2010na electronic workflow for a bioreactor · 2018-12-26 · electronic workflow for a bioreactor...
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Copyright ©2010 WBF. All rights reserved. Page 1
Presented at the
WBF Make2Profit
Conference
Austin, TX, USA
May 24-26, 2010
WBF
107 S. Southgate Dr.
Chandler, AZ 85226-3222
(480) 403-4610
www.wbf.org
Electronic Workflow for a Bioreactor
Christie Deitz
Sr. Principal Engineer
Emerson Process Management
12301 Research Blvd
Austin, TX 78759
USA
512-832-3240
512-832-3199
Joe Maguire
Automation Engineer
Bristol-Meyers Squibb
15 Queenstown Street
Devens, MA 01434
USA
267-250-7266
KEY WORDS
Electronic Workflow, MES, Bioreactor, Release by Exception
ABSTRACT
Automating workflow and eliminating paper batch records can provide many benefits, including
reducing deviations, expediting batch review and release, improving real-time inventory management,
and utilizing industry and corporate standards. BMS is currently in the commissioning stage of its new
state-of-the-art facility in Devens, Massachusetts. BMS’ objective was to create a paperless
manufacturing environment. To meet this objective, automation for the facility includes a process
control system (PCS) and a manufacturing execution system (MES) system. The project is unique
because, to date, it is BMS’ most extensive automation of workflow; that is, the manual instructions that
might be traditionally done using paper.
The project team learned some valuable lessons with regard to team organization and approach to
testing. They also made some key technical decisions around prompting, phase boundaries and recipe
design. This paper will explain many of the lessons learned using the bioreactor area of the project as an
example.
Copyright ©2010 WBF. All rights reserved. Page 2
PAPER
INTRODUCTION The Bristol-Myers Squibb Large Scale Cell Culture (LSCC) facility is located on an 89-acre site in
Devens, Massachusetts, 45 miles west of Boston. The facility will support the production of
ORENCIA® (abatacept), the company's biologic therapy for rheumatoid arthritis, as well as other
biologic compounds currently in development. BMS invested $750 million in the construction of the
facility. It has 120,000 liters of bioreactor capacity that will be capable of concurrent multi-product
production.
The vision for the project was to provide a state-of-the-art, fully automated process. The automation
goal was to be completely paperless and to support release by exception. In an FDA-regulated
environment, batch release requires someone to verify that all exceptions have been investigated and
signed off. Release by exception generally means that the approval and release of a batch is based on
the review and approval of ONLY the exceptions and the required remedial action taken. The reviewer
does not have to spend time sorting through the entire record to identify exceptions. Review by
exception also implies that exceptions can be reviewed and dealt with in real-time, not only when the
batch is completed.
Additionally, a system that supports review by exception can often reduce the number of exceptions by
enforcing rules in a real-time environment. For example, the system may not allow the operator to enter
an invalid response or may force the operator to sign before proceeding. A system that both minimizes
errors and allows real-time exception review can dramatically reduce the time that product is
warehoused, waiting to be released for sale, and therefore can reduce the cost of inventory. Using an
S95/S88 structured approach and an electronic workflow together with process control enables review
by exception.
For the LSCC project automation, BMS selected DeltaV as its process control system (PCS) and
Syncade as its manufacturing execution system (MES). They also selected several other systems such as
SAP business software, SmartLab for lab information management, and Maximo for instrument asset
management, all of which would need to communicate with the MES.
BMS broke ground for the facility in March 2007. It was operationally complete in 2009, and is
currently in the process of validation. The FDA submission will be filed in 2010.
ELECTRONIC WORKFLOW
Electronic workflow is paperless production, where electronic recipes handle both the manual and the
automated functions. For manual functions, the system provides electronic instructions and access to
electronic SOPs (standard operating procedures). As operators enter responses and data onto the screen,
the system provides error checks and enforces sequencing. For the LSCC project, the functionality was
divided between the PCS and MES components of the system. Table 1 shows how the functions were
divided.
Copyright ©2010 WBF. All rights reserved. Page 3
Table 1: PCS and MES Functionality
PCS MES
Instrumentation
Continuous Control
Batch Control (up to
Units/Phases)
Document Control
Material Management
Order Management
Equipment Tracking
Recipe Authoring
Workflow Execution
Electronic workflow automates the steps in manufacturing product and generating the batch record,
many of which were historically manual steps. Table 2 describes the steps and the role of electronic
workflow in each step.
Table 2: Electronic Workflow Examples
Manufacturing
Step
Examples of Role of Electronic
Workflow
How it ensures quality and/or expedites
review and release
Qualify
Equipment and
Facilities
Operator scans the barcode of equipment.
