Manufacturing Task Category

The manufacturing tasks form one of the key components of the decision-support tool and comprise mainly the product-manufacture activities (e.g. fermentation, chromatography) and ancillary steps of equipment-preparation (e.g. C1P, SIP) and regulatory-compliance (e.g. QC/QA and batch documentation). Each of the unit operations was simulated as an activity requiring resources. The same approach was applied to the modelling of equipment-preparation and regulatory-compliance operations. The hierarchical levels of the manufacturing activities were realised through the use of workspaces, upon which components can be placed. Each high- level task on a workspace can be broken down into its sub-tasks on their respective sub-workspaces. This is illustrated in Figure 3.3, which shows a product- manufacture recipe and an equipment-preparation recipe in their respective workspaces. In the process flowsheet workspace, a Start block and an End block were customised to control the proper simulation of the model. At the start of a simulation, the Start block generated an item to characterise the initial process stream. The resultant process stream from the final step of the process exited the End block. In this block, the total mass of the antibody-based product generated was updated.

The tool structure was arranged in a hierarchical task-oriented manner to represent the key tasks and resources in a manufacturing operation. Such an approach has recently been employed to model the manufacture of biopharmaceuticals (Farid et al., 2000b). Similar hierarchical decompositions have also been adopted to represent all phases during the process of drug development (Karri et al., 2001; Rajapakse et al., 2004). The framework in this research extended the hierarchy further to incorporate QC/QA activities and batch documentation (Figure 3.4). As depicted in Figure 3.4, the ancillary steps (e.g. equipment-preparation, QC/QA and batch documentation) were modelled separately from the product-manufacture steps. The hierarchical decomposition method proved useful in conferring maximal flexibility since it allows processes to be simulated at various levels of details.

P ro d u c t-m a n u fi manufacture recipe and an equipment-preparation recipe in their hierarchical workspaces. It consists of a series of product-manufacture tasks as well as related equipment-preparation tasks connected to form part of the biomanufacturing process.

- 7 9

-Chapter 3. Design M ethodology and Implementation o f BioPharm Kit

Figure 3.4. Hierarchical representation of manufacturing tasks. The ancillary steps of equipment-preparation (i.e. CIP, SIP) and regulatory-compliance are modelled separately from the product-manufacture tasks.

The manufacturing tasks possess the attributes of “processing time”, “cost of task”

and “number of cycles”. The “processing time” indicates the duration required to carry out the manufacturing task while the “cost of task” represents the total direct cost incurred in running the specific task. The task duration was given either a deterministic value or a probability distribution was used to reflect the randomness in the processing of the task. The “number of cycles” shows the total number of times the particular task is executed during a single simulation.

The sequence of functions used to customise a manufacturing task was as follows.

Functions were configured in the manufacturing tasks to carry out certain actions.

An “activation” function was created to activate the current task by using the process stream item flowing into the customised block from the prior step. This module of code included the Batch block to trigger the initialisation of the current block. The function compared the required and current equipment status before commencing the manufacturing process. If the two equipment states do not match, the relevant equipment-preparation tasks were activated. Both the Throw and Catch blocks provided in Extend were employed. The Throw block in a product-manufacture task was used to manipulate and activate the Catch block in the appropriate ancillary task,

ensuring the correct co-ordination between these two separately modelled manufacturing tasks. In the equipment-preparation tasks, the equipment was routed back to the relevant product-manufacture task using the Throw and Catch blocks again. The “activation” function also determined if there were available resources in the resource pool to meet the required demand and to allocate the required resources.

The resources were then batched together and delayed by the specified processing time using the Activity, Delay block.

After completion of the task, a “cost calculation” function was performed to determine the total direct operating cost. This function used the DE Equation block to determine the direct costs of running the manufacturing task. The renewable resources were routed back to their respective resource pools while the non­

renewable ones are discarded. The Throw and Catch blocks were employed to return the resources back to the resource pool and the Exit block was used to discard the non-renewable resources. For resources that posses hybrid characteristics, the total number of cycles was coded within the manufacturing task to enable the appropriate computation of cost and when to dispose of the resource. For instance, the cost of chromatography matrices was only added to the operational cost during their first cycle of usage. When their cycle limit was reached, the resource was disposed of.

The task block also had a function to automatically update the status of the equipment resource and to invoke the post equipment-preparation tasks. For instance, the status of a ‘sterile’ fermenter switches to ‘dirty’ after the fermentation process. The status of a ‘dirty’ fermenter changes to ‘clean’ after the CIP process.

Figure 3.5 shows the libraries containing the common tasks in a mammalian cell culture biomanufacturing environment.

