Finding the perfect fitHow to choose the right CMO for manufacturing your radiopharmaceutical

The nuclear medicine industry is undergoing a fundamental transformation, expanding

to offer more therapeutic products than ever before. As a result, large pharmaceutical companies are entering the market — first with Bayer and its acquisition of a novel alpha emitting pharmaceutical, then Novartis acquiring Advanced Accelerator Applications (AAA) and Endocyte. Others are following suit.

“There truly has been renewed attention and new inventions in radiopharmaceuticals,” said Jan Boerge Jakobsen, Managing Director of Bayer Norway. “The trend has been upward, and there’s huge interest. In the beginning, there was skepticism around alpha emitters. Once we began manufacturing them in Oslo, we demonstrated it was feasible. It’s not an issue anymore, and now several companies beyond Bayer are paying attention to this opportunity.”

“The radiopharmaceutical product line has indeed diversified,” added Chris Ignace, Vice President of Clinical, Scientific and Regulatory Affairs for Cardinal Health Nuclear and Precision Health Solutions. “Today, CMOs need to be ready not only for gamma diagnostics, but also alpha and beta therapeutics.”

As traditional pharmaceutical companies enter the radiopharmaceutical market for the

first time, what challenges do they face? And more importantly, how do they select the

right CMO (Contract Manufacturing Organization) to help overcome them?

The (r)evolution in nuclear medicine

“There truly has been renewed attention and new inventions in radiopharmaceuticals. The trend has been upward, and there’s huge interest.”

Jan Boerge JakobsenManaging Director Bayer Norway

To successfully manufacture a radiopharmaceutical, the drug sponsor and CMO must

collaborate to customize a four-part process: formulation, filling, volume and packaging.

“Unlike traditional pharma, it’s essential that we thoroughly develop this process upfront,” Thrasher explained. “The difference is that we have to build relatively complex enclosures or ‘hot cells’ around the product, from one end of the manufacturing process to the other.”

That includes putting formulation equipment inside of the hot cell, then moving the product into a filling process that must be built to accommodate both low and high volumes. Next, moving the product into the packaging process, putting it into the appropriate radiation safety lead container, labeling, boxing and preparing it for shipping.

“With traditional pharmaceutical manufacturing, having this level of detailed planning upfront isn’t as necessary. You can essentially pick the facility you want to manufacture in and perhaps modify the line to accommodate the product. You don’t need to build a hot cell that’s specifically designed to manufacture a particular radiopharmaceutical,” Thrasher said.

What is his advice to conduct this upfront planning? “Keep a complex thing simple. The simpler, the better,” he said. For example, design a line that can accommodate high volumes, run consistently and be easy to maintain. That way, if there’s an issue — such as a spilled vial of radioactive material — you can solve the problem faster and minimize downtime. “Just one broken vial can cost hours or even days of interrupted production. If the line is designed so poorly that you can’t easily reach the site of the spill to clean it up, that’s a big and costly issue.”

Overcoming unique manufacturing challenges

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“The challenge is meeting the higher volume requirements of therapeutics in the same safe handling environment that has been well established for diagnostic products.”

Shane ThrasherSenior Director, Nuclear ManufacturingCardinal Health Nuclear and Precision Health Solutions

“With a radiopharmaceutical, you’re dealing with a ‘melting ice cube.’ You have to be prepared to manufacture daily, not periodically.”

Luke AugustineVice President, Business DevelopmentCardinal Health Nuclear and Precision Health Solutions

Chief among these challenges is the difference in manufacturing nuclear vs. non-nuclear

pharmaceuticals. For example, due to their short half-lives, radiopharmaceuticals can’t be manufactured and stored as long as non-nuclear drugs. “It vastly changes the amount of drug that must be produced,” said Luke Augustine, Vice President of Business Development for Cardinal Health Nuclear and Precision Health Solutions. “With a traditional pharmaceutical, you’re trained to use every vial produced. With a radiopharmaceutical, you’re dealing with a

‘melting ice cube.’ You have to be prepared to manufacture daily, not periodically.” There are other fundamental differences as well, such as how the drugs are regulated and the additional training required for the safe handling of radioactive material.

“Manufacturing radiopharmaceuticals is a complex field requiring significant expertise,” Jakobsen said. “It starts with the need for unique technical capabilities, infrastructure, reliable manufacturing and distribution. There are also unique licensing and regulatory needs. The ideal CMO must have the capability to adjust to and execute the pharmaceutical company’s business model in each market. Because of this complexity, it’s important that we have a good fit with our CMO, and collaboration and partnership are keys.”

