The Impact of USP 797, USP 800 on Compounding Pharmacies

The advent of United States Pharmacopeia (USP) 797 and USP 800 has driven many hospitals and compounding pharmacies to develop and/or revise policies on sterile compounding of hazardous chemotherapies and biotherapies. In USP 797, the guidance establishes standards for sterile compounding to ensure accuracy and avoid contamination of sterile products.¹ On the other hand, USP 800 highlights recommendations and processes for the handling of hazardous drugs and includes guidance for health care personnel and facilities.² USP 800 was a necessary step to maximize the safety of health care workers and patients that are exposed to hazardous medications, but it also recommended many institutions reevaluate their facilities, equipment, processes, and staffing capacity, potentially costing millions of dollars.³

The National Institute for Occupational Safety and Health (NIOSH) defines criteria for designating a drug as “hazardous” and also provides a list of hazardous drugs with their different classifications. An important consideration is that the NIOSH guidance primarily focuses on hazardous drugs that are FDA-approved, but a health care institution may also handle other hazardous substances. In these cases, it is important to also refer to the Occupational Safety and Health Administration (OSHA) hazard communication standard, which requires employers to implement a system to identify and disseminate information about all hazardous chemicals that an employee may be exposed to.

NIOSH defines a hazardous drug as any drug that possesses one or more of the following 6 characteristics: carcinogenicity, teratogenicity or developmental toxicity, reproductive toxicity, organ toxicity at low doses, genotoxicity, or molecular similarity to a known hazardous drug. Using these criteria, the NIOSH list further stratifies hazardous drugs into 3 categories: 1) antineoplastic drugs, 2) non-neoplastic hazardous drugs, and 3) drugs with reproductive effects.⁴

Monoclonal antibodies have been developed and incorporated into the backbone for the treatment of various cancers, primarily because their specificity for cell targets have increased efficacy while minimizing toxicity.⁵ However, a matter of controversy is whether or not monoclonal antibodies should be treated as hazardous drugs primarily based on the fact that they possess antineoplastic activity even in the absence of data showing any hazardous characteristics (eg, teratogenicity). NIOSH’s perspective is that the large size of monoclonal antibodies prevents them from penetrating the skin or lungs and would be degraded by the gastrointestinal tract if ingested.

Furthermore, the only practical risk is an accidental needle stick, which contains very trace amounts of the monoclonal antibody.⁶ However, de Lemos et al argues that even if a single exposure does not result in a detectable systemic level, health care personnel may be handling these drugs repeatedly, which does pose a risk.⁷

For the purposes of providing a quick reference for health care personnel when engaging in hazardous compounding, we have created a table for the hazardous monoclonal antibodies on the NIOSH list (Table).^8-23 All of the hazardous monoclonal antibodies are conjugated to a known cytotoxic agent with the exception of pertuzumab. Every single monoclonal antibody on the list is classified by the NIOSH list as a Group 1 antineoplastic drug.

Teratogenicity and reproductive toxicity are expected from all of the monoclonal antibodies in the Table based on animal studies or their mechanism of action.^8-23 Genotoxicity was observed in animal studies for all of the hazardous monoclonal antibodies except for pertuzumab and moxetumomab pasudotox-tdfk. None of the listed hazardous monoclonal antibodies demonstrated organ toxicity at low doses. Carcinogenicity studies were not available, except for gemtuzumab ozogamicin and inotuzumab ozogamicin.

The hazardous classification of medications might change due to availability of new data, changes in the practice setting, and/or regulatory updates. In cases where there is a lack of data, the American Society of Health System Pharmacists (ASHP) may have additional guidance or forums for pharmacy staff to refer to when there are questions on drug handling.

