White Paper

September 2019 Dynamic Simulation

GAMP 5 and Dynamic Process Simulation

Introduction
This white paper describes the use of dynamic process simulation for Life Sciences organizations that follow the Good
Automated Manufacturing Practice (GAMP) 5 guidelines. GAMP 5 provides recommendations for the use of dynamic process
simulation, the selection of dynamic process simulation vendors, and the benefits of using dynamic process simulation for the
validated industries.

Dynamic process simulation software for operator training and system testing is a valuable tool for process automation
projects. Users in validated industries are interested in how the use of dynamic process simulation software is impacted by
their adoption of the GAMP Guide for validating automated systems.

When used correctly, dynamic process simulation software can help companies comply operate in accordance with
GAMP 5 guidelines by:

„„Providing more comprehensive testing of the process control system, resulting in better automation system performance.

„„Accelerating the System Acceptance Testing phase of a project, resulting in shorter project cycles and quicker time
to market.

„„Mitigating risk by more comprehensive system testing.

GAMP 5 Guidelines for Dynamic Process Simulation Software

The GAMP guidelines clearly state that the use of dynamic process simulation is acceptable for system testing. The guidelines
state that factory and site acceptance testing environments “…(e.g., test or operational) should be defined” which allows the
end user to leverage off-site testing to decrease costs and time associated with on-site testing.1 testing may be “…carried out
without connection to field instrumentation and may include an agreed level of dynamic process simulation”. GAMP also gives
guidelines for suppliers of dynamic process simulation software.

Certain system testing requirements lead to the use of dynamic process simulation for validated systems testing.

The first requirement is that “…all testable entities within scope of the specific test phase should be
baselined and placed under change control prior to the execution of the tests.”2

It is important that final software modifications are completed prior to testing and that the tested software is
not modified or changed after testing. This applies to the Software Integration Testing and System Acceptance
Testing phases of the project.

The second requirement is that application software, which is no longer needed, should be removed prior to
system testing, to avoid “dead” code.

The guidelines are clear: “dead” code is defined as application software that is “…left over…from development or
code changes.” The only instance in which unused code can be kept in the application software is when it is used
for future “…purposes of testing or for later diagnosis during support workaid to code maintenance…”3, in which
case it should be labeled, commented out, and documented. Application software used specifically for simulation
has no purpose once testing is complete and must be removed prior to Software Integration Testing and System
Acceptance Testing.

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GAMP 5 and Dynamic Process Simulation September 2019

These two requirements dictate the use of a non-intrusive testing interface, especially for Software Integration Testing and
System Acceptance Testing.

A non-intrusive testing interface allows the application software to run in a normal mode without any modification during
testing. This same tested application software can then run in a normal mode in the process controller without modification.
It also provides an external interface to the application software that does not require any additional code for testing. When
testing is completed, the non-intrusive interface can be shut down and no removal of “dead” code is required. Dynamic
process simulation software utilizing non-intrusive interfaces meets the requirements of the GAMP guidelines for process
control system testing.

Impact of System Testing and Qualification

Testing is a critical aspect of implementing a process control system in compliance with GAMP guidelines. “Testing also may
take place to meet other business or legal requirements, such as safety, health, environment, and finance such as SOX. If so,
unnecessary duplication of testing should be avoided.”4

The cost of testing and validating a process control system can be a large cost in an automation project. In addition, testing
has a major impact on project schedule and time to market. Process Control System testing is broken down into several
categories by the GAMP guidelines. The use of dynamic process simulation software can assist the validated user and
supplier during the Software Integration Testing and System Acceptance Testing phases of Installation Qualification (IQ) and
Operational Qualification (OQ).

Using process simulation software correctly positively impacts system testing by providing an environment for:

„„More complete and accurate testing of the process control system.

Medium-fidelity process models (which use mass and heat balances) have been used to provide realistic testing of validated
control systems, resulting in installed automation systems that make better quality product with higher yields as soon as
possible after System Acceptance Testing. The result is the user of a validated system meeting production and project
goals quicker.

„„Compression of project schedule and reduced time to market by using Factory and Site Acceptance Test results at multiple
instances and reducing on-site System Acceptance Testing.

During the Factory and Site Acceptance Tests, “There may be a need for specific tests to satisfy contractual requirements…
these are a pre-defined set of functional tests that demonstrate fitness for intended use and compliance with user
requirements. In such circumstances the test strategy should leverage these tests to satisfy GxP verification requirements
and avoid duplication.”5 The ability to leverage testing at multiple points allows the user to complete Factory and Site
Acceptance Testing in a shorter amount of time.

“When using test environments, the test strategy chosen should justify the equivalency of test results, i.e., justify that similar
results would have been achieved in the operational environment.”6 This testing equivalency is achieved by using a medium
fidelity first principles dynamic process simulation. By moving parts of the System Acceptance Testing to an offline system
and using dynamic process simulation software, the project schedule can be effectively compressed, resulting in an earlier
time to market. The use of dynamic process simulation software can have a significant impact on the success of a validated
process addition or process expansion project.

