What to Look out for in Aseptic Design

Merck has constructed a new 272,000ft² vaccine production plant in Durham, North Carolina. Even before it’s up and running, the New Jersey-based firm is planning to expand the facility with $100 million that will accommodate additional expansions. NGP spoke with Susan Behrens, Senior Director, Sterile Supply Strategy at Merck, about the custom made vaccine manufacturing facility.

NGP. How has your background prepared you for your current position?
SB. The one thing that has been really helpful in my career here at Merck is that my education and training was cross-disciplinary. I’ve moved through the organization, and have done a lot of different things, including aseptic processing on the bulk products, fermentation at large scale, working with molecular genetic transformation projects, and final product operations and production. It’s been an interesting background with an opportunity to see the pharmaceutical industry and the processing capabilities from a broad perspective.

NGP. You have directed process design activities for several facilities, including the Merck vaccine manufacturing facility in Durham. What do you look for in a custom design facility?
SB. The key targets for the Durham facility, or for any facility, are focused around making sure that we’re providing the highest quality product to the patient. At Durham, we’re providing vaccine products, which of course are sterile, so we must maintain the highest level of sterility assurance. A lot of the design was focused around that concept.

We selected a very highly automated processing system, which protects the product from contamination. We use airlocks with secured access systems to make sure that we have the right people in the right places as it relates to the material and personnel flow in the area. So all of the decisions were evaluated with the highest priority on product quality impact.

This was a brand new custom designed facility, so we looked early at a master plan for the entire site and wanted to make sure that it would accommodate any longer-term business needs. We have not yet planned for additional expansions beyond the one announced recently, but we have thought about how we would do additional expansion at the site.

It’s a design that’s based on a spine concept, where we connect the processing facilities through a spine which carries both personnel and utilities. This gives us the greatest flexibility in having additional expansions as we move forward. Also we did a lot of our design analysis based on total lifecycle cost. Rather than looking just at initial investment cost, we look across the lifecycle of the investment and think about the operating costs and other strategic drivers in making the decisions. It may be sometimes cheaper to make a lower investment in a design. But in reality, over the long term, the operational costs or the ability to actually execute the process from an operator’s point of view are impacted. And so if you think about those things at the beginning, we find that often times some of these higher capital investments are justified.

NGP. In terms of design, was there anything that was particularly important for you?
SB. In an aseptic design, a high degree of attention is on the material and personnel flow to make sure that we’re maintaining our aseptic segregation. Another thing is that we are working with viruses in this facility, so viral containment was another area that we had to focus on as we moved the design forward. And so positive pressures and providing appropriate decontamination capacity in the right places was a critical component.

NGP. You are expanding the site even before you got it up and running with $100 million that will accommodate for this. What are you planning to ad?
SB. The investment is an identical formulation filling and lyophilization module for vaccines. We’re looking to install a second module at Durham to increase the capacity to accommodate increased demand for our vaccine products.

We are also adding some analytical capabilities. We’re adding laboratories so that the site can do its own product testing and release. Initially, the first module will be sending samples for testing up to the existing laboratories. But with the new module, we will be moving the testing to the site as well.

And an interesting thing is that this module was part of that earlier master planning. We had already done drawings, and we thought about where we would put the lab, and where we would put the module. The utility runs and support structures were in place to allow us to move forward.

NGP. You are also responsible for the implementation of the Merck supply chain strategy for vaccines, biologics, and sterile products. Could you explain this strategy in more detail?
SB. The Merck supply chain strategy was developed in 2005. The implementation to this point was in support of the larger product base portfolio of chemical and pharmaceutical based products. Moving into vaccines, biologics, and sterile products, we really had to consider different aspects.

Over the last two to three years there has been a big transformation for our vaccine, biologic and sterile product supply chain because the portfolio is growing quite a bit. It includes Gardasil, which is our vaccine against cervical cancer and genital warts; RotaTeq which was developed to protect against rotavirus infection for infants; and Zostavax for prevention of shingles in elderly patients. The demand is increasing across the portfolio, both with the new and existing products. But at the time we went through the analysis, the new products were in the process of being approved and launched. We’ll be growing across global markets for these products, and we also have a very strong vaccine and biologics pipeline coming forward in the next few years. When we looked at the supply strategy that was developed originally, we thought about what did we need to do to drive success for this set of products.

NGP. What are your strategies around optimizing that supply?
SB. The challenges are looking at how to design a global supply chain with flexibility to accommodate the changing worldwide demand requirements. We’re expanding into a much broader global market than we had been in before with this set of products, and we need to think about how to meet that world-wide demand. We’re committed to the developing world and providing access to our products.

