It seems that Quality by Test is well on its way to being a thing of the past, and for good reason. With only one out of every 10 drug products actually making it to market (1), it is no surprise that pharma companies are increasingly eager to adopt measures to ensure quality and manage risk. Quality by Design (QbD) continues to be a hot topic across the life science industries, and as evidenced by the widespread adoption of QbD among manufacturers, there is no question about its benefits.

“The main issue with late-stage quality analysis is that it only detects and removes substandard products – it doesn’t prevent them from being created in the first place,” according to a recent PharmTech article on pharmaceutical QbD (2). “As pharmaceuticals become increasingly complex, it’s more important than ever that quality is designed into the products from the initial concept to ensure patient safety.”

As the pharma sector moves to implement pharmaceutical QbD, regulatory bodies such as the FDA work to provide a common understanding of key concepts, terminology and expectations. This article reviews the current understanding of pharmaceutical QbD and its primary elements.

Defining Pharmaceutical QbD

Establishing a definition of pharmaceutical quality is really the first step to incorporating it into the design and development of drug products, and as with most industry terms, it can be challenging to reach a consensus. Quality in general terms can be defined as products that meet scientifically derived product and process performance objectives, while exhibiting minimal variation within each batch and from one batch to another (3). More specific to pharma, ICH Q8 defines quality as the suitability of either a drug substance or drug product for its intended use (4). The director of the Center for Drug Evaluation and Research (CDER), Janet Woodcock, offers a similar yet more nuanced definition: a high-quality drug product as one that is free of contamination and reliably delivering the therapeutic benefit promised in the label to the consumer (5).

Unlike the empirical-based methods used in traditional product development and manufacturing methods, QbD is a scientific, risk-based approach that focuses on designing quality into a product from the earliest stages of planning to prevent quality failures from ever occurring and more readily address them if they do occur (6). Many companies practice different interpretations and variations of QbD (7), but most can agree that it comes down to fully understanding and controlling all aspects of the manufacturing process as they pertain to the critical quality attributes of a drug product (collectively known as the Design Space (4)). In addition to achieving a safer and more effective product, QbD affords more regulatory flexibility with respect to the Design Space, all of which translate into direct cost benefits for producers.

What these definitions have in common is a focus on achieving a reliably safe and effective end product to deliver better patient outcomes, providing obvious benefits to both consumers and pharma companies alike. Thus, the question drug makers are asking about QbD is not so much why, but how.

The question drug makers are asking about pharmaceutical #QbD is not so much why, but how, says @MCMasterControl http://bit.ly/2zw0424

5 Key Elements

Knowing the theory and benefits behind the concept of QbD is a critical step toward implementing it. And to bridge the gap between theory and practice, ICH Q8 along with other research initiatives have given us a solid starting point for implementation. Below are the key elements of a QbD program (9):

1. Quality Target Product Profile (QTPP): Identify the critical quality attributes (CQAs) of the drug product. The QTPP is a summary of the overall targeted quality characteristics of the end drug product, including dosage form, delivery systems, dosage strength, etc. It must account for the drug quality criteria (e.g., sterility, purity, stability and drug release) determined for the product. CQAs are the attributes of the finished drug product (or output materials), such as physical, chemical, biological or microbiological properties or characteristics and their acceptable limits, ranges or distributions, that affect the desired product quality and should be used to establish product and process development. They can be derived from the QTPP or from other sources, such as prior knowledge.
2. Critical Material Attributes (CMA): Product design and understanding, including the identification of CMAs. QbD has historically focused on process design, understanding and control, but these same aspects of the product are equally important, as they ultimately determine whether the product can meet patients’ needs and maintain performance throughout its shelf life. Thus, input materials must also be accounted for by determining their critical attributes (and acceptable limits, ranges or distributions), including physical, chemical, biological or microbiological properties or characteristics.

