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Custom RX LLC dba Custom Rx Pharmacy and Wellness Concepts

Reference #:

Custom RX LLC dba Custom Rx Pharmacy and Wellness Concepts

3510 N Ridge Road, Suite 900
Wichita, KS 67205-1224
United States


United States

November 7, 2018

pharmacy & wellness concepts

VIA EMAIL ONLY (ORAPharm3 _ Responses@fda.hhs.gov)

Brian D. Garthwaite, PhD.
U.S. Food and Drug Administration
Division of Pharmaceutical Quality Operations III

Re: Inspection of Custom Rx, LLC
Case# 559540
FEI#: 3013444075
Dates of inspection: 7/31/17-8/15/17
Inspector: Rita Kabaso

Dr. Garthwaite:

We are writing to respond to the Warning Letter issued by the U.S. Food and Drug Administration ("FDA") on October 18, 2018 pertaining to the inspection of the pharmacy located at 3510 Ridge Road, Suite 900, Wichita, KS 67205, conducted between July 31, 2017 and August 15, 2017. At the conclusion of the inspection, FDA issued a Form FDA 483 ("483") listing three (3) Observations. On August 20, 2017, the Pharmacy provided its response to the 483. On October 18, 2018, more than one year later, this Warning Letter followed.

We request that this response be included with the Warning Letter anytime FDA provides a copy of the Warning Letter to anyone outside FDA, otherwise publishes the Warning Letter, or when/if the Warning Letter is posted online. The Pharmacy also requested that its response to the 483 be posted online, and it does not appear that this was done. We again request that the Pharmacy's response to the 483 be included anytime FDA provides a copy of the 483 to anyone outside FDA, publishes the 483, or posts it online.

Before addressing FDA's concerns articulated in the Warning Letter, Custom Rx would like to reiterate that it engages in patient-specific pharmacy compounding. As a compounding pharmacy, Custom Rx is subject to the jurisdiction of the Kansas Board of Pharmacy and complies with the regulations of the Kansas Board of Pharmacy. Custom Rx also complies with the stringent, nationally-accepted quality control, quality assurance, and quality improvement standards defined in USP <795> and USP <797>. Compliance with the USP standards is required by the Kansas Board of Pharmacy.

Custom Rx understands that FDA maintains authority to regulate the manufacture of drugs. However, Custom Rx does not manufacture drugs. Rather, Custom Rx is a compounding pharmacy as contemplated by Section 503A of the Food, Drug & Cosmetics Act ("FDCA"). Thus, Custom Rx is required to comply with regulations that are applicable to compounding pharmacies, not with those applicable to drug manufacturers, which include current good manufacturing. practices ("cGMPs"). Custom Rx is subject to and operates in accordance with the requirements of the Kansas Board of Pharmacy and USP <795> and USP <797>. To the extent that the alleged violations or concerns identified in this Warning Letter are based on cGMP requirements, the Pharmacy disagrees that these constitute violations of the FDCA.

    I. Compliance with Requirements of Section 503A

FDA contends that certain of the Pharmacy's drug products failed to meet the conditions of Section 503A, and therefore, are not eligible for the exemptions from Sections 501, 502, and 505 of the FDCA. Specifically, FDA contends that 1) the Pharmacy did not receive valid prescriptions for individually-identified patients for a portion of the drug products it produced; and 2) that the Pharmacy used dinitrochlorobenzene and magnesium glycinate in certain of its compounded drug products.

A. Receipt of valid prescriptions for individually-identified patients

FDA's assertion that the Pharmacy did not receive valid prescriptions for individually-identified patients for a portion of the drug products it produced is not correct. At all times, the Pharmacy has only compounded drugs pursuant to valid, patient-specific prescriptions. The Pharmacy does not know what drug products the FDA investigator noted as being produced without receipt of valid patient-specific prescriptions, and these drugs are not identified in the Warning Letter. Nor does the Warning Letter explain FDA's specific concerns-i.e., whether the investigator observed a deficiency in a prescription(s), or whether the investigator believed the Pharmacy is producing drugs for dispensing by practitioners in their offices ("office use"), or some other concern. The Pharmacy does not currently compound any drugs for office use and was not engaged in compounding drugs for office use at or prior to the time of the inspection.1

