Better together – working with CMOs

Twenty years ago, a pharmaceutical company would generally only have looked beyond its in-house team for non-critical products or services. Fast-forward to today and outsourcing critical processes, from clinical research to commercial manufacturing, has become commonplace, a paradigm that allows pharmaceutical giants and start-ups to concentrate on their core strengths.

One area in which pharmaceutical companies often look for outside help is the manufacturing of clinical trial products; not only does this avoid expensive outlays on equipment, facilities and staff, it also increases companies’ flexibility and allows them to capitalise on specific areas of expertise that contract manufacturing organisations (CMOs) have honed over yearsof experience.

The pros of investing in a relationship with a reputable CMO for the manufacturing of clinical trials materials are clear. These organisations have facilities complete with the physical infrastructure and equipment to address early and ongoing product needs quickly, and the appropriate CGMP systems that have been developed to address the life cycle of a product.

“Early phase I products have fewer CGMP demands, but that changes as the clinical efforts moves into the phase II and later stages,” notes Phil Burns, co-founder of CRO-Consulting, which provides compliance, regulatory and operations consulting to the pharmaceutical and medical device industry. “Attempting to internally develop and maintain these systems requires a significant effort, and while it may seem quicker to ‘just do it’ internally, each progressive step has greater and greater demands.

The depth of experience supporting production and compliance influences the success of the effort, and often this experience may not exist internally.”

So what’s the downside? Initially, according to Burns, the cash outlay: “In reality the long-term costs may be less, but the outsourcing effort usually requires upfront payments and the company’s cash position may make this hard to support,” he explains.

“That view changes once the cost of capital equipment, material inventory and adequate personnel begin to factor into the internal costs for the same effort.

“A company needs to make strategic decisions of how best to invest in their research and growth efforts, what internal expertise they wish to develop and what should be contracted.”

Decision time

Once the decision has been made to outsource, it’s time to pick a partner. The first things to understand are the company’s internal needs and strategies. “From these, the types of resources required can be identified,” says Burns.

Those resources could range from physical ones, such as manufacturing equipment, clinical packaging, laboratory supports or shipping to clinical sites, to personnel resources like formulation development, logistics, quality, and regulatory and analytical expertise. “That identification then allows you to determine the best way to meet those needs, internally or externally,” Burns continues. “External is the quickest way to a lot of expertise, or it may allow greater flexibility of the internal resources, whether for new products or the different stages of the product.”

It’s also important that while the process of selecting a CMO for clinical and commercial manufacturing is the same on a fundamental level, there are some key differences. “The scale is usually where they differ,” Burns says. “Moreover, the clinical stage typically generates greater science demands on the project, like formulation, stability and analytics. It is hoped that, by the commercial stage, much of this is known, and then costs, capacity and efficiency become the focus.”

Next, depending on the type of drug being manufactured, there is a small list of must-have attributes any contract manufacturing partner should offer.

When it comes to biologics, these haven’t changed much over the years, according to Eric Langer, president and managing partner of BioPlan Associates, which has been a leading source of independent strategic information and analysis for the biopharmaceutical and life sciences industries for nearly three decades, and produces an annual report and survey on the biopharmaceutical manufacturing sector.

“Over the past ten years, we’ve found remarkable consistency in how these decisions are made,” he notes. “First, there are the basic must-have attributes every CMO must offer, such as ‘comply with my company’s quality standards’, and ‘protect intellectual property’.” These two have topped the list and, particularly the IP issue continues to increase as more companies actively engage in the tech transfer of their projects.”

Other issues, including how CMOs handle cross-contamination, are more operational, and these have continued to increase in importance as biologics CMOs take a more prominent role in the industry.

“The contamination issue, for example, grew from around 25% of respondents ten years ago, to 53% today,” Langer says. “However, separately, the dynamic nature of this industry segment may also be seen in this question. As single-use, disposable manufacturing technologies have begun to dominate clinical-trials-scale manufacturing, the issue of cross-contamination has diminished: five years ago, about 63% saw contamination as a critical issue. We expect this factor is becoming less important, simply because single-use devices can dramatically reduce the associated contamination risks.”

Finally, human factors also play a huge role in the CMO selection process. “Establishing a good working relationship with clients has topped the list in the past, with 71% of the industry regarding this as to be one of the most critical issues,” Langer explains. “Sticking to a schedule also remains a vital factor, though this issue has become a chronic challenge, with at least half of respondents noting it as ‘very important’ over the past decade. This suggests CMOs are continuing to work through how to manage the timelines for these very complex biological processes.”

Communication problems

It’s crucial to remember that a single CMO is unlikely to be able to provide all of the capabilities a pharma company requires to get a drug into clinical trials. For example, some CMOs may have the expertise to manufacture the substance, while others may be more focused on the fill-finish part of the process. Moreover, at the clinical stage of development, time is often of the essence, making it even more important for companies to have a strong base of contractors that can be drawn upon when needed.

As Burns stresses: “From a planning stage, [having a strong base of alternative contractors] is critical. Time has great value for a potential product. Time can’t be bought, but having the right supports can at least minimise its loss. Flexibility helps overcome the things you can’t predict. Those things can be problems outside your control, or unexpected opportunities to increase the clinical efforts.

“Alternatives also help keep projects on track, as the timing to find and use contractors has been addressed in planning, so the predicted schedule can be maintained. If a product shows early clinical success, how important to the company and society is it to be able to move quicker? This helps to define the criticality of alternatives.”

Maintaining strong relationships with contractors then becomes vital to success, and, as with personal relationships, the key is communication: about the needs, expectations, changes and stresses that are met throughout development.

“Doing this well requires planning on both sides, using clear goals, timing, and responsibilities to drive the project,” says Burns.” Formal communication at all stages supports this need, and opens the paths for frequent informal communications.”

He adds that that the way disruptions are addressed can also impact relationship maintenance: “If the team and individuals involved focus on the tasks to respond to disruptions, they can often get the plan back on track. In addition to focusing on the tasks, they need to focus on their team members. Don’t find fault, instead ask what needs to be done and how you can help. In that environment, team members can identify what isn’t working and what needs to be done to address it, and not waste time establishing blame. This requires supports from both organisations at all levels.”

Human touch

Langer agrees that the only way to make the sponsor-CMO relationship work is a significant focus from both sides on communication. “CMOs that seek to build long-term relationships need to focus as much on the human part of the equation as the technical,” he stresses. “While establishing a good working relationship might seem easy, clearly the data suggest there’s been slow uptake on the part of CMOs in improving this area, and this also shows up very clearly on the CMO side.

“When we separately asked the CMOs what problems they had with their clients, we found that ‘clients don’t communicate with us effectively’ topped the list every year, increasing consistently from 80% in 2010 to 100% of CMOs in 2013. This suggests that the problems of communication are growing as use of CMOs expands. Further, because many CMOs still seem to feel it’s the client that is not communicating effectively (putting the blame for miscommunication on the customers’ shoulders), it is unlikely this problem will be resolved in the near future.”

Whether a clinical trial product ends up being approved or not, a successful sponsor-CMO relationship will always have positive repercussions for the future.

“Success breeds success,” Burns concludes. “If a product makes it to approval, the company will then be generating revenues for future research. If it doesn’t, the clinical efforts can still exhibit the company’s ability to execute the research, which can then support their efforts for future funding.

“Effective partnerships can carry forward through commercial scale for some products, or result in transfers to other subsidiaries or business partners. The success and relationships established will always outlive the specific projects.”