Selection of starting materials
Design space. ICH Q8 and Q9 enable alternative approaches to the selection and justification of starting materials (2, 9). ICH Q8 defines
design space as "the multidimensional combination and interaction of input variables (e.g., materials attributes) and process
parameters that have been demonstrated to provide assurance of quality." Working within the design space is not considered
a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory postapproval
change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval. Knowledge
of the design space gained through the application of scientific approaches and quality risk management (ICH Q9) to the development
of a product and its manufacturing process is shared with regulatory agencies to establish risk- and science-based controls
that will be applicable throughout a product's life cycle.
The degree of regulatory flexibility gained through ICH Q8 and ICH Q9 is predicated on the level of relevant scientific knowledge
provided. The impact can be seen when contrasting the traditional versus the design space approaches to selecting starting
materials.
The traditional approach to starting material identification and development has involved only two steps:
- Provide minimal starting material information about the level and fate of impurities
- Define and maintain tight specifications for starting material and drug substances to compensate for limited synthetic knowledge.
In contrast, the design space approach involves the following:
- Select starting materials based on scientific understanding of the drug substance synthesis and available control mechanisms
- Understand the source, formation, and fate of impurities
- Understand how changes to the synthesis of the starting material may influence impurity profiles.
This knowledge should allow for risk-based decisions regarding regulatory flexibility (e.g., a shorter synthetic route with
more analytical controls, or a longer synthetic route with a reduced level of analytical controls that meet the desired quality
standards).
Discussion
Figure 3: Selection of drug substance starting materials is based on a balance between regulatory requirements and manufacturing
efficiency considerations. (IMAGE SOURCE/GETTY IMAGES)
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Although both industry and regulatory authorities have quality and patient safety at the forefront of their minds, the selection
of a starting material is a balance between appropriate regulatory control and sustainable economic manufacture (see Figure
3). Often the origin of the starting material lies in a complex supply chain of both commodity and custom manufacture, to
which it is not practical or economic to apply regulatory change control or CGMPs. Recently, FDA adopted a science- and risk
base approach (13) to ensure control of impurities and quality attributes, resulting in some guidances being withdrawn in
favor of ICH documentation.
A review of global regulatory guidance and the design space concept indicates that justifications for proposed starting materials
could be grouped into three themes: process control, analytical control, and change control. The successful selection of a
starting material is on a case-by-case basis dependent on the balance and weight of justification of these three themes.
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