Health

Insulin

Temperature-sensitive diabetes medication.

Why it matters · High-stakes patient access risk when cold chain or manufacturing breaks.

5

Inputs

10

Companies

4

Facilities

7

Source countries

How it's made

The process

  1. 01

    Microbial Fermentation

    Fed-batch fermentation using E. coli BL-21 (Novo Nordisk, Sanofi route) or Saccharomyces cerevisiae yeast (Eli Lilly, ~50% of global supply). Fermentation media: glycerol, yeast extract, tryptone, NaCl, ampicillin; lactose-induced expression of insulin precursor/proinsulin. E. coli forms insoluble inclusion bodies; yeast secretes proinsulin directly into culture supernatant.

  2. 02

    Harvest & Cell Lysis / Broth Clarification

    E. coli route: high-pressure homogenization to lyse cells; inclusion body isolation via membrane microfiltration or centrifugation. Yeast route: culture broth clarified by tangential flow filtration (TFF) to capture secreted proinsulin at ~5 g/L with 95% recovery. Both routes yield crude insulin precursor.

  3. 03

    Solubilization & Refolding (E. coli route)

    Inclusion bodies solubilized in chaotropic agents (urea or guanidine-HCl) then refolded to achieve correct disulfide bond formation (A6–A11 and A7–B7 bonds). Refolding yield and efficiency is a key process bottleneck. Yeast route skips this step — proinsulin is already correctly folded upon secretion.

  4. 04

    Enzymatic Processing (Trypsin Cleavage)

    Proinsulin enzymatically cleaved by trypsin and carboxypeptidase B to remove the connecting C-peptide, yielding two-chain insulin (A-chain + B-chain). For analogs (glargine): citraconylation removes impurities before cleavage; additional modifications introduce amino-acid changes at B-chain terminus.

  5. 05

    Capture & Intermediate Chromatography

    Multi-step chromatographic purification using ion-exchange resins: (1) Capto MMC multimodal cation exchanger for initial proinsulin/insulin capture from lysate; (2) Capto SP ImpRes for polishing — removes truncated insulin variants and host-cell protein impurities. Reverse-phase HPLC achieves ≥98.6% purity at final polishing step. Buffer exchange via TFF ultrafiltration membranes.

  6. 06

    Crystallization

    Purified insulin precipitated as zinc-insulin crystals by addition of zinc chloride (ZnCl₂, 0.005 M). Crystals form stable hexameric insulin complexes. Crystal size controlled by pH, zinc concentration, and temperature — determines absorption kinetics in final product (lente insulins use specific crystal sizes). Crystallization also serves as an additional purification step.

  7. 07

    Formulation

    Insulin crystals dissolved and formulated with excipients: m-cresol (2.3–3.2 mg/mL) as antimicrobial preservative and structural stabilizer, phenol, zinc, and buffering agents. Concentration adjusted to 100 IU/mL standard. Sterile filtration through 0.2 μm filters. Formulation varies by type (rapid-acting, long-acting) — glargine uses unique pH-dependent precipitation for extended release.

  8. 08

    Sterile Fill-Finish

    Formulated insulin aseptically filled into 10 mL multi-dose vials, 3 mL cartridges (for pens), or prefilled syringes under ISO 5 cleanroom conditions. Cold-chain packaging begins immediately — product must be maintained at 2–8°C throughout distribution. Each lot undergoes potency, sterility, endotoxin, and identity testing before release.

Where it comes from

Country dependencies

Weighted share of upstream inputs sourced from each country.

CountryWeighted shareInputs supplied to insulin
DKDenmark45%Recombinant Insulin API (Bulk Drug Substance)
SESweden40%Bioprocess Chromatography Resins
USUnited States22%Bioprocess Chromatography Resins · Recombinant Insulin API (Bulk Drug Substance)
FRFrance20%Recombinant Insulin API (Bulk Drug Substance)
DEGermany20%Bioprocess Chromatography Resins
JPJapan15%Bioprocess Chromatography Resins
INIndia5%Recombinant Insulin API (Bulk Drug Substance)

Who makes it

Supplier companies

10 companies in this supply chain, sorted by market share.

Novo Nordisk (NVO)
HQ DK45% share

World's largest insulin manufacturer. Controls ~33.7% of global diabetes care market; ~45% of human insulin. Operates the world's largest insulin production facility in Kalundborg, Denmark (produces ~50% of global insulin supply). Dominant in GLP-1 drugs (Ozempic/Wegovy); FY2024 revenue DKK 232B. Uses both E. coli and yeast fermentation.

