GE Healthcare
Life Sciences
GAMP5 - a lifecycle management
framework for customized
bioprocess solutions
imagination at work
GE Healthcare’s engineering department, Customized Bioprocess
Solutions (CBS), has designed and produced customized bioprocess
systems and columns for over two decades, mainly for customers
in the biotechnology and biopharmaceutical industries. Over time,
regulatory and validation requirements have demanded increased
efficiency, and now focus on a risk-based validation approach. CBS
has always been responsive to these changes, providing deliveries
based on significant understanding of the customer’s process and
quality requirements. In this paper we summarize how CBS works to
support equipment within a lifecycle approach based on ISPE baseline
guide 5 and ASTM E-2500 guidelines, with valuable contributions
from our customers, that go far beyond individual projects.
CBS supports the current lifecycle management model – tools,
procedures, and workflows that allow CBS to focus on the
significant GxP, process, and regulatory requirements throughout
the entire design, production, testing, and post-delivery phases
of a customized project. The aim of these activities is to increase
customer control of the projects, leading to more efficient validation
effort, reduced project time frames, and ultimately, enhanced quality.
2
Traditional vs. risk-based validation processes
GE Healthcare equipment and software are developed and verified according to structured and
documented procedures as required by Good Manufacturing Practice (GMP) standards, all defined
within the internal quality management system (QMS) of GE Healthcare and based on the international
standards EN ISO 9001 and ISO 13485. This allows for a consistent approach across all systems, enables
leverage of validation activities, and results in a much faster and efficient commissioning and
qualification (C&Q) phase, decreasing the start-up phase at the customer site (Fig 1). Furthermore, our
comprehensive toolbox of Good Engineering Practice (GEP) and C&Q strategies, procedures, and
templates, including standardized test methodologies and modular formats enable efficient, customerspecific validation lifecycle activities, such as change control verifications and requalifications
performed over the equipment lifetime.
Traditional validation method
Specifications
Design
Commissioning
and Qualification
Construction
GE Healthcare Validation Services approach
n
sig
De
ions
ificat
Spec
Planning
Construction
Commissioning and Qualification
Project time
Fig 1. Traditional validation method vs the GE Healthcare Validation Services approach. The GE Healthcare approach uses
a streamlined, risk-based approach to control costs and significantly reduce project time. Note that commissioning and
qualification activities are now ideally performed throughout the validation period, with customer involvement.
Historically, equipment qualification was considered a “one-off” activity necessary for using equipment
in regulated environments. Regulations now require a validation lifecycle approach to demonstrate
compliance throughout the equipment’s working life.
GAMP5 stresses a risk-based approach to validation, with increased emphasis on the control and
documentation of processes that are critical to intended use and process understanding. Furthermore,
the new risk-based approach in GAMP5 recognizes the value of supplier input, and leverages supplier
involvement based on the five key concepts within GAMP5 (Fig 2).
User
Develop
medicinal
products
Produce
medicinal
products
Market and
distribute medicinal
products
Product and process understanding
Life cycle approach within a QMS
Scalable life cycle activities
Science based quality risk management
Leverage supplier involvement
Supplier (of computerized
systems and services
Develop
products
and services
Deliver
products
and services
Maintain and
support products
and services
Fig 2. The risk-based approach to compliant GxP computerized systems under GAMP5. The five key risk-based concepts
within GAMP5 are shown.
3
The primary objective of any program related to equipment and/or facility validation is to assure
equipment and facility “fitness for use”. It is therefore important to have a deep understanding of the
product and process in order to be able to make risk-based decisions.
At CBS, our Subject Matter Experts (SMEs) help you to transform the Critical Process Parameters (CPPs)
and Critical Quality Attributes (CQAs) into the Functional Specifications (FS), thereby saving time and costs
during the system qualification. Figure 3 summarizes the responsibilities of customers and suppliers
within the GAMP5 risk-based framework.
Retirement
Customer responsibility
Operation
Regulatory aspects
Guideline compliance
URS
Master Validation plan
Installation
IQ
OQ
PQ
Quality & Project Plan
Design inputs:
Functional and detailed
specifications
Testing
Hardware
Software
Full equipment
Construction
Hardware
Software
Package configuration
Supplier responsibility
Fig 3. Customer vs. supplier responsibilities within the GAMP5 risk-based validation approach. URS = User requirement specification.
Validation and support policies for standard and
customized products
GAMP defines the equipment lifecycle approach as including all phases from concept and implementation
through to operation and retirement (Figure 3). Four major phases are defined for any computerized
system project (Figs 4 and 6). GAMP recognizes that suppliers can be valuable in assisting companies in
any or all phases of the lifecycle. Furthermore, GAMP differentiates between standard and customized
systems. Table 1 and Figure 5 illustrate the main differences between GE Healthcare’s standard and
customized automated systems and software with respect to GAMP requirements and equipment examples.
