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How is squalene manufactured for medical use?
Executive summary
Squalene for medical use is now produced by several routes: traditional extraction from shark liver and plant oils, and increasingly by engineered microbial fermentation (yeast, bacteria, algae) plus downstream enrichment and purification to pharma grade [1] [2] [3]. Recent reviews explain that metabolic engineering (MVA or MEP pathways), fermentation optimization and downstream purification are the core steps that determine yield, sustainability and regulatory suitability [4] [5] [6].
1. How squalene is made today: three broad supply chains
The historic commercial source is shark liver oil, and plant oils (olive, amaranth, rice bran, palm) are also used; modern commercial production is shifting toward microbial and plant-derived processes because of sustainability and regulatory pressures [2] [7] [1]. Microbial/biotechnological routes—using engineered yeasts, bacteria, cyanobacteria or oleaginous microbes—are the primary alternatives discussed in recent literature [4] [5] [8]. Evonik markets a plant‑based, GMP pharma-grade squalene (PhytoSquene®) produced from amaranth-derived oil with enrichment and membrane‑based purification for parenteral use, illustrating a non‑shark, pharmaceutical pathway [3].
2. The biochemistry: MVA vs MEP pathways and the enzymes manufacturers tweak
Squalene is a triterpene produced natively via the mevalonate (MVA) pathway in yeasts and via the methylerythritol phosphate (MEP) pathway in many bacteria; industrial strain engineering manipulates these pathways to channel carbon and reducing power into squalene rather than downstream sterols [4] [2]. Common genetic strategies include overexpressing rate‑limiting enzymes (for example HMG‑CoA reductase derivatives), knocking out competing enzymes like squalene epoxidase, and compartmentalizing pathways into organelles or droplets to increase storage [5] [9] [8].
3. From cell to material: fermentation and upstream scale‑up
Once a high‑producing strain is constructed, companies scale it in fermenters with medium optimization, feed strategies and sometimes CO2 enrichment (for photosynthetic microbes) to maximize titers; reviews emphasize reactor conditions and adaptive evolution as crucial process levers [5] [6] [8]. Reported microbial yields have historically been low relative to bulk needs, but recent engineering and process advances are improving titres toward commercial viability [10] [6].
4. Downstream: extraction, enrichment and pharma‑grade purification
Squalene is hydrophobic and typically requires solvent extraction or cell‑disruption followed by purification steps such as membrane fractionation, multistage separation and hydrogenation (when producing squalane) to reach the purity demanded for medical use [10] [11] [3]. Evonik’s PhytoSquene® process specifically mentions enrichment and nanomembrane filtration from amaranth oil to achieve GMP quality for vaccine adjuvants, showing how plant feedstocks plus robust downstream processing can meet pharmaceutical standards [3].
5. Quality, regulation and end‑use: what makes squalene “medical‑grade”?
Pharmaceutical applications—adjuvants for vaccines or parenteral excipients—require compliance with pharmacopeial standards and GMP production, which pushes manufacturers toward traceable, non‑animal sources and validated purification [3]. Reviews note that standardization, certification and clinical validation are still important hurdles for microbial squalene acceptance in medical formulations [8].
6. Tradeoffs and controversies: sustainability, cost and scalability
Shark‑derived squalene raises conservation concerns that have driven regulation and market pressure to switch sources; plant and microbial routes reduce animal welfare and biodiversity impacts but face challenges: microbial intracellular production complicates in‑situ extraction and can raise costs, and plant feedstocks have supply and land‑use considerations [2] [8] [1]. Academic and industry literature highlight that achieving competitive cost and consistent pharma quality is the central bottleneck for replacing traditional sources [6] [8].
7. Where reporting disagrees or remains incomplete
Sources agree microbial/plant routes are viable alternatives but differ on commercial readiness: some reviews emphasize still‑insufficient yields and high costs for microbial fermentation (citing low mg/L reports) [10], while newer engineering and process studies report significant advances and emerging commercial products [6] [3]. Available sources do not mention specific global production volumes or up‑to‑date price comparisons across shark, plant and microbial squalene suppliers—those data are not found in current reporting supplied here (not found in current reporting).
8. Bottom line for a reader: what to expect from the sector
Expect continued rapid technical progress: metabolic engineering, compartmentalization and fermentation scale‑up are improving yields, and plant‑derived GMP products (e.g., amaranth‑based PhytoSquene®) are already positioned for medical applications, while microbial fermentation remains an active area of research and emerging commercialization [5] [6] [3]. Stakeholders choosing squalene for medical use will weigh regulatory acceptance, traceability, sustainability and cost; these are the axes that determine whether a supplier is suitable for vaccine adjuvants or parenteral drugs [3] [8].