It Is Time to Recall USP General Chapter < 800 >

The United States Pharmacopeia (USP) Convention was first held in 1820 when 11 physicians gathered to set standards to ensure that a prescribed medicine would be the same, regardless of where it was created or where a patient lived. USP reference standards for pharmaceutical development and manufacturing confirm accuracy and reproducibility through rigorous testing and evaluation by multiple independent laboratories, including the USP, as well as commercial, regulatory, and academic laboratories. USP publishes publicly available, official documentary standards for pharmaceutical ingredients in the USP-National Formulary, which links directly with its pharmacy reference standards. The process for creating reference standards is complex, and involves extensive testing, analysis, and laboratory results—in short, science and evidence.

General Chapters on Professional Standards Shift Away From Evidence-Based Standards

The USP has been revered for its scientific, evidence-based standards, general chapters, and monographs on ingredients, products, and preparations of medicines. “Through our rigorous science and the public quality standards we set, USP helps protect patient safety and improve the health of people around the world.”¹ However, when it began to create standards for the professional practice behavior and operations of healthcare professionals, it veered sharply away from the use of science as the basis for its standards. These professional practice standards are written by volunteer committees recruited every 5 years. USP offers these committee members the chance to use their opinions as the basis for policy. “USP volunteers are called upon to utilize their best personal, professional, and scientific judgment to benefit global public health.”²

Many of the overly prescriptive details of both USP General Chapter 797 Pharmaceutical Compounding – Sterile Compounding (USP <797>) and USP General Chapter 800 Hazardous Drugs – Handling in Healthcare Settings (USP <800>) are simply the opinions of a very limited number of individuals, with little operational experience in nonpharmacy healthcare settings such as medical practices and other facilities.

Recommendations should not be made or suggested as mandates if there is a lack of defensible scientific, clinical, epidemiologic, and/or statistical evidence to support them. The harm that can be done to the healthcare system by encouraging compliance with non–science-based standards for professionals goes far beyond the mission or purview of the USP.

USP Is Heavily Invested in Expanding Its Published Chapters

The USP notes that it was granted the authority to create general chapters by the USP Convention, which is not an external regulatory or governing authority. The USP does not enforce its chapters but aggressively promotes them as enforceable, thus creating a ready market for the purchase of its general chapters. Once official, these standards must be purchased solely from the USP for individual use, and the cost is substantial. Purchasers include any interested or affected organization that may have the standards applied to them, as well as anyone providing guidance or choosing to use the standards as enforcement. The bottom line is that these “professional standards” have become an important source of income for the USP.

USP Standards Expand From Pharmacy to All Healthcare Settings

In recent years, the USP convened “Expert Committees” to author USP general chapters for professional practice standards, beyond the ingredient-based standards for which it was known. USP General Chapters 795 Pharmaceutical Compounding – Non-Sterile (USP <795>), USP <797> (2008 version), and USP <800> each delve specifically into the policies, procedures, training, facilities, documentation, and general operations of the entities to which the standards may be applied—a far cry from oversight of the ingredients of medicines.

Potential Negative Consequences of USP <800>

Expanding the focus of USP chapters to reach into the deepest aspects of healthcare operations brings with it a significant cost to society, facilities, and patients. Layering detailed onerous requirements for compliance with published standards can lead to negative consequences that may far outweigh the risks the standards were written to avoid. USP <800> is the most far-reaching of the 3 professional standards chapters, and the most controversial. In the introduction, it states that it shall apply to the receipt, storage, compounding, dispensing, administration, and disposal of sterile and nonsterile products and preparations for all healthcare personnel who handle hazardous drug preparations and all entities that store, prepare, transport, or administer hazardous drugs (eg, pharmacies, hospitals, and other healthcare institutions; patient treatment clinics, physicians’ practice facilities, or veterinarians’ offices). The Compounding “Expert Committee” is comprised of 15 members, with little diversity in their membership to include perspectives from the field of the affected entities.

The chapter appears to have been written from the perspective of an ideal, sterile world, with a lack of awareness of the real-world impact and application of the standards on the variation of care delivery in such diverse entities.

