Reference materials & certified reference strains

01Overview and value chain

Markers: [EC: WHO Biological Standardization programme & OECD BRC guidelines | OECD: Biotech & health | Regulator: FDA (USA), EMA (EU), NMPA (China)]

Reference materials and certified reference strains are the calibrated living standards of the bioeconomy: authenticated, publicly accessible microbial cultures and biological reagents against which identity, potency and purity are measured. The American Type Culture Collection (ATCC), founded in 1925 and holding more than 100,000 strains, now authenticates 3,938 reference genomes through its open genome portal; the Leibniz Institute DSMZ in Braunschweig maintains around 75,000 bacteria, fungi, yeasts and cell lines; and the UK’s NIBSC holds roughly nine in ten of the WHO International Standards that calibrate the potency of vaccines, insulin and cytokines worldwide. These biological resource centres (BRCs) operate under ISO 17034 reference-material-producer accreditation and the OECD BRC guidelines, and most are designated Budapest Treaty authorities for patent deposit of micro-organisms. Their output is the invisible substrate of reproducible biotechnology: a sterility test, an antimicrobial-susceptibility panel or a CAR-T potency assay is only as trustworthy as the reference strain it runs against.

The key directions of reference materials and certified reference strains are:

1. Authenticated type strains (Type-Strain Authentication): the nomenclatural type cultures that define a microbial species, deposited and cryopreserved under the International Code of Nomenclature of Prokaryotes (ATCC, DSMZ, NCTC).
2. WHO biological reference materials (WHO Reference Materials): International Standards and reference reagents that calibrate biological potency — NIBSC holds the majority of the WHO biological standards for biologics, from insulin to monoclonal antibodies.
3. Patent and biodiversity deposit (Patent Deposit): Budapest Treaty designated authorities (ATCC, DSMZ, CCTCC, MTCC) hold micro-organisms cited in patents, satisfying disclosure without revealing trade secrets.
4. Genome-authenticated reference reagents (Genome-Authenticated Reagents): reference strains whose whole genome is sequenced and published, closing the gap between classical culture and modern genomics (ATCC Genome Portal, NCTC 3000).

Sectoral value chain

[isolation & taxonomy] ──> [authentication & genome sequencing] ──> [cryopreservation] ──> [QC & accreditation]
                                             │
                                  (ISO 17034 / OECD BRC)
                                             │
                                             ▼
[distribution to labs] <─── [catalogue & deposit] <─────┘

Value chain levels

Cross-cutting technologies of the sector:

• Whole-genome authentication (Whole-Genome Authentication): long-read sequencing of type strains to fix the reference genome (ATCC Genome Portal, NCTC 3000 project).
• Vapour-phase cryopreservation (Vapour-Phase Cryopreservation): master/working banks at -150 °C below the liquid nitrogen line for long-term genetic stability.
• ISO 17034 reference-material production (ISO 17034 RM Production): accredited workflow producing certified reference materials with documented metrological traceability.

02US

The United States hosts the world’s largest and oldest biological resource centre, ATCC, whose authenticated strains anchor US pharmacopoeial and FDA QC.

type-strain authority, genome portal, pharmacopoeial QC

• ATCC: founded in 1925 in Manassas, Virginia, ATCC holds more than 100,000 authenticated strains and operates the open ATCC Genome Portal with 3,938 reference genomes, supplying the strains cited in USP general chapters for sterility and growth-promotion testing.
• Pharmacopoeial reference strains: USP <62> and antimicrobial-susceptibility panels rely on ATCC reference strains such as Staphylococcus aureus ATCC 25923 and Pseudomonas aeruginosa ATCC 27853.
• Budapest Treaty authority: ATCC is a designated international depositary authority (IDA) for micro-organism patent deposit under WIPO’s Budapest Treaty.

03CN

China’s reference-strain infrastructure is anchored by the China Center for Type Culture Collection, a designated patent-deposit authority serving both academia and the fast-growing domestic biotech sector.

type culture collection, patent deposit, biodiversity

• CCTCC (中国典型培养物保藏中心): based at Wuhan University, the China Center for Type Culture Collection is a Budapest Treaty international depositary authority holding tens of thousands of bacterial, fungal and cell-culture deposits.
• Biodiversity compliance: CCTCC supports China’s access-and-benefit-sharing obligations under the Nagoya Protocol by documenting the origin of deposited genetic resources.
• Domestic standards: MARA and NMPA reference workflows draw on CCTCC and related national culture collections for strain identity and QC.

