Best Practices in Manufacturing Inhalation Drugs

For inhalation drugs that are dosed via pressurized metered dose inhalers (pMDIs) and dry powder inhalers (DPIs), characteristics of the formulation and of the device are both crucial for optimal drug delivery. Pharmaceutical Technology spoke with Recipharm’s Robin Heath, head of New Product Innovation and Commercial Management, and Peter Hirst, commercial vice-president, about trends and best practices in manufacturing and filling these combination drug-delivery devices.

Trends in inhalation drug formulation

PharmTech: What do you see as key trends in inhalation drug formulation that are affecting manufacturing processes?

Heath and Hirst (Recipharm): We are seeing increasing use of engineered particles, such as spray drying, rather than traditional micronization in the formulations for pMDIs and dry powder inhalers DPIs. For DPIs in particular, we are seeing the filling of large volumes of engineered particles.

Traditionally, many existing drugs are low molecular weight crystalline substances, which can be micronized into a targeted size suitable for inhalation product development. These drugs are stable and well understood, and they are relatively low dose products in the range of micrograms. Many new drugs being developed, however, are complex biomolecules, which have issues with physical stability and are often delivered in higher doses owing to their low potency.

pMDIs are arguably at their simplest when prepared as a solution, but this [method of formulation] can be limited by the solubility of the drug and excipients. In addition, a recognition of new global pressures towards more sustainable products is driving the investigation into alternative propellants in pMDIs, providing new potential formulation opportunities.

The infrastructure to handle these complex drug products successfully is significant, with health and safety requirements, environmental conditions (temperature and humidity), and use of solvents to consider along with the physical handling of these free-flowing powders when it comes to device filling. These may pose a challenge for drug developers, and contract development and manufacturing organizations can bring their expertise and facilities to the forefront in this new wave of challenging inhalation drug development.

PharmTech: What are the considerations for choosing DPIs or pMDIs?

Heath and Hirst (Recipharm): Bespak by Recipharm manufactures both DPI and pMDI devices for a wide range of drug developer customers. We also manufacture clinical and commercial-scale finished products in DPI and pMDI formats at our Recipharm manufacturing facility in Holmes Chapel, Cheshire, United Kingdom. When selecting an appropriate device for a specific drug formulation, several factors must be considered:

• pMDIs as a platform are limited by the volume of the formulation in the metering chamber (typically <100 µl), and there are considerations with drug solubility if making a solution.
  
• In terms of protection from the environment, a pMDI formulation is contained within a sealed aluminium cannister, but there are opportunities for the formulation to interact with the elastomeric components of the valve. Reservoir DPIs contain bulk formulation, which is dispensed in small doses each time the patient actuates the device. The inherent design of this device type potentially leaves it more exposed to the elements, and it can be challenging to dispense doses accurately.
  
• Excipient compatibility is one of the most critical aspects during development for any inhalation platform. Although there are a limited number of approved excipients for inhaled products, they must be managed and screened for early in the process.

In addition, if a drug developer wishes to utilize a bespoke delivery device for patent protection purposes, then a DPI will be selected. These devices tend to be bespoke, rather than ‘off the shelf’, often requiring simultaneous development of the device, the formulation, and the filling and assembly process, all of which adds complexity into the product development and approval processes. 

Conversely, the design of a pMDI is generally more universal and more cost-effective. It does not require the design of a bespoke device, and the device is typically able to be filled using already installed filling equipment.

PharmTech: For pMDIs, what are the current trends in propellants, and how do these affect the overall drug delivery device? Does this also have an effect on the drug product formulation?

Heath and Hirst (Recipharm): In accordance with the United Nations 2016 Kigali Amendment to the Montreal Protocol to phase out hydrofluorocarbons (HFAs), there is a transition away from the current HFA propellants used in inhalation pharmaceutical products. The current HFAs have a high global warming potential, contributing to climate change.

There are at least two potential replacements currently undergoing safety evaluations: HFA152a and HFO1234ze. Both are compatible with surfactants and solvents used in inhalation drugs, meaning they pose few problems when it comes to formulation development.

However, there are issues that need to be tackled to ensure their future success. The relative flammability of HFA152a poses safety challenges on production lines. The compatibility of these replacement propellants with container closure systems must also be evaluated to ensure valve functionality. In addition, the industry must study the propellants’ ability to interact with APIs and excipients to ensure the drug formulation maintains optimum stability and acceptable extractable and leachable profiles.

Best practices

PharmTech: What are some best practices in designing and manufacturing this type of combination drug-delivery device? What are some of the ways that the drug developer and delivery device manufacturer need to collaborate on the initial design or for ongoing manufacturing?

Heath and Hirst (Recipharm): When designing and manufacturing an inhalation device, it is essential to consider both the interaction between the drug formulation and the device, and between the device and the patient, as well.

It is important to identify, optimize, and control the parameters that will influence the finished product’s performance, in terms of dose delivery and therapeutic effect. These include API particle size, device component dimensions, and the formulation. Manufacturing process parameters, such as time and temperature, are also important to consider.

PharmTech: What are some of the key considerations when scaling up a development process to a commercial-scale, good manufacturing practice process?

Heath and Hirst (Recipharm): Above all, it is important to design development processes with the commercial stage in mind.

Scale-up often entails moving to multiple items of equipment and the involvement of multiple people, which means a process that was originally designed at small scale using single items of equipment and a restricted group of people has to be replicated multiple times.

Developing robust processes, including robust analytical test methods with minimized variation of critical parameters, is key from the very beginning of the project to streamline scale-up. The ability to automate or at least semi-automate processes needs to be considered during the product development process. 

In addition, it is critical to ensure a robust manufacturing strategy is in place prior to industrialization. An understanding of the factors that influence the finished product batch size and manufacturing throughput is fundamental in determining both capacity and unit price.

Where commercial-scale equipment already exists, which is more often the case for pMDIs, product development should consider the process that is already installed and, where possible, design the new product accordingly. This forethought will save considerable development time and capital outlay associated with modifying existing equipment or procuring new.