What does it mean to “make” a drug? Most people would think first of manufacturing — big facilities with huge tanks, pipes, and valves all strung together with other strange equipment, taking in raw materials on one end and spitting out capsules or tablets on the other. Such things exist; I’ve seen them! But I know whatever I saw in the production plant is itself the end link in the long chain of activities that contribute to making a drug.
From a small amount of the molecular entity compounded by the medicinal chemist, scientists and engineers must formulate an end product and plot a process pathway that will produce clinical and commercial quantities that satisfy a battery of requirements such as dissolution, stability, and purity. And beyond those basics, making the drug continues with fill and finishing, delivery forms, packaging, distribution, and a host of other compartmental tasks. If you can visualize that chain from beginning to end, you will have a picture of the functions headed by Dr. Michael Thien, senior vice president of Global Science, Technology and Commercialization in the Merck Manufacturing Division.
“My responsibilities have three aspects: product development for manufacturing, technical support for our in-line products, and the conceptualization, construction, and start-up of the company’s capital assets — laboratories, manufacturing plants, and offices — overseeing about 1,500 people in support of $44 billion in annual revenue,” Thien says. In other companies, and by traditional pharma ways, he would likely be describing his role in narrower terms, perhaps covering only one of the “aspects” rather than all three, and fewer product forms than the full set of therapeutic proteins, vaccines, and small molecules his responsibilities now include.
Thien’s overarching purview has a unifying purpose. His primary task has been and is implementing a global program to restructure Merck’s far-flung manufacturing technical operations as a “boundaryless” organization, where workers of all disciplines interact constantly in ways that quickly solve problems, while capturing the knowledge accumulated from all of the individual and collaborative work.
His own team works with all of the company’s facilities and contractors around the world, confronting and diligently disassembling the physical, mental, and cultural barriers, or “boundaries,” between them. If plans succeed for this relatively young organization launched in November 2013, Merck will be among a select few Big Pharmas to break free of their legacy systems and traditions and to embrace new technologies and operating methods. (See also the sidebar, “No Boundaries for New Technology.”)
THE WAYS WE WERE
Thien describes the line of thinking company management took from operating the “old way” to the new way, with a global, “interconnected, interdependent” manufacturing organization uniting operations worldwide. “It had become abundantly clear we had been working in silos. The small molecule people worked on small molecules, the vaccine people worked on vaccines, therapeutic protein people worked on therapeutic proteins — you didn’t mix or match.” Management recognized, in some of the disciplines, people in different areas often shared the need for the same skillsets. Thien cites an example: Chemistry development, traditionally employed with small molecules, also applies to the new area of conjugate vaccines and antibodies. The next logical step was finding ways to encourage and optimize sharing of skills and knowledge among all three areas and hence, the idea of removing boundaries of all kinds between them.
“In this boundaryless organization, we can, with much greater alacrity, take people with skillsets in one area and apply them correctly to the technical or scientific problems in other areas,” Thien says. “Doing so allows us to get a much better picture of the science and engineering that underlies our processes and products and of the challenges we may face with a particular process or product.”
Boundaries can consist of many elements, tangible and intangible. But they are all institutionalized in the form of an organization as it has evolved over a long time. As Thien describes it, the solution was to perform an evolutionary leap.
“We had to overcome the organizational boundaries, but they were largely overcome by putting the new organization together,” he says. “We had to also overcome the business process issues. Vaccines did investigations differently than small molecules. We have now harmonized all that, taken those barriers out, so again, we can apply the right scientific expertise to the right work. And we have realized the creation of a boundaryless condition is, in itself, critical to accelerating the transition to a boundaryless state. We wanted people to be able to directly reach out to one another.”
The scenario Thien describes as the “before” state will be familiar to most readers. “In the past, if you wanted to get help from somebody in the network, you had to go up to your boss, who went up to another level with your request, which then went back down and over into another area for consideration while you waited for the response.”
