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Considerations for Handling Monoclonal Antibodies
May 2015 : Biologics - Vol. 12 No. 5 - Page #6

Creating safe handling processes for hazardous drugs has received increasing worldwide attention in recent years. In the US, the American Society of Health-System Pharmacists, the Oncology Nursing Society, the National Institute for Occupational Safety and Health (NIOSH), and the United States Pharmacopeia (USP) lead these efforts. Although the hazardous potential of drugs such as antineoplastics is well established, NIOSH recently categorized a variety of other drug classes as hazardous. The current NIOSH list includes chemotherapy medications, antiviral drugs, hormones, some bioengineered drugs, and other miscellaneous drugs (see TEXT BOX1). 

Among those listed are biological medications including vaccines, blood components, gene therapies, and drugs produced by recombinant DNA technology, such as monoclonal antibodies (MABs), which often are used to treat cancers and other serious medical conditions. Scientists can design MABs to target almost any biochemical or cellular component. Most of the targets for therapeutic MABs are present in healthy individuals. Although some MABs lead to the death of targeted cells, they are not conventional cytotoxic agents because they do not directly or indirectly damage DNA or RNA. Therefore, MABs as a class generally are not considered to be carcinogenic, mutagenic, or teratogenic for patients or the staff handling them. However, because insufficient evidence currently exists to either support or refute the hazard potential of MABs,2,3 it is prudent for health systems to carefully evaluate their safe handling practices. 

Safe Handling Challenges 
The majority of information available on potential MAB toxicity is related to systemic doses, leaving open to speculation how low-level, continuous exposure to MABs over long periods of time might affect health care workers.4 Possible exceptions are conjugates of MABs with cytotoxic drugs or radionuclides. For these agents, it is the conjugated effector molecule—not the antibody—that has been demonstrated to present the hazard.5

As a result of the paucity of data, there is a lack of consensus on how MABs should be treated with regard to hazard potential. Safety Data Sheets tend to pertain to industrial scale handling of raw material and do not translate easily to the clinical setting.2,3,6 Industry standards for the correct handling and exposure risk associated with MABs are conflicting or outdated. Operational and clinical issues—for example, vial sharing, preparation complexity, and medication error risk—influence the handling of MABs and must be considered.7

Routes of Exposure
Exposure to MABs, as with exposure to cytotoxic drugs, may occur during transport, storage, preparation, administration, spill management, and waste disposal. When evaluating the hazard potential of MABs, consider the implications of all routes of potential exposure.

Dermal absorption: Exposure through the skin is unlikely due to the large size of MAB molecules. However, dermal absorption, local irritation, and allergic reaction may be concerns for individuals with damaged skin.7 

Inhalation/mucosal absorption: Staff preparing MAB doses may be exposed to powdered or aerosolized particles, most likely via the nasal mucosal surface.7
 

Oral absorption: Although oral absorption (eg, hand to mouth) is a concern, it is likely that MABs would be broken down quickly by digestive track acids and enzymes before any substantial systemic impact could occur.7 The potential level of occupational exposure via this route is difficult to quantify; however, some nurses have reported being able to taste MABs while reconstituting them, suggesting some level of exposure occurs.3 

Exposure Risks
Potential toxicities of MABs arising from both product and patient factors include4:

  • Formation of neutralizing antibodies, which may not be of clinical significance, but may provoke allergy, anaphylaxis, or serum sickness
  • Loss of clinical response
  • Cross reaction with endogenous protein(s) with important biological function
  • Enhancement of immune system activity leading to cytokine storm (ie, hypercytokinemia) and, in severe cases, systemic inflammatory response syndrome.

Allergic and immunologic reactions may not require exposure to therapeutic doses. Research suggests the following explanations for this possibility4:

  • Long-term, low-grade exposure may lead to the formation of antibodies, which could cause allergic reactions of varying severity
  • Antibodies developed at work could adversely impact subsequent treatment of staff if they were to develop conditions requiring therapeutic treatment
  • Exposure to agents provoking cytokine release, particularly if this involves lung-mediated inflammatory mechanisms, is a concern

Also, the additive effect or cross-reactivity of these agents with endogenous proteins and other drugs to which health care workers may be exposed is unknown. Typically, a risk management assessment is advocated to determine procedures for the safe handling of any drug, but inherent difficulties exist with performing comprehensive risk assessments on MABs, including2:

  • The criteria for the definition of a hazardous drug are not necessarily adequate for proteinogenic drugs
  • Detailed mechanisms of action for some MABs are unknown
  • Human data are unavailable, and the results of animal experiments may not accurately reflect the effect in humans because MABs are humanized products
  • Researchers have assessed MAB toxicity after parenteral administration of therapeutic doses; exposure levels during occupational handling are lower and chronic 

A 2011 literature review, conducted by Halsen and Kramer, that assessed the risks to health care workers of long-term exposure to MABs, concluded that2,8:

  • All MABs evaluated were toxic for reproduction, with some also exhibiting mutagenic or sensitizing activity
  • A maximum acceptable level of occupational internal exposure over the long-term is not yet known
  • Precautionary measures should be taken to avoid external and internal exposure of workers
  • Injuries and accidental uptake must be avoided
  • Prohibitions and restrictions as outlined in the European Directive 2004/37/EC9 with regard to pregnant staff and nursing mothers must be adhered to, especially when external exposure is likely

As nurses, pharmacists, and technicians handle increasing numbers and doses of MABs used as cytotoxic agents, concern is mounting for females of child-bearing age because of the unknown impacts from low-level exposure.2 Given that the interactions of MABs with their cellular targets are not clearly understood, a cautious approach to handling MABs appears prudent. Therefore, implementing safe handling practices for MABs now may be judicious.  

