Coming of Age

As of Feb. 20, 2013, the U.S. Food and Drug Administration’s Pharmaceutical GMPs for the 21st Century – A Risk-Based Approach is 10 years old. Originally met with a mix of relief, hope and skepticism, this blueprint for pharmaceutical development has inspired more commentary than any FDA strategy position. Like most 10-year-olds, it is very much a work in progress.

GMPs for the 21st Century has profoundly influenced how drug companies manage risk, particularly but not exclusively with regard to manufacturing. The risk-based approach becomes particularly challenging given the backdrop of merger and acquisition activity and a heavier reliance on outsourcing for manufacturing and R&D. For manufacturing, this means negotiating the moving targets of productivity and supply chain demands. 

While specifically covering risk, quality by design, and process analytics, GMPs have invigorated science-based process development, nudging it away from what is merely comfortable to what is possible.

Adoption of PAT and QbD, promulgated as part of FDA’s 2003-2004 GMPs for the 21st Century, was slow at first but is accelerating. 

QbD required effort in terms of analytics and modeling (designing-in vs. testing-in quality), not to mention the implications of any “risk-based approach” for a risk-averse industry. Despite common belief, neither PAT nor QbD are mandated.

QbD case studies describing “home run” successes are increasing. Most involve what in many other industries would be viewed as common-sense measures for reducing cost and improving regulatory compliance. 

QbD’s practical benefits to manufacturers include fewer failed batches, less regulatory friction, process understanding, more efficient control of change, etc. Each of these benefits may be broken down further, but all at some level reduce to an improved bottom line. The real benefit to patients is not necessarily improved safety or efficacy, but more reliable supply and the optimal allocation of resources to research and development.

QbD uptake has followed reasonable timelines, says Mike Thien, Sc.D., SVP for Global Scientific, Technology, and Commercialization Operations at Merck (Whitehouse Station, NJ). “QbD represents a paradigmatic shift in how companies develop products,” he explains. “It’s a framework that focuses where companies will allocate resources in developing science and methods for a product. It’s no surprise it has taken this long.”

Merck was a QbD pilot participant, and soon decided to adopt the strategy for most of its new products. Like any company facing paradigm shift, Merck first aligned its R&D, commercialization, quality and regulatory leadership, then trained everyone else to exploit the tools of the QbD framework. After factoring in development and approval times, “10 years seems about right” to have reached this level of deployment, Thien says.

Merck’s QbD initiative resembles six sigma frameworks employed in other industries. As an early adopter, Merck management believed that if structured, risk-based quality initiatives worked for other industries, they could provide similar benefits for pharmaceuticals.

During the mid-to-late 2000s, industry leaders based their public rationalization of QbD on patient needs, which at the time seemed like a stretch. QbD was, after all, primarily a manufacturing exercise. Weren’t top companies already producing safe, effective products?

Yes, but as Thien explains, successful QbD begins rather than ends with the patient. It starts with identifying a patient’s needs, translating them into technical specifications for products and processes, and locating (and mitigating) risks that threaten fulfillment of those product/quality objectives. “We made great products in the past, but we were unable to focus resources as acutely, or immediately, on risk areas in light of specifications of patient needs. QbD enabled us to aim our best science at those highest-risk areas.”

Merck’s direct manufacturing benefits include processes that are more robust and reliable, with significantly fewer process-related deviations. For example, fewer assays are now required during release testing because quality assurance and modeling occur throughout the process, in real time, thanks to PAT. This results in lower cost of goods, a benefit that grows with product volume. “In some cases, PAT has enabled process viability, and thus led to the greener and higher-yielding processes that we now enjoy running at scale,” Thien says.

One could argue that corporate-wide initiatives like QbD are fine for well-heeled companies. That may have been true a few years into the initiative. Today, with best-in-class firms sharing their experiences at conferences, small and mid-sized manufacturers receive what amounts to a free education. Thien believes QbD’s prime benefit is its scientific, heads-on treatment of risk. “Risk assessment narrows your focus, to home in on where to invest resources to understand the process better, and the science behind it.”

Companies tend to create QbD programs in their own corporate image. At Janssen Pharmaceuticals (New Brunswick, NJ), QbD falls under the umbrella of “design to value” (DTV), a more encompassing quality initiative. According to Paul McKenzie, Ph.D., VP of Manufacturing and Technical Operations for Janssen Supply Chain, DTV assures the right mix of priorities around the “triangle” of R&D, commercial, and operations (including manufacturing and quality). “The other component is how we work towards standardizing our technology. Savings from standardization go to innovation, and further improving the QbD effort.”

