Case Study

Innovation With Single-Use: Merck Calls For Collaboration To Overcome Challenges

Single-Use: Merck Calls For Collaboration To Overcome Challenges

By Jeffrey Johnson, New Technology Lead and Director, Merck & Co.

Merck’s mission is to save and improve lives. After 125 years in the pharmaceutical business, a considerable amount of our effort to do this has been in major areas of care, such as diabetes, hospital acute care, oncology, and vaccines. Recently, there has been extensive focus on the latter two, as Merck has moved from a predominantly small molecule oral solid dosage company to one that recognizes biologics as the wave of the future. In 2014, Merck’s immunotherapy treatment, pembrolizumab (Keytruda®), broke new ground in the fight against cancer when it became the first FDA approved drug that blocks the PD-1 pathway. Today, Keytruda’s success has expanded from its treatment of melanoma to being an approved treatment for non-small cell lung cancer as well as for head and neck squamous cell cancer.

As the industry — and Merck — sees its pipelines expanding into these more targeted areas of treatment, the call for flexibility and speed gets even louder. Many feel an answer to this is single-use technology (SUT). SUT, as many are aware, offers significant benefits to biomanufacturers, such as reduced cleaning requirements, a smaller footprint, less capital investment, more flexibility, and reduced risk of cross-contamination. At Merck, there has been a continued momentum of sales in biologics and vaccines over the last 15 years. However, up until six years ago, we had not fully explored SUT or its full potential implementation in our facilities. That is, until an outside industry expert gave us the brutally honest assessment that we were “behind” when it came to SUT. To address this head-on, thought leaders from various departments within Merck coalesced into a network of single-use advocates who shared the common goal of facilitating the implementation of SUT at our company. This group became known as the Merck Single-Use Network, or SUN.

Working As A Single-Use Community To Explore SUT Potential

At the time SUN was established in 2010, 80 percent of all predicted growth in the pharmaceutical industry was expected to come from monoclonal antibodies (mAbs) and therapeutic proteins (TPs). Nonetheless, these drugs are complex and expensive to manufacture. For drugs that reach blockbuster status, batches are typically produced in large volumes; therefore, in those cases, large stainless steel bioreactors seem to make sense. However, newer mAbs and TPs are often for targeted populations and, as a result, are manufactured in much smaller volumes. So a decision had to be made about what type of facilities Merck should utilize for our diversified pipeline as it continues to expand.

To do so, a cross-functional team of Merck’s single-use experts, its engineers, and the finance group completed a net-present-cost analysis of the possible facility types: single-use, stainless steel, and a hybrid of the two. At a high level, net present cost is the time value of money. For example, stainless steel facilities require a considerable amount of capital upfront but less money spent in the future, because you don’t have to pay for single-use bags.

The team started by looking at the capital cost for each type of facility. A traditional stainless steel facility with six 15,000-liter (L) bioreactors has a capital cost of around $600 million. Reduce that to six 2,000 L stainless steel bioreactors, and the cost decreases to around $200 million, but the latter facility produces only about one-seventh the scale of product. Change that six 2,000 L facility to one with single-use bioreactors, and the capital cost goes down considerably to around $70 million. You still may be producing only one-seventh the scale as a large stainless steel facility, but you are also spending one-seventh of the capital. In these simple terms, single-use clearly has the advantage.

But this simple analysis does not factor in one very important detail — titer.

As the potential increases for biopharma to produce batches at a titer much higher than one gram per liter, which is what has typically been possible in the past, so do the facility options. It is imperative to take into account titer and what the demand for a drug is while considering each of these options. For example, a 15,000 L bioreactor in a stainless steel facility has a low cost per gram when operated near full capacity, but the capital cost is the highest ($600 million). If the drug is a blockbuster drug in high demand, this scenario makes the most sense. Start taking into consideration titer and how much the facility will be utilized (based on demand), and the decision of which type of facility to build becomes based on volume.

The following image is a net-present-cost (NPC) basis comparison among a stainless steel facility and a single-use facility. At a titer of 3 grams/liter, a single-use facility makes financial sense for volumes up to ~1,500 kg/year.

After completing this analysis, the team challenged itself — could there be a single-use facility that was lower NPC than stainless steel for all capacities?

The answer is yes! As titers increase, SUT looks even more favorable. For example, and as shown below, an intensified fed batch hybrid facility with 6 x 2,000 L single-use bioreactor (SUB) is economically favored vs. a stainless steel facility, no matter what capacity is required. 

In another analysis based off a number of assumptions, a continuous perfusion factory could have even greater economic advantages. While these assumptions still need to be experimentally confirmed and there are certainly still risks around single-use facilities, this analysis clearly shows the economic carrot is there to warrant further investments.

