FDA Issues Three Guidances on Pharmacy Compounding

[Submitted electronically to www.regulations.gov]
Division of Dockets Management (HFA-305)
U.S. Food and Drug Administration
5630 Fishers Lane, rm. 1061
Rockville, MD 20852

Re: Draft Compounding Guidances – Prescription Requirement Under Section 503A of the Federal Food, Drug, and Cosmetic Act; Hospital and Health System Compounding Under the Federal Food, Drug, and Cosmetic Act; and Facility Definition Under Section 503B of the Federal Food, Drug, and Cosmetic Act.

ASHP is pleased to submit comments to the U.S. Food and Drug Administration (FDA) regarding the three draft guidances – Prescription Requirement Under Section 503A of the Federal Food, Drug, and Cosmetic Act (the “Prescription Requirement Guidance”), Hospital and Health System Compounding Under the Federal Food, Drug, and Cosmetic Act (the “Hospital and Health System Guidance”), and Facility Definition Under Section 503B of the Federal Food, Drug, and Cosmetic Act (“Facility Definition Guidance”) – published April 15, 2016.

ASHP represents pharmacists who serve as patient care providers in acute and ambulatory settings. The organization’s more than 43,000 members include pharmacists, student pharmacists, and pharmacy technicians. For over 70 years, ASHP has been at the forefront of efforts to improve medication use and enhance patient safety.

ASHP thanks FDA for its efforts to develop a compounding regulatory framework that balances safety with patient and clinician access to essential compounded medications, and also recognizes the different distribution models in hospital and health system pharmacies. We share FDA’s commitment to safe compounded medications. ASHP advocated for passage of the Drug Quality and Security Act (DQSA), and we remain committed to ensuring that it is implemented in a manner that protects its goals.

FDA is an important partner in ensuring that pharmacists and the patients they serve can access safe and high-quality compounded medications. Thus, we were pleased that the draft guidances acknowledge the essential role of compounded medications in patient care. In particular, ASHP commends FDA for including guidance that seeks to address the unique care delivery models within hospitals and health systems, which differ significantly from traditional community pharmacy models, while maintaining appropriate patient safety. To help FDA structure the compounding regulatory framework to work with existing care delivery and quality systems, ASHP offers the following comments on the draft guidances.

1. Hospital and Health System Guidance: Hospitals’ and Health Systems’ Unique Delivery Systems Necessitate Tailored Guidance.

As noted, we support FDA’s efforts to structure the compounding regulatory framework to reduce barriers to care in inpatient settings or at alternate sites of acute care (e.g., outpatient clinics, ambulatory surgical centers, etc.). Tailoring compounding regulations to particular clinical settings decreases the chances of creating unintended access limitations, while still allowing FDA and clinicians to protect patient health and safety.

1. Compounding Definition Needs Clarification.

As a preliminary matter, ASHP suggests that FDA further clarify its definition of compounding. Although ASHP agrees with FDA’s use of a prescription for an identified individual patient as a differentiator between pharmacy compounding and manufacturing, FDA’s working definition of compounding is different than that used in hospitals and health systems. A consistent understanding of the definition of compounding would help FDA, hospitals and health systems, pharmacists, and other stakeholders to develop and implement a workable compounding framework.

In practice, the majority of what hospital pharmacists consider compounding is extemporaneously reconstituting and diluting injectable medications for administration to individual patients according to manufacturers’ instructions in approved labeling (a list of medications commonly compounded in hospitals/health systems is attached hereto as Addendum I). Such activities clearly fall within USP’s definition of a compounded sterile product,¹ but it is unclear whether they fall within FDA’s definition of compounding. If FDA’s intention is to exempt the preparation of a drug for immediate administration from the definition of compounding, then we recommend adding a qualifier to the FDA definition as follows:

“Compounding does not include mixing, reconstituting, or similar acts that are performed in accordance with the directions contained in approved labeling provided by the product’s manufacturer and other manufacturer directions consistent with that labeling, provided the drug is not subsequently stored or otherwise held.”