04EU

Europe operates a federated network of national culture collections and the world’s leading centre for WHO biological reference materials.

WHO standards, type cultures, Leibniz network

• NIBSC (UK): the National Institute for Biological Standards and Control is the WHO Collaborating Centre for Biological Standardization, holding roughly 90 percent of the WHO International Standards that calibrate the potency of vaccines, hormones and biologics globally.
• NCTC (UK): the National Collection of Type Cultures, hosted by the UK Health Security Agency and founded in 1914, is one of the oldest bacterial type-culture collections, with the NCTC 3000 project sequencing its historical strains.
• DSMZ (Germany): the Leibniz Institute DSMZ German Collection of Microorganisms and Cell Cultures in Braunschweig maintains around 75,000 cultures and is a Budapest Treaty depositary and a core European BRC.
• CECT (Spain): the Colección Española de Cultivos Tipo at the University of Valencia is Spain’s national type-culture collection and a member of the European infrastructure.

05Leading companies and research institutes

06Tech stack and innovations

The reference-material stack rests on metrological authentication, stable preservation and open data, each hardened by a century of culture-collection practice.

1. Whole-genome authentication (Whole-Genome Authentication):
   • long-read sequencing fixes the reference genome of each type strain, replacing 16S-only identification.
   • case: the ATCC Genome Portal publishes 3,938 authenticated reference genomes; NCTC 3000 sequences historical strains.
2. Vapour-phase cryopreservation (Vapour-Phase Cryopreservation):
   • master and working cell banks are held at about -150 °C in the vapour phase above liquid nitrogen to maximise genetic stability over decades.
   • viability, purity and identity are re-verified on retrieval against the release specifications.
3. Metrological traceability (Metrological Traceability):
   • ISO 17034 accreditation requires documented traceability and uncertainty for each certified reference material, mirroring ISO Guide 34 and the OECD BRC guidelines.
   • WHO International Standards from NIBSC assign International Units (IU) that harmonise biologics potency across manufacturers and regulators.

07Value chains and production pipelines

Industrial pipeline of a certified reference strain (ISO 17034 / OECD BRC)

┌───────────────────────────┐      ┌───────────────────────────┐
│ 1. Isolation & taxonomy   │ ───> │ 2. Authentication + WGS   │
└───────────────────────────┘      └───────────────────────────┘
                                                  │
                                                  ▼
┌───────────────────────────┐      ┌───────────────────────────┐
│ 4. QC release             │ <─── │ 3. Cryopreservation       │
└───────────────────────────┘      └───────────────────────────┘
              │
              ▼
┌───────────────────────────┐      ┌───────────────────────────┐
│ 5. Catalogue + deposit    │ ───> │ 6. Cold-chain distribution│
└───────────────────────────┘      └───────────────────────────┘

Stage 1: Isolation and taxonomy

A strain is isolated from an environmental or clinical sample and characterised by polyphasic taxonomy — phenotypic, biochemical and 16S/ITS markers — to establish its identity and nomenclatural type status.

Stage 2: Authentication and whole-genome sequencing

Identity is confirmed and a whole-genome sequence is generated and deposited in the public reference database, fixing the strain’s genetic blueprint for downstream QC and comparative genomics.

Stage 3: Cryopreservation

Master and working cell banks are prepared under axenic conditions and stored in vapour-phase liquid nitrogen at about -150 °C, with replicate banks for disaster recovery and long-term stability.

Stage 4: QC release

Each batch is released against viability, purity and identity specifications under ISO 17034, with a certificate stating metrological traceability and uncertainty for certified reference materials.

Stage 5: Catalogue and deposit

The authenticated strain is listed in the public catalogue with its passport data and, where relevant, accepted as a Budapest Treaty or Nagoya-Protocol deposit, generating a legal record for patents and access-and-benefit-sharing.

Stage 6: Cold-chain distribution

Orders from pharmaceutical, diagnostic and academic laboratories are fulfilled on dry ice or freeze-dried ampoules with full cold-chain tracking, closing the loop between the resource centre and the end-user assay.