Key Takeaways
Earlier CDMO involvement can bring manufacturing knowledge into drug development before molecule, formulation, process, and analytical choices become difficult to revisit.
Developability assessment can identify molecular properties that may later affect formulation, manufacturability, and CMC development.
Phase-appropriate formulation and analytical development can expose technical dependencies without prematurely fixing the final commercial product or methods.
Scale-up benefits from combining development knowledge with expertise in larger-scale equipment, facilities, and manufacturing operations.
Earlier CDMO engagement can support more continuous, bidirectional knowledge transfer without requiring premature commitment to a final commercial manufacturing partner.
Manufacturing Decisions Begin Earlier Than Manufacturing
The boundary between drug development and manufacturing is less distinct than a sequential development plan can suggest. Pharmaceutical development encompasses formulation, manufacturing process development and scale-up, analytical development, and the manufacture of investigational products, while the eventual commercial process draws on knowledge accumulated across those activities. Product and process understanding are expected to develop together and continue evolving across the product life cycle.1–3
That continuity matters because choices made well before commercial manufacturing can influence what becomes possible later. Drug substance characteristics can affect drug product development. Material attributes and process parameters identified during development can shape the control strategy. Knowledge generated through development and scale-up becomes part of the foundation for process validation and commercial manufacturing. The regulatory framework therefore does not position manufacturing knowledge as something that becomes relevant only after a clinical process has been established.3–5
For drug developers that rely substantially on external development and manufacturing capabilities, this creates a strategic question about timing. If expertise in process engineering, formulation, analytical development, scale-up, or the intended manufacturing environment resides at a contract development and manufacturing organization (CDMO), introducing that expertise only at formal technology transfer may mean that important development choices have already narrowed.
The case for earlier CDMO involvement is therefore not primarily a case for beginning manufacturing execution sooner. It is a case for making relevant manufacturing knowledge available while development choices remain responsive to it. That does not require prematurely fixing a commercial process or selecting a permanent manufacturing partner. It means recognizing that manufacturing considerations can become consequential long before manufacturing itself becomes the program’s dominant activity.
Developability Starts with the Molecule
Manufacturing considerations can begin before process development because some later chemistry, manufacturing, and controls (CMC) challenges originate in the molecule itself.
For small molecules, developability assessment occupies an interface between medicinal chemistry and subsequent CMC development. Physicochemical and biopharmaceutical characterization can help assess stability, formulation, and manufacturing requirements before a molecule advances into more resource-intensive development. Molecular properties can affect manufacturability and the formulation options available later.
The same basic principle applies to antibody-derived therapeutics, although the relevant attributes differ. Developability assessment can be performed during discovery to identify characteristics that may make a candidate more difficult to manufacture or progress through CMC development. When liabilities are identified sufficiently early, molecular engineering may still provide a way to address them rather than requiring later process and formulation development to work around an avoidable constraint.
This does not mean manufacturability should supersede biological activity or that manufacturing teams should dictate candidate selection. It means that a candidate’s development profile includes more than its intended biological function. Small molecule developability work can inform candidate-selection risk, while early biotherapeutic developability frameworks similarly connect discovery-stage characteristics with later product and process requirements.6,7
When the relevant formulation, process, or manufacturing capabilities do not reside within the development organization, some of that perspective may need to come from an external partner. Earlier access to manufacturing experience can help expose liabilities while candidate characteristics remain open to evaluation. The evidence does not support a universal requirement to co-design molecules with a CDMO, but it does support a narrower principle: manufacturability-relevant information is more useful when it reaches the program before the candidate has become effectively fixed.
Formulation Is Part of the Development Architecture
Once a candidate progresses, formulation provides another point at which product and manufacturing decisions intersect. Drug substance characteristics can influence drug product development, and formulation work can begin well before conventional late-stage development. Preformulation and formulation scientists may contribute around lead optimization, candidate selection, preclinical development, and preparation for first-in-human studies. Early formulation work includes identifying risks and selecting strategies capable of supporting the next stage of development.4,8
The implication is not that the final commercial formulation must be selected immediately. Early clinical needs can differ from later requirements, and pharmaceutical companies use different decision frameworks for formulation development. The value of early formulation work is that it provides information about the consequences of the molecule’s properties and the feasibility of possible product configurations while the development strategy remains adaptable.8
Formulation choices can also interact with other workstreams. In antibody–drug conjugate (ADC) development, formulation decisions can affect analytical sample preparation and method performance, creating a reason to consider formulation and analytical development together rather than as fully independent sequences. That is modality-specific practitioner evidence rather than a universal rule, but it illustrates how apparently separate development activities can become technically interdependent.9
When formulation development, manufacturing, or both reside at an external partner, earlier interaction can help ensure that formulation decisions are considered alongside the practical requirements of the processes that must support them. The goal is not to optimize prematurely for an uncertain commercial configuration but to identify foreseeable constraints before formulation, process, and analytical choices become more deeply interdependent.
