By Rob Wright, Chief Editor, Life Science Leader
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Even with more than 8,800 employees and an annual budget of around $3.2 billion, the FDA’s task of protecting the public health seems daunting, considering the complexity of products being developed by industry. Factor in other issues such as counterfeiting, terrorism, drug reimportation, and the globalization of drug discovery, development, and manufacturing, and you soon realize that working at the FDA is indeed quite a challenge.
Jeffrey Baker, Ph.D., is learning how true that statement is. Baker, who was hired in 2011, is the deputy director, office of biotechnology products at the FDA’s Center for Drug Evaluation and Research (CDER). His hiring is an example of how the FDA, in an effort to learn more about the industry it governs, brought in someone with extensive industry experience.
Having spent 20 years working for the likes of Eli Lilly and MedImmune, Baker arrived at the FDA with what he describes as his “industry toolbox,” which includes a Lean Six Sigma Black Belt — indicating significant competency with a variety of tools and techniques that represent the best practices for quality in process improvement. Perhaps more importantly, he brought a willingness to learn. “I am trying to share my relevant experiences and be an active listener, a student of folks who have been doing this for years.” With that mindset, Baker’s goal is to help develop a shared vocabulary and shared expectations between the FDA and industry, thereby making it not just a governing body, but an enabling body.
Developing A Shared Vocabulary
When Baker first joined FDA, one of the first things he wanted to do was to meet as many people as he could to gain a greater understanding of the organization. “I would introduce myself, and they would tell me who they were, followed by an alphabet soup of acronyms,” he explains. “I would then ask if they could tell me what their deliverables were, as I was new to the organization.” He says people would often respond with something like, “This is the department that I am in, and here is what I work on.” He quickly realized that the people were not specifically focused on providing deliverables, a common business term which encompasses task completion, metrics, and timely delivery of products. The FDA, on the other hand, generally views its mission as ongoing and part of a continuum to provide public-health solutions. “We have to be able to manage progression within that continuum, but we also have to complete tasks in a timely and high quality way,” says Baker. To help accomplish that goal, he began the process of developing a shared vocabulary. To his colleagues, he asked questions he was used to asking while working in the pharma industry, questions such as, “What are our goals? What are the value adds of certain activities?” For some people, the reaction was, “We are not a business.” But, the majority of people didn’t take that attitude and instead saw the benefit of taking a different approach to their jobs. “We need a shared vocabulary between the FDA and industry in order to have mutually successful shared outcomes,” Baker explains.
During another interaction with a colleague, Baker was listening to someone explain the hiring and onboarding process for a new FDA employee. To gain a better understanding of the process being described, he drew a workflow diagram. Other members of the FDA saw the drawing sitting on his desk and found it helped improve their own understanding of the process. Even though there was no new information in what he created, his approach of looking at the problem differently proved fruitful and was recently discussed at a director’s meeting as a means of teaching the hiring and onboarding process.
The Importance Of Shared Expectations
Both industry and the FDA are in the business of ensuring a reliable supply of safe, high-quality medicines which produce high-quality outcomes. To achieve this has historically involved long wait times. “When I was in the industry, we would have to explain to people that we cannot snap our fingers and have a building appear,” analogizes Baker. “It is a long lead-time item. Similarly with the FDA, navigating public policy and providing sound guidance are long lead-time items. But both industry and the FDA recognize that the pace of change is rapid, and the needs of the public are immediate.” For the FDA to successfully partner with industry and vice versa, in addition to having shared language, Baker believes in a shared set of expectations. One way the FDA partners with industry in developing shared expectations is the draft guidance process. This process also facilitates a level of open communication and helps the FDA to be a learning organization. When the FDA creates draft guidance, it is an iterative process involving a series of refinements. Through a synthesis of internal and external discussions between industry and the FDA, guidance is refined before becoming policy. A recent high-profile example involved the development of draft guidances on biosimilars. It included an attached Q&A sheet of commonly asked questions regarding the FDA’s initial interpretation of certain statutory terms and requirements of biosimilar development. By taking a proactive approach to addressing questions that could arise in early stages of biosimilar product development, the FDA aims to improve interpretation of the draft guidance, thereby enabling companies to effectively implement and provide commentary on the draft guidance. Some examples included how to request meetings with the FDA, what differences there are in formulation from the reference product, and how to request exclusivity. As to why the recently issued guidance is only considered to be a draft and not policy, Baker explains, “It is draft guidance because it is important that we give industry and the public a chance to respond and a chance to provide their input prior to finalizing. By the same token, the FDA needs to put it out there because biosimilars are being developed now. Industry and the FDA need to have shared expectations now.”
Another example Baker cites as a means for developing shared expectations is having members of the FDA attend and speak at industry conferences. For example, this past January, Vicki Seyfert-Margolis, senior advisor for science innovation and policy, spoke at the Conference Forum’s New Paradigms to Fund & Move Drug Development Conference in San Francisco, providing insight on how biotechs can better navigate the regulatory system. Baker recently participated in a roundtable at MIT and is scheduled as one of the keynote speakers at this year’s Interphex conference. Not only does this type of FDA involvement at industry events help foster a shared language and shared expectations, it assists in carrying out the transparency initiative set forth in 2009 by FDA Commissioner Margaret Hamburg, M.D.
