Network Qualification: What Is it; What Does it Involve?

JVT_May2007.qxd 4/23/07 8:04 AM Page 210 Network Qualification: What Is it; What Does it Involve? BY ESRA GUVEN, B.Sc.EE, PMP, CCNA WHAT IS A NETWORK? The Food and Drug Administration (FDA) defines a network as: An arrangement of nodes and interconnecting branches A system that connects several remotely located computers via telecommunications Networks are a combination of hardware and software that together allow devices to communicate. Networks allow applications operating on various computers to communicate with one another as shown in Figure 1. REGULATIONS AND WHY NETWORKS MUST BE VALIDATED The pharmaceutical drug and food industries are controlled by various International Regulatory Agencies throughout the world. The U.S. Food and Drug Administration (FDA) oversees one of the world's most demanding drug regulation and approval processes. The European Union s (EU s) ongoing efforts to transition to a single European Market continue to present the Pharmaceutical Industry with unprecedented opportunities and challenges. The EU offers a comprehensive and all-new analysis of its successful, centralized procedures and its less well-received mutual recognition procedures. In Asia, Japan represents the current pharma market giant. New Drug Approval (NDA) in Japan provides the first and only in-depth analysis of the drug development and approval processes in this mega-market. Regulatory Agencies require networks in the Pharmaceutical Industry to be qualified, because: Systems with an impact on product quality, safety, identity, and efficacy require validation. The Pharmaceutical Industry produces two critical items, medical products and data. Medical products are supported and marketed based upon the quality and meaning of the underlying data. The integrity and transfer of these data must be assured and maintained. Networks are systems that are actively involved in creating, modifying, maintaining, archiving, retrieving, and transmitting data. As depicted in Figure 2, in order to produce a quality product in the Pharmaceutical Industry, quality data is required. Quality data can only be produced in a qualified network environment. QUALIFICATION VS. VALIDATION There has always been confusion between the qualification of a Network and the validation of Networked Systems. Do not include the validation of networked systems in the scope of a network qualification. Before we get into the scope of network qualification, let us get a better understanding of: What is qualification? What is validation? What are the differences between qualification and validation? 210 Journal of Validation Technology

JVT_May2007.qxd 4/23/07 8:04 AM Page 211 Figure 1 Networks Allow Applications to Communicate Network ware application Software Application Software Application Figure 2 Why Networks Must be Validated Product Data Quality Network Qualification Needs (Requirements) Qualification is the action of proving that any equipment works correctly and leads to the expected results. The meaning of the word, validation, is sometimes broadened to incorporate the concept of qualification. Validation provides documented evidence, to a high degree of assurance, that the computerized systems are accurately and reliably installed and can perform their functions as intended for use. Validation is a lifecycle, and qualification is part of this lifecycle. Validation proves that the overall process works for a specific system. For example, the overall process needs to be validated for a specific application, while equipment hardware and software and the reference material used for the application should be qualified before or within the validation. Consider these terms as you look at the schematic shown in Figure 3. In Figure 3, a typical Computer System Validation (CSV) process is shown. First, create the validation plan and perform other validation activities, such as Installation Qualification (IQ), Operational Qualification (OQ), and Performance Qualification (PQ), where applicable. After performing all validation activities, summarize your findings in a report. Once the report is signed off, the computerized system is in a validated state. To maintain its validated state, a change control process should be in place. Any change to the system should go through the change control process. Depending on the change, you may perform all or some validation activities to ensure the affected process is once again in a controlled state. May 2007 Volume 13, Number 3 211

JVT_May2007.qxd 4/23/07 8:04 AM Page 212 oftware application Figure 3 CSV Lifecycle Process Validation Plan Typical Computerized System Validation (CSV) Lifecycle Process Installation Qualification Operational Qualification Performance Qualification Change Control Figure 4 Define the Network Qualification Scope Questions to be Asked: Which network elements will be included in the scope? Will the servers and computers be included in the network qualification? Will individual networked systems be included? Will qualification of all network layers be included? Will other infrastructure components be included along with the network? Will the LAN and WAN be included? Will the GXP computer systems and applications be included? 212 Journal of Validation Technology

