Quality By Design in Biologic Drug Development

As the biopharmaceutical industry continues to evolve and in response to increased interest from global regulatory agencies, the Quality by Design (QbD) integrated and proactive approach to drug development and manufacturing is transforming key processes.

QbD seeks to further reduce the risk associated with drug development and bring much-needed therapies to market quicker. As an example,  companies that implement QbD early can save money through increased product/process knowledge, less re-work, less product deviation, less product out of specification, fewer rejects and improved quality.

But, how can  companies ensure that rigorous, scientific risk-based approaches are used to bring better and safer therapies to market faster? To realize the full potential of this investment, QbD must link early and late-stage development with manufacturing and commercialization. Most importantly, applying QbD ensures a quality product reaches patients.

But let´s start from the beginning!

What is Quality by Design (QbD)?

QbD is an integrated and proactive approach to pharmaceutical development designed to ensure a drug product meets its desired quality specifications, and thereby, expected clinical performance. Prior to the usage of the phrase “Quality by Design”, the term “optimization” was more frequently used by global regulators, since it entailed optimization of drug development areas like formulation and process design.

In 2002, QbD had its unofficial start when the US Food and Drug Administration (FDA) launched the Pharmaceutical Quality for the 21st Century initiative to reduce risk and enhance the quality of pharmaceutical manufacturing.

In 2013, the FDA mandated QbD implementation throughout product and process design, quality target product profile (QTPP), critical quality attributes (CQAs) and other quality elements.

Today, global regulatory agencies – including the FDA, EMA, Japan’s Pharmaceutical and Medical Devices Agency (PDMA) and the Korean Ministry of Food and Drug Safety (MFDS) – use QbD during development to ensure product quality at the approval stage.

The goal of QbD is to facilitate a deeper understanding of the elements that go into creating a new therapy and designing quality into the product. The addition of “by design” emphasizes the importance of leveraging QbD to develop a robust process in early development in order to aid implementation in late-stage development and commercialization.

Applying Quality by Design to the Drug Development Process

Quality by Design has applications throughout drug development and understanding the critical quality parameters in any process allows developers to design procedures that support quality deliverables at any stage.

QbD principles are applied throughout:

  • Quality target product profiles (QTPPs);
  • Identifying critical quality attributes (CQAs);
  • Critical material attributes (CMAs);
  • Critical process parameters (CPPs);
  • Risk assessment and management;
  • Design of experiments (DoE);
  • Design space;
  • Process analytical technology (PAT);
  • Robust process design;
  • Process control strategies;
  • Product lifecycle management.

QbD tactics are useful in small molecule development, due to risks that are intrinsic in the formulation or the production process of these products. Instead, for biologics, much of the risk assessment and QbD principles focus on improving the titer, purity and maintaining sterility throughout all steps and into manufacturing.

Biopharmaceutical companies must perform QbD and phase-appropriate risk assessment and application of QbD principles throughout each stage of development, beginning with early development.

Use of QbD is more prevalent in late-stage development as well when  companies have more security in the knowledge that the biologic will succeed and reach patients. At this step, biopharmaceutical companies want to ensure that any outstanding issues with product robustness or process design have been resolved.

The Benefits of Quality by Design

Biopharmaceutical companies benefit from implementing QbD in numerous ways:

  • Meeting clinical trial timelines.
  • Creating less waste of time and resources.
  • Faster approval as regulatory agencies look for QbD elements.
  • Continuous process improvement.
  • Reducing manufacturing issues.
  • Challenging bad methods or processes.
  • Sharpened focus on procedures.
  • Quicker batch release and stability study generation.
  • Faster commercialization through the ability to scale up with no inherent defects.
  • Consistent sustained processes that can be Right First Time.

Companies that implement QbD at the outset can save money due to the increased product/process knowledge, less re-work, less product deviation, less product out-of-specification, fewer rejects and improved quality.

The Risks of Delaying Quality by Design

For some pharmaceutical clients, the worst-case scenario for not implementing QbD early enough can mean compromise timelines, costs and process approval. For biopharma companies the lack of QbD implementation is because they assume they are taking less financial risk if the biologic will not have successes. This may prove true in the short term, but can be costly in the long run.

Biopharmaceutical developers may also fear the unknown with QbD and not understand how it is relevant to their product. As more regulatory agencies utilize and enforce QbD, companies that do not leverage a proper risk- and science-based development process face challenges, like:

  • Product rejections and timeline delays.
  • Regulatory questions and concerns.
  • Inconsistent drug performance.
  • Adverse impacts to clinical trial endpoint data.
  • Risk of failure during commercial scale up.
  • Risk of regulatory deficiencies that could delay or deny their drug application.


Soon, all major regulatory agencies will require documented proof that QbD principles were used throughout the development process.

As QbD evolves from good practice to requirement, it presents a distinct advantage during the final regulatory filing from patient safety, technical capability and regulatory perspectives. However, QbD must link early and late-stage development with manufacturing and commercialization. Through early adoption and application of QbD, key pharmaceutical industry stakeholders can ensure that rigorous, scientific risk-based approaches are used to bring better and safer therapies to market faster.

The problem is that today, although more biopharmaceutical companies are willing to implement QbD, there are others that invest too little in it. The problem is that by not investing in QbD, biopharmaceutical companies may create a product and process that cannot be scaled up or manufactured consistently for commercial markets. By its nature, QbD seeks to reduce the risk associated with drug development and bring much-needed therapies to market quicker.

In these sense, it is important and critical that the outsourced partners have the skill set and experience in implementing QbD for future drug products. At 53Biologics by deploying a QbD approach, we enable clients to build the required quality into the product during the design and development phase by understanding the effects of material attributes and process parameters on Critical Quality Attributes (CQAs).

53Biologics strongly believes in the importance of effective QbD during the process development and involves a cross-functional team of analysts, process engineers, quality assurance, sourcing and manufacturing experts that help to consider right input variables during designing and developing the process.

Do you have any comments about this topic? Do you want to know more? Get in touch!


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