded in response to prescriber prescriptions for use with their own patients within their offices. Each product was labeled with, "This medicine was compounded in our pharmacy for use by a licensed practitioner only. This compounded preparation may not be resold." These compounded medications were not for use or amenable to self-diagnosis and treatment by individuals who were not medical practitioners.
As noted above, the product that resulted in the complaint was not adulterated by Rx3. Specifically, the hydroxyprogesterone caproate solution in question passed the FDA's own independent testing in that it was found to be negative for microorganisms, and all tubes and MEA plates showed no growth. Additionally, prior to dispensing the product was tested for potency, endotoxin, and USP <71> sterility. Furthermore, it was the crystals that developed from the severe cold temperatures the solution was exposed to in delivery to patients that readily dissolved upon warming and was not a result of contamination.
Notwithstanding the above, please note that Rx3 maintains the following policies and procedures and has taken the following steps since February 2014 to reduce the risk of contamination in response to the four items identified in the Warning Letter:
1. Systems for maintaining equipment used to control the aseptic conditions:
• The autoclave used for the sterilization of drug products such as Estradiol Pellets 22mg, and Testosterone Pellets 200mg, has been re-validated to establish a maximum load pattern. The autoclave was validated at (b)(4).
• Rx3's SOP for the autoclave has been updated to reflect that sterile water for irrigation is to be supplied to the autoclave for both cleaning and sterilization purposes. (Exhibit I)
• Rx3's SOP for the autoclave has been updated to reflect the changes made to the autoclave load validation form, as well as including a verification check on the results column for the biologicals indicator and sporview vials. (Exhibit I)
• Rx3 uses visual monitoring and (b)(4) to ensure incubator temperature consistency. Rx3 's SOP 2.200 entitled "Incubator" was updated, on February 21, 2014, to reflect the purchase and use of the (b)(4) data loggers. (Exhibit J). Each incubator is now equipped with a data logger that will provide a constant monitoring system for the incubators.
2. Systems and controls necessary to prevent contamination and mix-ups:
• As a traditional compounding pharmacy practice, Rx3 is in compliance with the guidelines of USP Chapter <797> regarding the appropriate use of disinfectants in the classified areas. Further, Rx3 selects its use of disinfectants in the classified areas by using Appendix II of the USP <797> page 79. (Exhibit K). Additionally, Rx3 Rotates through (b)(4) to prevent any bacteria from developing a tolerance to any one disinfectant products. Rx3 is currently using (b)(4) as its disinfectants.
• All disinfectants that are used in the ISO 5 laminar flow hoods are sterile. Only sterile (b)(4) or sterile (b)(4) wipes are used to wipe down and disinfect ISO 5 laminar flow hoods.
• Prior to dispensing, all products are inspected and verified by the dispensing pharmacist. The pharmacist's initials are recorded on the compounding log as well as the delivery ticket for each prescription. As part of Rx3's Continuing Quality Improvement, an additional documentation field has been added to sterile products to further document the inspection process that is performed by each pharmacist. The addition of this segment to every formula is an on-going process and we are working diligently to ensure that this documentation segment will appear on 100% of all logs in the near future. An in-service was conducted on March 6, 2014 to ensure that all appropriate staff members are up-to-date with the documentation process and a monitoring system for formula worksheets deficient of this documentation system will be put in place to identify and correct any formula worksheets that are not in compliance with SOP 4.50. (Exhibit L). Effective December 2014, a compliance audit of the formulas will be initiated to track the progress of this initiative. This information will be evaluated by the Continual Quality Improvement team. The additional documentation segment is as follows:
Sterile QC/Final Check by ______
___ Formula/calculations checked
___ Confirm integrity/clarity/no particles
___ Confirm packaging/ storage/labeling/no leaks
___ Confirm BUD/quantity/viscosity
___ Confirm sterility method/testing
___ Confirm bubble test (if applicable)
___ pH (if applicable)
3. Systems to prevent microbiological contamination and system for validation of aseptic and sterilization processes:
• Rx3 exceeds the garbing and gowning guidelines set for in USP <797>. (Exhibit M). Specifically, despite the lack of an express requirement, Rx3 only uses sterile full body suits. Furthermore, sterile technician A.T. has been given a copy of the garbing and gowning deficiency reported in the FDA 483. Additionally, sterile technician A.T. was retrained on appropriate garbing and gowning procedures on February 25, 2014.
4. Systems for monitoring environmental conditions:
• Rx3 has met or exceeded USP Chapter <797> guidelines regarding environmental monitoring including air and surface sampling. Policy and procedures referencing scheduled environmental monitoring are available upon request. Among other things Rx3 performs surface sampling (b)(4) while USP<797> only requires "periodic" testing. (Exhibit N).
• Rx3 complies with USP Chapter <797> guidelines regarding environmental monitoring including air and surface sampling. Specifically, Rx3 adheres to USP Chapter <797> referencing the competency evaluation of garbing and aseptic work practice located on page 58 and 59 of USP 797. (Exhibit O). Furthermore, Rx3 performs gloved fingertip monitoring (b)(4) along with our other surface sampling. (Exhibit C).
