Drug delivery

“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. “There are currently ten-plus CSTD brands on the market with dozens of components, 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 drug- handling 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 FDA- approved through the 510k pathway, which requires new products to be deemed ‘substantially equivalent’ to an already approved product. In order to make

World Pharmaceutical Frontiers / 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

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 – Frankie Petoskey of Seattle Genetics and her 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.

“There are currently ten-plus CSTD brands on the market with dozens of components, which makes it very difficult for drug manufacturers to test all different permutations for compatibility with different 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


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