[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: Docket No. FDA–2016–D–0271 – Hospital and Health System Compounding Under Section 503A of the Federal Food, Drug, and Cosmetic Act; Revised Draft Guidance for Industry; Availability.
ASHP is pleased to submit comments to the U.S. Food and Drug Administration (FDA) regarding the revised draft hospital and health system compounding guidance published on October 7, 2021. 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.
ASHP is the collective voice of pharmacists who serve as patient care providers in hospitals, health systems, ambulatory clinics, and other healthcare settings spanning the full spectrum of medication use. The organization’s nearly 58,000 members include pharmacists, student pharmacists, and pharmacy technicians. For 79 years, ASHP has been at the forefront of efforts to improve medication use and enhance patient safety.
FDA is an important partner in ensuring that pharmacists and the patients they serve can access safe and high-quality compounded medications. We commend FDA for crafting guidance that addresses the unique care delivery models within hospitals and health systems, which differ significantly from traditional community pharmacy models, while maintaining appropriate patient safety. Although ASHP is generally supportive of the risk-based enforcement approach outlined in the draft guidance, to assist the agency in finalizing a workable regulatory framework, we offer the following suggestions to strengthen the guidance and harmonize it with other existing regulations:
A. Harmonizing FDA Regulation with Existing Hospital and Health System Regulations Will Ease Compliance While Ensuring Safety.
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.
However, as noted in our comments on the 2016 draft guidance, hospitals and health systems face a thicket of overlapping federal, state, and local regulations. To the greatest extent possible, we urge FDA to revise its guidance to harmonize with other regulations, particularly the CMS conditions of participation. Specifically, we urge the following changes to the draft guidance:
- FDA Compounding Definition: FDA’s working definition of compounding is different than the commonly understood definition of the term as 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, pharmacists consider “compounding” to be the practice defined by the United States Pharmacopeia (USP), meaning any manipulation of a sterile product, including repackaging, reconstituting, and diluting injectable medications for administration to individual patients according to manufacturers’ instructions in approved labeling. As ASHP has noted in previous comments and in compounding listening sessions, over time minor deviations from product labeling regarding preparation have evolved to improve product performance and/or safety. In many cases, the product labeling is not updated after approval to reflect these changes. At minimum, we urge FDA to clarify that product preparation with minor deviations from product insert or product labeling instructions would not immediately qualify as FDA compounding.
- 24-Hour Use or Disposal Requirement: As noted in our 2016 comments on the original draft guidance, although ASHP agrees that non patient-specific compounding must be subject to reasonable limitations, FDA’s limitation on non-patient specific compounding should be evidence-based. We applaud the agency for removing the one-mile radius geographic limitation from the guidance, but remain concerned that the proposed 24-hour use or disposal requirement is arbitrary and not aligned with other hospital and health system regulation.
An urgent need for anticipatory preparations does not necessarily mean frequent use, which means the 24-hour limitation will result in waste of medications, especially those in shortage. For example, oral morphine solution may be prepared for urgent need in treating neonatal abstinence syndrome (NAS) caused by withdrawal in neonates dependent on opioids. The need for this intervention may be infrequent, but there is still critical urgency when the initial dose is required. Doses are often prepared in batches and stored in automated dispensing cabinets near the neonatal intensive care unit. Prepared doses would have to be discarded daily to meet this requirement. This example is true of many compounds prepared in anticipation of need; however, this example stands out because nonsterile compounds are rarely available from a 503B outsourcing facility.
ASHP urges FDA to adopt and alternative approach that would align with existing regulation and care delivery models but still provide clear limits on non-patient-specific compounding in hospitals and health systems. Specifically, we urge the agency to replace the 24-hour requirement with the USP compounding chapters <797> and <795> beyond-use dating (BUD) requirements. The USP chapters delineate the procedures and requirements for compounding nonsterile and sterile preparations. They focus 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 USP standards, all personnel involved in sterile compounding must undergo specific training and testing.
