Standardele Societăţii Internaţionale a Farmaciştilor şi Practicienilor în Oncologie (ISOPP) – selecţia aspectelor esenţiale 

Here are a few chapters of this Standard and their con­clu­sions ⁽¹⁾:

Working with dangerous drugs in sanitary facilities can cause skin rashes. It has been associated with infertility, miscarriages and birth defects, and raises problems with the possible occurrence of leukemia or other cancers. In order to provide workers with the highest degree of protection, employers must implement the necessary administrative and technical controls and ensure that workers apply rigorous procedures in handling dangerous medicines.

Employees’ work practices influence their own professional exposure and that of those around them. Employees must keep up to date with the information on the occupational risk of these medicines and ensure that the working practices they apply comply with current best practice recommendations.

These standards provide general guidance to help develop processes and procedures to facilitate safe working systems when working with cytotoxic drugs.

We provide you with the most important information on these standards, including the personnel protection measures that prepare these cytostatic solutions and the actions to verify these measures.

Section 5: Hierarchical order of protection measures

Industrial hygiene standards normally include an obligation to comply with a hierarchical level of protection order for employees in the workplace.

An example of this can be found in Directive 2004/37/EC of the European Parliament and of the Council from 29 April 2004 on the protection of workers from the risks related to exposure to carcinogens or mutagens at work.  Most national regulations and legal provisions on health and safety at work also include this obligation.

Taking into account the relevant legal provisions and regulations, the employer must carry out a risk analysis that includes the following steps:

a) the definition of the working areas to be assessed;

b) identification of hazards and inconveniences (as well as classification of substances);

c) the assessment of hazards and inconveniences;

d) specifying the measures necessary to apply;

e) testing and evaluating the effectiveness of the measures and identifying the resulting hazards.

The levels of protection measures in descending order of their importance. It is imperative that protection measures are implemented from level 1 to level 5.

Optimal efficiency:

1. Physical removal of danger.

2. Replacement of danger.

3. Isolation of persons from danger.

4. Changing the way staff work.

Minimum efficiency: 5. Protection of the worker by personal protective equipment (PPE).

Levels 1 and 2: Elimination and replacement

If a less toxic drug has equal or greater efficacy while having a similar or better side-effect profile, the replacement of the initial drug may be a variant to discuss with the curating oncologist. Changing to a less toxic drug is rarely possible in the treatment of cancer patients.

If levels 1 and 2 are impossible, insufficient or imprac­ti­cal, the following level shall apply.

Outsourcing of preparation is a means of disposal, but from the perspective of the whole health system, it still requires appropriate technical, administrative and control measures relating to PPE in order to comply with the hierarchy of measures at the external preparation site. The use of ready-to-administer products (RTA) is a recent progress that can also be considered locally as disposal, as no preparation is required in the hospital pharmacy. These measures reduce the number of potentially exposed workers within the organization.

Level 3:Technical and ventilation measures

The safety niche for cytotoxic drugs (CDSC) and aseptic preparation isolator (CAI) are level 3 measures. CDSCs provide controlled airflow, protection shields and HEPA filters. Because it provides through transfer boxes and gloves ports, as well as HEPA filters, a physical barrier between the product and the operator, remaining possible contamination when handling the medication or product. CSTDs provide an additional level of protection for employees, making contamination impossible when using effective transfer systems. Without CSTD, contamination inside the CDSC or CAC cannot be prevented or completely prevented.

As set out in section 10 and 26 of the ISOPP 2022 standard and jointly with the Occupational Health and Safety standards, current evidence does not suggest that there is a safe level of cytotoxic exposure, therefore cytotoxic exposure should be limited using CSTD until there is sufficient evidence to establish that practice without CSTD is safe for operators.

Once contamination has occurred, it will inevitably enter the environment. Technical and ventilation measures should be used for the preparation of cytotoxic medicinal products, together with levels 4 (administrative measures) and 5 (PPE).

Level 4: Administrative control measures and organizational measures

Administrative measures aim to minimize exposure time, the number of workers exposed, and maximize the effectiveness of technical measures. Some examples of administrative measures are system operational procedures (SOP), operator training and validation.

For the preparation of cytotoxic drugs within the CDSC and CAC, there must be training and validation procedures.

