David Doleski Encourages Industry to Participate in FDA’s Emerging Technology Efforts; Sanofi Case Study Reviewed

According to FDA, we are at a “critical moment” where new technologies and emerging fields are leading to “groundbreaking” discoveries and innovative approaches to developing and manufacturing new drugs—the so-called, “emerging technologies.”

Realizing this was the case, the agency’s strategic plan from nearly 10 years ago included its facilitation of the adoption of emerging technologies. The Center for Drug Evaluation and Research (CDER) has an Emerging Technology Program, and the Center for Biologics Evaluation and Research (CBER) has an Advanced Technology Program. Both aim to work with industry to help define scientific and regulatory hurdles to implementing the cutting-edge technologies and to solve them.

The CDER Emerging Technologies Program website says, “Regulatory science must be one step ahead to equip FDA with the necessary tools and methods to reliably assess the safety and efficacy of products derived from these new scientific developments, in order to bring the rewards of discovery safely forward to benefit patients.” It also recognizes that firms may be slow to embrace technologies that are new fearing long review times by FDA due to a lack of understanding of the technologies.

After nearly 28 years at FDA—in review, inspection, and compliance positions—David Doleski, now Compliance Head for Biologics Quality Operations at Sanofi, provided his insight into the agency’s emerging technology efforts and the reason he feels strongly about industry participation during his keynote presentation, “How Perspectives Change: From Regulator to Regulated” at the ISPE Aseptic Conference held in North Bethesda, Maryland, in early March 2020.

In the same presentation, Doleski also shared remarks regarding FDA hot button issues and building a positive relationship with the agency, available here.

Why is Industry Slow to Adopt?

In addition to what was discussed above, Doleski said another reason FDA is focused on emerging technologies is a belief in the agency that has been expressed at conferences and at Congressional hearings: That the pharmaceutical and biologics industries are not adopting advanced technologies at the same rate as other industries. The industry seems to have less of an embrace of advancing technologies.

“We can speculate as to the reasons,” he said, “but FDA realizes that this is the case, and agency personnel have looked inward and asked how they can facilitate the adoption of new technologies.”

The result is the creation of the agency programs, “which I think have been extremely useful at helping advance the state of technology in the industry,” Doleski emphasized.

Doleski said another reason FDA is focused on emerging technologies is a belief in the agency that has been expressed at conferences and at Congressional hearings: That the pharmaceutical and biologics industries are not adopting advanced technologies at the same rate as other industries. The industry seems to have less of an embrace on advancing technologies.

He noted that when he was at CDER he had various interactions with the Emerging Technology Team (ETT). The purpose of the EET is to identify and resolve potential technical and regulatory issues regarding development and implementation of novel technologies prior to filing the regulatory submission.

EET is a group of individuals “who are very engaged and trying to learn about the technologies. They want to work with individual companies to try to understand new technologies and what the regulatory hurdles are that companies perceive and try to work through the hurdles,” he said.

At FDA, Doleski was involved in continuous manufacturing projects with the EET. He recounted that there were “a lot of meetings with companies” about continuous manufacturing, and a lot of issues to be resolved because the current paradigm in the regulations and guidance had not anticipated that type of technology. “The agency made a real effort to be involved and to understand the issues and try to resolve them,” he said.

Doleski explained that the effort included meetings with companies and site visits. “Site visits are a great way for FDA to learn about the technology and to share their perspectives on that technology with the company,” he commented. “And it is a freebie—basically it is free consulting advice. FDA does a sort of mock inspection and there is no 483 at the end. You get their reviews and advice. It really is a great thing for a company.”