The chapter covers a wide range of standards, including the following:

1. Introduction and Scope
2. List of Hazardous Drugs
3. Types of Exposure
4. Responsibilities of Personnel Handling Hazardous Drugs
5. Facilities and Engineering Controls
6. Environmental Quality and Control
7. Personal Protective Equipment
8. Hazard Communication Program
9. Personnel Training
10. Receiving
11. Labeling, Packaging, Transport, and Disposal
12. Dispensing Final Dosage Forms
13. Compounding
14. Administering
15. Deactivating, Decontaminating, Cleaning, and Disinfecting
16. Spill Control
17. Documentation and Standard Operating Procedures
18. Medical Surveillance Glossary

Opinions Are Not Scientific Justification for USP <800>

Although there are 45 references listed at the end of USP <800>, there are no subscripts tying any of those references to details inside the document. The absence of tagged number references added at the end of the chapter for measures, standards, or requirements within USP <800> is a strong indicator that those measures, standards, and requirements are opinions, and are not based on scientific evidence. These references appear to be more of a reading list than actual scientifically annotated references supporting standards set forth in USP <800>. Most of them appear to be others’ opinions or writings of the members of the compounding committee, referencing their own opinions as support for the opinions leading to the USP <800> requirements. In some instances, the references note an expectation or finding that has no relevance to the compounding scenario. Opinions do not provide the scientific, evidence-based rigor that the USP delivered in its trademark ingredient standards.

Within USP <800> there are references to other published USP chapters that are built on the same lack of science-based evidence. Some of the references refer readers to informational chapters with 4-digit chapter numbers. The 4-digit USP chapters are not meant to be enforceable, but to provide information. USP <795>, <797>, and <800>, being more opinion than science, should have been published as 4-digit, rather than 3-digit, chapters, but that would not have provided the same reach and revenue opportunities that they currently provide.

Where Is the Science for Every Written Detail of USP <800>?

These are just a few of the details within USP <800> that make little sense from a scientific perspective.

• Exposure. The standards within USP <800> are driving to minimum zero levels of acceptable exposure, contamination, leakage, or the possibility of these occurrences. Even the Occupational Safety and Health Administration (OSHA) publishes permissible exposure limits and maximum exposure limits for various substances, noise levels, etc. According to the Material Safety Data Sheet for cyclophosphamide powder, a very common oncology drug with known toxicities, “No Occupational Exposure Limit or Short Term Exposure Limit has been identified.”³ OSHA would be the entity to decide the limits, but it hasn’t defined limits of exposure for all individual drugs on the National Institute for Occupational Safety & Health list that are targeted under USP <800>. If OSHA has not yet determined acceptable levels of exposure, why would the USP turn every healthcare facility upside down seeking minimum standards of zero exposure? It may be worth asking whether members of the USP Committee that wrote these standards are aware of what permissible exposure limits are.
• Facilities. Where is the science behind a standard stating that a sink must be a distance of ≥1 meter from a containment primary engineering control? Will a facility be fined and shut down if a sink is <1 meter away? Or, that ceilings must be cleaned at a minimum every month while floors should be cleaned daily and walls weekly? Or, that surface wipe testing should lead to zero evidence of contamination? How many parts per million of any substance found is acceptable? Not acceptable? Why must there be ventilation to the outside instead of common alternative solutions? What if the rooms are deep within a large building? What about rented medical offices with no access to the roof or external walls? One must wonder whether these details, like hundreds of others in USP <800>, are the result of compromise between different opinions among authors, and not evidence-based at all?
• Operations. USP <800> sets forth standards for every route that medications take from entry to disposal through a facility. Complete compliance will require significant disruption to staffing and process flow in facilities of all sizes. To what end? Where is the evidence for the cleaning, transport, and storage minimum requirements set out in the chapter? Why must personal protective equipment be disposed of within certain time frames and when leaving certain areas? Where is the evidence for those time frames and location parameters? They are not referenced.

Does the Emperor Have No Clothes?

Without scientific proof of the detailed requirements, no explanation for the one-size-fits-all standards, and no references to individual stated parameters, could USP <800> have been an exercise in creation of an ideal utopia for handling drugs developed by consensus, without consideration for real-world application? Does this really make sense? Why should a series of professional standards chapters be published and pushed onto the healthcare system without representation, proof, or consideration of the adverse consequences that could be triggered? Could it be a simple case of overreaching beyond the parameters of the science-driven mission and value of the USP for the sake of increasing influence and revenue? Is it now time for the healthcare community to stand up and say enough?

USP <800> is outdated, with insufficient scientific evidence presented for its components. This chapter was published on February 1, 2016, following comments, and has not been modified in the 6 years since. At the time, there was little scientific evidence supporting much of the recommendations, and in the Commentary on General Chapter Hazardous Drugs – Handling in Healthcare Settings USP 39 – National Formulary 34, First Supplement published on the same date, the USP responds to several questions about evidence with a statement that there is not yet any published evidence for the standard, but that “the Expert Committee will consider future revisions to this standard once more information becomes available.”⁴ It is irresponsible to set forth costly standards with an admission that the scientific evidence is not available.

