Challenges for Hospital-Based Compounding Pharmacies Meeting USP

On March 12, 2020, because of a final appeal, USP (United States Pharmacopeia) stated that their 2019 revision of the USP <797> was no longer enforceable. Still, the existing 2008 USP <797> would remain in place and would be enforceable. For most hospital compounding pharmacies, this did not affect how they operated their physical environments, budgets, and general practice. Some hospital-based pharmacies have already begun construction to be compliant with the new 2019 USP <797> regulations and with USP <800> when that becomes enforceable. Yet the choice for hospitals is challenging either way, and some simply aren’t fully compliant with the 2008 guidance and even further behind any future, final guidance which is even more stringent.

According to a survey conducted by industry magazine Pharmacy, Purchasing and Products in April of 2019, only 2% of the hospitals surveyed expected to be fully compliant to USP <797> by December 1st, 2019.¹ Meanwhile, another study conducted in 2018 by the U.S. healthcare company Critical Point discovered that 61% of the hospitals they surveyed fell below the requirements of the existing USP <797>, with the tougher guidance anticipated in 2019.² With requirements mounting yearly, hospitals have two choices: invest heavily in compliant infrastructure or look elsewhere.

Founded in 1820, USP (United States Pharmacopeia) is a scientific, nonprofit organization that establishes national standard operating procedures for the identity, strength, quality, and purity of drugs. The USP is a regulatory authority that establishes legally enforceable standards that apply to all settings in which medications are prepared for patients. The two applicable standards to compounding pharmacies in hospitals are USP <797> and USP <800>.

USP <797> provides guidelines for compounding sterile preparations, or CSP, while USP <800> (which is presently only informational) lays out the standards for the safe handling of hazardous drugs to minimize occupational exposure risks to health care workers. If and when the 2019 version of USP <797> is approved, then USP <800> will also become enforceable.

Together, USP <797> and <800> create an environment for compounding drugs that reduce the contamination risk and increase the safety level for healthcare personnel, patients, and the overall hospital environment. They establish a detailed criterion regarding compounding that must occur within a hospital pharmacy. These regulations expressly refer to patient-specific medications that must be prepared in a sterile environment and remain sterile when being administered.

Under the 2008 USP <797>, restrictions must be in place to limit the potential for contamination. Hospitals must have a cleanroom that is physically distinct from the rest of the hospital pharmacy. This room ensures the purity of the compounded pharmaceuticals. USP <797> also stipulates a need to protect those who handle potentially hazardous products, hazardous drugs, or hazardous materials from unwanted contamination; pharmaceutical ingredients can pose a significant risk to health care workers.

Hospital compounding facilities need a biological safety cabinet for compounding, a specific fume, and hood design, and a buffer area indicated by a line of demarcation with proper airflow. There needs to be a restricted access barrier system (RABS), also known as a glove box. Hospitals are also mandated to certify primary engineering controls and test the compounding area’s air quality every six months.

USP <797> and <800> apply to everyone involved in the sterile compounding of non-toxic <797> and hazardous drugs <800>. This includes pharmacists, pharmacy technicians, nurses, and physicians. Under the current USP <797>, staff training should teach best practices and core competencies for each employee in a hands-on, situation-based learning format combined with a written and practical exam. The staff training should cover everything from hand hygiene, garbing, gloved sampling, media-fill testing, and antiseptic handwashing. Also, staff must be trained in the correct sterile compounding principles and practices, including acceptable limits to be understood in case of an adverse event. These different training requirements need to be reviewed at intervals indicated in USP <797> (i.e., six months or 12 months).

As of 2020, the USP released revisions to the 2019 version that would align better with the 2008 interpretations for <797>, focused on potential risks around compounding performance procedures. The main differences were that Medium-Risk Level CSPs in the 2008 version looked at the complexity of the compounds, whereas the 2019 version looked at the location of compounding.³

These contradicting perspectives between the 2008 and 2019 versions of different risk levels posed a possible health risk to the public, which became even more of a threat once the pandemic hit the world. As hospitals have become overrun with COVID-19 patients, the risk of contamination has risen to a significant concern.

The USP outlined three degrees of risk in <797> when handling compounded sterile preparations (CSPs). These rigorous standards help determine the risk level of possible contamination of a CSP and the correct methods for handling these compounds.

Below are the risk levels for possible contamination of a CSP:

Low risk of contamination⁴

• Compounded within an ISO Class 5 environment
• Single-volume transfers used for sterile doses
• The measuring and transferring of simple aseptic must not be with more than three packages of manufactured sterile products

Similar to low-risk of contamination level CSPs, but with several conditions⁵

• Sterile products are to be given as individual small doses to multiple patients or one patient several times 
• No single-volume transfers, only complex aseptic manipulations

Compounding under the following conditions means CSPs are already contaminated or are at risk of contamination⁶

• CSPs is compounded and used with either a nonsterile ingredient or device  
• CSPs compounded outside of the designated ISO Class 5 environment
• Personnel while compounding are not wearing the correct PPE  
• Both purity and strength are only assumed and not verified

It’s important to note that these points act as guidelines rather than as a comprehensive set of rules, giving direction for handling the contamination of CSPs.

As of March 12, 2020, the USP revised the 2019 version of <797> because it was not compliant with the initial version from 2008. The 2019 version of <797> permitted that Category 1 compounding was acceptable in a segregated compounding area (SCA), which contradicted the 2008 requirements.⁷  

The 2008 version addressed compounding procedures based on how complicated the compound product was, such as the combined number and type of products. The 2019 version of <797> focused on designating compounding based on where the compounding location was, rather than on complexity. 

