Biopharmaceutical Companies Discover, Develop 

& Manufacture Protein Drugs

Mike Tarlov, Chief Biomolecular Measurement Division, MML

Gene of interest

Clone into

expression

vector

Transfer into

host cell

Purification Cell Culture Fill & formulation

Protein therapeutic

candidate
Success and Growth of Protein Therapeutics...

But Concerns That Trend May Be Unsustainable

• 7 of top 10 selling pharmaceuticals worldwide are protein therapeutics1

• 2015 sales of ~$115B for protein therapeutics in US... but are the fastest growing 

US healthcare cost2

• Growing demand and cost threaten to limit patient access 

1 Source: Evaluate Pharma, Sandoz analysis

2 Boston Globe, May 29, 2015

“High-priced “specialty drugs” represent just 1 % of the prescriptions for Blue 

Cross’ members, but 25 % of drug spending, a share that is rising rapidly. 

That’s not sustainable.” 2

Tony Dodek, Assoc. Chief Medical Officer, Blue Cross Blue Shield of Massachusetts
Measurement Challenges of Biologics Contribute to Cost of 

Manufacturing and Development

Monoclonal antibody

(~150 kDa)

Lipitor (<0.5 kDa)

• Manufacturing processes remain frozen

• Process change requires regulatory review

• Hinders adoption of innovative approaches/technologies to 

improve efficiency & product quality 

• Challenges in developing generic versions: biosimilars

• Regulatory pathway for biosimilars established in 2010

• Estimated cost savings of $250B through 2024 (Dr. Steve Miller, Express Scripts)

• First biosimilar approved March 2015, but not on market

“API” “Drug substance”
NIST Program in Biomanufacturing

• Measurement science, standards, and data to 

support development, manufacturing, & regulatory 

approval of protein therapeutics

• Extensive stakeholder input & interactions (regulatory, 

biopharma, instrument vendors, academia) 

• Relevant, innovative and robust tools

• Open data sharing, crowd-sourcing approach

Partners and Stakeholders:

“NIST Biopharmaceutical Measurment Roundtable” held annually since 2012
NIST Biomanufacturing Program Areas

Protein Stability/Biophysical Protein Structure

• Particulates, Aggregation

• (Surrogate Protein Particle SRM 1989)

• Flow microscopy 

• AFFF, SEC

• Stability predicting tools

• Neutron scattering

• Raman and Red edge spectroscopy

• Rheology

• Micro-viscosity

• Shear effects

(NISTmAb RM 8671)*

• Primary structure, modifications 

• Mass spectrometry

• MS library

• Peptides, glycans, glycopeptides, 

all modifications

• Protein folding 

• FT-IR, DSC/fluorimetry, Raman optical 

activity

• Higher-order structure 

• HDX-MS

• NMR

• Neutron scattering

• Cell line ID

• Multiplex PCR

• Production cell expression

• Fluorescence imaging

• Host cell 

• MS Library

• HCP peptides, glycans

metabolites

Production Cell Variability

2D NMR Mapping 

of mAb Structure

Building a Universal 

mAb Mass Spectral Library
NISTmAb Reference Material

PIs: John Schiel, Patricia Formolo

NISTmAb attributes:

• Humanized mAb (IgG1κ) donated by MedImmune LLC

• Frozen bulk “Drug-like substance”

First of its kind mAb (IgG1) reference material used for:

• Determining that measurement system is working properly

• Assessing performance of new analytical technologies

“Crowd-Sourcing” of NISTmAb characterization:

• Extensive interlaboratory characterization: Biopharma (11 companies, 44 

participants), FDA, instrument, academia

• Interlab study basis for 3 volume ACS book series. 1st volume published Dec. 

2014: http://pubs.acs.org/isbn/9780841230262

• To certify for concentration and issue as SRM by end of 2015

• Reference Data: peptide, glycan, glycopeptide spectra (~4000 spectra) as part of 

NIST MS Library; NMR and chromatographic data also