Consistency Is the New Compliance

Published on 28 October 2025

Why biomanufacturers are rethinking plasma-derived materials, reproducibility, and regulatory confidence

How tightening regulations and new data are reshaping expectations for material consistency and traceability.

Ask anyone in advanced therapy manufacturing “What keeps you up at night?”…the answer is usually the same; variability. Every batch tells a story, some of success, some of struggle. Manufacturers work hard to control what they can, the process itself. Yet no two processes or even individual runs for that matter are exactly alike. For example, in autologous cell therapy, patient-to-patient differences are unavoidable, inherent to the biology of the cellular starting material. In gene therapy and viral vector production, variability in titer often stems from differences in transfection efficiency largely due to inconsistency in raw material quality.  While biological variability in the cell product is inevitable, adding uncertainty from undefined raw materials doesn’t have to be part of the story. Even small differences in serum, albumin, or other media components can amplify inconsistencies downstream, impacting reproducibility, stability and regulatory confidence. 

As regulators tighten oversight, manufacturers are realizing that **consistency starts upstream**. Every reagent, buffer, and supplement affects product quality, reproducibility, and regulatory confidence.  According to the FDA’s 2024 draft guidance on human- and animal-derived materials, manufacturers should describe and justify all human- and animal-derived components used in production, including those applied early in the process or removed before final formulation (FDA, 2024). 

The EMA echoes this stance, requiring manufacturers to demonstrate full traceability of plasma from donor to finished product and to confirm viral safety through validated inactivation or removal steps (EMA, 2011).

Recent industry analyses highlight that regulators increasingly view the control of human- and animal-based substances as central to product quality, comparability, and patient safety (Compliance Insight, 2025).

Here’s the deal: relying on serum- or plasma-derived ancillary materials introduces a level of uncertainty that no process engineer wants to defend. Recombinant, chemically defined materials are changing that conversation—offering manufacturers a cleaner, more controllable path forward.

Three Classes, One Standard

Every material used in biomanufacturing plays a role in determining quality and consistency. Regulatory bodies now classify them under three broad categories: 

• Raw Materials: Used to manufacture the product or its intermediates. These include media components, salts, buffers, excipients, and process chemicals. They are consumed, transformed, or incorporated into the process or final product. Examples include amino acids, glucose, NaCl, base media powders, and the starting cell material for cell therapy.
• Ancillary Materials: Support production but are not intended to remain in the final product. They are often biological or complex, like recombinant proteins, enzymes, or growth factors. Examples include recombinant albumin, transferrin, cytokines, trypsin, or serum used in cell culture. Despite being ‘temporary’ they require the same level of oversight as raw materials.
• Reagents: Used for testing, monitoring, or validation rather than manufacturing itself. Examples include ELISA kits, PCR reagents, stains, and control materials.

No matter the category, the expectation is the same — traceability, consistency, and data to prove it.

Albumin: A Case Study in Material Definition

Albumin remains one of the most widely used proteins in biomanufacturing. It stabilizes biologics, supports cell culture, protects therapeutic cells during freezing, and acts as a carrier molecule in formulations. But not all albumins perform the same. Plasma-derived human serum albumin (HSA) is inherently variable, and that variability can compromise consistency and control. 

To demonstrate how defined materials improve reliability, InVitria scientists compared recombinant, animal-origin-free Optibumin 25 to plasma-derived HSA. The data revealed what process engineers have long suspected: when the material is defined, the process stays defined. 

1. Fewer Aggregates, Fewer Headaches

In analytical comparisons, Optibumin 25 contained approximately ten times fewer aggregates and showed significantly lower variance between lots (* *p* < 0.05 for mean; ## *p* < 0.01 for variance) (InVitria, 2025a). Why does that matter? Aggregates in plasma-derived proteins can act as a nucleation point that promote further aggregations under stress conditions such as agitation, shear forces, or air-liquid interferences during scale-up. Fewer aggregates mean a cleaner starting material that is less prone to particle formation and easier to handle across processing environments.  

 In biologics, vaccines, and viral vector manufacturing, high aggregate levels can lead to stability issues, filtration challenges, and potential immunogenic responses in patients. By starting with a recombinant albumin that contains fewer aggregates, manufacturers can improve process reliability and reduce the risk of patient exposure to unwanted particulate material. 

 

In virus production or protein manufacturing for vaccines or therapies, even small aggregate differences can alter downstream filtration performance or affect potency. By starting with a consistent recombinant albumin, manufacturers avoid the requalification work and comparability challenges that often accompany plasma-derived materials. 

Read more about this in the application note:  A Binding Advantage: Optibumin 25 Demonstrates Enhanced Drug Binding and Consistency over Plasma Albumin

2. Structural Integrity That Lasts

Inconsistent protein modifications are another silent issue with plasma-derived materials. For example, recombinant Optibumin 25 maintained 98–99% reduced Cys-34, compared to about 60% for plasma HSA (p < 0.0001) (InVitria, 2025b), and Optibumin 25 showed approximately tenfold lower lot-to-lot variability.

