Integrating Drug Substance and Drug Product to Reduce Risk Across Development

Key Takeaways

• DP requirements, such as dose, concentration, formulation, fill volume, route of administration, and storage, should begin influencing drug substance development early enough to avoid difficult or costly changes later.

• Separating DS and DP across multiple providers can create additional interfaces where timelines expand, process knowledge is lost, analytical approaches diverge, and accountability becomes more difficult to manage.

• Integrated DS and DP development is particularly valuable for sensitive biologics, including viral vaccines, viral vectors, and oncolytic viruses, where temperature, mechanical stress, hold times, and transport conditions can affect product quality.

• Shared analytical methods, project governance, and quality systems can improve continuity between DS and DP activities, supporting more efficient investigations and more confident interpretation of product and process data.

• Designing clinical manufacturing with commercial scale, filling strategy, presentation, process economics, and future supply requirements in mind can create a more reliable path from early development to commercial biologics manufacturing.

Drug substance (DS) and drug product (DP) have traditionally been developed and manufactured as distinct activities, often by separate internal teams or external partners. That model has supported countless successful products, but it also creates interfaces that must be carefully managed as a program advances. For increasingly complex biologics, decisions made during DS development can directly affect formulation, filling, storage, analytical performance, and the final product presentation. When those interconnected activities are divided among multiple organizations, the sponsor must also manage the operational consequences of that separation.

Each additional interface introduces another schedule, quality system, analytical approach, documentation structure, supply plan, and set of organizational priorities. Sponsors often compensate by building contingency into project timelines at every transition. A DS provider may protect its release schedule, the customer may add time for shipment, and the DP provider may buffer its filling slot against uncertainty upstream. Each decision is individually reasonable, but the accumulated effect can substantially extend execution.

Fragmentation also complicates accountability when something goes wrong. If an unexpected result appears during DP manufacturing or finished-product testing, the origin may lie in DS production, freezing, storage, transport, thawing, formulation, or filling. Multiple providers may each have met their formal obligations while none has complete visibility into the product’s history. Integrated development reduces those gaps by keeping technical knowledge, planning, analytical strategy, and accountability connected across the manufacturing chain.

The case for DS–DP integration therefore extends well beyond consolidating providers. It lies in reducing the number of places where knowledge, time, and accountability can be lost between development steps.

DP requirements should begin shaping development as soon as a viable product concept emerges, ideally before preclinical work fixes assumptions that may later prove difficult to change. The final target product profile will continue to mature as clinical information accumulates, but several fundamental attributes should already guide manufacturing decisions. Potency, dose, concentration, route of administration, fill volume, formulation constraints, and broad presentation requirements create the framework within which the DS process must operate.

A high-dose therapy that must be administered in a small volume, for example, may require a concentrated DS. Reaching that target can affect downstream recovery, aggregation, impurity clearance, stability, and formulation. Container format and fill volume can impose additional concentration or viscosity constraints. If the product will be frozen, DS development must account for freeze–thaw behavior, storage duration, and the conditions under which bulk material will ultimately be transferred into DP manufacturing.

The relationships become particularly evident with complex viral products. A clinical presentation may require extensive concentration during downstream processing, increasing both the concentration of the virus and the burden of residual impurities. The product may need to retain infectivity or replication competence through purification, formulation, freezing, thawing, and fill-finish. A concentration that is attractive from a clinical perspective may therefore approach a range in which aggregation, loss of biological activity, or unacceptable process losses become more difficult to control.

These interactions work in both directions. DP teams need to understand what the DS process can reproducibly deliver, while DS teams need visibility into formulation, filling, storage, and administration requirements early enough to adjust the process before those choices become difficult to change.

Formal technology transfer can communicate a manufacturing process, but documents cannot fully reproduce the accumulated reasoning that shaped it. A specification identifies an acceptable range. A batch record records the operations performed. Neither necessarily explains why a particular limit was selected, which alternatives were tested, what unexpected behavior appeared during development, or where the process historically operated close to its boundaries.

That context becomes valuable when downstream performance changes. A DP provider may receive released DS that meets every specification while knowing relatively little about subtle differences between batches, prior investigations, formulation sensitivities, or the rationale behind individual process parameters. Resolving an unexpected observation may require additional document requests, technical meetings, and sponsor-mediated discussions across organizations.