Although this change may appear minor, a clear, universally understood definition of what compounding is (and is not) is fundamental to the pharmacist’s understanding of the requirements of 503A and FDA’s interpretive guidances. We advise the FDA to reconcile the disparate definitions with USP, either as recommended above or as determined by the Agency.

2. Hospital and Health System Pharmacies Are Distinguishable from Community Pharmacies.

ASHP believes that FDA’s recognition of the differences between hospitals and health system pharmacies and community pharmacies is a good first step in adapting its guidance to address current pharmacy practice. To further underscore the importance of crafting a system that recognizes and accommodates these differences, we highlight several other factors that necessitate separate regulations.

• Patient responsibility: Hospitals and health systems are accountable for patient care outcomes. Thus, for the purposes of both quality and outcomes tracking, it is beneficial for hospitals and health systems to maintain full control over all elements of patient care, including pharmacy access. In-house compounding of medications facilitates adverse event tracking as well as oversight of care quality. Further, it allows hospitals and health systems to arrange pharmacy operations to provide patients and clinicians with compounded medications when they are needed, without significant wait times.


• Safety and Quality Regulations: While all 503A compounding falls under the purview of the state Boards of Pharmacy, compounding in hospitals cannot be disassociated from, and is itself subject to, other quality and safety standards applicable to hospitals and health systems. These include, but are not limited to, Centers for Medicare & Medicaid Services (CMS) regulations for reimbursement, Joint Commission (TJC) standards, U.S. Pharmacopeia (USP) chapters <797> and <800>, quality metrics (e.g., for accountable care organizations, patient-centered medical homes, etc.), and state and local department of health regulations. Hospitals and health systems are strongly incentivized to ensure that all facets of a patient’s treatment, including medications, are as safe and effective as possible. Strong 503A compounding programs are essential to this effort.


• Limited Compounding: Hospital pharmacists seek to avoid compounding medications when an FDA-approved, commercially-available therapeutic alternative is available. Compounding consumes resources and time and introduces additional risk into the medication-use process. Further, hospitals and health systems are not incentivized to compound on a large-scale. Drugs are often bundled, and, thus, not reimbursed separately, reducing or eliminating any financial incentive associated with compounding. Thus, in the hospital and health system context, compounding volume has some built-in limitations that are not applicable in other settings.

3. Standards Used to Restrict Hospital and Health System Compounding Should Be Evidence-Based.

Although ASHP agrees that non patient-specific compounding must be subject to reasonable limitations, FDA’s proposed geographic limitation on non patient-specific compounding carries unintended negative consequences for patient and clinician access to compounded medications. Following the publication of the guidance documents, ASHP convened several meetings with its members. During those meetings, members voiced serious concerns that imposing a geographic distance requirement could push compounding out of the pharmacy and back to the bedside. In order to comply with FDA’s proposed Hospital and Health System Guidance, hospitals and health systems would need to reconfigure existing care delivery models – many which have been heavily vetted by state Boards of Pharmacy and all of which are designed to maximize patient health and safety. To avoid disruption of functional delivery systems, ASHP urges FDA to consider an alternative approach that would align with existing systems but still provide clear limits on non patient-specific compounding in hospitals and health systems. Specifically, we support retaining the requirement that hospitals and health systems distribute compounded medications only to healthcare facilities under common control for use within the four walls of those facilities, but removing and replacing the one-mile radius limitation with a time-based standard.

Regarding the common control element, ASHP encourages FDA to look to hospitals’ and health systems’ comments on the draft guidances to fully define “common control.” Because alternative settings of care and smaller more remote hospitals are most in need of assistance providing high-quality compounded medications, ASHP supports a compounding framework that allows hospitals and health systems to continue supplying related alternative sites of care (e.g., ambulatory care centers, surgical centers, etc.) with compounded medications. It is important to note that compounded medications distributed to alternative settings of care are obtained and administered only pursuant to a physician’s order.² In addition, many of the medications provided are sterile injectables prepared for administration according to approved product labeling. These would fall into the compounding definition grey area outlined in Section A(1) above. For these reasons, ASHP suggests that a system with a centralized compounding and order fulfillment facility distributing small quantities of compounded products among facilities under a common hospital or health system umbrella is relatively low-risk.

