Streamline Your Pathway to IND with a Rapid Tox Approach

What is the tox material supply in the context of mammalian biologics?

Alejandro Fernandez-Martell: In drug development, tox material refers to the provision of pre-clinical drug substance materials used in good laboratory practice (GLP) tox studies. This material must be representative of the clinical material intended for FIH studies. The responsibility for the quality and suitability of the selected tox material lies with the drug developer, who must ensure that the tox material is representative of the clinical material and supported by a robust comparability assessment in the IND dossier. 

Quality requirements for tox material are not formally defined. Therefore, determining what those are for a program can be aligned to a drug developer's risk-benefit assessment. Using GMP batch for tox studies eliminates comparability risk, but significantly extends timelines, making it a rare choice. Instead, pre-GMP material is frequently used, which may come from clonal or pool sources. While pool-derived material can accelerate timelines, it may carry higher risk and therefore require a thorough analytical comparability assessment.

Why are pre-clinical tox studies considered a bottleneck in the path to FIH trials for biologics?

Fernandez-Martell: Tox studies play a pivotal role in assessing the safety profile of a drug candidate, and delays in tox material readiness can significantly impact IND timeline and cost. IND applications timelines have been shortened significantly, with drugs progressing from candidate nomination to IND application in as little as 9 to 12 months. For such rapid IND applications, companies must usually complete their tox animal studies within 4 to 5 months, which is a considerable time constraint with no room for delays.

Faster IND applications can be overwhelming for drug developers, especially small biotech companies, given that GLP tox studies are usually scheduled well in advance with a firm study initiation deadline. Any disruption on animal availability and/or research materials would delay the provision of pre-clinical toxicology data for IND applications.

What are the timeline benefits of Lonza’s rapid tox offerings?

Fernandez-Martell: Our rapid tox offerings are designed to supply early and consistent drug substance material for tox studies, giving small biotech companies additional time to evaluate the toxicology study data and stay aligned with IND submission timelines. By enabling earlier execution of toxicology studies drug developers gain extra critical advantages such as more time to identify potential safety issues, make informed go/no-go decisions, and initiate early engagement with regulatory agencies. In addition, early study completion provides a buffer to manage unforeseen delays and strengthens investor confidence by demonstrating progress and de-risking the path to clinical trials.

For example, our rapid tox offering for mAbs accelerates tox material generation by up to 50%. For standard concentration mAbs sufficient material can be produced within approximately 2.5 months post-transfection. For high concentration mAbs the timeline is around 5 months post-transfection. In the case of bsAbs, our rapid tox offering shortens the timeline by 30% and allowing drug sponsors to initiate tox studies as much as 2.5 months earlier.

How does Lonza achieve these faster timelines?

Fernandez-Martell: Our rapid tox offerings accelerate operations by focusing our efforts in four key areas: integrating early non-GMP drug substance material into process development, leveraging our expertise in drug product (DP) services, accelerating analytics turnaround times, and streamlining downstream processing workflows.

The path to reducing timelines requires a balance between speed and risk, beginning with the use of in-silico tools to de-risk development upfront and the integration of early non-GMP DS material in our development activities. Early non-GMP DS material enables faster development of potency assays and assessment of molecule liabilities and rheological properties of formulations. For standard mAbs, We benchmark these early assessments against historical data to accelerate the nomination of stable, clinically viable formulations

Our expression platform process supports rapid scale-up strategy with reduced risks from a chemistry, manufacturing, and controls (CMC) perspective, while our robust platform analytical methods streamline tox material generation by delivering reliable insights into the product’s critical quality attributes, which ensure confidence in early development decisions. Our integrated capabilities and cross-functional expertise allow simultaneous execution of key development activities, including purification development, downstream pilot processing, analytical method development and in-process analytical testing, accelerating delivery without compromising quality.

Our focus on these four pillars enables faster decision-making and smoother transitions to GMP manufacturing, both of which can help facilitate the timely delivery of high-quality tox material. Our robust and scalable platform processes and methods enable rapid development at the highest quality to drive regulatory compliance.

For which types of molecules is rapid tox most appropriate?

Fernandez-Martell: The rapid tox offering is appropriate for mAbs and bsAbs, including both standard concentration (5-50 mg/mL) and high concentration (51 to 150 mg/mL) formulations. This approach is particularly beneficial for biologics where rapid assessment of safety profiles is critical for advancing development timelines.

