Summary

Invensys offers

proven Environmental

Monitoring System (EMS)

solutions—from Entry up

to High Availability—to

help customers meet

the particular challenges

of the Life Sciences

Industry.

Business Value

The FDA, EMEA and

other Life Sciences

regulatory bodies

require monitoring

environmental critical

process parameters that

affect product quality

and patient health.

Monitoring environmental parameters might seem as easy as simply recording some low frequency data. This is not the case. Life Sciences regulatory bodies call significant attention to environmental “critical process parameters.” If a pharmaceutical company is not able to show a proper audit trail for relevant data, a medicine cannot be released. Hence, secure data management and storage are vitally important.

Proper reporting, alarm management and sensor calibration are each relevant and contribute to simple, effective solutions. Ease of expansion and integration with HVAC or building management systems help minimize life-cycle costs. Modular, incremental validation based on proven “code fragments” and functions maximizes process availability when changes are introduced. Invensys’ EMS Industry Solution Blueprint provides a structured environment designed to promote rapid innovation and to avoid “reinventing the wheel” by learning from past experiences and leveraging the contribution of all involved parties to help deliver a risk-free, on-time and on-budget EMS solution.

Environmental MonitoringSystem (EMS) At A Glance

RULES TO BE APPLIED“Where environmental conditions could reasonably be expected to have an adverse effect on product quality, the manufacturer shall establish and maintain procedures to adequately control these environmental conditions. Environmental control system (s) shall be periodically inspected to verify that the system, including necessary equipment, is adequate and functioning properly. These activities shall be documented and reviewed.” - FDA 21 CFR Part 820.70 Production and Process Controls, section c.

EMS criticality is dictated by the impact of the process parameters being monitored on product purity, safety, quality, and efficacy (21 CFR Part 211), not the functionality of the EMS itself.

Control and monitoring of storage and production environments have become an important issue in the Pharmaceutical Industry. The FDA, EMEA and other regulatory bodies require accurate measurement and storage of critical process parameters (CPPs), and, in the U.S. if the storage medium is electronic, the methods used must comply with 21 CFR Part 11.

The FDA also states in its 21 CFR Part 203.32a that: “Manufacturers; authorized distributors of record and their representatives shall store and handle all drug samples under conditions that will maintain their stability, integrity and effectiveness and ensure that the drug samples are free of contamination, deterioration, and adulteration.”

There is virtually no pharmaceutical production where the monitoring of environmental parameters is not required.

•21CFRPart203,211,600and820

•USP31GeneralNotices

•FDAGuide—SterileDrugs

•FDAGuide—CGMPforPhase1Drugs

•EUGuidetoGMP—PartI&IIandAnnex1Revision

•FDACompliance-Chapter56

•PIC/SPE005,PE009,PI005,PI007,PI012

•FDAGuidetoInspections

•FDABiotechnologyInspectionGuide

•ICHQ7A

Some regulatoryrules in place:

GUIDANCES AND REFERENCESThe International Society for Pharmaceutical Engineering (ISPE) Baseline® Guides provide detailed information and recommend practices for implementation of EMS and HVAC systems in pharmaceutical facilities. Often EMS is mixed/embedded within HVAC or BMS (Building Management System)/BAS (Building Automation Systems) control systems. Over the last five years, it has been common practice to consider BMS/BAS systems as the sum of a ‘validated’ EMS plus a ‘GEP’ HVAC (with Access and Fire controls considered as ‘options’). The latest information can be obtained by joining the ISPE HVAC Community of Practice (CoP).

“It is common practice to qualify monitoring systems (sensors, transmitters, indicators, recorders, alarms, etc.) for those parame-ters defined as critical and to use GEP to ensure the development and maintenance of a robust control system“ A-1.6.17

“It may be possible to monitor, record, and alarm with portable or other instrumentation which is not a part of the HVAC control system in order to avoid validating control system vendor’s proprietary software” B-6.8

“It is possible to monitor, record, and/or alarm with portable or other instrumentation, which is not part of the HVAC control system” C-7.4.2

“It may be preferable that the monitoring and documenting of these “GMP Critical Parameters” should be isolated from any HVAC (Building Management System: BMS) control systems, to avoid qualification complications” D-5.8.2

“When specifying systems to control HVAC, the following should be considered: • HVAC’s industrial nature in cleanroom applications may not justify use of PLC- or DCS-based solutions • pharmaceutical HVAC can be controlled satisfactorily using HVAC industry control systems”

Other factors that may support use of PLC- or DCS-based systems; however, these are unlikely to offer baseline solutions.“ D-8.7.1

Some reference guides:

