Guest Editorial by Dainius Guzauskas CMC Professional, former Project Leader at Rentschler Biopharma, former Senior CMC – Regulatory Manager at InflaRx
Recent Complete Response Letters (CRLs) from the FDA have sparked fierce debate across industry forums, with many calling for CMC to be repositioned at the center of drug development. The scrutiny is warranted — but the industry risks overcorrecting. Rather than assigning blame, the more productive response is honesty: about biotech–CDMO friction points, about the development inertia of recent years, and about what genuinely good strategic positioning looks like.
This guest editorial covers three areas:
- CMC and the industry’s attunement gap — why recent CRL findings reflect execution and prioritization failures, not a fundamental CMC crisis, and how integrating clinically validated data can sharpen development strategy
- Simplifying biotech-CDMO relationships — how to select partners, set honest expectations, and share knowledge in ways that actually move programs forward
- Strategic positioning for biotechs — how clinical relevance, regulatory assets, and genuine scientific engagement can elevate your status as a priority client
Section I. CMC is not in crisis, industry lacks attunement to it
The macro environment at play – higher available funding in the industry during COVID, the drive to capture new therapeutic modalities-indications, and a plethora of M&As have pushed the speed-to-patient throttle significantly.
Many teams paused their ongoing strategies, waterfalled into new development areas, and inflated their staff numbers. In such a complex industry of inter-relationships, not all systems and partners can equally respond to pressure. When pace increases rapidly, we cannot assume that processes-workflows-systems (of all CMC activities), often regarded as more established and more technology mature, input into the overall program would yield flawlessly. Many of the CRL findings related to GMP, site inspections, and compliance were not the result of gaps in CMC science. They were the result of existing QA systems, documentation requirements, and compliance procedures not being followed.
Historically, program development timelines were primarily driven by clinical milestones, with CMC schedules to be inserted within their critical path. Clinical is even considered the primary output, and CMC is supportive input. The reasons why the clinical paradigm holds more gravitas in therapeutic development are rather justified.
Nevertheless, consider how many cases related to process validation, characterization packages and control strategy were a result of sponsors pressuring timelines or overriding practices and recommendations of CDMOs whilst “accepting all risk”? For established modalities, the CMC challenges lie rarely in construct or process knowledge but in execution, given cost and timeline constraints. The majority of noted findings are resolvable not by recentering CMC into the forefront in rebound but by improving attunement to it.
Notably, in order to tackle the far greater (cross-functional) challenge in terms of knowledge – biomarker/disease target(s), endpoints and proxy relationships – the industry ought to integrate the CMC toolbox closer to the gap between the physiological target(s) of interest, the optimal MoA and translation to (Q)TPP. The majority of CQAs and their classification rely on CMC input and manufacturing history rather than clinical validation — a formulaic approach that worked in the past but is increasingly inadequate under today’s regulatory scrutiny.
If the majority pre-clinical/early stage pCQAs are carried through late-stage CQAs, if all specification parameters hold equal (i.e. high) importance, it indicates a limited clinically-significant knowledge to patients and hints to a formulaic approach. Such static strategies worked successfully in the past, however, beyond the increasing regulatory scrutiny, teams should intensify focus on increasing analytical (extended) characterization with enhanced collection of clinically qualified data informing clinical and translational efforts.
Notably, for novel therapeutics (e.g. CGT) in which the process is the product, production-to-patient distribution is critically short-lived and clinical administration is more multiplex, the distinction between acting roles of clinical and CMC is less pronounced.
Section II. Simplifying CDMO-biotech relationships
Features beyond Strategic Fit
It is valuable to approach the CDMO selection process with a presumption that there is a good (strategic) fit for every firm. For new modalities, strategic fit often requires further mutual alignment towards a desired target collaboration. Thereby, beyond the fundamental due diligence of assessing for tangible and specific development and manufacturing experience, IT-systems-software interfaces, partner network management, quality-regulatory track records, consider the B2B interface of current compatibility vs. future strategy including the following:
Size. Internal shifts occur in CMC enterprises concerning the ability to tolerate and control flexibility attributable to their size. With increasing size, firms increasingly reduce flexibility to service packages, formalize KPI compliance, and resource allocation for internal and client projects. For biotechs, it results in individual relationships and reputational influence commanding less, thereby other elements require development. For small biotechs without (traditional) potential to be strategically prioritized, reconsider approaching a large or incumbent CDMO (specifically for early development work) where flexible capacity is not readily available, and monitor growth trajectory.
