## How Are Biomanufacturers Removing Impurities Effectively in 2026?

Residual host cell proteins (HCPs), DNA, and trace metal impurities remain the primary quality threats in biologics manufacturing — and the industry's answer in 2026 is orthogonal chromatography stacks, ICP-MS trace element profiling, and bioinformatics-guided upstream design deployed together, not sequentially. According to a GEN roundup published August 17, 2026, leaders from Agilent, MilliporeSigma, and Repligen described the specific technologies underpinning effective impurity control across upstream and downstream workflows. Three themes dominate: the shift toward modality-specific [downstream processing](https://synbiointel.com/glossary/downstream-processing) strategies, the rising regulatory pressure to adopt LC-MS for HCP characterization early in process development, and the role of supply chain resilience — tested concretely when a ferric ammonium citrate (FAC) sourcing disruption forced rapid analytical comparability work. For manufacturers of complex biologics, the collective message is that no single platform suffices; the question is how tightly these orthogonal layers are integrated.

---

## Upstream: Stopping Impurities Before They Enter the Process

The consensus across contributors is that impurity control starts well before the bioreactor. Bioinformatics-driven liability assessment — analyzing sequences and cell line characteristics computationally — can flag HCP accumulation risks before process development begins. Clone selection and high-throughput upstream optimization are cited as tools to prevent upregulation of lipases and proteases, enzymes that drive oxidation and protein unfolding but that cells express as stress responses under prolonged culture.

MilliporeSigma's contributors highlighted stringent raw material qualification as a parallel upstream lever. Their use of ICP-MS for multi-element profiling allows precise characterization of low-level metal impurities — particularly relevant because trace metals can catalyze oxidative degradation of protein therapeutics. Engineered cell culture media, designed to reduce variability at the point of impurity ingress, paired with supplier qualification and risk-based raw material selection, round out their upstream framework.

The FAC case study in the GEN roundup is worth unpacking. When alternative sourcing introduced FAC with markedly different trace element profiles, MilliporeSigma used its integrated chemical manufacturing expertise and ICP-MS platforms to engineer a replacement solution aligned with historically established baselines. The stated outcome: defined impurity targets preserved process comparability and avoided customer reformulation. This is a concrete example of how analytical infrastructure becomes a supply chain asset, not merely a QC function — a distinction that CDMOs and enterprise biologics manufacturers should internalize as geopolitical supply pressures persist.

---

## Primary Harvest: The Undervalued First Line of Defense

Depth filtration at primary harvest receives attention in the roundup that it rarely gets in public discourse. Contributors described effective depth filtration combined with charged media as the first physical separation step, working simultaneously through size exclusion and electrostatic, hydrophobic, and hydrogen bonding mechanisms. As upstream processes intensify — higher cell densities, longer culture durations — the clarification burden at harvest increases proportionally. Underinvesting in this step pushes a larger impurity load into the chromatography train, compressing column lifetimes and complicating downstream economics.

The roundup notes that viral inactivation also contributes to impurity reduction: the precipitation of impurities during inactivation, when followed by charged depth filtration optimized for pH and conductivity, provides an additional clearance mechanism that is often treated as incidental rather than designed.

---

## Downstream Purification: Modality-Specific, Multimodal, and Increasingly Orthogonal

Affinity chromatography remains foundational for bulk clearance of primary product-related impurities — the roundup from Repligen reinforces this position explicitly. But the more technically interesting discussion in the GEN piece concerns what happens in polishing steps.

For standard biologics, multimodal resins combining ion exchange (IEX), hydrophobic interaction chromatography (HIC), and hydrogen bonding are described as providing "powerful synergistic polishing" for aggregates, fragments, stubborn HCPs, endotoxins, viruses, and residual affinity ligand. The explicit goal is a product pure enough to support liquid formulation studies — formulation stability being where residual impurities most visibly manifest as shelf-life problems.

For oligonucleotides, the strategy diverges: orthogonal ion-pairing reverse phase (IP-RP) and anion exchange (AEX) chromatography are cited as the tools of choice to resolve sequence failures and closely related variants — a technically demanding separation problem given the structural similarity of truncated oligo sequences to full-length product.

A specific challenge flagged by contributors — HCP-target molecule-histone complexes, sometimes called "hitchhiking" HCPs — underscores why generic affinity protocols are insufficient for complex modalities. These complexes survive standard wash conditions and require enhanced wash strategies designed to disrupt the interaction specifically.

---

## Regulatory Trajectory: LC-MS for HCP Characterization Is Becoming Mandatory

Perhaps the single most consequential signal for process development teams: contributors note that changes to regulatory guidance now mandate future HCP characterization using LC-MS informed early in process development. This is not a future aspiration — it is a compliance trajectory that affects how development resources should be allocated today. LC-MS provides the resolution to identify individual HCP species rather than relying on aggregate ELISA signals, enabling more defensible regulatory filings and earlier identification of immunogenicity-relevant proteins.