JVT_May2007.qxd 4/23/07 8:04 AM Page 213 SCOPE OF NETWORK QUALIFICATION You just started qualifying the Network. The network has been there up and running for years, and you don t know where to start. First, you must define the scope. You just started planning the network qualification. The network is a giant system and you have no idea how to start, where to start, or how to outline the project boundaries. Create a good plan and define the scope clearly within the plan. Ask yourself the relevant questions listed in Figure 4. You will find helpful answers to these questions in the following sections of this article. Network vs. Networked System Networked systems are computerized systems running on networks. Let us consider these terms from a different perspective. Looking at our highways, streets, and communities on a map, we see a big city which we will call our network. This network includes different communities which represent the networked systems as shown in Figure 5. For this example, let us say we are working in a building in the Business Area located in Community 3, as shown in Figure 5. The product will come to us from a Factory located in Community 2. We will inspect the product and send it to the customer via airplane. So, the product must reach Community 4, the City Airport, from Community 3, the Business Area. To be able to ensure the customer receives good quality of product; we must validate each community (City Airport, Factory, and Business Area) as well as qualify the Highway. Similarly, we must validate networked systems while qualifying networks. The cars, traveling on the Highway from Factory to Business Area, and from Business Area to Figure 5 Network and Networked Systems Highway City Airport COMMUNITY 4 Networked System 4 Residential Area COMMUNITY 1 Networked System 1 Business Area COMMUNITY 3 Networked System 3 Factory COMMUNITY 2 Networked System 2 May 2007 Volume 13, Number 3 213

JVT_May2007.qxd 4/23/07 8:04 AM Page 214 City Airport, carry the product. In our case, the bits and bytes flowing from server to client or client to server carry data. Here, networked systems are the communities and networks are the highways. Network qualification deals mostly with the highways while individual networked system validation takes care of the communities. In other words, network qualification makes sure that there are no obstructions in the way, and that the data reaches their destinations without any loss. In light of these similarities, network qualification should consider network devices (e.g., switches, routers, firewalls, Virtual Private Network (VPN) routers), installation or decommissioning of network hardware or software, and the connection of LANs via WAN links, as these elements of the network provide data flow on the network. It is recommended that the network qualification should not deal with individual networked computer systems within the entire network such as Laboratory Information Management Systems (LIMS), Manufacturing Resource Planning (MRP), and Electronic Document Management Systems (EDMS). Validating a networked computer system or application is not in the scope of network qualification. Validating a networked system requires qualifying its individual components (such as the applications running on each computer) and authorized access to the system as well as qualifying data transfer between related computers. The diagram in Figure 6 shows a typical client/server networked system connecting client computers in the manufacturing plant and offices to the system server. Clients are connected to the server through a switch. The server uses a relational database with customized applications for data management; for review, backup, archiving, and retrieval of data; and for generating electronic signatures compliant with 21 CFR Part 11. The validation scope for the networked system in Figure 6 would include the clients, PLC's, application server, and database. The Installation Qualification (IQ) and Operational Qualification (OQ) of the switch would be the scope of the network qualification. Scope in Terms of Network Layers Networks consist of seven layers called an Open System Interconnection (OSI) reference model. The OSI reference model is the primary model for network communications. It describes a method of how information or data moves from one computer to another. In the OSI reference model, there are seven numbered layers, each of which illustrates a particular network function. Figure 7 demonstrates the scope of network qualification according to the network layers. For the functional description of each layer, see Figure 8. Each individual OSI layer has a predetermined set of functions that it must perform in order for communication to occur. Figure 6 Typical Networked System OFFICE MANUFACTURING Client Client Printer PLC PLC Scanner Application Database Switch 214 Journal of Validation Technology

