Survey of Microfluidic Technology Trends and Perspective on

Hurdles to Market Entry for Point of Care Diagnostics

Leanna M. Levine, Ph.D.

President, ALine, Inc. www.alineinc.com

Outline

2

Why Point of Care?

Microfluidic POC Testing by Product Category

Market Segments and Development Activity

Microfluidic POC Products

Getting from Concept to Market

Manufacturability

References

Why Point of Care?

• Timely, though not necessarily more convenient or

less expensive

• Fewer errors in handling and information relay

• Supports patient compliance

• Promotes patient participation in their healthcare

• Supports Evidence based medicine -> ultimately

lowering the overall cost of healthcare delivery[1]

“Lean and keen by short vein-to-brain time”[3]

Current State of Technology

Two platform technologies that represent the

overwhelming majority of revenue for products on

the market:

– Electrochemical glucose tests (100 billion tests/yr)

– Lateral Flow Assays (LFA) (hCG alone; 10 million tests/yr)

– Everything else: < 10 million tests/yr

Analytical & Clinical Performance Criteria:

• Limit of Detection

– Glucose [mM]

– hCG [nM]

• Accuracy in Range

– 95% of Glucose measurements: +/-15mg/mL <75 mg/mL; +/- 20% >75 mg/mL

– LFA visible above a threshold, variability of +/- 10% to 20%

• Predictive Value

– Outliers lower correlation with reference tests -> lower predictive value

– Not adequate for tight glycemic control

– LFA provides yes/no answer, but require follow up lab test for quantitation

Alere (Epocal) “Epoc” Blood Analysis System using SmartCard Technology

Class of Assay Product CatagoriesConcentration

Range

Detection

Method

Example POC

ProductQual. Quant.

ChemistryGlucose, electrolytes,

blood gas uM - mM direct

iStat, Clinitek,

Epocalx

Immunoassays

HbA1c, cardiac markers,

substance abuse,

infectious diseases,

pregnancy,

rapid coagulation, CRP

fM- nM signal Amp

Nanogen,

BioScan,

Nanomix, Banyan

x x

Nucleic Acidgenotyping(warfarin, CF)

infectious diseasesaM

target amp +

signal amp

Cephied,

GenMarkx

Microfluidic POC Testing

Market Segmentation and Development Activity

• First world

– Hospital Clinic (replace large, bulky, clinical analyzers), Physician Lab, Emergency Medicine

– Consumer

• Resource limited

– Developing world -> infectious diseases,

– Fieldable Applications-> bio-threat monitoring, community clinics, environmental

• Urgent need for diagnostic tools for treatable infectious diseases (WHO, Gates Foundation, etc.) – MRSA, respiratory infections, TB, STDs, HIV, diarrhoeal diseases, e.g.

• Market needs incrementally better tools (re-purpose or extend existing technology) – Quantitative lateral flow platforms

– Paper-based systems

– Manufacturing approach well known

“An Imperfect Test is Better than no Test”

• Quantitative, multiplexed, sample-to-answer

• New enabling platforms (detection, microfluidics, reagents)

• Military/HSA funding

• Highly specific, high risk

• Nucleic acid analysis predominates

• Niche markets

• Route to manufacture not well understood

A Perfect Test for an Imperfect World

Company Fluid Movement Reagents Detection Manufacture Analyte Market

Epocal electroosmotic Dried electroactivethin/thick film roll to

rollSM hospital bedside

Abaxis centrifugal Dried optical injection molding Pveterinary, FDA

approval human

Nanomix pneumatic Blister + Dried electrochemicallaminate + injection

molded componentP ambulance/emerg

Cephied pneumatic/pumps Dried fluorescenceinjection molded

multi component NA bio threat, hospital

TearLab capillary flow none electroactive laminate SM doctor' office

iSTAT capillary flow N/A injection molding SM doctor's office

Advanced Liquid

Logicelectrokinetic on-off chip reservoirs fluorescence, injection molding NA Neonate