New sites/newly acquired sites. Be cautious of the tendency to select (de novo) established or acquired sites by large or incumbent firms and CMC vendors. Do not assume that identical quality philosophy, which cannot be captured by QAAs and SOPs, will be transferred to a newly acquired site. Do not automatically presume that companies excellent at technology scale-up or other complex core competencies will be able to replicate such in another site-region-culture.
Impact awareness. Notably for smaller and emerging biotechs, refrain from the expectation to radically alter the CDMO’s approach to Development or Quality practices – even if systemic issues are recognized. Conversely, the risk of being a smaller player alongside a Pharma client at a CDMO may yield counter benefits if a site/firm is relatively new. In such cases, the resource load required for tuning operations, mock-ups, and integrated readiness is partially handled by higher bargaining power and resource actors.
Strategic fit should be fundamentally tackled during the assessment-selection process and network interactions. As in every relationship, hold and work around your partner’s weaknesses, allow for strengths to reign. Similar to aviation, do not take off in situations where you’d find yourself wishing you were on the ground.
Set expectations and show work vs. manage expectations and justify homework?
Honesty is the fundamental currency in biotech-CDMO relationships. I’ve witnessed many where both parties communicate their preferences for close collaboration-strategic relationships, while proceeding to act out according to their internal playbooks. How many biotechs profess a desire for close collaboration, then refuse to share their Module 3 dossiers? CDMOs maintain a good pulse of sponsors requesting strategic privilege without reciprocating with transparency, program strategy updates, or clear resource commitments.
Great value is realized by internally clarifying and externally communicating what relationship is to be established – beyond Term Sheets, MSAs, and QAAs. Not all CDMO-biotech relationships require close collaborations and strategic partnerships to reach program milestones. Many resources are saved for small biotechs by setting and upholding expectations while requesting CDMOs to provide results as deliverables. Unfortunately, a common pattern arises where sponsor expectations become fluid and thereby dynamically managed, to which CDMOs often respond by overexplaining activities or even justifying their homework. Such a relationship dynamic, if not designed with intention (e.g. regulatory procedure), is very taxing resource-wise, is likely unsustainable in the long run, and is preemptively avoidable.
A note for small-emerging biotechs – if you are not certain about such dynamics, communicate it! CDMOs or any CMC vendor will attempt to offer fitting colleagues with strengths in educating and accommodating your teams while delivering the work.
Follow commitment, capitalize on, and challenge knowledge
Communicate objective and follow commitment. All managers, group leads, and heads of function in CDMOs (or any service providers) know the following too well. It is difficult to mitigate the slump in individual and team motivation when the sponsor repeatedly pressures for scope-capacity-timelines appraisal without advancing to execution. Any sponsor (regardless of their size) loses soft reputational points when exploring options where an expectation of urgency or commitment was signalled. Reputation is palpable and affects extended teams in conversations where you are not present. Correspondingly, if all of your inquiries for development or capacity are urgent, the issue may not be the CDMO’s lack of capacity for immediate response.
Capitalize knowledge. Biotechs underestimate the breadth of knowledge residing at CDMOs (incl. small-medium size firms). Many biotechs slumber and gatekeep information regarding changes to their expression system or modifications in their construct sequence as a solution to past issues – only to find that this stagnates problem-solving during development challenges. If your project requires speed-to-clinic from the CDMO, the prerequisite for progress is not pressure but full developmental transparency. Following suit, relevant troubleshooting information lies within the draft report files where all internal comments are not resolved, within the assay failures which are not reportable according to internal procedures/SOPs – all hands on deck!
Challenge knowledge. Pertinent to novel modalities as well, biotechs underestimate how often CDMOs provide new, potentially critical information about their construct after years of pre-clinical (internal) work. Verifying CDMO’s knowledge is a valuable tactic, although exercise moderation. Request to disseminate properties with additional sequences, commit to characterization workpackages with in-house samples, seek details into DoE approaches. CDMOs are keen to demonstrate knowledge in the most efficient way possible. The challenge is reciprocal – prepare to justify specification requests. Cautionary note: not all CDMOs and associated vendors will be able to impart new insight, nor will they be able to provide exceeding effort. Avoid personalizing such occurrences to your project, as many external and institutional factors – such as the business cycle of the CDMO and associated vendors – influence capacity, speed, and service customization.
