Close of play25 May 2021
Given the lack of standardisation on shape, size and material for closed-system transfer devices (CSTDs), many pharmaceutical companies are struggling to ensure their products work with the array of them in use worldwide. The problem is compounded when CSTDs – originally designed to protect users while handling drugs – are used to hold high-value biologics, for which compatibility issues could have major financial consequences. Jim Banks speaks to Amgen process development scientist Twinkle Christian about potential solutions.
Closed-system drug transfer devices (CSTDs) are commonplace in hospitals, clinics and research labs – any environment in which drugs are handled. Their fundamental purpose is simple: protect users from coming into contact with a drug and, by extension, prevent the drug itself from being contaminated.
The US National Institute for Occupational Safety and Health (NIOSH) defines a CSTD as “a drug transfer device that mechanically prohibits the transfer of environmental contaminants into the system, and the escape of the hazardous drug or vapour concentrations outside the system”. As such, it has to preserve the quality of a drug until it is administered to a patient. Inevitably, there are risks in the use of CSTDs. If they are not properly handled, or if their design does not meet the requirements of a particular use case, then contaminants could enter the system or users could be exposed to harmful substances. If hazardous drugs, such as those used in chemotherapy, leak, then the consequences could be dire. Alongside risks to patients and healthcare professionals, there are other risks to take into account, principally the danger that high-value biologics could be rendered unviable by the use of a CSTD that is not fit for purpose. “This is not a new issue,” says Twinkle Christian, process development scientist in the Drug Product Technologies Department at Amgen. “In 2015, the FDA issued a warning against using a specific CSTD with a chemotherapy drug. It was found that the material of construction interacted with an excipient in the drug formulation and could result in a breakdown of the CSTD material.” Christian, who co-authored a report published in 2020 entitled ‘Challenges of using closed-system transfer devices with biological drug products: An industry perspective’ in the Journal of Pharmaceutical Sciences, has almost 15 years’ experience in formulation development across diverse modalities. She has led the advancement of multiple programmes from early discovery to clinical trials and commercialisation. Drawing on her expertise in the high-concentration formulation and delivery of biologics, she has looked closely at the limitations of CSTDs in their emerging use cases.
“Several studies have found that there are significant differences in the design and performance of commercially available CSTDs,” she says, “which can give rise to technical challenges with respect to drug product compatibility, both physical – as in stopper coring and variable hold-up volume – and chemical – as in the potential impact on product quality due to exposure to certain materials of construction.
“Right now, there are around 20 CSTDs on the market, which makes it very difficult for drug manufacturers to test all different permutations for compatibility with different drug products.”
Much room for improvement
Lack of investment in CSTDs is not the problem. Awareness of the potential risks of handling hazardous drugs has grown, leading the healthcare industry to seek better solutions. Christian and others also see a need for new and better devices. As it stands, a recent review of 23 studies by medical research charity Cochrane found ‘no evidence for or against adding CSTDs to the safe handling of hazardous medicines’. NIOSH, however, recommends the use of CSTDs throughout the hazardous drughandling chain, from pharmaceutical compounding to patient dose administration. Though the concept of CSTDs clearly makes sense, there is an urgent need to ensure they are robust and reliable, and that they are used properly.
A key problem is the lack of standardisation in design. The market is awash with unique CSTDs using different materials and lubricants, resulting in variations in performance parameters. “The primary concern with CSTDs is the potential compatibility issues,” Christian explains. “These devices are FDAapproved through the 510k pathway, which requires new products to be deemed ‘substantially equivalent’ to an already approved product. In order to make the performance of these devices more consistent, we would like to see more stringent requirements on product design and performance.”
In a paper entitled ‘Overcoming challenges of implementing closed-system transfer device clinical in-use compatibility testing for drug development of antibody drug conjugates’ – also in the Journal of Pharmaceutical Sciences – Frank Petoskey of Seattle Genetics and his co-authors highlight the need for more in-depth research into the complexities of CSTDs to better understand the potential for leachables or extractables to pass into drug products.
In examining FDA-approved CSTDs, Petoskey et al simulated the compounding and administration of a late-phase IgG1 antibody-drug conjugate (ADC), then analysed the compound using visible and subvisible particle counts by light obscuration and micro-flow imaging, physical stability by size exclusion chromatography, and biological activities by relative potency. The results revealed that, with one CSTD, subvisible particles entered the ADC during compounding. The conclusion was that clinical in-use testing with new devices is essential, as increasingly novel and complex designs mean that CSTDs are not interchangeable. Each may have its own specific use case, so individual devices require testing in specific applications to ensure that they perform to the required standards.
