Applying Lean &Design for Six Sigma (DFSS) Methodology to build Quality in Drug product made via 3D Printing (i.e. Additive manufacturing) technique

Transcription

1 Applying Lean &Design for Six Sigma (DFSS) Methodology to build Quality in Drug product made via 3D Printing (i.e. Additive manufacturing) technique

2 Applying Lean &Design for Six Sigma (DFSS) Methodology to build Quality in Drug product made via 3D Printing (i.e. Additive Manufacturing) technique 3 rd Annual Quality Conference, ASQ Vancouver, May 2016 Dr. Shruti U. Bhat Innoworks Inc. Canada

3 About Shruti: Shruti U. Bhat, PhD (Tech.) MBA, Lean Six Sigma Black Belt. Founder Director, Lean Innovation and Business Process Design, Innoworks Inc. Canada. Cover Story published in GMP Special issue of Express Pharma, May 2016 Books Authored: Asia s leading Trade magazine with a combined readership of 700,000 across 6 countries! Books In-press: Reach Shruti: Shifting Paradigms BC Ltd. Innoworks Inc. Canada Shruti.Bhat@Innoworks.ca

4 Rationale for project initiation: Model drug ISDN The sponsor company has a good market share for ISDN products, the company wanted to find ways to further increase profit margins. VoC data revealed there is Variation of drug levels in blood found with marketed extended release formulations. This triggers occurrence of serious adverse reactions in patients. In addition, there is improper therapeutic disease management. Have several doses in one capsule so as to avoid multiple dose administration during the day. This would be specially beneficial to senior patients who may forget to take their medicines on time. The New formulation should be Rate-Programed Release, should exhibit same pharmacodynamics as marketed formulations but different pharmacokinetics to avoid occurrence of side effects. Novel SPANSULE Additive Manufacturing Technique Continuous Innovation Cycle Six Sigma in Product Design Quicker ROI Lean Innovation

5 Comparative study: Novel SPANSULE Quicker ROI Dish Pelletizer (Raw material waste 14%, Large processing times) Extruder- Marumerizer (RM Waste 9%, Medium processing times) Additive Manufacturing Continuous Innovation Cycle 1 Lean? Innovation Six Sigma in Product Design Pointers: How LEAN helps Product Development: (RM waste 6%, Medium processing times) 3D Printer with fully enclosed pan (For prototyping) RM waste < 1%, Short processing time 2-3 hours. 1. Choose Equipment that reduces material and time waste. Continuous process Vs Batch process. 2. Use Technology that allows existing people to operate. No Job loss!

6 Factors Critical to Product Acceptance were collected and studied to create a Cause Effect Diagram to initiate Product Design using DFSS and DOE Figure 1: Cause- Effect Diagram for Design- Developing ISDN Extended- Program Release Capsule for Once Daily dosage.

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8 Figure 1: Few examples of Pareto charts; Drying time impacts Tap density of pellets, Binder concentration impacts pellet hardness and all three X parameters impact pellet size.

9 The Nonpareil pellets were starters for making anti-angina drug product. PK- PD model uses Doebrinska Welling Equation Nine different polymers have been evaluated using 12 Run Plackette- Burman Design. Note: Hardware, software applications were pre-validated (DQ,IQ,OQ,PQ) for each experimental run as per USFDA guidelines. Final process: 19-Drug- polymer laminations

10 Inference: Formulation from experiment VIII was selected as the Prototype. Ex vivo comparisons between Prototype and Reference were established. Reliability testing of prototype was done at accelerated temperatures, humidity and UV light as per ICH and USFDA regulations. Figure 4: Time series plot of results of 12 Run Fractional Experimental Design: Drug release kinetics Vs Time. Efficacy of the Prototype was studied in In vivo in healthy human volunteers in a hospital setting as per USFDA Good Clinical Practices guidelines. Systolic blood pressure, Diastolic blood pressure, Heart rate were measured post administration of drug product. Data was analyzed statistically, using Paired t test.

