In Vitro–In Vivo Correlation (IVIVC) and Its Integration Within a QbD Framework

When IVIVC is embedded within a QbD paradigm, it creates a direct scientific bridge between what we develop in the laboratory and how the drug behaves in the human body. The QTPP defines the desired clinical performance—specifically the target Cmax, AUC, and Tmax of the formulation. IVIVC plays a crucial role here by showing how in-vitro dissolution can predict these in-vivo pharmacokinetic outcomes.

From the QTPP, we derive the CQAs, of which dissolution behaviour and release kinetics become clinically significant. IVIVC strengthens the identification of these CQAs by quantifying how sensitive the product’s in-vivo exposure is to any shift in dissolution. For example, if a small change in dissolution statistically alters AUC or Cmax, that dissolution parameter becomes a high-risk CQA from a clinical standpoint.

On the material side, CMAs such as polymer viscosity, grade, level, API particle size distribution, and solubility class directly influence in-vitro release. IVIVC helps confirm which CMAs truly affect systemic exposure. If polymer viscosity slows in-vivo absorption predictably, this CMA becomes clinically relevant and must be tightly controlled. Conversely, if particle size changes do not affect predicted plasma profiles, IVIVC allows regulatory justification for more flexible specifications.

Similarly, CPPs—including granulation end point, coating thickness, compression force, or drying time—are linked to dissolution changes. IVIVC converts this link into clinically meaningful impact by quantifying how these CPP-driven dissolution shifts translate into PK changes. This knowledge enables a more rational control strategy: parameters that affect therapeutic performance are controlled more tightly, while those that show no IVIVC linkage can be given wider operating ranges.

The design space itself is built by combining the relationships between CMAs/CPPs, dissolution behaviour, and IVIVC predictions of PK exposure. Within this design space, any formulation or process change is expected to maintain target clinical performance without requiring fresh BE studies. Because IVIVC predicts the in-vivo outcome of in-vitro changes, it becomes a powerful scientific and regulatory tool to justify broader dissolution limits, flexible manufacturing ranges, and post-approval modifications across sites, scales, or suppliers.

In summary, IVIVC operationalizes QbD by creating a continuous chain: CMAs and CPPs influence in-vitro performance; in-vitro dissolution is quantitatively mapped to in-vivo behaviour; and this mapping defines criticality, design space, and regulatory flexibility. Thus, IVIVC becomes a high-value element of QbD, enabling clinically relevant specifications, biopredictive dissolution methods, efficient risk management, and lifecycle control strategies aligned with ICH Q8, Q9, and Q10 principles.

Read also: QbD and DoE in Pharmaceutical Development

Resource Person: Moinuddin Syed. Ph.D, PMP®