Understanding risks with injectable medicines
Medicines administered by the injectable route provide several clinical advantages such as rapid onset of action, high bioavailability and avoiding the pharmaceutical challenges of oral administration such as drug degradation by stomach acid and reduced bioavailability.
However, the consequence of errors or contamination can result in severe patient harm when medicines are administered by injectable routes. Injectable medicines bypass the body’s natural defences against microorganisms, such as the skin and gut. If the medicine is contaminated (for example, during reconstitution) this poses a significant risk of infection, especially to immunocompromised patients. All injectable medicines are therefore administered using aseptic non-touch technique (ANTT) to reduce the likelihood of contamination.
Ideally, all injectable medicines would be provided as licensed, sterile, ready-to-administer products. However, this is often unfeasible because many drugs degrade when exposed to factors like heat, water, and oxygen.
As a result, many injectables are presented as a sterile powder or concentrate that must be reconstituted or diluted prior to administration. The reconstitution or dilution process is sometimes referred to as ‘aseptic manipulation’.
It is essential to remember that the finished product cannot be sterilised, and it cannot be tested without destroying the product, so assurance of accurate content and sterility is achieved by strict adherence to good practice principles.
Regulation and good practice in aseptic manipulation
All licensed medicines are supplied with instructions in their Patient Information Leaflet (PIL) and Summary of Product Characteristics (SmPC), and where relevant for injectable medicines these documents include instructions for manipulation.
Medicines should be prepared in accordance with the SmPC and administered immediately following manipulation. If it is necessary and appropriate to deviate from the SmPC or if the medicine is not to be administered immediately, this activity must be performed in a pharmacy aseptic unit.
Manipulation in clinical areas for immediate use
Aseptic manipulation of medicines in clinical areas is termed ‘reconstitution’. Reconstitution is defined as the dissolving, dispersing, mixing or dilution of a medicine for immediate administration in accordance with its SmPC.
Manipulation in pharmacy aseptic service units
Manipulation in a pharmacy aseptic unit enables injectable medicinal products to be made and stored in advance of administration. Labelled, ready-to-administer medicines are manufactured under an MHRA manufacturer’s Specials authorisation or prepared under Section 10 exemption from the Medicines Act 1968 (via Regulation 4 of the Human Medicines Regulations 2012).
Understanding risks when manipulating injectable medicines
Manipulation is associated with several risks that can lead to patient or staff harm. It is essential that all the different risks are fully understood so that they can be adequately controlled.
Microbial contamination
Microorganisms live on skin, hair, clothing, in water and surfaces such as cardboard. They can also become airborne meaning microorganisms are present in most environments, even very clean ones. These can cause severe harm if injected.
When injectable medicines are manipulated, the integrity of the container keeping the product sterile is compromised, so there is a risk of microorganisms contaminating the medicine.
The likelihood of microbial contamination is increased in environments that contain more microorganisms. The use of complex methods, multiple manipulations and multiple containers also increases the risk of contamination.
Microbial proliferation
If microorganisms are introduced during manipulation they may proliferate during storage or administration increasing the risk of sepsis. Proliferation tends to increase with
- increased temperatures, such as storage at room temperature or during administration at near-body temperatures (approximately 32oC)
- the presence of nutrients, for example in medicines containing lipids, amino acids and glucose
- increased time between preparation and administration
- increasing duration of administration
Dose errors
When injectable medicines are manipulated errors may occur. These may include errors in
- medicine and diluent selection and identification
- calculations
- volume measurement
- manipulation method
- labelling
Such errors are more likely to occur in busy environments with many distractions, and where the method of reconstitution requires difficult calculations, multiple steps and unfamiliar methods.
Chemical degradation
Licensed medicines are presented in a way that ensures that they contain the required amount of active drug at the end of their shelf life. Once the medicine is manipulated degradation may occur, in some cases rapidly. This may mean that the product no longer contains the required amount of active drug at the point of administration and harmful degradation products may form.
