PHASE 1= 300 patients consisting of pregnant and non pregnant women… <results shld show low values of the 3 biomarkers being tested in non-pregnant women> <opposite shld be observed in results displayed in pregnant women.>PHASE 2= 500 Patients consisting of only pregnant women, but with varying degree of pre-eclampsia risk factors. (detected by conventional methods- doppler ultrasound, hbpressuree.t.c.) <expected result- device is alrite if it reads high levels of biomarkers in womehn in which conventional methods has proved they are at risk of pre-eclamsia.>Phase 3: here only pregnant womehn with ova 75% chance of having pre-eclampsia are tested. A normal correct result will show d expected increased in
Approval from the hospital institutional review boards.Consent from the patients Train staff in proper use of the device. Diagnosing with Saphid™ strips along with other methods of diagnosing pre-eclampsia. Such as ELISA test, liver and kidney function tests.The clinical record of the patient will be reviewed after the patient has delivered to assess if the patient had pre-eclampsia or not.The data will be collected, analysed and stored in a way to ensure patient anymosity and confidentitality. The Saphid™ will be individually accessed for specificty, selectivity, positive and negative predictive values and false-positive and false-negative values. Check for discrepancies between our strip and other methods of diagnosis.
Manufacturing Plan and Costing Mr. P. Waghmare Miss H. Gwani Miss V. Varkey Miss S. Jain Your Safe delivery… our Mr. D. Igwe utmost concern Mr. A. Awosusi
Contents Introduction G7 Technology: Working Principle Product Development of SaphvidTM Product Development: Gantt Chart and Costing Clinical Trials and Their Validation Manufacturing process in detail Summary
G 7 Diagnostic kit Strip: SaphvidTM Intended Use: Early detection of Pre-eclampsia. Device Used: Triage Meter Need of the hour: • No effective diagnostic method available • 12% of maternal deaths
Comparison Existing G7Technology Technology S.No. Biochemical Marker Use of three Marker:Plasma Concentration Manifest Trimester 1 Trimester 2 Preeclampsia Use of one -PlGF Marker: PLGF 1. -sEng sflt-1 (Soluble fms- -- high Early increase -sflt like tyrosine kinase) 2. Soluble Endoglin -- high Early increase Fluorescence (sEng) nanoparticle Gold antibody for antibody with quantification 3. fluorescence Placental Growth low low further Factor (PlGF) decrease
SaphvidTM : Working Principle Reaction Chamber PlGF Array of Antibodies sEng sflt
Product Development of SaphvidTMValidation of raw Validation materials Assembly Verification of strip
Product Development : Step 1Validation ofraw materials
Raw Materials Validation Composition and film Strip material forming temperature Nanoparticles N-WCPC Model 3788Strip Western Blot, TME, IHC Antibody screening in correlation with WB + IP in cycles Polystyrene latex Solubility test Filter test β-Ratio testing
Product Development : Step 2 Validation of raw materials Assembly• Preparation of 3 layer plastic base (strip)• Create micro capillary path on the strip• Coat the reagents on the strip• Integrate filter over reagents
Product Development : Step 3Validation of Strip Marker Control (pg/mL) Pre-eclampsia (pg/mL) Sflt-1 1458.8- 4117.6 1615.7-8274.5 PlGF 65.8-285 47.4-151.8 sEng 3573.8-6238 5401-17617.4 If [sflt- 1]/ [PlGF] > 45 High chances of Pre-eclampsia
Product Development: CostingS.No. Tasks Start Date Duration (days) End Date Cost involved (£000) 1 Market and customer analysis 25-07-2010 90 23-10-2010 10 (Business plan draft) 3 Identifying the protein markers 25-07-2010 260 11-04-2011 Nano particles testing 25-07-2010 150 22-12-2010 2 Funding 04-11-2010 90 02-02-2011 4 Screening the Antiobodies 1 and 2 23-12-2010 90 23-03-2011 7 5 Contract with suppliers 12-04-2011 90 11-07-2011 10 6 Design Consutlants/ Manufacturers 11-08-2011 90 09-11-2011 5.85 7 Assembly process and testing 10-11-2011 180 08-05-2012 4 8 Product layout optimization 08-05-2012 90 06-08-2012 1.7 9 Quality Control and Assesment 20 Product Validation 24-03-2011 300 18-01-2012 Product Verification 08-05-2012 120 05-09-2012 Feedback 06-08-2012 30 05-09-2012 10 Legal 10-10-2010 600 01-06-2012 30 filing a patent (UK, Europe, world) licencing liability therapeutical consequences reliability of results 11 Salary 247Extras: Capital 100 Lab facility development 25 Total 460.55
Clinical Trial Design: UK 10 50 5 Hospitals Regions Hospitals per RegionTest 20patients per No of • Week 12 Req. 2 Strips/patient Hospital test • Week 19
Hospitals in major regions: •University Hospital (Coventry) •West Midlands •The royal london hospital • London •Royal Bournemouth (general hospital)•South west England • •East of England •Hinching BrookeMajor hospital •East midlands Region •Royal Berkshire hospital •Yorkshire and Humber s •North east England •Bradford royal infirmary •North west England •Sunderland royal hospital •Wales •South west England •James cook university hospital •Countess of chester hospital •Trowbridge community hospital http://www.performance.doh.gov.uk/tables97/index.htm