A. ISPEGoodPracticeGuide– Heating,Ventilation,and

AirConditioning(HVAC)–Sep2009

B. ISPEBaseline®Guide– Volume1:Bulk

PharmaceuticalsChemical–2ndEd.Jun2007

C. ISPEBaseline®Guide–Volume2:OralSolidDosageForms–2ndEd.Nov2009

D. ISPEBaseline®Guide– Volume3:Sterile

ManufacturingFacilities–1stEd.Jan1999

APPROACH - FIT TO ADOPTIndependent Integrated Monitoring Systems GMP and non-GMP EMS/BMS are often monitored independently through segregated solutions and then integrated later. Integrating independent EMS, BMS and CEM systems results in:

• a sizable decrease in validation efforts • elimination of sensor duplication and wiring • integrated diagnostic and alarm management • energy and maintenance optimization

A reasonable approach is to employ an independent system for alarming and managing critical process parameters. The BMS (BAS, HVAC) control system is limited to control and maintenance information required to manage a facility.1

It is a common practice to validate (qualify) an environmental monitoring system (EMS) for those parameters defined as process critical and to use good engineering practices (GEP) to ensure the developments and maintenance of a robust control system (BMS, BAS, HVAC).2

The implementation of independent monitoring systems also may bring the added benefit in terms of minimizing the risk of simultaneous failure of control and monitoring functions.3

Adopting Invensys’ unique ‘software marshaling’ results in avoiding sensor duplication for ease of maintenance, increased precision and quality data to the BMS, while maintaining the EMS and BMS systems segregated for ease of validation compliance.

________________________________________1 ISPE GPG - HVAC - Page 180 (8.5.1).2 ISPE GPG – HVAC - Page 188 (8.5.6).3 ISPE PE – Use of BMSs and EMSs in Regulated Environments (Vol. 25, No. 5) – Page 13, 1st sentence.

Themostscalable,reliable,innovative,faulttolerantandcosteffectiveEMSsystem

CollaborativeapproachleveragingOpenConnectivity,ActiveIntelligenceandAdvancedGraphics

FastDeployment—FastResults

Engineeringeffortreducedby50%includingGAMPdocumentation

ComprehensiveInvensysGlobalEcosystem

CRITICAL PROCESS PARAMETERSCritical process parameters should be managed by an EMS integrated with, but separated from, a BMS (BAS, HVAC). This approach provides the quality unit with a record from a validated system of room conditions during process operations, without the need for a formal change control process for the HVAC control system (an engineering charge control is still required, which typically is more manageable and less extensive in its scope, e.g. it may include only some set points and some hardware in the system).

According to the product impact on patient safety each of the parameters listed above could be classified as ‘critical’ 4, 5, 6, and 7 (CPPs related to CQAs) requiring to be managed under a GMP ‘qualified’ framework. Critical parameters are part of direct impact systems as defined in the ISPE Guide – Volume 5: Commissioning & Qualification.8

Usual Critical Process Parameters: Additional parameters: • Temperature (T) • Door status • Relative humidity (RH) • External temperature • Differential pressure (DP) • AHU(s) status • Airborne particles (AP) • AHU(s) operating mode • Air changes (AC) • Room occupancy • Terminal HEPA filters status

________________________________________4 ISPE GPG - HVAC (2.2.1), (8.5.6.1)5 ISPE Guide – Volume 1: Bulk Pharmaceuticals Chemicals – 1st Ed. Jun 1996 – (6.4, Table 6-1), (6.8)6 ISPE Guide – Volume 2: OSD Forms – 2nd Ed. Nov 2009 - (3.1.1), (3.1.2.3), (3.1.2), (6.3.6), (7.1), (7.4.1)7 ISPE Guide – Volume 3: Sterile Manufacturing Facilities – 1st Ed. Jan 1999 – (5.4.2), (5.8.1), (5.8.2), (8.2.1), (12.1.2), (12.2), (12.2.1)8 ISPE GPG – HVAC - Page 35 (2.3.1).

CriticalProcessParameters(CPPs)asthosethathaveahighprobabilityofaffectingproductqualityattributesiftheydeviatefromstatedlimitsforadefinedperiodoftime.

CPPsarederivedfromtherelevantCriticalQualityAttributes(CQAs).8

CPPsshouldbeidentifiedasearlyasthewritingoftheUserRequirementsSpecification(URS).