Why does this matter? Cys-34 is the only free cysteine residue in albumin and plays a key role in its antioxidant and binding functions. When this site becomes oxidized, albumin loses part of its protective capacity, and those oxidation levels can vary significantly between plasma donors and between manufacturing lots (Oettl & Marsche, 2005).

This oxidation heterogeneity, along with other uncontrolled post-translational or chemical modifications in plasma-derived albumin, adds yet another layer of variability that recombinant, chemically defined Optibumin 25 eliminates. Its consistent molecular structure supports reliable performance across storage and processing, reinforcing the link between structural consistency and process reproducibility.

 

For cell therapy, gene therapy, and vaccine manufacturing, maintaining that reduced, unmodified form of albumin means fewer reactive oxygen species, less cell stress, and more predictable outcomes. In short, structural integrity equals functional reliability. 

Read more about this in the application note: Thiol by Combat: Enhanced Covalent Conjugation with Recombinant Albumin Compared to Human Plasma-Derived Albumin

3. Purity Without Additives

Here’s something most developers don’t realize… plasma-derived albumin isn’t pure albumin.  To survive heat pasteurization, it’s stabilized with additives such as sodium octanoate and N-acetyl-tryptophan. These stabilizers protect the protein during manufacturing and storage, but they can also bind to albumin and occupy sites that influence its structure and ligand-binding behavior. The concentration and binding effects of these additives can vary between plasma-derived preparations, introducing another layer of process variability. Because stabilizer levels and binding effects can vary between plasma-derived albumin preparations, they introduce another potential source of lot-to-lot variability that recombinant albumin avoids (Harm et al., 2018) 

Recombinant Optibumin 25, in contrast, is produced without stabilizers or preservatives, giving scientists greater control over formulation design and downstream outcomes such as cell health, consistency and reproducibility. 

This purity is especially valuable for applications that rely on sensitive analytical assays or direct clinical use—such as vaccine adjuvants, cell therapy media, or cryopreservation formulations. When the albumin is chemically defined, you don’t have to worry about additive residues or carry-over documentation. 

The Problem with Serum-Derived Materials

Serum- and plasma-derived products bring along a host of issues: source variability, undefined composition, and contamination risk. Even when screened and treated, these materials can still contain unexpected substances. Researchers have detected multiple pharmaceutical compounds in plasma pools, reflecting widespread medication use among donors and the potential transfer of trace drugs into plasma-derived medicinal products (van den Oever, Volkers, & Koedam, 2019).

And as shown in multiple studies, including a 2025 report from Technische Universität Berlin, the undefined nature of serum continues to undermine reproducibility (Nessar et al., 2025). 

A review from researchers at DiscGenics highlighted this same concern in the context of cell therapy manufacturing. They noted that during cell isolation and expansion, media reagents are a major source of variability and must be carefully controlled to reduce risk. Of particular concern are undefined materials containing animal- or human-derived components and proprietary media formulations with undisclosed compositions. The authors also observed that while fetal bovine serum (FBS) has long been used to drive cell growth and differentiation, its variability and disease-transmission risk have prompted many to explore alternatives such as human platelet lysate—yet these substitutes can also change cell phenotype and potency, or introduce additional variability due to their own manufacturing challenges (Harris, Suliman, & Nagra, 2019).

 As shown in multiple studies, including a 2025 report from Technische Universität Berlin, the undefined nature of serum continues to undermine reproducibility (Nessar et al., 2025). 

Beyond safety, there’s a practical cost. Each source-derived material adds extra layers of validation, testing, and regulatory justification—each one a potential bottleneck. Recombinant, animal-origin-free alternatives remove that uncertainty entirely, providing transparency, lot-to-lot control, and global consistency. 

From Definition to Compliance

When materials are defined, compliance follows naturally. The consistency of recombinant albumin simplifies documentation and eliminates donor-traceability requirements, making comparability assessments faster and easier. Defined materials also align directly with current FDA and EMA expectations for raw material qualification and process control. 

The Alliance for Regenerative Medicine’s 2024 annual report highlights that as advanced therapies move toward commercial scale, control and qualification of raw and ancillary materials are becoming critical to manufacturing reliability and regulatory success (Alliance for Regenerative Medicine, 2024). 

Here’s the takeaway: replacing  serum– or plasma-derived reagents with recombinant, chemically defined materials doesn’t just improve product quality, it streamlines regulatory pathways. For companies facing tight review timelines, that can mean the difference between months of delay and first-pass approval. 

The Bottom Line

As the industry shifts toward more reproducible, transparent biomanufacturing, the message is clear: definition drives confidence. By eliminating the uncertainty of donor-derived materials, manufacturers can deliver consistency regulators can verify and performance scientists can trust. 

 Optibumin 25 exemplifies how defined materials translate scientific rigor into measurable results, offering purity and consistency that support safer, more reliable, and more compliant biomanufacturing. 

Learn more about Optibumin 25

Contact us to learn how InVitria’s recombinant, chemically defined, animal-origin-free materials can help you strengthen process reproducibility, streamline regulatory documentation, and reduce variability at every stage of manufacturing.