Supplies these inputs

Recombinant Insulin API (Bulk Drug Substance)

Replaceability

Substitutability 10% · 36 mo to replace

Business segments

  • Insulin (World #1 — ~45% Global Market)30% rev
  • GLP-1 Drugs (Ozempic + Wegovy + Victoza)55% rev
  • Rare Disease + Hemophilia15% rev

Life sciences tools company (Marlborough, MA; wholly-owned by Danaher Corporation since $21.4B acquisition of GE Healthcare Life Sciences in 2020) that manufactures Whatman membrane filter papers and sterile filtration products alongside its dominant chromatography resin (Capto, Sephadex, Sepharose series) and bioreactor (WAVE, XDR) platforms. Cytiva is the successor to GE Healthcare Life Sciences and Amersham Biosciences. Whatman-branded products include nitrocellulose and mixed cellulose ester membranes used in sterile filtration, diagnostics, and laboratory applications. Cytiva's role in sterile filtration is secondary to Merck KGaA and Pall — Whatman filters are more prevalent in laboratory/QC applications than primary pharmaceutical manufacturing sterilization — but Cytiva's ownership alongside Pall within Danaher creates the world's most concentrated supply position in biopharmaceutical manufacturing consumables. Danaher's combined Pall + Cytiva platform spans filtration, chromatography, bioreactors, and cell culture media — covering essentially every critical consumable step in a biologics manufacturing process.

Supplies these inputs

Bioprocess Chromatography Resins

Replaceability

Substitutability 10% · 36 mo to replace

Business segments

  • Protein A Chromatography Resins (World Dominant)35% rev
  • Single-Use Bioreactors + Cell Culture30% rev
  • Filtration (Whatman + Sterile)20% rev
  • Laboratory Instruments + Services15% rev

Second-largest insulin manufacturer; invented the first commercial insulin (1923). Uses Saccharomyces cerevisiae (yeast) fermentation exclusively. Markets Humalog (lispro), Basaglar (glargine), and Lyumjev. Also dominant in GLP-1 market (Mounjaro/Zepbound). FY2024 revenue ~$45B.

Supplies these inputs

Recombinant Insulin API (Bulk Drug Substance)

Replaceability

Substitutability 10% · 36 mo to replace

Business segments

  • Insulin (First Commercial Insulin, 1923)15% rev
  • GLP-1 (Mounjaro + Zepbound = Tirzepatide)45% rev
  • Oncology (Verzenio + Kisunla)25% rev
  • Immunology + Neuroscience15% rev
Sanofi (SNY)
HQ FR22% share

Third of the global insulin oligopoly. Markets Lantus (glargine) — historically the world's best-selling insulin — and Toujeo. Uses E. coli fermentation at Frankfurt plant. WHO-prequalified for insulin glargine. Divesting insulin business in some regions as GLP-1 market grows.

Supplies these inputs

Recombinant Insulin API (Bulk Drug Substance)

Replaceability

Substitutability 10% · 36 mo to replace

Business segments

  • Dupixent (Dupilumab — Fastest-Growing Drug in History)35% rev
  • Vaccines (Sanofi Pasteur)25% rev
  • Insulin (Lantus/Toujeo) + Rare Disease25% rev
  • Multiple Sclerosis + Immunology15% rev

Supplies these inputs

Bioprocess Chromatography Resins

Business segments

  • Laboratory Products and Biopharma Services34% rev
  • Life Sciences Solutions25% rev
  • Analytical Instruments16% rev
  • Specialty Diagnostics10% rev

German science company (Darmstadt; family-owned since 1668) life sciences division (MilliporeSigma in US) produces Fractogel EMD bioprocess chromatography resins alongside its Millipore filtration products and Sigma-Aldrich research chemicals. Fractogel resins (Fractogel EMD SO3-, Fractogel EMD TMAE) are an alternative to Cytiva's Capto resins for cation and anion exchange steps in biologics purification — primarily used by biomanufacturers seeking to reduce single-supplier dependence on Cytiva. Merck KGaA's same Darmstadt facility that makes sterilizing filters for pharmaceutical manufacturers (Durapore, Millipak) also produces the Fractogel resins used in the same manufacturers' upstream purification trains.

