A Guide To QbD For Small Molecule Drug Product Manufacturing Excellence

By Navneet Kaur, Alkermes, Inc.

In the early 2000s, the quality by design (QbD) concept was introduced to the pharmaceutical industry and became a vital element of regulatory standards. This shift was marked by the introduction of the International Council for Harmonisation (ICH) guidelines, particularly ICH Q8 (Pharmaceutical Development), which was finalized in 2005 and updated in 2009.

Since then, the pharmaceutical industry has developed more robust processes, and the approach of leveraging QbD to achieve manufacturing excellence is game-changing in the pharmaceutical sector. The ICH Q8 guideline emphasized a systematic approach to pharmaceutical development, incorporating QbD principles. This approach encouraged manufacturers to build quality into products from the design stage rather than relying solely on end-product testing. QbD also became linked with ICH Q9 (Quality Risk Management) and Q10 (Pharmaceutical Quality System), which further supported the implementation of QbD concepts in the pharmaceutical development process.

The U.S. FDA 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.”

QbD Features And Principles

QbD in the pharmaceutical industry is built on a handful of features and principles that focus on ensuring pharmaceutical products’ safety, efficacy, and overall quality. These fundamental principles include determining the quality target product profile (QTPP), identifying critical quality attributes (CQAs), understanding critical process parameters (CPPs), and developing a risk management and control strategy.

Quality target product profile (QTPP): Determining the QTPP is the first step in developing a product using QbD principles. ICH Q8 (R2) defined QTPP as “a prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the drug product.” It includes identifying critical attributes of the drug, including dosage form, dosage strength, route of administration, release profile of the formulation, therapeutic effect, stability of the product, and container closure system.

Critical quality attributes (CQAs): QTPP becomes the base for establishing appropriate CQAs, which are required to be monitored or controlled during the product development process. This provides a quality check during the development and becomes a process for building quality.

Critical process parameters (CPPs): These are essential variables in the manufacturing process that can significantly influence the CQAs of a product. CPPs include elements such as temperature, mixing speed, pH levels, reaction time, and pressure, all of which can affect the final product. In the QbD framework, the initial task is to determine which process parameters impact CQAs. This requires a comprehensive understanding of the manufacturing steps and how each contributes to maintaining or affecting the desired product quality.

Risk management and control strategy: Risk management is essential in QbD and ensures that risks to product quality are systematically identified, evaluated, controlled, and mitigated throughout the product life cycle. This approach follows the framework provided by ICH Q9 Quality Risk Management guidelines and applies a structured, scientific method to reduce the probability of quality-related issues. Risk identification involves analyzing every stage of product development and manufacturing to detect any factors that could threaten safety, efficacy, or consistency. Brainstorming to understand the process, process mapping, and review of historical data is performed to identify risks. Failure modes and effects analysis (FMEA) is the most common tool for this activity. The types of risks include variability in raw material quality, equipment malfunction, and inadequate environmental control that could impact the CQAs of a product. Risk assessment is performed in terms of severity, probability, and detectability. Once the risks are identified, appropriate control strategies, such as CPPs, are established, and a comprehensive plan that integrates controls for materials, processes, equipment, and environment to mitigate risks to product quality is developed.

Benefits Of QbD In The Pharmaceutical Sector

A QbD approach assists organizations in better understanding and improving their product and process designs to ensure they manufacture the highest quality products. This methodology is a pathway to manufacturing excellence. Applying the principles of QbD helps pharmaceutical companies accomplish several critical goals:

