Turn CMC Into a Competitive Advantage

Five key considerations for building a successful CMC strategy How to guide The world leader in serving scienceIntroduction A significant number of therapeutics, even those built on a strong biological foundation, slow down or stall in development before they ever reach a patient. The cause of this is rarely what scientists expect but can be explained by the latest regulatory data. Analysis of 202 FDA complete response letters (CRLs) found that approximately 74% cited chemistry, manufacturing, and controls (CMC)-related issues, with manufacturing deficiencies and product quality concerns leading the list.1 Likewise, 40% of investigational new drugs (INDs) are seeing delays linked to CMC gaps, with smaller biotech companies disproportionately affected.2 The term CMC broadly encompasses the regulatory framework governing how a drug is made, tested, and controlled. For biologics in particular, regulatory agencies evaluate CMC as a fundamental component of the product itself. Unlike small molecules, which can be chemically defined with precision, biologics—such as monoclonal antibodies (mAbs)—are inherently shaped by the manufacturing process. Changes in cell line, culture conditions, purification strategy, or formulation can directly alter a molecule’s structure, function, and safety profile. CMC failures can be costly, but they are rarely sudden and are typically the consequence of decisions made earlier in development. This is understandable; when timelines are tight, resources are limited, and speed is the priority, it can be tempting to choose processes that generate material quickly rather than those that are fully understood and controlled. This creates a significant risk, especially for emerging biotech companies, which often lack in-house expertise and only integrate CMC considerations at later development stages. This guide sets out five practical steps that process development scientists and biotech teams can take to build a stronger CMC foundation from the outset. Insufficient stability data Poor process control and batch variability GMP and facility readiness gaps Incomplete product characterization Scale-up and comparability challenges CMC Failure Figure 1. Overview of the most common CMC failure modes seen across the industry. 2Five key considerations Step 1: Make CMC part of your scientific strategy from the start One of the most consequential mistakes in early biotech development is treating CMC as a downstream activity. In practice, the decisions made earliest in a program often have the greatest long-term impact on manufacturability, regulatory success, and speed to market. Each decision, whether it’s selecting a cell line, expression system, upstream process conditions, purification approach, or analytical control plan, carries implications for the scalability, manufacturing, characterization, and control of any product that you are developing. Upstream and downstream process development are closely interconnected, and changes in either can directly affect a biologic’s critical quality attributes (CQAs), consistency, and comparability profile. For instance, a cell line chosen for high expression at early stages may later prove difficult to transition to good manufacturing practices (GMP) and might show high levels of batch-to-batch variability. Likewise, transitioning expression systems—for example, from transient HEK293 cells to a stable CHO mammalian cell line—may alter post-translational modification profiles, resulting in changes to CQAs and creating additional manufacturing and comparability challenges during scale-up. In either case, there will be a need for process redesign and additional compatibility studies, all of which increase cost and slow down development. Similarly, downstream purification strategies that appear effective at laboratory scale may become difficult to scale efficiently or may fail to adequately control impurities, aggregates, host cell proteins (HCPs), or viral clearance requirements during later-stage manufacturing. To avoid these pitfalls, teams should build a CMC roadmap alongside a clinical development plan. This does not require resolving every manufacturing challenge at the outset, but it does mean thinking about scalability, control, and comparability from the earliest stages of program design. Figure 2. Impact of decisions over the development timeline. The cost, risk, and difficulty of change increase as development progresses. Early decisions have the greatest downstream impact, while changes made at later stages become increasingly costly and complex. Tip: For each early process decision, don’t just ask “Does this work now?” but also ask “Will this work at GMP scale, and can I demonstrate that to a regulator?” Keeping this question in mind from the start reduces the risk of costly CMC remediation further downstream. Late changes are costly and risky Changes at later stages increase timelines, costs, and regulatory risk. High leverage window Changes at later stages increase timelines, costs, and regulatory risk. Cost, risk and difficulty of change $$$ $ + Development stage Discovery Preclinical