The system checks the status of the
equipment and allows the operator to
proceed only if it is the appropriate
equipment with the correct status.
Prevents inadvertent use of incorrect
equipment.
Verify Materials Operator scans the barcode of material.
The system checks the status of the
material and allows the operator to
proceed only if it is the appropriate
equipment with the correct status.
Prevents inadvertent use of incorrect
material.
Batch Execution Electronic work instructions (EWIs)
prompt operators to perform manual tasks
and enter data as appropriate. These
EWIs provide links to Standard Operating
Procedures (SOPs) and Material Safety
Data Sheets (MSDSs).
Electronic work instructions kick off
automated process operations such as
filling vessels.
Performs calculation. Process deviations
and out-of-spec data generate notifications
for QA review.
Enforces correct sequence of action.
Prompts operators if data is out of range
to help prevent data entry errors.
Generates notifications for QA review in
real-time for process deviations and out-
of-spec data.
Copyright ©2010 WBF. All rights reserved. Page 4
Manufacturing
Step
Examples of Role of Electronic
Workflow
How it ensures quality and/or expedites
review and release
Operations
Review
When all workflow is complete, the data
is compiled and a notification for
operations review is launched.
Notification is launched in real-time.
View is provided that displays
information relevant to operators.
QA Review The Electronic Batch Record (EBR) is
presented in a checklist form for QA
review
Notification is launched in real-time.
View is provided that displays
information relevant to QA in checklist
format.
Batch
Disposition
QA e-signature is collected to approve
and archive EBR and disposition the
batch.
Disposition occurs real-time and EBR is
automatically archived. Any changes to
EBR generate a new version that is
forwarded to document management.
LSCC is currently in the process of executing the electronic workflows on the equipment. Table 3
shows the recipes that have been successfully run at site to date.
Table 3: Executed Electronic Workflows
Upstream Processes Downstream Processes
Inoculation Lab
150L Bioreactor
750L Bioreactor
Basal Media Vessels
(All of the above were cleaned, steamed,
batched and transferred.)
Hydrophobic Interaction
Chromatography (HIC) Column
Centrifuge
Buffer Preparation and Hold
BIOREACTOR WORKFLOW
The development of the automation for the bioreactors started with the development of the units and
phases. A similar approach was followed throughout the plant for two reasons: (1) the equipment
requirements had already been defined, which logically led into equipment automation requirements,
and (2) the use of MES and electronic work instructions was relatively new to BMS. The project team
had much more experience with traditional S88-base process control system-level control. Therefore, a
bottom-up approach came naturally.
A classic S88 approach was used for the development of the bioreactor automation, Figure 1. First,
control modules such as valves, motors, indicators and graphic displays were created. Next, the
equipment module layer was added. Examples of equipment modules include pH control, dissolved
oxygen control, transfer line control, and steam supply line control. Finally, unit-level control, including
Copyright ©2010 WBF. All rights reserved. Page 5
phase logic, was added. Example phases include Media Fill, Equilibrate, Inoculate, Growth, Harvest,
CIP and SIP.
The expectation was that electronic work instructions would kick off phases. Also, in many cases, the
phase and EWI need to communicate within a phase. One example is addition of bagged media to a
bioreactor. An electronic work instruction in the bioreactor recipe starts the unit phase in the process
control system. The unit phase puts equipment into the proper position and then waits for an electronic
work instruction to prompt the operator to scan the material barcode. The system checks to ensure that
the material was good, and then the electronic workflow walks the operator through the manual steps to
connect the bag to the pump. Finally, the unit phase runs the pump to complete the charge. The
electronic workflow efforts had not been started at the time; however, the interactions were mostly
known based on process requirements.
Around the time that the work on unit phases was completing, efforts were ramping up for the electronic
workflow. Since electronic workflow was new for BMS, the project team spent some time up front
working out the general approach to the project. To start with, the process engineers needed a way to
Figure 1: Example Bioreactor Graphic
Copyright ©2010 WBF. All rights reserved. Page 6
communicate to the automation team what the operators needed to do to make product. In addition, they
needed a framework to help them get started more quickly than a blank page. To meet these needs,
BMS created a flowcharting tool, Figure 2.
The flowcharting tool provided some templates to show standard functions such as material checks and
equipment checks. It also allowed free-format electronic work instructions (EWIs) for the process
engineers to use to communicate requirements. In addition, the flowcharting tool allowed the process
engineers to show functions happening in parallel on different process units by using different vertical
columns, or swim lanes, for each unit. Figure 2 shows an example of the flowcharting of bioreactor
requirements using the tool.
Workflow for
Wave Bioreactor
Workflow for 150L
Bioreactor
Standard Construct
for CIP Sequence
EWIs
Free-format EWIs
After requirements were established, the electronic workflow was approached in a bottom-up fashion.