Good engineering practice
Concept
and design
DQ, System impact
Project
and build
Release
Implementation
operation and
verification
FTR, ITR, IQOQ, P11
Retirement
DC
Risk management, design and change management, knowledge management
Fig 4. General project workflow within GAMP for computerized systems. DQ = Design qualification, FTR = Functional test records,
ITR = Installation test records, IQOQ = Installation Qualification and Operational Qualification, P11 = 21 CFR part 11,
DC = Decommissioning.
4
Table 1. GAMP category relationships for standard and customized chromatography and filtration systems
Standard
Customized
Definition
GE Healthcare plan and
definition (concept phase)
Customer plan and definition
(concept phase)
Equipment examples
ÄKTAcrossflow™
ÄKTApilot™
ÄKTAprocess™
UniFlux™
BioProcess™ chromatography
systems
GAMP software category
4
5
GAMP hardware category
1
2
GAMP validation requirements
(GE Healthcare)
See Figure 5
See Figure 5
GAMP validation requirements
(customer)
Validate only part of the system
Validate complete system
and verify operation vs requirements
Approver of design documents
GE Healthcare
Standard systems BioProcess filtration systems
Customer
Customized systems
Market requirement
specifications
Performance testing
System acceptance
testing
Functional specifications
Software design
specifications
User requirement
specifications
Performance testing
System acceptance
testing
Functional specifications
Software integration
testing
Software design
specifications
Software module
specifications
Software integration
testing
Software module
testing
Software module
specifications
Software module
testing
Build product
Code modules
Category 5 (custom)
specifications
Custom testing
Configuration
Fig 5. Software module development milestones for standard (category 4; figure to the left) and customized (category 5; figure to the right) automated
chromatography and filtration systems. The figure is modified from: GAMP Good Practice Guide: Testing of GxP Systems. ISPE, Tampa, Florida (2005).
GE Healthcare Quality Management System
An important factor ensuring the equipment’s fitness for use is a stringent quality assurance and
internal management system. GE Healthcare Life Sciences is strongly committed to the GMP key
principles of a Quality Management System (QMS), in compliance with ISO international standards.
The principles of the QMS include a commitment to customer satisfaction, compliance with laws and
regulations, employee involvement, continual improvement, and a shared quality culture. GE Healthcare
Life Sciences holds a global certificate for the ISO 9001 standard.
The QMS is maintained to ensure that both customer and regulatory requirements are met. Furthermore,
our QMS, which is used globally throughout Life Sciences, is continually assessed to maintain its suitability,
adequacy, and effectiveness. All processes and systems are designed to enable continual improvement
and thereby create better value for our customers.
5
Project management
CBS project management is fully integrated within the GE Healthcare Life Sciences QMS for
the manufacture of customized equipment. Figure 6 shows the representative milestones in
a CBS project including delivery and support.
Quotation
phase
Project
planning
Production
and
Verification
Design
Delivery and Support
Installation
and Validation
Request for
quotation
Project kick off
meeting
Design
review
Functional
acceptance test
Support
Training
Service
Technology review workflow
Initial
regulatory
evaluation
Extended Technology
regulatory
review
evaluation
Technology
review
closing
Fig 6. A typical sequence of project phases employed at CBS for customized systems (GAMP category 5).
The customer is normally involved in all phases of the project sequence.
Quotation phase
CBS can support the end-users and buyers in the User Requirements Specification
(URS) process by using tools (e.g., URS templates, system configurator) to help define
any type of system, and any kind of relevant requirements that the customer may need
to include. Impact and Risk Assessments are important steps in the URS process, and
CBS together with Life Sciences Validation Services can offer support in identifying
boundaries of no impact, indirect impact, and direct impact systems.
Design input
Software configuration
Define functions &
develop models
Design phase
Each project is unique and a Quality and Project Plan (QPP) outlines any project specific
requests customers may have and how these will be handled. A series of technology
reviews, with input from CBS Subject Matter Experts (SMEs), ensures end-user technical
requirements are fulfilled and included in the design, as well as assuring Quality by
Design (QbD) customer inputs. Regulatory requirements are dealt with using a riskbased approach.
Fail
Pass
Identify test for
functional test plan
Customers are highly involved in the design process through extensive formal design
reviews together with the CBS project team. Before manufacturing commences,
customer approval is required. During the entire project, change control procedures
embedded in the QMS are used to secure any necessary changes after initiation of
equipment manufacturing.
Software development work follows well-defined industry standards to allow for full
auditing of development steps, thorough documentation, and quality management
in accordance with ISO 9001. Our automated systems are normally controlled by
GE Healthcare’s widely used UNICORN™ control software, with process control strategies
enabling effective Process Analytical Technology (PAT). Other control software (e.g., PLC)
solutions are also available. Software development follows internal standard operating
procedures (SOP) for the configuration of the system strategy (Fig 7).
Production verification and release phases
Equipment is installed at CBS test premises and subjected to a wide range of
functional tests. Functional tests are executed in a test environment that resembles
the production environment for the systems, with all media and utilities connected.
Test results are collected step-by-step and compared with predetermined test results
extracted from the acceptance criteria.