Recall a known metaphor in the industry – particularly for first product, emergent biotechs, and small pharma – your partners are aware that it is your first and/or most important newborn. For the birthing house of CDMOs, your newborn is important but is (likely) not so unique. Everybody in the relationship wants for the newborn to thrive – do not helicopter with knowledge or past experience, listen to CDMO’s recommendations.
Section III. Strategic Positioning — how biotechs can become Priority Clients
Defining Clinical Relevance. There is a naturally elevated interest to engage in a FIC potential, new therapeutic modalities or BIC candidates in areas where Standard of Care carries many trade-offs (e.g. pain management). The recognition by the industry and societal impact of addressing unmet clinical needs offers a valuable undercurrent affecting all parties involved. Furthermore, such developments often imply higher production volumes per year after approval. Batches per year are fundamental – small biotechs with higher production volumes set themselves for potential prioritization over Pharma with low clinical demand and production estimates.
Developing Regulatory assets such as breakthrough and orphan designations, PRIME, accelerated reviews adds strategic weight to your program. These entail fundamental implications to client strategy, regulatory considerations, review timelines – exemplified by more frequent and dynamic interactions with agencies and a higher probability of scope or even strategic changes. An overall understanding of the importance of these elements resides at CDMOs (and all CMC vendors), albeit providing updates to your partner teams would ensure sensitivity is maintained. Avoid notifications only and aim to translate and discuss the impact of these developments into daily operations.
Importantly, the evolving nature of these items denotes that previous experiences may not be directly transferable. Consider the orphan designation: with intensified interest since 2010s, such an asset was correctly assumed for higher regulatory flexibility both in terms of clinical protocol design and CMC submission package. As of 2026, such an assumption for CMC is more risky – particularly if approached via established modalities (mAB-like). Regulatory agencies are slow to bring leaner submission packages into real-world effect for mature technologies albeit recent efforts are observed. Conversely, for new modalities earlier in the adoption cycle (e.g. CGT), regulatory flexibility is readily available.
Interest the scientist in everyone. One of the most fundamental yet overlooked momentum drivers is the (scientific) interest of everyone involved in your project. Following negotiations and project initiation, you will interact with client-facing team members – engagement starts here. Invite development, QC, and manufacturing colleagues troubleshooting your problems into TCs. You will access an extra level of detail not available in routine slide deck updates and not captured in development reports. Share extended characterization data or in-house experimentation findings, consider their input into your experimental design. Comparatively, employees on CDMO teams are granted to practice their translational-communication skills and feel more embedded in the project. Your team’s desire for detail and comparison is met by scientists’ desire to realize their work’s impact. It is a natural win-win. During site visits, leave the conference room and go to the laboratory.
Is it truly (strategically) significant? Absolutely. At the baseline level, external team members will take the extra consideration, will fervently examine relevant cases and will naturally gravitate towards your project. Inherently, there is a scientist in every function. Attempt to entrain that node of curiosity in the CDMO’s project team as it cascades to other functions – enthusiasm accumulates and transfects. In due course, balance engaging curiosity with project (impact) significance.
Cultivate 4 Features of (any) Biotech as Priority Client
- Do not fall short of being agile and responsive. Avoid a common pitfall of expanding biotech teams to start lagging in decision-making or review timelines.
- As per work with multiple vendors, verify experimental conditions, statistical approaches, and protocol inputs. Different vendors differ at setpoints for seemingly standard features (i.e. Room temperature), standard procedures (e.g. sample preparation/aliquoting) thereby diligently cross-check to avoid further “contributions” to ever-present development challenges.
- Ensure an archive of development history remains within your biotech, incl. people. Assume future tech transfer, new partnerships, or licensing – knowledge gets disjointed within the reports, deviations, and change controls. Your early employees, partners, and consultants are an invaluable and expedited heritage.
Mitigation of recent challenges does not require seismic restructure but disciplined attunement to knowledge gaps, CMC execution, and partnership dynamics. To facilitate the knowledge of therapeutic output, the industry should tread beyond static CMC strategies by dynamically integrating clinically validated data and advanced analytical characterization. Biotechs can thrive by setting clear expectations, sharing knowledge openly, challenging capabilities, and leveraging clinical relevance with regulatory assets to establish strategic priority.
Dainius Guzauskas is a seasoned CMC Professional, former Project Leader at Rentschler Biopharma, and former Senior CMC – Regulatory Manager at InflaRx
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