Raising The Bar In Radiopharmaceutical Manufacturing

By Katie Anderson, Chief Editor, Pharmaceutical Online

Radiopharmaceuticals are nothing new, having been around for over 50 years. Recent advances of radiopharmaceuticals as therapeutic drugs for cancer treatment rather than just diagnostic tools; however, has brought them back into the forefront with elevated popularity. Though any in-demand drug will encounter challenges in scale-up, radiopharmaceuticals face their own set of obstacles, being that they are, well, radioactive.

Ratio Therapeutics chief commercial and manufacturing officer, Scott Holbrook, joined me to discuss how his team at Ratio Therapeutics is tackling the challenges of radiopharmaceutical manufacturing. As he jokes, they aren’t reinventing the wheel…just raising the bar.

Established Nuclear Guidelines

There are well-established guidelines for the handling, manufacturing, packaging, and transportation of radiopharmaceuticals. The guidelines are established and regulated by the Nuclear Regulatory Commission (NRC) and the Agreement States.  On top of traditional pharma knowledge and skillset, operators at radiopharmaceutical facilities must have additional knowledge and training. Their licensure and the licensure of the facility to handle such materials is managed by the state. This compliance is crucial to the safety of the manufacturer personnel and the patient, with no room for deviation.

Holbrook explained that it is not so much that you comply with these regulations (because all nuclear medicine manufacturers must comply), but how well you stay on top of continuous training and monitoring of compliance.

At Ratio Pharmaceuticals, operators not only undergo the required training on the state and federal level, but they also have company-specific training. “It happens on an ongoing basis. Every year, even throughout the year, the staff are trained. We have to have proof of adequate training.” The on-site personnel responsible for handling these materials are Authorized Users, and their daily on-site oversite is provided by the Radiation Safety Officers, both position requirements being set by state and federal regulatory bodies.

Though being granted a license for radiopharmaceuticals is certainly an accomplishment, it is something not to be taken for granted. “Being granted a license to possess and use these materials is not a permanent grant forever. We're subject to very frequent audits either on a regular recurring basis or for cause. So we have to remain in good standing with regulators to be able to possess these materials into the future. You can't just assume that once you've met the bar, you're good forever,” furthered Holbrook.

Unique Aspects of Drug Design

For Ratio Therapeutics, the bar starts to rise with the manufacture of its drug product. It begins with its rigorous qualification and validation of its starting materials. The company then assembles the precursor and the radioactive component together in its own manufacturing process. Like any radiopharmaceutical, it has developed its own process with chelators, linkers and scaffoldign to create the drug product. Though the radioactive isotopes are unstable, there are slight alterations in the production process that can make them easier to handle and change how successful they are in the body.

One example is chelator Macropa. “It enables labeling the drug components with Actinium-225, which is a radionuclide, with the non-radioactive carrier [Trillium]. Macropa has been shown to label components with Actinium-225 very efficiently,” explained Holbrook. The chelator’s chemistry makes manufacturing easier and improves the in vivo stability of the drug product.

There is also the company’s scaffolding, Trillium, which improves the delivery of the drug. “It is a PK modulator, which allows the drug's residence time in the blood to be changed. We can shorten or lengthen the amount of time in the blood plasma by using a characteristic of this Trillium scaffolding to make the drug more or less attracted to components in the blood,” added Holbrook.

Being Radionuclide Agnostic

To remain competitive in its field, Ratio Therapeutics has taken a more agnostic approach to radionuclides. Rather than focusing on just one radionuclide, it has created manufacturing redundancy with both its manufacturing capabilities and third party manufacturers to ensure it can select the right radionuclide for the target. “Investing in our manufacturing—the technology, human resources and facilities—allows us to choose the radionuclide that’s best for the application of the drug product holistically. We believe in being very quantitative and selecting a radionuclide that best matches both the cancer indication as well as the drug, the design of the drug itself and the timing of the drug as it is administered to the time that it hits the tumor resonance time and is excreted from the body,” furthered Holbrook.

To accommodate the different types of emissions, the facilities have to have safety measures in place. Gamma rays, for example, require thick lead shielding. Alpha emittors like Actinium-225 do not require heavy shielding; however, they do require safeguards in HVAC. “If you wanted to work with the opposite ends of the spectrum of types of radionuclide emissions, you would need a facility that both incorporates thick enough shielding for gamma or even beta emissions, but also has the special kind of handling of the air exhaust, to ensure that there could be no alpha emitter that could be inhaled inadvertently by the staff.  If you want to have a facility that's future-proof and able to accommodate and host all of these different radionuclides, you would have to consider the special, unique characteristics or considerations with each type of radionuclide, and incorporate all of those in your facility design, cleanroom design, and shielding plan for the facility,” added Holbrook.

