AEROSET® & ARCHITECT® cSystem™ MULTIGENT® Lithium REF 8L25 Target Launch: EU December 2007 US January 2008

Agenda Launch Strategy Clinical Utility Methodology Sample Handling Reagent Handling Calibration Quality Control Reportable Range Interference Precision Method Comparison CAP Performance Reaction Graphs Troubleshooting tips Questions and Answers

MULTIGENT® Lithium Launch Strategy There will be separate list numbers assigned to the reagent and calibrator products for E.U. and U.S. use. U.S. list numbers will be distributed from Chicago for use in Canada, Latin America and the U.S. E.U. list numbers will be distributed through Delkenheim to remaining countries. Controls Clin Chem Control 1 ( REF 6K3020) and Clin Chem Control 2 ( REF 6K3021) are available for E.U. use. Abbott will not market controls for U.S. use (Ranges for appropriate Bio-Rad controls have been established) There are no differences in the application or formulation between the U.S. and E.U. products. Complaint handling: Abbott has responsibility for initial complaint registration. Sentinel (the vendor) will investigate level II complaints.

MULTIGENT® Lithium Launch Strategy – Assay Disk A disk will not be available at assay launch Assay files must be entered manually using the package insert. The MULTIGENT c Systems disk is targeted for 2nd quarter of 2008. The disk will be available in conventional and SI units versions, however because of the prevalent use WW, Lithium assay units will be in SI units (mmol/L) on both disks. No AEROSET disk will be produced.

Clinical Utility of Lithium Used in the treatment of manic depressive psychosis. Elevated levels can cause intoxication. Early symptoms include apathy, sluggishness, drowsiness, lethargy, speech difficulties, tremor, muscle weakness and ataxia. Long-term lithium therapy has been reported to cause hyperparathyroidism in some individuals with resulting hypercalcemia.

MULTIGENT® Lithium Methodology Methodology: Colorimetric CAP Code: 1428 Chemical Reaction: Note: Schematic diagrams are for representative use only and do not reflect the actual chemical structure.

MULTIGENT® Lithium Methodology Description of Chemical Reaction: A substituted-porphyrin chromogen reacts with lithium at alkaline pH to form a Li+/chromogen complex. The resulting absorbance change is directly proportional to the concentration of lithium in the sample. The formation of a complex between the chromogen and lithium is quite specific due to accommodation of the small ionic radius lithium ion (73 pm) within the chromogen core. Formation of complexes between the chromogen and the larger sodium(113pm radius) and potassium (151 pm radius) ions have not been observed. Li+/chromogen complex exhibits an absorbance maximum peak between 475nm and 495nm and an absorbance minimum between 505nm and 525nm.

MULTIGENT® Lithium Sample Handling Specimen Requirements: Serum Plastic tubes With or without gel barrier Plasma Sodium Heparin K2-EDTA Do NOT use Lithium Heparin Note: Glass tubes and K3-EDTA were not tested.

MULTIGENT® Lithium Sample Handling Sample Tubes tested and found acceptable:

MULTIGENT® Lithium Sample Handling Specimen storage: Stored specimens must be inspected for particulates. If present, mix and centrifuge the specimen to remove particulates prior to testing. Sample volume = 6 uL System performs a Standard sample dilution of 1:20.17 using 6 uL of sample and 115 uL of saline diluent An Automated Dilution protocol is available. The standard sample dilution is diluted 1:2 by using 3 uL of sample with 115 uL of saline diluent

MULTIGENT® Lithium Reagent Handling Reagent is liquid, ready-to-use, single reagent kit. Storage: 2 to 8°C. Protect from light. Store reagent in the box. Unopened kit is stable to the expiration date. Remove any air bubbles with an applicator stick. Reagent onboard stability is 18 days.

MULTIGENT® Lithium Calibration Calibration stability is 5 days Uses MULTIGENT® Clin Chem Cal Calibrator kits contain lithium and enzymatic creatinine values with the 2nd lot 70566. Lithium reagent kit stuffer will contain lithium Clin Chem Cal values for previous lots of calibrator. Information on calibration standardization is in the Calibration section of the Lithium package insert.

MULTIGENT ® Lithium Calibration Curve - ARCHITECT® Note: Cal 1 concentration is automatically determined by the instrument dilution factor (1:20.17). The Calibrator concentration entered in the Configure assay parameters screen for this example is 1.52.

MULTIGENT ® Lithium Calibration Curve -AEROSET®

Quality Control The following controls have been tested and initial control ranges have been assigned for AEROSET and ARCHITECT Bio-Rad Liquid Assayed Multiqual Controls, Lot # 45540, Exp Date: 01/31/2009 and Lot # 45550, Exp. Date: 09/30/2009 Bio-Rad Lyphochek Assayed Chemistry Control, Lot # 14140, Exp Date: 12/31/2008 and Lot # 14150, Exp Date: 09/30/2009 Bio-Rad Lyphochek TDM Controls, Lot # 57160, Exp. Date: 6/30/2009 and Lot # 57170, Exp. Date: 10/31/2010

Quality Control The Sentinel manufactured ClinChem Controls are available for use outside of the US. These controls will not be launched for use with the U.S. Lithium kit.

