- Bond Pharmacy, Inc. dba Advanced Infusion Solutions
DUANE MORRIS LLP
190 SOUTH LASALLE STREET, SUITE 3700
CHICAGO, IL 60603-3433
PHONE: +1 312 499 6700
FAX:+1 312 499 6701
FIRM and AFFILIATE OFFICES
RACHAEL G. PONTIKES
DIRECT DIAL: +1 312 499 6757
PERSONAL FAX: +1 312 277 6903
Mark Rivero, Compliance Officer
U.S. Food & Drug Administration
New Orleans District
404 BNA Drive
Building 200, Suite 500
Nashville, TN 37217-2597
Re: Bond Pharmacy, Inc. d/b/a Advanced Infusion Solutions' Response to Warning Letter --Ref#: 2017-NOL-06
Dear Mr. Rivero:
We represent Bond Pharmacy, Inc. d/b/a Advanced Infusion Solutions ("AIS"), and hereby submit to the U.S. Food & Drug Administration ("FDA") this letter in response to FDA's Warning Letter dated March 1, 2017 (the "Warning Letter") to AIS. Please note that AIS received the Warning Letter on March 2, 2017.
AIS wishes to emphasize that it takes the issues identified in the Warning Letter very seriously. AIS is a compounding pharmacy acting in full compliance with all relevant state laws governing the practice of pharmacy. There is no dispute that AIS complies with Section 503A of the Federal Food, Drug, and Cosmetic Act ("FDCA"), as it compounds exclusively pursuant to a patient specific prescription. As such, AIS is governed by state law and it is the state boards of pharmacy-not FDA-that act as AIS's primary regulator. Moreover, as a pharmacy compliant with Section 503A, AIS is exempt from certain requirements under the FDCA reserved for drug manufacturer, like FDA's current good manufacturing practices ("cGMP").
Therefore, contrary to FDA's suggestion, AIS is not "producing drugs that violate the [FDCA]." As the Warning Letter does not identity any federal law of which AIS is in violation, AIS requests that this statement be retracted.
Furthermore, according to FDA's published policy on warning letters, "the agency position is that Warning Letters are issued only for violations of regulatory significance."1 The issuance of the Warning Letter to AIS is entirely inappropriate for the following reasons: (1) the Warning Letter applies regulatory standards that do not apply to AIS as a compounding pharmacy in full compliance with Section 503A; (2) even if these standards did apply to AIS (they do not), AIS addressed all of FDA's concerns as demonstrated in its November 16, 2015 response to FDA's Form 483 and as further demonstrated below; and (3) simply put, none of the observations set forth in the Warning Letter rise to the level of "regulatory significance" required under FDA's stated policy. AIS respectfully requests, therefore, that FDA withdraw its Warning Letter.
I. AIS Is a Section 503A-Compliant Pharmacy Subject to State Law-FDA Should Not Apply cGMP Or Any Other Standard To AIS.
AIS is a pharmacy that provides unique specialized medication for identified individual patients pursuant to a valid prescription issued by a licensed prescriber. Thus, pursuant to Section 503A, AIS is primarily regulated by state law which incorporates United States Pharmacopeia ("USP") Chapter 797 governing sterile preparations. As it is, the states interpret and enforce their own laws, and FDA's Form 483 observations, as well as its Warning Letter, do not (nor could they) identify any state law, state regulation, or USP <797> standard of which AIS is in violation. Under Section 503A, AIS is also exempt from, among other things, cGMP requirements. Nevertheless, FDA appears to apply cGMP standards or something other than the standards set out in USP <797> to AIS. For example, FDA continues to claim that AIS is required to use sterile wipes, although USP <797> does not require the use of sterile wipes in the cleanroom suite. Likewise, FDA appears to claim that AIS is required to use sterile gowning and to avoid exposed facial skin in the ISO 5 work area, although USP <797> does not require such practices. FDA appears to be suggesting that AIS is compounding "under insanitary conditions" because it is not compounding in conformity with cGMP. Yet, FDA's application of cGMP or any other standard to AIS is utterly improper.
Furthermore, the Warning Letter appears to improperly hold AIS to standards outside applicable state and federal law to determine if its compounds are prepared under insanitary conditions and are therefore adulterated under Section 501(a)(2)(A) of the FDCA. For example, the Warning Letter cites that FDA observed "the storage of [stock] solutions in an unclassified area for further use after the container closure system had been punctured multiple times, and therefore compromised, throughout the assigned expiry period." The Warning letter seems to rely on this observation as an example of FDA's suggestion that AIS may be compounding drugs under insanitary conditions. However, the stock solution practices that FDA observed cannot form the basis for any suggestion that AIS may be compounding under insanitary conditions, as these practices are compliant with the general principles outlined in USP <797>. FDA cites no applicable state or federal law or regulation under which FDA's observation of AIS's treatment of stock solutions is improper.
