In this article Paul Davies and Paul Kippax from Malvern Instruments examine how a QbD approach can inform analytical instrumentation design and manufacture, focusing on the benefits for those who go on to use the equipment. Examples from the development of the Mastersizer 3000 particle size analyzer demonstrate the practicalities.
The last decade has seen a shift within the pharmaceutical industry towards a design space approach to development and manufacture, an agenda underpinned by ICHQ8, Q9 and Q10 and the concept of Quality by Design (QbD). However, because a design space approach naturally focuses attention on the areas of a project that are potentially the most vulnerable to failure it has broader value for risk management. Within the pharmaceutical industry, those most confident and comfortable with QbD are beginning to extend its application beyond the product development path to, for example, the deployment of analytical equipment and associated method development, validation and transfer. The roots of the integrity of analytical data lie in the approach taken to the design and manufacture of the analytical instrument. Analytical instrument companies that align themselves with a QbD philosophy can therefore offer pharmaceutical customers the reassurance of closely similar working practices and products that meet the exacting standards of the industry.
Defining the QbD approach
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- International Conference of Harmonization document Q8(R2) (ICHQ8). The central idea of QbD is that quality should be built into a product from the outset. It is an approach based on the development of a thorough understanding of the variables that impact performance, quantification of the risks associated with those impacts, and knowledge-based risk mitigation. Figure 1 shows an accepted QbD workflow for the development of a pharmaceutical product. The first step is to define how the product must behave to deliver the required clinical efficacy. This definition is called the Quality Target Product Profile (QTPP). Subsequent steps involve identifying the variables that must be controlled to deliver that defined product performance, and the best way of implementing the necessary control. This approach of first defining exactly what performance is required, and then systematically developing the knowledge and control strategies to deliver this, is highly pertinent to the process of developing new analytical instrumentation. A rigorous approach to development, with an emphasis on product and process understanding, sound science and quality risk management, can be usefully applied in instrument design. Figure 2 shows a simplified version of the product design process that Malvern Instruments uses for instrument development, across all of its products and how it maps onto the established QbD workflow. The target or QTPP for the QbD workflow is derived from a Market Requirement Specification (MRS) which summarizes the features that are currently desired by the customer population. Within pharmaceutical development this may be an improved pharmacological feature, such as a tightly controlled delayed drug release profile, and will be most often based on clinical requirements. For the analogous instrument design workflow the MRS may pertain to a wider measurement range or a smaller instrument footprint; features that can be identified from customer feedback and/or in-house brainstorming by a development team with extensive application expertise. The resulting list of development targets satisfies the QTPP definition of “a summary of customer requirements that must be delivered to market the product”. The next steps of the Malvern design process involve reviewing the feasibility of building a product to meet the critical requirements identified from the MRS: the user requirement specification (URS). This involves generating ideas as to how to meet the URS and identifying the critical features of the instrument that will confer the desired level of performance. These are the ‘Critical to Quality Attributes’ (CQAs) of the system. Once selected, these are considered as part of the feasibility specification for product, where the design required to meet the URS is selected. As part of this, methods such as Failure Mode Effects Analysis (FMEA); Design for Six Sigma (DSS); Design for Manufacture (DFM) and Design for Assembly (DFA) are applied. These reflect the need to look at the design of the instrument from the perspective of consistent production, as well as delivered performance. An important milestone within the feasibility assessment is construction of the first ‘x-model’, to prove the design concept. The x-model is designed to work like the finished product. It enables realistic exploration of the technology and its performance, but may look quite different from the final design. An iterative process follows, during which several x-model versions may be built as the design space is established. This consists of a range of acceptability for each CQA. Once all of the CQAs are fully understood, the final x-model has been built and assessed, and the design space for the instrument is approved, several alpha models are manufactured. This is the point at which the development process begins to focus on how the instrument will be manufactured, in significant quantity, to meet the defined QTTP. In other words, what control strategies will be necessary to ensure a robust supply of instruments of the required quality? A supply chain is established to provide components for the alpha models which are built to deliver the QTPP and to both work and look very much like the product as it is intended to be marketed. The performance of the alpha models is tested with standard reference samples with well-defined characteristics as well as customer samples which are relevant to the target market. Checks are also made to ensure that all relevant regulatory requirements are fully met. The second stage of developing a control strategy involves building a larger population of beta units, typically many tens of units. This provides more instruments for testing, enables a wider assessment of the manufacturing process and refinement of the supply chain. At this stage any standard operating procedures (SOPs) associated with manufacture of the instrument are finalized and full IQ/OQ documentation is delivered. Referring back to pharmaceutical product QbD, this part of the development cycle can be seen as analogous to scaling up the process, the move from producing a small quantity within the lab to kilogram quantities on a pilot plant process line. A critical element of this second control stage is that the instruments are now tested with real samples. Malvern distributes a number of beta units to selected customers so that a diverse range of ‘real-world’ samples can be measured using them. This provides assurance that the instrument will be operable as envisaged by potential users and robustly deliver acceptable data for different types of samples. Success at this stage is marked by sign off of a design review, following which the instrument passes into commercial manufacture. The process described above, from publication of the final MRS to full product launch, can take several years depending on the complexity of the product and related peripherals. However QbD calls for an ongoing process of continuous improvement and so this simply marks the end of one critical stage in a cycle that will wrap around the lifetime of the instrument. To read the full article, click hereMalvern Instruments provides the materials and biophysical characterization technology and expertise that enable scientists and engineers to understand and control the properties of dispersed systems. These systems range from proteins and polymers in solution, particle and nanoparticle suspensions and emulsions, through to sprays and aerosols, industrial bulk powders and high concentration slurries. Used at all stages of research, development and manufacturing, Malvern’s materials characterization instruments provide critical information that helps accelerate research and product development, enhance and maintain product quality and optimize process efficiency. Our products reflect Malvern’s drive to exploit the latest technological innovations and our commitment to maximizing the potential of established techniques. They are used by both industry and academia, in sectors ranging from pharmaceuticals and biopharmaceuticals to bulk chemicals, cement, plastics and polymers, energy and the environment. Malvern systems are used to measure particle size, particle shape, zeta potential, protein charge, molecular weight, mass, size and conformation, rheological properties and for chemical identification, advancing the understanding of dispersed systems across many different industries and applications. Headquartered in Malvern, UK, Malvern Instruments has subsidiary organizations in all major European markets, North America, Mexico, China, Japan and Korea, a joint venture in India, a global distributor network and applications laboratories around the world. www.malvern.com severine.michel@malvern.com
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