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The Art of Scaling a Custom Assay

From Bench to Clinical Scale: Broad Clinical Labs’ Approach to Scaling a Custom Assay

Translating a high-performing custom benchtop assay into a reliable, clinical-grade operation at scale is technically challenging. Assays developed in controlled research settings are optimized for sensitivity and scientific utility, but are rarely designed for the reproducibility, automation compatibility, and regulatory documentation required in clinical-grade production. Closing that gap requires foresight and deliberate re-engineering of the assay—and the earlier that process begins, the more efficient the journey will be.

The Core Problem Is Reproducibility at Scale

An assay that performs reliably with one operator, manually prepared reagents, and a controlled sample set will often degrade when exposed to liquid handling automation, batch processing, cross-platform concordance, and the variability of real-world clinical samples. This reflects the substantial differences between small-scale performance and high-throughput production environments.

The challenge is compounded in the clinical context. Clinical-grade operation requires documentation and validation of every process deviation. Design decisions that seemed inconsequential at the benchtop level can become compliance liabilities at scale. Analytical validation parameters, such as accuracy, precision, limit of detection, and limit of quantification, must be established and verified. For programs moving toward clinical trials, the documentation trail must be structured to withstand regulatory review.

The most consequential misstep is treating scale-up as a transfer. It is a re-engineering effort, and the scope of that effort is best understood and planned for early.

Designing for Scale Before Scale Is Needed

In the traditional custom assay development partnership model, assay design falls to the research team while platform and workflow engineering are performed by a service provider. It is frequently at the point of handoff—from the research team to the service provider for scale-up—where technical problems like reagent incompatibilities, protocol weaknesses, and reproducibility failures surface. Resolving these issues during scale-up is substantially more costly than addressing them earlier in development.

Broad Clinical Labs (BCL) addresses this by collaborating with partners during the assay design phase, building workflows that account for scalability from the beginning. This includes deliberate choices about how an assay will integrate with a partner’s sequencing platform, informatics pipeline, and LIMS environment. It also requires an accurate read of where a partner is in their development trajectory.

In early discovery, a fit-for-purpose assay is one that generates reliable output at a reasonable cost and turnaround. As a program approaches clinical trials, that definition expands to include analytical validation, CLIA and CAP compliance, and documentation that would hold up under regulatory review. An assay architecture that anticipates this progression during the design phase avoids the need to substantially rebuild it when regulatory requirements come into focus.

BCL has experience across major platform chemistries, including Illumina®, PacBio®, Roche®, and NEB®, across a range of assay types. That operational depth informs design decisions early and reduces the likelihood of encountering platform-specific constraints when they are most costly to address.

Automation Infrastructure Built Around Each Assay

BCL’s high-throughput infrastructure is designed around the specific requirements of each assay rather than shaping a custom assay to “fit” a standardized platform. Three variables define the automation design: speed, scale, and batch size. These variables often compete, making it essential to define priorities before design begins.

For example, a workflow requiring same-day turnaround on small sample volumes has different automation requirements than one processing thousands of samples in weekly batches. Resolving that distinction during the design phase, rather than after infrastructure has been committed, avoids expensive reconfiguration.

BCL structures each assay workflow into discrete, independently validated units. This modularity allows individual steps to be upgraded or scaled without destabilizing the broader pipeline, which is a meaningful operational advantage as research and development programs grow and change.

BCL applied this approach in collaboration with Delve Bio, scaling their metagenomic next-generation sequencing (NGS) platform for infectious disease diagnostics nationwide. Metagenomic NGS presents a signal-to-noise challenge distinct from targeted sequencing: pathogen reads must be resolved from a high background of host DNA and RNA. Scaling required parallel optimization of wet-lab inputs (sample types, extraction protocols) and the bioinformatics pipeline. Maintaining diagnostic sensitivity as automation was introduced proved to be the central engineering challenge and it required close coordination between BCL’s wet-lab and informatics teams throughout.

The Benefits of Consolidated Services

When a study integrates genomics, transcriptomics, and proteomics, processing those workflows at a single site offers an often underestimated advantage. Shared sample aliquoting strategies, coordinated quality control checkpoints, and a unified chain of custody make cross-omic data normalization easier. Harmonizing data generated by separate vendors under independently optimized conditions is considerably more difficult than designing for harmonization from the start.