Analytical Development Should Inform Decisions
Analytical development follows a similar logic. Analytical procedures used during clinical development can apply the scientific principles of ICH Q14 in a phase-appropriate manner, allowing analytical understanding to mature as the program advances. The objective is a procedure fit for its intended purpose, with the level of development matched to the needs of the stage.10
This makes it important to distinguish early analytical understanding from premature analytical lock-in. Final commercial methods do not need to be fixed before sufficient product and process knowledge exists. At the same time, analytical development should not be treated merely as documentation that follows decisions made elsewhere. Analytical procedures help generate the information needed to understand product attributes, process performance, and the implications of development changes.1,10
That information contributes to the control strategy as development progresses. Quality attributes, process parameters, and analytical approaches may initially support clinical manufacturing and later be refined as additional product and process understanding accumulates.
When analytical development and manufacturing are distributed across organizations, coordination before formal transfer can therefore be valuable. The analytical strategy must ultimately operate within the manufacturing and control environment in which the process is executed, while development teams depend on analytical information to understand changes made along the way. Earlier interaction creates more opportunity to identify gaps before analytical and manufacturing strategies have developed separately for too long.
Design for Scale While the Process Can Still Change
Scale-up makes the value of manufacturing expertise especially visible because development-scale process knowledge and manufacturing-scale equipment knowledge are not interchangeable. The U.S. Food and Drug Administration’s (FDA) process-validation framework describes commercial process design as drawing on knowledge gained through development and scale-up and recommends integrated teams that include expertise in areas such as process engineering, analytical chemistry, manufacturing, and quality.3
ICH implementation guidance likewise states that scale-up risk should be considered during development of the control strategy. The assessment can account for processing equipment, facility environmental controls, personnel capability, experience with particular technologies, and prior knowledge. These factors are not always apparent from laboratory work alone because the manufacturing environment introduces its own operating realities.5
A practical pharmaceutical example demonstrates why different forms of expertise matter. A scale-up risk methodology applied to processes still under development combined chemists’ understanding of the process with engineers’ knowledge of large-equipment functionality. The teams identified scenarios that could threaten operation at larger scale, ranked them by risk, and used that ranking to prioritize further development. The method was intended to bring engineering knowledge into process development while it could still direct additional work.11
That example concerns collaboration within a pharmaceutical organization, not outsourcing, but it provides a useful analogy for the CDMO relationship. A drug developer may understand its molecule and development process in depth, while the intended manufacturer understands how processes interact with its own equipment, facility, systems, and operating practices. A CDMO therefore contributes a different body of knowledge, not better knowledge of every aspect of the program, but knowledge of how a process must function in a manufacturing environment.
Combining those perspectives earlier can help focus development on areas most likely to become scale-sensitive and identify where additional work would most reduce uncertainty before transfer. The evidence supports integrating process and engineering knowledge during development; applying that principle through an external manufacturing relationship extends the same logic across organizational boundaries.11
This does not mean creating the final commercial process during early clinical development. Early programs may require speed, limited material consumption, and fit-for-purpose solutions. The more useful objective is to understand whether the process in use today preserves a credible path toward later requirements. A phase-appropriate process can remain intentionally provisional while developers identify which elements are likely to require further work as scale and manufacturing context change.
Facility fit adds another dimension when manufacturing is outsourced. Equipment, capabilities, technologies, and controls can differ across manufacturing sites, and those differences can matter when a process moves from one setting to another. Considering that context during development can make scale-up and transfer more deliberate rather than treating facility compatibility as a question to address only after the process has been established.5
Technology Transfer Should Transfer Understanding
Formal technology transfer is often the point at which development and manufacturing organizations must convert accumulated product and process knowledge into routine execution. ICH Q10 defines the goal of technology transfer as moving product and process knowledge between development and manufacturing and between manufacturing sites. That knowledge becomes a basis for the manufacturing process, control strategy, process validation approach, and continual improvement.2
ICH Q11 extends knowledge management explicitly to technology transfer involving contract manufacturers. Product and process knowledge should be managed through the life cycle, and the understanding needed to execute the manufacturing process and control strategy should be shared across the sites involved.4
Technology transfer therefore involves more than transmitting specifications, procedures, and process descriptions. Those materials remain essential, but the receiving organization also needs the development knowledge and process understanding that underpin the process and its controls. That is the distinction between transferring instructions and transferring understanding.2,4
The regulatory implementation framework is especially relevant to outsourced manufacturing because it states that knowledge transfer in contract manufacturing should be considered in both directions between the parties. The receiving manufacturer is not simply absorbing information. Its knowledge of equipment, facilities, and manufacturing operations can reveal areas where further clarification or development may be necessary.5
Research focused specifically on biopharmaceutical contract manufacturing reinforces the importance of this interface. Review of industry practice combined with surveys and interviews of contract manufacturers and customers identified technology-transfer challenges and project delays and emphasized shared ownership and managed expectations as characteristics of a stronger transfer culture.12
Earlier CDMO involvement can change the context in which formal transfer occurs. Instead of asking the receiving organization to build its understanding largely from a completed transfer package, product and process knowledge can accumulate progressively across the relationship as development advances. That does not eliminate transfer risk, nor does the evidence establish that early engagement universally prevents delays. It does create more opportunity for the bidirectional exchange of knowledge that both regulatory guidance and contract manufacturing research identify as important.