Level 5: Personal protective equipment

The use of PPE is the last protection barrier for workers and must be preceded by technical and administrative measures to minimize the presence of toxic products in the environment. Gloves, masks, gowns, goggles or visors and other equipment create a temporary barrier between contamination and the operator. It is recom­men­­ded to provide training on equipping and disfitting properly with and PPE. Safe working practices should be incorporated into SOPs and regularly reviewed and updated. All staff should be trained in accordance with these procedures, and the performance should be assessed regularly.

Section 6: Sterile reconstitution units for cytotoxic medicinal products and personal protective equipment

Sterile cytotoxic reconstitution units shall ensure the protection of the product and persons handling the medicinal products. Aseptic handling of medicinal products must take place in a controlled environment to ensure the sterility of the finished product. Additional protective measures are needed to ensure the safety of operators.

6.1. Centralized preparation

The centralized preparation of cytotoxic parenteral medicinal products should be implemented to protect the final product from microbiological and particle contamination and to protect persons handling it from exposure to cytotoxic medicinal products. Taking into account the pharmaceutical analysis and the quality control system implemented, centralized preparation improves the quality of the preparation and the safety of patients. The centralization of services also provides economic benefits. Centralization is usually done in the pharmacy. Many institutions have their own pharmacy with a preparation unit located in an oncological outpatient or near the stationary section where chemotherapy is most commonly administered. This facilitates the transport of cytotoxic drugs and better communication between pharmaceutical staff, doctors and care personnel. Under no circumstances should care personnel be allowed to prepare or reconstruct cytotoxic substances in the clinical section.

6.2. Preparation units

Due to the risks of chemical contamination of the environment and chemical cross-contamination, the reconstitution and preparation of cytotoxic drugs should be carried out in a room with a controlled area – a clean room, technically referred to as “Containment Secondary Engineering Control” (C-SEC). The clean room must be ventilated from the outside, with autonomous heating, ventilation and air conditioning (HVAC) systems dedicated to these tasks, provided with similarly dedicated equipment. Aseptic preparation insulators (ACOS) may not require the imposition of these requirements.

Access to the clean room must be restricted to trained personnel. A warning sign must make this clear. It is recommended to use standard symbols and colors to identify cytotoxic substances.  A text such as “cytotoxic preparation area” should be used for this sign, or “Restricted access to authorized personnel”.

We list below the necessary characteristics to be followed for proper preparation of cytostatic solutions, namely:

6.2.1. Clean room class.

6.2.2. Differential pressures.

6.2.3. Change of air.

6.2.4. External discharge of air from the working area.

6.2.5. Temperature and humidity.

6.2.6. Access of staff to the clean room.

6.2.7. Crossing hatches (precinct – SAS).

6.2.8. Storage room.

6.2.9. Monitoring of facilities and premises.

6.2.10. Microbiological monitoring.

6.2.11. Removal of particles from the air.

6.2.12. Certification and quality assurance.

6.2.13. Validation.

6.3. Clothing and PPE

The selection and use of PPE must ensure the sterility of the finished product and protect the operator. PPE must be worn to protect personnel during the reconstitution of cytotoxic medicinal products and other activities in which they may come into contact with cytotoxic medicinal products.  Activities include unpacking of medicinal products, handling of bottles or finished product, labeling of medicinal products containers or disposal of waste.  PPE includes gloves, gowns or suits, boots or shoe covers, masks, head coverings and safety goggles.

The specific protective equipment required will depend on the classification of the room in which the operator works. The highest level of protection is allocated for A/B areas, where aseptic handling is performed (CDSC in a class B room).

Section 7: Insulation systems, including closed transfer system devices (CSTD)

7.1. Insulation systems for primary packaging

In the late ’90s, several studies indicated that vials and vials delivered by pharmaceutical companies may be contaminated externally with the cytotoxic drug. In some cases, contamination was detectable in up to 30-50% of the tubes examined. This was the result of contamination during the manufacturing process (e.g., foam or dust formation from the powder medicine) and/or inadequate flushing of the bottles before packaging. Many companies now devote more attention to this problem, but with different levels of success.