Christian and her colleagues point out a similar issue, focusing on antineoplastic agents used in oncology drugs. Safety is a high priority, as the small-molecule antineoplastic agents that commonly feature in cancer treatment will attack both cancerous and healthy tissue, making it essential that healthcare workers are not exposed to their effects. But while much has been done to evaluate the performance of CSTDs for small molecule drug containment, there has been very little evaluation of such devices for use with biological products, such as monoclonal antibody drugs, which specifically target cancer cells, but are also classified as antineoplastic agents. “Another important consideration is that there likely needs to be studies that look at whether these devices truly need to be used with biologic drugs,” says Christian. “Data we have seen suggests that the potential risk/benefit with biological drugs may not be positive.”
Both NIOSH and the US Pharmocopoeia (USP) Convention’s delayed USP 800 Hazardous Drugs protocol recommend the use of CSTDs in the compounding and administration of hazardous drugs. “USP recently developed a new chapter with guidelines, which includes the use of CSTDs, for handling drugs that are considered hazardous and references the Hazardous Drug List published by NIOSH,” explains Christian. “In recent years, NIOSH has begun including some biologics on the list, which has resulted in increased use of CSTDs with biologic drugs.”
“This is important because most biologics are very different to traditional antineoplastic drugs in that there is very low risk of exposure from inhalation or absorption through the skin,” she adds.
Given some of the contamination risks with biologic drugs, the USP decision could soon be looked on as further evidence of the limitations of insufficiently precise regulation. What has emerged from the work of Christian and others is that the unified CSTD test protocol to assess the performance of CSTD systems does not look in depth at the potential incompatibility of drug products with the individual components in any given CSTD.
In essence, the problem is not with the devices themselves, but with the approach taken for their use. As CSTD designs proliferate, as their complexity increases and as the nature of the agents they contain evolves, regulation must keep pace and more research must be done to assess specific devices in specific use cases. At present, statements forbidding the use of CSTDs with incompatible hazardous drugs in USP 800 are compromised by the fact no guidance is provided for how or by whom an incompatibility is established, or what constitutes an incompatibility. It’s just one example Christian and her co-authors highlight in arguing that the lack of clarity around CSTD requirements and the room for interpretation across facilities “make it challenging for drug manufacturers to anticipate how their products will be handled, to understand how compatibility with CSTDs should be established, or to place limits around the application of CSTDs to their products”.
Christian and her colleagues recommend a number of actions. The first and, by implication, most important is for regulators to give feedback on the use of CSTDs for biological drug products. Their belief is that a comprehensive compatibility study with each commercial CSTD type should be undertaken for each investigational product, though they recognise that this would cause delays in bringing drugs to market. Nevertheless, health authorities need to understand the interaction between new drugs and the CSTDs with which they might be used.
Alongside the need for more in-depth analysis comes a need for healthcare professionals to be trained in how to use CSTDs in specific settings, so that neither the device nor the person using it is introducing more risk. The report advocates for more CSTD education and in-person training at clinics to promote better understanding of how each component – and each unique combination of components – will perform.
This would be a big task and no one is suggesting it would be simple, but the adoption of a standard operating procedure for the handling of CSTDs would be a good starting point.
While it may not be possible to study in detail the interaction of every type of commercially available CSTD with a new biological product, more clarity about potential risks and procedures for mitigating those risks is sorely needed. This will only come from a combined effort by regulators, device manufacturers, drug developers and front-line healthcare workers.
USP 800 on CSTDs
Containment supplemental engineering controls, such as CSTDs, provide adjunct controls to offer an additional level of protection during compounding or administration. Some CSTDs have been shown to limit the potential of generating aerosols during compounding. However, there is no certainty that all CSTDs will perform adequately. Until a published universal performance standard for the evaluation of CSTD containment is available, users should carefully evaluate the performance claims associated with available CSTDs based on independent, peer-reviewed studies and demonstrated containment reduction.
A CSTD must not be used as a substitute for a containment primary engineering control when compounding. CSTDs should be used when compounding hazardous drugs (HDs) when the dosage form allows.
CSTDs must be used when administering antineoplastic HDs when the dosage form allows. CSTDs known to be physically or chemically incompatible with a specific HD must not be used for that HD.
Source: US Pharmacopeia