Special drug designations require close collaboration and excellent communication for success.

Internal communication within cross-functional teams and collaboration with the sponsor and everyone else in the value chain are crucial. And excellent project management capabilities are needed to facilitate the simultaneous completion of multiple tasks under accelerated timelines by multiple parties.

These were some of the key takeaways from the panel discussion on ‘Special Drug Designations – Accelerating Discovery, Development & Approval’, which took place at the Pre-Connect Congress before CPhI Worldwide 2016 in Barcelona on 3 October. It was chaired by Dr. Cynthia Challener of That’s Nice.

“The development of designated drugs and other niche therapies requires unique combinations of skills,” Dr. Challener said. “Many, such as highly potent compounds, have complex synthetic routes and/or specialized manufacturing needs… Sponsor companies therefore often rely on service partners across the value chain with the experience and capabilities to manage complex projects in reduced timeframes.”

In 2014, noted Dr. Stephen Munk, CEO of Ash Stevens, FDA issued guidance on four different ‘expedited pathways’ to approval for drugs treating serious conditions: Accelerated Approval, Fast Track, Priority Review and Breakthrough Therapy. Drug manufacturers are responding: over 60% of the novel drugs approved in both 2014 and 2015 fell into one of these categories.

Wes Wheeler, CEO of logistics provider Marken, noted that special designations “require specialized handling” and often have “real criticality implications for both the trial and the patient”. Moreover, since many of the drugs are made in small batches and are very expensive, supply chains must be integrated to minimize overages and get them on time to patients anywhere in the world.

For Marken, communication issues start with understanding the advanced protocol and the cycle time for batch manufacture, clear lanes of communication about where drug product needs to be moved or destroyed, understanding where the placebo is sourced for each country in the trial and track-and-trace visibility on all deliveries. On-demand labelling, Wheeler ventured, might also be explored “as a way to expedite the movement and balancing of drugs around the world”.

Looking Ahead
The 21st Century Cures Act of 2015 identified, among other things, the need to streamline clinical trials through greater adoption of adaptive trial designs. This enhances the need for “an environment where you have to be nimble and flexible and ensure communication flow is constant”. Likewise, cell and gene therapies, which Wheeler sees as Marken’s future, require logistics with strong communication pathways, not least because the clinical and commercial supply chains will be one and the same.
Accelerated approval does not mean any compromise on safety or efficacy. “The FDA gives you no breaks for special designations,” said Kristine Senft, VP of marketing & sales at Hovione. “You go through the same pathway to validate drugs but with a timeline condensed to about half of the normal one, so you need to think about efficiencies to shorten it.”

Senft noted three ‘must-haves’ for CDMOs: a robust quality culture, in which everyone understands that this is about the patient and losing one patient is not just a loss of time but the loss of a life; close collaboration, acting as an extension of the sponsor; and, excellent internal collaboration from R&D to scale-up, project management and sales all coming together.

“The FDA cuts you no slack. They ask the same number of questions and do an equal number of pre-approval inspections as with standard drugs,” Munk agreed. Ash Stevens has dealt with all too many companies populated by medicinal chemists who readily assume their 50 mg of product is ‘industrializable’ and thus fail to address process development and scale-up under accelerated timelines.

To overcome this challenge, the company has teams work in parallel, one following the medchem route to make the first 100 grams, another looking at scale-up and industrialization, especially with regard to impurities. With the ongoing push for Green Chemistry, alternative solvents should be considered. “The whole team must attack the problem so that the route can be deemed viable.”

With niche markets and low volumes, special designation products bring specific operational, production and other challenges to CDMOs, Senft continued. They must adapt by being even more agile, possibly rethinking their manufacturing networks and remaining flexible. Small volume products may one day be big; Gleevec, for example, was once an orphan drug and is now a 15-20 tonnes/year product. Pharma, she added, could learn much from other industries that have dealt with personalization and from biopharma in its use of disposable reactors.

Marken has similarly dealt with multiple challenges of managing logistics under accelerated timelines. Drug product, Wheeler said, is usually made from one site to minimize risks but then may be distributed worldwide. Special designations, more often than standard drugs, are likely to be temperature- and time-sensitive, and the patients may be very dispersed. The mechanism of delivery and patient identification issues also present challenges.

With accelerated timelines, “excellent project management skills are an absolute must for all partners in the value chain,” said Munk. Managing the different activities within and between all suppliers and the sponsor is essential. To pick just one, clinical trial material production at the CDMO must be co-ordinated with trial planning and patient enrollment at the CRO. Bumps in the road are inevitable, so skilled project managers must keep projects on schedule.

In Case of Emergency
All cited recent examples of an unexpected issue in an accelerated project that called on project management skills. Hovione and a client, Senft said, had a critical situation where support teams practically lived together in a ‘war room’, day and night, until it was resolved. An Ash Stevens client had a problem with a vacuum being “too good”, which a project manager and an engineer solved using nitrogen.

New manufacturing strategies can also help. “When CMC gets in the critical path, as often happens with breakthrough designations, you need to find ways to develop, scale up and validate your processes at an unprecedented speed. But speed does not mean cutting corners,” Senft said.

In this context, she saw particular potential for flow chemistry and continuous tableting, which both offer the potential of eliminating scale-up work because the same process and equipment can produce more simply by running for longer. Quality by Design and process analytical technology can also combine powerfully.

The conclusion all three panelists came back to, however, was the need for communication and deep collaboration to deliver product at the same quality but twice the speed.