Summary

The Pharmaceuticals

segment of the Life

Sciences Industry is

very heavily regulated.

Advanced simulation

is a key tool to address

the requirements faced

by Pharmaceutical

companies around

the world.

Business Value

Invensys’ Simulation

Solution allows

customers to save

time and money and

provides a high level

of confidence in their

validation programs.

It is flexible and

customizable to meet

demanding customer

requirements.

INTRODUCTIONThe Life Sciences Industry and its Pharmaceuticals segment hold the distinction of being among the world’s most heavily regulated environments. One cannot have a Pharma-related discussion without using the endless acronyms that permeate the common language: 21 CFR Part 11, GAMP, FAT, IQ, OQ and URS are just a few, all part of the ‘validation’ process.1

Simply stated, validation — as enforced by the U.S. Food and Drug Administration (FDA) and other equivalent regulatory bodies around the world — requires Pharmaceutical companies to provide documented evidence of each step of the manufacturing process and prove that each step of every process does exactly what it purports to do, every time. The industry must demonstrate control over all of the processes it uses: development, quality, manufacturing, supply chain, etc. This control ensures the safety, quality and efficacy of the medicines that so many people depend on every day.

As a consequence of this regulatory burden, the Life Sciences Industry was slow to undertake automating their manufacturing processes. While others such as Chemicals and Specialty Chemicals consistently moved to apply new technologies and improve operational performance, the Life Sciences Industry was typically hesitant to implement new technologies which could require unknown or excessive amounts of testing. Restrictive FDA audit findings led Life Sciences companies to focus on meeting regulations, not on improving manufacturing. The regulatory burden peaked in the late 1990s. In 1995, the Good Automated Manufacturing Practice (GAMP) forum issued the GAMP Guide for Validation of Automated Systems in Pharmaceutical Manufacture. GAMP became the user community’s forum to respond to governmental regulations, and companies used it as an avenue to warn the regulatory bodies of their heavy burdens which were hindering technological progress.

________________________1 See Glossary at end of document.

Trends in PharmaceuticalsEffective Use of Simulation

Pharmaceutical Manufacturing Facility

A CHANGING INDUSTRYIn response to the industry’s concerns, the FDA released its report titled Pharmaceutical cGMPs for the 21st Century in 2004. This policy allows companies to be innovative and apply risk-based technology approaches to improve manufacturing and validation strategies. The Life Sciences Industry can no longer afford to rely on techniques and methodologies for manufacturing and validation that were used in the past, as the industry is more competitive, customers are increasingly price conscious, and efficiency is crucial. Companies are increasingly concerned with the timely release of product to the market, operational excellence and overall profitability. The industry is also moving from an organic-based synthesis of drugs to biologic products. Biologic synthesis is more complex and requires technological solutions to allow flexibility, optimization and compliance. Advanced simulation is a key tool to address these requirements. Simulators, developed in collaboration with Research & Development, can help reduce a new product’s time-to-market by facilitating scale-up. Simulators can support complex controls qualification, assist with change control by predicting process behavioral changes prior to actual implementation and increase operator training effectiveness. They can also be used to test design strategies and assist with changes to process flow, something that is particularly important for contract manufacturers.

HOW SIMULATORS CAN BE USEDA simulator can be used to qualify the controls of a process before the actual manufacturing start-up of a new drug. The controls qualification activity allows the simulator to be used to:

• Validate permissive logic • Create and test recipes and logic sequences such as SIP, CIP and start-up (e.g., test emergency sequences and/or sequences which may be dangerous to personnel or damaging to equipment)

• Pre-tune control loops • Evaluate controls stability • Qualify graphics displays • Implement qualified controls at the real manufacturing facility • Develop process model (see figure below) • Test control loops to assist with commissioning (see figure on next page) • Test and validate changes during the post-start-up phase, reducing production downtime to perform the modification and re-qualify the control system

Typical Fermentor Process Model

Simulation Control modifications that are required for start-up and proper operation can be validated on the simulator and then implemented at the manufacturing site. Invensys customers who have taken advantage of this type of testing and pre-startup training opportunity have experienced nearly flawless first-time start-ups. The elimination of extra validation (design changes and rework) during the start of manufacturing is by itself a common justification for the simulator purchase.

Another benefit is the ability to carry out personnel training, such as for Operators, Instrumentation Technicians and I&C Engineers. Simulators facilitate Operator familiarization on the control system and process areas in scope. This allows end-users to try out the system and give feedback early in the project life cycle, when the cost of changes is low.

Simulator technology can also reduce the technology transfer time from laboratory-scale manufacturing to large-scale production. For example, process development groups are using modeling to improve the predictability of bioprocesses. Simulators can use ‘black-box’ models to better inform process experimentation and scale-up.

SIMULATOR SOLUTIONSThe Invensys Simulation Solution consists of two integral components: a process model and a controls emulation.

• Invensys' SimSci-Esscor™ brand DYNSIM modeling solutions provide the ability to model various kinds of equipment to the required level of fidelity such as:

° High fidelity – where the process behavior is well understood and there are no proprietary concerns

° Medium fidelity – where the process behavior is reasonably understood and/or there are proprietary concerns

° Low fidelity – tieback models where process behavior is not understood or is less important for training

• Invensys’ virtual emulation solution for Foxboro®-based controls, FSIM Plus™, provides the simulation for the Foxboro I/A Series® System controls. This solution requires no hardware control processors (CPs) for the system and can handle multiple CPs, minimizing switching between areas.

Temperature Control Loop

Invensys, the Invensys logo, ArchestrA, Avantis, Eurotherm, Foxboro, IMServ, InFusion, SimSci-Esscor, Skelta, Triconex, and Wonderware are trademarks of Invensys plc, its subsidiaries or affiliates. All other brands and product names may be the trademarks or service marks of their representative owners.

© 2011 Invensys Systems, Inc. All rights reserved. No part of the material protected by this copyright may be reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, broadcasting, or by any information storage and retrieval system, without permission in writing from Invensys Systems, Inc.

Invensys Operations Management • 5601 Granite Parkway III, #1000, Plano, TX 75024 • Tel: (469) 365-6400 • Fax: (469) 365-6401 • iom.invensys.com

• Invensys’ virtual emulation solution TRISIM Plus™ for Triconex®-based applications provides the simulation for Triconex systems.

• Invensys’ translation utilities allow translation of Allen-Bradley RSLogix controls into control models that can be imported into DYNSIM.

• Many third-party controls vendors (such as Emerson DeltaV) provide control emulations of their Distributed Control System (DCS) controls. Invensys software has the ability to work with most third-party control emulations.

GLOSSARY • 21 CFR Part 11 – Code of Federal Regulations related to the U.S. Food and Drug Administration (FDA) guidelines on electronic records and electronic signatures

• cGMPs – Current Good Manufacturing Practices • CIP – Clean-In-Place • FAT – Factory Acceptance Test • GAMP – Good Automated Manufacturing Practices • IQ – Installation Qualification • OQ – Operational Qualification • SIP – Steam-In-Place • URS – User Requirement Specification

Rel. 09/11 PN I-LS-0109