Continuous Manufacturing

Transcription

1 Continuous Manufacturing

2 Continuous ing in the Industry Continuous processing has been adopted by the majority of process industries for the manufacturing of fluids (i.e. liquids and gasses) and solids (e.g. granular and sheet materials, etc.) Examples: Food industry (bakery mixes: powder blending) Chemical industry: (fuels, polymers) Concrete industry (blending) Paper industry (secondary solid production) How come Pharma is more batch oriented? Regulatory definitions for release support concept of batch processing Requirement for material traceability and quality verification Lack of suitable technologies (continuous process equipment, control technology, advanced instrumentation to measure in line) Small production volumes (compared to other industries)

3 Classic Oral Solid Dosage production Delay Delay Delay Delay Raw Material 1 to 2 months to release Granulator Blender Dryer Blender Tablet press Coating High inventory including work in progress, long changeovers, disconnected processes, high process losses, off line analysis, low asset utilization,

4 Oral Solid Dosage today: islands of automation ERP EBR Work instructions, logistics, WIP, material tracking MES Raw Material Granulator Blender Dryer Blender Tablet press Coating

5 PAT enabled direct compression continuous tablet manufacturing Raw Material 1 Raw Material 2 Raw Material 3 Raw Material 4 Feeder Blender NIR Blend uniformity Tablet Press Reject NIR Tablet contents Coating solution End product Coating pan

6 Continuous ing in secondary mfg Wet Granulation Dry granulation & direct compression Hot Melt Extrusion

7 Oral Solid Dosage Mfg processes Excipients API Excipients Wet Granulation Wet Mixing Drying Milling Mixing Granulation Roller Compaction Mixing Roller Compaction Milling Mixing Tablet Compression Coating Direct Compression Mixing Mixing Packaging Unit operations which are continuous as long as they are fed with input material Unit operations which can be made continuous given an appropriately designed process and control strategy

8 Benefits of continuous manufacturing Reduce manufacturing footprint and CAPEX Consistent quality, less scrap, higher yield, Right First Time Less WIP, less interactions, reduce inventory Do more with less. Less energy, less material, less resources, High potent drugs require safer solutions, reduce risk for exposures to environment More process understanding, in-line/online measurement of CQA, higher level of automation Faster to market, no scale up, Real Time Product Release, shorter cycle time

9 Notes from Keynote Janet Woodcock, Director CDER FDA International Symposium on Continuous Manufacturing of Pharmaceuticals May 20-21, 2014 Regulatory Hurdles? No specific FDA regulations or guidance exist about continuous manufacturing, other than the definition of lot 21 CFR Lot - a batch, or a specific identified portion of a batch, having uniform character and quality within specified limits; or, in the case of a drug product produced by continuous process, it is a specific identified amount produced in a unit of time or quantity in a manner that assures its having uniform character and quality within specified limits. Batch - a specific quantity of a drug or other material that is intended to have uniform character and quality, within specified limits, and is produced according to a single manufacturing order during the same cycle of manufacture Nothing in FDA regulations or guidance prohibits continuous manufacturing Continuous manufacturing consistent with FDA s Quality by Design (QbD) efforts The greatest regulatory hurdle is the concern by manufacturers that regulators will balk at implementing these processes

10 control evolution: Quality by Design (QbD) Quality by Inspection Current state Variable output Inconsistent Quality End product testing & Inspection Variable input Fixed High Low Pass or Fail Reject Out of Spec Quality by Design Desired future state Variable input Real time monitoring and control Dynamically adjustable High Low Consistent Quality output Parametric release Pass! Facilitated by Analytical Technology and Advanced Control Risk & Science based Approach

11 End product quality predictions Feed forward Feed Backward controls Api Input material characteristics control parameters Dispense & Blend Excipients control parameters Wet Granulation Liquid addition control parameters Drying Loss On Drying (NIR) control parameters Blending / Lubrication Lubricant excipient Content Uniformity Particle size (Malvern) control parameters Compression Assay Dissolution/disinteg ration (NIR) Weight Hardness Thickness control parameters Coating Raman Coating substance Coating thickness control parameters Packaging Coating solution

12 Univariate data Sample data data Chemometry Tools Quality and other Predictions Measurement models PV SIPAT Data alignment + preprocessing Extended calculations Monitoring Qualitative data Simatic IT UniLab LIMS Samples PV Collects multivariate data Simatic PCS 7 Collects all univariate data Recipe control Basic process control Advanced process control Multivariate sensors Univariate sensors

13 Totally Integrated Automation System Architecture for continuous ERP Workflow, Material genealogy tracking Real Time Product Release Reporting MES Raw Material PAT and Model execution SIPAT SIPAT Integrated Line Visualization and operation Quality check SIMATIC WinCC/PCS7 Blender Dryer Coating Feeding Granulator Granulation Drying Tablet press Lubricant/ Blending Compression In/At line check Coating

14 Continuous to Sub-Lot Release ERP ERP sends WO to SIT EBR U_P Unit Procedure CQA Critical Quality attribute CPP Critical Parameter MVDA Multi-Variate Data DCS Distributed Control System ebr Electronic Batch Record WO Launch Continuous WO Time Slice Creation Create Sub WO CPP Launch Continuous Procedure CPP Launch Continuous U_P s & Operations CQA CQA MVDA SIT EBR SIT Batch PCS7 DCS SIPAT PAT Aa EBR launches the continuous WO, monitors any Time Slice creation triggers: Material Inputs Product Outputs / Packaging CQA out of spec Other Business Rules Sub WO is created and tracks: Materials Equipment People CPP s; CQA s of the continuous stream Converts continuous stream into sub-lots for release

15 Continuous to Sub-Lot Release Create Sub WO Sub-Lot 3 CQA Release Create Sub WO Scrap CQA Create Sub-WO EBR Report: Materials Equipment People CQA/CPP s Create Sub WO Sub-Lot 2 CQA High Low If Sub-Lot CQA s are in Spec: Release By Exception Launch Continuous Procedure T 0 Create Sub WO Sub-Lot 1 CQA T 1 T 2 T 3 If Out of Spec: Create Alert/Deviation Quality to investigate Disposition Sub-Lot T 4 Time Slice Triggers

16 Historian Digitalization Portfolio XHQ Dashboards Manual Operations Automated Recipe Unit Procedure PCS7 DCS SIMIT Preactor Scheduling ebr Simatic Batch CQA CPP CQA CPP PAT Analyzers WO INFO ERP QC Lab LIMS Aa SIPAT Manual operations and workflows are integrated to the DCS using SIMATIC Batch which orchestrates the automated steps Quality and Production data flows between the different systems and can be collected in a production database, historian, or collected into the XHQ dashboard solution Multi Variate Data U_P Unit Procedure CQA Critical Quality Attribute CPP Critical Parameter MVDA Multi-Variate Data DCS Distributed Control System LIMS Lab Info Mgmt System ebr Electronic Batch Record