Dynamic process simulation can also be used for sites following GAMP 5 to reduce the risk of implementing new code or
changes to the control system that may impact product and the patient. Changes to the control system should be evaluated to
“…determine the overall impact that the computerized system may have on patient safety, product quality, and data integrity
due to its role within the business process.”7 Any proposed changes can first be tested to determine impact in the simulation
system before implementing on the live system.

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Impact on Project Risk Mitigation

One of the benefits of following the GAMP guidelines is a structured way of assessing and mitigating risk for the validated
system. In addition to the business benefits of following the GAMP guidelines, some more benefits are “…identification and
management of risks to patient safety, product quality, and data integrity.”8

The use of dynamic process simulation software is an effective tool for addressing identified areas of risk by providing a
realistic environment for both training and testing. Operations staff is trained on critical and/or risky process operations and
failure modes of batch processes or critical batch phases are tested without effecting process integrity. Dynamic simulation
allows for the ability to determine the “…impact of proposed changes as part of change management” 9 in a more extensive
and rigorous manner.

The investment in dynamic process simulation software for control system testing and operator training can be justified alone
by the benefits of mitigating risk due to the high value of product and cost of downtime in the validated industries.

Typical justifications

„„Reducing off-spec batches – typically, $1,000,000 savings per saved batch

„„Reducing unscheduled downtime – typical savings of $50,000 per hour downtime

„„Reducing FDA, OSHA, and EPA violations – typical fines of $100,000 and up

„„Testing code changes, batch recipes, SOPs, etc. in more realistic environment

Automation Design Review Internal (Virtual) Commissioning SAT/

Pre FAT SFAT
Activities Meetings Testing and Start-up Commissioning

Accepted Controls
Base Module and Graphics
Configuration Configuration

Tiebacks and
Pilot Model

Simulation Pilot Model Simulation Support & Model Reintegration Operator

Integration FAT
Activities Development Development and Snapshots Training

Typical Development Cycle of Process Simulation for Validated Processes.

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Operator Training use of Dynamic process Simulation Software

Training faculty who use computerized systems is essential to ensure safe and compliant production procedures. GAMP
guidelines reviews the responsibilities of training that each regulated company should abide by, including:

„„“Establish the necessary training needs, including users, suppliers, data centers, IT departments, engineering, maintenance

„„Provide training to satisfy these needs

„„Evaluate the effectiveness of the training

„„Ensure that staff are aware of the relevance and importance of their activities

„„Maintain appropriate training records”10

The use of a dynamic simulation for operator training allows for a complete and comprehensive training curriculum. Operators
can be trained on specific process upset scenarios and graded based on their performance and responses. Operators can
be trained on operating procedures, familiarizing them on process and batch changes. Training through means of dynamic
simulation guarantees exposure to process upsets and conditions that may not be seen often on the live system, meaning
operators are better prepared to respond to different conditions in the operating environment.

GAMP Requirements for Suppliers of Process Simulation Software

The GAMP guidelines distinguish between the process control system validation requirements and the validation requirements
of tools such as dynamic process simulation software. “Layered software is not subject to specific functional verification
although their features are functionally tested and challenged indirectly during testing of the application…infrastructure
software tools are generally highly reliable, and significantly removed from any aspect of patient risk.”11 However, the
guidelines state that the tools and the supplier of the tools should be well chosen.

General Requirements

„„The supplier should have a documented software development and quality program that complies with industry best
practices quality systems.

„„The dynamic process simulation software should be applicable for process control system testing and operator training and
not designed primarily for other uses (such as process design).

„„The dynamic process simulation software should be “…commercially available, standard tool…” and is “…configured for a
specific business process”12. The application should be delivered as object code or executable programs and not require
the user to modify source code under standard use. “Complex systems may require a further hierarchy of specifications
covering hardware design specifications and configuration specifications”.13

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GAMP 5 and Dynamic Process Simulation September 2019

Practical Application of Process Simulation Technology

When using dynamic process simulation software with automation systems following GAMP guidelines, the following should be
considered for best practice results:

Test with Simulation

“When using test environments, the test strategy chosen should justify the equivalency of test results, i.e., justify that similar
results would have been achieved in the operational environment.”14

„„The use of a Medium Fidelity dynamic simulation process model provides equivalency of control system testing results in a
cost-effective, easy to manage implementation. This is largely based on a medium fidelity model that uses first-principles
based process interactions, equipment which is modeled per plant design specifications, a pressure-flow network, material
and energy balances, and IO interactions across the span of the process being tested; providing a dynamic simulation
model that responds much like the real process would.

„„“There may be a need for specific tests to satisfy contractual requirements, which are typically called acceptance tests.
Typically, these are a pre-defined set of functional tests that demonstrate fitness for intended use and compliance with
user requirements.”15

The
{{ medium fidelity dynamic simulation process model approach has been proven effective and meets these
requirements. A simulation platform that is easy to use will allow selective, incremental improvements for process models
(ie: most case additional process design data entry) to meet specific test requirements. In such circumstances the test
strategy should leverage these tests to satisfy GxP verification requirements and avoid duplication.