11 Statistical evaluation of Prototype and Reference products by studying Systolic-Diastolic blood pressures and Heart rates in healthy human volunteers. Conclusions of Product Design phase: Drug release exhibited by Prototype indicates steadystate release from capsule, with profiles matching the Reference product. Prototype passes 80 < ϴ < 125 % compliance criteria. Prototype is READY for scaleup and commercialization. Figure 5: Comparability evaluation between Prototype (P) and Reference (R): Systolic and Diastolic blood pressures and Heart rate match post administration of 40 mg anti-angina capsule in healthy human volunteers

12 Why 3D Printing process for Pharmaceuticals? 3 Novel SPANSULE Additive Manufacturing Technique? Continuous Innovation Cycle Quicker ROI Lean Innovation Output: 1 Kg/hour in R&D model Vs 350 g/h in other machines. Cost: Additive manufacturing was found to be 250% cheaper than Dish Pelletizer, Extruder-Marumerizer, Fluid Bed Coater. Excellent option to curtail rising drug products costs globally. Six Sigma in Product Design The Design space is wide, operator friendly and accommodates potential human errors/ special cause deviations at production line with Zero Impact to product Quality, Safety and Performance. Hence, manufacturing process is Risk Averse.

13 Key Benefits from DFSS implementation to Other Manufacturing Industries: DFSS typically leads to wide and operator friendly Design space. It follows All or None Law. Hence, it a boon to both Production and In-process Quality Control (IPQC) people! DFSS allows quicker ROI to keep Continuous Innovation cycle to keep running Novel Product Quicker ROI Improved Manufacturing Continuous Innovation Cycle Lean Innovation Six Sigma in Product Design

14 Key Benefits from DFSS implementation to Other Manufacturing Industries: DFSS methodology generally leads to Novel products, consequently patent protection, revenues. DFSS creates products with efficient production and packaging processes. No scope for Re-work. Better Operations Management! Novel Product Quicker ROI Continuous Innovation Cycle Improved Manufacturing Lean Innovation Six Sigma in Product Design

15 About Innoworks Inc. Innoworks is a Canadian Consulting company and a Design Studio, with offices in Calgary, Vancouver and Mumbai (India). Innoworks caters to clients worldwide, offers new quality based cost-effective ways of Product Design, Innovation & Intellectual Property Management, and Business Process Design. CONSULTING SERVICES: Innovation Management-New Product Design and Development. Lean Innovation. Product Lifecycle Management. Patents And Intellectual Property Management. Continuous Improvement- Facility Development. Business Transformation. Process Improvement / Re-design. Leadership Development and Organizational Excellence. Change Management. Vendor and Contract Management. Business Analysis. Identify Strategic Partners And Alliance Management. Business Process Mapping.

16 About Innoworks Inc. Quality Improvement-Implementing Quality Management Systems. Risk Management. Audits And Due Diligence. Quality-by-Design (QbD) Planning and Implementation. Operations Improvement-Manufacturing Management. Productivity Improvement And Cost Control. Value Stream Mapping. Resource Optimization And Capacity Management. Conflict Management. CRO and Clinical Study Management. Contract Research And Manufacturing Management. Testing Laboratories. Inventory Management. Supply Chain Logistics Management.

17 About Shifting Paradigms Shifting Paradigms Business Media is Learning Center Division of Innoworks Inc. It is your Full-Spectrum Knowledge Service Provider for creating all formats of Informational & Learning products, Corporate E- Learning Modules, Training and Executive Education. Our Mission: Helping public and private sector organizations become more innovative, productive, efficient and cost-effective. Our Specialization: We specialize in providing Training services and Learning products for following industry verticals:healthcare. Pharmaceuticals & Over-the-counter (OTC). Medical Devices. Bulk Drugs. Chemicals. Lab Testing & Diagnostics. Natural Health Products (NHP). Vitamins & Supplements. Biotechnology. Foods. Beverage & Confectionary. Cosmetics.

18 About Shifting Paradigms Our Services and Products: Training is provided in different formats- On-site (as seminars, Lunch & Learn sessions, workshops). On-line (as Web based self-paced study module). On-line (as Webinars). Virtual classroom (via Skype). Self-Help guides, Audio and Whitepaper via coaching. Tele-coaching. On Phone (via PDF, audio books and podcasts). Videos.

19 Thank You! Cover Story published in GMP Special issue of Express Pharma, May 2016 Asia s leading Trade magazine with a combined readership of 700,000 across 6 countries! Books Authored: Books In-press: Reach Shruti: Shifting Paradigms BC Ltd. Innoworks Inc. Canada Shruti.Bhat@Innoworks.ca