JVT_May2007.qxd 4/23/07 8:04 AM Page 215 Figure 7 Scope of Network Layers Layer 7 Layer 6 Layer 5 Application Layer Presentation Layer Session Layer Individual Networked Computer Systems Validation Scope Layer 4 Transport Layer Layer 3 Layer 2 Layer 1 Network Layer Network Device: Routers Data Link Layer Network Device: Switches Physical Layer Network Wiring Network Qualification Scope Figure 8 Functional Description of Layers Layer Name Functional Description 7 Application Interface between network and application software 6 Presentation Data representation 5 Session Keeping data separate from different applications 4 Transport Reliable or unreliable delivery, end-to-end connections 3 Network Logical addressing and best path selection 2 Data Link Framing and local addressing 1 Physical Moving of bits between devices (binary transmission) Specification of voltage, wire speed, and cable pin outs May 2007 Volume 13, Number 3 215

JVT_May2007.qxd 4/23/07 8:04 AM Page 216 Layer 7: The Application Layer This is the OSI layer that directly affects the user. It provides network services to the user s applications. It differs from the other layers in that it does not provide services to any other OSI layer. TELNET is an example of the application layer. Layer 6: The Presentation Layer This layer ensures that the information which the application layer of one system sends out is readable by the application layer of another system. The presentation layer translates between multiple data representation formats. It is concerned with data structures and negotiation data transfer syntax. Layer 5: The Session Layer The session layer establishes, manages, and terminates sessions between two communicating hosts. The session layer provides its services to the presentation layer (it manages data exchange between presentation layer entities). Layer 4: The Transport Layer The transport layer segments data from the sending host system and reassembles the data into a data stream on the receiving host system. The transport layer establishes, maintains, and properly terminates virtual circuits. In providing reliable service, transport error detection-and-recovery and information flow control are used. Layer 1: The Physical Layer The physical layer defines electrical, mechanical, procedural, and functional specifications for activating, maintaining,and deactivating the physical link between end systems (data transmission across the network media). Characteristics, such as voltage levels, timing of voltage changes, physical data rates, maximum transmission distances, physical connectors, and other similar attributes, are defined by physical layer specifications (various types of networking media). As shown in Figure 9, the first four network layers are data flow layers which include the: Physical Layer Data Link Layer Network Layer Transport Layer It is recommended that the first four network layers should be covered in the scope of network qualification. Although the top three layers are not in the scope, you may use these layers as a tool for testing. For example, TELNET is an application layer tool that can be used to perform a test to determine whether a remote router can be accessed. A Figure 9 Data Flow and Application Layers Layer 3: The Network Layer This layer provides connectivity and path selection between two end systems that may be located on geographically diverse networks. The network layer is concerned with logical addressing (IP). Layer 2: The Data Link Layer At this layer, data packets are encoded and decoded into bits. The data link layer provides reliable transit of data across a physical link. The data link layer is concerned with physical addressing (MAC), network topology, media access, error notification, ordered delivery of frames, and flow control. Application Layer Presentation Layer Session Layer } Transport Layer Network Layer Data Link Layer Physical Layer } Application Layers Data Flow (Host) Layers 216 Journal of Validation Technology

JVT_May2007.qxd 4/23/07 8:04 AM Page 217 successful TELNET connection indicates that the services of lower layers function properly. Network vs. Infrastructure A network is a system consisting of transmission channels and supporting hardware and software that connects several remotely located computers via telecommunications. In practice, this includes physical items, such as cables, switches, and routers, as well as the network device operating system, network management servers, and network management software that allow the transmission of data on the network. Infrastructure comprises both the desktop and general support services. The desktop will be the general office or business applications and utility programs available when users log onto the network. Backup, recovery, disaster recovery, help desk, and problem management support services comprise the second part of infrastructure. Infrastructure includes computers, network, base software, and service applications. The table in Figure 10 lists examples of infrastructure elements. In light of these definitions, network is part of the infrastructure, but not entirely as stated in Figure 11. Figure 12 shows that network qualification is separated from other infrastructure components and GXP applications. Other infrastructure components should be out of the network qualification scope so that you do not get lost in the maze of logic. Validation of other infrastructure components, such as backup applications, should be handled separately. A. Infrastructure Facilities Power Main feed(s) and emergency generators UPS: batteries required replacement Circuits and capacities vs. loading Outlets: physical type, voltage, amperage Fire Detection and Suppression System type and ratings Outlets and zones System controls HVAC Chiller units: cooling towers Temperature controls Figure 10 Infrastructure Examples Infrastructure Elements: Devices Applications Networks Examples: Computers, Servers, Printers File Transfers, E-mail Local Area Networks (LANs), Wide Area Networks (WANs), Cables, Routers, Switches Figure 11 Overall Scope of Infrastructure Qualification The Overall Scope of Infrastructure Qualification A. Infrastructure Facilities B. Servers C. Client Desktops D. Network E. Infrastructure Applications May 2007 Volume 13, Number 3 217