Therefore, we disagree with FD A's contention that the Pharmacy has produced drug products that are adulterated because they were not produced in compliance with FDA's current good manufacturing practices ("cGMPs"). The Warning Letter contends that the FDA investigator "observed significant CGMP violations at the facility." CGMP standards are applicable to facilities that manufacture drug products and to FDA-registered outsourcing facilities. The Pharmacy is not a drug manufacturer or an outsourcing facility and is required to comply with the standards set forth in USP <797> and <795>. Pretermitting whether it is appropriate to apply cGMP requirements to a traditional compounding pharmacy like Custom Rx that is regulated by and which operates in accordance with State law, the fact remains that the Pharmacy only compounds drug products pursuant to valid prescriptions for individually-identified patients. Therefore, we disagree that with this alleged violation of the FDCA. Likewise, we disagree with the contention that the Pharmacy has produced drug products that are misbranded or that the Pharmacy was required to have new drug applications on file. We hope that the above explanation is sufficient to assure FDA that all of the Pharmacy's drug products are compounded pursuant to valid prescriptions for individually-identified patients and thus resolve the alleged violations of the FDCA that are based on this assumption. If not, we request that FDA please clarify its concerns and/or provide additional information.

B. Use of dinitrochlorobenzene and magnesium glycinate

The Pharmacy informed the FDA investigator that it would cease compounding drugs using dinitrochlorobenzene and magnesium glycinate. The Pharmacy has not used either of these substances in compounding since the inspection and does not intend to do so unless and until they are added to the list of bulk substances approved for use in compounding. The Pharmacy notes that FDA has not articulated any patient-safety concerns with respect to the Pharmacy's drug products that were compounded using these substances.

    II. Allegedly Adulterated Drug Products and Corrective Actions

A. Observations identified in Form FDA 483

FDA now alleges that, based on the inspection of the Pharmacy, certain of the Pharmacy's drug products violate the FDCA. FDA contends that the investigator noted that drug products intended to be sterile were prepared, packed, or held under insanitary conditions, causing the drug products to become adulterated under section 501(a)(2)(A) of the FDCA. The Warning Letter bases this contention on the following practices observed at the Pharmacy relating to the use of Dawn detergent, media fill procedures, performance of cleaning after smoke studies, and critique of compounding personnel's aseptic technique. We appreciate that FDA agrees that the corrective actions described in the Pharmacy's response to the 483 are satisfactory. We have addressed below the follow-up questions pertaining to these Observations that FDA raised in the Warning Letter, and hope that this information is sufficient to resolve any remaining concerns on FDA's part. As discussed below, we do not believe that any of these practices violate the FDCA or constitute insanitary conditions.

1. Your response stated that a different cleaning agent is being used to clean all glassware used in the ISO classified areas. However, your response did not specify the name of the new cleaning agent or whether other changes were made on how glassware used in sterile production is cleaned.

In its response to the 483, the Pharmacy explained, "all sterile products released by Custom Rx for dispensing have passed appropriate sterility and endotoxin testing. USP 797, which sets the standards for compounding operations, does not specifically address criteria for glassware detergents. In fact, cleaning supplier validation falls squarely under cGMP, which does not apply to Custom Rx.

However, to increase the effectiveness of our cleaner and decrease potential surface residue, a different cleaning agent was ordered and is now in use to clean all glassware that will be used in ISO controlled areas within the pharmacy. The manufacturer of the new cleaning agent can provide sample trace analysis, certificates of analysis, lot traceability, consistent manufacturing, ingredient toxicity data, and ingredient reactivity information.

Custom Rx will continue to rinse all glassware used for sterile compounding with sterile water for irrigation and to use dry heat to depyrogenate all glassware used for critical compounding. "

Following the inspection, the Pharmacy implemented the use of Aquet, manufactured by SP Scienceware, to clean glassware used in sterile compounding operations. The Certificate of Analysis and SDS for this detergent are attached hereto. The Pharmacy did not make any other changes to its procedure for cleaning glassware used in sterile compounding operations at that time. It is the Pharmacy's understanding that FDA did not identify any concerns other than the use of Dawn detergent in the Pharmacy's processes for cleaning glassware.

