Compounding hazardous medicines

Case scenario

You are working in a compounding pharmacy and are presented with a prescription for an oral tacrolimus suspension for Patrick, aged 8, who has had an organ transplant. Due to the hazardous nature of tacrolimus, compounding the medicine requires
strict adherence to safety guidelines. You begin by reviewing the prescription and consulting the stability data and available formulations for compounded oral tacrolimus suspension. You gather the necessary ingredients and equipment required.

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Introduction

Hazardous medicines play an important role in modern healthcare, offering treatment for diverse diseases and conditions, such as cancer or the prevention of transplant rejection. However, their handling and compounding pose substantial risks to healthcare workers (including pharmacy staff) and others.

This article aims to provide pharmacists with an overview on how to prevent risks associated with handling or compounding hazardous medicines. It discusses the importance of personal protective equipment (PPE), various containment systems and validation processes, and details essential guidance and information resources.

What are hazardous medicines?

Hazardous medicines are drugs that are known to cause harmful effects, including carcinogenicity, developmental toxicity (including teratogenicity), reproductive toxicity, genotoxicity or organ toxicity at low doses.^1,2

New drugs with structure or toxicity profiles that mimic existing hazardous drugs, or drugs with product information or safety data sheets that include safe handling information, are also considered hazardous medicines.^1,2

Hazardous medicines include commercial products, compounded medicines, and ingredients of compounded medicines. They should all be treated similarly, according to an assessment of the exposure risk to healthcare workers and others.² 

Medicines used in cancer chemotherapy, sex hormones, certain antivirals, gene therapy, highly sensitising or highly irritant substances, medicines that can cause infection (i.e. Bacillus Calmette-Guérin instillation), nicotine and certain monoclonal antibodies are examples of hazardous medicines.²

Handling and compounding hazardous medicines

The handling and compounding of hazardous medicines can pose significant risks to healthcare workers and others. The occupational exposure risks to healthcare workers are mainly through internalisation of the hazardous substance through ingestion, aerosol inhalation or absorption through skin and mucous membranes.¹

To prevent adverse health effects, these medicines may require safe handling precautions by healthcare workers. Hazardous medicine compounding is considered complex compounding.²

Essential considerations

The following are essential considerations when undertaking hazardous medicines handling or compounding^2–4:

• Before handling or compounding hazardous medicines, pharmacists must undertake appropriate training and validation of skills (e.g. validated workplace training or training course).
• Regulatory requirements that pharmacists must comply with include, but are not limited to, occupational health and safety regulations. See Table 1 for resources that can be used to ensure pharmacists are following the latest guidelines and best practice. It is important to note that this list of resources is not exhaustive, and pharmacists should also consult any additional guidelines specific to their practice setting, as well as the regulatory authorities in their state or territory. Regularly reviewing these and staying up to date with new guidelines is essential.
• A risk assessment must be performed before handling or compounding a hazardous medicine. This should be based on the toxicity of the substance, the potential routes of exposure, and the types of control available. For example, a pharmacist opening tacrolimus capsules to use the contents to make a tacrolimus suspension poses a higher risk of unintended exposure to tacrolimus than if a pharmacist was to repackage sealed tacrolimus capsules.
• A process risk assessment should also be conducted to examine each of the steps taken when handling hazardous medicines, including receipt of starting material, compounding, packaging, transport, administration, and waste management.
• All staff handling hazardous medicines should be familiar with the Material Safety Data Sheet (MSDS) of the medicine they are handling. The
  MSDS is useful in showing hazards identification and toxicological information, and first aid measures required if exposure occurs. Staff knowledge on location and access of MSDSs should be checked periodically.
• There are several levels of protection measures available to ensure safety of staff. Personal protective equipment (PPE) and containment systems are two important factors to prevent staff exposure to hazardous medicines and will be discussed further below.

For more information, see the new ‘Handling or compounding hazardous medicines’ chapter in the Australian Pharmaceutical Formulary and Handbook (in APF26 or APF digital).

Personal Protective Equipment

PPE acts as a barrier between the hazardous medicine and the person, preventing direct contact and exposure to potentially harmful substances.

Different levels of PPE are required depending on the activity carried out. For example, dispensing oral dosage forms of a commercial product would have different PPE requirements to compounding hazardous medicines from raw materials. The Victorian Therapeutics Advisory Group (VicTAG) provides a useful PPE recommendation chart.

The effectiveness of PPE used for handling or compounding hazardous medicines should be supported by reputable evidence. This means that the PPE should have been tested against a range of chemicals and medicines for resistance or permeability.³ Pharmacists should purchase PPE from reputable suppliers and review the evidence of protection against the hazardous medicines to be handled or compounded.