Instituting a USP BUD time-based standard would better align FDA’s requirements with other existing hospital and health system regulations. As evidenced by the CMS1 and TJC2 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) 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 24-hour use or disposal requirement would result in significant unnecessary product wastage and potential access problems related to additional Pyxis and automated dispensing cabinet (ADC) refills that are in direct contravention of CMS and TJC care and quality standards, making simultaneous compliance with both difficult. However, keying compounding limitations to USP <795> and <797> would solve the compliance problem and ensure that FDA regulation harmonizes with other evidence-based regulations.
Limiting non patient-specific compounding in hospitals and health systems based on USP BUD standards also 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 QSA, state Boards of Pharmacy would retain responsibility for oversight of hospital and health system compliance with USP 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 compounding compliance.
Finally, we urge FDA to further clarify what it considers “transfer” out of the pharmacy. Our understanding from the recent listening session and from the guidance itself is that transfer would include loading into Pyxis machines and ADCs. If that is the case, this definition directly conflicts with some state Boards of Pharmacy requirements that explicitly consider Pyxis and ADCs to be under a pharmacy department’s control. Additionally, we remain unclear as to whether transferring product from one hospital pharmacy to another on the same campus or within the same system would trigger the 24-hour requirement. We urge FDA to harmonize its definition of “transfer out of a pharmacy” with state definitions that explicitly include Pyxis and ADCs within a hospital or health system’s pharmacy department control.
B. Supporting the Development and Expansion of a Robust 503B Market
ASHP has long supported the development of a robust 503B marketplace. ASHP considers 503Bs essential to a strong supply chain, but we remain concerned that, at present, 503Bs do not have the capacity to meet all system needs. Unfortunately, members continue to encounter significant wait times and longer turn-around times when purchasing from 503Bs that suggests 503Bs 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. 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. 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.
Nonsterile preparations are not commonly available from 503B outsourcing facilities. Therefore, ASHP asks FDA to consider the impact of this guidance on nonsterile compounded medications prepared in anticipation of a medication order – for example the aforementioned neonatal oral morphine preparations.
ASHP does not object to considering the lack of policies and procedures for purchasing from a 503B a risk factor for hospitals and health systems who do not meet FDA’s proposed three-pronged safe harbor. However, we strongly encourage the agency to provide more detail about its expectations for such policies and procedures. Specifically, does the agency anticipate that hospitals/health systems will have a policy in place for procuring non-patient-specific compounds that fall outside of the safe harbor from a 503B, or does it expect to see a purchase contract in place with a 503B for those products?
Further, to remove lingering quality concerns related to 503B purchases, we recommend that FDA create a system for updating 483 reports. At present, the reports are posted without any detail regarding subsequent amelioration or correction of deficiencies. These standing reports can contribute to reluctance by hospitals and health systems to rely on 503Bs because the hospital/health system remains solely responsible for medication quality under CMS and TJC standards. Additionally, if FDA hopes to see more hospitals register as 503Bs, it should consider creating 503B guidance specific to those sites. The very small number of hospitals registered as 503Bs is a strong indicator of the barriers that remain to successful 503B registration and compliance for these organizations.
C. Additional Recommendations.
ASHP appreciates FDA’s willingness to engage with stakeholders as the agency finalizes its compounding framework. While the November 17th telephonic listening session was helpful, we urge the agency to consider convening an additional listening session in the near future. We would welcome the opportunity to bring in members who can provide the agency with frontline accounts regarding hospital compounding operations, as well as ongoing difficulties/issues with 503B purchasing and registration. Further, given the unique nature of hospital and health system compounding, it may be beneficial for FDA staff to directly observe hospital compounding processes. We would welcome the opportunity to set up a visit with a hospital or health system if it would be beneficial to guidance development.
ASHP appreciates the opportunity to provide FDA with feedback on the revised draft guidance. 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) 664-8617 if you have any questions or if we can provide any additional information.
Sincerely,
Michael Ganio, Pharm.D., M.S., BCPS, BCSCP, FASHP
Senior Director, Pharmacy Practice and Quality
Center on Medication Safety and Quality
ASHP
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. Note that not all of these preparations will be compounded in anticipation of a prescription.
- 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 ( 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 ( 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.
- Buffered lidocaine solution for various bedside procedures.
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1 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”).
2 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”).