James Berrie: The offers launched by Lonza recently are primarily associated with mAbs and bispecifics, however some elements of these rapid delivery program could also be applied to other more complex modalities. For example, if a Lonza client already has a formulation nominated and subject to an aligned analytical strategy then a rapid tox timeline could be pursued.

What is the difference between the rapid delivery of tox material for standard and high concentration mAbs?

Fernandez-Martell: The standard and high concentration formulations differ in complexity and development needs. Standard concentration mAbs use both a platform buffer formulation and stable pools for early supply of representative tox material; this is also known as the Pool for Tox approach.

Pool for Tox keeps tox material off the critical path by decoupling tox material production from lead clone selection. As per traditional IND timelines, the final GMP clinical batch uses the lead cell line, and therefore, this approach requires analytical testing at the GMP stage to demonstrate comparability between pools and clonal material. Lonza has demonstrated strong alignment between pool and clonal-derived material.

On the other hand, high concentration mAbs require formulation development to address challenges related to viscosity, product stability, and manufacturability. This runs in parallel with the lead clone selection, and by the time the formulation buffer is nominated, the clonal cell line is also available. Therefore, both tox and FIH clinical materials are produced from the same clonal-derived cells. The approach for high concentration mAbs is more time intensive, but it provides a closer alignment with the final GMP product to ensure safety and minimize development risks.

Why is Pool for Tox used only for standard concentration mAbs?

Fernandez-Martell: “Pool for Tox” is most effective when formulation development is not on the critical path. Standard concentration mAbs benefit from well-established manufacturing platforms and predictable biophysical properties. Our Drug Product Services team leverages deep formulation expertise to rapidly assess buffer suitability through a formulatability study, requiring only a formulation confirmation study thereafter. This approach eliminates the need for formulation development and enables early tox material production from stable pools that closely mirrors the final GMP product

In contrast, high concentration mAbs and bsAbs often face viscosity and stability challenges, requiring a comprehensive formulation development, which results in longer development timelines compared to standard mAbs. It’s also important to note that bsAbs also require a more extensive purification development workflow compared to mAbs. For these molecules, the lead clonal cell line is usually selected before the formulation buffer is nominated. As a result, tox material is generated using the final clonal cell lines, rather than from a pool of clones.

Berrie: Pool for tox approach for high concentration mAbs and bispecifics is not precluded on a technical basis; it’s more of a practical consideration. If a program has already been established prior to landing in the Lonza network, then formulation and some analytical elements may not be on the critical path as might normally be expected and in such cases a pool for tox approach could be extremely beneficial where the tox testing window is short.

What is the rationale for the waving of the formulation study for standard concentration mAbs?

Eddy Berthier: For standard concentration mAbs, the formulation study is not entirely waived; it's replaced by a confirmation study. The main difference is that the formulation nomination is now happening at the end of the formulatability screening to determine whether the molecule is a platform fit. This allows the pilot to proceed without waiting for the confirmation study completion. The confirmation study is meant to mitigate risk to the program and provides critical data ahead of the non-GMP DP and GMP batches. Based on our extensive experience, the platform fit is likely to provide enough confidence whether a platform formulation would be suitable.

How much additional risk is taken in the formulation studies to enable the acceleration of the timeline?

Berthier: For standard concentration mAbs, the risk mostly lies with the ability to select the correct platform formulation. We mitigate this risk with the formulatability screening and by scheduling the formulation confirmation study before the non-GMP drug product and GMP drug substance are manufactured. For high concentration mAbs and bsAbs, the use of design of experiment (DoE) and screening tools allows us to progress the program faster without increasing risk to the formulation study.

What advantages does Pool for Tox offer compared to traditional clonal cell lines?

Fernandez-Martell: Pool for Tox offers a significant time advantage by speeding up tox material production, often 2.5 months ahead of traditional clonal approaches. It achieves this by bypassing both formulation development and cell line selection process.

The resulting tox material is representative of the final GMP product, especially when supported by robust analytical comparability data. This approach not only helps drug developers initiate toxicology studies faster and maintain regulatory confidence, but also provides greater flexibility in meeting IND submission target, making it a strategic tool for programs where speed is critical and risk is manageable.

Berrie: There is a widely held view across the industry in that a pool for tox approach not only benefits the timeline but also brings some technical benefit in that the pool of cell lines expressing the same product can be considered to afford a ‘worst case’ material supply compared with the subsequent clonal GMP supply to clinic.

How is comparability between Pool for Tox material and a clonal GMP batch demonstrated?