The first step was creating the basic building blocks, which are called “instructions” or “manual phases.”
Examples of these include prompting an operator with a message and requiring a signoff, checking
hygienic status of a vessel, and providing an operator with a link to an SOP. A library of common
manual phases was built for the entire project. This enabled the team to take advantage of a modular,
object-oriented coding approach.
Next, the recipes were built up from the manual phases and the automation phases using the recipe
authoring tool. Figure 4 shows an example of recipe authoring. The manual phases and the automation
Figure 2: Example of Bioreactor Workflow Requirements Flowchart
Copyright ©2010 WBF. All rights reserved. Page 7
phases can be built into operations, operations built into procedures, procedures into process segments,
and process segment into master recipes.
The project team made a decision that, for this project, automation phases would be grouped into
automation operations – without any manual work instructions. Examples of automation operations
include Media Charge, Equilibrate, Growth, Harvest, CIP and SIP. In most cases, one automation phase
was wrapped in one automation operation. However, in some cases, such as CIP, the several phase
instances required to completely CIP a vessel were included. Then, manual and automation operations
were built into unit procedures, as shown in figure 4. Unit procedures are the highest level recipe that
executes on a single process unit: for example, a 20K production bioreactor. Examples of unit
procedures are Production Bioreactor Equilibrate, Production Bioreactor Growth, and Production
Bioreactor Harvest. These recipes contained all of the automation and manual steps required to perform
their function.
Unit procedures were built into procedures, which can execute across
multiple units. An example of a procedure is the 20K Production
Bioreactor, which does the preliminary equipment checks, prompts the
operator to do the required manual equipment assembly, and executes
the Production Bioreactor Media Charge, the Production Bioreactor
Equilibrate, Production Bioreactor Growth, and Production Bioreactor
Harvest unit procedures – complete with instructions for all of the
manual interactions required such as sampling. Finally, these
procedures were built into process segements and master recipes. For
this project, a master recipe contained a single process segment, and a
process segment contained a single procedure.
A combined team of BMS and their automation supplier Emerson
wrote the recipes for the project. Engineers from the supplier created
the manual instructions to use as building blocks. Then BMS
automation engineers, with some consultation from the supplier, led the
team for each process area workflow, such as the bioreactor area.
Supplier engineers, most of whom had experience developing the
automation phases, helped build the operations, unit procedures,
procedures, process segments and master recipes. The combined team
performed software testing of the workflow recipes prior to deployment
on site. This approach leveraged the best skills of both companies.
LESSONS LEARNED
Overall, the executing and testing of the workflows at site has gone
smoothly. As would be expected for a project of this magnitude, some
changes and corrections have been required at site. Mostly, these
changes have been related to conforming to the equipment, now that it
is installed and in-use, or changing the order of instructions. Some
examples of changes to the bioreactor workflows include:
• Sampling instruction details
• Timing of when to install base bag for pH adjustment
Figure 3: Example Manual
Phase Library
Copyright ©2010 WBF. All rights reserved. Page 8
• Instructions for standardizing pH and DO probes
• Valve differences (different manual valve arrangement than design assumptions) for
steam-on and -off sample apparatus
Executing a project of this size and magnitude was a learning experience for the entire project team.
Some recommendations the project team suggest to others starting an electronic workflow project
include:
1) Finalize vision and requirements early and document them. On a large project, this helps
get and keep everyone marching in the same direction.
2) Make key decisions early. The earlier the team can set the direction on, for example,
standard approaches to common problems, the more quickly the entire team can start
making progress toward completion.
3) Integrate the development of electronic workflow and traditional automation. For the
LSCC project, the automation work was nearly completed before the electronic workflow
engineering was really started. Doing the work more in parallel would force the team to
think through more of the issues while making changes is still relatively easy.
4) Balance perfecting software against getting it done. Sometimes finding a workable
solution quickly is better than taking weeks or months to perfect a solution.
5) Be open to execution strategy adjustments. On LSCC, many schedule and planning
decisions were placed in the hands of the engineers to realistically estimate time lines.
6) Bring in plant operations and manufacturing personnel early. They have critical insight
into the operators’ perspective and how the process will work.
At the time this paper was written, LSCC was still in the process of executing the electronic workflows
on the equipment. The recipes that have already been run at site have been successful; although, as is
always the case, some minor modifications have been required. Based on efforts to date, the Devens site
seems to be on-target for using electronic workflow to achieve its goals of paperless production and
review by exception.
Copyright ©2010 WBF. All rights reserved. Page 9
Figure 4: Recipe Authoring of Manual and Automation Components
Automation
Components in
Blue
Manual
Components
in Green