Will the Pharmaceutical Industry Ever Get to Six Sigma?

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A recent paper coauthored by FDA’s Lawrence Yu and Michael Kopcha describes how the industry might modernize drug manufacturing.

In June, some who have been working (or even simply observing) the pharma industry for a while had to feel a sense of déjà vu when Lawrence Yu and Michael Kopcha’s “The Future of Pharmaceutical Quality and the Path to Get There” appeared in the International Journal of Pharmaceutics.

The spirit of the paper resembled that of publications from the early 2000s, when FDA’s Office of Pharmaceutical Sciences, led by Ajaz Hussain, brought the work of Deming, and concepts like process analytical technology, into mainstream pharma’s vocabulary. FDA openly invited experts from other industries to present best practices at science board meetings, discussed at industry meetings how pharma could develop supplier quality management systems like the automotive industry's, and often asked why manufacturing had to be the industry’s “stepchild” function. 

Over ten years later, some might argue, little has changed.  The industry remains at 2 to 3 sigma quality levels (308,537 defects per million opportunities for 2 sigma, compared with 3.4 defects per million for 6 sigma, as defined in the paper).  While the quality of new drugs has improved, shortages and recalls continue to be seen, particularly for legacy products, and, for many drug companies, manufacturing is far less important than clinical goals, evidenced by the number of complete response letters, 483s and Warning Letters that FDA presents manufacturers with each year.

However, pharma’s future will be Six Sigma, the authors state, as the industry moves from management- to performance-based regulation, and toward specifications that are based on clinically relevant goals. Currently, it relies on a combination of the two approaches, with management-based approaches still required for more complex products.

The paper reaffirms the mission statements articulated over 10 years by CDER Director Janet Woodcock, and touches on all the programs and concepts that the agency has advanced over the years to help modernize manufacturing and quality:  PAT, quality by design (QbD) and its core concepts, emerging technologies (including continuous manufacturing as well as automated processes), the need to reduce variability, and the idea of continuous improvement and operational excellence.

It also brings up the need for companies to establish a “culture of quality,” and all that it entails, from senior management commitment to operator engagement.

These changes still seem extremely ambitious, especially since product complexity and production targets have increased so dramatically for most pharmaceutical manufacturers over the past 10 years, but some progress is being made.  One area where more active exploration is occurring is in continuous manufacturing.  Once considered only for new products, continuous is also being adopted for legacy products, for APIs, and in biopharma. At the very least, more unit operations are being run continuously, and a growing number of generics companies are being sold on its ability to reduce the cost of goods sold. FDA has been collaborating on pilot projects to study continuous processing and the challenges it presents.


On a broader level, the Agency has also instituted some important changes, with relatively little fanfare.  In May 2017, for example, with its Program Alignment initiative, FDA’s Office of Regulatory Affairs realigned staff so that inspectors specialize in one area, e.g. food, pharmaceuticals, biologics, devices, instead of trying to do everything. This simple change promises to bring specialized skills to individuals within each group, to improve communication and coordination of efforts, and, in the future, should result in faster and more systematic and objective inspections, and, to throw the term back at the regulators, less variability.

In 2014, the Agency also established an Emerging Technologies Team  to advise companies and colleagues within FDA. Senior science policy advisor Tara Gooen Bizjack described it as a small cross functional group with representation from all relevant CDER review and inspection programs.  It aims to support adoption of innovative technology to modernize drug development and manufacturing in cases where the FDA has limited review or inspection experience in that field.

In addition, FDA has been steadily increasing its recruitment of chemical engineers, an important minority in the industry workforce that will be crucial to getting more drug manufacturers to embrace different methodologies.  Yu, who has a chemical engineering degree and studied with Hussain, is one example of a new FDA leader, with chemical engineering background rather than the traditional MD degree.  Like his mentor, he brings an academic (rather than a hard-boiled industrial) background, and some of the idealism that presents, to FDA.

Yu's and Kopcha's paper presents a look back and acknowledgement of the foundations set in the past, while outlining the challenges to come in redefining quality in more modern terms. Pharma’s journey to the long-awaited “desired state” may not prove easy or fast, but at least it is under way.

In August, Pharmaceutical Technology will look at some of the obstacles to modernizing and improving drug manufacturing and how they are being overcome, both by drug manufacturers and the regulatory community.