It is strongly recommended that cytotoxic drug vials be sealed in a plastic coating to limit any possible contamination to the outside of the tube. This plastic coating should also cover the bottom of the tube. For this purpose, many manufacturers currently supply cytotoxic drugs in thermocontractable plastic film. Some manufacturers supply cytotoxic drugs encapsulated in molded plastic containers, specially designed to limit any possible contamination and also to protect them from any shock during transport. Many manufacturers currently provide cytotoxic substances in this way. Individual packing in shock absorber material is required.

The test reports shall document the ability of the packaging to adequately isolate all contents in the event of a vial or ampoule breaking. It is the responsibility of pharmaceutical manufacturers to ensure that the external surfaces of the drug bottles are not contaminated. An objective way to ensure the commitment to deliver noncontaminated products is to require an analysis by an independent laboratory detailing the quantities of the product on the outer surface of the first vial(s), as well as the middle and the last vial(s) in the prepared batch (see also Section 2.1.6). Pharmacists should favor manufacturers who take this issue seriously and are willing to work together to ensure that the bottles are not contaminating.

7.2. Closed drug transfer system (CSTD) devices

CSTD has been developed for use in the preparation and administration of cytotoxic drugs.  The most complex definition of a CSTD is presented by NIOSH.

A CTSD is a drug transfer device that mechanically stops the transfer of contaminating materials from the environment into the system and releases dangerous concentrations of drugs or vapors outside the system. Studies have shown environmental contamination and occupational exposure to cytotoxic drugs substantially lower when using CSTD compared to traditional techniques. Exposure could have occurred during routine handling of drug vials and vials, aseptic preparation, drug administration, and cytotoxic waste disposal. In most countries, the use of CSTDs is recommended, according to European Directive 37/2004, implemented in Romania through GD 1093/ 2006 revised in 2022 and entered into force on March 11, 2024. CSTDs may be used in addition to collective and individual protection measures and means.  Contamination of the outer surfaces of the bottles and packaging remains a problem and contributes to the spread of contamination on surfaces and work areas during the work carried out. In 2012, the U.S. Food and drug Administration (FDA) issued the ONB product code for CSTDs, but no performance standards were set to obtain 510(k) authorizations. Therefore, concern remains whether approved CSTDs are really closed systems.

Section 10: Monitoring contamination with cytotoxic drugs

The risk that handling cytotoxic drugs poses to healthcare professionals depends on the inherent toxicity of the drugs and the degree of exposure that the professional can reach during daily activities. There are various routes of exposure to cytotoxic drugs in sanitary facilities. While skin pathways and inhalation are probably the most common, hand-to-mouth exposure and accidental needle stings can also contribute to this exposure.

Exposure limits for toxic chemicals have been established in many professional environments. No exposure limits have been established for concentrations of cytotoxic drugs in suspension. However, some exposure limits have been set for soluble salts of platinum and inorganic arsenic, which would include cytotoxic drugs: cisplatin, carboplatin and arsenic trioxide.

Sampling by erasing surfaces and sampling for suspended drugs were the two main procedures for determining workplace contamination with cytotoxic drugs. These procedures have been used in many other professional environments to determine the level and degree of contamination in the workplace and to establish safety levels for hazardous substances.

Some pharmaceutical manufacturers have developed occupational exposure limits (OELs) to be used in production facilities. However, these OELs are used in the context of handling a single drug in a production line that is almost entirely automated. For hospital pharmacies, OELs are not suitable.

For genotoxic products, including many antineoplastic drugs, there is no safe level – the goal should be zero contamination.

In this context, in order to be able to have effective monitoring of contamination, we need to look at the following issues, namely:

• Exposure conditions.
• Environmental contamination.
• Sampling strategies.
• Surface sampling and analysis.
• Sampling air.
• Alternative techniques.

For the most commonly used cytotoxic drugs, sensitive methods have been developed. But because many cytotoxic drugs and other dangerous drugs are used in the healthcare environment, studies can only estimate global exposure. In order to reduce chemical contamination, it is necessary to assess workplace hazards, handle medicines safely, and use and maintain equipment properly. Monitoring of environmental contamination by surface removal is recommended at least once a year to check cleaning procedures and potential exposure of health workers to cytotoxic drugs, but it is important to follow institutional procedures. Monitoring of environmental contamination is also recommended one month after major changes occur in the area where cytotoxic drugs are prepared or administered, such as moving furniture.

Autor corespondent:Constantin Jelescu E-mail: constantin.jelescu@transferpharma.ro 

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

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