The USP in <797> indicates the policies and procedures to maintain high-level drug and patient safety. To adhere to USP <797>, pharmacies need regulations to cover unique situations during compounding. Below is the required length of time for beyond-use dates (BUDs) for category 1 and 2 facilities:

(PEC/C-PEC located in an SCA or C-SCA) beyond use date (BUD) is⁸:

• 12 hours or less at controlled room temperature
• 24 hours or less when kept refrigerated

(located in a Buffer Room with an Anteroom) beyond use date can be⁹:

• More than 12 hours at controlled room temperature
• More than 24 hours when kept refrigerated

Pharmacists can use these policies and procedures as reference materials when faced with new uncertain circumstances, giving them the tools to know what to do and record their actions.

With hospitals already behind the curve for the new USP guidance, the pressure to maintain compliance is mounting. Most hospitals are not prepared, revealing a real risk to compliance, which can impact their patient’s safety.

Two of the main challenges for in-house, hospital compounding as it relates to the requirements of USP<797> and USP <800> are cost and physical facility limitations such as square-footage and HVAC.

Complying with the necessary ventilation requirements of the 2008 USP <797> alone can cost a hospital a great deal of money. According to an article by the National Institutes of Health (NIH), hospitals requiring capital upwards of $1 million for the redesign of each compounding area is not uncommon¹⁰. This is the reason why many hospital compounding pharmacies are looking at alternatives such as 503B Outsourcing.

Unlike other capital expenditures, redesigning a hospital’s compounding pharmacy to meet the specifications of the 2008 USP < 797> or the newer specification once USP <800> becomes enforceable does not generate any increased revenue for the hospital. Ensuring the hospital pharmacy’s physical space is compliant involves more than moving a few walls and adding a few ventilation hoods. Both the current USP <797> and the new USP <800> set strict infrastructure requirements, including new primary engineering controls or upgrades to architectural features. A hospital would be obligated to hire engineers, environmental health experts, space planners, and architects to evaluate and draw up new designs for the space to meet these requirements. Furthermore, a construction team would be required to bring these designs to life.

A significant roadblock many established hospitals face in achieving compliance is the lack of physical space. When a modern, integrated hospital has fully developed campuses, the possibility to build the pharmacy’s required separate rooms or buffer area is often not an option. Without such new, dedicated space, many hospital compounding pharmacies will fail to be compliant.

Outsourcing medicine preparation to a 503B sterile compounding pharmacy, like QuVa Pharma, is an attractive alternative that an increasing number of hospitals are choosing. With 503Bs regulated by the FDA and following cGMP (current good manufacturing processes), hospitals can confidently purchase compounded sterile products in ready-to-administer presentations from a safe and reliable source. 503B’s like QuVa Pharma can comply with the FDA’s regulations, therefore reducing the overall risk of compliance.

In a report by the OIG (Office of the Inspector General), they recommended that the FDA further communicate with hospitals about the importance of obtaining their non-patient specific compounded drugs from outsourcing facilities¹¹.

An FDA-registered, national 503B provider, such as QuVa Pharma, has the cGMP expertise, pharmaceutical-grade manufacturing scale and capacity, regulatory experience, and a proven, industry-leading FDA compliance record that address hospitals’ concerns about Outsourcing. QuVa Pharma understands hospital CSP (compounded sterile product) needs and has a deep and broad portfolio of products to address evolving in-hospital patient care needs. QuVa Pharma is uniquely positioned to help hospitals achieve a more resilient and reliable drug supply. 

As hospitals grapple with the challenges of space and cost as part of the USP <797> and <800> regulations, a clear solution is emerging; work with an industry-leading 503B partner like QuVa Pharma. With such a partnership, a hospital can develop a relationship that becomes a valuable extension of their pharmacy team. By shifting the medicine production to outside the hospital, they can focus limited resources on other important issues, like improved patient care, without sacrificing pharmaceutical quality.

1. The State of Pharmacy Compounding 2019,  https://www.pppmag.com/digitalmag/Main.php?MagNo=235&PageNo=1#page/15
2. The 2018 Critical Point USP <797 Compliance Study,  CriticalPoint: <797> Gap Analysis
3. The Joint Commission, Update on Medication Compounding Compliance, Aug 20, 2020, https://www.jointcommission.org/resources/news-and-multimedia/blogs/
4. Kluwer, Wolter, What is USP 797 and how to stay compliant, Sept 13, 2019, https://www.wolterskluwer.com/en/expert-insights/what-is-usp-797-and-how-to-stay-compliant
5. Kluwer, Wolter, What is USP 797 and how to stay compliant, Sept 13, 2019, https://www.wolterskluwer.com/en/expert-insights/what-is-usp-797-and-how-to-stay-compliant
6. Kluwer, Wolter, What is USP 797 and how to stay compliant, Sept 13, 2019, https://www.wolterskluwer.com/en/expert-insights/what-is-usp-797-and-how-to-stay-compliant
7. The Joint Commission, Update on Medication Compounding Compliance, Aug 20, 2020, https://www.jointcommission.org/resources/news-and-multimedia/blogs/
8. Setra, Everything You Need to Know About USP 797, Jan 18, 2019, https://www.setra.com/blog/everything-you-need-to-know-about-usp-797
9. Setra, Everything You Need to Know About USP 797, Jan 18, 2019, https://www.setra.com/blog/everything-you-need-to-know-about-usp-797
10. USP <800> Adds Significant Safety Standards, May 2017, www.ncbi.nlm.nih.gov/pmc/articles/PMC5398627/
11. U.S. Department of Health and Human Services OIG, “Most Hospitals Obtain Compounded Drugs From Outsourcing Facilities, Which Must Meet FDA Quality Standards”, report OEI-01-17-00090, June 2019.