Chemical degradation pathways and rates can vary from medicine to medicine and are affected by factors such as temperature, light, oxygen and mixing with diluents.
Particulate contamination
Opening glass ampoules may result in contamination with glass fragments, so a filter must be used.
Risks to operators
The Health and Safety Executive Control of Substances Hazardous to Health (COSHH) regulations require control of operator exposure to hazardous substances, including medicines such as cytotoxics. While in their container there is minimal risk of exposure, but this can occur during manipulation, or if there is a spillage.
Control of risks in different settings
The likelihood of error, contamination, proliferation, degradation or harm to operators as outlined above differs between clinical areas and pharmacy aseptic units, so different controls are appropriate in the different settings.
Clinical areas
In clinical areas the risks are controlled in the following ways:
Microbial contamination and proliferation
In a clinical setting there is a significant risk of microbial contamination. Although disinfection, aseptic non-touch technique (ANTT) and the use of sterile single-use consumables reduces the likelihood, contamination does still occur because the environment naturally contains microorganisms.
Manipulation of injectable medicines is performed immediately before administration so that any introduced microorganisms have less time to multiply and proliferate. Infusion should start immediately and be completed within 24 hours of the product being made. This does not eliminate the risk of patient infection but reduces its likelihood. Parenteral nutrition should only ever be manipulated in a pharmacy aseptic suite because it promotes microbial growth.
Errors
Selection, calculation, measuring and dilution errors are more likely in busy clinical settings with multiple distractions and where independent checking may not be practised. Understanding when a check adds value to medication processes (SPS page) provides more information on controlling these risks.
Chemical degradation
When medicines are used immediately after manipulation there is no significant risk of degradation, provided the instructions in the SmPC are followed.
Operator exposure
Hazardous medicines may present risks during manipulation so local risk assessment is required. In some cases, for example cytotoxic medicines, adequate control of exposure will not be possible so these must be made in pharmacy aseptic units.
Pharmacy aseptic units
Pharmacy aseptic units operate under a framework of standards and guidance designed to control the following risks:
Microbial contamination and proliferation
The risk of microbial contamination during manipulation is significantly reduced because the facilities, equipment and working practices are designed to exclude microorganisms. Microbial contamination can still occur despite these controls. Medicines prepared in aseptic units should therefore be stored refrigerated to slow microbial proliferation, provided this does not impact physicochemical stability.
Routine and frequent monitoring gives assurance that these controls are effective.
Errors
Standardised worksheets and procedures guide the process so the likelihood of errors is minimised. Calculations, product selection, and preparation steps are independently checked and supervised to detect errors before the product is released for use.
Chemical degradation
Extended storage and handling outside the manufacturer’s instructions increases the risk of chemical degradation. Pharmacy aseptic units use scientific data and other evidence to make informed decisions which ensure the medicine remains fit for use throughout its shelf life.
The SPS Aseptics Stability tool and stability for aseptic services (SPS page) (registration needed) provide more information.
Hazardous medicines
Hazardous medicines are handled in pharmaceutical isolators to minimise operator exposure. Safe working practices reduce the likelihood of spills, and impermeable, smooth surfaces in pharmacy aseptic units enable effective cleaning if spills do occur.
Governance for injectable medicines
As part of the overall Medicines Policy, every NHS Trust should have an injectable medicines policy that defines governance structures and the approach to minimising risks to patients and staff, wherever injectable medicines are manipulated. A template policy is available from the Pharmaceutical Aseptic Services Group (PASG) (registration required).
A risk assessment should be undertaken to
- identify high-risk products for manipulation in pharmacy aseptic service units
- identify appropriate risk mitigation measures for medicines manipulated in clinical areas.
Our articles on preparation risk assessments for ATMPs (SPS page) and risk assessment of preparation of monoclonal antibodies (SPS page) provide further information.