JVT_May2007.qxd 4/23/07 8:04 AM Page 218 Cooling zones and capacities vs. loading Security Keycard readers, combination locks, alarms Authorized entry list B. Servers Server Hardware Base system and memory I/O (Input/Output), NIC (Network Interface Card) and storage Server Software Operating system OS configuration settings Network protocols and ports Service-dependent including web server, DBMS, file/print services C. Client Desktops Should be specified and qualified as a family Enforce commonality of Hardware and Software D. Network Routers, Switches, Hubs, Firewalls, VPNs, etc. Hardware configuration of each major Network Component, Interface or Management Cards Software Configuration, Operating Software version, and Configuration settings LAN WAN Intrusion Detection System (IDS) De-Militarized Zone (DMZ) E. Infrastructure Applications Enterprise Network Management Real-time view of network and system status Network Configuration Management Highly capable of directly managing the configuration of network components such as CiscoWorks Client Desktop Management Hardware and software inventory, server monitoring, virus protection Application and Database Management LAN and WAN Local Area Networks (LANs) are those networks usually confined to a small geographic area, such as a single building, a group of localized buildings, or a site. LANs are not necessarily simple in design; some may link many thousands of systems and service hundreds of users as in a corporate LAN. Any new LAN connected to an existing LAN should be qualified whether the building is GXP impacted or not, since a newly added LAN might affect GXP areas. A network often may be installed without supporting a GXP application or area and then later in its life be requested to support a GXP area. It can be very difficult to retrospectively qualify a network. Wide Area Networks (WANs) are those networks installed on a wide geographical area, typically linking multiple sites. LANs are often connected via WAN links to create an Intranet. Qualify any new WAN links connecting LANs between sites. SCOPE OF CONTINUOUS NETWORK QUALIFICATION PROCESS After you maintain your network in a compliant state, any change to the network should be performed through a Computer Systems Change Control form process. The network is a dynamic environment and changes rapidly. Network changes should be classified based upon risk to the business including regulated activities. It is recommended that a network change control system be established to provide flexibility to address various types of changes. The changes should be classified based upon risk to the business that includes GXP compliance risks. The level of testing required depends on the complexity and seriousness of the change. Depending upon the type of network change, this can have an impact on network availability, reliability, data integrity, and security. For example, network changes can be classified as high risk, medium risk, low risk, and no risk. The risk level has an impact on validation and other activities. The table in Figure 13 reflects examples of high and medium types of network changes and their corresponding validation activities according to the risk type. 218 Journal of Validation Technology

JVT_May2007.qxd 4/23/07 8:04 AM Page 219 Figure 12 Overall Scope of Infrastructure Qualification Application Systems Validation Apps 1 Apps 2 Apps 1 Apps 2 Infrastructure Qualification Qualified Client PC O/S Hardware DBMS O/S Hardware Qualified Server Routers, Switches, Hubs, Firewalls, VPN, IDS, etc. Qualified Network Figure 13 High and Medium Risk Network Changes and Validation Activities Risk Category High Medium Example Changes Changing ISP(Internet Service Provider) Implementing a new technology on the network (balancing, distribution layer) Adding additional network devices such as routers and switches Replacing an existing network device Validation Document/Activity Change Control form required IQ/OQ/PQ Protocol IQ checklist(s) OQ/PQ test procedure(s) IQ/OQ/PQ Report Change Control form required IQ Checklist(s) OQ/PQ test procedure(s) IQ/OQ/PQ Report May 2007 Volume 13, Number 3 219