With the rise of therapeutic radiopharmaceuticals, there’s another challenge as well:

producing product in high volumes. “Consider that a patient may need only one or two vials of a diagnostic product, while that same patient may need multiple doses of a therapeutic drug. The challenge is meeting the higher volume requirements of therapeutics in the same safe handling environment that has been well established for diagnostic products,” said Shane Thrasher, Senior Director of Nuclear Manufacturing for Cardinal Health Nuclear and Precision Solutions.

New challenges for a new world

Manufacturing capability Does the CMO have the proven expertise to manufacture the drug?

“All radiopharmaceuticals are difficult to manufacture,” said Paul Gotti, Vice President of Operations for Cardinal Health Nuclear and Precision Health Solutions.

“It’s the difference between being a chef and a short order cook.” How can a pharmaceutical company determine if a CMO is the right fit for its drug?

• Review the list of drugs that the CMO manufactures.

• Assess the quality of the technology transfer group. This is the team that ensures the pharmaceutical company’s drug innovations and processes are successfully transferred to the CMO as actionable production activities.

• In particular, be sure that the technology transfer will occur at the facility where the drug will be manufactured.

Distribution Can the CMO consistently deliver the product where it needs to be and when? Because of the product’s short half-life, it’s critical to have a nationwide nuclear pharmacy network with a local presence. The advantages include being able to drive the product to its destination vs. the greater expense of traveling by air. To help ensure that distribution goals are met consistently, pharmaceutical companies may have more than one CMO, with each assigned to a particular geography.

Shipping expertiseRadiopharmaceuticals are considered “hazardous materials” by the Department of Transportation (DOT) and the International Air Transport Association (IATA). Whether you’re shipping by land or air, it’s essential to remain complaint with the applicable regulations. Does the CMO have the depth of DOT and IATA expertise you need? For example, Cardinal Health ships literally thousands of these packages every day.

Key considerations for CMO selection

“All radiopharmaceuticals are difficult to manufacture. It’s the difference between being a chef and short order cook.”

Paul GottiVice President, OperationsCardinal Health Nuclear and Precision Health Solutions

A CMO can play a key role in the success of your novel radiopharmaceutical.

“By outsourcing manufacturing to the right CMO, a pharmaceutical company has a scalable solution that enables it to focus more on core priorities such as drug development and commercialization,” said Augustine. “The right CMO will not only follow cGMP practices and have deep regulatory expertise, but also be flexible with product capabilities and have the infrastructure and resources to meet tight deadlines.”

Here are 12 key considerations to help guide your own CMO selection:

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Facility designCan the CMO help you design your manufacturing facilities and processes with distribution in mind? “The aim is to design the beginning with the end in mind,” said David Pellicciarini, Vice President of Pharmacy Safety, Practice and Technical Operations for Cardinal Health Nuclear and Precision Health Solutions. That includes collaborating for continuous improvement, such as sharing the best practices learned at one manufacturing facility with another producing the same drug. For example, Bayer leveraged lessons learned at its U.S. manufacturing facility in Indianapolis, Indiana with the original operation in Oslo, Norway.

Also, does the CMO have “track and trace” capabilities all the way to the point of care? This is especially important during the “last mile” of the product’s journey, when the pharmaceutical company may find it difficult to maintain visibility.

Product utilizationThe goal is to use as much of the product you manufacture as possible. That requires your CMO to understand the role distribution plays and develop a comprehensive plan to help minimize waste due to decay. “To accomplish this, first decide whether to use a centralized nuclear pharmacy or network of local nuclear pharmacies, based on distribution considerations. That helps determine where you locate the manufacturing facility,” Augustine said. Another consideration: a centralized pharmacy may have more product returns, while a local pharmacy can handle cancellations more easily.

Regulatory expertiseAssess the CMO’s experience with regulatory affairs and review its track record. Does it have strong relationships with regulatory bodies such as the Nuclear Regulatory Commission (NRC), FDA and state boards of pharmacy? Does it have the expertise to hold its own NDAs (New Drug Applications) with the FDA? Can it assist you with developing the appropriate regulatory strategy for your product and assist with package inserts, filings, post-marketing commitments and so on? Many variables impact that strategy, such as whether the product is weight-based or a standard dose.

Quality systemsCan the CMO integrate with your existing quality systems? Can the CMO operate both clinical and commercial modes under tailored systems? If you don’t have these systems already in place, can the CMO help you develop them? Note that quality systems can vary by product.