• All appropriate pharmacy personnel, including all pharmacists were given a copy of SOP 1.40 sections 3.5.3-184.108.40.206 during a retraining in-service meeting on February 25, 2014 the sections of SOP 1.40 were discussed, and demonstrated. (Exhibit P).
• On January 29, 2014, (b)(4) ran visual smoke pattern tests in Rx3's (b)(4). The (b)(4) hood did pass its visual smoke pattern tests, documentation is included. (Exhibit Q). Rx3 has policy and procedures in place that require adequate testing of each hood to be performed (b)(4) by a qualified vendor. As mentioned above, the vendor is now required to review these policy and procedures prior to testing the cleanroom.
• Effective February 21, 2014 all of Rx3's smoke studies are performed under dynamic conditions. Per USP Chapter <797> recertification is to be performed (b)(4), Rx3 was most recently recertified in July 2014.
• Rx3 monitors and records its pressure gauges during each day of operation as required by USP Chapter <797>. Rx3 currently uses the software (b)(4) to monitor all tasks during each day of operation. This software has been customized to include all the monitoring parameters recommended, including, but not limited to, pressure gauges. Management is notified immediately in the event that a value is out of range or if a reading is delayed in its recording. Additionally, the software provides tracking and review of quality systems, trending and analysis reporting by person, and up to date education pertaining to USP<797>.
• Rx3 uses various methods when contracting with outside pharmacy vendors. Specifically, Rx3 uses direct laboratory vendor information as well as other industry references to determine appropriateness when selecting a contracted testing laboratory. Recently, Rx3 has implemented a Vendor Qualification form to further demonstrate a vendor's competency. (Exhibit R).
Furthermore, Rx3 has amended the SOP 3.10 entitled "Inventory Control" to reflect the use of the "Rx3 Compounding Order Compliance Form". (Exhibits S & T). In an effort to include best practices into the operations at Rx3, this form will be filled out completely and a copy attached to each wholesalers invoice for all orders received. All products checked in using this form will be inspected for damages and uniformity.
Compounded Drug Products That Are Essentially Copies of a Commercially Available Drug Product
Although Rx3 compounded a hydroxyprogesterone caproate solution that is similar to the Makena product, Rx3's product had a different base oil. Furthermore, consistent with 21 U.S.C. § 353a(b)(D), Rx3 did "not compound regularly or in inordinate amounts" of the hydroxyprogesterone caproate solution product. As noted previously, Rx3 only compounded hydroxyprogesterone caproate solution based on patient-specific prescriptions, all of which identified allergy risks that necessitated the use of a (b)(4) base, effective January 31, 2014, Rx3 is no longer compounding any quantities ofhydroxyprogesterone caproate solution.
Rx3 is engaged in on-going quality and safety assurance activities. Rx3 has in place a Continual Quality Improvement team that meets (b)(4) to evaluate trends and concerns. Rx3 is committed to maintaining the highest standards of practice and works diligently to comply with the compounding industry standards. Since February 2014, has initiated several quality improvement initiatives. Rx3 has implemented the software (b)(4) to allow for effective monitoring and enhanced compliance with USP <797> requirements. Management receives immediate notification of overdue tasks, exceptions and out of range measurements. This software also provides educational tools and references to staff members and trending analysis features for management to evaluate. Additionally, sterile full body suits are now required in the cleanroom. Also, the workflow through the cleanroom has been re-evaluated and labeled to reflect a linear process to the facility design, creating singular entrance and exit points. Rx3 will continue to evaluate our operating procedures to ensure high quality standards are maintained.
Furthermore, as described above, Rx3 made several additional operational and policy changes following the February 2014 FDA inspection. Since February, Rx3 has had two third party evaluations of our facilities, one of which was PCAB and the other a private contractor with a USP<797> sterile compounding focus. Rx3 is committed to evolving with compounding pharmacy practice and has sought out expertise to ensure the quality and practice of Rx3 compounding pharmacy as a traditional compounding pharmacy. Furthermore, as part of its PCAB accreditation, Rx3 has submitted numerous policies, procedures, and other documentation, and has been subject to a detailed inspection by PCAB. It is because of these and other efforts that Rx3 continues to illustrate a commitment to high standards of pharmacy practice. Finally, to further reduce risks and to achieve heighted compliance with federal guidelines, Rx3 now compounds for human use only in response to patient-specific prescriptions.
Thank you very much for considering these comments. I have responded to the best of my ability to the Warning Letter. I have always had and will continue to put my patient's health, welfare, and safety first. I am dedicated to the profession of pharmacy, committed to ensuring the safety and quality of Rx3's compounding services, and always open to the opportunity to improve my understanding of and compliance with applicable regulations and law.
Please do not hesitate to contact me for additional clarification at 804-717-5000. I can also be reached by electronic mail at email@example.com. I would very much appreciate the opportunity to resolve any lingering concerns the FDA may have regarding issues raised in the Warning Letter.
Christopher K. Currin, R.Ph.
Managing Partner and Director of Pharmacy