In addition, we disagree with FDA's conclusion that the Pharmacy's use of Dawn in its cleaning regimen constitutes or resulted in an insanitary condition. The Pharmacy acknowledges that FDA need not show that drugs are actually contaminated in order to conclude that they are adulterated. However, the fact that Dawn cleaning agent was used as a part of the Pharmacy's cleaning regimen does not require the conclusion any glassware was contaminated or that any drugs were contaminated. As mentioned, this practice complies with state law and USP <797>. There is no evidence that any glassware was contaminated, no evidence that any drug products were actually contaminated, and there has never been any report of patient harm.

2. Your response indicated that changes were made on how your cleanroom area is cleaned after 3rd party entry including how this cleaning is documented. However, your response did not provide sufficient information regarding these changes.

In our response to the 483, we explained, "The smoke studies performed (via a 3rd party certification company as part of our semi-annual certification) utilized a glycol base. Glycol-based smoke studies have the potential to leave a residue on surfaces, and a full cleaning was not properly documented following this procedure. Policies have been updated and a full cleaning is to be performed and documented following any 3rd party entry to our cleanroom prior to any compounding activities. Retraining on this policy has occurred for all sterile personnel involve. Documentation of cleaning is to include areas cleaned, time of day cleaning was performed, and appropriate cleaning agent used."

The concern articulated by FDA in the 483 was that cleaning was not performed following completion of smoke studies in ISO areas. The Pharmacy has committed to ensuring that cleaning is performed and documented following any third party entry into the cleanroom before compounding resumes. Cleaning will be performed as provided for by the applicable SOPs setting out cleaning procedures, which are already in place. The Pharmacy is unsure what other information FDA needs to evaluate the adequacy of its response. The Pharmacy is willing to answer any specific questions that FDA has about its response or cleaning procedures should FDA wish to clarify or elaborate on its concerns.

3. Your response described the changes made to your media fill procedure to ensure it is representative of your aseptic drug operations. However, a copy of the revised media fill procedure was not included with this response. Further, your response did not indicate the date by which this new media fill procedure would be implemented.

In its response to the 483, the Pharmacy explained that it had updated its SOP to reflect a more representative process. The Pharmacy also explained that a new incubator was ordered to accommodate the larger media fills, and that the media fill procedure would be performed for all appropriate personnel once the incubator was in place and validated. At the time the Pharmacy responded to the 483, an exact date by which this process would be completed was not known. The incubator was ordered on September 5, 2017, and the revised media fill SOP was implemented on October 11, 2017. A copy of that procedure is attached hereto. Employee Zach Meinhardt successfully completed the large batch medial fill procedure on November 14, 2017 and again on June 26, 2018.

The Pharmacy acknowledges that media fills are a critical component of validating proficiency of personnel engaging in aseptic compounding operations. However, we disagree with FDA's conclusion that this observation constitutes an insanitary condition. It appears that FDA is contending that any purported deficiency in training or skill validation constitutes an "insanitary condition." We feel this is an overly broad interpretation of the term "insanitary condition." Such an interpretation leads to the conclusion that any deficiency in training or skill validation constitutes a violation of the FDCA, irrespective of whether there is any evidence that the deficiency was likely to have or actually resulted in actual contamination of critical compounding areas, equipment, or materials, or that drug products were actually contaminated. The fact that the most recently performed media fill procedure did not simulate the largest batch routinely compounded does not automatically mean that compounding personnel are not competent to perform those aseptic operations; it does not mean that compounding personnel failed to adequately perform aseptic operations; and it does not mean that any drugs were exposed to contamination or that they became contaminated.

Lastly, with respect the investigator's Observation pertaining to compounding personnel's aseptic technique, the Pharmacy reiterates its original response to the 483, including that observation of compounding processes exceeds the scope of FDA's authority under the FDCA.

