Sponsored by Serán Bioscience
Accelerating Complex Drug Products with Less Material
In an industry where complex molecules and first-in-human (FIH) formulations often come with very limited API supply, material-sparing strategies are central to efficient CMC development. In the webinar “Material Sparing Approaches to Rapid Development and Scale-Up of Complex Drug Products,” presented by Pharmaceutical Outsourcing magazine and sponsored by Serán Bioscience, Cindy Chung, PhD, Principal Engineer at Serán Bioscience explored how carefully designed bench-scale work can inform scale-up, de-risk manufacturing, and shorten timelines from FIH to launch.
The webinar was framed around a few core questions: how material-sparing strategies accelerate CMC development for complex molecules, how bench technologies can generate representative test articles, and how integrated approaches - combining technology selection, enabled intermediates, and patient-centric design - ensure that early decisions support long-term product advancement. Chung took a deep technical dive into two specific strategies: tablet compression and dry granulation, showing how both can be executed in material-sparing ways while maintaining a clear line of sight to commercial scale.
Serán’s Science-First, Right-From-the-Start Approach
Chung began by situating the discussion in Serán’s broader development philosophy. Serán is located in Bend, Oregon, and describes itself as a science-first, data-driven CDMO with deep experience in bioavailability enhancement, amorphous solid dispersions (ASDs), particle engineering, and solid oral dosage forms. The organization “employs a right from the start approach,” focusing on robust, scalable early-phase formulations with a clear line of sight to commercial products rather than treating early clinical formulations as disposable prototypes.
“We’re pioneers in innovation,” Chung noted, emphasizing Serán’s efforts to improve core technologies and develop new ones to meet future industry needs. She positioned Serán as both a technical and strategic partner, inviting sponsors to engage early so that development choices made for Phase 1 can carry through to commercialization.
At the heart of this strategy is Serán’s “Right From the Start” CMC paradigm. By using material-sparing approaches to enable commercially relevant, advanceable formulations beginning at Phase 1, the team aims to avoid costly reformulations or bridging studies later in development. This approach shortens development timelines and helps products to launch more quickly than traditional drug product development timelines typically allow.
Chung focused on the first-in-human product development stage, particularly on how bench-scale prototyping positions a program for success at scale. “We’re really looking at how we can use bench-scale prototyping to position ourselves in early development for success when scaling up,” she explained.
From Target Product Profile to Technology Selection
Serán’s material-sparing strategies start with integrating bench-scale techniques into a comprehensive development plan guided by a target product profile (TPP) or a well-defined problem statement. From this starting point, the team performs an initial developability assessment of the molecule, which in turn informs technology selection and bench-scale rapid prototyping.
A key tool in this step is the Developability Classification System (DCS), which Serán uses as a guide to technology selection and formulation development. The DCS is based on molecular properties and biorelevant solubilities throughout the GI tract. It mirrors aspects of the Biopharmaceutics Classification System (BCS), using permeability on the Y axis and solubility on the X axis, but goes further by subdividing class 2 (solubility-limited) molecules into two groups: one that is purely dissolution-limited and one that is truly solubility-limited.
Chung explained that once a molecule is classified, Serán overlays the DCS output onto a technology selection tool to decide, for example, whether a solubility-enhancing approach is needed and what form is best suited for that enhancement. While these DCS concepts are not new to the industry, Serán tailors them to the specific TPP or problem statement, considering factors such as dose and species. This tailoring helps efficiently guide the formulation approach and predict how much additional fraction absorbed an enabled formulation might provide over a non-enabled formulation.
Once technology selection is made - say, choosing an amorphous solid dispersion manufactured by spray drying - the team moves into rapid bench-scale prototyping.
Material-Sparing Bench-Scale Prototyping and Representative Test Articles
Rapid prototyping at Serán is built around bench-scale methods that use scalable process parameters to create truly representative test articles. During this stage, the team evaluates the form, formulation, and architecture of test drug products for manufacturability, performance, and stability.