Direct patient benefits are more easily ascribed to quality initiatives under the broader DTV concept than with conventional QbD, which is, after all, a manufacturing strategy. One success story involved creating a sustained-release form of an antipsychotic medication within a therapeutic category where non-compliance is legendary; the other involved a similar strategy for an anti-HIV medicine. “As patients get value, Janssen gets value,” McKenzie says.

Quality, supply and regulatory uncertainties are the most-cited reasons for the slow adoption of manufacturing innovations for new processes, and even slower uptake for existing ones. 

Although common in other process industries, continuous manufacturing has long been shunned by pharmaceutical manufacturers. That is changing in a big way.

Novartis and the Massachusetts Institute of Technology are engaged in a 10-year program that hopes to integrate all steps of pharmaceutical production — from synthesis to dosage form — within one over-arching process. The Novartis-MIT Center for Continuous Manufacturing (CCM) hopes to replace discrete unit operations with a seamlessly continuous process. 

“Continuous manufacturing will speed com-mercialization of new medicines because it does not involve interruption,” says Juan Andres, Head of Global TechOps at Novartis. 

Potential advantages of continuous manufacturing include smaller production facilities, lower capital costs, energy and waste minimization, raw material economies, process and market flexibility, and the potential to incorporate process analytics and quality by design. 

“Once you go to continuous, you begin to have continuous monitoring, so it’s much easier to control quality,” says MIT chemical engineering professor Klavs Jensen, a CCM participant and developer of the flow chemistry used in the project.

Continuous manufacturing could produce tablets in as little as a few days. By employing smaller systems and built-in waste minimization, continuous manufacturing has lower environmental impact as well. 

CCM successfully completed a prototype process in 2011, and by 2012 had fully integrated a control system to automate the continuous manufacturing process. Researchers are focusing now on scaling up production with the plan to ultimately implement continuous manufacturing technologies across the entire Novartis portfolio.

Writing in Industrial & Engineering Chemistry Research in 2011, Spencer Schaber and co-authors analyzed the potential cost savings for producing 2,000 tons of a pharmaceutical product through continuous vs. batch manufacturing. Although yields were somewhat lower for the continuous process under investigation, product recycling and lower equipment requirements more than compensated. Additionally, capital expenses were between 20% and 76% lower for the continuous process, while operating expenses fell by 40%. “Even when yields in the continuous case are lower than in the batch case, savings can still be achieved because the labor, materials handling, CapEx, and other savings compensate,” Schaber wrote. These savings are in line with CCM’s estimates of 15% to 50%. 

“We see the future of pharmaceutical manufacturing as continuous,” says Bernhardt Trout, Professor of Chemical Engineering at MIT and Director of CCM. “That includes continuous flow together with a systems approach, integration and advanced control. We can use a lot of chemistry in continuous that we couldn’t use in batch.”

The CCM project involves “new technologies across the board,” according to Trout, from new, high-yield chemistry exclusive to continuous manufacturing, to novel work-up, drying, and dose-forming technologies, including coating. “These approaches are model-based and incorporate end-to-end process control, leading to a huge reduction in total process time, greater energy efficiency and lower cost.”

Continuous processing involves a change in mindset, with significant shifts for process developers who must now view plants holistically rather than as a string of unit operations. But few limits exist, either on scale or molecule type. “It just needs to be done,” Trout says. “A key will be selecting the first molecule to process continuously.”

University-industry manufacturing collaborations are not new, but their frequency appears to be increasing. 

One focus of Rutgers University’s NSF-funded Research Center for Structured Organic Particulate Systems (C-SOPS) is the efficient production of active pharmaceutical ingredients. When the center opened in 2006, its director, Fernando Muzio, deemed prospects for continuous pharmaceutical manufacturing “debatable.” But much has occurred in the last seven years. 

“Process Analytic Technology is now widespread, QbD is increasingly becoming part of the standard language in process development, and modeling methods are spreading rapidly,” Muzio says. “Continuous manufacturing is now identified by the FDA as a manufacturing megatrend for the next 25 years.” 

One of GMPs’ most exciting after-effects has been a more flexible approach to manufacturing that encompasses the entire product portfolio, including anticipated products through mergers and acquisition activity. High-value core products should remain within large companies, advises John Lindner, Life Sciences VP at Celerant Consulting (Richmond, England), while marginal product lines may be more profitably outsourced. Companies should therefore prepare for a complete reconfiguration of their supply chain footprint.