Requirement and Standards
MABs present a unique and, as yet, ill-defined hazard risk for health care workers. Given the current lack of data and consensus regarding the hazard potential of these agents, each organization must determine and implement appropriate practices to help ensure the safe handling of these products. 

It is unlikely that all MABs will be subject to the same level of safe handling requirements given their differing uses and toxicities. Ideally, all MAB doses should be prepared in the pharmacy in a manner consistent with current USP <797> practice standards. At a minimum, those preparing and administering MABs should use personal protective equipment (PPE), such as gloves and masks. 

When used as part of oncology treatment regimens, current standards for all drugs used for this purpose should be followed. In the absence of established guidelines for handling MABs, or specific MAB product information, handle and prepare MABs in accordance with established procedures for cytotoxic or biohazardous medications. In addition to using PPE, considerations may include segregated storage or other storage requirements unique to specific MAB products, the preparation of MABs within a biological safety cabinet, and the use of a closed system drug-transfer device. 

Incorporate safe handling practices for MABs into pharmacy staff training programs on the storage, aseptic preparation, and distribution of drug products. Finally, because of the potential for the formation of antibodies to MABs, consider occupational health screening of staff for MAB exposure. 

Moving Forward 
Biotherapy is a frontier still in its infancy. Just as the development of novel therapeutic agents continues to evolve, so must associated practices for the safe preparation and handling of these products, particularly because their potential hazards are not fully elucidated. It is prudent for organizations to take the necessary precautions and establish safety procedures sooner rather than risk adverse events later. As new MABs become commercially available, pharmacists, nurses, infection control staff, and the organization’s pharmacy and therapeutics committee should remain knowledgeable about their toxicities, their unique preparation and administration requirements, and the potential risks to staff of occupational exposure.

 


James R. Rinehart, RPh, MS, FASHP, is a health system pharmacy management specialist and a consultant and principle of Winovation Associates, LLC. He received his BS and MS in pharmacy from the University of Wisconsin Madison and completed an administrative residency at the University of Wisconsin hospitals and clinics. James is a member of the clinical advisory board of the Institute for Safe Medication Practice’s Medication Safety Alert newsletter, acute care edition, and is a past chair of the ASHP Section of Pharmacy Practice Managers.

 

James A. Jorgenson, RPh, MS, FASHP, is chief executive officer and chairman of the board of Visante, Inc, and Visante Limited. Before joining Visante, Jim was chief pharmacy officer and vice president of Indiana University Health, where he was responsible for the design and operation of the system’s pharmacy services supporting IU Health’s integrated delivery network. 

 


TEXT BOX

Drugs considered hazardous by NIOSH include those that exhibit one or more of the followingsix characteristics in humans or animals1:

  • Carcinogenicity
  • Teratogenicity or other developmental toxicity
  • Reproductive toxicity
  • Organ toxicity at low doses
  • Genotoxicity
  • Structure and toxicity profiles of new drugs that mimic existing drugs determined hazardous by the above criteria

References

  1. Department of Health and Human Services. Centers for Disease Control and Prevention. National Institute for Occupational Safety and Health (NIOSH) List of Antineoplastics and Other Hazardous Drugs in Healthcare Settings, 2014. http://www.cdc.gov/niosh/docs/2014-138/pdfs/2014-138.pdf. Accessed April 22, 2015.
  2. South Australian Health. Safe Handling of Cytotoxic Drugs and Related Wastes: Guidelines for South Australian Health Services 2012. http://www.sahealth.sa.gov.au/wps/wcm/connect/f8aa68004b3f6cf6a340afe79043faf0/SafeHandlingOfCytotoxicDrugsRelatedWastesGuideline-PHCS-120515.pdf?MOD=AJPERES. Accessed April 22, 2015.
  3. Guideline for the Preparation or Manipulation of Monoclonal Antibodies (MABs) and Related Compounds Such as Fusion Proteins, Used in the Treatment of Cancer. Pan Birmingham Cancer Network NHS, July 2012. http://www.uhb.nhs.uk/Downloads/pdf/CancerPbPreparationOfMonoclonalAntibodies.pdf. Accessed April 22, 2015.
  4. Langford S, Fradgley S, Evans M, et al. Assessing the risk of handling monoclonal antibodies. Hosp Pharm. 2008;15:60-64. 
  5. Summerhayes M, Cole J. Assessing the risk of handling monoclonal antibodies (letter to the editor). Hosp Pharm. 2008;15:138. URI 10006654.
  6. Alexander M, King J, Lingaratnam S, et al. A survey of manufacturing and handling practices for monoclonal antibodies by pharmacy, nursing and medical personnel [published online ahead of print November 14, 2014]. J Oncol Pharm Pract. doi: 10.1177/1078155214559113.
  7. Alexander M, King J, Bajel A, et al. Western & Central Melbourne Integrated Cancer Service. Australian consensus guidelines for the safe handling of monoclonal antibodies for cancer treatment by healthcare personnel (2014). http://www.wcmics.org/guidelines/20140422_MABs_Guidelines.pdf. Accessed April 22, 2015.
  8. Halsen G, Krämer I. Assessing the risk to health care staff from long-term exposure to anticancer drugs—the case of monoclonal antibodies. J Oncol Pharm Pract. 2011;17(1):68-80. 
  9. The European Parliament and the Council of the European Union. Directive 2004/37/EC, April 29, 2004. http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2004:229:0023:0034:EN:PDF. Accessed April 22, 2015.

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