6
Test in simulated
environment
Risk
assessment
input from
technology
review
Install software
configuration on
system computer
Fail
Functional test
on system
Pass
Fail
FAT
(If applicable)
Pass
Release software configuration
and create documentation
Fig 7. The workflow followed when developing
new UNICORN software modules.
The same functional tests serve as a template for the Factory Acceptance Test (FAT), and together with
customer specific tests, they comprise the FAT protocol. Deviations are documented on fault log sheets,
and if changes need to be implemented they are handled via change control. All test results have to be
approved by the customer before product release. After product release, the equipment is packed and
delivered to the customer.
GE Healthcare Life Sciences Validation Services
In line with the new approach favored in GAMP5, GE Healthcare has
adopted a broader, long-term approach to its equipment service
offerings. This lifecycle management approach includes a new
range of programs aimed at simplifying the maintenance, service,
and upgrading of equipment. GE Healthcare Life Sciences Validation
Services provide a comprehensive suite of streamlined validation
services to support the equipment through its entire lifecycle.
Benefits of engaging GE Healthcare Life Sciences
Validation Services:
• Significant reduction in time for equipment qualification
• Consistent verification support throughout product lifecycles
• Proven history of GxP compliant equipment and satisfied
customers, including the world’s leading pharmaceutical and
biotech companies
• Global network of field support and cGMP trained service staff
• Predictable costs and timelines
Validation products include Installation and Operational Qualifications, 21 CFR part 11 and EU Annex 11
verifications, Change Control Protocols (CCP), Requalifications (RQ), Standard Operating Procedures (SOP),
and Decommissioning. These activities can be transformed into a full modular approach, in accordance
with the new trends within C&Q, and are available either as single items, or as components of a larger
periodic or lifetime service agreement with GE Healthcare (Brochure: GE Healthcare Validation Services,
GE Healthcare, 28-9642-88 Edition AA, 2009).
After-sales support
GE Healthcare Life Sciences Service agreements are tailored to your needs, ensuring that your system
is maintained optimally and your total cost of ownership is predictable during its lifecycle. A Service
Agreement extends the life of your system through planned maintenance of critical components, and
insures your investment against unexpected breakdown costs. The added-value of the knowledge and
expertise of our highly trained field service engineers ensures that you can rely on expert service and
first-class application support, giving you the peace of mind you need to keep your research moving.
Service Agreements provide:
• Confidence in your results through regular Preventive Maintenance visits and part replacements
• Predictable ownership costs, as rates are guaranteed for the duration of the contract
• Minimized disruptions with priority response from our trained Service Engineers
Preventative Maintenance (PM) forms the core of our service offering and keeps your system running
in peak condition and assists in meeting regulatory compliance. The PM forms the core of our service
offering. PM maximizes performance and minimizes downtime by preventing problems before they occur.
Preventative Maintenance:
• Ensures the quality of your results through replacement of critical components and extensive testing
• Extends the life of your system
• Enables traceability via visit records
• Replacement of all components subject to wear
7
GE Healthcare Life Sciences your partner for the future
With an emphasis on quality and lifecycle management, CBS has
delivered more than 2000 systems and 8000 columns worldwide to
a wide range of biotechnology and biopharmaceutical companies
for a wide range of applications. In addition, GE Healthcare
Life Sciences Validation Services has supplied validation documentation
to more than 4500 of these projects. Manufacturing sites that
have used CBS equipment and validated them with the support of
GE Healthcare Life Sciences Validation Services, have been audited
numerous times by the FDA and other inspection agencies.
We can ensure efficient C&Q and ongoing verifications of your
equipment to fulfill current regulations, interpretations of regulations,
and compliance, with documentation support throughout the
entire lifecycle. Our focus is on supplying our customers with high
quality equipment, controlled project management, and lifecycle
management, all based on customer needs and in line with current
regulatory requirements.
Strong customer relationships have always been central to our work
and are the main impetus for our focused project teams here at CBS.
We develop new solutions together with our customers and GAMP
guidance visualizes the need for strong customer collaboration in
the future.
For local office contact information, visit
www.gelifesciences.com/contact
GE, imagination at work, and GE monogram are trademark of General
Electric Company.
ÄKTA, ÄKTAcrossflow, ÄKTApilot, ÄKTAprocess, AxiChrom, BioProcess,
UNICORN, and UniFlux are trademarks of GE Healthcare companies.
All third party trademarks are the property of their respective owners.
www.gelifesciences.com/cbs
GE Healthcare Bio-Sciences AB
Björkgatan 30
751 84 Uppsala
Sweden
© 2011 General Electric Company—All rights reserved
First published Feb. 2011.
All goods and services are sold subject to the terms and conditions of
sale of the company within GE Healthcare which supplies them. A copy
of these terms and conditions is available on request. Contact your local
GE Healthcare representative for the most current information.
GE Healthcare UK Limited, Amersham Place,
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UK
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Munzinger Strasse 5, D-79111 Freiburg
Germany
GE Healthcare Bio-Sciences Corp.
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USA
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Japan
imagination at work
28-9898-73 AA 02/2011