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QbD-Based RTR: A Systems Engineering Approach

    QbD-Based RTR: A Systems Engineering Approach

    by Jose Menezes, 4TUNE Engineering

    Today, many assume that real-time release (RTR) is about testing a product quality real-time at the end of its manufacturing process and then from the result obtained deciding about lot release (viz., RTR testing).  RTR of products – pharmaceutical dosage forms or any other products whose quality is defined by multiple specifications – is not about the “end-of-pipe” use of fast quality control methods such as spectroscopic techniques (e.g., NIR) as these are neither sensitive, specific or accurate enough to measure all necessary release specifications that a formulated product must meet.

    There are at least three growth areas for spectroscopy-based PAT monitoring tools use in QbD-based RTR testing. First, using whole-samples spectra to assess a process state. Second, fusing spectral information with process data or information (e.g., process variables or other PAT tools). Third, using fused and non-fused spectral information across multiple unit-operations for feed-forward control, recipe management and multivariate supervisory control activities.

    Multi-parametric PAT monitoring enables several parameters to be measured on the same sample simultaneously, with the extra benefit of highlighting the correlation of different parameters on a whole sample.  That increases the capabilities for process fault detection and diagnosis, real time. Also, those techniques will be more able of capturing scale effects as these show up clearly when whole samples are considered, thus potentially leading to faster process prototyping and scale-up cycles than before.

    Clearly, QbD is about having a robust process capable of controlling by design all possible sources of variability that impact product quality (e.g., controlling feed-forward the effect of raw-materials lot-to-lot variability). For QbD and RTR to materialize, specially in regulated industries such as pharma and biopharma, PAT tools need to be used as in-process tools, preferably on whole samples, exploiting their intrinsic fingerprinting capabilities, so that any disturbances on process conditions or on the feed-stocks used as raw-materials, can be detected and tightly controlled.

    Whole process samples more faithfully capture the real process state (e.g., a matrix with products and reagents contains information on stoichiometries) than say filtered aliquots after undergoing elution on a chromatography column3. The use of PAT tools on at-line samples analyzed close to the process or by in-situ probes through equipment windows is one of the most effective ways to monitor multiple process parameters simultaneously, with the extra benefit of highlighting the correlation of different parameters. The technological and business impact of such capabilities is very significant as many industry accounts detail (visit www.4tuneengineering.com/references.html for examples).

    The better the process is, in terms of process knowledge and available controls, the better the product quality will be: by use of reliable process control strategies critical to quality process variables (known in QbD as critical process parameters) can be manipulated to ensure that all product quality attributes (viz., all those critical to patient or customer needs) are consistently met throughout the life-cycle of both process and product.

    A whole process analysis connecting raw materials to processing to end-product properties must be adopted comprehensively, in parallel to a time-wise integration of data, information and knowledge acquired throughout process development, industrialization and commercialization.  QbD implementation and RTR can only happen if these two perspectives are present and combined under proper data-, information- and knowledge- management systems. The future looks promising for systems engineering applications in the fields of pharma and biopharma design, development and manufacturing.

    4TUNE Engineering is a knowledge-based engineering company with 10 years experience in the pharmaceutical area. We are experts in technologies that support the life-cycle of PAT/QbD solutions across the industry. To learn more visit www.4TuneEngineering.com or contact us at info@4TuneEngineering.com

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