Earlier Engagement Is Not Premature Commitment
The case for earlier involvement should not be confused with a requirement to select the final commercial manufacturing network at the beginning of development. Early-stage programs contain substantial uncertainty, and the appropriate external relationship depends on the knowledge and capabilities a program needs at a given point.
ICH Q10 provides a useful framework for thinking about those relationships without prescribing a particular commercial model. Before outsourcing activities, a pharmaceutical company should assess the suitability and competence of the other party, define responsibilities and communication processes, and monitor performance. Ultimate responsibility for assuring control of outsourced activities remains with the pharmaceutical company.2
Within that framework, earlier involvement could, depending on the program, center on developability, formulation, analytical work, process development, scale-up assessment, or manufacturing feasibility without automatically determining where future commercial supply will reside. The relevant question is whether an external capability can improve the information available for the current development decision.
Maintaining that distinction also guards against optimizing too early for a manufacturing configuration that may never become relevant. Early development should remain capable of learning and changing. The rationale for earlier engagement is strongest where manufacturing knowledge can improve current decisions without forcing the program into commitments that exceed what is yet known.
Bring Manufacturing Knowledge in While Optionality Remains
The timing question for a drug developer is less about selecting an arbitrary milestone for CDMO engagement than about recognizing when important choices are beginning to narrow later options.
Before a candidate is fixed, developability information may affect molecular selection or design. Before formulation strategy becomes more established, downstream requirements may expose constraints worth addressing. Before a process becomes embedded in clinical supply, scale-up knowledge may identify areas that warrant additional development. Before formal technology transfer, the intended manufacturing organization may be able to contribute knowledge that would otherwise enter the program only after the process has largely taken shape.2,6,8,11,13
For companies with broad internal CMC and manufacturing capabilities, much of that expertise can enter development without involving an external organization. For companies that depend on CDMOs for substantial portions of development and manufacturing, the same principle points toward earlier access to external expertise. What matters is less who owns the knowledge than whether it reaches the development team at a point when it can still influence decisions.
That is the strongest case for earlier CDMO involvement. It does not require every process to be commercialized earlier, every method to be finalized sooner, or every company to commit to a manufacturing partner before uncertainty has resolved. Manufacturing knowledge has its greatest ability to shape development while the molecule, formulation, analytical strategy, and process still retain room to change. By the time technology transfer becomes the first meaningful manufacturing conversation, some of that optionality may already have been spent.
References
1. Q8(R2) Pharmaceutical Development. Guidance for Industry. U.S. Food and Drug Administration. Nov. 2009.
2. Q10 Pharmaceutical Quality System. Guidance for Industry. U.S. Food and Drug Administration. Apr. 2009.
3. Process Validation: General Principles and Practices. Guidance for Industry. U.S. Food and Drug Administration. Jan. 2011.
4. Q11 Development and Manufacture of Drug Substances. Guidance for Industry. U.S. Food and Drug Administration. Nov. 2012.
5. “Q8, Q9, & Q10 Questions and Answers — Appendix: Q&As from Training Sessions (Q8, Q9, & Q10 Points to Consider).” U.S. Food and Drug Administration. Aug. 2012.
6. Agarwal, Prashant, et al. “Trends in Small Molecule Drug Properties: A Developability Molecule Assessment Perspective.” Drug Discovery Today. 27: 103366 (2022).
7. Zurdo, Jesús, et al. “Early Implementation of QbD in Biopharmaceutical Development: A Practical Example.” BioMed Research International. 2015: 605427 (2015).
8. Zane, Patricia, et al. “In Vivo Models and Decision Trees for Formulation Development in Early Drug Development: A Review of Current Practices and Recommendations for Biopharmaceutical Development.” European Journal of Pharmaceutics and Biopharmaceutics. 142: 222–231 (2019).
9. Barry, Conor S. “The Role of Contract Manufacturing in Antibody–Drug Conjugate (ADC) Drug Substance Development – Strategies for Successful Engagement.” AAPS PharmSciTech. 27: 255 (2026).
10. Q14 Analytical Procedure Development. Guidance for Industry. U.S. Food and Drug Administration. Mar. 2024.
11. Muller, Frans L, and J M Latimer. “Anticipation of Scale Up Issues in Pharmaceutical Development.” Computers & Chemical Engineering. 33: 1051–1055 (2009).
12. Ujam, Layth. “The 5C Framework and Maturity Assessment: a New Approach to Technology Transfer in Biopharmaceutical Contract Manufacturing.” Level 3. 15(2): Article 8 (2020).
13. Zhang, Weijie, et al. “Developability Assessment at Early-Stage Discovery to Enable Development of Antibody-Derived Therapeutics.” Antibody Therapeutics. 6: 13–29 (2023).
