The supply chain forum: four pillars of capsule-based dry powder inhaler (cDPI) optimisation (part I)

Affordable and patient-centric, capsule-based dry powder inhaler (cDPI) combinations are providing the flexibility developers need to optimise the delivery of their increasingly complex pulmonary formulations

Because cDPI is proving to be such an efficient pulmonary drug delivery route for an expanding list of indications, there’s increasing interest in leveraging the potential of the modality among drug innovators and developers.

The key to a successful cDPI combination product stems from aligning the chemical and physical attributes of the different components and engineering them to work in concert to deliver the dose reliably and accurately.

Recently, Lonza Capsules and Health Ingredients hosted a Virtual Innovation Day roundtable to explore the cDPI innovation value chain and discuss developments with experts Frédérique Bordes-Picard (FBP) from Lonza, Mirjam Kobler (MK) from lactose excipient manufacturer, Meggle, Patrick Goncalves (PG) from filling equipment supplier Harro Höfliger and Marko Franza (MF) from DPI device manufacturer Berry.

cDPI combination success rests on four important pillars: formulation and flow, capsule compatibility, filling flexibility and device form and function. Everyone invited to the roundtable had one thing in common: each forms a key pillar of the cDPI product development value chain.

So, how does the sum of their individual contributions add up to a whole of greater value to drug developers? Dr Kevin Robinson began the dialogue by exploring how to prepare DPI formulations for flight.

KSR: Formulation must play a key role in optimising APIs for inhalation, so what do developers need to understand about chemistries and excipients in DPI formulations?

Mirjam Kobler

MK: The successful development of most DPI formulations depends on lactose as a carrier material for the active pharmaceutical ingredient (API). Lactose is a proven vehicle for inhaled APIs.

Of course, developers need to carefully consider the device, the dose’s primary packaging (in this case the capsule, magazine or reservoir) and, ultimately, its filling and finishing early in formulation.

When it comes to DPIs in combination with its device and packaging, there are many synergistic aspects that developers need to consider. Ideally, all functional and formulation interactivity should be carefully evaluated at the beginning of development.

A carrier material is such a pivotal excipient for a DPI formulation. Particles that can be delivered to the lungs are typically in the size range of 1–5 µm.

Unfortunately, these materials come with a big disadvantage; they can be very, very cohesive. This leads to variation, poor flow and processability. Dispersing the API as formulated in the lung requires a carrier material.

It supports the function of airborne delivery and can improve both dispensing and metering. For many current formulations, lactose is the choice of carrier for DPIs.

Patrick Goncalves

PG: Of all the things to consider regarding DPI formulation and effective downstream commercial-scale manufacturing, don’t forget its compatibility with feeding and filling operations. Within the DPI world, there are three semistandard inhaler technologies to choose from: reservoir, blister and capsule.

Although we are focusing on capsule-based inhalers, when it comes to filling and finishing any of the three packaging modalities, it’s important to understand the critical role of the powder-feeding process.

Regardless, manufacturing a highly “feedable,” flow-oriented formulation for any DPI is a good place to start to ensure the therapeutic and commercial success of the product with payers and patients.

FBP: That’s true! For cDPIs, it’s the overall compatibility and functionality of the “triangle” of shared critical parameters that developers have to get right: the device, the powder (formulation) and the capsule. For each of these components, there are a number of critical attributes that are important to identify and key issues to mitigate.

Optimal DPI formulation composition and dose are generally defined by particle mass, particle size distribution (PSD) and their shape or morphology. Chemistries need to offer several other functional attributes to the mix as well, such as chemical stability, hygroscopicity and the ability to deagglomerate.

Generally speaking, the optimal performance of an inhalable dry powder formulation depends on the aerodynamic particle size distribution (APSD) and the emitted dose’s fine particle mass (FPM).

KSR: Given that cDPIs rely on capsules, a proven oral dose technology, what makes capsules such a solid choice for combined inhalable therapeutics?

Frédérique Bordes-Picard

FBP: There is an increasing interest in the inhalation route throughout pharma development. Both the innovative clinical pipeline as well as the 505(b)(2) route have promising programmes under way, and the industry has been consistently identifying new indications for DPI formulations and the application of cDPIs across the therapeutic spectrum.

Treatment affordability and patient access are two more reasons why the cDPI combination is increasingly considered for the pulmonary delivery of DPI formulas. Simple, patient-friendly cDPI devices can cost less and offer simple, straightforward actuation, mobility and reliable metered dosing.

These attributes support affordability and payer value — the keys to better patient access — especially in developing economies with underdeveloped healthcare systems.

There are a number of parameters to consider when it comes to cDPI technology selection. Patient compliance and user friendliness come first. However, regarding capsule-based designs, there are additional advantages to think about:

  • with current state-of-the-art technology, the capsule acts as both primary packaging and delivery device
  • capsules are thoroughly integrated into the user experience with designers leveraging both audible and visual cues to support confident dose delivery and better patient compliance
  • the simple design of these devices requires fewer manufacturing resources to produce; from a cost-of-goods perspective, cDPIs are less expensive to make overall, especially when combined with the cost-efficiencies associated with high-volume capsule manufacture.

KSR: With the understanding that all elements of a capsule-based DPI have to work in concert, what do device designers and drug product developers need to know about capsule/device compatibility?

FBP: When specifying capsules for an application, one thing is certain: there is no such thing as a “standard” capsule for a cDPI application. First, the capsule must be functionally compatible with the device.

Secondly, it must be of a suitable size to contain the dose and, lastly, chemically compatible with the formulation. Key capsule technology parameters affecting DPI performance include polymer choice, dimensions/weight, powder retention/residual lubricant content, water content, mechanical resistance and microbiologic characteristics.

Marco Franza

Regarding device compatibility, opening principle, penetration/cutting resistance, powder retention characteristics and patient interactions all come into play in cDPI capsule specification.

That’s why Lonza CHI doesn’t offer a “single” standard capsule for DPIs. To span the needs of developers, we offer a full portfolio of customisable capsule solutions based on different polymers and compositions.

MF: Single-dose reusable DPIs now account for a growing portion of the global DPI market. According to our research, most single-dose reusable DPIs are capsule-based.

Generally, all these devices employ some sort of system to make the dose contained in the capsule accessible to the airflow the device generates. This occurs one of three ways:

  • opening the capsule by separating the body and cap
  • cutting the capsule (with blades)
  • piercing the capsule (with needles).

As Mirjam confirmed, when considering the aerodynamics and compatibility between specific chemistries, as well as interactions with propellants and particle morphologies relative to activation, formulation development has not been easy.

That’s why access to a platform using capsules, which are proven to be compatible and functional with most DPI chemistries, is key to further application and effective development.

Capsules also deliver functional characteristics to the device and have become integral to performance. The mechanically actuated cDPIs available to developers today spin the capsules to deliver a high degree of controlled and repeatable turbulence.

The aerodynamics of the spinning capsule help to create an aerosol of powder that’s delivered by actuating the device.

Far from being just a protective container, the capsule plays an essential role in a complex dynamic system that ultimately influences the pharmaceutical performance of the drug substance.

That is great synergy and shows that capsule-based DPIs are truly among the higher performing devices available in terms of emitted dose and respirable delivery ratios.

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