II. AIS Has Addressed All Issues Raised By FDA.
Notwithstanding AIS's objections to the Warning Letter, it should be noted that following receipt of FDA's Form 483 more than seventeen months ago, AIS undertook a comprehensive review and evaluation of FDA's observations, as well as AIS's compounding operations, and took a variety of actions. AIS communicated this information to FDA in its November 16, 2015 response to the Form 483. Please note that AIS's cooperation with FDA should not be interpreted as a waiver of any of the above objections.
Specifically, in response to the Form 483, AIS addressed the following:
• Operator Transition from ISO 7 to ISO 5 Area: FDA notes that its investigators observed "an operator not disinfecting or changing their gloves prior to introducing them into the ISO 5 area from the ISO 7 area and after touching non-sterile material." AIS responded to this observation at page 11 of its response to FDA's Form 483, wherein it stated that AIS reviewed its procedures and determined that its procedures were in full compliance with USP <797> standards for pharmacy staff working in controlled environments. See Exhibit 1, Attachment A at 11. Despite this determination, AIS conducted re-education training on USP <797> standards for all of its staff and translated FDA's observations into key performance indicators ("KPI") to ensure that the conduct of all cleanroom personnel remained in strict compliance with USP <797> standards. Id.
• Garbing Procedure: FDA notes that its investigators observed "multiple operators with non-sterile gowning and exposed facial skin were observed leaning into the ISO 5 work area." With respect to non-sterile gowning and exposed facial skin, FDA does not list any such observation in its Form 483; therefore, this is the first instance where AIS has been made aware of such an observation. Please note that USP <797> does not prohibit the use of non-sterile gowning and exposed facial skin in the ISO 5 work environment. AIS has reviewed its policies and procedures, and can verify that AIS only uses sterile gowning (to be clear, AIS continues to and was using only sterile gowning at the time of the inspection) and that it monitors and immediately remediates any deviation from sterile compounding best practices and USP <797> standards related to exposed facial skin.
With respect to FDA's observation that "operators ... were observed leaning into the ISO 5 work area," AIS responded to this observation at page 12 of its response to FDA's Form 483, stating that AIS reviewed its policies addressing the conduct of personnel in controlled environments (PHA-412) and determined that it was in compliance with USP <797> standards. See Exhibit 1, Attachment A at 12. Nevertheless, AIS conducted re-education training on USP <797> standards and sterile compounding best practices for all of its staff, and translated FDA's observations to a KPI in order to ensure that the conduct of all cleanroom personnel remained in strict compliance with USP <797>.
• Stock Solutions: FDA notes that its investigators observed that AIS "exposed stock solutions, intended to be sterile, to lower than ISO 5 quality air." Specifically, FDA observed "the storage of stock solutions in an unclassified area for further use after the container closure system has been punctured several times, and therefore compromised, throughout the expiry period."
In response to FDA's Form 483 observations, AIS reevaluated its procedures related to stock solutions, and elected to treat all stock solution containers as a single dose vial in accordance with USP <797> standards for single dose vials. To that end, AIS has modified its procedures in the following three ways:
(1) All stock solutions are packaged in multiple containers, with each container treated as a single-dose vial. Each stock solution container is accessed via a needle-free access device. See Exhibit 2, identifying the needle-free access device currently used by AIS. Each container is punctured only once, and the needle-free connector maintains the integrity of the container and acts as a barrier to bacterial ingress;
(2) After the initial access of the stock solution container via a needle-free connector, the stock solution is maintained exclusively in an ISO 5 environment and is disposed of after a period of no more than six hours; and
(3) Due to the additional steps identified above, and to ensure that each step is strictly followed, AIS has dedicated a pharmacist specifically to manage the storage, use, and integrity of stock solutions.
The above procedures ensure that no stock solutions are punctured and used in compounding in unclassified areas.
• Wipes: FDA notes that its investigators "collected a sample of unused wipes" and that testing results "identified microbial contamination, including spore-forming bacteria." As AIS stated in its email to you dated December 10, 2015, USP <797> does not require the use of sterile wipes to handle non-sterile API. Nevertheless, in response to FDA's Form 483, and as a best practice, AIS now only uses sterile wipes in the ISO 5 environment.
In closing, AIS would like to emphasize that it takes compliance with all applicable state and federal laws governing its pharmacy practice and the Warning Letter very seriously. AIS shares FDA's goal of ensuring that patients in need of custom compounded medications receive the highest quality preparations. The Warning Letter does not identify any federal law of which AIS is in violation and appears to apply regulatory standards that do not apply to AIS as a compounding pharmacy in full compliance with Section 503A. Since FDA's inspection and its Form 483 issued in October 2015, AIS has identified, addressed, and corrected all of FDA's concerns raised in its Form 483 and Warning Letter.
As none ofthe observations set forth in the Warning Letter rise to the level of"regulatory significance" required under FDA's stated policy, we respectfully request that the Warning Letter be withdrawn and a closeout letter be issued without delay.
Very truly yours,
Rachael G. Pontikes
1 4-1-1- Warning Letter Procedures, FDA Regulatory Procedures Manual, https://www.fda.gov/downloads/ICECI/ComplianceManuals/RegulatoryProceduresManual/UCM074330.pdf.
March 23, 2017
VIA EMAIL AND EXPRESS MAIL