ASEPTIC PROCESSING, TODAY AND FUTURE

TODAY S REALITY AND NEEDS Today s Reality Change / smaller batches: High volumes set ups not easily adjustable to low volumes; Biopharma, clinical batches, personalized medicine and gene therapy products as well as Start ups require small volumes Needs Traditional manufacturing Aseptic rooms (curtains, RABS ) Some still using manual and semiautomatic operations; e.g. visible particles inspections, set ups, filling Operator manual interventions Regulatory authorities concerned about public risk; more scrutiny, and challenge ANNEX 1, MRA US-EU, Russian, Chinese Flexibility; smaller batches, simple and quick set up changes, affordability for mass market Advancement of New Technologies New facility designs, new technologies to manufacture, fill, monitor, control and test Need to separate operators from process Improved facilities, processes, technologies, understanding, training Simplify operations to ensure compliance 2018 PAREXEL INTERNATIONAL CORP. / 3 ALL RIGHTS RESERVED

ISSUES AND POTENTIAL CAUSES Issues and Concerns Dirt, foreign material, visible particles, leaking, underfilling/ empty containers, cracks, microcracks, device/ injector system not fully working Sterility assurance concerns Cleaning/ potential of cross contamination Stability concerns Potential Causes Facility design, manufacturing process design Deficient processes, complexity in set ups/ operations Old technologies to manufacture, fill, monitor, control test Operators not separated from the process, interventions Poor understanding, poor training Poor validation support Poor quality system 2018 PAREXEL INTERNATIONAL CORP. / 4 ALL RIGHTS RESERVED

REGULATORS CONCERN; HOW MANUFACTURERS CLAIM TO REMAIN IN AN STATE OF CONTROL Sterility Assurance Data Governance Personnel Qualification, Validation Premises and Equipment Aseptic processing areas deficient in their design Facility and equipment are not designed or maintained to assure cleanliness Inadequate in process controls to prevent critical/ major defects Insufficient environmental/personnel monitoring and incomplete environmental and personnel monitoring investigations Media fills not being fully representative; interventions Lack of procedures to protect against microbiological contamination and its oversight Qualification/ certification of operations and operators; justification of access to Class A and B Poor aseptic behaviors 2018 PAREXEL INTERNATIONAL CORP. / 5 ALL RIGHTS RESERVED

FUTURE ASEPTIC PROCESSING AND FACILITY DESIGN Promote automation, isolation and robotics product understanding on the design phase robotic inspection systems and PAT Look for augmented reality, digitally controlled operations, advanced vision systems, process monitoring/ control in place Use big data and analytics to confirm processes are controlled, capable and robust 2018 PAREXEL INTERNATIONAL CORP. / 6 ALL RIGHTS RESERVED

FUTURE ASEPTIC PROCESSING AND FACILITY DESIGN Look to improve simplicity, reduce risk and improve control through new technological solutions Look To: Eliminate operators direct interventions in Class A Promote gloveless isolation Design simple set ups, minimal moving parts, minimal change overs to reduce particles automatized inspection processes in place Promote sterilization in place, close systems Promote Data Integrity through technological solutions 2018 PAREXEL INTERNATIONAL CORP. / 7 ALL RIGHTS RESERVED

REFERENCES Robotics Solve Aseptic Filling Challenges; Automated robotic arms manipulate nested trays and containers inside closed aseptic filling systems. Jun 20, 2018. By Jennifer Markarian. Equipment and Processing Report. Volume 11, Issue 7. Pharmatech.com vanrx.com/robotics-in-pharmaceutical-manufacturing. July 13, 2018 www.sterilinerobotics.it https://www.fedegari.com/wp-content/.../emerging-gloveless-robotic-technologies.pdf. fedegari.com. Emerging Gloveless Robotic Technologies in Aseptic Manufacturing for Personalized. Cytotoxic Drugs. S. Mauri. Manager, BU Integrated Projects 2018 PAREXEL INTERNATIONAL CORP. / 8 ALL RIGHTS RESERVED