Are Drugmakers Using Yesterday's Quality Strategies?

Drugmakers sometimes are reluctant to adopt new, and potentially superior, process technology for fear of the regulatory response. Such hesitation may reflect an incomplete understanding of quality by design (QbD), which partly is intended to encourage process improvements. To find out how well industry is applying QbD, and what benefits the approach can bring, Equipment and Processing Report talked to Moheb M. Nasr, director of FDA’s Office of New Drug Quality Assessment.

EPR: How do pharmaceutical facilities use QbD and risk analysis to develop compliant manufacturing processes?

Nasr: The firm usually conducts a risk assessment of the manufacturing process and  the key critical quality attributes of the product prior to developing the control strategy. The strategy can be based on extensive experimentation or on in-house prior knowledge of the formulation and manufacturing process. A control strategy that’s developed based on conducting risk assessment, product and manufacturing-process understanding, will lead to better control of the process and minimization of process variability.

EPR: How much does QbD rely on established technology, and how much does it depend on new or emerging technology?

Nasr: All of these tools and approaches have been available for a long time. What was lacking was a commitment from industry to systemically use the QbD approach, appropriate guidelines, clarity of regulatory expectations, and business justification. There is no need to wait for new technologies. Having said that, I would argue some of the new approaches to development and manufacturing, such as continuous manufacturing, more reliance on modeling to develop a quality-control strategy, and real-time release testing, will provide added benefits. All of these things that are not routinely used now will help take QbD implementation to a new level.

EPR: What have we gained during the time that QbD has been established?

Nasr: We as regulators have more confidence in the quality of pharmaceutical products that are developed and manufactured using QbD because we know they were developed based on good science, based on the relevant risk to the patient, and on a control strategy that provides higher assurance of quality. We also are more aligned with international regulators about how to evaluate quality in regulatory submissions.

Using quality risk management in association with, or as part of, QbD helps industry better use resources during development. That means focusing more on areas of high risk, and less on areas where there is no risk to the patient. QbD also provides flexibility in manufacturing operations. Under QbD, the manufacturer can make changes to the manufacturing process without regulatory filings, as long as it is operating within the design space. Another benefit is the industry’s ability to reduce the cost of end-product testing because it relies more on real-time release testing. Also, because of the knowledge learned during development and the flexibility of the regulatory approach, the manufacturer can scale up the manufacturing process without waiting for more expensive experimentation and regulatory filing.

EPR: Is FDA ever reluctant to accept process controls developed through QbD?

Nasr: No. It all depends on providing an appropriate scientific justification for the proposals. If there is a lack of sufficient information, we ask for clarification and additional information. But if the information is there, we are happy to provide such flexibility.

In the last few years, the agency has been taking a more proactive approach by learning more about new and upcoming technologies before they are implemented and included in regulatory submissions. For example, the concept of continuous manufacturing is becoming very important. My office, in the last few years, participated in collaborative research with the University of Washington in Seattle to better understand the use of microreactors and continuous manufacturing. That was done to allow our reviewers to have a better understanding and to be able to evaluate the technical information if and when [it is] submitted in regulatory filings.

Also, I have been going to meetings and workshops and explaining how the current regulations are applicable to new technologies. There is always a concern from industry: “Can we use this new technology with the existing regulation?” I felt like I had to explain the flexibility in the existing regulation that allows the use of new technologies. For the most part, industry is concerned about what can happen from the regulatory side. That’s why I feel like we should take an active approach and pre-empt their concern by explaining how new technologies fit within the existing regulation.

EPR: How successful has the industry been in adopting QbD?

Nasr: I think industry is making a great effort to better develop and design manufacturing processes. I think the area that needs more work is the development of a modern quality strategy that is appropriate for these new technologies, rather than relying on the old checklist approach to control strategies. More work is needed to make existing quality systems more aligned with the QbD approach and new technologies. I think that can be done by adopting and meeting the expectations of ICH Q10.