1. Best Automation Practices in a Greenfield Startup 10 March 2015 Jay Roderick Sr. Validation Mgr. Baxter Healthcare Jonathan Wood Sr. Mgr. Engineering Sequence

2. AGENDA Introduction Baxter Overview Regulatory Objectives Automation Design Workflow Obstacles to Overcome Revised Automation Design Workflow Effect on Automation and Equipment C&Q Summary Q&A

3. Baxter Overview (Program Covington) Announced plans in April 2012 to build a greenfield campus near Covington, Georgia Capital investments at site to exceed $1 billion over next 5 years Create more than 1,500 full-time positions in Georgia and more than 2,000 jobs in total across multiple US locations More than 1 million total gross square feet on 160-acre site

4. Program Covington by Sub-project F W1 I A B C D Q E U W2 Y1 Y2 S

5. Support Growth of Plasma- Based Therapies Covington site will significantly increase Baxter network capacity for biotherapeutic therapies Products to be manufactured include: – Immunoglobulin (IG) therapy for patients with primary immunodeficiency diseases (PI) and multifocal motor neuropathy (MMN) – Albumin products, which are primarily used as plasma-volume replacement therapy in critical care, trauma, and burn patients

6. Regulatory Landscape Regulatory FoundationQuality Expectations 2005: ICH Q8, ICH Q9 2006: FDA: Quality Systems Approach to Pharmaceutical cGMP Regulations 2007: ASTM E2500-07 2008: ICH Q10, EU GMP Vol. 4 update, Annex 20 2011: FDA: Process Validation: General Principles and Practices Pharmaceutical and Biopharmaceutical Products: -Safe -Efficacious -Correct Identity -Perform consistently as described in the label, over their shelf life -Manufactured in a manner that ensure quality

7. Commissioning, Qualification and Validation Planning Identify the requirements and impact of this project Define the scope Identify activities that will be managed Define company/department responsibilities Perform detailed process Risk Assessments Perform robust Design Review / Design Qualification Describe commissioning and leveraging strategy Describe the strategy for computers/automation Identify documents to be developed and managed Identify a suitable approach to process validation Commissioning Plans Validation Plans Design Verification (DR/DQ) Risk Assessments Site Validation Master Plan Strategy Document

8. Quality System Integration for a Greenfield Project Risk Management Design & Construction Validation Quality System Overall Project Quality Systems Construction Quality Management Plan (CQMP) Design Qualification Good Engineering Practice (GEP) Start-up Commissioning Qualification Vendor Quality

9. Quality System Processes – Key to Regulatory Compliance Early and continued investment in: Design Reviews Quality Risk Assessments Design Qualification [ISPE: Applied Risk Management for Commissioning and Qualification]

10. Quality System Processes 1 Design Review Planned and systematic reviews of specifications, designs and design development. Quality Risk Assessment Part I Systematic process for the assessment, control, communication and review of risk to the quality of the product and the safety of the patient. Design Qualification The documented verification that the proposed design of the facilities, systems and equipment is suitable for the intended purpose. QRA Part II Regulatory Compliance (1) Slide taken from ISPE Reg. Compliance Presentation (R. Chew, C. Susla) A robust Design Review is critical to proper system operation obtaining Regulatory Compliance within budget and schedule constraints

11. Design Review / Design Qualification Approach Design Verification = 2 steps = DR + DQ  Requirements defined in approved procedure and templates  Assessment that the design is suitable for the intended purpose  For System’s Critical Aspects – DR/DQ provides traceability for each requirement to the engineering control strategy ASTM E 2500-07  Planned and systematic reviews of specifications, designs, and design development and continuous improvement changes performed as appropriate through the life-cycle of the manufacturing system

12. ASTM E2500 – 07 Process Flow GOOD ENGINEERING PRACTICE PRODUCT KNOWLEDGE PROCESS KNOWLEDGE COMPANY STANDARDS REQUIREMENTS DESIGN SPECS VERIFICATION ACCEPTANCE RELEASE RISK MANAGEMENT DESIGN REVIEW CHANGE MANAGEMENT REGULATIONS

13. V-Model (Ideal World) QP URS FRS SDD Code FAT/ SAT IQ OQ PQ Report PLAN SPECIFY CODE VERIFY REPORT

14. Automation Design Workflow Develop FRS Identify Design Gaps Preliminary Design Review Initiate Engineering Punchlist Release FRS to Integrator Informal Design Review with Integrator Integrator releases Design Team reviews Design Integrator addresses issues SAT with Process and Manufacturing Perform Design Qualification Proceed to Startup