Clinical Trials • No of Subjects:300 Phase • Target: women- pregnant & non- 1 pregnant (below menopause) • No. of Subject: 500 Phase • Target: All are pregnant women but with varying 2 degree of vulnerability (High & Low Risk) • No. Of Subject:1000 Phase • Pregnant women in week 12 and 19 and with are at 3 high risk (>75% risk of pre-eclampsia)
Steps of Clinical Trials• Approval: Hospital board• Patient consent• Train staff in proper use of the device• Use Saphid™ strips with traditional methods• Review clinical record of the patient• Data collection• Assessment of The Saphid™ strip• Check for discrepancies between our strip and other methods of diagnosis
Manufacturing Process: Overview Specification To • Validated Raw• Inspection & Manufacturer Materials Approval • Raw Material • Filter, Polystyrene• Contract Latex, Antibodies, • Product & Strip Material (Agreement) Process Identify Materials from Manufacturer Supplier
Manufacturing processProduce the plastic base• Three layers of strip material assembled together Create the capillary path on the base with a laser Coat the reagents on the strip Integrate the filter over the reagents FINAL STRIP
Manufacturing process information Process Parameters Scale Pilot scale Full scale Equipment Automated and Programmed Temperature 15 – 20˚C Relative Humidity 1- 5% Sterilisation steps and aseptic conditions to be followed during the entire manufacturing process. Manufacturer of SaphvidTM : Raupack Limited 131 High Street, Old Woking, GU22 9LD, United Kingdom, tel: +44 (0)1483 736800 fax: 736810, email@example.com
EQUIPMENT QUALIFICATION Design • Verifies system design as per UserQualification (DQ) Requirement Specification (URS). Operational • Verifies system operations satisfying allQualification (OQ) functional requirements. Installation • Verifies system installation as specified inQualification (IQ) the design. Performance • Verifying that system performance satisfies all performance requirements includingQualification (PQ) those specified in the URS.
Manufacture Process validation and evaluation• Batches: • Number • Batch size • Place and date of manufacture • Yield • Batch purpose (Validation, stability, clinical trial)• Process • Equipment • Process parameters • Validation protocol• Results • Critical steps • In process control • Finished product specification.
Manufacturing Process Control of Critical steps and Intermediates Manufacturing step Test Item Methods Acceptance criteriaAfter assembly of strip Thickness, width and Vernier calliper 99-100% material lengthAfter creating capillary Depth, diameter of Laser Micrometer 98-100% path on the base with capillary and uniformity laser. After coating nano- Fluorescence Fluorometer 99-100% particle fluorescent antibodies After coating the Quantity and activity Antigen test and laser micrometer 99-100% antibody arrayAfter placing filter and Position and diameter Visual inspection 98-100%time gate and sample Laser micrometer and vernier port calliperAfter placing filter over Appearance Visual inspection 98-100% strip components After strip assembly Appearance, mass, Visual inspection, weighing and 99-100% selectivity and test with pre-eclamptic blood specificity. sample.
Gantt Chart: Manufacturing (Pilot ) 07-Sep-12 04-Feb-13 04-Jul-13 Identify Manufacturer Contract (Agreement) Raw material specification Process Specification + SOP Phase 1: 300 (630) Phase 3: 1000 (2070) Quality Check Instructions (define and printing) Packaging Identifying centresProtocol for conducting clinical trials Analysis of Results Regulatory Approval
Suppliers:Raw Materials Specification SuppliersStrip material Plastic material Millipore CorporationFilter material PA66, Polyamide Yuexing sailaqi gauze filter co. Ltd.Fluorescent FluoroNanogold-anti-human Fab- Universal Biologicalsnanoparticle- linked Alexa Fluor 488antibody PlGF Human Endoglin/CD105 MAbSecondary (Clone 166713), Mouse IgG1 R & D systemsantibodies Human VEGF R1 (Flt-1) MAb (Clone 49560
Packaging 25 packs Strip wrapped in foil to keep out moisture Instruction manual
Failure mode and effect Failure mode Possible effect Corrective action 1.Identify finding Mistakenly switching (review) Wrong result Proper labelling of event Assessment/ rawReview samples effectiveness of and report material trays Reportcorrective actions Contamination of raw Unreliable result Proper storage of raw materials materials Wrong analysis for the Unreliable result Print out the samples analysed from 4.Close finding measurement file 2.Evaluate finding key steps (verification) (disposition)Corrective action trackingand implementation Corrective action plan. 3.Resolve finding (implementation)
Summary•Cost of product development estimated at GBP 460,000•Steps involved in clinical trials•Estimated units of strips to be manufactured: •Year 1: 4,000,000•Total costs associated with manufacturing: •Year 1: GBP 4,442,500