Shelf-life Challenges: Radialysis and QC

Once of the largest manufacturing challenges in radiopharmaceuticals is the volatile nature of the isotope itself. You don’t want to stabilize it, of course, because its mode of action is the inherent instability of its radioactivity. However, you want to prevent radialysis, or the emissions damaging the molecule.

Radialysis is an example of a challenge that's common in the radiopharma industry that has to be overcome by several different strategies that are kind of known. “There are lots of techniques around various stabilizers that are known to be used in radiopharmaceuticals to help mitigate any kind of loss of stability associated with scale-up at higher concentrations of radionuclide.”

Though Ratio Therapeutics does have a quality team that functions similarly to a traditional pharma manufacturer, the rate at which they complete their tasks is different.

“We have so many batches being manufactured, and the cadence and timing of quality-related activities may occur daily here. You have to perform the quality control-related release tests associated with manufacturing a product, and have someone from the quality unit who has release authority review all of the required release testing criteria, quality control activities, and, performs a release on a batch maybe daily. All of the kind of CGMP and quality systems are now electronic and digital, so we have the ability for folks from the quality team and even manufacturing operations to view data in real time all day, both locally as well as at the corporate level.”

Quality control is a daily activity at Ratio, where the team is constantly assessing compliance with its SOPs and procedures, according to Holbrook. “We have the ability to engage third-party companies that specialize in performing audits for readiness for an inspection,” noted Holbrook. He continued that there is a robust investigation with any failure.

“There are constant activities around reviewing open or closed investigations to ensure proper CAPAs have occurred. And a good quality system is not a static entity or activity. It's a continuous improvement. Investigations will occur that reveal where there could be an area of improvement. And ideally, if you've done a good investigation, you found a root cause of that, and quality and operations become aware of it, then we have kind of a continuous, constant improvement of our quality management system,” he explained.

This means that the quality and operations teams are assessing themselves on a daily and weekly basis to ensure continuous improvement of the quality management system.

This continuous quality culture prepares them for an audit, even if not planned.

Hub and Spoke Transportation

The shelf-life of a radiopharmaceutical requires special accommodation for packaging and shipping. As Holbrook notes, the Department of Transportation has specific guidelines for the transportation of radiopharmaceuticals that large well-known transportation and private transportation companies alike must adhere to. Transporting a material to point of use does have opportunity for failure points to occur.

Holbrook added that if you are not able to scale-up the batch to be stable for several days for nationwide shipping, there are options. “If you're not able to scale up the batch and have it be stable for several days, then it may require manufacturing more batches during the week to achieve the same output, or another potentially viable strategy is manufacturing the product on East Coast and West Coast every day. Of course, this drives up cost, and increases regulatory and quality oversight.

Ratio takes a hub and spoke approach to transporting the drug product to point of care, according to Holbrook. Because it is located at a major transportation hub, in some instances, it is able to ship the drug product to the end user, but in others, its third party manufacturing partners have regional facilities for further distribution to clinics and hospitals.

“These partners are experienced and have proven track records for transporting these materials from large transportation hubs, like where I am today in Salt Lake City,

either end-user large hospital customers, or to our third-party CDMO sites for further distribution,” he continued. He added that many of these partners already have existing daily deliveries to hospitals and clinics, so it is just a matter of getting its drug product to those locations for distribution.

Expanding To Other Indications

Holbrook is looking forward to the maturation of radiopharmaceuticals as a therapeutic drug. Right now, he knows that there have only been a few indications for therapeutic radiopharmaceuticals, but he believes that will all change.

“I think we're at the very early phase of a large, you know, exciting growth opportunity. I think for all companies in this space to be successful, we need to have more products and additional indications show safety and efficacy,” added Holbrook.

There has been a good amount of investment and excitement around a few drugs in the category, but Holbook worries that future investment will be pointed at competing drugs in the same category rather than new indications for category expansion.

“What I would like to see is proof of efficacy and safety in other cancers, other indications that are not associated with prostate cancer or neuroendocrine cancer. While it's great to continue to see improvements in drugs in those disease categories, it would be great to see some drugs that are in earlier stages of clinical, show efficacy for broader types of cancer,” Holbrook furthered.

Nevertheless, Holbook highlights that experts project a great deal of growth in radiopharma. That excitement drives companies like Ratio to continue to raise the bar, not only in the science for better efficacy, but in manufacturing, transportation, and patient care.