JVT_May2007.qxd 4/23/07 8:04 AM Page 220 CONCLUSION Let us now answer the questions asked when we defined the scope of network qualification: Question Answer Comments Which network elements will be included in the scope? Will the servers, and computers be included in the network qualification? Will individual networked systems be included? Will qualification of all network layers be included? Will other infrastructure components be included along with the network? Will the LAN/ WAN be included? Will the GXP computer systems and applications be included? Network devices: switch, router, hub, firewall, VPN, etc. LAN, WAN NO. NO. NO. NO. YES. NO. Leave the servers, applications, clients out of the scope. Handle these through different projects for each system. See above. Validating a networked system requires qualifying its individual components (such as the applications running on each computer) and authorized access to the system as well as qualifying data transfer between the related computers. Handle these through different projects for each system. Include the first four network layers in the network qualification scope. The top three layers should be in an individual application validation scope. The network is part of the entire infrastructure. Validation of other infrastructure components, such as data centre applications, should be handled separately. LAN/WAN should be qualified under network qualification. The network is first qualified. New GXP applications can be added relatively easily knowing that the network is under control and qualified. 220 Journal of Validation Technology

JVT_May2007.qxd 4/23/07 8:04 AM Page 221 ABOUT THE AUTHOR Esra Guven is the Senior Consultant, Computer Systems Validation and Compliance at Apotex Inc. Esra has eight years experience in the Pharmaceutical Industry. She presently serves as a Senior Consultant for Network Qualification, IT Systems, and Production Systems in the area of Computer Validation. Esra holds a B.Sc. in Electronics Engineering, and a degree in Computer Programmer Analysis. She is also a Cisco Certified Network Associate (CCNA) and a Project Manager Professional (PMP). Esra can be reached by phone at 905-851-1396 or by e-mail at either eguven@apotex.com or guvene@hotmail.com. DISCLAIMER The information and opinions expressed in this article are those of the author and not those of her employer. In no event will the author be liable for any damages or claims in connection with the use of the information and opinions expressed in this article. The reader is responsible for using his or her own judgment in the application of the information contained herein. REFERENCES 1. Global Knowledge. Understanding Networking Fundamentals. M3100C-005, February 2002. 2. Global Knowledge. Interconnecting Cisco Network Devices (ICND) Volumes 1 & 2, Cisco Systems GK-97-1653-01C. 3. Ludwig Huber and Rory Budihandojo. Qualification of Network Components and Validation of Networked Systems, Part I. Pharmaceutical Technology, October 2001. 4. Cisco. Cisco Internetworking Terms and Acronyms. <http://www.cisco.com/univercd/cc/td/doc/cisintwk/ita/> 5. FDA. Glossary of Computerized System and Software Development Terminology. <http://www.fda.gov/ora/inspect_ref/igs/gloss.html> 6. FDA. 21 CFR Part 11; Electronic Records; Electronic Signatures, Validation. Draft Guidance for Industry. August 2002. 7. Conference: Network Infrastructure Qualification and Systems Validation. Institute of Validation Technology. Philadelphia, PA. October 7-9, 2002. CSV DBMS DMZ EDMS EU FDA GXP HVAC IDS IP IQ I/O ISP LAN LIMS MAC MRP NIC NDA OQ OS OSI PLC PQ UPS VPN WAN Article Acronym Listing Computer System Validation Database Management System De-Militarized Zone Electronic Document Management System European Union Food and Drug Administration Good Laboratory, Clinical, Manufacturing, etc., Practice Heating, Ventilation, and Air Conditioning Intrusion Detection System Internet Protocol Installation Qualification Input/Output Internet Service Provider Local Area Network Laboratory Information Management System Media Access Control Manufacturing Resource Planning Network Interface Card New Drug Application Operational Qualification Operating System Open System Interconnection Programming Logic Control Performance Qualification Uninterrupted Power Supply Virtual Private Network Wide Area Network May 2007 Volume 13, Number 3 221