MULTIGENT ® Lithium Reportable Range (Serum and Plasma) Reportable Range = 0.10 to 3.51 mmol/L* Linear within +/-5% or 0.075 mmol/L whichever is greater Limit of Quantitation = 0.10 mmol/L* *Note: Alternate (conventional) units are mEQ/L which are numerically equivalent to mmol/L.

MULTIGENT Lithium Interference Note: A single spiked sample was used to test for Interference from Calcium, Copper, Iron, Magnesium, Potassium, Sodium and Zinc. That is why the Lithium concentration, bias and % Recovery are identical.

MULTIGENT® Lithium Precision The precision of the Lithium assay is < 5% Total CV or < 0.075mmol/L SD, whichever is greater. Representative data from a 20 day study based on Clinical and Laboratory Standards Institute (CLSI) protocol NCCLS EP5-A9 are summarized below.

MULTIGENT® Lithium Method Comparison Results from the MULTIGENT Lithium assay on the ARCHITECT c 8000 System and the AEROSET System were compared with the results from the Trace Infinity Lithium Assay on a Hitachi 911. Results from the MULTIGENT Lithium assay on the ARCHITECT c 8000 System were compared with the results from atomic absorption spectrophotometry (AAS).

MULTIGENT® Lithium Method Comparison Results from the MULTIGENT Lithium assay on the ARCHITECT c 8000 System and the ARCHITECT c 16000 System were compared with the results on the AEROSET System.

Lithium CAP Performance CAP Proficiency Testing (PT) for MULTIGENT Lithium assay was performed in-house on the Architect c8000 analyzer using CAP PT materials : CHM-06, CHM-07, CHM-08, CHM-09 and CHM-10. All samples were within 10% or 0.15 mmol/L as per our approved Product Requirements Document. 2007 CZ-B CAP Survey Results (Information Only) MULTIGENT All Method Mean CHM-06 2.498 2.34 CHM-07 2.321 2.18 CHM-08 1.163 1.12 CHM-09 1.944 1.83 CHM-10 1.561 1.48

ARCHITECT® Reaction graph (Low Range):

ARCHITECT® Reaction graph (High Range):

AEROSET® Reaction graph (Low Range):

AEROSET® Reaction graph (High Range):

Troubleshooting Tips Observed Problem: Elevated patient results Probable Cause(s) CorrectiveAction(s)____ Use of Lithium heparin Use serum, Sodium heparin or EDTA anticoagulant tubes blood collection tubes as described in the reagent package insert.

Troubleshooting Tips Observed Problem: Calibration stability does not meet labeling Probable Cause(s) Corrective Action(s)____ Exposure of reagents to light Store unopened reagents in the original carton until use. Keep reagent carousel covers closed when not accessing reagents.

Questions and Answers Why are there two separate list number products used for the US and ex-US? Answer: More effective Distribution Strategy

Questions and Answers Why won’t the Clin Chem Controls be approved for US use? Answer: The number of users of Clin. Chem. Controls in the US would be very small, if at all.

Why do the reaction graphs for the low and high range samples progress in opposite directions? Answer: Recall the reaction equation. Note: Schematic diagrams are for representative use only and do not reflect the actual chemical structure. Reaction of Free porphyrin with Lithium leads to complex formation and a shift of the spectrum characteristics of the free porphyrin. The spectrum shift is characterized by a decrease of the Absorbance at 524 nm and by an increase at 476 nm. At low lithium concentration the difference between Prim-Sec wavelengths produces positive values At high lithium concentration the difference between the 2 wavelengths produces negative values

Why do the reaction graphs for the low and high range samples progress in opposite directions? (cont’d) 476 nm 524 nm Note: Schematic reaction graphs are for representative use only, may not reflect the reaction in entirety. The bold line depicts the absorbance response over time of lithium and porphryin in solution with no reaction taking place. The dashed line depicts changes that take place over time during the reaction: A positive absorbance change at 476 nm, the secondary wavelength with li-porphyrin complex formation A negative absorbance change at 524 nm, the primary wavelength A shift in the reaction graph towards the longer wavelength

Why do the reaction graphs for the low and high range samples progress in opposite directions? (cont’d) The lithium reaction graphs plot the absorbance difference (Primary – Secondary) as a function of time. Given the complexity of the Primary and Secondary wavelengths progressing in opposite directions, this difference has a downward trend at lower concentrations and an upward trend at higher concentrations. Note: The reaction graphs show insignificant change in absorbance from reads 2-8, demonstrating > 90% reaction completion by the 2nd read.