Incorporating Quality by Design in the Pharmaceutical Manufacturing Process
Lum KwongToh, Regional Marketing Manager Asia Pacific, West Pharma

The current pharmaceutical market has faced a variety of challenges, including increasing expectations for quality from end-users and regulatory agencies driven by concern for patient safety. The pharmaceutical and biotech industry as a whole has had a series of regulatory challenges relating to issues such as lack of cGMP compliance, high end-of-line rejections and lack of best practices for compliance in general. Such incidents can cause drug shortages, which also have a direct impact on meeting patient needs. The cost for such issues to both companies and patients is significant.

Industry suppliers play a critical role to help pharmaceutical manufacturers meet the needs of patients and regulators. As the industry evaluates the adoption of Quality by Design (QbD) techniques as a way to address these challenges, it needs to turn its focus from ascertaining drug product quality predominantly by end-product testing to achieving effective and efficient manufacturing processes by harmonising pharmaceutical development, quality risk management and pharmaceutical quality systems through science-based quality manufacturing.

The goal during QbD development is to have predefined objectives with emphasis on the product and understanding the manufacturing process. An in-depth understanding of container closure components along with their manufacturing process will enable science-based decisions to support pharmaceutical manufacturing control strategies.

Aspects of container closure systems critical to drug product quality can be established during the drug development cycle by identifying potential attributes of the component and applying various risk management tools. It is possible to combine and coordinate process knowledge from multiple-unit operations to achieve a holistic picture of the entire drug manufacturing process, which can incorporate the science of component manufacture. An understanding of how drug formulation and component manufacturing process factors affect quality will lead to:
  • Effective technology that will reduce setbacks when moving from development to commercialisation, realising time and cost savings
  • Data-driven knowledge to identify critical quality attributes and establish control strategies
  • Specifications based on how and why the rubber formulations, components and process factors impact drug product quality
  • Benefits throughout the lifecycle of a given product through trending of data for proactive management and effective continuous improvements

Elements of the QbD Approach
The importance of the container/closure system to the efficiency of the manufacturing process and the quality of the final drug product is significant and should not be minimised. The QbD approach takes into consideration the entire supply chain from raw materials through distribution and drug packaging. Quality characteristics are engineered to meet the requirements of the pharmaceutical manufacturer and help promote protection/compatibility of drug product.

There are three critical elements to a true QbD pharmaceutical product. These are:
Drug product
Drug manufacturing process
Container/closure system

Convergence of these three operations is vital to establishing the critical quality attributes necessary for control of the drug product and the process to enable continuous improvements (See Figure 1).

The following important QbD elements can be used to develop and produce components with a commitment toward enhancing drug product quality:
  • Quality Target Product Profile (QTPP)
  • Critical Quality Attribute (CQA)
  • Quality Risk Management (QRM)
  • Knowledge Management (KM)
  • Critical Process Parameter (CPP)
  • Control Strategy (CS)
  • Lifecycle Management (LCM)
  • Continuous Improvement (CI)

The QTPP forms the basis for drug product formulation and process development in a QbD framework. A series of considerations should be made for the QTPP of a sterile product. Some of these considerations include the desired product performance based on the intended clinical setting, dosage strength and delivery mode, pharmacokinetic characteristics, drug product quality criteria, sterility and the container closure system itself, just to mention a few.

Scientific rationale and quality risk management are used to define CQAs and CPPs for a given product and process in support of achieving the QTPP.

The information developed to determine the CQAs and CPPs will help to:
  • Develop control strategy
  • Ensure quality of the product throughout the product lifecycle
  • Increase product and process knowledge
  • Increase transparency and understanding for regulators and industry
  • Evaluate changes
Consideration of all these factors during development of elastomeric components can achieve a well-understood component and robust processes that 1) deliver a component meeting the QTPP and 2) are controlled by defined steps within the manufacturing process. During commercial-scale manufacturing, the proactive trending of component performance on a continuous basis provides a major advantage through early detection of potential issues and further optimisation of the control strategy to ensure reliable level of high-quality components.

Managing Total Cost of Ownership
As the industry evaluates its Total Cost of Ownership (TCO) model, it will begin to adopt QbD techniques. Such an adoption requires a significant up-front investment. However, QbD delivers an improved, data-driven output providing manufacturers with superior product and process understanding that minimises process risk, emphasises patient-critical quality requirements and enhances drug product effectiveness. A more efficient process results in a final deliverable that is a much higher quality product with well-understood and controlled sources of variation. (See Figure 2)

When industry evaluates its Total Cost of Ownership model, the importance of the use of a primary package component that has been developed and produced by QbD techniques should be a significant consideration. Such a product will minimise variability downstream by pushing improved understanding and controls upstream into the supply chain. Risks such as end-of-line rejects, loss of production capacity and compliance inadequacies will be minimised, driving cost of ownership down significantly.

The adoption of QbD by suppliers to the industry is the future. Although some pharmaceutical companies are still grappling with the adoption of this new model, forward-thinking suppliers have already implemented this technique.

Products have been developed using the systematic, science-based approach encouraged by the regulatory agencies. Such a development process can deliver a product to the industry that provides the ultimate product and process understanding; has quality built around the patient; improves transparency; and provides improved Total Cost of Ownership to the pharmaceutical customer.

Total Cost of Ownership is the analysis of price, risk, quality, service and delivery performance in evaluating the overall cost of a product versus its benefit. If the use of a certain product solution can minimise manufacturing downtime, lower end-of-line rejections, minimise compliance and regulatory risks, and provide other related benefits, then the positives associated with this product are worth an incremental price differential.

End-of-line rejections due to component defects are an example where Total Cost of Ownership benefits can be clearly recognised for the pharmaceutical customer. In a case study, a move to an improved component allowed a customer to reduce rejections from 0.75 per cent of all filled vials to 0.02 per cent . Not only is this a significant cost savings in dealing with the rejected drug product and its final disposition, it allows more product to go out to market for use. This minimises concerns with product shortages in the field, helps to manage capital expenditures more effectively and ultimately allows more revenue to be generated for the pharmaceutical or biotech company.

Regulatory expectations are that pharmaceutical and biopharmaceutical companies understand their supply chain and are accountable for assuring the inputs into the finished drug product are of highest quality.

The use of components based on a holistic QbD process assures the company it is using a well-understood product that has been developed to achieve highest patient safety and lowest risk for the pharmaceutical manufacturer. At the center of a Total Cost of Ownership analysis by the company must be hard-dollar savings coupled with the consideration of significant savings in dealing with fewer regulatory and quality challenges, potential loss of revenue and the long-term negative impact to brand equity. Additionally, if saved resources can be better applied to other areas of the business, the potential benefits are exponential.

Suppliers that provide components critical to the drug manufacturing process or drug product should consider QbD as a critical input to the pharmaceutical supply chain as it directly supports a lower Total Cost of Ownership model.

  1. ICH Quality IWG Points to Consider Guide for ICH Q8/Q9/Q10 Guidelines
  2. Nasr, Implementation of Quality by Design (QbD) Current Perspectives on Opportunities and Challenges Topic Introduction and ICH Update Office of New Drug Quality Assessment