The opposite pathway is equally important. A problem first observed in DP may have originated much earlier. Visible or subvisible particles may arise during formulation or filling, but they may also be connected to aggregation, raw materials, freeze–thaw conditions, or earlier DS handling. An unexpected stability result may require review of the entire process history rather than only the final manufacturing step.

Separate providers can collaborate effectively, and fragmented models have supported many successful products. The limitation is that collaboration across organizational boundaries rarely provides the same level of transparency as teams working within a common system. Different providers have distinct contractual scopes, commercial incentives, and areas of accountability. When an issue crosses those boundaries, time can be spent establishing ownership before the technical root cause is fully addressed. Within an integrated model, teams can work against shared technical objectives, common timelines, and the same quality framework.

The practical value of integration therefore depends as much on continuity of knowledge as on continuity of manufacturing.

The consequences of fragmentation are not identical for every modality. Some mature and well-characterized biologics can tolerate shipment, intermediate storage, and transfer between manufacturing locations with relatively predictable impact. In those programs, separate DS and DP providers may remain technically practical even though the sponsor still assumes additional coordination and transfer responsibilities.

Sensitive viral products create a different risk profile. Viral vaccines, viral vectors, and oncolytic viruses can be affected by temperature, mechanical stress, extended hold times, and repeated handling. Some must preserve infectivity or replication competence, while others introduce specialized containment or transport requirements. The greater the product’s sensitivity, the more consequential each movement between operations becomes.

Under those conditions, logistics become part of the technical process. Shipping conditions, storage time, thawing strategy, transfer configuration, and the timing of subsequent processing can all influence the material that ultimately reaches DP manufacturing. A released DS batch may remain within specification at departure while accumulating stresses during the transition that become visible only later.

Closer integration can reduce some of that exposure. DS and DP teams can coordinate hold times, storage conditions, formulation requirements, filling windows, and analytical testing against a common schedule, while fewer external transfers can reduce transport-related temperature or containment risks. The less forgiving the product, the greater the value of reducing unnecessary handoffs and fragmented ownership.

Analytical strategy provides another important source of continuity between DS and DP. Where scientifically appropriate, using the same or closely aligned methods across both stages allows teams to evaluate product attributes without adding unnecessary differences in how those attributes are measured.

The efficiency benefit is straightforward. Developing two similar methods to answer essentially the same question creates additional qualification, documentation, training, transfer, and maintenance requirements. More importantly, separate providers may use different instruments, procedures, reagents, or data-processing approaches. Even when both methods are valid, those differences can complicate interpretation when teams are trying to determine whether an apparent change reflects the product or the test itself. Achieving truly aligned analytical methods can be particularly difficult when DS and DP reside with separate organizations.

Shared analytical methods can create a more continuous body of analytical data spanning the process. If an attribute changes between DS release and DP testing, teams have a stronger basis for investigating whether the difference emerged during storage, formulation, filling, or another intervening activity. Analytical scientists can also participate across both sides of the process, contributing a product-quality perspective to decisions that might otherwise remain concentrated within individual manufacturing functions.

For complex biologics, this role extends beyond release testing. Stability-indicating methods, impurity assays, particle measurements, and product-specific functional assays can help teams understand how manufacturing and handling affect quality throughout the product life cycle. Analytics can therefore act as a common technical language between DS and DP, supporting both efficiency and more confident interpretation of process performance.

Offering DS and DP within the same corporate portfolio creates the possibility of integration, but operational value depends on how programs are governed, how information moves, and whether technical teams work toward shared product-level objectives.

At IDT Biologika, programs are organized around a dedicated program manager with responsibility for coordinating the project across functions. Cross-functional teams can include process development, analytical development and testing, quality assurance, DS production, DP engineering and manufacturing, and relevant commercial and financial functions. Rather than working against separate departmental schedules, those teams operate from an overall project plan containing shared work packages, dependencies, and milestones.

That project structure extends into governance. Internal steering committees provide oversight from functional leadership, while joint steering committees with customers maintain alignment around timing, priorities, risks, and major decisions. The aim is to ensure that one function does not optimize its activities without visibility into what another function needs to achieve next.

