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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