In place of the arbitrary one-mile geographic limitation, ASHP urges FDA to consider allowing hospitals and health systems to use the USP chapters <797> and <800> beyond-use date (BUD) timeframes for handling of non-hazardous and hazardous sterile compounding. USP <797> delineates the procedures and requirements for compounding sterile preparations. It focuses on ensuring that compounding pharmacies provide the conditions and institute practices to prevent harm to patients from microbial, chemical, or physical contamination; excessive bacterial endotoxins; variations in product strength; or poor-quality ingredients. Further, in order to meet <797> standards, all personnel involved in sterile compounding must undergo specific training and testing. Similarly, USP <800> describes the standards for the handling and administration of hazardous drugs with patient safety, worker safety, and environmental protection taken into consideration.

Further, instituting a <797> time-based standard would better align FDA’s requirements with other existing hospital and health system regulations. As evidenced by the CMS³ and TJC⁴  standards, the traditional community pharmacy dispensing model (i.e., where the patient presents a prescription for a compounded drug, and the pharmacist then compounds pursuant to that prescription while the patient waits) on which the guidance documents are substantially premised, does not fit hospital and health system practice. Acutely ill or injured patients should not have to wait for their compounded drugs. As proposed, the one-mile radius would result in wait times and access problems that are in direct contravention of CMS and TJC care and quality standards, making simultaneous compliance with both impossible. However, keying compounding limitations to USP <797> would solve the compliance problem and alleviate the wait time and access concerns associated with the one-mile radius.

Limiting non patient-specific compounding in hospitals and health systems based on USP <797> and <800> BUD standards makes sense from the risk and quality perspective. Using a BUD standard would address two of FDA’s primary concerns with non patient-specific compounding in hospitals and health systems. It would limit the amount of product that could be created, and it would ensure that that product is used in a timely fashion. As intended by DQSA, state Boards of Pharmacy would retain responsibility for oversight of hospital and health system compliance with <797> standards, freeing FDA to focus on the 503B program. This state Board oversight would be augmented and backstopped by TJC accreditation surveys and CMS reviews that concentrate heavily on USP <797> compliance.

FDA has suggested that, should the one-mile radius create difficulties, 503B outsourcing facilities (hereinafter, 503Bs or outsourcing facilities) can fulfill hospital and health system needs. ASHP considers 503Bs essential to a strong compounding framework, but we remain concerned that, at present, 503Bs do not have the capacity to meet all system needs. Specifically, the wait times and longer turn-around times that some of our members have encountered when purchasing from 503Bs suggests that they are already straining to meet demand. Outsourcing facilities typically make large batches of compounded drugs and are not equipped to provide tailor-made products to hospitals and health systems. While many of our members rely on 503Bs, they also recognize that these outsourcers are limited in what they can produce. As a result, hospitals and health systems compound products to meet their own unique patient needs and do so in quantities significantly below a 503B’s volume.

Due to the nature of certain medications (e.g., timing, risk level), hospitals and health systems may not be able to ensure medication access by purchasing from a 503B outsourcing facility. Instead, under the proposed framework, nurses and other non-physician, non-pharmacist personnel may be forced to compound on demand, relying on smaller biological safety cabinets or compounding facilities. Thus, rather than having an advanced centralized compounding operation staffed by the most experienced pharmacy personnel, nurses and physicians may be preparing compounded medications in less-sophisticated spaces. Particularly in settings that do not have around-the-clock pharmacy staffing, prohibiting access to compounding services from another pharmacy within the hospital or health system increases the potential for adverse events. In practice, the one-mile radius could actually compromise patient health and safety, increasing adverse events and negatively affecting patient outcomes. Conversely, our suggested <797> BUD standards fit within current delivery models and adequately control non patient-specific compounding volume while concurrently safeguarding patient access and limiting adverse operations impact.

