Having discussed formulation issues, capsule/device compatibility and the advantages of capsules for combined inhalable therapeutics in part I, I ask the panel what aspects of filling and finishing DPI formulations need to be better understood to support commercial product development.
Patrick Goncalves
Patrick Goncalves (PG): Although it may be the last piece of the puzzle, in some ways the filling and finishing of capsules should be considered first. It’s very important to understand how formulation can affect manufacturing as early as possible in development.
Powder feeding DPIs can be challenging, especially with the micronised powders and engineered particles used in popular formulations. The top challenges DPI formulators face when filling/finishing capsules are:
- powder segregation: separation of the individual components
- powder agglomeration (cohesion): when powder accumulates between particles
- adhesion/cohesion: interactions between powdered particles in flow and equipment surfaces
- powder flow: associated with issues related to low density, soft spray dried particles.
Powder segregation is often caused by incorrect mixing, storage (creating an uneven distribution of the API) and incorrect feeding (which leads to segregation within the powder blend).
Segregation can also occur during the sieving process and during sliding (because of different friction coefficients) as well as from high falling distances.
Segregation is not optimal. If not mitigated, segregation leads to poor content uniformity and an increased risk that fine powder particles will get lost. Segregation may also lead to a drop in assay (loss of active on machine surfaces).
At this point, however, there are a few potential areas for mitigation, including modifying the powder formulation (adding magnesium stearate) or modifying the powder feeding system.
Marco Franza
Agglomeration is another formulation-induced issue between machine and chemistry. Often, cohesion among particles occurs according to the ambient conditions of the environment, including temperature, humidity and the moisture content of the formulation.
All of that can lead to unpredictable changes in the flowability of the powder and may require several additional powder preparation steps (sieving, conditioning, ionisation, etc.) to mitigate at commercial volumes.
Dealing with cohesion, adhesion and similar undesired flow-limiting properties can be challenging. If not addressed, issues can compound, increasing variations and other quality and process control issues.
Fortunately, powder feeding technology suppliers such as Harro Höfliger have years of development work behind them and have introduced innovations to mitigate formulation and environmental issues and support the optimal feeding of powdered formulations.
These include beam, auger, pneumatic assist and vibration feeding, fluidisation and bag systems. There are many challenges associated with handling powdered DPI formulations. Often, the focus is just on the filling, but not on the feeding process. Powder feeding and flow are critical to product manufacturing success.
KSR: With device design and functionality being an important development frontier for cDPIs, what design and engineering innovations are driving better performing, patient friendly devices?
Marco Franza (MF): A key focus of device engineers is how the capsule is punctured and the number of needles to use for best effect and flow. Most current device designs use from one to eight needles per device.
The choice of piercing mechanism impacts other design choices, such as how the capsule is set in motion during the inhalation phase. Berry has found that placing the capsule horizontally and piercing it at the two polar tips seems to be a particularly effective concept as it makes full use of the centrifugal forces generated by the capsule’s spinning motion.
Frédérique Bordes-Picard
This is challenging engineering because a highly refined piercing unit is required to generate clean and consistent holes in the capsule. The result is lower, patient-friendly airflow rates in the range of 20 L/min, which propel and disperse the formulation gently.
KSR: With that in mind, what does the future look like for cDPI device design and formulation development?
MF: The digitalisation of inhalation devices is encompassed by the macro trends of precision medicine and outcome-based care. There is a growing shift towards personalised medicine and innovative drug delivery systems that’s reshaping pharma and healthcare.
Market trends and the greater focus on the costs associated with healthcare are prompting governments and insurance providers to control them more effectively and deliver better outcomes at a lower price.
This has led to a movement beyond chemistry to digital solutions that support dose compliance and other patient care goals. Engineers at Berry recently introduced an innovative cDPI design that integrates an electronic module into a single-dose capsule-based DPI.
The electronic module records timestamps of inhalations and a range of parameters, something that could improve the management of respiratory disease and enable more timely and effective preventive interventions.
Frédérique Bordes-Picard (FBP): Pulmonary pathologies remain one of the key targets for inhalation. There are still unmet needs in this area. An estimated 65 million people suffer from moderate to severe chronic obstructive pulmonary disease (COPD), which makes it the third leading cause of death worldwide.
Asthma is similarly entrenched, especially when you consider that more than 15% of children are affected, making it the first and most common chronic disease among them.
We now have studies under way for indications in infectious disease, the central nervous system and cardiology. It is interesting to note that only 44% of those projects are new molecular entities.
As mentioned, many promising compounds are in the 505(b)(2) development landscape, wherein developers are looking to either reposition existing generic molecules or associate known molecules with DPIs to improve the treatment of existing pathologies.
Because of their legacy, there will always be a place for DPIs to treat chronic conditions such as COPD and asthma. However, as capsule-based delivery can offer more economical and sustainable DPI development paths to developers, it’s earning respect and a featured place in pulmonary drug development and delivery innovation.
Featured companies
- Companies:
- Meggle AG
- Harro Hoefliger Verpackungsmaschinen GmbH
- Berry Global