To turn such crooked lines into straight ones, Merck created its own social media hub called the Virtual Technical Network (VTN), which can connect any member with any other, regardless of function or rank. “We set up about 25 online communities, so people can blog to any or all of them. If you belong to, say, the sterile processing community and have an issue in our sterile plant in France, you can just pop your query into that worldwide community, and anyone in the community can now respond to your email. Generally, we have found about 50 to 60 percent of the responders are people whom the questioner didn’t know or had never met before. But now, here it is — you get an answer from anywhere in the world within 24 hours, and you have access to a hugely rich set of information to help you solve your problem.”
Dr. Michael Thien
Senior Vice President of Global Science, Technology and Commercialization Merck Manufacturing Division
Thien says one of the VTN’s advantages is it encourages responses from people who not only have the requisite expertise but also the essential motivation and interest in addressing the issue at hand. “That discretionary effort along with their expertise makes a huge difference.”
TOOLS OF THE TRADE
Beyond the structural barriers to instituting a “boundaryless” organization, Thien says, subtler walls presented the greatest hurdles. “We come across the personal biases of people in one area against those in other areas: ‘They can’t possibly have the right knowledge or expertise to help me with my problem.’ We had worked hard to get rid of the organizational lines that prevented people from moving around and communicating. We had worked hard to harmonize the business processes. But to really eliminate all the boundaries, you have to change the culture.”
Teaching people how to communicate their issues in the proper context, and to define or identify what kinds of expertise they needed to tap, helped in one way. Another solution was to increase the bandwidth — to broaden the access to embrace the full set of expertise areas that might apply. “In a boundaryless organization, I may have to ask the broader question to help me with my issue. I may not even know what I don’t know. How can I appeal to the broader community? How can I move knowledge or technical processes or people to the work to get a better answer?”
The organization recently put up its own “open source” or, as Thien clarifies, “open posting” board to broaden such lateral communications, with the added motivation that employees can also appeal for help with temporary work surges. “Let’s say I have two weeks' worth of bio assays backed up in some development work. I can post a request, such as, ‘Does someone in small molecules want to get experience in bio assays?’ If someone has the interest and the time, and provided they get their boss’ agreement, we can let that resource flow to the task.”
Thien says the organization is now extending the boundaryless idea to other parts of the company and outside entities. It is reaching out to Merck’s manufacturing partners, along with its sister groups in the company’s research labs, to create a flow of resources between those areas and the commercialization, science, and technology area
ROGUE WAVE RESPONSES
With every reformation, the unexpected occurs. Asked if any “rogue waves,” or unanticipated disruptions, had crashed upon his shores in implementing the boundaryless mission, Thien laughed.
“Yes, there are times when our little boat was toppled. When we put our Virtual Technical Network together, one of the things we didn’t expect was the hesitancy of people to post their problems, despite the obvious appeal of having access to all of the organization’s expertise. When we asked them why, the responses were varied, but amounted to ‘I don’t want to look dumb.’ We had to take on a cultural battle to get everyone to understand the importance of making their problems visible. We created an expectation that the group leader would ask whether a person had posted the problem or question on the VTN. We also gathered many success stories of how people had used the network, and the success stories were typically from early adopters. We distributed those stories everywhere. We put them out in email bulletins, we had them in our newsletter, we talked about them in our town halls, and we let people know they are the stories of what the future should look like.”
It took about a year and a half to turn the tide so people routinely posted their issues on the network, says Thien. But just as the first challenge receded, the second rogue wave splashed ashore: fear of answering questions replaced the fear of posting them. “People were concerned that, if they posted an answer and the answer tuned out to be wrong, they would look like idiots.”
It took another educational campaign of new expectations and success stories to get people to understand that “nobody will advance if everyone doesn’t offer up their expertise,” he says. “The world is self-correcting. If you post an answer, someone may say, ‘Actually it’s not X, it’s Y.’ And people will move along. There’s no embarrassment. In fact, isn’t it better that you know the truth rather than continue in the falsity you’ve been living with?” Once again, 18 months of effort changed the culture, and posting answers became the new normal.
“We very successfully brought everyone around, and now we have a thriving Virtual Technical Network with over 2,000 members,” Thien says. "Every day there are dozens of questions being asked on the network and people getting answers within 24 hours.”