The advantages of a single-partner relationship can extend beyond the lab. For programs operating at national scale, pre-analytical variability in sample collection represents one of the highest-risk steps in the workflow. BCL’s direct-to-patient kitting service delivers validated collection materials and standardized instructions directly to participants across all 50 states. This reduces variability at the point of collection and removes the need for independent site-based collection logistics, which makes population-scale studies and decentralized clinical trials operationally and economically more feasible. Further, this approach helps to increase enrollment and participation rates by reducing the burden on patients, ensuring that diverse populations can contribute to and benefit from genomic advancements.

Long-Term Scientific Value

The interpretation of genomic data today is likely to change as more information is made available. Variant classifications change as population databases expand, functional studies accumulate, and clinical guidelines evolve. A variant classified as one of uncertain significance (VUS) at enrollment may be reclassified as pathogenic years later. BCL retains the analytical infrastructure to support re-interpretation of partner data as research advances. This continuity preserves the longitudinal scientific value of the original study.

A Structured Partnership for Scalable Science

Scaling a custom assay from benchtop to clinical-grade production draws on expertise across assay design, automation engineering, regulatory compliance, bioinformatics, and logistics. BCL’s Contract Assay Services function as a centralized engine for scale. We engage with partners across all domains, from early design decisions through long-term operational support, functioning as an integrated extension of the partner’s scientific team.

For teams at any stage of custom assay development and scale-up, BCL’s Contract Assay Services can accelerate the path from discovery to clinical impact. Contact us to discuss how we can support your project.

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Sean Hofherr

Chief of Clinical Strategy and Product Development, Broad Clinical Labs

Sean Hofherr is dual board certified by ABMGG in Clinical Biochemical Genetics and Clinical Molecular Genetics. Sean serves as the Chief of Clinical Strategy and Product Development at Broad Clinical Labs. In this role at BCL, Sean is able to leverage his extensive experience to guide the clinical vision and delivery across the organization. Sean most recently served as the Chief Operating Office at Fabric Genomics, which focuses on the use of AI and Bioinformatics for Clinical Interpretation of whole genome sequencing. Prior to Fabric, Sean was the Chief Scientific Officer and CLIA Director at the commercial reference laboratory, GeneDx.

Sean received his B.S. degree in Microbiology and Cell Sciences from the University of Florida before earning his Ph.D. in Molecular and Human Genetics from Baylor College of Medicine. Sean completed clinical fellowships in Clinical Biochemical Genetics and Clinical Molecular Genetics at the Mayo Clinic.

Danielle Perrin

Chief of Staff, Broad Clinical Labs

As Broad Clinical Labs’ Chief of Staff, Danielle Perrin advises and supports colleagues on the executive leadership team in BCL’s strategic planning and execution. She builds and leads new organizational functions and processes and leads critical projects, as well as driving effective information flow, decision making, and execution throughout the organization. An operations leader with a business, engineering, and biology background and 20+ years of experience in the genomics field, Perrin has a track record of driving operational excellence and building and scaling both physical and business processes. During her career at Broad, which started in 2003 at the tail end of the Human Genome Project, Perrin has led laboratory operations and R&D teams in Broad’s Genomics Platform, as well as fulfilling senior advisory and leadership roles in the Broad Institute’s COO and CFO offices.

Perrin received her B.S. in Biology and M.E. in Biotechnology Engineering from Tufts University and her M.B.A. from the MIT Sloan School of Management.

Tim De Smet

Chief Commercial Officer, Broad Clinical Labs

As Chief Commercial Officer of Broad Clinical Labs, Tim De Smet leads BCL’s business development, alliance management, external project management, and customer support teams. A Broad Institute employee since 2008, De Smet has held leadership roles and managed teams of various sizes in Broad’s Genomics Platform and clinical lab, spanning laboratory operations, finance, and informatics, and has expertise in work design, financial modeling, and high scale laboratory and business operations.

De Smet received his B.S. in Biochemistry and M.B.A. from Northeastern University.