Improving manufacturing agility, while closely managing core products and competencies, is not a new idea. Innovator firms have farmed out packaging, formulation, printing and over-the-counter (OTC) manufacturing for decades. Lindner extends this strategy to reducing “SKU” creep — the proliferation of products around a specific active ingredient or set of actives, particularly for OTC medicines or off-patent molecules. Companies should view this type of redundancy in the same way as non-core activities, products and therapeutic areas: outsource, divest or partner-out.

Thus, the conflict between marketing, which seeks greater complexity, and manufacturing, which prefers streamlining. Commercial experts were taught in business school, to expand product lines horizontally, and increase the footprint as much as possible. 

“But that creates unwarranted complexity for manufacturing. Rather than producing 57 varieties in various sizes, packaging and formulations, consider consolidating the footprint for groups of these products and consider which should be retained and which should be moved externally,” Lindner advises. 

On the flip side, many processes now employ platform strategies that supply consistency and predictability. Currently all the rage in biologics manufacturing, particularly for monoclonal antibody manufacture, platform processes employ identical unit operations, and often nearly identical culture media, for molecule classes. 

“Platform processes help speed deployment of products from R&D out through commercial,” explains Janssen’s McKenzie, “not only from the perspectives of time and cost, but for reliability and reproduceability.”

At Janssen, platforming is not restricted to therapeutic proteins. The manufacture of Zytiga, the company’s small-molecule prostate cancer drug, is based on platform methods. So is Janssen’s ibrutinib, another non-biologic indicated for blood cancers. Ibrutinib, that has received one of FDA’s first “breakthrough therapy” designations, which accelerates development of drugs for serious diseases that show substantial improvement over existing medications. 

One of Janssen’s initial QbD platforming successes was the successful move from perfusion cell culture (how Remicade is produced) to more standard fed-batch cultures. “This enabled us to standardize the entire process, down to raw ingredients,” McKenzie says. Another improvement leading to quality and consistency was the move from animal product-derived media ingredients to animal component-free media, a move that the biotech industry has been slow to adopt.  

Platforming has carried over to “visualization” of all process steps, upstream and downstream, from the number of chromatography columns to the quality bar Janssen sets for aggregates and other impurities. “Every unit operation is specified, using the same vocabulary every time. This is something I hope we can continue to expand on, not only as a company, but as an industry. We want our products, not how we run our centrifuges, to serve as our differentiators.”

From a strategic standpoint, mergers and acquisitions occur to realize pipeline and therapeutic area complimentarity. Depending on how strategists account for the incremental production capacity such dynamics could affect manufacturing and supply chain strategy as well. Companies operating in advanced economies simultaneously face flattening domestic demand and competition for emerging markets.

Combined, these factors create moving goalposts for manufacturing-based pharmaceutical firms that must continue to meet shareholder-value goals while navigating labyrinthine regulations while minimizing supply interruptions.

Compare this situation to just 20 years ago, when everything was static and predictable, where reasonable inefficiencies were tolerable and asset utilization could hover around 50% without causing much concern.

So the conundrum for today’s pharmaceutical manufacturing and supply chain strategists is they no longer have clearly defined targets set in stone. “Technical operations, manufacturing, and engineering people have difficulty fathoming this,” Lindner notes. 

Mergers and acquisitions provide opportunities to optimize product footprints — as opposed to merely expanding them. From a manufacturing perspective, they force companies into consolidating manufacturing capacity (as well as other services) across locations, therapeutic areas and product groups. Lessons learned from these exercises apply to new and existing facilities as well, including those outside the merger “corral.”

You may have noticed that the last decade’s mergers and acquisitions have not all proceeded swimmingly. “Without a robust integration process to bring together thought leaders and functions, and assure that backup services are well integrated, the apparent profit and margin benefits of acquisitions can become diluted,” says Lindner.

Many of the “seismic” shifts in the pharmaceutical and biotechnology industries over the GMPs decade affect manufacturing either directly or indirectly: the dearth of New Chemical Entities, mergers and acquisitions, outsourcing, biosimilars, emerging markets, safety-related regulation, and quality initiatives, reimbursement and profitability issues, to name just a few. 

This has led top firms to redefine their business objectives, Lindner says, away from selling individual products towards fully servicing therapeutic areas through a combination of drugs, services and devices. Examples include a diabetes drug, free counseling and partnership ith a device company specializing in home-based glucose monitoring, vs. simply selling the medicine.