"Now we are putting in a very disciplined after-action review process, modeled after a Navy Seals program."
Dr. Michael Thien
Senior Vice President of Global Science, Technology and Commercialization Merck Manufacturing Division
HARVEST OF KNOW-HOW
Solving problems in making products is only one facet of the organization without boundaries, however, as the company views it. If that were all, each solution would be an ephemeral insight. Even beyond problem-solving, all activities in the line of production constantly inject a more lasting and valuable asset into the organization: what it learns at every step. Thien explains.
“In our new product development area, for example, we make two things. We make the kilos for clinical trials, and we make knowledge — knowledge about the product, about the process, and about the methods. We believe it is critically important to capture the knowledge we create in an explicit way so it is easy to reuse it.” Thus, he says, the organization created a “knowledge management strategy” with four parts: capture and categorize product knowledge, continuously build on technology-platform knowledge, share implicit knowledge through the VTN, and record critical knowledge from company experts in transition to another job or retirement.
Capturing, categorizing, storing, and retrieving knowledge, from all of the operations falls to an IT infrastructure built to handle the job. Such computing power helps handle the capture of so-called implicit knowledge as Thien explains. “We know that 70 to 80 percent of all knowledge is implicit or tacit; it is not written down anywhere; it consists of what people carry in their head. That was one of the purposes of the Virtual Technical Network: capture that knowledge in the form of conversation strings so we can use it again.”
For the fourth part of the strategy, recording critical knowledge, the group borrowed a concept from Shell Oil for a program called R.O.C.K. (Recording Of Critical Knowledge), which uses a programmed interviewing technique for people in transition to capture what they know on various topics, then put the knowledge in a reusable form, and make it available to the entire community.
Thien says one major lesson gleaned from implementing the knowledge management strategy is that all of the associated activities must transpire in the normal flow of work. “People should not see the recording of knowledge as something extra to their job, but as critical to their job. They are knowledge workers, and knowledge management has to be an integral part of their job.”
More recently, Thien’s group has added a fifth part to the strategy: implementation of a formal after-action review process. “We had a lot of lessons learned where nobody learned the new lessons. You might create a deck of PowerPoint slides that went up to the highest person possible in the company, but nothing really changed because we didn’t get the right information to the right people and change the right things. Now we are putting in a very disciplined after-action review process, modeled after a Navy Seals program, so we can have effective lessons learned where people truly do learn the lessons.”
Another lesson was to take instructive examples from other industries. Thien says the company looked for good models in the manufacturing and new-product development spaces of the pharmaceutical industry and came up empty-handed. So it went outside of the industry to work with some of the giants, such as IBM and NASA, for which knowledge management is absolutely critical. “We just attended the annual knowledge management conference that NASA holds just for its knowledge stewards, as one of the only two external companies to be invited this year to speak about our knowledge management efforts to the NASA knowledge team.”
Harvesting, organizing, and applying knowledge in the boundaryless organization has already produced some significant results, according to Thien. Merck made headlines in October when the FDA approved its cancer immunotherapy product Keytruda (pembrolizumab), the first FDA-approved anti-PD-1 (programmed cell death protein) therapy for metastatic melanoma. (See the series, “Combination Cancer Immunotherapy — A Virtual Roundtable,” beginning in our September 2014 issue.)
Thien describes the Keytruda mobilization: “We recognized it was going to be a significant undertaking to get this monoclonal antibody out and into the public. We used our boundaryless organization to essentially funnel resources from all over the Global Science, Technology, and Commercialization (GSTC) areas to the Keytruda team, so the team could be fully staffed and work at an extremely rapid pace. That was a huge benefit because we were able to accomplish the deployment very quickly and continue to pull those resources almost at will as the needs occurred, while we moved this product rapidly through the pipeline and through manufacturing readiness. We are now working to do the same in other areas of the business.”
The no-boundaries approach applies to all three areas of Thien’s responsibility: product development, in-line product technical support, and capital assets. As an example of support for in-line products, an expert from the material science lab for small molecule drugs could come in to help solve a problem with particulates in a vaccine.