For smaller biotechs and [CDMOs](https://synbiointel.com/glossary/cdmo) without in-house LC-MS infrastructure, this represents a real capability gap. The analytical bar for IND and BLA filings is rising, and instrument access alone is insufficient without the bioinformatics workflows to interpret complex HCP proteomes.

Agilent's Bio-inert LC platforms are specifically called out in the roundup for minimizing metal interactions that can compromise protein integrity or mask low-level impurities — a design consideration relevant precisely because metal contamination from instrument surfaces can confound the very HCP measurements regulators are increasingly scrutinizing.

---

## What This Means for the Industry

The roundup reflects a maturing field where the headline technologies — affinity chromatography, depth filtration, viral inactivation — are well established, but the differentiation increasingly lies in integration depth, analytics rigor, and supply chain resilience. Three implications stand out:

**Analytical infrastructure is now a manufacturing asset.** MilliporeSigma's FAC case study illustrates that ICP-MS capability enabled a supply disruption to be absorbed without customer reformulation. That is a commercial differentiator, not just a QC function.

**Modality-specific purification is replacing one-size-fits-all platforms.** Oligonucleotides, large proteins, and increasingly complex bispecifics each require tailored chromatography strategies. Platform processes that served the antibody era are being retooled.

**Early LC-MS for HCP characterization will separate compliant from non-compliant development programs.** Teams that build this capability during lead optimization rather than at the BLA stage will have a structural regulatory advantage.

The skeptical read: this GEN roundup is a curated vendor perspective, not independent benchmarking data. Agilent, MilliporeSigma, and Repligen all have commercial interests in the technologies they describe. Independent head-to-head data on multimodal resin performance, depth filtration efficiency under intensified upstream conditions, and ICP-MS sensitivity thresholds in complex media would be more actionable for process development decisions.

---

## Key Takeaways

- **HCP control starts computationally**: bioinformatics-driven clone selection and upstream optimization reduce lipase and protease expression before purification begins
- **Depth filtration at primary harvest is undervalued** and increasingly critical as upstream cell densities intensify
- **Multimodal resins** combining IEX, HIC, and hydrogen bonding are the current standard for polishing aggregates, fragments, endotoxins, and residual affinity ligand
- **Oligonucleotides** require orthogonal IP-RP and AEX chromatography to resolve closely related sequence variants
- **LC-MS for HCP characterization** is moving from best practice to regulatory expectation — teams without this capability face a compliance gap
- **Supply chain resilience** requires embedded analytical infrastructure: MilliporeSigma's FAC disruption response demonstrates ICP-MS as a change management tool
- **No single platform suffices** — effective impurity control in 2026 is an integrated, orthogonal stack problem

---

## Frequently Asked Questions

**What are the most common impurities in biomanufacturing downstream processing?**
The primary categories are process-related impurities — host cell proteins (HCPs), host cell DNA, and media components — and product-related impurities such as aggregates and fragments. Residual affinity ligand, endotoxins, and viruses must also be cleared to defined levels for regulatory compliance.

**Why are host cell proteins particularly difficult to remove in biologics manufacturing?**
HCPs are a heterogeneous mixture of hundreds of individual proteins, some of which form stable complexes with the target molecule or with histones ("hitchhiking" HCPs). These complexes survive standard affinity wash conditions and require specifically designed enhanced wash strategies. ELISA-based aggregate HCP measurements can mask individual problematic species, which is why LC-MS characterization is increasingly required.

**What is the role of ICP-MS in biomanufacturing impurity control?**
Inductively coupled plasma mass spectrometry (ICP-MS) provides multi-element profiling of trace metal impurities in raw materials and process streams. Trace metals including iron can catalyze protein oxidation; ICP-MS enables precise characterization and specification of these low-level contaminants, supporting raw material qualification and comparability assessments during supply chain changes.

**How do purification strategies differ between monoclonal antibodies and oligonucleotides?**
Antibody purification typically uses Protein A affinity chromatography for capture followed by IEX and HIC polishing. Oligonucleotide purification relies primarily on orthogonal ion-pairing reverse phase (IP-RP) and anion exchange (AEX) chromatography to resolve truncated sequence variants and other closely related impurities that affinity resins cannot discriminate.

**What regulatory changes are driving LC-MS adoption for HCP characterization?**
Regulatory guidance changes cited by industry contributors indicate that LC-MS-based HCP characterization will be expected early in process development for future filings. This moves beyond aggregate ELISA measurements to individual protein species identification, enabling detection of immunogenicity-relevant HCPs and providing a more defensible regulatory package for INDs and BLAs.