To Issue 142
Citation: Allmendinger A, Mahler H-C, “Anticipating and Mitigating Challenges in the Commercialisation of Prefilled Syringes & Injection Devices – a Technical Drug Product Perspective”. ONdrugDelivery, Issue 142 (Feb 2023), pp 24–26.
Andrea Allmendinger and Hanns-Christian Mahler both at ten23 health, provide an insight into the challenges of integrated development of drug product and device design and fill-finish manufacturing operations.
Ready-to-use (RTU) delivery devices such as prefilled syringes (PFSs), autoinjectors, pens and large-volume injection devices are designed to facilitate administration for the end-user. This allows for self-administration, for example, in case of subcutaneously (SC) administered products, or increases patient safety, for example, for intravitreal (IVT) products administered by a healthcare professional.
“The commercialisation of a combination product, such as a PFS or cartridge-based OBI, presents several key challenges during the technical development and manufacturing of the drug and drug/device combination product.”
The commercialisation of a combination product, such as a PFS or cartridge-based on-body injector (OBI), presents several key challenges during the technical development and manufacturing of the drug and drug/device combination product. This article provides a broad overview of most important challenges from a technical perspective and highlights the importance of integrated development of drug product and device design and fill-finish manufacturing operations.
The selection of a suitable formulation for the API is essential to stabilise the product at the intended storage temperature over the desired shelf life. In particular, selection of the final dose, and therefore concentration of the API, is key as it defines the fill volume of the final drug product. For ophthalmologic products applied to the vitreous humour, the maximum injection volume is currently believed to be 100 μL. For SC administered products, injection volumes have been traditionally considered as limited to volumes of 1 mL or less.
However, knowledge and experience in the clinical setting is increasing with regard to tolerability and usability, and SC administration has recently been facilitated by the development of highly concentrated formulations of greater than 50 mg/mL at injection volumes up to 1, 2 or sometimes 3 mL. The question of what the limit is for SC volumes remains open, but it is inspired by the recent commercialisation of 10 mL cartridge-based OBI device of FUROSCIX (furosemide – scPharmaceuticals).
Besides molecular/biochemical product stability, one of the main technical challenges of highly concentrated formulations is the exponential increase in viscosity with increasing protein concentration. Notably, viscosity is dependent on temperature and shear rate, and subtle variations of protein concentration, even within specifications, can lead to drastic changes in viscosity. Viscosity is associated with both challenges during filling, but also an increase in the injection forces required to administer the product. The latter needs to be mitigated by device design to guarantee functionality and adequate injection time upon stress, stability and transport testing to maintain patient usability.
The variability of components also plays a major role in potential product liabilities and risks. For example, the variability of the inner diameter of the needle used for injection impacts injection forces significantly (by the power of 4, according to Hagen-Poiseuille’s law).
“The drug product manufacturing capabilities must be aligned with the requirements of the device partner and primary packaging supplier to ensure that the drug product will adhere to agreed parameters.”
PRIMARY PACKAGING CONTAINERS RTU CONFIGURATIONS
Combination products are typically filled in RTU primary packaging containers, such as syringes or cartridges, preferably in nest/tub configurations. This means that the container is provided in prewashed and pre-sterilised configuration and ready for filling. However, this implies that device attributes must comply with final drug product requirements throughout the supply chain until the point of filling. This includes the performance of the device and safety relevant parameters, including the risk of potential contaminants, such as absence of micro-organisms (maintenance of sterility) or particles. In particular, novel containers, an increasing number of which have been entering the market lately, require a thorough and, sophisticated characterisation of the primary packaging container and product compatibility. Specifications of primary packaging material must be carefully designed and assessed with the final drug product quality requirements in mind.
However, “traditional” glass containers, such as glass syringes, also require a thorough characterisation of material attributes impacting the injectability over the intended final product-use time and contaminants, such as particle load, must still be assessed (and minimised). In essence, the characterisation of the primary components, with the end quality in mind, is key.
Testing the primary packaging material’s compatibility with the drug product solution and its stability is essential, even more so if novel containers are used. Characterisation should include extractables and leachables testing, container closure integrity and product quality including, for example, particle contamination. Stability testing of drug product filled into the primary containers includes a panel of biochemical and pharmacopeial endpoints that cover critical quality attributes (CQAs), including content and purity, and obligatory CQAs, such as (sub-visible and visible) particulates.
The drug product manufacturing capabilities must be aligned with the requirements of the device partner and primary packaging supplier to ensure that the drug product will adhere to agreed parameters. The drug product manufacturer needs to be capable of reliably and consistently filling the related primary packaging containers (e.g. larger-volume cartridges, syringes or special containers), ideally offering RTU containers.
The filling process is especially challenging for highly viscous and low-volume products. The manufacturer should be able to handle a highly viscous product from the processing side, such as by choosing between different pumps, and be able to choose between weight or volume fill.
In general, overfills must be minimised as this is likely to result in significant cost savings. This is especially important for IVT products. Administration volumes of IVT products are in the range of 10–100 μL, which is often much less than the minimal volume that can be filled by most sterile facilities and contract manufacturing organisations. As a result, most products for IVT use are significantly overfilled. In addition, this also means that syringes for IVT use need to be manipulated by the final user, preferably a healthcare professional, by either expelling air or volume, which is also referred to as “downdosing”. However, this carries a risk of variability in the volume administered.
Another challenge arises during (air) transport. The design of fill volume and allowable headspace with the chosen primary packaging is key as the transport conditions may lead to stopper movement, which may impact container integrity and, hence, potential loss of sterility. Therefore, a bubble-free plunger setting at the manufacturer facility allowing for minimal headspace, as well as the control of the plunger stopper position and stoppering under vacuum to allow reduced plunger compression (for example, for silicone-free container closure systems) is beneficial.
Joint and integrated development between product development – including formulation design – and selection of primary packaging container, device design and manufacturer is essential to transfer product knowledge, facilitate troubleshooting activities and enable successful commercialisation. Challenges and failure modes need to be appropriately assessed a priori, and appropriately mitigated and managed. This includes appropriate formulation development, manufacturing process design and holistic consideration of the interplay of the formulation and raw materials, primary packaging, fill process unit operations, usability and administration, as well as all their acceptance criteria and specifications, in order to yield a safe and efficacious final product.
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