Manufacturing: Integrated Dissolution-Absorption Testing

In the fast-paced, competitive world of generics manufacturing, processes such as integrated dissolution-absorption testing can mean the difference between first to market and obscurity

Dan Klevisha at Pion

Generic medicines play a critical role in expanding patient access to treatments that are safe, effective and affordable. These drugs contain the same active pharmaceutical ingredient (API) as the reference product and must demonstrate comparable clinical performance when used according to the approved labelling.

While the API in a generic small molecule drug must match that of the reference product, the overall formulation does not need to be identical. Manufacturers have flexibility in selecting excipients to improve manufacturability, stability and supply chain considerations. However, changes to formulation can influence how the API dissolves and is absorbed in the body. As a result, developers must carefully assess whether formulation differences impact bioequivalence.

Bioequivalence is defined under 21 CFR 314.3(b) as the ‘absence of a meaningful difference in the rate and extent to which the active ingredient or moiety becomes available at the site of action when administered at the same molar dose under comparable conditions in a properly designed study’.1

Regulatory authorities, including the US Food and Drug Administration and the European Medicines Agency, require demonstration of bioequivalence as a condition of approval. These studies are intended to confirm that the generic product performs consistently with the reference drug, supporting both regulatory approval and patient confidence in lower-cost alternatives.

To establish bioequivalence, developers typically employ in vitro dissolution testing, particularly for poorly water-soluble APIs, before advancing to clinical evaluation. These early studies are used to screen formulations, attempt to predict in vivo bioavailability and identify the most promising candidates. While human bioequivalence studies remain the definitive assessment, they are costly and time-consuming, highlighting the need for more predictive in vitro approaches earlier in development.

For decades, dissolution testing has served as a foundational tool in pharma development, guiding formulation decisions and acting as a proxy for in vivo performance. At its core, dissolution testing measures how quickly and to what extent a drug dissolves in a given medium. While an assessment of dissolution behaviour is essential, it represents only part of the equation. Absorption – the process by which dissolved drug crosses biological membranes and enters systemic circulation – is equally critical. Without insight into this step, dissolution data alone can be misleading.

Reliance on dissolution data alone can create a false sense of confidence and may obscure meaningful differences in absorption, ultimately undermining efforts to demonstrate bioequivalence of the generic to the reference product. This limitation of dissolution data becomes particularly evident when formulation changes are introduced. Differences in polymers, surfactants or manufacturing processes can lead to divergent absorption profiles, even when dissolution results appear comparable. In such cases, enhanced dissolution does not translate into equivalent bioavailability, increasing the risk of failure in vivo. The challenge is especially pronounced in generic development, where excipient variability is permitted. Without tools that capture both dissolution and absorption dynamics, developers may unknowingly advance formulations with a high risk of failing bioequivalence studies.

The limitations of dissolution testing for determining bioequivalence are more pronounced for poorly soluble drugs, such as amorphous solid dispersions (ASDs), lipid-based formulations and nanosuspensions. ASDs can be leveraged in generic versions of innovator drugs to enhance dissolution of poorly soluble molecules, which represent a high percentage of small molecules on the market.1 By dispersing the drug in an amorphous polymer matrix, ASDs enable the generation of supersaturated solutions in the gastrointestinal tract, dramatically increasing apparent solubility.2

While ASDs can produce order-of-magnitude increases in solubility, these large shifts can introduce unintended consequences in intestinal absorption. The mechanisms that drive improved dissolution, such as supersaturation, also create highly dynamic, non-linear systems that are difficult to predict. For example, the same solubility enhancing excipients used to generate supersaturated solutions may also negatively impact absorption, giving an overall decrease in bioavailability that cannot be predicted using dissolution testing alone.

Regardless of the strategy applied, when formulation decisions are guided by incomplete data, the downstream impact can be substantial. Failed or borderline bioequivalence studies – which typically occur late in development, after significant investment in formulation optimisation, manufacturing scale-up and clinical preparation – can trigger a costly and time-consuming sequence of events:

• Reformulation and re-testing

• Delays of six to twelve months or more

• Additional clinical and regulatory costs.

Failed bioequivalence studies can also negatively impact competitive positioning. In the highly competitive generics market, timing is critical. Delays can mean forfeiting first-to-market advantage, including valuable exclusivity periods. The financial implications can reach tens or even hundreds of millions of dollars in lost revenue. Even in branded drug development, delays in late-stage programmes can shift market dynamics, allowing competitors to gain ground.