Remote Testing

„„“Acceptance may be carried out in two stages, Factory Acceptance and Site Acceptance. Factory Acceptance Testes
(sometimes abbreviated to FAT) are performed at the supplier site before delivery to show that the system is working well
enough to be installed and tested on-site. Site Acceptance Tests (sometimes abbreviated to SAT and sometimes called
System Acceptance Testing) show that the system is working in its operational environment and that it interfaces correctly
with other systems and peripherals.”

A dynamic
{{ simulation of a process allows for the flexibility to test automation configurations remotely and before
equipment is physically installed or delivered. This allows for more cost-effective FAT and SAT while maintaining the high
level of validation testing. When an automated test script is developed and applied to Software FAT, this increases the
effectiveness of the acceptance phase and allows for the ability to have product delivered to the patient sooner.

Hard Copy Evidence

„„“Regulatedcompanies should take a justified and documented decision, based on impact, novelty, and complexity, on how
much hardcopy test evidence is to be retained, as this can be a significant overhead.”16

The
{{ standard approach to completing a Software FAT involves forcing values then manually recording the output, which
allows for human error on both the testing and record keeping sides. Using automated scripts for Software FAT will
generate a report after running which reduces human error for testing and recording while decreasing the amount of time
needed for both steps.

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Lifecycle Use

„„“Efficient
change management should be executed in parallel with configuration management. Key elements include…
assessment of the impact of the change in the application, the underlying infrastructure, the people (users and engineering
support staff), and the documentation…leveraging the risk assessment information from the original project and assessing
any new risks introduced by the change to define the strategy for maintaining compliance – this includes the need for any
regression testing.”17

Most
{{ validation standards of practice when making a change to a computerized system include an assessment of the
change, be it non-functional or a functional change. This standard approach is a valuable way to measure the impact of a
proposed change, but without testing it against a dynamic process simulation the assessment is based more upon opinion
than proof. The application of simulation in this validation assessment would be a tool to prove more changes are non-
functional and therefore do not require to go back through the validation process.

Automated Testing

„„“Test scripts should contain the details of the tests…Separate test cases may be prepared for some tests, which may
describe complex test data sets, test methods, test input data, test environment set-up, and expected results. When testing
small or simple systems, test specifications, test inputs, test environment set-up, and expected results may all be covered
within a single document.”18

An
{{ automated testing tool can be utilized as a means of capturing details during a test. By specifying what command (set,
ramp, verify, etc.) should be executed and recording the systems response, Software FAT can be completed automatically
while also creating a document to provide a permanent record of the testing. This creates an opportunity to reduce testing
time and probability of human error.

„„“Automated test execution tools can be used to improve test execution efficiency and effectiveness…can be used both for
black box testing and white box testing. They can significantly improve the efficiency and coverage of regression testing.
Regression tests performed by an automated test execution tool may be based on an existing manual
executed specification.”19

By
{{ using a saved script for automated control system testing, the same test (using the same automated testing script)
can be repeated after any control system configuration change. This is an effective mean of identifying and eliminating
regression errors introduced in control system configuration changes.

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GAMP 5 and Dynamic Process Simulation September 2019

GAMP and Dynamic Process Simulation

Dynamic Process Simulation is a proven technology for a process control system testing and operator training tool in
compliance with the GAMP Guide for Validation of Automated Systems. Dynamic Process Simulation Software can help
companies with validated processes comply with GAMP guidelines and improve their process performance by providing:

„„More comprehensive testing of the process control system, resulting in better automation system performance.

„„Project schedule reduction and quicker time to market through reduction of on-site System Acceptance Testing.

„„Effective mitigation of risk by more comprehensive system testing.

Dynamic process simulation software is the best choice for users of validated systems wanting to attain these business results
and comply with GAMP guidelines.
1 – Appendix D5, Section 4.5, GAMP A Risk-Based Approach to Compliant GxP Computerized Systems, Copyright ISPE 2008.
2 – Appendix D5, Section 5.1, lbid.
3 – Appendix D4, Section 3.1.6, Ibid.
4 – Section 8.5.1, lbid.
5 – Appendix D5, Section 4.5, Ibid.
6 – Appendix D5, Section 4.4, lbid.
7 – Appendix O11, Section 4.3.1, Ibid.
8 – Appendix M3, Section 3, Ibid.
9 – Section 5.3, Ibid.
10 – Section 6.1.3, Ibid.
11 – Appendix M4, Section 3.1, Ibid.
12 – Appendix D5, Section 9.3, Ibid.
13 – Section 4.2.6.3, Ibid.
14 – Appendix D5, Section 4.4, lbid.
15 – Appendix D5, Section 4.5, lbid.
16 – Section 8.5.3, Ibid.
17 – Section 8.7, Ibid.
18 – Appendix D5, Section 4.1.3, Ibid.
19 – Appendix D5, Section 8, Ibid.

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