Jim Meldrim

Chief Technology Officer, Broad Clinical Labs

As Chief Technology Officer, Jim Meldrim sets the vision for Broad Clinical Labs’ informatics systems, including the hardware and software used for sample intake and tracking, data production, analysis, and delivery. Having held a variety of laboratory and informatics-focused leadership roles at Broad, spanning R&D and production operations, Meldrim has been a leader and innovator in the generation, management, and analysis of genomic data since 1999, beginning with sequencing data generation for the Human Genome Project.

Meldrim received his B.S. in Biology from Cornell University.

Sheila Dodge

Chief Operating Officer, Broad Clinical Labs

As Chief Operating Officer, Sheila Dodge leads Broad Clinical Labs’ process development and implementation activities, as well as lab operations, financial planning and operations, quality & compliance, and core business processes. A Six Sigma Black Belt with extensive experience in process development and high throughput genomics operations, Dodge is an expert in work design and in collaborating with a range of collaborators, scientists, engineers, and technology partners to rapidly integrate new technologies and operationalize innovations. A member of the Broad Institute since 2001, Dodge is an Institute Scientist and lectures at the MIT Sloan School of Management on operations, dynamic work design, and visual management techniques.

Dodge received her B.A. in biochemistry and molecular biology from Boston University and her master’s degree in biology from Harvard University. She earned her M.B.A. from MIT Sloan School of Management.

Heidi Rehm, Ph.D., FACMG

Chief Medical Officer and Clinical Laboratory Director, Broad Clinical Labs

Heidi Rehm is board-certified by ABMGG in Clinical Molecular Genetics and Genomics and serves as BCL’s Chief Medical Officer and Clinical Laboratory Director. She oversees BCL’s regulatory requirements, leads the clinical team performing genomic interpretation and variant analysis, and guides BCL’s efforts in genomic testing for clinical and research use. She is also an Institute Member of the Broad and co-director of the Medical and Population Genetics Program. Rehm is also the Chief Genomics Officer in the Department of Medicine and Genomic Medicine Unit Director at the Center for Genomic Medicine at Massachusetts General Hospital, working to integrate genomics into medical practice. She is a principal investigator of ClinGen, providing free and publicly accessible resources to support the interpretation of genes and variants. She co-leads both the Broad Center for Mendelian Genomics, focused on discovering novel rare disease genes, and the Matchmaker Exchange, which aids in gene discovery. She is Chair of the Global Alliance for Genomics and Health, a principal investigator of the Broad-LMM-Color All of Us Genome Center, co-leader of the Genome Aggregation Database (gnomAD), and a Board Member and Vice President of Laboratory Genetics for the American College of Medical Genetics and Genomics.

Rehm received her B.A. degree in molecular biology and biochemistry from Middlebury College before earning her M.S. in biomedical science from Harvard Medical School and Ph.D. in genetics from Harvard University. She completed her post-doctoral training with David Corey in neurobiology and a fellowship in clinical molecular genetics at Harvard Medical School.

Niall Lennon, Ph.D.

Chair and Chief Scientific Officer, Broad Clinical Labs

As Chair and Chief Scientific Officer of Broad Clinical Labs, Niall Lennon leads the team and sets the scientific and clinical vision for the organization. Dr. Lennon joined the Broad Institute in 2006 and has since contributed to the development of applications for every major massively parallel sequencing platform across a range of fields. In 2013 Dr. Lennon led the effort to establish a CLIA licensed, CAP-accredited clinical laboratory at the Broad Institute to facilitate return of results to patients and to support clinical trials. More recently, he has led efforts to achieve FDA approval for large-scale genomics projects (NIH’s All of Us Research Program) and for Broad’s own clinical diagnostic for COVID-19 testing operation, which returned 37+ million results to patients. Dr. Lennon is a principal investigator of the eMerge and All of Us projects, an Institute Scientist at Broad, Associate Director of Broad’s Gerstner Center for Cancer Diagnostics, and an adjunct professor of biomedical engineering at Tufts University, where he teaches Molecular Biotechnology.

Dr. Lennon received a Ph.D. in pharmacology from University College Dublin and completed his postdoctoral studies at Harvard Medical School and Massachusetts General Hospital. He holds an executive certificate in management from the MIT Sloan School of Management.