Recently, the FDA gained full membership in the Pharmaceutical Inspection Convention Scheme (PIC/S). This is another example of how the FDA is working to develop shared expectations with industry. “This is a big deal,” states Baker. “When I was in industry, the FDA was not a full member. There were 36 other countries that were. I think it really shows the agency’s commitment in aligning with and projecting influence on the global standards.”
Quality By Design Is Just Good Business
QbD is a concept first outlined by quality expert Joseph Juran who believed that quality could be planned. QbD principles were adopted by the FDA as a vehicle for the transformation of how drugs are discovered, developed, and manufactured. Baker sees QbD as a reiteration of developing shared expectations, not as a ticket to regulatory relief or a shortcut. “QbD is about providing a very high level of assurance that we have control of process and product,” he states. Utilization of QbD by companies enhances the FDA’s decision making, which uses a risk-based decision-making (RBDM) approach. RBDM is defined as a process that organizes information about the possibility for one or more unwanted outcomes to occur into a broad, orderly structure that helps decision makers make more informed management choices. Since the sponsors are the technical experts and the ones who know the most about the products being developed, it is their responsibility to demonstrate and explain processing controls to the FDA. Baker sees QbD as good business because it emphasizes reproducibility in meeting expectations and demonstrates product control. “A process that is in control is a process that itself reproducibly meets expectations. If a company cannot crisply articulate the expectations of a manufacturing process from beginning to end and the measures by which it is going to demonstrate control, then it is very difficult to say the process is in control and therefore consistently reproducible,” Baker states. His advice for industry to demonstrate QbD — be transparent with the FDA. Further, he believes industry can benefit from using a variety of statistical and decision-science tools currently available in identifying and implementing a reproducible control strategy. “The organizations that are able to pull upon the disciplines of statistical process controls, measurement systems analysis and component of variance analysis and use them in a facile and efficient way are coming out with very solid data-driven decisions,” he affirms.
Baker sees the heart of QbD as not being very different from the principles of process validation, which include define, demonstrate, document, and maintain. By define, he says you need to identify and justify the measures that assure a process or product will meet expectations. With regard to demonstrate, Baker asks, “What does the process look like when it runs correctly?” Companies need to demonstrate they can actually perform in the defined envelope. By document, quite simply, Baker says to write it down. As for maintain, companies need to provide some reasonable level of assurance as to how they intend to operate in the prescribed manner. Define, demonstrate, document and maintain is something Baker developed at Eli Lilly. By bringing this concept from industry to the FDA, Baker exemplifies how the FDA is developing both shared vocabulary and shared expectations to serve as a governing and enabling body.
“Executives who make sourcing decisions really need to fully assess the total manufacturing capability of that outsourcing opportunity,” says Baker. By capability, he is not referring to statistical capability or Cpk (process capability index, a measure of how close a facility is to its targeted goal along with how consistent it is with average performance), but rather to systemic ability to deliver. He believes executives making the outsourcing decision need to see the process as not about buying grams of material from another shop, but more of a means of delegating the manufacturing responsibilities of one organization to another. “I think there is a disproportionate amount of attention paid to whether a process can be executed in a physical plant as opposed to whether a reliable high-quality product is going to be released in a timely way,” he states. When due diligence is done and when those decisions are made, Baker advises executives to look at the whole picture. Manufacturing capability assessments should include the quality and depth of local technical support, integrity and transparency of quality systems, and the ability to allow people to make high quality risk-based decisions quickly. Understanding manufacturing capability is critical to making a successful outsourcing decision. “Very rarely does a capacity-based failure arise because we try to put 3,000 liters in a 2,000 liter tank,” he states. According to Baker, capacity problems arise because there is a poor understanding of queue time, switch-over time, and the time associated with transactional or review processes within the supply chain or quality system. “All of these things can cut the actual practical capacity to a fraction of the theoretical capacity,” he relates. “Capacity is not what a plant can deliver per unit time, but what a plant is very likely to deliver over time.” As outsourcing has increased in popularity, so has the enthusiastic marketing of manufacturers touting capacity. Unfortunately, Baker believes this has resulted in an increase in pain of failure to both clients and the public, especially in multiproduct or multisponsor plants. Baker’s message to executives — approach capacity management systemically and use dynamic and stochastic modeling tools to be very data-driven in understanding capacity and probable outcomes. Baker believes that to gain a better understanding of capacity management when making an outsourcing decision, start by developing a team with a diversity of disciplines and backgrounds, including individuals who are experienced in manufacturing and system engineering. Also, seek team members with experience in statistical outcomes and decisions sciences. Baker also suggested the use of a variety of statistical analysis programs such as JMP or Mathcad. Baker concludes that companies must see outsourcing of manufacturing not as a cost center, but a value center. When deciding to outsource, Dr. Baker advises companies to thoroughly understand why they are choosing to outsource. “If you are outsourcing to gain additional capacity, to defer capital investment, to manage a value-add tax situation, or to manage headcount of a specific core discipline, the value proposition of why you are outsourcing needs to be assessed in that light,” he states. Baker believes we will see a continuing increase in strategic partnering. He sees this as being quite different from outsourcing. “In strategic partnering, there is shared pain and shared gain,” he says. “You succeed and fail together. I think folks sometimes mistakenly think that’s not the case with outsourcing.” Baker puts it this way, “You can contract out activities, but you cannot contract out responsibilities.”