References

1. United States Pharmacopeia. General Chapter <797> Pharmaceutical Compounding – Sterile Preparations. Updated 2021. Accessed September 2021. https://www.usp.org/compounding/general-chapter-797
2. United States Pharmacopeia. USP General Chapter <800> Pharmaceutical Compounding – Sterile Preparations. Updated 2020. Accessed September 2021. https://www.usp.org/compounding/general-chapter-hazardous-drugs-handling-healthcare
3. Beans BE. USP <800> Adds Significant Safety Standards: Facility Upgrades Needed to Protect Employees From Hazardous Drugs. P T. 2017;42(5):336-339.
4. Department Of Health And Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health. NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings, 2016. Published 2016. Accessed September 2021. https://www.cdc.gov/niosh/docs/2016-161/pdfs/2016-161.pdf
5. Kaur N, Goyal A, Sindhu RK. Therapeutic Monoclonal Antibodies in Clinical Practice against Cancer. Anticancer Agents Med Chem. 2020;20(16):1895-1907.
6. Department Of Health And Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health. Hazardous Drugs: Draft NIOSH List of Hazardous Drugs in Healthcare Settings, 2020; Procedures; and Risk Management Information. Published 2020. Accessed September 2021. https://www.federalregister.gov/documents/2020/05/01/2020-09332/hazardous-drugs-draft-niosh-list-of-hazardous-drugs-in-healthcare-settings-2020-procedures-and-risk
7. de Lemos ML, Badry N, Kletas V, et al. Safe handling of monoclonal antibodies: Too large to be hazardous? J Oncol Pharm Pract. 2018;24(3):218-220.
8. Department Of Health And Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health. NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings, 2016. Published 2016. Accessed April 2022. https://www.cdc.gov/niosh/docs/2016-161/default.html
9. Department Of Health And Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health. NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings, 2020 Draft. Published 2020. Accessed September 2021. https://www.cdc.gov/niosh/docket/review/docket233c/pdfs/DRAFT-NIOSH-Hazardous-Drugs-List-2020.pdf
10. Department Of Health And Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health. Hazardous Drugs: Draft NIOSH List of Hazardous Drugs in Healthcare Settings, 2020; Procedures; and Risk Management Information. Published 2020. Accessed September 2021. https://www.federalregister.gov/documents/2020/05/01/2020-09332/hazardous-drugs-draft-niosh-list-of-hazardous-drugs-in-healthcare-settings-2020-procedures-and-risk
11. Kadcyla™ (ado-trastuzumab emtansine). Prescribing information. Genentech, Inc; 2020. Accessed September 2021. https://www.gene.com/download/pdf/kadcyla_prescribing.pdf
12. Enhertu™ (fam-trastuzumab deruxtecan-nxki). Prescribing information. Daiichi Sankyo, Inc; 2021. Accessed September 2021. https://daiichisankyo.us/prescribing-information-portlet/getPIContent?productName=Enhertu&inline=true
13. Perjeta™ (pertuzumab). Prescribing information. Genentech, Inc; 2021. Accessed September 2021. https://www.gene.com/download/pdf/perjeta_prescribing.pdf
14. Trodelvy™ (sacituzumab govitecan-hziy). Prescribing information. Immunomedics, Inc; 2021. Accessed September 2021. https://www.gilead.com/-/media/files/pdfs/medicines/oncology/trodelvy/trodelvy_pi.pdf
15. Mylotarg™ (gemtuzumab ozogamicin). Prescribing information. Pfizer Inc; 2021. Accessed September 2021. http://labeling.pfizer.com/ShowLabeling.aspx?id=9548
16. Besponsa™ (inotuzumab ozogamicin). Prescribing information. Pfizer Inc; 2018. Accessed September 2021. http://labeling.pfizer.com/ShowLabeling.aspx?id=9503
17. Adcetris™ (brentuximab vedotin). Prescribing information. Seagen Inc; 2019. Accessed September 2021. https://seagendocs.com/Adcetris_Full_Ltr_Master.pdf
18. Padcev™ (enfortumab vedotin-ejfv). Prescribing information. Astellas Pharma US, Inc; 2021. Accessed September 2021. https://astellas.us/docs/PADCEV_label.pdf
19. Polivy™ (polatuzumab vedotin-piiq). Prescribing information. Genentech, Inc; 2020. Accessed September 2021. https://www.gene.com/download/pdf/polivy_prescribing.pdf
20. Blenrep™ (belantamab mafodotin-blmf). Prescribing information. GlaxoSmithKline; 2020. Accessed September 2021. https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Blenrep/pdf/BLENREP-PI-MG.PDF
21. Zynlonta™ (loncastuximab tesirine-lypl). Prescribing information. ADC Therapeutics; 2021. Accessed September 2021. https://www.adctherapeutics.com/wp-content/uploads/2021/04/pi.pdf
22. Lumoxiti™ (moxetumomab pasudotox-tdfk). Prescribing information. Innate Pharma; 2020. Accessed September 2021. https://www.innatepharmapi.com/lumoxiti/lumoxiti-pi/
23. Tivdak™ (tisotumab vedotin-tftv). Prescribing information. Seagen, Inc; 2022. Accessed April 2022. https://seagendocs.com/Tivdak_Full_Ltr_Master.pdf