Benefits Of Pharmaceutical Quality By Design (QbD): Considerations For Drug-Device Combination Products And Partnerships

With a focus on patient outcomes, QbD achieves quality through understanding of all components and processes, with a detailed understanding of risks and how they can be mitigated. The concept of designing quality into pharmaceutical products was first introduced in 2004 by Janet Woodcock, Center for Drug Evaluation and Research. The QbD process continues to mature for the development and manufacture of pharmaceutical products and is more prevalent than ever. The conventional approach to drug development is to test-in quality based on the end product, whereas, quality can be designed-in with a QbD approach.   A constituent part of a drug-device combination product, such as a plunger, follows the principles of QbD by identifying and mitigating risks to patients by meeting the predefined requirements for the final system.  If the plunger is not designed with the end application in mind, then it can only be tested-in based on multiple trials with the delivery device.

This article considers how West Pharmaceutical Services, Inc. (West) employs QbD for elastomer components – in particular NovaPure^® plungers for prefilled syringes shown in Figure 1.

Figure 1. NovaPure^® plungers in a prefilled syringes

High-quality packaging components and delivery systems significantly contribute to patient safety. As a result of concerns for risk to patients, the U.S. Food and Drug Administration (FDA) and other regulatory agencies around the world are requiring drug makers to develop and institute improved quality processes in the manufacturing of drug products and their container closure and delivery systems. Patient safety is at the forefront of considerations in the pharmaceutical industry, with high expectations from patients and care providers for quality in injectable medicines. Parameters for injectability and examples of inputs to the design determine the critical quality attributes (CQAs) will include: leakage, force of injection, travel force, break loose and glide force. Examples of studies conducted to understand risks to these requirements include: rib design and dimensions, stress and strain curves over time for plunger travel force and break loose and extrusion (BLE) as illustrated in Figure 2 below.

Figure 2. CQA examples (from left to right): rib design and dimensions, stress and strain curves over time for plunger travel force and break loose and extrusion

Biologics and Increased Regulatory Focus on Quality

There continues to be a steady rise in new biologic and biosimilar drugs coming onto the market to treat chronic conditions such as multiple sclerosis and certain autoimmune diseases. Additionally, biologic therapies show promise for helping acute conditions, such as certain types of cancer, become manageable chronic conditions by targeting specific components of a disease in ways never thought possible before. Certain therapies can have specialized needs around containment and delivery. Home administration is preferred for certain treatments and is driving the demand for auto-injectors or pen injectors. The plunger plays a key role in the deliverability of medicines and is an important feature of a drug-device combination product.

Quality is particularly at the forefront with the influx of new biologic and biosimilar drugs. For example, biologics can have sensitive chemical compositions that pose the potential for interaction with materials traditionally used for packaging and delivery systems. In particular, the fact that many sensitive biologics are coming on the market as drug-device combination products is spurring regulatory agencies to closely scrutinize the compatibility of packaging components with injectable drugs and their delivery systems. Regulatory guidelines related to pharmaceutical development, risk and quality management, and product lifecycle management contribute to ensuring increased focus on quality within the pharmaceutical industry.^,,,5

QbD principles were designed to promote an understanding of the drug product and manufacturing process starting with product development. During the design and development process, a QbD-driven approach should include:

• Defining the quality target product profile (QTPP) as it relates to quality, safety and efficacy;
• Assessing patient risks and linking to critical material attributes and process parameters;
• Identifying potential CQAs of the drug product for quality impact to be studied and controlled; and
• Linking CQAs to critical process parameters (CPPs) and control strategy.

These same QbD principles can be applied to a drug-device combination product. The NovaPure® plunger plays a major role in the safe and effective delivery of the drug product. Patient safety can be affected based on the performance of the delivery system; the drug product CQAs can be affected by incompatible materials. The plunger design, choice of materials, manufacturing and assembly are critical to the quality of the final drug-device combination product.  A host of interrelated factors can have an impact on quality, such as: materials of construction, elastomer curing and processing, hardness, dimensions, particles and product interactions. The elastomer manufacturing CPPs are essential to ensure the plunger will meet the engineering requirements.  A failure mode and effects analysis (FMEA) was conducted to understand risks and build consistency during the manufacturing process. The areas of manufacturing and processing with highest risk for failures were indicated by a cause and effects analysis. More than 200 process parameters and 40 process steps were considered.  The process steps were ranked based on the impact to the CQAs as displayed in Figure 3. The critical steps in the manufacturing process were then identified for evaluations relative to potential failures. Processes were optimized to ensure the manufacture of highest plunger quality consistent with the QTPP.

Figure 3. Process step ranking based on the impact to the CQAs

In this new era, the adoption of QbD principles in the design and manufacturing of packaging and delivery system components for injectable drug products helps to ensure that how the therapy is contained and delivered is engineered with these stringent and specialized needs in mind.

Partnering to Enhance Quality

The scientific, risk-mitigation based QbD approach is fast becoming an essential strategy for bringing high-quality biologics to market quickly and efficiently while identifying and controlling potential quality concerns. Use of QbD principles ensures that components are developed using science-based and data-driven decisions, and that they meet critical specifications. The knowledge gained throughout the QbD process can be used on an ongoing basis to maintain continuous improvement by the manufacturer to enable:   

• Improved Functionality – High-quality components, such as plungers, can enhance the functionality of prefillable syringes and self-injection systems. Using QbD principles can help to optimize the functional and dimensional performance of a delivery system to improve the consistency of injections and the rate of injection times.
• Patient Confidence – A self-injection system needs to function consistently and reliably for patients to have confidence. QbD designed components allow for larger-size delivery systems and greater dosing volumes which may enable home administration, encourage device use and more accurate dosing.
• Efficient Manufacturing – Employing a QbD approach in the manufacturing process can significantly reduce variation from part to part. This can help facilitate more efficient manufacturing processes and support a reliable supply of drug products.

Efficiency in manufacturing and the ability to meet critical compliance standards are essential to compete in today’s market. Integrating delivery device components in the development process can be key for pharmaceutical manufacturers. Upfront costs can be balanced by managing costs in an effort to provide a product that meets the requirements of payers along with facilitating profitability to support adequate business reinvestment. If the drug-delivery device is considered too late in the development cycle, product quality can be compromised, and delays can occur that can influence the commercial manufacturing process. Early partnerships between pharmaceutical companies and drug delivery device companies help pharmaceutical manufacturers select consistent components and mitigate potential risks associated with issues with injectability for clinical studies and throughout the drug product lifecycle.

NovaPure® and FluroTec® are registered trademarks of West Pharmaceutical Services, Inc., in the United States and other jurisdictions.

FluroTec® technology is licensed from Daikyo Seiko, Ltd.

¹ Woodcock J. The concept of pharmaceutical quality. Am Pharm Rev 2004; 1–3.
² ICH Harmonised tripartite guideline pharmaceutical development Q8(R2). www.ich.org. Accessed on November 6, 2019.
³ ICH Harmonised tripartite guideline quality risk management Q9. www.ich.org. Accessed on November 6, 2019.
⁴ ICH Harmonised tripartite guideline pharmaceutical quality system Q10. www.ich.org. Accessed on November 6, 2019.
⁵ ICH Harmonised tripartite guideline lifecycle management. www.ich.org. Accessed on November 6, 2019.