Shabbir Mostafa, global key account director for Recipharm Inhalation Solutions, looks at the techniques to reduce time to market during inhalation drug development and manufacturing.
Time concept
Developing an inhalation drug product is a complex process, with the tech transfer and scale-up stage particularly difficult to manage. While drug companies often have in-house expertise for drug discovery, initial development and small-scale production, few can manufacture inhalation drugs for clinical trials and – assuming they win approval – commercial supply. By far the most effective way of overcoming this is to work with a partner that has expertise and established production capabilities. Better still, there are also advantages to engaging with a CDMO that can offer an end-to-end service from drug development to manufacture, reducing complexity.
Challenges of inhalation drug development
Respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD) represent one of the greatest healthcare challenges and are driving an increasing need for more innovative and effective treatments. As a non-invasive approach for local treatment of a broad range of debilitating lung diseases, pulmonary drug delivery is increasing in popularity. Despite the many benefits, when developing treatments that use this delivery mechanism there are several challenges that manufacturers will want to consider.
The cost of developing a new inhalation therapy drug is high and access to significant funding is required if this route of administration is going to be pursued. While this may not be a challenge for large pharma companies, it can put immense pressure on small start-ups. The need for drug/device combinations also adds further to development costs, not to mention the budget required to run a successful clinical trial.
From a formulation perspective, manufacturers must ensure that they are choosing the right dosage form for their target. This might be a dry powdered inhaler (DPI), metered dose inhaler (MDI) or a nebuliser. The relative ease of using a DPI makes it the most popular choice for manufacturers. The formulation can be manufactured into a solid-dose and then simply filled into a capsule. Whereas MDIs tend to be more of a standard design and of lower cost, DPIs offer two medical device options, including the capsule design or a reservoir filled DPI.
Manufacturers must also be able to prove to the regulatory authorities that their device doesn’t have any impact on the drug or formulation. In the early stages, companies have been known to focus their attention on getting their formulation into patients and fail to think about the complete development picture. By the time they reach a Phase III trial and introduce a medical device, they begin to encounter issues that haven’t been thought through during their initial planning, resulting in delays and escalating costs.
Working with a CDMO
Working with a CDMO partner can provide manufacturers with access to experience which they may not have within their own organisation. By helping an organisation to focus on its end goal, whether that is to get a product to a proof of concept stage and achieve a sale or to take it all the way to market, a CDMO will be able to advise on how best to formulate a product to ensure it reaches this point.
CDMOs can also shape their service offerings to the specific needs of customers’ projects. A generics company might, for example, be developing a generic version of an MDI and want a fast development time, a bio-equivalence study, followed by tech transfer and manufacturing. A CDMO would have the staff and breadth of experience to accommodate this.
Larger pharma companies might want to take advantage of the flexibility that working with a CDMO can bring. They may not have the capacity to manage the development stage in-house, and so will choose to outsource this element. The company may then opt to tech transfer back the manufacturing into their own facility. Or vice versa, the pharma company might have the capacity to do the development but not the manufacturing. Working with a CDMO means organisations can pick-and-choose the services that they use.
A CDMO with inhalation drug development experience will understand the intricacies involved, as well as the complexities of analytical testing with next generation impactors (NGIs), extractables and leachables (E&L). Many smaller companies will likely not have these capabilities in-house. Indeed, as mentioned earlier, when you look at the inhalation space overall, there are lots of development companies that manage formulation development and early phase clinical trials, but there are very few that can offer commercial manufacturing as well. Depending on what a manufacturer requires, a CDMO will be able to offer formulation development, analytical development and device testing and filling, in addition to clinical and commercial manufacturing. To ensure the greatest flexibility, manufacturers might also want to consider partnering with a CDMO that has experience of working with a wide variety of medical device companies and platforms. Many will be limited by their ability to only provide certain devices.
Which CDMO partner to choose will ultimately depend on what a manufacturer is looking for. For example, do they want an end-to-end service from development to clinical phase or management of a specific area such as formulation. A complete overview of the inhalation experience of any CDMO should be requested, including information relating to E&L and analytical services. This information is essential for risk-management and knowing that a CDMO partner has the knowledge to be able to deal with any challenges that may arise. Inhalation products also require specific equipment, such as NGIs and Anderson testers. The availability of these should also be clarified with the CDMO.
Manufacturers may also want to review a CDMO’s experience of global compliance requirements for inhalation products. Having a partner that can assist in navigating the regulatory landscape can help alleviate the potential for any approval issues further down the line.
Tech transfer
At the tech transfer stage, if a CDMO has been involved with a product during the development stages and has been able to look at how it has moved from early formulation to clinical, they will have already formed a good understanding of how the product should be scaled. This will help enable seamless transfer from small to large scale production in a commercial facility.
An experienced CDMO will develop a product with commercial manufacture in mind and will understand the unique challenges faced, pre-empting any issues that may occur during the scale-up from clinical development into commercialisation. A further advantage of a CDMO is that multiple functions work together ‘under one roof’. It is straight forward for internal development teams, tech transfer teams and commercial teams to communicate and work together to understand any challenges.
Tech transfer varies considerably between products. If a 505(b)(2) route is being pursued, this will likely make the process much faster. For a new application/product, tech transfer could be much slower. The device used can also make a difference. A CDMO will look at the whole process from start to end, so that they understand tech transfer throughout the entire lifecycle.
Manufacturers should also be aware of several pitfalls that can arise during tech transfer. Failure to have considered the drug device combination during the initial stages is one of the most common issues and may lead to problems with scalability. How a device is filled can also be problematic at this stage. While in the early stages a capsule may have been filled by hand, there may be challenges around the flow of the formulation into the capsule when this process is automated at large scale.
Another potential challenge is that when an MDI is developed on a very small scale, there is a need to think about volume as it progresses. If it’s a suspension, consideration needs to be given to how this will be maintained during manufacture and whether it will be agitated or mixed. On a smaller scale filling is very quick and these things do not need to be considered in the way that they do for scale-up. Working with a single CDMO partner will provide access to expert guidance at every stage and can save companies both time and costs.
Reducing time to market
Time to market varies depending on whether a product is a new MDI or DPI, or a product that can be taken down the abbreviated 505(b)(2) route. Irrespective of this, manufacturing should always be front of mind, even at the initial stages. Understanding the end product will establish if an early formulation can realistically be modified to fit the product that a manufacturer desires. It will also give insight into the type of equipment that will need to be used during the manufacture.
Early insight can also save time by recognising whether a product would be best suited to an MDI route using a standard off the shelf device that is amenable to a standard manufacturing line, or whether a DPI route is a better option. Although a DPI route often requires additional time to develop bespoke equipment, manufacturers can benefit from a more complicated design that is difficult for competitors to copy.
To reduce time to market, a good rule of thumb is to keep everything as simple as possible, especially when it comes to the formulation and the device.
Conclusion
The development of inhalation drug products is being driven by the increasing potential of pulmonary routes of administration for local therapies, offering the benefits of formulation stability combined with patient-friendly and effective drug delivery. Working with a CDMO that has a deep knowledge of inhalation products can help to reduce risk and manage the complexities associated with developing and manufacturing these types of products, while streamlining the processes of transfer and scale-up. Timelines can also be reduced by developing drugs with the end goal in mind.