PPE that should be considered for hazardous medicine handling or compounding includes^3–6:

1. Gloves: help protect the hands and skin from direct contact with hazardous substances. It is important to select gloves that are specific to hazardous medicines, such as chemotherapy gloves which are made of materials that provide superior chemical resistance.
Some references also recommend using two pairs of gloves for
handling of chemotherapy; this should be documented as part of the risk assessment.

2. Gowns: are worn to protect the body and clothes from contamination. Disposable gowns made of impermeable materials are preferred, as they can be disposed of after use to prevent tracking hazardous materials from the compounding rooms to other areas. Gowns should be long-sleeved and cuffed, to cover the entire body. Since most hazardous spills occur to the front of the body, gowns should fasten at the back, to allow the safe removal of a soiled gown. Any soiled gown should be disposed of as hazardous waste immediately; a gown soiled with cytotoxic material should be disposed of as cytotoxic waste.

3. Respiratory protection: Compounding a hazardous medicine can generate airborne particles, dust, or vapours that can be harmful if inhaled. Respiratory protection, such as N95 masks, or more protective respirators, should be used to filter these particles and protect the respiratory system. This is especially important when compounding with hazardous powders and vapours. Specific respiratory protection is needed against inhalation of gases, vapours, or liquid splashes.

4. Eye and face protection: Safety goggles or full-face shields should be worn to protect the eyes and face from potential splashes or spills. A combination of both should be considered if a full range of protection for the face and eyes is needed. Personal glasses or spectacles are not a substitute for protective eyewear.

5. Shoe covers: are recommended to prevent contamination of shoes and
to minimise the risk of tracking hazardous medicines outside the compounding area. Disposable shoe covers made of impermeable materials should be used and changed regularly to maintain cleanliness and reduce cross-contamination.

6. Head covers: such as disposable bouffant caps or hoods, are used to cover the hair and prevent the contamination of the compounding area. They also provide protection
from contact with hazardous residue.

It is essential for compounding personnel to receive proper training on the correct usage and disposal of PPE. This includes instruction on the proper sequence of donning and doffing PPE, as well as the disposal of contaminated PPE.^3,4

Regular inspection and maintenance of PPE is crucial to ensure its effectiveness. Gloves should be inspected for any signs of damage or wear and changed as necessary. Gowns and other disposable PPE should be discarded after each use to avoid cross-contamination and maintain a clean environment.^3,4

Containment system

The containment primary engineering control (C-PEC) is a critical component in ensuring the safety and integrity of hazardous medicine compounding. It refers to the specialised equipment and facilities used to contain and control hazardous medicine within the compounding area. The C-PEC serves as a barrier between the compounding personnel and the hazardous medicine, preventing the release of harmful particles or vapours into the surrounding environment.^3,4

The most used C-PEC in hazardous medicine compounding is the biological safety cabinet (BSC), specifically designed to maintain a controlled environment. BSCs are classified into three different types based on their design and airflow patterns – Class I, Class II, and Class III^3,4:

1. Class I BSCs: provide personnel and environmental protection by drawing contaminated air away from the operator. Class I BSCs are useful for
the preparation of non-sterile hazardous medicines.

2. Class II BSCs: provide personnel, environmental, and product protection through a combination of downward and rearward sterile airflow and all feature a high-efficiency particulate air (HEPA) filter, which removes harmful particles and prevents their release into the surrounding environment. Class II BSCs used for cytotoxic compounding must not exhaust air into the cleanroom and should have total exhaust into dedicated exhaust exits.

3. Class III BSCs: also known as glove boxes, provide maximum containment for handling high-risk or extremely hazardous medicines. They are completely enclosed and feature two sets of gloves, through which compounding activities are performed. These are generally used in dealing with highly infectious microbiological agents and are not found in compounding pharmacies.

In addition to BSCs, other C-PECs commonly used include compounding aseptic containment isolators (CACIs) and isolator technology. CACIs combine the benefits of a ventilation system and a physical barrier to ensure the safe handling of hazardous medicines. They are typically used for low and medium-risk compounding and provide protection against cross-contamination.^3,4

Isolator technology involves isolating the compounding process within a fully enclosed system, eliminating any potentially harmful substances from
being released into the surrounding environment. Isolators used in hazardous medicine compounding operate at a negative pressure and rely on gloves and airlock systems for operator access.^3,4

BSCs and CACIs both need to be placed in a specific compounding area that is separate from the rest of the facility and is dedicated and controlled to minimise the risk of exposure of pharmacy personnel, the public and the environment to hazardous medicines. The controlled area is also referred to as Containment Secondary Engineering Control (C-SEC).^2–4

When using any type of C-PEC, it is crucial to regularly monitor and validate their performance to ensure they are functioning as intended. This includes regular certification, maintenance, and airflow velocity tests to verify proper containment and protection at least once a year. Ongoing training and education of compounding personnel on proper C-PEC usage and maintenance are also essential to minimise risks and ensure the safety of all individuals involved in hazardous medicine compounding.^3,4