Phase I-III Commercial manufacturing 3Step 2: Invest in process understanding early Regulatory agencies not only require evidence that a biologic works; they also need proof that its CQAs and critical process parameters (CPPs) are clearly understood. In practical terms, this means knowing which upstream and downstream process parameters affect glycosylation, aggregation, potency, impurity clearance, yield, potency, and overall product quality. Quality by Design (QbD) principles provide a structured framework for building this understanding early. Rather than establishing a fixed process and characterizing it retrospectively, a QbD approach uses systematic experimentation to explore the design space from the outset. Small-scale and high-throughput experimentation are valuable tools here, enabling teams to screen a broader range of conditions and variables before committing to a process platform. For downstream bioprocessing, early process understanding is equally important. Purification steps such as chromatography, filtration, and viral clearance must be designed not only to achieve target purity and yield, but also to maintain product quality and process consistently, and demonstrate effective viral safety. Understanding how purification parameters influence CQAs helps establish a more robust control strategy and reduces the likelihood of comparability issues later in development. Figure 3. Quality by Design (QbD) cycle for early process understanding. An iterative approach where experiments generate data, data analysis identifies CQAs and CPPs, and findings are used to refine the process. Repeating this cycle builds a robust, scalable process and supports consistent product quality. Tip: Document process rationale continuously and in detail. Regulatory reviewers will expect to see the scientific logic behind key process decisions, not just the outcomes. A well-maintained development record is also invaluable during technology transfer and any future process changes. Quality by design A continuous learning loop Experimental design Data analysis Process refinement Data generation 4Step 3: Design for scale-up, not just for now A process that performs well at bench scale may not automatically behave the same way in a GMP bioreactor. Changes in vessel geometry, mixing dynamics, oxygen transfer rates, shear stress, and hold times all influence the product profile in ways that are difficult to predict without deliberate planning. Discovering these differences during late-stage manufacturing can be the most disruptive and expensive problem in biologics development. Systems and process formats should be selected not only for their performance at early stages, but also for their ability to translate predictably to clinical and commercial manufacturing scales. For example, single-use bioreactor technologies offer significant advantages because they help minimize the potential for contamination, enable rapid changeovers between batches, and are increasingly available across a scalable range of volumes. This allows you to maintain continuity of the platform from development through to GMP production. The same scalability considerations apply to downstream operations. Selecting purification technologies and process formats that can transition predictably from development through commercial manufacturing is critical for maintaining process consistency and reducing technology transfer risk. Platformready technologies, including scalable chromatography resins, filtration systems, and prepacked columns, can help simplify process transfer between development and GMP manufacturing environments while improving reproducibility across scales. Risk mitigation during scale-up is also greatly supported by access to Thermo Fisher Bioprocess Design Centers (BDCs). These specialized facilities bring together process development, analytical characterization, and scale-down modeling expertise to support process optimization and scale-up. By using scaled-down models to simulate GMP conditions and identify potential failure modes before they arise at full scale, development teams can make betterinformed decisions earlier and avoid costly redesigns. Figure 4. Designing for scale early helps prevent delays. Prioritizing rapid progress without considering future manufacturing requirements can lead to scale-up challenges, technology transfer delays, GMP manufacturing issues, and delayed IND readiness. Tip: During Phase I process design, map out what your Phase II/III manufacturing platform will need to look like. Scalable cell line stategry Rework during scale-up Titer-only optimization Transfer delays and failures Material/control issues in GMP Delays in IND readiness Robust reliable process Faster, smoother tech transfer Confident, on-spec manufacturing IND-ready analytics Early development Scalable decision Speed-driven risk Process development Scale-up & tech transfer GMP manufacturing IND submission 5Step 4: Build a robust analytical and characterization strategy Detailed product characterization is not just a regulatory requirement; it also provides significant scientific value. Understanding a biologic’s