ReportingDetermine if the CMO can accommodate the level of reporting required. This includes not only the standard reports the CMO may have available, but also the ability to customize reports based on your needs. To generate this level of reporting, the CMO should have the technology to help ensure supply chain visibility from the front line to the point of care.

Communication Is there one point of contact for everything from billing administration to training and more? Just as important, can you keep accessible lines of communication open with the CMO? That’s key to having visibility across the entire supply chain, as well as identifying and resolving issues quickly.

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“The aim is to design the beginning with the end in mind.”

David PellicciariniVice President, Pharmacy Safety, Practice and Technical OperationsCardinal Health Nuclear and Precision Health Solutions

Depth of consulting resourcesCan the CMO not only help design a manufacturing facility, but also provide support from clinical trials through commercialization?

For example, the right CMO can function as much more than a manufacturer during a clinical trial. “We’re looking down the road at commercialization from day one,” said Richard L. Green, Director of Radiopharmacy Practice for Cardinal Health Nuclear and Precision Health Solutions. This may involve an optimization of technology and processes to meet commercial demand with robust capabilities. “You want a CMO that can help make your drug successful. This is about helping customers serve more patients with fewer vials, manufacturing steps and shipments,” Green said.

As another example of consulting resources, the right CMO may have health physics (radiation safety) consultants available to help ensure customer readiness. This could include appropriate licensing, as well as designing and developing a hot lab where the radiopharmaceutical is handled at the customer site prior to patient administration.

Brand experienceFor pharmaceutical companies of all sizes, maintaining a consistent brand experience is essential. A CMO needs the flexibility to accommodate brand-related needs, such as custom packaging and supporting customer expectations for such brand attributes as speed, quality and reliability.

CommercializationDoes the CMO have a track record of successfully supporting commercialization activities, including offering additional sales and marketing services? Look for a CMO with these additional capabilities and service offerings:

• Highly knowledgeable about the radiopharmaceutical market and knows what it takes to successfully launch a new product.

• Understands market dynamics and is skilled at uncovering clinician insights to create compelling messaging and promotional plans. The goal: to educate clinicians on the features and benefits that differentiate products in the marketplace.

• Has established relationships with leading healthcare institutions and access to decision makers.

• Supports ordering and billing capabilities.

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“This is about helping customers serve more patients with fewer vials, manufacturing steps and shipments.”

Richard L. GreenDirector of Radiopharmacy PracticeCardinal Health Nuclear and Precision Health Solutions

“From in-depth commercial assessment and customer targeting to multi-phase launch planning, we use a collaborative and cross-functional approach to develop and execute commercial strategies that drive broad awareness and accelerate adoption of new products.”

Erin SummersVice President, MarketingCardinal Health Nuclear and Precision Health Solutions

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“Whether a pharmaceutical company is large or small, they have two needs in common,” Pellicciarini said. “Both need speed to market and risk management. By using the selection criteria above to determine which CMO is right for you, you’ll be in a stronger position to meet both needs.”

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Bayer was seeking to create a manufacturing facility in the United States for the alpha

emitting pharmaceutical it was manufacturing in Oslo, Norway. How did the global pharmaceutical company ultimately choose the CMO services of Cardinal Health Nuclear and Precision Health Solutions?

“Cardinal Health is very strong on collaboration and the ability to support our business case,” Jakobsen said. They are very customer focused, ready to listen to concerns, extremely adaptive and quick to develop new and creative solutions. That was very impressive, which made them score very high on our collaboration criteria.”

On the path to choosing Cardinal Health, Bayer reviewed the capabilities of several CMOs. The aim was to evaluate each for its potential alignment with and ability to support the drug’s business case in the U.S. That included having a Bayer technical team assess and compare each CMO based on a set of technical capabilities criteria. “It was a very rigorous process,” Jakobsen said.

Cardinal Health assisted Bayer with the design of its U.S. manufacturing facility in Indianapolis, Indiana — applying lessons learned from the alpha emitting pharmaceutical’s first manufacturing location in Oslo, such as hot cell design. “Then, we added new innovations such as a massive radiation air control system and inspection packaging line,” Thrasher said. This new thinking has since been applied to the original facility in Oslo.

Leveraging the quality and regulatory experience of Cardinal Health, Bayer could accelerate timelines for facility commissioning, validation and registration. That included engaging with NRC and local FDA authorities early in the process. “In the radiopharmaceutical space, it is especially true that time is money,” Ignace said. “A sponsor should look for proactive behavior in their CMO while maintaining a compliance mindset.”