Charles River Labs pneumatic Dried fluorescence injection molded SM Process Water

Hemicron capillary flow Surface optical injection molding clotting doctor's office

GenMark mechanical Spotted electrochemicallaminate + injection

molded componentNA Hospital Lab

BioSurfit centrifugal Dried optical injection molded P,NA Hospital Lab

Daktari pneumatic Blister + Dried electrochemical injection molding C fieldable

HandyLab (BD Max) pneumatic Dried rtPCR injection molded P Hospital Lab

Microfluidic Technologies Used in POC Products

• Reagent Storage, Delivery, Waste – Dried, lypholysed – Liquid Blister Packs

• Sample processing – On/off board; Lysis, Separation, Dilution,

Metering

• Pumping – Pneumatic ,Electroosmotic, Mechanical

• Timing and fluid circuit – Sequential, branched, gated

• Detection and Multiplexing – Electroactive, optical, fluorescence

• Instrument interface – Alignment, manifold, orientation

• Instrument size, weight, power and cost

Many Technology Solutions to Choose From: Hurdle… Integration

The first 95% of the engineering effort is “easy”, The last 5% will uncover all the design flaws

associated with interfaces. • Reagent Storage , Delivery, Waste

– Kinetics of dissolution – Blister burst and expelling air

• Sample processing – Introduction, dilution, separation

• Pumping – On or off board, venting

• Timing and fluid circuit – Actuation routines, instrument checks

• Detection and Multiplexing – Cost and sensitivity, alignment

• Instrument interface – Pins, clamps, gaskets, o-rings

• Assembly

From IVD Technology, June, 2009

What GenMark has to manage: • Component sourcing

• Reagent sourcing

• Reagent spotting

• Component Assembly

• Instrument Design, Mfg.

• QC

• Labeling, Packaging

Cost of packaging > Cost of the Disposable

Claros Disposable (credit card size)

• Injection molded part 15%

• Labor and facilities 15%

• Reagents, packaging, lids… 70%

How will you sell it?

Most developers do not have market access • Sell the technology (nice for investors sometimes, but founders are usually very diluted)

• Sell product into distribution (they’ll expect a 40 -60% discount from your retail price)

How will you make a profit?

Consumer Pays 10.00$

Distribution Costs 5.00$

Required Gross Margin 3.00$

Packaging 1.00$

Assembly 0.70$

COGs 0.30$

Distribution of Costs

Design for Manufacture

• Work backwards from the final product

• Product Risk Analysis for every component in the assembly

• Solve the biggest problems first.

• Precision is expensive; design out if possible; if not choose the manufacturing method that will provide it at the least cost at volume

- roll to roll mfg.

- injection molding

Manufacturing Methods

Mass or Flow Manufacturing Batch or Flexible manufacturing

Method Flow of material is linear through the process, equipment fixed, and produces one product

Material moves through each type of operation in a group,

equipment is adaptable to different products

Flexibility None - every piece of equipment linked together for production of a single product

Some - equipment is modular and mobile to maximize work

flow efficiency

Capital Investment

High Capital Investment + High NRE

Low Capital Investment + Low NRE

>1 MM/yr <1 MM/yr

$ $$$$

$$ $$

1MM parts/yr = 1 part every six seconds (85k parts/month)

References:

“Commercialization of microfluidic point-of-care diagnostic devices”, Curtis D.

Chin , Vincent Linder and Samuel K. Sia;

Lab Chip, 2012, Advance Article, DOI: 10.1039/C2LC21204H,

27 Jan 2012

“Point of Care Diagnostics: Status and Future”, Vladimir Gubula, Leanne F. Harris,

Antonio Ricco, Ming X. Tan, David E. Williams

Anal. Chem, 2012, 84,487-515

“Point-of-care testing, Now and in the Near Future”. M. Fokkert & R.J. Slingerland,

www.acutecaretesting.org, Jun 2008