• Quality: Companies can establish a safe product of the desired quality. QbD aids in improved product quality and consistency to ensure identified CQAs are met consistently throughout production.
• Enhanced risk management: QbD reduces the likelihood of product recalls, rework, or failure by identifying and mitigating risks early in the process.
• Consistency: By optimizing processes and maintaining consistency with QbD, companies can lower the need for extensive end-product testing and reduce waste from defective batches. This leads to cost savings by minimizing the use of excess materials and reducing the occurrence of failed batches.
• Accelerated development and time to market: QbD integrates product development with manufacturing processes, reducing trial and error and providing a structured approach to reaching product quality goals faster. This speeds up product development timelines by streamlining the design process, resulting in quicker regulatory approvals and faster time to market.
• Regulatory compliance and streamlined submission processes: QbD uses scientific evidence to support product quality and safety, aligning with the expectations of regulatory agencies like the FDA and EMA. This approach enhances the submission process, resulting in quicker approvals and fewer regulatory hurdles, as QbD-based submissions are viewed as more thorough and scientifically reliable.
• Enhanced process understanding and controls: QbD emphasizes a thorough understanding of the product and its manufacturing process. This includes identifying CPPs and CQAs. Doing so offers greater insights into how variations in raw materials, equipment, or processes can affect the quality of the product, enabling better control and more predictable results.

Examples Of Successful Case Studies Performed In Alignment With QbD Principles

Several organizations in the industry have already begun to reap the benefits of employing a QbD framework as part of their product development processes.

The evaluation of metformin hydrochloride (HCl) tablets offers an example of how a QbD approach has been applied for formulation design and evaluation. Metformin, which is available in commercial forms under several brands, including Glucophage, “is used as first line therapy in type II diabetes, due to its efficacy and safety in controlling hemoglobin A1c, reducing weight and decreasing cardiovascular mortality rate among people affected by the disease.” In this study, researchers aimed to develop direct compression metformin HCl 500 mg tablets by using suitable excipients and assess the formulation results to reach optimum formulation.

The study concluded that applying a QbD approach with QTPPs and CQAs in the development of Metformin HCl formulation allows for a higher assurance of the intended tablet quality and performance. The researchers concluded:

• Quality control results from formulations are inputted into a QbD simulation program, which assists in optimizing the formulation.
• Design space has been effectively utilized to refine the formulation’s composition, enabling the prediction of an optimal formulation.
• The design space methodology has proven to be a valuable tool for this purpose.

The development of the manufacturing process for drug substance arzoxifene hydrochloride offers another valuable case study in QbD, beginning with a traditional approach and later transitioning to an enhanced method. This study primarily aims to highlight the benefits of QbD, particularly in relation to impurity control strategies. By conducting design space studies at the process extremes, a greater range of organic impurities and elevated levels of typical impurities in the intermediates were observed. This approach fosters a deeper understanding of the purification capabilities of the process and leads to more comprehensive and robust intermediate specifications and analytical methods. The findings indicate that maintaining all synthetic steps within the design space ensures that byproduct impurities in the intermediates remain below the acceptable levels identified in subsequent processes, thus allowing the drug substance to meet its critical quality attributes. With a thorough application of an advanced process development strategy, quality was integrated into the arzoxifene hydrochloride drug substance. Consequently, real-time release testing for intermediate batches to enhance process efficiency and reduce costs associated with unnecessary tests was suggested.

These concepts were not recognized decades ago, and QbD principles were not practiced in the pharmaceutical world. Achieving manufacturing excellence and consistently producing an acceptable quality drug product was very challenging. Today, QbD and manufacturing excellence are pivotal in the pharmaceutical industry, and some companies have already demonstrated how employing this strategic approach can improve product development processes, mitigate compliance risk, and increase operational efficiencies and cost-effectiveness. It’s vital for pharmaceutical companies to develop a solid understanding of the principles of QbD and manufacturing excellence. Implementing these features at each step of the product development process will ultimately maximize these concepts’ potential and ensure the highest quality products.

About The Author:

Navneet Kaur is a senior manager of regulatory affairs at Alkermes, Inc., a global biopharmaceutical company headquartered in Massachusetts. She has 13 years of experience in the pharmaceutical sector and is an expert in quality, compliance, and CMC regulatory affairs. Kaur holds a bachelor’s degree in chemistry (hons), a master’s degree in chemistry (hons) from Guru Nanak Dev University, and a master’s degree in regulatory affairs for drugs, biologics and medical devices from Northeastern University. Contact her at neet1202kaur@gmail.com.

The opinions expressed in this article are those of the author. They do not purport to reflect the opinions or views of her employer.