2. Prescription Requirement Guidance: Documentation Requirements Raise Concerns.

Our comments on the Prescription Requirement Guidance focus solely on the FDA’s proposed documentation requirements for prescriptions and the 30-day supply limit on anticipatory compounding.

• 30-Day Supply Limit: If FDA replaces the one-mile radius with our proposed <797> time standard, we question the necessity of documenting the amount of anticipatory compounding done by a hospital or health system. Under the revised <797> standards⁵, BUDs are limited to a 28 days, except for frozen items, which are neither compounded nor used in hospitals, unless available as an FDA-approved product. Further, hospital and health system pharmacies typically make no more than a 24- to 72- hour supply of medications in advance to avoid waste. Given these factors, which deter mass production of large batches and reduce the likelihood that a hospital or health system will compound medications more than 28 days in advance, we question the necessity of applying the 30-day supply limit documentation requirements to hospitals and health systems. While we agree that the 30-day supply limit is not unreasonable, it seems superfluous in the hospital/health system context.


• Prescription Documentation: FDA proposes that when a prescription or medication order does not clearly state that a compounded medication is needed, the pharmacist should contact the physician to ask for a rationale for compounding. In practice, not only would this create delays in care, it would likely strain relationships between physicians and pharmacists. Further, this requirement seems to bleed into oversight of practice, raising concerns about the conflicting state Boards of Pharmacy and Medicine requirements. If FDA believes that prescriptions should carry a rationale for compounding, the responsibility for providing and documenting that rationale should rest with the prescriber.

3. Facility Definition Guidance: Flexibility Would Facilitate 503B Outsourcing Facility Registration.

As noted above, ASHP advocates for a strong compounding framework. We believe that a robust 503B outsourcing facility program is essential to realizing the DQSA’s goals. For many of our members, 503Bs are a vital link in their compounding supply chain. Others are either considering or have considered registering as outsourcing facilities. To facilitate growth of the 503B program, we encourage FDA to introduce greater flexibility into the registration process and to enhance information sharing and education around 503B operations.

• Facility Definition: FDA’s draft Facility Definition Guidance defines “facility” for the purposes of 503B to include “all activities, equipment, appurtenances, and materials part of such a facility if they are related to human drug compounding under the supervision of the facility’s management at the same street address, or in the same building, or in buildings located in close proximity to one another” [emphasis added].⁶  It is unclear whether FDA would consider buildings that are on a hospital campus to be the same geographic location or in “close proximity” to one another. While ASHP appreciates the importance of a uniform quality standard for 503B products, imposing such a sweeping definition may limit the number of hospitals and health systems that can, realistically, register as 503B s for several reasons. First, because hospitals and health systems have designed their facilities around care delivery, 503B requirements must be overlaid on existing systems. These systems may already contain state-of-the-art pharmacies and compounding facilities within close proximity to other buildings in which compounding is also taking place. Because 503Bs are unable to produce every compounded medication for a hospital or health system, such small-scale 503A compounding is necessary to meet urgent patient and clinician needs. If the facility definition is read to mean that anything produced on the same campus as a 503B facility would need to meet 503B standards, then this 503A compounding would be prohibited. If, as ASHP believes, FDA hopes to expand the 503B program, we suggest that the Agency reconsider its expansive definition of “facility.”


• 503B Information-Sharing: Discussions with our members also indicate that hospitals and health systems continue to have questions about interpreting 503B inspection reports. ASHP fully supports publication of 483 inspection findings, but the reports offer little context or insight into the level of risk associated with various findings. Further, although the 483s are posted, information regarding 503B responses is not made public nor are the reports ever cleared or reconciled. Information related to a 503B’s response to a 483, particularly quality improvements undertaken by the 503B, could ease any hospital or health system concerns associated with purchasing product from a 503B outsourcing facility.

ASHP appreciates the opportunity to provide FDA with feedback on the draft guidances. We look forwarding to continuing to work with FDA to develop a workable and effective compounding regulatory framework. Please contact me at [email protected] or (301)-664-8698 if you have any questions or wish to discuss our comments further.

