It seems that Quality by Test is well on its way to being a thing of the past, and for good reason. One out of every 10 drug products make it to market¹, so it’s no surprise that pharma companies are eager to adopt measures to better ensure quality and manage risk. Quality by Design (QbD) is one of those measures and it’s becoming more widely adopted by manufacturers in the life sciences industry.

“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 PharmTech article on pharmaceutical QbD². “As pharmaceuticals become increasingly complex, it’s critical that quality is designed into products from the initial concept to ensure patient safety.”

As the pharma sector moves to implement QbD, regulatory bodies such as the U.S. Food and Drug Administration (FDA) are working to provide a common understanding of key concepts, terminology and expectations around the practice. This article reviews the current understanding of pharmaceutical QbD and its primary elements.

What Is Pharmaceutical QbD?

Quality can be defined as end products that meet specific objectives, having minimal variation within each batch and from one batch to another. In other words, the product is safe and reliably delivers its intended therapeutic benefit³. That said, QbD is a scientific, risk-based approach to designing quality into a product at the earliest stages of planning.

Many companies practice different interpretations and variations of QbD. Still, most can agree that it comes down to fully understanding and controlling all aspects of the critical quality attributes of a drug product — collectively known as the Design Space⁴.

The Design Space is proposed by the applicant and subject to regulatory assessment and approval. However, once approved, changes occurring within the Design Space are not subject to regulatory post-approval notification — a significant benefit of QbD.

Companies that implement QbD:

• Develop safer and more effective products.
• Have more regulatory flexibility with respect to the Design Space.
• Experience direct benefits related to cost savings and faster time to market.

Providing reliable, safe and effective end products delivers better patient outcomes. Both consumers and pharma companies reap the benefits of this approach. Thus, the question drug makers are asking about QbD is not so much why, but how.

5 Key Elements of QbD

Knowing the theory and benefits behind QbD is a critical step toward implementing it. To bridge the gap between theory and practice, the International Conference on Harmonization (ICH) Q8 and other research initiatives give us a solid starting point. Below are the key elements of a QbD program⁵:

#1: Quality Target Product Profile (QTPP) that identifies 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. These include 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.

The CQAs are the attributes of a finished product (or output materials). These include the physical, chemical and biological or microbiological properties that need to be within an acceptable limit, range and distribution to ensure the desired QTPP.

#2: Product design and understanding, including the identification of critical material attributes (CMAs).

Historically, QbD focused on process design, understanding and control. These same aspects are equally important to product design. They ultimately determine whether the product can meet patients’ needs and maintain performance throughout its shelf life.

The CMAs are the physical, chemical, biological or microbiological properties or characteristics of an input material that should be within an acceptable limit, range or distribution to ensure the desired QTPP.

#3: 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 product. They should be monitored and controlled before and/or during production to ensure the process produces the desired QTPP.

#4: Control strategy that includes specifications for the drug substance(s), excipient(s) and drug product, as well as controls for each step of the manufacturing process.

Knowledge gained through QbD activities is used to develop 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 for testing and qualifying the end product as being fit for use.

#5: Process capability and continual improvement.

Process capability is a measure of the ability of the process to consistently develop products that meet customers’ needs. When a process is in a state of statistical control, the process is stable enough that any variabilities in output to the acceptance criteria can be considered random and attributable to chance or inherent variability (“common cause”).

This element of QbD allows for early detection and mitigation of common-cause variabilities. This makes it easier for companies to fine tune and redirect the process to more consistently achieve targeted results.

The Future of QbD

QbD is becoming more mainstream among forward-thinking companies of all sizes. This is largely due to the wider availability of the necessary knowledge, technology and tools. The FDA and other 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. Some questions may remain, but QbD is clearly here to stay.

To learn more about the importance of QbD in product design and achieving compliance, view the white paper “Common Reasons for FDA 483 Inspectional Observations in Biologics Manufacturing Environments.”

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. Understanding Pharmaceutical Quality by Design https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4070262/. Accessed October 16, 2017.