Quality by design (QbD) is a concept that has become firmly established in the pharmaceutical and biotechnology world. The ICH, FDA and EMA have been working on the implementation of QbD in the life cycle of medicinal products for many years, resulting in the ICH Q8, Q9 and Q10 guidelines. However, it did not stop there. Modelled on the solutions for product development, analogous solutions for analytical method development and validation were introduced in 2022. With this article, I begin a series on quality by design and its application in biotechnology and pharmaceutical product development.
What is Quality by Design?
The concept of quality by design first appeared in 1986 although many of its elements were already known and used earlier. The concept itself, developed by Joseph M. Juran, assumes that the quality of a product can be planned> Furthermore, the author of the concept believes that all quality problems arise from the quality planning process.
In order to be able to talk further about quality by design, we must first clarify for ourselves what the author of the concept meant by quality itself. Juran described this in the document entitled Quality Trilogy. According to him, quality has two definitions. The first is to have all the properties and functions that guarantee customer satisfaction. In short, the product must work properly. If the product does not work as it should, the customer is dissatisfied. The second definition of quality is the reliability of the functions I have just written about. In short, if it happens that the functions sometimes do not work or it happens that they work improperly it also affects the customer’s dissatisfaction. According to Juran, the design of any product should be done by considering the needs of the customer. Looking at the biotech and pharmaceutical market, the customer is not only the patient but also physicians, drug reimbursement agencies or regulatory agencies.
How to develop a product with QbD?
The first stage of QbD-based product development is to identify customers. This is an often neglected stage, especially for potential products developed in academic centres. Failure to understand the market and customer needs can result in investment in projects that have no chance of commercial success.
Knowing the customers’ needs allows the functional design of the product to begin and the specification of all the quality objectives it must meet. The next stage is to develop a process that will be able to produce a product with the assumed quality properties. The final stage is to apply the appropriate process control.
Tools used in QbD
Product quality planning should be seen as a process. As the product develops, we gain more and more knowledge about it and can use this knowledge in the design and improvement process. Among the most commonly used tools in QbD are: Target Product Profile (TPP), Quality Target Product Profile (QTPP), risk analysis, Design of Experiment (DOE), control cards or process capability. QbD is also often combined with other systems such as Lean Six Sigma.
QbD w branży biotechnologicznej i farmaceutycznej
Quality by Design was initially most popular in the automotive industry. The FDA began work on implementing its principles in 2008. In 2011, an international working group was formed under ICH. The group’s work resulted in the Q8 guidelines in 2017 followed by Q9 and Q10.
QbD approach in the development of pharmaceutical product
Target Product Profile (QTPP)
The process of developing a pharmaceutical product should start with the creation of a Target Product Profile. This is a simple conceptual document describing the basic properties of the finished product. It should include information such as mode of action, target population, presumed therapeutic effect, route of administration or dosage regimen. This is key information for the subsequent planning of the relevant product, process and studies. A separate article will be dedicated to the topic of TPPs.
Critical Qualuty Attributes
The next step is to identify critical quality attributes. The more we know about the medicinal substance, its manufacturing process, the better we can identify the critical quality attributes. Once they are identified, we proceed to assess their criticality. We assess their potential impact on drug efficacy and patient safety. To do this, we use appropriate risk analysis tools.
Quality Target Product Profile
The next step is to create the QTPP, which is the quality target product profile. This profile defines all the quality criteria of the product. It is therefore a guideline for the scientists developing the process. If the final product does not meet the requirements stipulated in the QTPP, the process is not yet sufficiently optimized.
Design of Experiment
The guidelines for developing a manufacturing process clearly state what should be documented. A good manufacturing process is not only about the optimum conditions under which it is to be carried out. It is also a defined and measured workspace in which the process does not generate a defected product
During process development, the workspace must be defined. For this purpose, statistics and design of experiments (DOE) comes to the rescue. By using statistical modelling, it is possible to determine not only the most optimal process conditions, but also the range of parameters and variables in which the process can occur.
Through the use of DOE, many benefits can be achieved. That includes the definition of appropriate ranges for critical process parameters, the definition of acceptance criteria for intermediates and key process steps, faster processing of deviations.
Down-scaling is nothing more than the development of a laboratory-scale model of a manufacturing process. Most often, it is a secondary scaled down manufacturing process with an appropriate statistical description that enables the results of the laboratory scale process to be ranslated up to the industrial scale.
Having such a model makes it possible, among other things, to qualify new raw material and material suppliers, explain deviations and OOS results, or facilitate technology transfer.
Monitoring the manufacturing process offers a number of benefits. Firstly, we gain knowledge of the manufacturing process on a long-term scale. Secondly, by analysing trends, we can detect changes in the process earlier and react in good time to prevent the production of defective batches.
Not only process
Quality design is not just about the manufacturing process. The methodology can be applied in many areas. In recent years, ICH has worked to implement QbD in the area of analytical method management. This resulted in the release of drafts of two documents in March 2022. ICH Guideline Q2 on the validation of analytical methods and also the brand new ICH Guideline Q14 discussing issues related to the development of analytical procedures. At the same time, similar developments appeared in the US Pharmacopoeia.
The application of the quality design in the development and management of the manufacturing process has many benefits for the manufacturer, the regulator and the patient. By identifying risks, variables and using statistics in optimising the process, the manufactured product is characterised by high quality, safety and efficacy. Defining quality criteria at an early stage also enables more efficient project management by clearly setting out the objectives needed to be achieved. It is therefore no surprise that QbD has taken hold in the pharmaceutical and biotechnology industries.
In future posts, we will continue to explore the application of quality design.
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- Juran, J.M. (1986). “The Quality Trilogy: A Universal Approach to Managing for Quality”. Quality Progress.
- ICH Q8 – Pharmaceutical development – Scientific guideline
- ICH Q9 – Quality Risk Management
- ICH Q10 – Pharmaceutical Quality System
- ICH Q11 – Development and Manufacture of Drug Substances