Validation and record keeping

Validation plays a pivotal role in hazardous medicine compounding as it offers crucial insights into the functionality of processes, equipment, and systems. By evaluating and verifying performance, accuracy, and reliability against predetermined standards, validation ultimately ensures the safety and effectiveness of the engineering controls and processes.^3,4

The validation process for hazardous medicine compounding typically involves several key elements^3,4:

1. Process validation: This focuses on the compounding procedures and practices used to prepare hazardous medicines. It includes evaluating the consistency and reliability of compounding processes to ensure that the desired outcomes are consistently achieved. Process validation involves verifying critical parameters, such as cleaning and measuring.

2. Equipment validation: Equipment used, such as automated compounding systems, BSCs or CACIs, must be validated to ensure their performance and effectiveness. This involves verifying accuracy and functionality, airflow, air quality, and containment capabilities to maintain a controlled environment. Performance verification and certification of equipment, including regular maintenance and calibration, should be contracted to National Association of Testing Authorities (NATA) accredited providers to ensure that appropriate standards are adhered to.

3. Documentation and record keeping: Proper documentation and record keeping are essential in the validation process. Accurate and detailed records should be maintained to document all stages of the compounding process, including materials used, personnel involved, equipment used, environmental monitoring results, and any deviations or corrective actions taken. These records serve as evidence of compliance and provide a historical reference for validation activities.

Compounding sterile hazardous medicines should also involve rigorous environmental monitoring and sterility testing. In some instances, container closure integrity testing may also be required. Regular review and reassessment of validation processes are necessary to ensure that they are up to date with current regulations and industry best practices.^3,4

Knowledge to practice

In addition to following good compounding practices, pharmacists must possess a comprehensive understanding of the risks associated with the medicines they handle during compounding. When working with hazardous medicines, it is imperative to implement and document appropriate strategies to mitigate these risks.

All personnel involved in handling or compounding hazardous medicines must receive thorough training to comprehend the risks associated with these medicines, enabling them to make informed decisions, take responsibility for adhering to proper procedures, and foster an environment conducive to discussions that promote continuous improvement.

Pharmacists should prioritise staying up to date with the latest evidence and guidelines and commit to regular reviews of their procedures to ensure ongoing adherence to best practices.

Conclusion

With pharmacists playing a crucial role in the handling and compounding of hazardous medicines, a comprehensive understanding of the associated risks is paramount. By diligently adhering to the necessary requirements and accessing reliable resources, pharmacists can uphold the highest standards of patient care and prioritise occupational safety throughout the handling and compounding process. This commitment ensures the well-being of those involved in the handling and compounding process and safeguards the integrity of the compounded medications.

Key points

• Pharmacists involved in hazardous medicine handling and compounding must comprehend the risks and implement appropriate strategies
  to protect all personnel involved.
• Correct training and equipment, supported by appropriate risk assessment and management, protection measures and validations are key to ensuring the safe handling and compounding of hazardous medicines.
• Pharmacists should refer to key resources and stay updated with the latest evidence and guidelines.

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References

1. Connor TH, MacKenzie BA, DeBord DG, et al. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings. Cincinnati, OH. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health. 2016.
2. Sansom LN, ed. Australian pharmaceutical formulary and handbook. 2024. Compounding; [updated 2024 Feb 16]. At: https://apf.psa.org.au/compounding/good-compounding-practice-0
3. USP <800>: Hazardous drugs–handling in healthcare settings. Rockville, MD. United States Pharmacopeial Convention. 2016.
4. International Society of Oncology Pharmacy Practitioners. ISOPP Standards for the Safe Handling of Cytotoxics. J Oncol Pharm Practice 2022;28(3 (supplement)):1–126.
5. Victorian Therapeutic Advisory Group. Handling of Hazardous Medicines Victorian Framework. 2021. At: ,victag.org.au/VicTAG_Handling_of_Hazardous_Medicine_Framework_Nov_2021_Final.pdf
6. Easty AC, Coakley N, Cheng R et al. Safe handling of cytotoxics: guideline recommendations. Current oncology (Toronto, Ont.) 2015;22(1):e27–e37.

Our author

Dustin Wee Tong Sim (he/they) BPharm PG Cert Pub Hlth is a pharmacist with a diverse background in hazardous and sterile compounding, including experience in oncology and a TGA licensed sterile compounding facility. He has also contributed his expertise to setting up a cancer project in Malawi for Doctors Without Borders, highlighting the importance of safe practices in hazardous drug compounding.

Our Reviewer:

Joe Tsai BPharm (Hons), MPharmPrac, MSHP, BCGP Quality and Clinical Trials Pharmacist.