B. New concerns identified in Warning Letter

In the Warning Letter, FDA has now identified five (5) additional concerns based on its review of the documentation it collected from the Pharmacy during the inspection. As an initial matter, the Pharmacy is concerned that FDA is now raising issues that were not cited in the 483. These issues were not raised during the inspection, and the FDA investigator did not verbally cite these issues as potential violations of USP standards, Federal or state law, or as presenting any patient safety concerns during the duration of the inspection. The inspection began on July 31, 2017 and finally closed on August 15, 2017. The investigator reviewed hundreds of pages of the Pharmacy's records. At the conclusion of the inspection on August 15, 2017, FDA issued a 483 containing three Observations pertaining to the use of Dawn detergent, media fill procedures, performance of cleaning after smoke studies, and critique of compounding personnel's aseptic technique. The Pharmacy responded to the 483 on August 20, 201 7. Now, more than one year after the Pharmacy's response to the 483, FDA has raised additional concerns with the Pharmacy's compounding practices not raised in the 483.

It is the Pharmacy's understanding that raising concerns with compliance status or patient safety should occur contemporaneously with the inspection. According to FDA's internal policies for inspection procedure, FDA investigators are supposed to discuss problems at the close of each day of the inspection, if at all possible. (See 2017 Investigations Operations Manual, Chapter 5-Establishment Inspections.) At the end of the inspection, all issues cited are listed on the 483. Section of the Manual, which pertains to written observations, directs the investigators to, "[u]pon completing the inspection and before leaving the premises, provide the highest management official available your inspectional findings on an FDA 483 - Inspectional Observations. See Section 704(b) of the FD&C Act [21 U.S.C. 374 (b)] and IOM 5.2.3 and 5.2.7." Section also states that 483s should be issued at the conclusion of the inspection and prior to leaving the premises. Raising these issues earlier (ideally, at the inspection) would have allowed the Pharmacy an opportunity to explain its practices, to offer information that might have assuaged FDA's concerns, or to discuss modifications to its practices to ameliorate FDA's concerns about patient risk.

Custom Rx further notes that the scope of FDA's inspection of the Pharmacy exceeded the FDA's authority under Section 704(a) of the FDCA. Section 704(a) expressly provides that the FDA's inspection authority relating to "records, files, papers, processes, controls, and facilities" does not apply to pharmacies like Custom Rx that maintain establishments in conformity with applicable local laws regulating the practice of pharmacy and which are regularly engaged in dispensing prescription drugs or devices upon prescriptions of licensed practitioners as a part of the regular course of their business. The collection and review of documentation upon which the following concerns are based is beyond the scope of FDA's inspection authority.

In an effort to fully cooperate with FDA and alleviate any remaining concerns about the Pharmacy's compounding operations, the Pharmacy responds to FDA's new inquires as follows.

1. Your firm applies Peridox RTU to surfaces within your cleanroom area for two (2) minutes. Based on publically available efficacy data from the manufacturer, this contact time is not sufficient for the use of Peridox RTU as a sporicidal agent.

The Pharmacy is unsure why FDA believes that the Pharmacy's practice at the time of the inspection was to apply Peridox RTU for two (2) minutes. The Pharmacy's SOPs do not state that Peridox R TU should be applied for two minutes. The Pharmacy has always used the product in accordance with the manufacturer's instructions. The Pharmacy has updated its SOPs to clarify that Peridox RTU should be applied for three (3) minutes to maintain sporicidal activity.

2. The tryptic soy agar (TSA) plates used for surface sampling do not contain neutralizers to inactivate residual disinfectants. Further, the log used to document environmental monitoring results lists one (1) result even though surface sample plates are incubated at two (2) different temperatures. Therefore, your environmental monitoring program may not provide adequate information on the quality of your cleanroom areas.

The TSA plates do in fact contain neutralizers to inactivate residual disinfectants. Specifically, they contain Lechithin and Tween® 80. According to the manufacturer, Hardy Diagnostics, these substances neutralize germicidal or disinfectant residues.2 The Pharmacy has been using these plate since December of 2015; an invoice reflecting purchase of these plates is attached by way of example.

Regarding FDA's concern about the documentation of environmental monitoring results, the documentation log reflects whether the plate shows growth levels outside accepted parameters after incubation at either temperature. That is, for a passing result to be documented, the plate must pass at both temperatures. If it passes at only one temperature, then a failing result will be documented. The passing or failing result is not documented until the plate is incubated at both temperatures. We hope this resolves FDA's concern.

