Building a business case
Figure 5: Steps in the quality-by-design process.
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CDMOs will typically have worked with a larger variety of complex processes and challenging molecules than their counterparts
in individual sponsor organizations. The knowledge base gathered during many years and the experience gained in resolving
complex problems can immensely help the sponsor through the steps in the QbD process (see Figure 5).
A CDMO can design a phase-appropriate QbD strategy to build quality into the product being developed. An experimental plan
should conserve API and consider time and cost. A CDMO can help in performing an in-depth scientific risk assessment that
will help in justifying the investment in a QbD exercise.
Because the financial investment in QbD to a small or medium sized organization can be huge, it is important for the CDMO
and sponsor to jointly build a business. It is not always possible to put a financial value on everything we do. There also
are business risks to this investment, such as the possibility of the project costing more, taking longer, or even failing
due to a variety of developmental reasons.
A QbD case study at Patheon
Figure 6: Quality-by-design process flow for a drug product (DP).
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A case study illustrates the QbD process wherein Sponsor X developed a drug product and process in partnership with Patheon,
by using QbD principles to ensure desired safety, efficacy, and quality of the product. Figure 6 depicts the overall QbD strategy that was used.
A combination of prior knowledge and experimental assessment during development were used to identify performance requirements
(i.e., Stage 1), develop process understanding, and conduct the criticality analysis. In Stage 2, critical quality attributes
(CQAs) of the drug product were defined. An initial risk assessment was performed in Stage 3 to determine which process steps
and materials could control product CQAs. Stage 4 included a detailed criticality analysis which evaluated the functional
relationship between critical and key process parameters and CQAs to establish the design space. The design space included
the control ranges of the key processing parameters and in-process parameters (IPCs) used to meet the CQAs for a safe, efficacious,
and chemically stable drug product. The design space defined by normal operating ranges (NORs) and proven acceptable ranges
(PARs) in conjunction with material and product CQAs formed the basis of manufacture of the drug product. Process failure
mode and effect analysis (FMEA) was conducted (Stage 5) prior to validation (Stage 6), followed by continuous verification
and improvement during commercial operation (Stage 7).
Figure 7: Criticality analysis process flow. CQA is critical quality attribute.
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A detailed criticality analysis was conducted on each material attribute. Each aspect of the material was designated as critical,
key, or noncritical based on its potential to impact a CQA as illustrated in Figure 7.
Using the above systematic approach based on sound science and quality risk management, Sponsor X filed a QbD-based new drug
application that was subsequently approved, and the product has been successfully launched in the marketplace.
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