REQUIREMENTS AND FUNCTIONSAlso known as “Scope of Supply”. Requirements should be described in the User Requirements and Quality Plan documents. Main factors to consider when specifying sensors and devices for CPP monitoring (GMP relevant): • Accuracy, repeatability, stability and failure modes • Alarm requirements • Design point and tolerance (Hi-Lo range) • Operation thresholds and validated acceptance criteria • Maintenance and calibration requirements

Required system functions need to be addressed as well: • Sensor operating modes and failure detection • Alarm management • Local displays, operator practices, site or company standards • Security (redundancy, time stamping, data archiving) • Reporting, Electronic Batch Records, Records requirements • Back-up and recovery • Calibration

Most of these come from existing procedures, equipment in place, site best practices, corporate guidance, and regulatory predicate rules.

Riskassessmentisusedasaprocesstoevaluatetheimpactofsystemsorcomponentsonproductquality.Costtothebusinesshastobeconsideredaswell.

Foracomplex,centralizedsystem,theremaybeseveral“users”includingengineering,systemanddataowners,subjectmatterexperts,andqualityassurance.ItisimportantthattheneedsofallstakeholdersarecapturedandalignedintheURS.

Aneffectiveapproachwhenconductingtheriskassessmentistoassesseachcomponent(e.g.,room,laboratory,utilityarea),equipment,andfunctions(e.g.,alarmannunciationandreporting,datahistorian,network).

SOLUTION ARCHITECTURESThe Invensys Environmental Monitoring System is designed to satisfy the requirements of prominent regulatory bodies (e.g., U.S. FDA and its 21 CFR Part 11). The EMS offers: • Scalability, from a single room to a plant-wide solution • Simplified validation using flexible and modular standard ‘code fragments’ functions based on a dedicated EMS object

• Centralized and/or remote monitoring of facilities and equipment • Intelligent alarm capability for early warning of process deviations • Secure management and storage of environmental data and audit trails

• Facilitated enhancement and expansion • Predictive maintenance planning • Integrated with Invensys Facilities Management System application • Integrated with Invensys Corporate Energy Management application

Four different ‘template’ architectures are available: • Entry: designed around Eurotherm recorder proven functionalities. One or more recorders (paper or paperless) can be networked providing local visualization and tamperproof data logging. Sized for one or more rooms, equipment and cold stores.

• Simplex: looking for a cost-effective Microsoft Windows®-based operator station with a few distributed I/O devices and web reports, easily expanded and validated? If so, this is the solution. Ideal for warehouses, laboratories and climatic chambers.

• Redundant: unique fully hot redundant solution, with built-in ‘store & forward’ and Wonderware SQL Historian. Designed for manufacturing, sterile facilities, and large facilities.

• High Availability: large, object-based, hardware agnostic, fully redundant, time proof, and ‘state-of-the-art’ solution. For all ‘critical’ applications.

Fromnewplanttorefurbishment:

•Performariskassessment

•Identifynew/existingCPPs

•Selectthe‘bestfit’architecture

•Expand/maintainleveragingthe‘complianceoriented’area-roombased’codefragments’madeavailablebyInvensysEMSblueprint.

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

Rel. 08/11 PN I-LS-0104

DOCUMENTATIONA key requirement for EMS solutions is validation. Where environmental conditions (e.g. temperature, humidity, differential pressure, air flow, sterility, containment) have a direct impact on product purity, safety, quality or efficacy, they need to be monitored against predetermined limits and logged. In this case, the BMS/EMS system used for collecting and logging the data needs to be validated.Each EMS project will require the following sets of documentation:

• Project Planning Documents: AF&IDs, Design Basis, Air Balance, Critical Instruments Specification, Health & Safety Procedures. Many of these docs are ‘Critical master documents’ and to be provided as ‘as-build’ versions.

• GEP and Validation Documents: Risk Assessment, Traceability Matrix, User Requirements, Project Plan, Quality Plan, Design Specification, Test Protocols, IQP, OQP, PQP, and Thermal Mapping

• Other GEP Documents: Drawings Package, Bill of Material, Calibration SOP, Handover Checklist, Operator Manuals, Contractual Ts&Cs, Sub-contractors Quality Systems, Expediting-Inspecting-Delivery Control Procedures

• Commissioning & Qualification Documents: Test Protocols and Test Results, Acceptance Criteria

Most of these documents will be part of the EMS Blueprint. Invensys Compliance Services Team is available during project planning and execution.

For additional information, refer to Heating, Ventilation, and Air Conditioning (HVAC), Section 6, “Documentation Requirements”, ISPE Good Practice Guide, September 2009.

Initial RiskAssessment

Iteration asrequired

Code Modules

Module (Unit)Specification

Module (Unit)Testing

User Testing ofControls & Procedures

Functional RiskAssessment

Testing of SystemControls

User Req.Specification

RequirementsTesting

FunctionalSpecification

FunctionalTesting

ConfigurationSpecification

ConfigurationTesting