3. Your firm uses several outside laboratories to conduct potency testing on some of the sterile drug products produced. However, one of these laboratories uses non-qualified test methods to determine the strength of sterile drug products. The use of non-qualified potency test methods may not reliably provide valid results, which puts patients at risk.

The Pharmacy uses two laboratories to conduct potency testing: Eagle Analytical and ARL Bio Pharma. Both of these laboratories are FDA-registered facilities. FDA does not state in the Warning Letter which specific laboratory uses non-qualified test methods, nor does FDA state which test methods it contends are non-qualified. Based on the limited information provided in the Warning Letter, we cannot evaluate the factual basis for FDA's concern, perform a meaningful investigation, or implement corrective action. The Pharmacy is confident that the laboratories with which it contracts perform testing in conformance with the requirements of USP <797>, however, should FDA wish to provide additional information or clarification about its concern, then the Pharmacy can attempt to provide a response.

4. You have not conducted an endotoxin challenge study to demonstrate that your dry heat oven is capable of achieving the depyrogenation parameter of 250° C for 30 minutes.

An endotoxin challenge study was initiated on August 16, 2017. Documentation of the study showing results within accepted parameters is attached hereto.

5. We also noticed that your firm uses different temperature units to describe sterilization and depyrogenation temperature parameters. For example, the media fill temperature parameter is listed in degrees Fahrenheit (250° F) while the temperature parameter for stoppers and terminally sterilized drug products is listed in degrees Celsius (273° C and 160° C [testosterone lot 06132017@9 respectively). In addition, the depyrogenation temperature is also listed in degrees Celsius (250° C). You may want to consider using the same temperature unit to describe the temperature parameters for your sterilization and depyrogenation operations to ensure that the temperature used is lethal to microorganisms and does not damaged the materials being processed.

We appreciate FDA's suggestion that the Pharmacy use the same temperature unit, whether Celsius or Fahrenheit, in its SOPs for sterilization and depyrogenation processes. We are confident that our sterile compounding personnel are thoroughly trained on and deeply familiar with both of these processes and can and do carry them out safely and effectively. To date, we are not aware of any instances of confusion or error occurring because certain protocols use Celsius for temperature parameters and others use Fahrenheit. That said, the Pharmacy is always working to ensure the highest quality in its compounding operations and to promote patient safety, which is our top priority, so we will take this suggestion under consideration.

The Pharmacy reviewed its records carefully to identify the document(s) showing different temperature units as described by FDA-specifically, where "the media fill temperature parameter listed in degrees Fahrenheit (250° F)". We believe that the document to which FDA refers FDA is a batch-data confirmation page that is printed directly from the autoclave. We have changed the autoclave's settings to use Celsius.

We hope that these responses resolve any remaining concerns the FDA may have regarding sterile compounding and patient safety at Custom Rx.


Jan R. Gerber, Owner
President/CEO of Custom Rx, LLC


1 The Pharmacy also notes that office use compounding is legal in the State of Kansas and reiterates that the Pharmacy is a state-licensed pharmacy that is subject to the rules and regulations of the Kansas Board of Pharmacy. However, the Pharmacy acknowledges that it is FDA's position that office use compounding by state-licensed pharmacies is not permissible even where permitted by state law.

2 According to the manufacturer's website, "Hardy Diagnostics Tryptic Soy Agar (TSA) with Lecithin and Tween® 80 contains digests of soybean meal and casein that provide amino acids and other nitrogenous compounds, making it a nutritious medium for many microorganisms. Sodium chloride is added to maintain cellular osmotic equilibrium. Lecithin and Tween® 80 are added to the formulation to neutralize germicidal or disinfectant residues. Neutralization of these residues reduces their inhibitory effect which ultimately results in lowering of microbial count. Quaternary ammonia compounds are neutralized by Lecithin, while phenolic disinfectants and hexachlorophene are neutralized by Tween® 80. Together, Lecithin and Tween® 80 neutralize ethanol." More information can be found at https://catalog.hardydiagnostics.com/cp_prod/Content/hugo/TrypticSoyAgarLecTween.htm

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