Given these risks, there is increasing interest in approaches that provide a more complete picture of formulation performance earlier in development. Integrated dissolution-absorption testing represents an essential approach.

Integrated testing solutions are designed to simulate drug absorption by measuring the movement of compounds across a biomimetic lipid-coated artificial membrane that separates a donor compartment, representing the intestinal environment, and an acceptor compartment, which represents the blood. This design allows for continuous, real-time measurement of drug concentration on both sides of the membrane, enabling detailed assessment of drug dissolution, permeation, and the effects of different formulation strategies and excipients. A growing body of evidence and industry experience suggests that integrating dissolution with absorption assessment provides more clinically relevant and strategically valuable insight. Beyond improving confidence in the bioequivalence of two formulations, this shift has important implications for development timelines, portfolio decisions and commercial outcomes. By simultaneously measuring how a drug dissolves and how it permeates a biological membrane, these methods offer a more clinically relevant view of in vivo behaviour. Rather than optimising for solubility alone, developers can evaluate the full pathway from release to absorption enabling:

• Early identification of formulations with poor absorption characteristics

• Head-to-head comparison of innovator and generic formulations

• More informed selection of lead candidates.

Importantly, these insights can be generated within days or weeks, allowing teams to iterate quickly and make data-driven decisions before committing to costly downstream activities.

While the scientific benefits are clear, the strategic business implications of integrated dissolution-absorption testing are equally compelling. By reducing uncertainty early in development, this combination testing supports:

• Faster development cycles, where fewer late-stage surprises translate into fewer delays

• Improved portfolio decisions by which resources can be allocated to formulations with the highest likelihood of success

• Lower development costs by avoiding failed studies, rework and associated expenses

• More predictable outcomes as better data leads to greater confidence in regulatory and clinical performance

• First-to-market advantages.

The value extends beyond individual programmes to the overall efficiency and competitiveness of the entire pharma organisation.

This approach also aligns with broader regulatory trends. Health authorities are increasingly emphasising clinically relevant, mechanistic understanding of drug performance. There is growing interest in in vitro methods that can reliably predict in vivo outcomes, particularly as part of efforts to reduce reliance on animal studies and improve development efficiency.

Despite its advantages, adoption of integrated dissolution-absorption testing remains at an early stage. Many organisations continue to rely primarily on traditional methods, in part due to regulatory familiarity and established workflows. However, leading-edge pharma companies and contract development and manufacturing organisations, particularly those working extensively with complex formulations such as ASDs, are embracing this approach. In some cases, developers have gone so far as to deprioritise traditional dissolution data altogether, focusing instead on absorption-driven metrics that better reflect clinical performance. This shift highlights the understanding that optimising for dissolution alone is no longer sufficient.

As drug molecules continue to evolve, formulation strategies are doing the same. The increasing prevalence of poorly soluble compounds, the growing use of enabling formulations like ASDs and the competitive pressures of the generic markets are driving the need for more predictive approaches for defining bioequivalence.

Dissolution testing will undoubtedly remain a cornerstone of pharma development. But its role is changing; rather than serving as a standalone predictor of clinical success, it is becoming one component of a more comprehensive framework that incorporates absorption as well.

For companies willing to adopt this approach, the benefits extend beyond improved formulations to also include faster timelines, reduced risk and stronger commercial outcomes. In the generics industry where the margin for error is slim, this shift is not just advantageous, but essential for continued success.

References:

1. Visit: ecfr.gov/current/title-21/chapter-I/subchapter-D/part-314/subpart-A/section-314.3

2. Pandi P et al (2020), ‘Amorphous solid dispersions: An update for preparation, characterization, mechanism on bioavailability, stability, regulatory considerations and marketed products’, Int J Pharm, 586, 119560

Dan Klevisha is chief executive officer of Pion, where he leads the company’s strategic direction and growth through innovation. Dan is an accomplished executive with a proven track record of scaling technology-driven businesses, and has contributed to multiple key pharma transformations including process analytical technology, the introduction of handheld raw material testing solutions and wide-scale programmes for spectroscopic-based counterfeit drug screening programmes. Today, Dan is focused on technology to help drug developers accelerate and de-risk drug formulation using simultaneous dissolution-absorption analysis and in vitro predictive bioavailability tools.