Non-Sterile Compounding

Protect Workers During Nonsterile Hazardous Drug Compounding: Yes, the Risks are Real!

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By: Melanie Dorey R.Ph.T and Kate Douglass, MS, RN
The authors gratefully acknowledge Jennifer Mosher BScPharm, RPh for the review of this article.

Many pharmacy professionals may focus only on antineoplastic chemotherapy agents when considering hazardous drug (HD) compounding. However, both sterile or nonsterile HD compounding includes many additional non-antineoplastic drugs from the National Institutes of Occupational Safety and Health (NIOSH) List of Hazardous Drugs in the Healthcare Setting, 2016[1]

Examples of non-antineoplastic hazardous drugs commonly compounded in nonsterile compounding pharmacies are included below.

Examples of HDs Commonly Compounded from Active Pharmaceutical Ingredients (APIs) in Nonsterile Compounding Practices

Group 2 Group 3
Non-antineoplastic drugs that meet 1 or more NIOSH criteria for an HD and those with Manufacturer’s safe-handling guidance (MSHG)

Estrogen/Progesterone combination topical
Azathioprine suspension
Spironolactone suspension
Tacrolimus suspension

Non-antineoplastic drugs with primarily reproductive adverse effects

Testosterone topical
Topiramate suspension
Misoprostol liquid
Clonazepam suspension
Valproic acid suspension

Since the 1970s, evidence has mounted that occupational exposure does indeed pose a risk to healthcare workers who compound, administer, transport, receive, manipulate, and handle these medications. The NIOSH website on Hazardous Drug Exposures in Healthcare includes links to literature on the acute, chronic, and reproductive effects of health exposure to HDs.[2]

It’s hard to justify continuing business as usual when workers, patients and their families may be exposed to these known dangers because the NAPRA Model Standards for Pharmacy Compounding of Non-sterile Preparations[3] are not followed.

Know the Required Standards for Compounding

Specific nonsterile dosage forms (e.g., liquids, semi-solids, and solids) of drugs listed above are compounded in community and hospital pharmacies. It is the responsibility of pharmacy owners, Directors, Designated Managers, and every registrant to protect staff from occupational exposure to HDs.

The NAPRA standards and the NIOSH Alert Preventing Occupational Exposure to Antineoplastic and Other Hazardous Drugs in Health Care Settings[4] best practice guidelines are more likely followed when compounding the antineoplastic medications in Group 1 of the NIOSH List. Pharmacies compounding nonsterile preparations containing drugs in Group 1 must follow all the requirements of Level C in the NAPRA Model Standards.

Drugs listed in Group 2 and 3 may be overlooked or not considered a hazard by those preparing hazardous drugs. However, there are several considerations to determine the level of requirements needed.

  • Level C requirements must be followed if “large quantities of active pharmaceutical ingredients (APIs) are used routinely.”[5]
  • NAPRA standards also require an evidence-based evaluation of cumulative risk: “if small quantities of several different preparations, each of which individually has low risk, are compounded within the same timeframe, then the total cumulative risk must be considered”.
  • Even if compounding a small quantity, a risk assessment of the API may indicate that Level C requirements are needed.

There is room for interpretation of these standards. What is a large quantity of API? How often is routinely? These decisions are left to the risk assessment of each pharmacy about how these HDs will be handled. Since handling these according to Level C requirements takes time and increases cost, many pharmacy professionals elect to do less than Level C activities.

These authors believe that since no minimum safe exposure amount to HDs has been determined, Level C activities should be followed in almost all cases and that from a safety perspective, it is always best to defer to the higher standard.

How Do We Make HD Compounding Safer?

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Adjust your mindset. Do you hear yourself saying “This is the way I’ve always done it and we’re ok”? There are decades of data evaluating worker exposure to hazardous medications and the effects it has on the human body, for example the secondary malignancies identified in patients following treatment.[6]

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Evaluate all drugs and APIs compounded at your location annually that are in NIOSH Groups 1, 2 and 3. By understanding the type of hazard each drug poses, a meaningful risk assessment can be performed for each of these drugs. Document your assessment of risk on the master formulation record for each preparation. It may be helpful to keep a list of all HDs compounded at your organization with its risk assessment as a quick reference.

