Quality by Design for Generic Drugs - Pharmaceutical Technology

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Quality by Design for Generic Drugs
The authors relay the outcome of a two-day workshop that brought together regulators and generic-drug industry representatives.


Pharmaceutical Technology
Volume 33, Issue 10, pp. 122-127

Risk assessment and design space

ICH Q9 Quality Risk Mangement indicates that,

The manufacturing and use of a drug product necessarily entail some degree of risk... The evaluation of the risk to quality should be based on scientific knowledge and ultimately link to the therapeutic benefit to the patient. The level of effort, formality and documentation of the quality risk management process should be commensurate with the level of risk (5).

Performing a risk assessment before pharmaceutical development helps manufacturers decide which studies to conduct. Risk assessments are often driven by knowledge gaps or uncertainty. Study results determine which variables are critical and which are not, which then guide the establishment of control strategy for in-process, raw-material, and final testing. There were questions during the workshop about how risk-assessment processes should be described and included in regulatory submissions.

ICH Q8(R1) defines design space as,

The multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality. Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post-approval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval (1).

Because design space is potentially scale- and equipment-dependent, the design space determined at the laboratory scale may not be relevant to the process at the commercial scale. Therefore, design-space verification at the commercial scale becomes essential unless it is demonstrated that the design space is scale-independent. Currently, generic-drug sponsors obtain information about acceptable ranges for individual CPPs and CMAs at laboratory or pilot scales. Sponsors may occasionally conduct these studies with appropriate design of experiments, including multivariate interactions, which will create a design space at the laboratory or pilot scale. Such a design space, however, will have limited regulatory flexibility because the regulatory scientists will be unable to determine whether the design space is still valid at the commercial scale unless sponsors can provide additional information that shows the design space is scale-independent or actual verification data at the commercial scale.

Workshop discussions demonstrated that there is confusion among industry and regulatory scientists about the connection between design space and QbD. Many believe design space and QbD are interchangeable terms. This is incorrect. For generic-drug applications, design space is optional. QbD can be implemented without a design space because product and process understanding can be established without a formal design space (6). It should be pointed out that implementation of QbD is strongly encouraged by FDA. For some complex drug substances or drug products, implementation of QbD is considered a required component of the application.


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