Is the Pain Worth the Gain of Announcing Standards?

These standards are so far-reaching that one would hope that the creators understood the implications of each requirement. USP <800> is not yet official but has been published since 2016 as if it were inevitable. Some state boards of pharmacy have reviewed the chapter and chosen not to accept or endorse it for lack of evidence supporting the standards. Others have unfortunately blindly accepted what the USP has published and incorporated parts of it in their states. Many hospitals and medical practices have reviewed the standards and questioned how they could possibly afford the cost and disruption of full compliance.

Patients have already lost access to treatments because of compounding changes made in USP <797> (2008 version) that are being carried forward into USP <800>. Many hospital pharmacies chose to stop preparing a first-line standard-of-care treatment for bleeding in bladders. We do not know to this day how many patients went through the trauma of having their bladders removed when bleeding could not be stopped because the authors of the USP <797> (2008 version) decided that a primary treatment now had to be treated as high risk based on their vision of ideal compounding regulations. See my article titled "Alum Irrigation, a Standard of Care, Is Once Again Readily Available for Treatment of Hemorrhagic Cystitis" (page 24) for details on this situation.

Providers in one state were cited, fined, and told to stop treating patients by an overzealous inspection board citing required blind compliance to USP <797> (2008) and USP <800> standards. Their patients missed crucial ongoing treatments because the nearest alternative provider was a 2-hour drive north and it was winter. Eventually, the inspection board realized the impracticality of the rigid standards and these patients are once again receiving needed care in their community medical offices.

With any set of standards, there should be consideration of the impact of compliance versus the impact of noncompliance. It appears that USP <800> was written in a real-world void, not cognizant of the cost of full compliance for the healthcare system and patients. There is a point at which every standard should be measured for common sense risk of compliance and adverse consequences that may arise for either compliance or noncompliance.

What Can Providers Do?

Comments have not been accepted on USP <800> since 2016. I believe it is important to write to the USP and clearly state the following concerns regarding this chapter:

1. USP <800> has not been touched in more than 6 years, and yet is still expected to be made official without any review.
2. USP <800> sets forth measures, standards, and requirements that are not founded in scientific evidence and are not even supported with itemized references.
3. USP <800> was not created with representation from the affected healthcare facilities and providers. It overreaches in its requirements and would adversely impact the operations, facilities, and processes of healthcare delivery systems, thus hurting patients’ access to care, without consideration of the real-world environment.

The following requests can also be made:

1. USP <800> should be recalled immediately and reopened for review.
2. The USP <800> committee should include representation from affected treating providers from small, medium, and large healthcare facilities, as well as medical practices, in addition to pharmacy personnel.
3. USP <800> standards should be transparently scientific and evidence-based. If they cannot be, the chapter should be moved to the 4-digit informational chapter status.
4. Public commentary should be sought on any version of the chapter since there has been no chance for commentary in 6 years.
5. Any professional standards should be posted as informational, rather than enforceable, to allow for discussion at the state levels between affected providers and state boards.

Correspondence can be directed to the USP via Nurisha Wade, Vice President, Healthcare Quality and Safety Center of Excellence, at This email address is being protected from spambots. You need JavaScript enabled to view it..

Conclusion

It is time for the medical community to stand up for their patients, and challenge these standards, which have been presented without scientific rigor or evidence, and which do not consider the risks associated with compliance or the impact on patients. We all want to provide safe, effective care in a manner that is also safe for our staff, but there is no justification for roughshod mandates without scientific justification or common sense in application. Please feel free to reach out to me directly at This email address is being protected from spambots. You need JavaScript enabled to view it. if you have any questions or information.

References

1. United States Pharmacopeia. About USP. www.usp.org/about. Accessed March 30, 2022.
2. United States Pharmacopeia. Call for candidates. https://callforcandidates.usp.org/node. Accessed March 30, 2022.
3. Pfizer. Material safety data sheet: cyclophosphamide powder for injection. Updated September 13, 2012. https://cdn.pfizer.com/pfizercom/products/material_safety_data/PZ00021.pdf. Accessed March 30, 2022.
4. United States Pharmacopeial Convention. General chapter <800> hazardous drugs – handling in healthcare settings USP 39–NF 34, first supplement. February 1, 2016. www.uspnf.com/sites/default/files/usp_pdf/EN/USPNF/usp-nf-commentary/gc__800_commentary_final.pdf. Accessed March 30, 2022.