Fernandez-Martell: Comparability is demonstrated through a combination of rigorous analytical and biochemical characterization of critical product quality attributes like purity, protein structure, glycan distribution, charge variants, aggregation levels, process-related impurities and potency. Analytical techniques such as HPLC (high-performance liquid chromatography), CE-SDS (capillary electrophoresis with sodium dodecyl sulphate), icIEF (imaged capillary isoelectric focusing), and bioassays are used to confirm that pool-derived material is representative of the final clonal GMP batch.

Any observed differences are evaluated for their potential impact on safety and efficacy. When supported by strong platform knowledge and prior comparability data, this approach provides regulatory confidence that the tox material is suitable for IND-enabling studies.

Berrie: The challenges are on a practical rather than technical level. When we look at our in-house data, pool material for mAbs is shown to be very similar to the final selected cell line. The consideration here is whether you want to take a lot of material to lay down a reference standard for future GMP batches or just enough for the first GMP batch. This is a strategy we would discuss when determining whether you were interested in a Pool for Tox approach or a rapid tox approach.

Could you speak to the experience of the teams supporting rapid tox?

Fernandez-Martell: Our rapid tox programs are driven by highly experienced, cross-functional teams with deep expertise in cell line development, upstream and downstream processing, analytical sciences, and drug product formulation. The Drug Product Services team brings extensive knowledge in formulation development, enabling rapid buffer evaluation and selection.

We have extensive experience leveraging stable pools for both process development and tox material supply, enabling us to consistently meet accelerated timelines. Our robust process and analytical platforms are designed to scale efficiently while maintaining the highest quality standards. Collectively, our teams have successfully supported clients in implementing accelerated tox strategies by delivering large-scale and high-quality material that meets stringent regulatory standards, helping them advance toward key development milestones with confidence. This collective experience enables us to deliver high-quality tox material on accelerated timelines.

Can you please elaborate on what DSP technological improvements have been made to accelerate development?

Fernandez-Martell: Certainly, we’ve made several targeted improvements in DSP that have significantly accelerated our development timelines. For standard mAbs, we introduced parallel DSP workflows, which allow us purification development to run concurrently with DSP pilot operations. For bsAbs and high concentration mAbs, we enhanced our purification throughput and speed for material supply, allowing the delivery of large material quantities for process development in just two weeks

We also strengthened communication between pilot labs, the formulation team and purification development teams, while tightening integration between analytics and process development to reduce turnaround times for critical assays. These enhancements have enabled faster and more coordinated execution.

Berrie: For our bsAb rapid tox offerings, the technological improvements we implemented sped up analytical turnaround time. With correct chain pairing and correct homodimers, mass spec assay turnaround time is improved, enabling us to generate the material, purify it, and provide the formulation team with that material. In terms of developing the purification process for the large scale tox supply, we've made significant enhancements to our bsAb platform evaluation to conduct high throughput screening of a library of chromatography resins. This is often done in a plate format, which saves on a huge amount of material and time.

What is the maximum number of candidate molecules that you can assess in parallel before the selection of a lead molecule to progress to IND?

Berrie: These numbers are nominally identified to align with the timelines associated with these rapid tox offers but ultimately with the flexible approach offered at Lonza, there is no real limit to the number of candidates and the number can be subject to discussion and agreement prior to program initiation.

Berthier: Our formulatability screening is designed as a platform and developability assessment, which means that you may want to have this study as a standalone when you are transitioning from research to early development. We designed it to support multiple candidate molecules in parallel at standard concentration and two candidate molecules for the high concentration approach. The subsequent formulation study will happen only with the candidate you select.

Do you consider viral clearance study timelines prior to IND submission?

Berrie: That’s an important point because this is an activity usually associated with the later phases of a timeline. To deliver rapid tox material to expand the tox testing window for our clients, we have modified only the material flows and activities associated with the early part of the program. You would still take samples from the GMP batch using the clonal cell line for the viral clearance study for the regulatory submission and, for the tox material, no viral clearance study is required.

Do these timelines assume only Lonza proprietary cell lines?

Fernandez-Martell: Yes, that is correct. Our rapid tox offerings are based on a full platform fit, which includes the use of Lonza’s proprietary GS Xceed® cell lines. Our platform is optimized for speed, scalability, and regulatory compliance, enabling efficient stable pool generation and early tox material production.

How much lead lot stability data can clients assume to have at the time of GMP drug product batch completion to assign a reasonable shelf life for clinical use?

Berthier: All these timelines would offer three-month stability data from the non-GMP drug product batch at the time of IND filing and one month will be available for the GMP drug product. Typically, the GMP drug product study would run for 24 to 36 months.