Building a Framework for Quality by Design - Pharmaceutical Technology

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Building a Framework for Quality by Design
The author describes the framework needed to implement QbD and achieve the deeper process understanding that is fundamental to QbD.


Pharmaceutical Technology
Volume 33, Issue 10

Increased process understanding

Process understanding is fundamental to the whole QbD approach. Regulatory flexibility comes from showing that a given process is well understood. According to FDA, a process is generally considered to be well understood when the following conditions are met:

  • All critical sources of variability are identified and explained
  • Variability is managed by the process (8).

Product-quality attributes can be accurately and reliably predicted within the design space established for the materials used, process parameters, manufacturing, environmental and other conditions.


Figure 2: The interrelationship between variation, process understanding, and risk reduction. (FIGURE IS COURTESEY OF THE AUTHOR)
Process understanding is needed not only for product and process development, but also for successful technology transfer from development to manufacturing and from site-to-site, which includes transfer to contract manufacturing organizations (9–11). It is very difficult, if not impossible, to successfully and effectively create, operate, improve, or transfer a process that is not understood.


Table II: Tools for developing process understanding. (TABLE IS COURTESEY OF THE AUTHOR)
Process variation, process understanding, process risk, and compliance are related (see Figure 2). Understanding and reducing process variation increases process understanding, which in turn leads to reduced risk and improved compliance. QbD and its associated statistical tools help increase the understanding of process variation. The tools for developing process understanding (see Table II) include those of process analytical technology (PAT) as outlined below:
  • Multivariate tools for experiment design, data acquisition, and analysis
  • Process analyzers
  • Process-control tools
  • Continuous improvement
  • Knowledge management


Figure 3: Tools for developing process understanding. (FIGURE IS COURTESEY OF THE AUTHOR)
The Lean Six-Sigma tools are also useful in developing process understanding (see Figure 3) (12). A combination of some, or all, of the PAT and Lean Six-Sigma tools may be applicable to a single unit operation or to an entire manufacturing process and its quality assurance.

Studies critical to developing and assessing process understanding include assessment and improvement of the following:

  • Process stability, capability, and robustness
  • Measurement of process control, quality, and robustness
  • Process models developed using statistical DOEs and other techniques to predict process performance and create the design and control spaces
  • Understanding of how the process can fail using failure-modes-and-effects analysis (FMEA).


Case study: quality by design in late-stage development
After conducting these studies, the risks in the process and thus to the patient are better quantified and understood, thereby enhancing compliance. The identification, characterization, analysis, and interpretation of variation in the performance of the product, process, and analytical methods are central to these studies.


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