A Guide to Pharmaceutical Quality by Design


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EDITOR’S NOTE
This article is part of a series of highly popular blog posts that we are republishing to share their important topics with a wider audience and with those who may be new to GxP Lifeline.

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 sciences 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,” said a PharmTech article on the topic of 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.”

With adoption of pharmaceutical QbD on the rise throughout the pharma sector, regulatory bodies such as the U.S. Food and Drug Administration (FDA) work to further develop a common understanding of key concepts, terminology and expectations.

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, says @PharmTech Group http://bit.ly/30iGqDl

Defining Pharmaceutical QbD

Establishing a definition of pharmaceutical quality is really the first step to incorporating QbD into the design and development of drug products, and as with most industry terms, it can be challenging to reach a consensus.

In general, quality 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). Specific to pharma, ICH Q8 (R2) defines quality as the suitability of either a drug substance or drug product for its intended use(4). Janet Woodcock, the director of the Center for Drug Evaluation and Research (CDER), offers a similar yet 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 greater 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 drugmakers are asking about QbD is not so much why, but how.

The question drugmakers are asking about pharmaceutical #QbD is not so much why, but how, says @MCMasterControl http://bit.ly/30iGqDl

5 Key Elements

To bridge the gap between theory and practice, ICH Q8 (R2) along with other research initiatives(8) have given us a solid starting point for implementing pharmaceutical QbD. 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 (CMAs): 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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  4. 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 (R2) 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.

  5. 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.

  6. 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 ever 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 larger 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.

#QbD is now on the rise among forward-thinking #pharma companies of all sizes as the required knowledge, technology and tools become more established and widely available, says @MCMasterControl http://bit.ly/30iGqDl

However, despite the efforts she and others have already made to advance our understanding of pharmaceutical quality, Woodcock believes there is still work to be done when it comes to manufacturing quality, an equally critical element of QbD.

“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.”

She continued, “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?’”

What we do know is that the FDA, the European Medicines Agency (EMA) and other key regulatory authorities support a risk-based approach to and the inclusion of QbD principles in the development and production of drug products. The latest ICH Quality Guidelines Q8 to Q11 also address different aspects of QbD as they apply to the pharma industry. 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. 2016. Clinical Leader.

2. QbD: Improving Pharmaceutical Development and Manufacturing Workflows to Deliver Better Patient Outcomes. 2017. Pharmaceutical Technology.

3. Quality by Design Part 1: You Can’t Design Something You Don’t Understand. 2016. GxP Lifeline.

4. ICH Q8 (R2) Pharmaceutical Development. 2009. International Council for Harmonisation.

5. The Concept of Pharmaceutical Quality. 2004. American Pharmaceutical Review.

6. Juran’s Quality Handbook. 1999. McGraw Hill.

7. Active Pharmaceutical Ingredients: Development, Manufacturing, and Regulation. 2009. CRC Press.

8. Report From the EMA-FDA QbD Pilot Program. 2017. European Medicines Agency and U.S. Food and Drug Administration.

9. Understanding Pharmaceutical Quality by Design. 2014. AAPS Journal.

10. Is Quality by Design Just for Big Pharma? 2012. GxP Lifeline.

11. Janet Woodcock’s Quality Agenda at CDER. 2014. Pharmaceutical Online.


 

2016-nl-bl-author-beth-pedersenBeth 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.