A common quality management system provides another layer of connection. Deviations, changes, investigations, documentation, and release activities can be managed within one quality framework rather than reconciled across unrelated systems. Analytical teams can work across DS and DP, and project leadership can maintain visibility into both technical and operational dependencies.

Co-location and broad capabilities make integration possible; governance determines whether those capabilities truly function as a single comprehensive manufacturing system. As more contract development and manufacturing organizations (CDMOs) expand their end-to-end offerings, that distinction will become increasingly important for sponsors evaluating partners.

Integration also helps connect clinical manufacturing decisions with the requirements of eventual commercial supply. Early-stage companies may reasonably prioritize near-term clinical milestones and conserve capital until proof of concept becomes clearer, but a process developed for initial clinical supply still needs a credible path toward later scale.

For DS and DP, that means considering the two sides of commercialization together. DS scale-up must produce batch sizes that make sense for DP operations. Filling capacity and presentation requirements can influence optimal batch sizing. Concentration, formulation, and storage conditions affect the number of usable doses produced from a batch. Process economics eventually depend on how efficiently the complete manufacturing chain operates rather than the cost of either DS or DP alone.

Sponsors are increasingly asking these questions during clinical development, including how a DS process will scale and whether the resulting batch size, concentration, presentation, and fill strategy can work together economically at commercial scale. IDT has seen customers enter clinical projects already wanting to understand potential commercial scale and cost rather than simply requesting clinical material and postponing the rest of the discussion.

This principle also reinforces a broader lesson from development programs: decisions made for an immediate clinical milestone can have consequences far downstream. A commercial process does not need to be fixed during early clinical development, but a small-scale process should have a plausible route toward larger production, and the intended DP should remain compatible with the DS process that will have to supply it.

Late-stage technology transfers illustrate what can be lost when continuity breaks. Programs move between CDMOs for many legitimate reasons, including capacity, geography, business strategy, equipment requirements, or persistent process challenges. The receiving organization may bring substantial platform knowledge and manufacturing expertise, but it still needs access to the history of the product to apply that expertise effectively.

IDT continues to receive late-stage transfers, including programs in which unresolved development issues have persisted into phase II or phase III. If the previous development history is fragmented or unavailable, the receiving team may need to repeat experiments, generate additional data, or reconstruct the rationale for decisions made earlier in development.

That work carries a direct cost. An experienced receiving team can troubleshoot and improve a process, but experience cannot substitute for missing evidence about exactly what happened during previous development and manufacturing campaigns. Continuous involvement from development through commercial manufacturing preserves more of that institutional knowledge, keeping previous investigations, technical decisions, analytical results, and process history accessible when questions emerge later.

Technology transfer will remain necessary across the industry, and capable CDMOs must be able to receive programs developed elsewhere. Every transfer, however, involves a knowledge-management challenge alongside the technical work. Preserving as much of that history as possible can reduce the amount that must be reconstructed as the product advances.

Operational integration ultimately depends on infrastructure that can support the complete manufacturing sequence at appropriate scale. IDT Biologika has continued investing across DS manufacturing, high-speed filling, automated inspection, packaging, analytical testing, and supporting operations to connect clinical development with larger-scale supply.

Digitalization represents a further layer of that integration. Electronic batch records and shared digital systems can improve visibility across departments, streamline review, shorten the time required to access manufacturing information, and preserve a more continuous process history. IDT has already introduced electronic systems in packaging and DS operations and continues working toward broader implementation.

The significance extends beyond replacing paper. When information from DS, DP, inspection, testing, and packaging becomes easier to access across functions, teams can investigate deviations with a more complete view of the product, monitor project status more efficiently, and reduce another class of manual handoffs between departments. Digital connectivity can reinforce the organizational integration created through shared project teams and governance.

The wider CDMO market is moving in the same direction. Customers increasingly ask providers to support larger stages of the product life cycle, and many CDMOs are building integrated offerings in response. IDT does not position the trend itself as unique; differentiation increasingly depends on how effectively an organization turns its capabilities into coordinated execution.

Products do not recognize organizational boundaries. Their quality reflects the complete history of how they were developed, manufactured, stored, tested, and handled. DS–DP integration creates value when the manufacturing organization mirrors that continuity through shared knowledge, analytics, quality systems, governance, and accountability, creating a stronger path from clinical development to reliable commercial supply.