For any pharmaceutical company with a drug candidate, the objective is to provide safe and effective medicine for patients. For a drug to be deemed “safe and effective,” all the underlying precursors, intermediates, other materials, as well as the entire manufacturing and quality assurance process must function at the highest levels.
Quality – and its impact on safety and efficacy – is at the very heart of what we do in the pharmaceutical industry. It is also a term whose meaning has morphed and expanded over time. Over the last several decades alone, we’ve seen quality shift into a formalized process required by the FDA. That formal process is called QbD – or Quality by Design.
Quality By Design: A Robust Process Focusing on Risk Assessment
QbD is a systematic approach to drug development requiring drugmakers to build quality into the product, rather than relying on the traditional approach – Quality by Control (also referred to as “QbC”). This outmoded methodology offers limited flexibility with the manufacturing process, and it emphasizes the quality of the final product.
The International Council on Harmonization (ICH) defines QbD as “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.”
Within the QbD framework, scientists demonstrate that they have a complete understanding of a product across development, scale-up and manufacturing. The QbD methodology requires thorough data analysis and risk assessment from initial engagement through commercialization. Formulators need to prove to regulators that they can anticipate the impact of certain risk factors and provide solutions to mitigate those risks. QbD shows the FDA that reproducibility has been factored into the manufacturing process.
An article at BioProcess International (Challenges in Implementing Quality By Design: An Industry Perspective) reminds us that QbD is not a new concept, and has its roots in design of experiment (DoE) dating back to the 1930s.
The FDA began incorporating QbD into the regulatory process in 2006 to enhance consumer protections and improve manufacturing performance. With a focus on risk assessment and continuous improvement, the QbD framework emphasizes long-term product safety.
Key Components of Quality by Design
The QbD framework includes three major components: product understanding, process understanding and control strategy.
- Product Understanding: During this phase, scientists begin to create a target product quality profile detailing the product’s desired characteristics. The team gathers data and assesses known factors about all of the drug’s components. They also perform risk assessments, with the objective of having solutions prepared to mitigate any risks that may arise.
- Process Understanding: Once the team feels confident about the product, the focus shifts to building a thorough understanding of its process. In this phase, scientists design a formulation that meets the target product quality profile. They can begin designing the manufacturing process, which includes identifying parameters and attributes to consistently produce the desired quality. Analytical and process scientists continue focusing on data gathering and risk assessment throughout this phase, ensuring they feel confident in the product and their design process.
- Control Strategy: The third aspect of the QbD framework addresses identification of the various controls which influence product consistency and quality. The process development team leverages risk assessment strategies to understand which variables in the product and process can be changed without affecting the safety and efficacy of the drug.
The Benefits of QbD
Is drug development safer and faster with QbD?
Under the traditional Quality by Control framework, drugmakers had no opportunity to make changes in processes and controls. Each time a change was needed, the regulatory process had to be restarted. The ability to make some changes is a huge benefit of QbD, which allows for minor updates to the regulatory documents.
All of this translates into a continuous opportunity for improvement. Once the drug has gone to market, the process doesn’t end.
For drugmakers, this can be significant – in terms of both cost and speed. Typically, when the FDA is more flexible, drugs can get to market faster. QbD can help drive this acceleration, as the robust nature of the process ensures rigorous consumer safety.
Despite the upfront investment of time and capital, QbD shortens development timelines and reduces the cost of drug development. The comprehensive nature of the process means there is a better chance of success on the first try. It also means there is a smaller chance of costly recalls. In addition, time-to-market typically improves because the application approval time is faster and minor changes don’t require a full stop. Generally, there is also more confidence in the quality of the drug.
From Biopharmaceutical Processing (Implementation of QbD for Manufacturing of Biologics—Has It Met the Expectations?) comes another benefit of QbD:
“Application of QbD principles during evaluation of safety and efficacy in the preclinical testing can significantly lower the chances of failure in the more expensive clinical trials that follow.”
QbD has immeasurably improved the drug development process, but there is no getting around the upfront time commitment. The process development, analytical and formulation teams need time for extensive research, critical thinking, and yes, even failures. (We always say that if you haven’t had failures, you haven’t tested the product enough.)
The QbD process is not the cheap route. It is important to factor in batch failures, which leads to another concern—upfront costs. Active ingredients are pricey, and the team can end up discarding batches that are not going to be sold. (This is where selecting the right CDMO & sourcing partner comes into play: they need to have strong enough relationships with vendors to ensure the best prices on APIs.)
The advantages of QbD far outweigh any disadvantages.
Over the last 15 years, we’ve learned that the key to success with QbD is collaboration and transparency. LGM’s successes are often attributable to our formulation team, which actively engages with other departments early and often during drug development. And while the use of QbD may involve more from our team, the benefits to both consumers and the drug sponsor are immeasurable.