Supplies these inputs

Bioprocess Chromatography Resins

Replaceability

Substitutability 15% · 36 mo to replace

Business segments

  • Life Science (MilliporeSigma)40% rev
  • Healthcare (Branded Pharma)30% rev
  • Electronics (EMD Electronics / Versum)30% rev

Japanese bioscience and chromatography subsidiary of Tosoh Corporation (TYO: 4042, HQ Tokyo; ~¥900B revenue); produces TOYOPEARL brand bioprocess chromatography resins — the primary alternative to Cytiva resins for protein A (Protein A resin for antibody purification), hydrophobic interaction, and ion exchange chromatography in biologics manufacturing. Tosoh Bioscience's Protein A resins (TOYOPEARL AF-rProtein A and similar) are validated alternatives to Cytiva's MabSelect series for monoclonal antibody purification — one of the few Cytiva process alternatives with sufficient regulatory documentation for biologics manufacturers to qualify. Tosoh Corporation also manufactures specialty vinyl chloride resins, chlor-alkali chemicals, and other industrial chemicals alongside its bioscience chromatography business — a Japanese conglomerate spanning plastic pipes, caustic soda, and biologics purification from one Tokyo industrial company.

Supplies these inputs

Bioprocess Chromatography Resins

Replaceability

Substitutability 15% · 36 mo to replace

Business segments

  • Chlor-alkali & Inorganic Chemicals38% rev
  • Organic Chemicals25% rev
  • Specialty Materials & Engineering Plastics22% rev
  • Bioscience (TOYOPEARL)15% rev

Intas Pharmaceuticals (Ahmedabad Gujarat India; privately held; founded 1976 by Hasmukh Chudgar; ~$2.4B revenue est. 2022) is the world's largest manufacturer of cisplatin and carboplatin APIs and one of India's largest private pharmaceutical companies. Intas operates its international generic injectable business under the brand Accord Healthcare (UK-registered subsidiary). Intas's Ahmedabad/Sanand API manufacturing complex in Gujarat was the single most important source of cisplatin API for the US market, supplying an estimated 50-60% of US cisplatin imports from its Gujarat facilities. In November 2022, FDA investigators conducting a pre-approval inspection at Intas's Ahmedabad manufacturing facility (FEI 3003889748) discovered hundreds of trash bags filled with shredded quality-control documents — evidence of deliberate document destruction intended to conceal data integrity violations. FDA issued a Form 483 with 10 observations. The FDA subsequently issued a Warning Letter in December 2022. Intas voluntarily ceased API production at the facility. The resulting API supply gap triggered the worst US oncology drug shortage in a decade, beginning in February 2023 for cisplatin and April 2023 for carboplatin. The Intas-Accord shortage became the central case study for pharmaceutical supply chain concentration risk.

Supplies these inputs

Recombinant Insulin API (Bulk Drug Substance)

Business segments

  • Global Generics (Accord Healthcare)47% rev
  • India Formulations (Branded Generics)31% rev
  • API and Contract Manufacturing14% rev
  • Biologics and Biosimilars8% rev

Indian biotechnology and pharmaceutical company (NSE: BIOCON; Biocon Biologics listed separately; HQ Bangalore; ~₹150B revenue for Biocon group); Biocon is India's largest biopharmaceutical company and a major producer of complex small molecules and biologics including cyclosporine A API and immunosuppressants. Biocon Limited was founded in 1978 by Kiran Mazumdar-Shaw — one of India's most prominent female entrepreneurs — as an enzyme fermentation company, starting in a garage with ₹10,000 in capital. Today Biocon is a ~$3B revenue pharmaceutical company producing insulin biosimilars, cancer biologics, and complex small molecule APIs including cyclosporine A. The same Biocon that produces the cyclosporine A API for generic dry eye drops also produces trastuzumab biosimilar (Herceptin equivalent for breast cancer) and insulin analogs for diabetes — one Indian startup from 1978 spanning oncology, endocrinology, and ophthalmology API supply chains.

Supplies these inputs

Recombinant Insulin API (Bulk Drug Substance)

Replaceability

Substitutability 40% · 24 mo to replace

Business segments

  • Biosimilar Insulins (World #1 by Volume)40% rev
  • Oncology Biosimilars30% rev
  • Immunology Biosimilars20% rev
  • Small Molecule APIs + Industrial Enzymes10% rev