structure, function, purity, potency, and stability creates a scientific foundation on which to build process control, batch release, and comparability. Despite the importance of product characterization, analytical deficiency is a recurring theme across complete response letters and has derailed programs at advanced stages of development. Addressing this problem retrospectively, after years of development have taken place, is a time-consuming and costly CMC remediation activity that developers would rather not face. Developing fit-for-purpose analytical methods enables real-time monitoring of process performance, supports the identification of CQAs and CPPs, and builds the body of characterization data that will ultimately support regulatory submission. A stability program should be initiated as early as practicable because real-time stability data cannot be generated retroactively, and insufficient shelf-life data is a straightforward but serious reason for regulatory delay. The analytical strategy should also be designed with technology transfer in mind. Methods that are poorly documented, inconsistently applied, or validated only for a single site create friction at every subsequent transition. Tip: Begin building your analytical toolkit in parallel with process development, not after the process is already in place. The characterization data generated early can become the foundation of your regulatory package and a reference point for every process change that follows. Common analytical deficiencies cited in CRLs Undefined impurities Inconsistent potency assays Limited stability data 6Step 5: Know when to partner with the right specialists Many of the CMC challenges that emerge in late-stage development are the consequence of key decisions being made without the expertise needed to anticipate their downstream implications. For emerging biotech companies, which frequently operate with lean teams and limited in-house CMC capability, this is one of the most significant risks along the development path. Outsourcing manufacturing capacity is now standard practice, but many effective partnerships go beyond this. Engaging an experienced development and manufacturing partner as a CMC co-strategist fundamentally changes the trajectory of a program. Early involvement allows a partner to contribute to process design decisions, flag potential regulatory concerns before they become problems, and ensure that the development path is aligned with GMP expectations from the outset. Early partnership also enables a smoother technology transfer. When a partner has been involved in process development from the beginning, they understand the process rationale, the key variables, and the control strategy. This shared ownership significantly reduces the risk of process failures, comparability concerns, and delays during GMP transition. Key capabilities to look for in a development partner Integrated upstream and downstream process development Analytical characterization expertise Access to GMP-ready infrastructure Experience supporting regulatory submissions Continuity of support from early development through to commercial manufacturing Tip: Think of your development partner as part of your CMC team, not an external vendor. The earlier that relationship is established and aligned with your scientific and regulatory strategy, the more value it will deliver. 7Learn more at thermofisher.com/bioprocessforbiotech What success looks like The most successful biotech programs are not simply those with the best molecules; they are those in which manufacturing, analytical, and regulatory considerations are treated as core scientific priorities from the earliest stages of development. While it is not possible to eliminate all risk from drug development, continuity of expertise is becoming increasingly central to how emerging biotech companies manage and minimize risk from discovery to clinic, then from clinic to patients. Manufacturers often achieve this by working with a trusted, integrated partner that can help bring the entire process together in one place. Partner with Thermo Fisher Scientific to make your CMC strategy count From early development through to commercial manufacturing, an integrated approach to CMC can help you avoid costly delays and build a stronger foundation for success. If you’re planning your next phase, now is the time to align your CMC strategy. Book a consultation with our specialists to get started References 1. Slabodkin G. FDA’s CRLs reveal 74% of applications rejected for quality, manufacturing issues. Pharma Manufacturing. July 14, 2025. pharmamanufacturing.com/ all-articles/article/55302937/fdas-crls-reveal-74-of-applicationsrejected-for-quality-manufacturing-issues 2. Foster B. Why gene and cell therapies are stalling at the FDA. Drug Discovery News. August 3, 2025. Available from: drugdiscoverynews.com/ why-gene-and-cell-therapies-are-stalling-at-the-fda-16527 For Research Use Only. Not for use in diagnostic procedures. © 2026 Thermo Fisher Scientific Inc. All rights reserved. All trademarks are the property of Thermo Fisher Scientific and its subsidiaries unless otherwise specified. APN-13947550