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3. Design Space: Process design and understanding, including the identification of critical process parameters (CPPs) and a thorough understanding of scale-up principles, linking CMAs and CPPs to CQAs. As the name implies, CPPs are the elements of the development process that have a significant influence on the appearance, purity, yield, etc. of the final drug product, and must be monitored before and/or during production. Collectively, this constitutes the Design Space, defined by ICH Q8 as “the multidimensional combination and interaction of input variables and process parameters that have been demonstrated to provide assurance of quality.” The Design Space is proposed by the applicant and subject to regulatory assessment and approval but once approved, changes occurring within the Design Space are not subject to regulatory post-approval notification, an obvious and major benefit of adopting QbD.
4. Control Strategy: Specifications for the drug substance(s), excipient(s) and drug product, as well as controls for each step of the manufacturing process. The knowledge that is gained through the aforementioned QbD activities culminates in the establishment of a control strategy. Its purpose is to identify and control any sources of variability in input materials, product specs, unit operations or production processes, and ultimately to test and qualify the end product as being fit for use.
5. Process capability and continual improvement. Process capability measures the variability of a manufacturing process that is in a state of statistical control, meaning when the process is so stable that any variabilities in output to the acceptance criteria can be considered random and attributable to chance or inherent variability (“common cause”). Where in a non-QbD development process, variations are more likely to first be discovered during commercial production, this element of QbD allows for early detection and mitigation of common cause, and continuous fine tuning and redirection of the process to more consistently and accurately achieve results closer and closer to the target value. 

The Future of QbD

Because pharmaceutical QbD requires considerable resources (time, money, personnel, expertise, etc.) to implement, it gained momentum initially among big pharma companies (10). But QbD is now on the rise among forward-thinking companies of all sizes, particularly as the required knowledge, technology and tools become more established and widely available. Despite efforts she and others have already made to further our understanding of pharmaceutical quality, Woodcock believes there is still work to be done in the area of QbD.

#QbD is now on the rise among forward-thinking #pharma companies of all sizes, says @MCMasterControl http://bit.ly/2zw0424

“Actually, we defined the quality of a pharmaceutical product a long time ago: fitness for use,” Woodcock stated in a Pharmaceutical Online article (11). “It delivers the properties described on the label and is not contaminated. But the other piece is, what is quality in manufacturing? And that’s really what we are focusing on. Right now, a lot of the industry delivers quality products by throwing away, by wasting, up to 35 percent of what’s produced, and we don’t believe that amounts to quality manufacturing. We’ve been exploring this question extensively with industry in a very open process: ‘What metrics might we use that would measure the quality of your manufacturing processes?’”

But what we do know is that the FDA, EMA and other key regulatory authorities support a risk-based approach and the inclusion of QbD principles in the development and production of drug products. QbD is also thoroughly addressed in the latest ICH Quality Guidance documents Q8 to Q11, each covering different aspects of the concept. So while some questions may remain, QbD is clearly here to stay.

References

1. The High Price of Failed Clinical Trials: Time to Rethink The Model https://www.clinicalleader.com/doc/the-high-price-of-failed-clinical-trials-time-to-rethink-the-model-0001. Accessed October 18, 2017.
2. QbD: Improving Pharmaceutical Development and Manufacturing Workflows to Deliver Better Patient Outcomes http://www.pharmtech.com/qbd-improving-pharmaceutical-development-and-manufacturing-workflows-deliver-better-patient-outcomes. Accessed October 25, 2017.
3. Quality by Design Part 1: You Can’t Design Something You Don’t Understand https://www.mastercontrol.com/gxp-lifeline/quality-by-design-part-1-you-can't-design-something-you-don't-understand. Accessed October 19, 2017.
4. ICH Q8 (R2) https://www.fda.gov/downloads/Drugs/Guidances/ucm073507.pdf. Accessed October 16, 2017.
5. The concept of pharmaceutical quality, Janet Woodcock, American Pharmaceutical Review, 2004.
6. Juran’s Quality Handbook, Joseph Juran and A. Blanton Godfrey, McGraw Hill, 1999.
7. Active Pharmaceutical Ingredients: Development, Manufacturing, and Regulation, Second Edition, Stanley Nusim, Taylor & Francis Group, 2010.
8. Final Report from the FDA-EMA pilot program for the parallel assessment of quality-by-design elements of marketing applications https://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/ucm552716.htm. Accessed October 23, 2017.
9. Understanding Pharmaceutical Quality by Design https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4070262/. Accessed October 16, 2017.
10. Is Quality by Design Just for Big Pharma? https://www.mastercontrol.com/gxp-lifeline/quality-by-design-just-for-big-pharma. Accessed October 23, 2017.
11. Janet Woodcock’s Quality Agenda at CDER https://www.pharmaceuticalonline.com/doc/janet-woodcock-s-quality-agenda-at-cder-0001. Accessed October 23, 2017.

Beth Pedersen is a content marketing specialist at the MasterControl headquarters in Salt Lake City, Utah. Her technical and marketing writing experience in the enterprise software space includes work for Microsoft, Novell, NetIQ, SUSE and Attachmate. She has a bachelor’s degree in life sciences communication from the University of Wisconsin-Madison and a master’s degree in digital design and communication from the IT University of Copenhagen.