The advantage of using a single-use concept is that you can start considering innovative concepts in a modular plug-and-play facility. Many refer to this type of facility as the “facility of the future.” In this configuration, clinical trials can be done in a 2,000 L bioreactor and then that same reactor can be used for the initial launch of the product. A modular facility also gives you the option of erecting just one facility at launch and then, if necessary, quickly building duplicate modules in multiple locations if and when they are needed. This reduces the possibility of lost resources when investing in a stainless steel facility you do not ultimately end up using at anywhere near full capacity.

There are still many questions to be answered when it comes to the implementation of single-use and continuous processing facilities, and Merck is trying to work through these by testing some of these innovative concepts in-house. Through the single-use community established by SUN, we are sharing our experiences and lessons learned across the entire Merck network. We believe this is the type of collaboration needed not just within our own company but across the industry to conquer the challenges and fully utilize the advantages with SUT.

Reduce SUT Risks Through Industry Collaboration

With every benefit that comes with implementing SUT, there seems to be an obstacle that comes with it. Table 1 shows some of the most well-known benefits and their related obstacles.

The potentially high risks some of these obstacles present is likely the reason we are still seeing stainless-steel facilities being built today, despite SUT benefits. However, by working together, the industry can lower these risks and increase the rate of SUT adoption. Today there are a number of groups working on different projects to overcome SUT obstacles. These include:
 

  • Food and Drug Administration (FDA)
  • U.S. Pharmacopeial Convention (USP)
  • European Pharmacopoeia (EP)
  • American Society of Mechanical Engineers (ASME)
  • American Society for Testing and Materials (ASTM)
  • Parenteral Drug Association (PDA)
  • International Society of Pharmaceutical Engineering (ISPE)
  • Bio-Process Systems Alliance (BPSA)
  • BioPhorum Operations Group (BPOG)
     

As shown in the image below, these groups make up a hierarchy of “alphabet soup,” with the industry community groups of BPSA and BPOG at the bottom. BPSA is composed mostly of suppliers, while BPOG is pharmaceutical manufacturers, including Merck. The goal for BPOG and BSPA is for suppliers and users to come together as one, regardless of company, and work together to push through the issues plaguing them and determine the next best steps for the industry as a whole.

Courtesy of Jim Vogel and BioProcess Institute

 

Once something becomes an industry standard, then the FDA knows what to ask and what to look for during evaluations. If everyone is on the same page, there is potential to facilitate navigation of what are typically complex regulatory pathways.

For example, to simplify the industry’s approach to the selection and implementation of SUT, there has been a tremendous push by some SUT advocates to establish standards around single-use, particularly with equipment connectivity. While there are certainly concerns from suppliers about standardization (as they feel they’d no longer be able to differentiate themselves in the market), benefits for them do exist. The biggest is that by moving forward with a plug-and-play approach where all suppliers’ equipment interconnects, customers take comfort in knowing that re-supply will almost always be available (through one supplier or another). It would also reduce customization, which lowers costs for both the supplier and the user. By building this interconnectivity, single-use adoption will likely increase and the market for suppliers will become even bigger.

At Merck, SUN has reduced the variability of what equipment is being selected for all Merck facilities by creating a catalog of single-use components that have already been internally validated. This makes selection and use easier for Merck users because now all they have to do is pick something out of the catalog and go, thus improving efficiencies and saving time. Similar efforts at other companies could be a great way to work toward reducing variability and facilitating efficient SUT implementation.

As industry groups like BPOG and BPSA work toward this effort of standardization, the agreed-upon guidelines can eventually move up “the alphabet soup” hierarchy. Merck is an active member of BPOG, where there is a current focus on change notifications, user requirements for SUT, leachables, and extractables.

Other standardization efforts across the hierarchy of industry groups include:

  • BPSA – defined guidelines on particulates, initiation of task forces for change control and integrity testing
  • ASTM – working on single-use extractable standard, planning to issue single-use testing standards
  • ISPE – working to publish a single-use guide
  • PDA – published Technical Report 66 on single-use systems, which gives users critical concepts or points to consider when implementing SUT in a facility

These are certainly not the first efforts of these groups, and they will not be the last. As they continue to work toward facilitating and accelerating single-use adoption, it is the responsibility of every member of the pharmaceutical industry to determine what their role should be in these efforts. Through collaboration and open communication, we can unite to advance the implementation of SUT and thus the mission of the pharmaceutical industry to improve the lives of the patients who depend on us.      

About Author

Jeffrey Johnson is currently the New Technology Lead and Director, Global Science, Technology and Commercialization at Merck & Co., Inc., where he is responsible for the assessment of new manufacturing technology for Merck's vaccine, biologics, and sterile manufacturing processes. He is also the co-leader of SUN — Merck's Single-use technology initiative. Prior roles include Director of BioProcess Engineering, responsible for business case and concept development for new vaccine and biologics capital projects, and Director of Network Management for Therapeutic Protein Commercialization. Prior to Merck, he worked for Genzyme Corporation, Raytheon Engineers, and ARCO Chemical Co. He holds a BS in Chemical Engineering from the University of Rochester, a MS in Chemical Engineering from the University of Pennsylvania, and a Certificate in Biotechnology from Tufts University.