2010na electronic workflow for a bioreactor · 2018-12-26 · it has 120,000 liters of bioreactor...

Copyright ©2010 WBF. All rights reserved.

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

[email protected]

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

[email protected]

Joe Maguire

Automation Engineer

Bristol-Meyers Squibb

15 Queenstown Street

Devens, MA 01434

USA

267-250-7266

[email protected]

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.

http://www.wbf.org/


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.


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.


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


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


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


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


• 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.


Figure 4: Recipe Authoring of Manual and Automation Components

Automation

Components in

Blue

Manual

Components

in Green

2010na electronic workflow for a bioreactor · 2018-12-26 · it has 120,000 liters of bioreactor...

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