How Bayer found the right fit

“This is a total solution vs. a menu, where every stage connects — from manufacturing to pharmacy to distribution. There’s total visibility, because all three stages work in concert and not in silos.”

Paul GottiVice President of OperationsCardinal Health Nuclear and Precision Health Solutions

“Having end-to-end capabilities is ideal now, as we continue improving our business case.”

Jan Boerge JakobsenManaging DirectorBayer Norway

One approach to CMO selection is choosing an organization that offers volume

manufacturing, pharmacy and distribution all from a single source. With this model, each stage seamlessly connects to and informs the other from the manufacturing facility all the way to the patient.

This end-to-end solution can be beneficial at any stage of manufacturing for late-stage clinical trials and commercialization — and for any size of organization. “For smaller pharmaceutical companies, it provides the speed and efficiencies vital when working with limited resources. For larger companies, it assists with risk management by providing greater control over the entire manufacturing and distribution process,” Pellicciarini said.

“It’s an entire ecosystem that provides greater efficiency, accountability and intimate knowledge of the product’s journey all the way to the patient,” Thrasher added.

“By providing pharmaceutical companies with the option of a totally turnkey solution, we empower them to focus on other priorities.”

A pharmaceutical company may not need a comprehensive solution from day one. “But it’s advantageous to tap the deepest pool from the beginning, so those resources are there when you need them,” Green said. “A traditional CMO is essentially a copy machine. But our broader skills can help you quickly execute adjustments you may need.”

“Offering an end-to-end solution wasn’t the original key to our choosing Cardinal Health,” Jakobsen explained. “Having end-to-end capabilities is ideal now, as we continue improving our business case.”

Once a pharmaceutical company selects a CMO, what can it do to continually

improve results? To advance its alpha emitting pharmaceutical’s business case, Bayer and Cardinal Health Nuclear and Precision Health Solutions collaborate on several levels. First, there are weekly meetings with operational supply chain and manufacturing teams. “We’re very pleased with the openness of sharing technical performance, identifying issues, doing root cause analysis and developing solutions as needed. It works very well,” Jakobsen said.

Then, the two organizations meet once per quarter to review general manufacturing, quality and distribution performance. Annually, they get together to review the broader relationship, discuss issues and determine how to further strengthen results. “The collaboration works perfectly,” Jakobsen said. “Since our U.S. facility started production in 2017, we’re meeting our goals to maintain a robust and sustainable supply. Everything is continuing to develop in the right direction. When there are issues, Cardinal Health is very eager and committed to resolving them. In the future, we will continue to explore new ways together to improve our business case.”

Choosing an end-to-end solution

Collaborating for ongoing success

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“I see a trend where CMOs are getting engaged earlier with clinical support.”

Chris Ignace Vice President Clinical, Scientific and Regulatory Affairs Cardinal Health Nuclear and Precision Health Solutions

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While the gap between nuclear and non-nuclear pharmaceutical manufacturing

is still there, it’s closing. “The primary difference is the handling of the radioactive material itself,” Thrasher said. “As we continue to apply new technologies, the goal is to make nuclear manufacturing as identical as possible to traditional, with the exception of handling nuclear waste.”

“We’re in a period of peak growth for therapeutic radiopharmaceuticals,” Augustine added. With the support of the right CMO, pharmaceutical companies can succeed throughout the evolution — relying on the CMO for the resources and expertise to help successfully bring their novel radiopharmaceuticals to market.

Next steps

As nuclear medicine continues to evolve, so too is the role of the CMO itself. “I see a trend where CMOs are getting engaged earlier with clinical support,” Ignace said. “This may include Phase 0 research, where the drug has never been injected into any patient. This is the polar opposite of the Phase 3 support that CMOs have traditionally provided. We see more demand now for clinical support far earlier in the process.”

In effect, this trend is an integration of CRO (Contract Research Organization) and CMO capabilities, yielding a CDMO model (Contract Development Manufacturing Organization). Cardinal Health Nuclear and Precision Health Solutions already provides not only commercial manufacturing services, but also early-stage clinical support.

As a CDMO in the radiopharmaceutical industry, Cardinal Health offers pharmaceutical companies full end-to-end capabilities throughout the development and manufacturing processes. “We offer a unique set of pharmacy-based as well as commercial manufacturing capabilities across diagnostic and therapeutic modalities, with drug products covering high and low energy spectra — alpha, beta and gamma emitting isotopes,” Ignace said.

The future of CMOs