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Your Safe delivery… our utmost concern
Manufacturing Plan and Costing
Mr. P. Waghmare
Miss H. Gwani
Miss V. Varkey
Miss S. Jain
Mr. D. Igwe
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
ComparisonExisting
Technology
Use of one Marker: PLGF
Fluorescence antibody for
quantification
G7 Technology
Use of three Marker:
-PlGF
-sEng
-sflt
Gold nanoparticle antibody with fluorescence
S.No. Biochemical Marker Plasma ConcentrationTrimester 1 Trimester 2
Manifest Preeclampsia
1. sflt-1 (Soluble fms- like tyrosine kinase)
-- high Early increase
2. Soluble Endoglin (sEng)
-- high Early increase
3. Placental Growth Factor (PlGF)
low low further decrease
Reaction Chamber
Array of Antibodies
PlGF
sEng
sflt
SaphvidTM : Working Principle
Validation of raw materials Assembly Validation of
strip Verification
Product Development of SaphvidTM
Product Development : Step 1
Validation of raw materials
Raw Materials Validation
Strip
Strip material
Nanoparticles
Antibody screening
Filter test
Polystyrene latex
Composition and film forming temperature
N-WCPC Model 3788
Western Blot, TME, IHC in correlation with WB + IP in cycles
β-Ratio testing
Solubility test
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 3
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
Validation of Strip
Product Development : Gantt Chart
Market and customer analysis(Business plan draft)
Identifying the protein markers
Nano particles testing
Funding
Screening the Antiobodies 1 and 2
Contract with suppliers
Design Consutlants/ Manufacturers
Assembly process and testing
Product layout optimization
Quality Control and AssesmentProduct Validation
Product VerificationFeedback
Legal
25-Jul-10 02-Nov-10 10-Feb-11 21-May-11 29-Aug-11 07-Dec-11 16-Mar-12 24-Jun-12
File patent
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 20Product Validation 24-03-2011 300 18-01-2012Product Verification 08-05-2012 120 05-09-2012Feedback 06-08-2012 30 05-09-2012
10 Legal 10-10-2010 600 01-06-2012 30filing a patent (UK, Europe, world)licencingliabilitytherapeutical consequences reliability of results
11 Salary 247Extras: Capital 100
Lab facility development 25
Total 460.55
Clinical Trial Design: UK
10
Regions
50
Hospitals5 Hospitals per Region
20patients per HospitalTest
• Week 12• Week 19
No of test
2 Strips/patientReq.
Major Region
s
•West Midlands• London•South west England •East of England •East midlands •Yorkshire and Humber •North east England •North west England•Wales•South west England
Hospitals in major regions:
http://www.performance.doh.gov.uk/tables97/index.htm
•University Hospital (Coventry)
•The royal london hospital
•Royal Bournemouth (general hospital)• •Hinching Brooke hospital
•Royal Berkshire hospital
•Bradford royal infirmary
•Sunderland royal hospital
•James cook university hospital
•Countess of chester hospital
•Trowbridge community hospital
Phase 1
• No of Subjects:300• Target: women-
pregnant & non-pregnant (below menopause)
Phase 2
• No. of Subject: 500• Target: All are pregnant
women but with varying degree of vulnerability (High & Low Risk)
Phase 3
• No. Of Subject:1000• Pregnant women in week
12 and 19 and with are at high risk (>75% risk of pre-eclampsia)
Clinical Trials
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
• Inspection & Approval
• Contract (Agreement)
Identify Manufacturer
• Raw Material • Product &
Process
Specification To Manufacturer
• Validated Raw Materials
• Filter, Polystyrene Latex, Antibodies, Strip Material
Materials from Supplier
Manufacturing Process: Overview
• Detailed Instructions
• To Manufacturer
SOP
• Define Process• Batch Size
Details• Quality Check
Manufacturing • Quality Check• Printing &
Labeling
Packaging
Manufacturing Process- cont.
Manufacturing process Produce 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 informationProcess Parameters
Scale Pilot scaleFull scale
Equipment Automated and Programmed
TemperatureRelative Humidity
15 – 20˚C1- 5%
Sterilisation steps and aseptic conditions to be followed during the entire manufacturing process.
Manufacturer of SaphvidTM :
Raupack Limited131 High Street, Old Woking, GU22 9LD, United Kingdom, tel: +44 (0)1483 736800 fax: 736810, [email protected]
EQUIPMENT QUALIFICATION
•Verifies system design as per User Requirement Specification (URS).
Design Qualification (DQ)
•Verifies system operations satisfying all functional requirements.
Operational Qualification (OQ)
•Verifies system installation as specified in the design.
Installation Qualification (IQ)
•Verifying that system performance satisfies all performance requirements including those specified in the URS.
