For companies in the Life Sciences industry, today’s climate—a mixture of competition, regulation, increasing consumer awareness, and continually evolving knowledge and capabilities—presents manufacturers of pharmaceuticals, medical devices, biologics, and combination products with a choice: maintain the status quo in product design, manufacture, and testing, or join the forward motion of the industry as well as the FDA in embracing the holistic and dynamic approach of Quality by Design (QbD).
A system in the making
QbD is relatively new to the Life Sciences, having made inroads first in the automotive industry with Joseph Juran’s “Trilogy” of Plan, Control, and Improve. In this iterative process, Juran equates quality with the presence of reliable features that will perform to the satisfaction of the end user. The goal of QbD, then, is to eliminate flaws that would compromise performance, and to enhance the efficacy of the product’s desirable features.
Within the FDA, QbD’s most recognizable precursor is the Quality System Regulation (QSR) put in place for the medical device industry in the 1970’s and revised in the 1990’s. QSR emphasizes flexibility in establishing design controls—also a hallmark of QbD.
QbD found its footing within the pharmaceutical industry with the FDA’s 2004 final report on “Pharmaceutical CGMPs for the 21st Century—A Risk-Based Approach,” and was bolstered by the International Conference on Harmonisation (ICH) Quality Implementation Working Group’s “Points to Consider” for implementation of ICH Q8 (focused on gaining a deeper understanding of product and process), Q9 (focused on leveraging this knowledge to mitigate risk), and Q10 (focused on supporting quality throughout the entirety of the product lifecycle).
The FDA approved its first new drug application submitted following the principles of QbD in 2006 with Merck’s Type II diabetes drug Januvia, and Genentech (Roche) secured the first QbD-based Biologics License Application in 2013 for Gazyva, a biologic used in conjunction with chemotherapy in the treatment of leukemia.
What is QbD?
As defined in ICH Q8, QbD is “a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.”
QbD is a consumer-centric risk-based approach that relies on science and statistics to ensure the safety and efficacy of the product in question. It’s frequently said that QbD moves testing and verification “upstream,” meaning that, unlike traditional approaches to quality control which rely heavily on batch testing, the QbD approach brings quality assessment in on the ground floor, in the early phases of design.
QbD involves the following key elements, outlined in ICH Q8:
- Defining the Target Product Profile (TPP) and Quality Target Product Profile (QTPP)—defining the characteristics a product needs to possess for it to be safe and effective, and the qualities that need to be assessed to determine of the profile has been met (tests for stability, uniformity, etc.).
- Identifying Critical Quality Attributes (CQA’s)—identifying the “physical, chemical, biological, or microbiological propert[ies] or characteristic[s] that should be within an appropriate limit, range, or distribution to ensure the desired product quality.” In a risk-based approach, CQA’s are identified and ranked according to the severity of harm an end-user could experience if the attribute falls outside the appropriate range.
- Risk Assessment—used to identify Critical Process Parameters (CPP’s) whose variation may introduce risk by impacting whether a CQA falls within the appropriate ranges to ensure safety. A product with a CQA of content uniformity may have CPP’s like number of revolutions and particle size.
- Design Space—established by considering the interplay of CQA’s and CPP’s to determine the acceptable ranges in process and material attributes for product quality. Once Design Space has been established, a manufacturer working within that space can generally make changes to the product without seeking new FDA approval.
- Control Strategy—ensures consistent product quality by formulating processes to manage variables. These controls allow for much greater flexibility for manufacturers to innovate and make changes without introducing instability or risk.
- Lifecycle Management—provides the opportunity for continual enhancement with an iterative approach to assessment and design.
The benefits of QbD for FDA regulated industries
QbD offers a host of benefits for FDA regulated industries willing to invest the time up front to learn the principles and apply them to their products. Here are just a few:
- Introducing quality assessment earlier in the design process saves time and money over the course of the product’s lifecycle and reduces the frequency of recalls.
- QbD cultivates innovation by allowing companies to make changes within the product’s Design Space without resubmitting for FDA approval.
- The system emphasizes deeper knowledge of the product and process and provides for real-time as well as multivariate testing; this increases quality and can speed time to market.
- The control strategy in QbD is risk-based and occurs early in the product’s design, rather than being so heavily reliant on end-product testing; this shifts the focus to greater awareness of consumer safety, as well as earlier and repeated opportunities for quality improvement.
- The traditional approach tends to be reactive, responding to problems once they occur; QbD builds quality into the design, and its iterative nature allows for proactive improvement of product quality.
Incorporating QbD into your product planning and design
The good news is that QbD principles are based on the regulations referenced in ICH Q8, Q9, and Q10; they’ve been around for over a decade now, and so are often not unfamiliar to companies in the Life Sciences industry.
What remains is for organizations to implement the principles in a systematic way. This starts with learning the QbD system and how it can be applied in your company to your products. Depending on the level of knowledge already in place, this could take the form of an internal in-service, or perhaps make use of an external source for consultation and/or training and education.
Leadership is also critical in supporting the culture needed to implement and sustain the risk-based, iterative approach of QbD. It’s not just a new system, but a paradigm shift that involves a high level of cross-functionality. Shifts of this nature do not occur in a vacuum, but need to be interwoven into the fabric of an organization.
QbD is not a quick fix, but it is a way to invest early on in product quality and consumer safety, both of which will pay dividends in consumer trust, regulatory compliance, increased revenue, and greater room for innovation.