Chung stressed that the test articles must be genuinely representative. They are designed to:
- Support in vitro–in vivo correlations (IVIVC).
- Provide material for analytical method development.
- Enable accelerated, predictive stability studies that explore both physical and chemical stability under temperature and moisture stress.
Because the intermediate drug product produced at bench scale has representative properties, particularly particle size, it can be used to screen candidate dispersions, evaluate IVIVC, and assess intermediate stability. Critically, it also provides a representative amorphous solid dispersion that feeds directly into downstream drug product prototyping (e.g., tablets).
Serán’s custom-built bench spray dryers play a key role here. Chung emphasized that many organizations can produce spray-dried dispersions at small scale, but what sets Serán apart is its ability to do bench-scale spray drying with representative atomization and drying kinetics. These features allow the company to use thermodynamic models to scale up spray drying while minimizing material requirements.
With representative test articles in hand, Serán also employs predictive modeling to inform packaging risks and packaging conditions, leveraging stability and moisture-uptake data generated at the bench.
Tablet Compression Strategy: Using Tensile Strength as the Scalable Anchor
The first detailed strategy Chung presented focused on tablet development and compression. She showed a bench-scale dry granulation tablet process train and contrasted a common assumption - that capsules are inherently faster and more suitable for early phases - with Serán’s experience. With the right material-sparing bench-scale processes, Serán can streamline tablet development and offer tablets as a viable FIH option, potentially avoiding later reformulation or bridging.
To connect bench-scale work with process-scale rotary tablet presses, Serán uses a compaction simulator and a hardness tester, focusing on key material properties. The scalable parameter at the center of this strategy is tensile strength of the tablet. Tensile strength is a critical material attribute because it impacts both disintegration and friability. It is also independent of tablet hardness and geometry, providing broad flexibility as tablet strengths and geometries change with dose adjustments throughout clinical development.
For screening tablet performance, Serán uses:
- Disintegration time as a surrogate for dissolution.
- Friability as a measure of mechanical robustness.
Chung shared an example from Serán’s enteric ASD polymer platform, where they evaluated a variety of dispersion drug loadings and dispersion loadings within the tablet. By targeting a disintegration time under five minutes and friability under 0.3%, they could identify a range of tensile strengths that reliably met tablet critical quality attributes (CQAs).
This tensile strength window becomes the central scalable attribute that links bench-scale compaction simulator experiments to process-scale rotary tablet presses.
CTC Profiles: Compatibility, Tabletability, and Compressibility
To translate tensile strength targets into process parameters, Serán generates CTC (compatibility, tabletability, compressibility) profiles at the bench scale using the compaction simulator. These profiles connect the key material attribute (tensile strength) to a critical process parameter (compression stress) and to solid fraction.
Chung defined the three components:
- Compatibility: the relationship between tensile strength and solid fraction; this reflects an intrinsic material property and is not impacted by manufacturing technique or scale.
- Tabletability: the relationship between tensile strength and compression stress.
- Compressibility: the relationship between solid fraction and compression stress.
By generating these CTC profiles, Serán can:
- Produce bench-scale test articles that are representative of target tablets at process scale and meet CQAs.
- Explore the full tablet design space to determine where the formulation sits within an acceptable manufacturing window.
- Ask key questions such as:
- Can the target tensile strength range be easily achieved within realistic compression stress ranges?
- Is there sufficient sensitivity between compression stress (CPP) and tensile strength (key material attribute), or is the design space too tight?
Chung emphasized that when done correctly, CTC profiles not only guide bench-scale test article preparation but also provide a quantitative framework for assessing manufacturability risks at commercial-scale compression conditions.
Evaluating Throughput and Dwell Time with the Compaction Simulator
Scaling up tablet compression is not only about hitting the right tensile strength; it also involves increasing throughput. Another critical process parameter is turret speed on rotary tablet presses, which affects dwell time.
