Pharmaceutical Quality by Design

Quality is an integral aspect of pharmaceutical products, primarily because these products directly affect people’s health. Focusing on product quality during each step of the manufacturing process is desirable but challenging, and this has led to the emergence of pharmaceutical quality by design (QbD).

Quality by design is not a new concept. It was first developed by Dr. Joseph Juran, who believed that quality needs to be designed into the product rather than tested and that all quality problems are related to the way the product was designed. QbD was later integrated into the manufacturing processes of many industries, including the pharmaceutical, healthcare, and medical devices industries.

Today, the US Food and Drug Administration (US FDA) encourages the adoption of QbD principles in medical product/drug development, manufacturing, and regulations. Considering the US FDA’s emphasis on quality by design principles, all pharmaceutical professionals need to understand the key elements of QbD and how they facilitate pharmaceutical development and continuous improvement.

What are the Elements of Quality by Design?

Let’s first understand a simplified definition of QbD: When you’re applying the quality-by-design approach to pharmaceutical product development, your first step should be to identify the characteristics critical for your product’s quality from the patient’s perspective. Then, these qualities need to be evaluated from formulation and manufacturing perspectives. That is, you should assess how formulation and manufacturing processes affect these characteristics of your quality. Finally, you should tweak formulation and manufacturing processes to ensure the product quality meets patient expectations.

This simplified explanation of QbD depends on five key steps.

Step 1: Quality target product profile (QTPP) development

A quality target product profile (QTPP) summarizes the ideal quality characteristics that a pharmaceutical product needs to demonstrate the highest safety and efficacy during use. The QTPP is developed by considering some or all of the following:

• The intended use of the product in clinical settings
• The administration route and delivery systems
• Dosage strength, form, and frequency
• Formulation of quality criteria for the intended

Ultimately, the QTPP includes a list of the critical quality attributes (CQAs) of the final drug, such as size, shape, and colour. The CQAs are often defined within a range, allowing the manufacturer some flexibility during manufacturing.

While the actual QTPP includes numerous CQAs, the importance of each CQA depends on how severely it will affect the final drug. For example, in the case of pills, the shape may affect a patient’s desire to consume them but will not affect their efficacy. Hence, in this scenario, shape is not considered a very important CQA.

The lack of a well-defined QTPP can lead to time and resource wastage because a lot of trial and error will be required to develop the “ideal drug”. Hence, it is necessary to consider all the drug's quality attributes before actual manufacturing commences. Typically, the QTPPs of new pharmaceutical products are developed once they have been approved for manufacturing, i.e., they have passed the research and development stage.

Step 2: Product design and understanding

Once the QTPP is developed, product designing can commence. In any field, product design determines whether the product meets customers' expectations and needs. In the pharmaceutical industry, product design determines the drug’s shelf life, performance, efficacy, and safety.

In the pharmaceutical quality by design approach, this step aims to help the manufacturer develop a robust drug that delivers the desired QTPP. As product design is flexible, the following aspects should be considered when developing the ideal product design:

• Physical, chemical, and biological properties of the drug
• Excipient type, grade, and variability
• Interactions between the drug and excipient
• Critical material attributes (CMAs) of the drug and excipient
• Formulation optimization study results

Step 3: Process design and understanding

Once the design of the drug is made and well understood, the pharmaceutical manufacturing process should be designed and understood. A pharmaceutical manufacturing process comprises many operations that result in the desired quality. Note that the entire manufacturing process doesn't need to be in either batch or continuous mode. Instead, some operations can be in the batch mode, while others operate in the continuous mode. Hence, each aspect of the manufacturing process designed for the drug needs to be well understood.

A process is considered “understood” if:

• All sources of variability are identified and explained (which will allow the manufacturer to tune the process in case of quality lapses).
• The variability in the process is managed within a certain limit (i.e., there are no major quality lapses).
• All product quality attributes are predicted.

Achieving this is not difficult. Here are some steps that can be followed:

1. Identify all process parameters that can affect the process performance.
2. Determine which process parameters are high risk (i.e., will significantly affect the process).
3. Establish “acceptable” ranges for each high-risk parameter by conducting experiments.
4. Develop a control strategy for all parameters. (See the next step for more information.)

As each manufacturing process is a summation of smaller operations, such a comprehensive understanding of the process can reduce variability and ensure consistent product quality.

Step 4: A control strategy

When appropriate product and process design studies are performed, a good control strategy can be developed. A good control strategy should include 3 levels.

• Level 1: In this level, automation is used to monitor the CQAs of output materials. To this end, the attributes of input materials are monitored, and process parameters are adjusted to variations in these attributes to ensure the attributes of the drug fall within the acceptable range.
• Level 2: This level aims to reduce end-product testing. As the quality by design principles encourage a thorough understanding of the manufacturing process and product, they help manufacturers understand the impact of variability in raw material attributes on in-process materials, downstream processing, and final drug quality. Hence, by understanding this impact, manufacturers can make changes upstream and reduce downstream or end-product testing.
• Level 3: This level relies on strict material attributes and process parameters and hence involves considerably more end-product testing. This level is usually applied when manufacturers lack understanding of the manufacturing process and drug, which means they don’t integrate QbD principles during drug development. This is primarily because when quality by design principles are not implemented, an “acceptable” variability is not established; hence, every deviation requires oversight.

Step 5: Process capability and continuous improvement

Process capability includes studying the inherent variability in a stable, well-established process. This is done to identify process improvement opportunities that will remove the causes of variability in the process, thus making it more consistent and reliable. This is typically achieved in the following manner:

1. The problem is defined.
2. Key aspects and parameters of the problem are defined, and relevant data is collected.
3. The collected data is analyzed to identify cause-and-effect relations among parameters.
4. Based on these relations, the parameters are improved or optimized.
5. Pilot runs are performed to identify process capability.
6. Other continuous improvement opportunities in the improved process are identified.

Bottom Line

Currently, the US FDA mandates the implementation of some of these principles. However, all pharmaceutical quality by design principles are rarely implemented in the pharmaceutical industry, leading many pharma companies to use level 3 control strategies. However, as you probably understand from reading this article, QbD principles are a tool that can increase the efficiency and quality of pharmaceutical products. The implementation of QbD principles can reduce costs, time-to-market, and resource wastage, all of which will be beneficial for pharma companies that have to manage multiple drug pipelines at the same time.

FAQs

1. Why should companies implement quality by design in production?

Quality by design can improve the quality of the final product while reducing product variability, costs, and time-to-market, which will lead to higher revenue and profits.

2. How is QbD different from traditional quality improvement approaches?

Traditional approaches focus on end-product testing to improve the product quality. By constrast, QbD encourages designing and building the desired quality into the final product.

3. Can QbD be applied to existing products?

Yes, QbD can be applied to all products. However, this may require some tuning of existing QbD principles.