Another, more general example of noboundary support is in the supply of clinical- trials material. Thien mentions the unit has not missed a clinical delivery since the new organization has been in place.
“We have a certain sense of confidence that comes from knowing that our processes are as robust as they can be, and the people developing those processes know they can tap into any discipline required to help them characterize and understand the processes. If we are working on a biocatalytic chemistry step, we know we can bring in people from the therapeutic-protein area to help us understand a particular behavior of the biocatalyst or enzyme we are using. This has made us a stronger organization with more robust processes even in the clinical supplies area, so we are better equipped to make every clinical delivery in the right quantity, with the right quality, and at the right time.”
OUTSIDE THE BOX
Reorganizations of any kind tend to be inward-looking. But how does the boundaryless organization — using knowledge management and open sourcing internally — translate into benefits for customers, however they may be defined?
“We have internal and external customers,” says Thien. “A plant manager at one of our sites knows the power of the entire network is available to work on any problem at the site. The problem will get a significant and completely deterministic response from our technical network worldwide. But one of the other areas where this boundaryless approach has paid off is in our support of external suppliers. We provide technical support as necessary to our CMOs when we have issues with products and processes. It may not be apparent to our external partners, but we are using the entire network to solve their problems, just as we do with our internal partners.”
Thien says the advantages of the network extend to “customers” outside the industry, such as regulators. A simple case in point is the availability of the network’s expertise to help sites appropriately prepare for, or respond to, preapproval inspections (PAIs). More generally, the company can make its panmodal teams — encompassing small molecules, vaccines, and therapeutic proteins — available to speak with regulators about issues that affect them all, such as statistical sampling.
The network can also produce some leverage with payers. Thien offers an example of sending a technical team along with a commercial team to visit some of Merck’s biggest clients and discuss their problems and challenges — in one case, resulting in a packaging improvement for a particular product.
“The areas we work in are not typically of the highest concern for payers. But we do ask them to tell us about any problems they encounter in using our products, and we try to find ways to address those problems.”
Looking outside also means looking at the future. Thien says his group conducts an annual strategic review for that purpose. “Let’s look at the world around us and ask the question, Has anything changed? And if things have changed, what do we need to do to modify our picture of the future state to better serve the manufacturing division, the company, and our patients?” And, as with all new or renewed organizations such as the Merck Manufacturing Division, the future will be the ultimate judge of whether, in Thien’s analogy, the steps it takes over time are the right steps, in the right direction.
No Boundaries For New Technology
Under Merck Manufacturing’s new “boundaryless” structure, the company is beginning to move into more advanced manufacturing technologies and methods — and in a deliberate fashion. Dr. Michael Thien, senior vice president of Global Science, Technology and Commercialization (GSTC), says his area has created a “picture of our future state,” compared it to the current state, and developed five “challenges” for the current year in categories that reflect his new organization:
New technology adoption. “We are looking at new technologies in every single area of what we do. We’re looking at new types of biocatalysis in our drug substance area, continuous processing for our drug production, new platforms in vaccines and therapeutic proteins, single-use technology for formulation and filling, and so on. We have technical projects going on in each of those areas. That’s our first big challenge."
Right first time (RFT) in new product launch. “100 percent right first time for all of our new-product introductions. We have a team working on implementing RFT activities for product validations across vaccines, therapeutic proteins, and small molecules."
Continuous improvement and stabilization. “We have a team totally focused on this for all of our in-line products.” (See “Merck's Continuous Process Improvement," Life Science Leader, July 2014.)
Boundary busting. “Another team is working on boundarylessness itself, harmonizing processes, creating the open sourcing work, looking at how we can align all of this with career development opportunities, and so on."
Prioritization. “How do we come up with a prioritization and resourcing mechanism for this new organization? All of those challenges have come out of the creation of this new organization that covers all of Merck’s major businesses and modalities.”
The GSTC area has also laid down some principles for adoption of new tools and methods. “We want new product introductions without drama,” Thien says. “We know that when you introduce new products and there are new processes, things may go wrong. But we want to make sure we have mitigated our risks and followed our timelines, so, when something does happen, it is not a dramatic disruption.”