Using the compaction simulator, Serán examines how tabletability and compressibility profiles shift as dwell times shorten with higher turret speeds. Longer dwell times correspond to slower turret speeds, while shorter dwell times reflect faster production rates. By comparing CTC profiles at different dwell times, the team can see how much the profiles shift and whether they risk falling outside the acceptable design space at higher throughputs.
Chung explained that this analysis identifies manufacturability risks associated with faster turret speeds. Representative tablets compressed under these simulated conditions are evaluated for visual appearance and mechanical defects such as microcracks or surface stress patterns, which may emerge as throughput increases.
The compaction simulator is also used to explore potential sticking issues at the bench scale using only small material quantities. This enables early mitigation of tooling-related defects before large-scale campaigns.
Chung summarized that, within Serán’s ASD tablet platform, the consistency of CTC profiles across various dispersion and tablet loadings demonstrates that tensile strength targets lie in a safe, robust design space. Because the platform encompasses both formulation (composition and architecture) and a well-understood scalable process train, Serán can move rapidly and material-sparingly through development. These techniques and concepts—using tensile strength as a scalable parameter and CTC profiles to define tablet design space—can be applied not only to ASD tablets but to any tablet development program, whether based on crystalline or amorphous drug products.
Dry Granulation Strategy: Scaling from Slugging to Roller Compaction
The second strategy Chung highlighted involved dry granulation, particularly scaling from bench-scale slugging to roller compaction. At bench scale, this process involves making “slugs” on a compaction simulator and then milling those slugs via a bench-scale mill.
Chung noted that, like others in the field, Serán employs a model-driven approach to scale dry granulation, drawing on prior work (she refers to “Susa’s model”) showing that, for known material properties and defined roller geometries, it is possible to scale between roller compactor platforms across different brands and throughput capacities. Serán’s goal was to leverage this model to bridge from bench-scale to roller compactor scale.
Once again, the scalable parameter is tensile strength, but now for ribbons or granules rather than the final tablet. Granule or ribbon tensile strength influences:
- The downstream tablet CTC profile.
- Granule particle size distribution (PSD).
- Blend uniformity and powder flow properties.
Because tensile strength of ribbons or granules is difficult to measure directly, Serán uses solid fraction as a measurable trait, taking advantage of the fact that compactibility is a material property. The team targets a tensile strength indirectly by targeting a solid fraction range for ribbons and granules.
Chung illustrated that as material passes through each unit operation—powder to ribbon or slug to tablet—it loses some compressibility. To preserve enough compressibility for final tablet formation, Serán defines a target solid fraction range for ribbons and granules that leaves sufficient “headroom” for tablet compaction.
On a tabletability plot (tensile strength vs. compression stress), Chung showed that when slugs made on the bench and ribbons produced on a roller compactor have matching solid fractions, the resulting tabletability profiles align within the target design space. This confirms that solid fraction can serve as a bridge variable between bench slugging and roller compaction.
Predicting Roll Force from Bench Data
To convert a target ribbon solid fraction into a roller compactor setting, Serán uses a simplified form of Susa’s model, which relates ribbon solid fraction to roll force at a defined roll gap. The model contains terms for bulk solid fraction and a compressibility factor K, both of which can be extracted from simple uni-axial compression experiments on the compaction simulator.
Chung described the workflow used to validate this predictive approach:
- At bench scale, slugs were produced on the compaction simulator and their solid fraction was measured manually.
- From uni-axial compression on the same material, Serán calculated the compressibility factor Kand the bulk solid fraction.
- These values were input into the simplified Susa model to predict a roll force expected to deliver the target ribbon solid fraction.
- The predicted roll force was then applied on a Gerteis Mini-Polygran roller compactor, ribbons were produced, and ribbon solid fraction was measured using a geometric method.