15. Functional Requirements Compilation FRS Manufacturing Input URSSOO P&IDs CPPs Process Eng. Input

16. FRS Content Variables FRS Content = ƒ(a) + ƒ(b) + ƒ(c) + ƒ(d) + ƒ(e) a = Sequence of Operations b = P&ID (instrumentation feedback) c = Process Engineering Input (Process Knowledge) d = Manufacturing Input (Product Knowledge) e = Varying experience (leads into inconsistency across process areas)

17. Preliminary Design Review Assemble team of SMEs consisting of Process Engineers, Automation Engineers, and Manufacturing Systematically break down FRS with P&IDs to ensure content achieves desired functionality Establish Engineering Punchlist to document open issues that need to be addressed

18. Turnover to Integrator Approve FRS internally and turnover to Integrator SMEs (Process, Manufacturing, and Automation) to meet with Integrator to ensure requirements are understood Answer questions from integrator throughout software development period

19. Integrator Delivers Design…Now What? All SMEs from Design Review group review and provide comments Integrator addresses comments SAT is scheduled

20. Site Acceptance Testing Attended by same SMEs (Process, Manufacturing, and Automation) Also may include Validation representation, in the event documentation will be leveraged Opportunity for team to see graphics, equipment module functionality, and recipe progression in an offline environment

21. Design Qualification Pre-requisite: Punchlist items from SAT are resolved Documented verification that the proposed design of the facilities, systems and equipment is suitable for the intended purpose Proven through traceability of URS, FRS, and SDS Proceed to Start-up

22. Obstacles to Overcome Process Engineering and Manufacturing will be attending Equipment FATs during same time frame as Software Design Reviews, so limited time for thorough design reviews Design specs are typically code dumps that are difficult to navigate through to provide meaningful input Design is constantly changing, which adversely impacts software design Green-field projects are comprised of resources with various backgrounds and have multiple opinions about functionality of equipment Lack of Communication (As design changes, the team must be notified) Multiple issues lists for documenting engineering changes Pressure to streamline C&Q activities leads to starting too early with verification deliverables

23. Revised Automation Design Workflow Identify Similar Control Schemes Develop FRS Identify Design Gaps Preliminary Design Review Initiate Engineering Punchlist Release FRS to Integrator Informal Design Review with Integrator Integrator releases Design Convert Design to Reviewable Format Team reviews Design Integrator addresses issues SAT with Process and Manufacturing Perform Design Qualification Proceed to Startup

24. Identify Similar Control Schemes Review P&IDs and Sequence of Operation documentation to identify similar control schemes for Utilities and Process Typically applies to Temperature Control, Agitator Control, and Pressure Control Creates consistency and also eliminates redundant testing downstream Only test unique schemes once

25. Design Specification Example Requires navigation through multiple database (EMs), recipe, and unit class docs for thorough review Not a trivial task Review alone is an insufficient Design Review Convert to more usable format to ensure a robust review from Process and Manufacturing

26. Converted SDS Format Header EMDescriptionInitializeCharge WFICharge GAA V100-YV01Sprayball InletClosedOpenClosed V100-YV02Diptube InletClosed Open V100-YV03GAA InletClosed Open V100-YV04Alcohol InletClosed V100-YV05Agitator CIPClosed RECIPE PROGRESSION Forces Process and Manufacturing to revisit P&IDs to ensure software design achieves desired functionality Example of an Inlet Header for a Buffer Vessel (EM-V100-INLT)

27. Effect on Automation and Equipment CQV Activities If class-based functionality is not effectively used, more unique testing will be required for Automation and Equipment Inadequate Design Reviews will lead to issues discovered as part of CQV activities and will result in Over-budget and Delayed Schedule Waste commissioning that was intended to be leveraged towards qualification

28. V-Model (Real World) FRS SDD Code FAT/ SAT IV OV Lack of Process/Product Knowledge leads to re- programming and multiple iterations of qualification Design Qualification doesn’t catch inadequate Design Review Delays due to re- programming will adversely affect schedule and budget Introduces parallel activity of validation and change control

29. Ultimate Outcome FRS SDD Code FAT/ SAT IV OV

30. Better Outcome

31. Summary Variability identified as part of FRS Content Equation can be mitigated by robust design reviews with key personnel Risk-based testing methods will not be effective if the design reviews are not adequate Creates snowball effect that leads to a project that is over-budget and delayed

32. Q&A

33. FRS Outline 1.Overview (includes Purpose and Scope) 2.Operator Interface (Graphics to reflect P&IDs) 3.Devices (Analog & Discrete that feedback to DCS) 4.General Control (Equipment Module Functionality, i.e. TCMs, Agitators, Pressure Control) 5.Automated Operations (Batch Control – S88) 6.Interlocks 7.Alarms (CPPs) 8.Interface with Other Systems (Packaged Systems)