One of the keys in optimizing the supply chain is enhancing the understanding of processes in general, and really being able to use that scientific basis to drive better controlled processes. With access to more information about the process as it’s happening, we will be able to drive more efficient, lean operations, and controls around the whole supply chain.

Probably the final key of the optimization of our supply chain is people. They are the critical component. We’re looking at what do we need to do to attract, develop, and retain employees that have the right skill sets, because the area is pretty complex, and there are operational risks and scientific challenges throughout the supply chain. We’re looking for key personnel to be able to drive us into the future.

NGP. In supporting full-scale manufacturing of vaccines and sterile products, what are the most common difficulties you deal with, and what are your resolutions?
SB. One of the biggest challenges is probably demand uncertainty. We don’t have a crystal ball, and we have to have a supply chain that can accommodate changes in requirements very quickly. We do that by thinking about early planning for capital investments, adapting our capacity so that we can support multiple products, and thinking about how we optimize inventory throughout the supply chain so that we have it in the right place in order to be able to meet the demand as it changes over time.

This particular portfolio of products is interesting in that the demand doesn’t follow the same type of growth curve as a small molecule or standard solid dosage product. They tend to be single-use-type products. And the uptake is dependent on policy decisions and government decisions. We have a different type of demand curve and a different type of supply requirement. We try to think about, in advance, how we want to factor in utilization and the capacity to accommodate those changes in demand.

Another issue in this portfolio of products is around process variability. In biopharmaceutical manufacturing, there’s more operational risk, and it’s a significant focus for the industry overall. We’re using biological processes themselves to make biological molecules, and the process can be affected by many different factors, including the media components, subtle changes in trace elements in the media, temperature controls, mixing, inoculation and harvest timing – even operator technique.

In order to try and mitigate the impact of those large numbers of variables, we do a lot of intensive process development activities upfront, identifying what are the critical process parameters that are going to impact product quality. As everyone in the industry does, we do a lot of process and facility validation to make sure that we can reproductively meet all those CPPs and deliver a product consistent with what was effective in the clinic.

One of the main challenges there is identifying highly technical qualified employees with an attention to detail to insure that we have dependable operations. It’s critical that we have people who understand how each detail and step can impact the quality of the final product. We do a lot of training and identifying in our recruiting the type of people who are going be able to do that on a day-to-day basis.

NGP. What are your strategies to increase efficiency?
SB. From a streamlining point of view, we’re looking at a lot of factors, like bringing materials to the line, thinking about the organization around our operations, the actual operators and supervisors, and what the best organization is to support them to keep an ongoing flow. We’re looking to implement lean principles across the board and drive the variabilities down in order to propagate a broader certainty and more efficient operations across the entirety of the supply chain from beginning to end. We think a lot about end-to-end – how does it match up?

There are very different process operations for bulk versus the finished product formulation and filling, and then finally the packaging requirements and distribution, and all of them have different levels of complexity. The bulk processes can be very long and can take on the order of months in some cases. The formulation and filling operations can be quite short, but they’re still supported by assays, which take quite a bit of time to do.

Bioassays inherently continue to be variable, as well as the processes. Sterility testing is critical, but it can’t ensure that we meet all the product standards, so sterility testing is supported by extensive process controls and quality systems in the formulation and filling area. The potency and product characterization assays are also biologic and are more complex, resulting in higher variability than the high-performance liquid chromatography (HPLC) assays used for small molecules. Those have to be extensively studied during development and conducted in a very rigorous manner by highly trained disciplined employees in order to minimize that variability. So we’re looking at raw materials, the labs, the process operations themselves, and how to be more efficient and reduce variability across all those steps.

NGP. Where will you concentrate your efforts in the future?
SB. Right now Merck is transforming itself. We’re working to develop an end-to-end culture with a “One Merck” perspective to meet the global demand for the products and toward introduction of new medicines and vaccines which are on the horizon.

My personal commitment is to continue to enhance our supply chain design, looking backward into the pipeline, and thinking about how to accommodate some of the strategic drivers we’ve learned about and bring them forward ready for lean operation in a very efficient production.

Another area where we’ll continue to focus is the availability of key talent. As the business is growing globally, we’re looking for a global workforce that will be able to bring their experience across a broader set of opportunities. We’ll be looking at organizational designs and programs for recruiting each individual with a focus on results, and how we’re going to bring those people in to the organization to help us support the growth in this portfolio over the next three-to-five years.

A chemical engineer with a bachelor’s degree from the University of Michigan and a doctorate from the University of California at Berkeley, Susan Behrens feels that the chemical engineering degree has been helpful in terms of the processing capabilities she works with in the pharmaceutical industry. She studied mostly biotechnology processing, including fermentation and cell culture separation sciences, protein stability, and how to optimize and improve processing.