Generic Batch Procedures for Flexible Manufacturing

Transforming a pharmaceutical manufacturing facility from a multiple-campaign, multiple established product-based operation, to one that can also accommodate single-development product campaigns is a challenge. Even so, this feat was accomplished successfully at one of Eli Lilly’s bulk pharmaceutical production buildings. See diagram.

03/01/2009


Transforming a pharmaceutical manufacturing facility from a multiple-campaign, multiple established product-based operation, to one that can also accommodate single-development product campaigns is a challenge. Even so, this feat was accomplished successfully at one of Eli Lilly’s bulk pharmaceutical production buildings. Historically, this production building provided full batch control of the processes and ran multiple campaigns of the same products. However, due to a shift in the product mix at the site, this facility was also called upon to run single campaigns of development products. These single-run campaigns require a higher level of manufacturing flexibility involving the options available to modify the process as necessary, while maintaining the highest available quality and throughput. The challenge was to maintain the existing ISA88 compliant control system structure for existing product campaigns, while accommodating the needs of development product processing into the control system framework, and continuing to minimize the risk of operator error. [Read about the Eli Lilly and Company Comprehensive Compliance Program . ]

Traditional full batch control creates a sequence of the entire process-specific recipe. This is fine for products you make again and again, but is not flexible enough for single-development product campaigns. Generic batch offers greater flexibility, but without the operator error pitfalls of manual procedures.

Traditional full batch control creates a sequence of the entire process-specific recipe. This is fine for products you make again and again, but is not flexible enough for single-development product campaigns. Generic batch offers greater flexibility, but without the operator error pitfalls of manual procedures.

The active pharmaceutical ingredient (API) manufacturing facility in question has processed multiple products in multiple repeated campaigns over the last 20+ years. Its general control and operational philosophy was full batch control during product processing, and “manual-matic” control during setups and cleandowns. In manual-matic control, the equipment is automated via equipment modules, with the operator responsible for initializing and starting the required modules, using the desired parameter values in the correct sequence. A typical reactor has equipment modules configured for vent/pressure, temperature, agitation, charge header, discharge header, and recirculation/sample loop control. Utilizing full batch control for all product processing engrained an associated culture in the facility operating personnel. The operators typically relied on batch control and only knew this approach for product processing. Operators rarely used lower level techniques such as manual-matic control for processing and usually called upon separate automation support personnel these occurrences.

Changing culture

Accommodating flexibility for the new mission would challenge all established manufacturing concepts. Development products require flexibility and nimbleness on the part of the manufacturing facility and all of its support systems, including the control infrastructure. To keep the changes more manageable, the facility was divided such that half would be dedicated to products that require multiple repeated processing campaigns, while the other half would be dedicated to development products with single short processing campaigns.

Early on, the batch control automation development and configuration step emerged as both costly and a potential bottleneck when preparing and executing a setup for a new development product campaign. This proved especially true if the new development process had significant modifications before or during the setup, and when implementing process modifications during the campaign. A project team was assembled to formulate a strategy for implementing flexible control for the development side of the building.

Since manual-matic control was already available via equipment modules on every reactor and other equipment such as centrifuges, scrubbers, and vacuum pumps, the project team initially focused on changing the operating culture through more detailed documentation (e.g., manufacturing tickets and patrol lists) and operator refresher training for using the equipment module layer in the control system. However, the team realized that manual-matic control required significant operator interaction and decided to attack that issue.

Creating new methods

The project team set out to develop a control system component that could encompass a complex sequence of equipment module manipulations over a single unit (i.e., a reactor) or multiple units. This component would not be process specific, so it would not be full batch control in the normal sense, but it would be sequence specific, allowing operators to input the values for process parameters as applicable. This new creation was christened a generic batch or unit procedure. These are non-process specific batch or unit procedures, and provide a fixed sequence for a complex operation. They reside in the batch application layer of the software and allow an operator to specify the process parameter input values when creating a given batch or unit procedure (see “Alternative control heirarchies” graphic.)

The team foresaw the need to implement a limited process-specific batch procedure when required for a high-risk safety portion of a process. This approach was designated a mini batch procedure and can provide traditional full batch control, but only for a portion of the process.

With those new additions, there are now four control procedure levels available:

  • Manual-matic control—Single general task function via equipment modules (automated groups of devices, e.g., for reactor temperature or pressure control).

  • Generic batch control—Sequencing of multiple units for a complex operation or sequencing of a significant unit operation. Process parameter inputs available upon initiation.

  • Mini batch control—Sequencing of a portion of the process-specific recipe, particularly for high-risk safety operations.

  • Full batch control—Traditional sequencing of entire process-specific recipe.

The objective of generic batch and unit procedures is to minimize the potential for operator entry error and standardize the sequence for a complex operation. A typical complex operation using manual-matic control involves manipulation of multiple equipment modules several times for a given process step, including changing or verifying several equipment module input parameters. A generic batch procedure reduces the overall number of operator entries by fixing the sequence, eliminating parameter entries that should not change value for a standard approach, and eliminating the need to verify all equipment module parameter values when starting an equipment module. Generic batch and unit procedures were developed for a group of complex operations:

  • Vacuum distillation from tank to tank, or from tank to distillate receiver;

  • Atmospheric distillation from tank to tank, or from tank to distillate receiver;

  • Transfer from tank to tank;

  • Setup of a tank;

  • Idling of a tank;

  • Tank dry-up;

  • Tank load cell check; and

  • Thermal cycling of tank contents.

When working with generic batch procedures, operators enter parameters during batch creation by promoting parameters, or deferring lower level parameters to higher level. The beauty of this method is that an operator can combine several lower level parameters to a single common batch or unit procedure level parameter by promotion. This can reduce the input parameter set the operator has to deal with (see screen graphic.) Each parameter can be modified during this batch creation step prior to loading the particular batch.

For a typical development process, simple operations or single general task functions are executed using equipment modules, while complex operations are executed via generic batch or unit procedures.

The operational and reference documentation to accommodate generic batch and unit procedures was modified significantly, and updated to include enough detail to ensure an average operator (or even a below-average operator) could easily understand the required input parameters and sequencing involved. A job aid was created to show the sequence involved and input parameter utilization within a generic batch or unit procedure. Additionally, the patrol list (which accompanies the processing ticket and provides more specific details to the operator) was updated to show where to use specific procedures and to indicate the input parameter values required via tables.

Generic batch and unit procedures have minimized the amount of interaction required between the operator and the control system during complex operations. They provide a more consistent approach to complex operations when compared to lower level control system elements such as equipment and control modules, and reduce the potential for operator error. This new control system component has been successful through several steps of a development product and will be a feature of future development product campaigns.


Author Information

Aaron Wood is an associate engineering consultant for Eli Lilly & Company. Reach him at wood_aaron_r@lilly.com .




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