Sincerely,

Jillanne M. Schulte, JD
Director, Federal Regulatory Affairs

¹USP, Chapter <797>: Pharmaceutical Compounding – Sterile Preparations, (It is important to note that while FDA states that compounding does not include products prepared according to package labeling, FDA-approved labeling (i.e., the product package insert) rarely describes environmental quality (e.g., ISO Class air designation, exposure durations to non-ISO classified air, personnel garbing and gloving, and other aseptic precautions by which sterile products are to be prepared for administration)).
²Critical access hospitals must have pharmaceutical services, which require review of a medication order before it can be dispensed. In ambulatory care settings, an on-site physician authorizes use of the compounded sterile preparations, making it easier to clarify any questions about a medication order.
³ See CMS, Revised Hospital Guidance for Pharmaceutical Services and Expanded Guidance Related to Compounding of Medication (Oct. 30, 2015), available at https://www.cms.gov/Medicare/Provider-Enrollment-and-Certification/SurveyCertificationGenInfo/Downloads/Survey-and-Cert-Letter-16-01.pdf (“Preparation of drugs or devices in anticipation of prescription drug orders based on routine, regularly observed prescribing patterns”; “Medications must be available for administration to patients when needed, including when the pharmacy is not open. Methods to accomplish this when the pharmacy is not open could include, but are not limited to, one or more of the following: automated dispensing units outside the pharmacy, night cabinets, contracted services after hours via telepharmacy contracting, on-call pharmacists, etc.”; [The medication distribution system may include] “use of a floor stock system (i.e.; storage of pharmaceutical and over-the-counter drugs on the patient care unit), as long as the drugs are secured and controlled”).
⁴ See Joint Commission, Hospital Accreditation Standards (2016), (“Hospital leaders, in conjunction with members of the medical staff and licensed independent practitioners, decide which emergency medications and their associated supplies will be readily accessible in patient care areas based on the population served”; “Emergency medications and their associated supplies are readily accessible in patient care areas. (See also PC.03.01.01, EP 8)”; “Whenever possible, emergency medications are available in unit-dose, age-specific, and ready-to-administer forms”).
⁵ We refer here to the draft revision of USP Chapter <797>, available at http://www.usp.org/sites/default/files/usp_pdf/EN/USPNF/usp-gc-797-proposed-revisions-sep-2015.pdf.
⁶ FDA, Facility Definition Under Section 503B of the Federal Food, Drug, and Cosmetic Act (April 2016) at p. 3, lines 99-100, available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM496288.pdf.

Attachment I:
Medications Commonly Compounded in Hospitals and Health Systems

As requested, we are providing the agency with examples of compounded drugs typically prepared in hospitals and health systems. Please note that, with the exception of the first three bullets, these agents are appropriate for use only in the inpatient setting and are not suitable for large-scale production. We estimate that the sterile drugs below account for 10% or less of total sterile preparations dispensed in hospitals.

• Dye- and alcohol-free oral preparations for children and patients with sensitivities or allergies.
• Pediatric liquids formulated to mask bitter drug tastes and improve tolerance.
• Sugar-free preparations for diabetic patients.
• Preservative- or excipient-free injectables for neonates to eliminate benzyl alcohol and/or propylene glycol.
• Preparation of injectables in low-sodium vehicles for hypernatremic patients.
• Aliquots of concentrated medications, which are then diluted to prepare fractional doses of adult medications for neonatal or pediatric patients (e.g., fentanyl, morphine).
• Repackaged shortage injectables to reduce waste and conserve scarce drug supplies.
• Concentrated opioid solutions for spinal or intrathecal injection.
• Ophthalmic solutions for topical administration or for injection that are not commercially available (e.g., cefuroxime, vancomycin, amphotericin B, anti-viral drugs).
• Irrigation solutions with antimicrobials for abdominal or trauma surgery.
• Phenol injection for neurolysis.
• Formalin, silver nitrate, and alum bladder irrigation for intractable hemorrhagic cystitis.
• Cocaine ophthalmic drugs for differential diagnosis of Horner syndrome if false-negative results with apraclonidine are suspected or if patient cannot tolerate apraclonidine.