Create Therapies Confidently With Quality by Design

The biotechnology and pharmaceutical industries must adapt to new advancements to develop new therapies for patients with unmet needs. In this exciting time, there are a range of advanced modalities to keep up with, including cell and gene therapies, novel vaccines and antibody–drug conjugates.

New therapies bring welcome relief to patients struggling with rare or hard-to-treat diseases. However, these novel approaches require rigorous advancements in quality control measures to evolve alongside them. In this article, I will discuss one of the leading quality control strategies being implemented by pharmaceutical manufacturers: Quality by Design.

What is Quality by Design?

Quality by Design (QbD) is a concept first outlined in 1992 by the renowned quality management expert Dr. Joseph M. Juran in his book Juran on Quality by Design: The New Steps for Planning Quality Into Goods and Services. The primary goal of QbD is to apply a risk-based approach to product development.

QbD characterizes the multidimensional design space by using experiments to define the acceptable range of process/system parameters and minimize the possibility of quality failure at any clinical stage.

QbD is already a widespread engineering product development practice and has been well known in medical device development for over 30 years. However, it has more recently been applied to pharmaceutical development in order to provide high-value products to customers.

In its August 2002 report, the US Food and Drug Administration (FDA) advocated for incorporating robust quality methodology of product development across the healthcare industry, and other global regulatory authorities followed suit. Since then, the industry has been enhancing and modernizing the regulation of pharmaceutical manufacturing and product quality for the 21st century.

Following this trend, more contract development and manufacturing organizations (CDMOs) have started embracing QbD principles to better align with industry best practices and to better serve clients.

How to implement QbD

One of the most critical steps in establishing a QbD approach is to define your product's key attributes and link them to process parameters. For example, when grilling a perfect medium steak, we first need to define a range of characteristics that must be preserved before/during the grilling process. Based on each characterization, we must then define each grilling process – such as setting optimized grill temperature, precise measurement of ingredients by gram, and perfect room temperature for overall cooking – and fall within the specific range to create an appetizing and safe-to-consume medium steak. 

For a pharmaceutical or biologic therapy, the descriptive summary of these key attributes is outlined in what's known as the quality target product profile (QTPP). The QTPP establishes the key characteristics required for the drug to be an effective therapy.

After establishing the QTPP, product design is assessed for potential areas of variability. Subsequently, critical quality attributes (CQA) of the design must be adequately identified to prepare for thorough process validation, which entails establishing acceptable ranges, developing protocols for measurement, and implementing data collection/analysis.

Then, you must examine the drug design process and define critical process parameters (CPPs), similar to how chefs must properly prepare ingredients, set the correct internal temperature, and cook for the appropriate time. Likewise, you must identify the critical material attributes (CMAs) for all drug components to ensure product quality. Much like cooking ingredients, the raw materials used for therapeutic products can vary considerably and always influence the outcome.

QbD is a robust system because of its multivariate approach, which simultaneously analyzes multiple process parameters to determine the optimal range and limits for a robust drug therapy product. The risk management for the potential variability of both CMAs and CPPs is considered to ensure the final product is robust, efficacious, safe and manufactured with a repeatable and reproducible process.  

Why invest in QbD?

Establishing and maintaining a QbD process is a significant investment of a company’s time and resources. The discovery and development of a new therapy is always an exciting prospect, but companies unfamiliar with QbD may be hesitant to take the time to implement it – especially when under time pressure with project timelines. However, while QbD does represent an upfront investment of time and money, it is a prudent and effective long-term strategy.

Investing in QbD upfront is not only financially savvy due to long-term cost savings, but it's endorsed by regulatory agencies. The FDA and EMA scrutinize novel therapeutics to ensure products are safe for the market. A comprehensive review of biological license application (BLA) rejections by the FDA (also known as "refuse-to-file letters") found that roughly one in five rejections were due to deficiencies in drug quality.

A properly implemented QbD approach offers an upfront solution to this problem by baking robustness into all processes, thereby satisfying the patient safety and product quality requirements of regulatory agencies, allowing companies to file applications with increased confidence. 

Of course, drug approval can be achieved without QbD; however, bringing a drug to market without a thorough understanding of the drug design and production process is a significant risk for pharmaceutical companies. In fact, trying to implement robust quality processes after the product design phase is extremely challenging – it can result in substantial delays, contribute to drug shortages and even lead to product recalls. These adverse outcomes detrimentally impact a company’s reputation, finances and professional relationships.

QbD can be thought of as a proactive risk-removal strategy. Its systematic approach to process development and improvement ensures that no unknown areas of unaddressed risk within the manufacturing process could cause delay or disruption.

QbD prepares companies for the future

The strength of QbD lies in its ability to mitigate and eliminate risk during drug development, and its implementation has long-term benefits. For instance, QbD can be used to continually refine and improve production processes, and the work required to characterize the critical components of a given therapeutic allows companies to deepen their understanding of the product.

QbD enables a disciplined, data-driven approach to process improvements, allowing companies to invest their research resources smarter and more efficiently. Once a drug product is approved and commercialized for industry, pharmaceutical companies will often use data and documentation provided by QbD to evaluate continuous improvement opportunities.

As machine learning (ML) and artificial intelligence (AI) become increasingly powerful, QbD can help companies generate the large datasets needed to inform these systems. QbD can identify the critical characteristics to monitor, generate a robust dataset and prepare the manufacturing process for further optimization. QbD ensures that a given therapy can be maintained at a high quality throughout its many iterations, allowing companies to feel confident in the product’s lifespan.

Quality by Design is a valuable asset for any pharmaceutical manufacturing company, providing short- and long-term benefits. It encourages companies to deeply understand their therapy’s design characteristics and create a detailed product profile that can ultimately streamline the regulatory filing process, eliminate unnecessary risk and facilitate further optimization and adaptation of the product as they move forward. Importantly, it ensures that things go right the first time so that new and promising therapeutics reach patients as quickly and smoothly as possible. 

About the author:

Introduced to QbD in the early 2000s, Songyoung Kim, principal scientist and director of downstream development at Samsung Biologics, has rigorously implemented QbD-led practices in downstream process development/characterization and tech transfer of biosimilar and drug products at various global biotechs for over 21 years. At Samsung Biologics, he is in charge of designing CDO process development by QbD principles.