Plotting the prediction accuracy showed data centered around zero, indicating good agreement between predicted and actual ribbon solid fractions. This confirmed that bench-scale measurements could reliably predict process-scale roll forces.
Bench-Scale Milling Parity and Granule Quality
Compaction is only one half of the dry granulation process; milling is the other. Serán uses a Gerteis hand mill at the bench scale and compares its output to that of process-scale equipment such as the Gerteis Mini-Polygran and Mini-Pactor.
Chung presented particle size distribution plots for granules milled at two different solid fractions and with two different screen sizes. The PSD curves produced by the hand mill overlaid closely with those from the larger roller compactor systems. This demonstrated that the bench-scale hand mill produces granules with comparable PSD to process-scale equipment across multiple conditions.
This parity is critical because scalable granule tensile strength and PSD translate to representative powder flow and CTC profiles for tablets. Granules produced at bench scale can therefore be used as representative test articles for evaluating performance and stability during rapid prototyping.
Quantitative Powder Flow Assessment at Bench Scale
In the Q&A session, audience members asked how Serán predicts defects and confirms that bench-scale granulation truly reflects process-scale behavior. One question focused on which bench-scale measurements best predict microcracks and sticking on larger, faster rotary tablet presses; another asked about which powder flow metrics are used to confirm scalable and representative flow characteristics.
For microcracks, Chung explained that Serán:
- Sets the compaction simulator to emulate faster turret speeds (shorter dwell times) expected at higher throughput.
- Collects CTC profiles across a range of main compression forces to see how tabletability and compressibility shift.
- Examines the resulting tablets visually for microcracks, noting at which tensile strengths they occur and whether cracks appear on the dome or band.
Microcracks are often associated with rapid elastic recovery during the compression cycle. To mitigate this, Serán may adjust:
- Pre-compression settings to influence elastic recovery.
- Formulation composition.
- Granulation conditions.
If dome cracking is observed, this may indicate tablets that are too soft, prompting an increase in tensile strength targets or a change in tablet geometry.
For sticking, Serán uses custom plain and debossed tooling with low-mass replaceable punch tips compatible with the compaction simulator. These allow direct measurement of how much material adheres to the punch under relevant turret speeds and main compression forces. By running different formulations through this setup, the team can quantify the impact of composition and process conditions on sticking risk.
On the powder flow question, Chung noted that PSD can be measured by sieve analysis. On larger scales, a Ro-Tap may be used; at smaller scales, a sonic sifter is preferred because it requires only a few grams of material. To characterize flow itself, depending on material availability, Serán typically employs:
- Bulk and tapped density measurements.
- Flodex testing to determine the minimum orifice size that supports gravity flow.
- A ring shear cell tester to measure the flow function coefficient (FFC), which quantitatively describes powder flow behavior.
Together, PSD parity and these flow measurements confirm that bench-scale granules will behave similarly in subsequent compression and blending steps at scale.
Material-Sparing Bench Work as the Foundation for Rapid, Robust Development
Chung closed by tying both strategy showcases back to the central thesis of the webinar: material-sparing bench-scale approaches, when combined with appropriate models and equipment design, allow development teams to generate representative test articles with minimal material, while gaining deep understanding of the manufacturing design space.
By:
- Starting from a clear TPP and developability assessment.
- Using DCS to guide technology selection.
- Generating representative intermediates via bench-scale spray drying.
- Anchoring tablet development on tensile strength and CTC profiles.
- Applying model-based dry granulation scaling from bench slugging to roller compaction.
- Quantitatively assessing flow and mechanical risks at small scale.
Serán aims to shorten tablet development timelines and avoid costly reformulations and bridging studies later in the lifecycle.
“In today’s environment, where everyone is trying to move as fast as they can with limited material,” Chung concluded, “material-sparing approaches are the key to rapid right-from-the-start development. By designing our bench work to be representative of process scale, we can enable efficient, reproducible, and robust manufacturing while minimizing material use and maintaining quality and speed to clinic.”