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, info@raupack.co.uk

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

THANK YOU !