81

-Chapter 3. Design M ethodology and Implementation o f BioPharmKil

P r o d u c t-M a n u fa c tu r e T a s k s

\m

" C h r o m a to g r a p h y "

" M e m b ra n e filtra tio n "

E q u ip m e n t-P r e p a r a tio n T a s k s

" C le a n in g -in -p la c e

" S te rilis in g -in -p la c e "

" E q u ilib ra tio n "

" R e g e n e ra tio n "

R e g u la to r y -C o m p lia n c e T a s k s

" B a tc h d o c u m e n ta tio n "

Figure 3.5. Examples of manufacturing tasks in libraries. The task categories include the product-manufacture, equipment-preparation and regulatory-compliance tasks. Any component in a library can be copied and pasted onto the appropriate workspace.

3.7.1.1. P roduct-m anufacture tasks

The product-manufacture tasks, such as the fermentation and chromatography processes, come into direct contact with the antibody-based products. This category of tasks has the same characteristics as the manufacturing task category. In addition to the characteristics of the manufacturing task category, the product-manufacture task category possesses a function to perform mass balance calculations during the execution of the task. Appendix B shows the sequence of functions for a product- manufacture task and the detail of the “Check Equipment Status” function as an illustration of the coding within each function. Some tasks such as chromatography possess a function to determine the duration of the manufacturing steps. A special function is also created to allow the user to specify whether QC/QA steps are required for that particular task. In a typical biopharmaceutical plant, quality control and assurance is normally carried out for all major process steps. The default value to carry out QC/QA for a product-manufacture task is set to true. Since the batch documentation steps are carried out for mostly all tasks in the biopharmaceutical plant, they are coded as necessary tasks after finishing the product-manufacture tasks.

3.7.1.2. Equipment-preparation/Intermediate-material-preparation tasks

The CIP, SIP, equilibration, regeneration and re-equilibration processes make up the equipment-preparation activities in a biopharmaceutical plant. The equipment resource is processed in these tasks, prior to the start and after completion of a product-manufacture task. These tasks have the common characteristics as the manufacturing task category. The equipment item from a product-manufacture task was routed to these preparation tasks using the Throw and Catch blocks. Upon completion of the preparation process, the equipment status was then updated and returned back to the appropriate product-manufacture step or back to the resource pool. For example, a ‘clean’ chromatography column resource in the chromatography process is routed to the chromatography column equilibration preparation step. Its status is modified to ‘equilibrated’ and is then allocated back to the chromatography step. The status switches to ‘dirty’ at the end of the chromatography process step and is routed to the CIP task before returning back to the resource pool.

The intermediate-material-preparation tasks consist of material preparation activities such as media and buffer preparation. These tasks have the common characteristics as the manufacturing task category. Such tasks are triggered by the product- manufacture tasks. Upon activation of the preparation process, the utilisation level of the resource pool for the appropriate resource is adjusted.

3.7.1.3. Regulatory-compliance tasks

Manufacturing decisions are often complicated by the need to comply with the ever- increasing demands for regulatory conformation and the emphasis on QC/QA. These regulatory compliance activities are critical for controlling the consistency, quality and safety of biologies. Existing software packages often omit regulatory- compliance activities in a cGMP-manufacturing plant. Including these support activities is necessary to improve the ability of the model to estimate more accurately operative measures such as costs and resource utilisation. The prototype tool permits the incorporation of such cGMP activities, which are modelled as explicit ancillary tasks in their respective workspace (Figure 3.6).

8 3

-C hapter 3. Design M ethodology and Implementation o f BioPharmKit

R egu latory C o m p lia n c e R e cip e D etails

Sam ple QC/QA staff

"QC/QA"

Batch O perator

"Batch docum entation"

Regulatory-con recipe

Lot O perator

'Lot review"

Figure 3.6. A typical regulatory-compliance task recipe. The QC/QA step for all the manufacturing tasks is modelled as one unit operation. The same applies to the modelling of the batch documentation and lot review activity.

The regulatory manufacturing practices within the plant consist of in-process testing, batch documentation and lot review steps. These cGM P activities adopt the same attributes and functions from the manufacturing task category. The QC/QA step for all the manufacturing tasks was modelled as one unit operation. The same applied to the modelling of the batch documentation and lot review activities. The batch documentation activities were automatically activated at the end of each product- manufacture task while the QC/QA steps were triggered based on the user specifications. These regulatory-compliance steps were simulated concurrently with the main product-manufacture tasks. In a typical biomanufacturing plant, these regulatory activities are only carried out during specific working hours. A function was configured to customise the scheduling of these regulatory steps for operation only during a particular period. A Queue, Decisional block was employed to hold the item during out-of-operating work hours and release the item for processing only within operating hours.