Many pharmacies prepare hormone replacement therapies using APIs. For example, estrogen is located in Group 2 of the 2016 NIOSH List where it is listed as an NTP (known to be human carcinogens under the National Toxicology Program) and has a black box warning for endometrial cancer and cardiovascular risks. It is also important to mention that estrogen has been moved to Table 1 in the draft NIOSH List of Hazardous Drugs in Healthcare Settings, 2020.[7] Even though estrogen is not an antineoplastic, exposure can pose health risks to pharmacy personnel handling this medication without the proper personnel and environmental controls. Anyone near the location of compounding, such as patients and family may also risk exposure if proper environmental controls are not in place.

icon of powder

Consider how to safely process powders. Unless appropriate controls are in place, any time powder is used or produced where other staff members are working (or customers are waiting), they are exposed to that HD. So, when tablets of drugs in Group 2 or 3 are being crushed, will powder or dust be released into the air? What about when tablets that are brittle and powdery are split? Think of all the times you have weighed API powders and seen particles in the air. And even then, there are likely other particles you can’t see. Therefore, it is important to put in the right environmental controls into place. Even when compounding liquids or semi-solids, environmental controls must be in place in the event of a spill.

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Understand the impact of WHMIS classification on compounding requirements. Another important element to consider is that NAPRA states that hazardous materials classified by Workplace Hazardous Materials Information System (WHMIS) as representing a health hazard, such as those that are very irritating to the respiratory tract, the skin or the mucous membranes must be compounded under Level C requirements.

Almost all API in powder form is considered a respiratory hazard and requires a risk assessment, but if your pharmacy uses a large amount of API, even those not on the NIOSH list, or compounds them routinely, then these compounding activities will need to follow Level C requirements.

Prioritize Worker Safety

There are options for facilities who compound HDs with limitations on space and budget. Outsourcing HD compounding to a pharmacy nearby that has fully implemented the NAPRA standards may make the most sense especially if your facility prepares very few nonsterile HD preparations.

If outsourcing is not an option, renovation will be necessary, which would include a separate negative pressure room, exhausted to the exterior, and a containment primary engineering control (C-PEC) for nonsterile HD compounding activities. The C-PEC must exhaust air to a specific location outside the building (preferred) or through redundant (double) HEPA filters. A NAPRA-compliant compounding room alone isn’t enough.

Comprehensive standard operating procedures (SOPs) must detail all aspects of compounding activities, including deactivation, decontamination and maintenance of the compounding area, personal protective equipment to be used by staff, material management and drug handling, packaging, and transport. Staff must know and understand the SOPs and their competency to carry them out must be evaluated.

These improvements will require appropriate resources and commitment to change and consistency in application but are a necessary part of effectively protecting workers from the real hazards presented by compounding HDs.

  1. NIOSH. NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings, 2016. Retrieved on 1/25/22.
  2. NIOSH. Hazardous Drug Exposures in Healthcare. Effects of Occupational Exposure. Retrieved 1/25/22.
  3. National Association of Pharmacy Regulatory Authorities (NAPRA). Model Standards for Pharmacy Compounding of Non-Sterile Preparations. March 2018. Retrieved 1/25/22.
  4. NIOSH. NIOSH Alert 2004-155. Preventing Occupational Exposure to Antineoplastic and Other Hazardous Drugs in Health Care Settings. Retrieved 1/25/22.
  5. NAPRA. Model Standard for Pharmacy Compounding on Non-Sterile Preparations. Page 12. Retrieved 1/25/22.
  6. Roussel C et al. Meta-analysis of chromosomal aberrations as a biomarker of exposure in healthcare workers occupationally exposed to antineoplastic drugs. Mutation Research/Reviews in Mutation Research. (2017). Retrieved 1/25/22.
  7. NIOSH. NIOSH List of Hazardous Drugs in Healthcare Settings, 2020. DRAFT. Retrieved 1/5/22.

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