Performance Qualification (PQ)
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 criteria
After assembly of strip material
Thickness, width and length
Vernier calliper 99-100%
After creating capillary path on the base with
laser.
Depth, diameter of capillary and uniformity
Laser Micrometer 98-100%
After coating nano- particle fluorescent
antibodies
Fluorescence Fluorometer 99-100%
After coating the antibody array
Quantity and activity Antigen test and laser micrometer 99-100%
After placing filter and time gate and sample
port
Position and diameter Visual inspectionLaser micrometer and vernier
calliper
98-100%
After placing filter over strip components
Appearance Visual inspection 98-100%
After strip assembly Appearance, mass, selectivity and
specificity.
Visual inspection, weighing and test with pre-eclamptic blood
sample.
99-100%
Gantt Chart: Manufacturing (Pilot )
Identify Manufacturer
Contract (Agreement)Raw material specification
Process Specification + SOP
Phase 1: 300 (630)Phase 3: 1000 (2070)
Quality CheckInstructions (define and printing)
Packaging
Identifying centresProtocol for conducting clinical trials
Analysis of ResultsRegulatory Approval
07-Sep-12 04-Feb-13 04-Jul-13
S.No. Tasks Start Date Duration (days) End Date Costing (000) GBP
1 Identify Manufacturer 07-09-2012 25 02-10-2012 2.5 2 Inspection and Approval 22-09-2012 20 12-10-2012 2 Contract (Agreement) 13-10-2012 10 23-10-2012 3 Raw material specification 04-11-2012 15 19-11-2012
1 Product specification 13-10-2012 20 02-11-2012 Process Specification + SOP 19-11-2012 75 02-02-2013 4 Manufacturing (Batch Size) Phase 1: 300 (630) 03-02-2013 7 10-02-2013 12.6 Phase 2: 500 (1050) 15-08-2013 10 25-08-2013 18.9 Phase 3: 1000 (2070) 01-03-2014 20 21-03-2014 37.26 5 Quality Check 11-02-2013 7 18-02-2013 0.5 6 Instructions (define and printing) 19-02-2013 7 26-02-2013 0.075 Labels 27-02-2013 7 06-03-2013 0.12 Packaging 07-03-2013 7 14-03-2013 0.375 Quality Check 15-03-2013 7 22-03-2013 0.5 7 Storage 23-03-2013 2 25-03-2013 0 8 Transport 26-03-2013 1 27-03-2013 2 9 Clinical Trials Identifying centres 04-11-2012 60 03-01-2013
5 Consent from patients and hospitals 24-11-2012 60 23-01-2013 Protocol for conducting clinical trials 04-11-2012 30 04-12-2012 Documentation 28-03-2013 7 04-04-2013 0.1 Analysis of Results 05-04-2013 10 15-04-2013 0.1
10 Regulatory Approval 16-04-2013 180 13-10-2013 3.511 Salary 88 R&D Manager 45 Manufacturing Manager 28 Marketing analyst 15 Total 189.74
Cost of manufacturing (Pilot scale)
Cost of manufacturing (full scale)
S. No. Activity Cost GBP (000)(1st year) Cost GBP (000)(2nd year) Cost GBP (000)(3rd year)
1 Salary 299 299 310
2 Manufacturing the strip 4000 4500 5610
3 Packaging 80 87.5 115.5
4 Instructions 24 30 39.6
5 Labelling 30 25 33
6 Quality Check 3 3 3
7 Transport 2 2.5 3.5
8 Documentation 1.5 1.5 1.5
9 Analysis 3 3.5 4
Total 4442.5 4952 6120.1
Suppliers:Raw Materials Specification Suppliers
Strip material Plastic material Millipore Corporation
Filter material PA66, Polyamide Yuexing sailaqi gauze filter co. Ltd.
Fluorescent nanoparticle- linked antibody
FluoroNanogold-anti-human Fab'-Alexa Fluor 488
Universal Biologicals
Secondary antibodies
PlGF
Human Endoglin/CD105 MAb (Clone 166713), Mouse IgG1
Human VEGF R1 (Flt-1) MAb (Clone 49560
R & D systems
Packaging
Strip wrapped in foil to keep out moisture
25 packs
Instruction manual
Failure mode and effect
1.Identify finding (review)
2.Evaluate finding (disposition)
3.Resolve finding (implementation)
4.Close finding (verification)
Assessment/ event Report
Corrective action plan. Corrective action tracking and implementation
Review and report effectiveness of corrective actions
Failure mode Possible effect Corrective action
Mistakenly switching samples
Wrong result Proper labelling of raw material trays
Contamination of raw materials
Unreliable result Proper storage of raw materials
Wrong analysis for the samples analysed from key steps
Unreliable result Print out the measurement file
•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
Summary