Examples of Emerging Technologies Encouraged by FDA

Here are some examples of emerging technologies that Doleski provided. This is taken from the FDA website. It covers a wide variety of technologies, and the website lists many more:

• Continuous Manufacturing of Drug Substance
• Continuous Manufacturing of Drug Product
• Single Use Systems
• 3D Printing
• Continuous Aseptic Spray Drying
• Controlled Ice Nucleation for Lyophilization Processes
• Next Generation Sequencing
• Closed Aseptic Filling System
• Isolator and Robotic Arm for Aseptic Filling

Doleski Encourages Participation in the Emerging Technology Programs

“If you meet the criteria for either the CDER or CBER program, I strongly encourage you to participate,” Doleski said. “There is some time investment involved. You have to develop the presentations, go through the meetings, and think critically about the important issues and what needs to be resolved.”

To participate in the CDER program, according to CDER’s website, (a) the proposed technology must have the potential to improve product safety, identity, strength, quality and purity, and (b) the new technology must include “one or more elements subject to quality assessment for which the agency has limited review or inspection experience. Examples of such elements include an innovative or novel:

• Product technology (e.g., dosage form or packaging such as a container and closure system)
• The manufacturing process (e.g., design, scale-up, or lifecycle approaches)
• Control strategy (e.g., testing technology or process controls)

A company can submit a written request to participate in the program at the time it plans to submit an Investigational New Drug Application (IND), an original or supplemental New Drug Application (NDA) Abbreviated New Drug Application (ANDA), or Biologics License Application (BLA) or an application-specific Drug Master File (DMF). Specific instructions are included on the CDER’s Emerging Technology Program webpage.

“You will receive a lot of individualized attention from FDA,” Doleski said. “There is a lot of interaction with agency personnel, and potential issues can be resolved at an early point.”

He noted that FDA reviewers, investigators, and leadership are very engaged in the programs. “When it comes to application reviews or inspections, there is a lot of competition within the FDA to be involved in emerging technology activities. It is seen as something that is career-enhancing. Those involved, for example, in a continuous manufacturing process review got a lot of attention and visibility.”

In addition, “there is a lot of excitement—not so much from an individual standpoint, but from a public health standpoint—excitement about facilitating the adoption of new technologies.”

On May 21, 2020, CDER Director Dr. Janet Woodcock, through her twitter account, shared a message of encouragement regarding the use of advanced technologies in the U.S.

Emerging Technology Case Study: Sanofi’s Transition from Conventional Filling Lines to RABS and Isolators

Doleski began his discussion of a case study at Sanofi by acknowledging that RABS (Restricted Access Barrier Systems) and isolators have been around for decades—they are not brand new technology. But it is something that FDA has identified as being an emerging technology.

“Why is that the case? I think it is because in the industry we do not have 100% adoption of barrier isolators. We are still in the transitional period going from traditional filling lines to isolators or to RABS. I would like to share the journey we have been on at Sanofi.”

In 2012, Sanofi embarked on a program to phase out aseptic finished product manufacturing that were conventional Grade A with Grade B surrounding. At that time, the company conducted an inventory of its filling lines and identified 68 conventional sterile product filling lines in the global Sanofi industrial site network that needed an upgrade.

The company set out to upgrade these to either full barrier isolation or a RABS. “There was a huge corporate investment in this process, both a financial investment and an investment in time, effort, and resources, and developing global standards and procedures,” Doleski emphasized. “It was a big deal.”

Why is that the case? I think it is because in the industry we do not have 100% adoption of barrier isolators. We are still in the transitional period going from traditional filling lines to isolators or to RABS. I would like to share the journey we have been on at Sanofi.

David Doleski

There was an assessment of the current state of the filling lines. For some of the lines it was not possible to go completely to a barrier isolator, which was the goal. He said the company looked at each of the existing lines to assess state of control, including environmental monitoring and media fill data. For some of them that were in a good state of control, they chose to go to a RABS situation. For others they went forward with barrier isolators.

Over a period of eight years, we went from 18 isolators to 34, from 11 RABS to 49, and from 68 conventional filling lines to a small handful. In cases where barrier isolators are not possible, RABS are extremely desirable. “It was a big effort, but well worth it, and we are not done yet,” Doleski concluded.

¹ CDER’s Emerging Technology Program webpage