1. Compliance From The Ground Up September 18, 2013 Earlene Gibbons Director, Operational Technology

2. Unique Opportunity Green Field Construction –Solid Dose Manufacturing –200,000 sq. ft. facility –New Equipment Blank Slate –No existing systems –No in house experience –No additional team members No formal budget allocated for GxP systems –However…

3. Zero to GxP in 8 Months 100% Outsourced Manufacturing to Insourced Manufacturing Systems to support the facility, manufacturing, and quality required identification, procurement, installation and qualification The schedule of system installations had to be prioritized and integrated into the construction schedule

4. GxP Systems Building Management Calibration Management Maintenance Management Document Management ERP / Materials Management QMS LIMS / Chromatography Data

5. First Things First One of the first systems required to be available for use was a calibration management system –Manufacturers Bench Calibrations –Installation Calibrations –Validation Calibrations The calibration management system availability had to be closely coordinated with the BMS startup and commissioning

6. Calibration Automatic, mechanical, or electronic equipment or other types of equipment, including computers, or related systems that will perform a function satisfactorily, may be used in the manufacture, processing, packing, and holding of a drug product. If such equipment is so used, it shall be routinely calibrated, inspected, or checked according to a written program designed to assure proper performance. Written records of those calibration checks and inspections shall be maintained. CFR 211.68

7. Selection Requirements System RequirementsVendor Selection Criteria Regulatory CompliantProject Management Services Part 11 CompliantImplementation Services Ease of UseTraining PaperlessUnderstanding of Best Practices ScalableOn–Going Support Reporting (Standard & Ad Hoc)Reputation ConfigurableCustomer Service Cal / PM HarmonizationLife Sciences Industry Experience Audit Trail

8. With a little help from our friends…

9. Startup & Commissioning Start up is the series of events required to turn equipment or systems on for the first time Equipment Commissioning is the process of testing equipment to verify it functions according to the design specification Commissioning is performed under Good Engineering Practice (GEP)

10. Validation / Qualification Installation Qualification documents that the equipment was installed correctly: –Design features –Installation conditions –Environmental conditions –Calibration and PM schedules –Safety features –Software documentation –Spare parts list –Vendor documentation / Turn-over package Equipment Validation/ Qualification is documented evidence that provides a high degree of assurance that the equipment requirements and specifications are met and will fulfill its intended purpose

11. RAM Implementation Project Planning Data Migration –External Calibration Manager to RAM Validation SOPs Training Go-Live

12. Master Data Accurate Consistent Secure Scalable

13. Asset Management Blue Mountain RAM is the system of record for our equipment / asset management Types –Equipment –System –Location –Personnel –Loop Classification –Critical / Direct –Non Critical / Indirect

14. Calibration A calibration management program ensures equipment and instruments are calibrated according to written instructions The calibration management program must document the calibration date, person performing the calibration and the date due of the next calibration Calibration Periods –Manufacturers Recommended intervals –Daily –Monthly –Quarterly –Semi Annually –Annually –After an event

15. Preventive Maintenance Preventive maintenance should be performed at appropriate intervals to prevent equipment malfunctions that are preventable with regular monitoring PM activities include visual inspection of the equipment, following the manufacturers recommendations for routine maintenance and regular inspection / replacement of parts that routinely wear out or fail

16. Preventive Maintenance The equipment classifications identified and assigned for calibration management provide the foundation for the maintenance management program. –Unique Equipment Numbers –Preventive Maintenance Plans –Work Instructions (R3) –Historical Maintenance Records –Scheduling –Training –Spare Parts –Utilities

17. Quality Assurance Review and approve new and / or edited records for equipment, instruments and systems entered into RAM MDT Standards New Assets Calibrations PM Val (upgrade) SS (upgrade) WPT (upgrade)

18. Day to Day Compliance Calibration and Preventive Maintenance are required to maintain the equipment in good working order Quality review of both calibration and PM activities can be performed by exception – reviewing only the records that are out of tolerance Ease of reporting Calibration and Maintenance activities provides regulatory authorities / auditors with the documentation of maintaining the equipment in compliance with cGMP

19. Compliance Compliance is not optional! Non-Compliant organizations risk –Warning letters –Delays in getting product to market –Losing market share to competitors Compliance is mandatory!

20. Corporate Compliance RTP upgrade to R3 Silver Spring upgrade CalMan to R3 Leveraged existing rules, workflows Workflow Improvements Integration with ERP and other corporate systems Multi-Site Harmonization

21. Corporate Compliance Consistent Support Structure Consistent approach to compliance On-boarding New Facilities Global Harmonization

22. References Code of Federal Regulations, Title 21, Part 210 –Current Good Manufacturing Practice in Manufacturing Processing, Packing, or Holding of Drugs Code of Federal Regulations, Title 21, Part 211 –Current Good Manufacturing Practice for Finished Pharmaceuticals Blue Mountain RAM User Manual