Building PFDs for Biotech Processes

Course Overview and Information

• Subject Code: SCIE90011

• Subject Title: From Lab to Life

• Institution: The University of Melbourne, Faculty of Science

• Instructors:

  • A/Prof. Greg Kubik

  • Dr. Daniel Czech

  • Dr. Heshan Peiris

• Module Title: Building PFDs for Biotech Processes

Intended Learning Outcomes (ILOs)

By the conclusion of this lecture, students are expected to be able to:

• Define the concept of a Process Flow Diagram (PFD) and clearly distinguish it from related diagrams, such as Block Flow Diagrams (BFDs) and Piping and Instrumentation Diagrams (P&IDs).

• Identify the fundamental elements comprising a PFD, including unit operations, process streams, process boundaries, and major utilities.

• Construct a basic PFD for a biotechnology process that successfully integrates upstream and downstream processing steps.

• Explain how PFDs serve as essential tools for communication, design iteration, and subsequent Techno-Economic Analysis (TEA) and Life Cycle Assessment (LCA).

• Implement pedagogical conventions and best practices to ensure PFDs are readable, useful, and professional.

Defining the Process Flow Diagram (PFD)

• Working Definition: A Process Flow Diagram is a schematic representation of a process that:

  • Illustrates the main unit operations (encompassing both specific equipment and major procedural steps).

  • Visualizes the primary material flows connecting these operations.

  • Represents the process structure at a level of detail appropriate for:

    • Understanding the end-to-end functionality of the process.

    • Identifying points where material enters the system, undergoes transformation, or exits the system.

    • Supporting the development of approximate mass and energy balances.

Comparative Hierarchy of Process Diagrams

Process representation occurs at varying levels of complexity:

• Block Flow Diagram (BFD):

  • Represents a very high-level overview.

  • Consists of a few simple blocks (e.g., "Upstream," "Downstream").

  • Primary use context: Early concept discussions and high-level strategy.

• Process Flow Diagram (PFD):

  • Indicates intermediate detail.

  • Shows the main equipment and specific unit operations.

  • Illustrates all major material streams and distinct process sections.

  • Primary use context: Serving as the basis for TEA, LCA, and functional design discussions.

• Piping and Instrumentation Diagram (P&ID):

  • Provides high-detail plant drawings.

  • Exhaustively depicts equipment, pipes, valves, instruments, and control loops.

  • Primary use context: Detailed engineering phases, construction, and operational maintenance.

The Strategic Importance of PFDs

PFDs act as the central nervous system of process design because they:

• Facilitate a Shared Visual Language: They bridge the communication gap between diverse stakeholders, including biologists, engineers, quality assurance personnel, TEA/LCA analysts, and management.

• Enable Whole-Process Thinking:

  • They demonstrate how upstream (cell culture/fermentation), downstream (recovery/purification), and finishing (formulation) steps interface.

  • They help reveal bottlenecks, critical process steps, and integration challenges.

• Provide Data Support for:

  • Mass Balances: Tracking the movement and conservation of material.

  • Techno-Economic Analysis (TEA): Identifying required equipment, volumes, throughput capacities, and consumables.

  • Life Cycle Assessment (LCA): Quantifying material and energy flows for environmental impact studies.

  • Risk and Robustness Analysis: Identifying locations where potential failures could propagate through the system.

Core Elements: Unit Operations

• Representation: Each major process step is represented as a box. Individual steps are categorized within these units.

• Typical Biotech Unit Operations:

  • Upstream: Media preparation, Seed Bioreactor, Production Bioreactor.

  • Primary Recovery: Centrifuge, Micro Filtration, Ultra Filtration.

  • Purification: Chromatography, Diafiltration.

  • Formulation / Finishing: Formulation tank, Sterile filtration, Aseptic filling.

• Design Conventions for Unit Operations:

  • Use concise and descriptive labels (e.g., "Seed Reactor 1", "Protein A Column").

  • Align boxes logically according to process order, typically moving from left to right or top to bottom.

Core Elements: Process Streams

Streams represent the flow of material between unit operations and are categorized as:

• Inputs: Raw materials, media, and buffers.

• Intermediates: Harvested broth, clarified feed, and elution fractions.

• Outputs: Final products and waste streams.

• Identification Methods:

  • Numbering: (e.g., $S-101$, $S-102$).

  • Naming: (e.g., "Harvest broth", "Product eluate").

• Physical and Quantitative Characteristics:

  • Composition: The specific chemical or biological makeup.

  • Flowrate: The quantity of material per unit of time or per batch.

  • State: The physical phase (liquid, solid, gas), temperature, and pressure.

• Example Quantitative Stream Data:

  • Stream $H-101$ (Crude broth): $100\,L$, Temperature $8\,^{\circ}C$.

  • Stream $P-101$ (Cleared broth): $80\,L$, Temperature $8\,^{\circ}C$.

  • Stream $W-101$ (Wet biomass): $20\,kg$.

  • Stream $W-102$ (Retentate/biomass): $5\,L$.

Core Elements: Process Boundaries

It is critical to define what occurs inside versus outside the modeled system:

• Inside the Boundary: All core unit operations necessary for production, recovery, purification, and formulation/finishing.

• Outside the Boundary:

  • Supplier Processes: The production of raw materials before they reach the facility.

  • Downstream Distribution: The logistics of getting the product to the user.

  • End-of-life Disposal: Generally excluded from PFDs unless the LCA boundary is explicitly extended.

• External Interfaces:

  • External Inputs: Raw materials, media, utilities, packaging, and device components.

  • External Outputs: Final product to the consumer, emissions, and waste streams designated for treatment.

Core Elements: Utilities

Utilities are often not fully drawn as lines but are noted or annotated because they impact capacity and cost. Key utilities include:

• Heating and Cooling: Steam (for sterilization and heating), cooling water, or chilled water.

• Gases: Compressed air, Nitrogen ($N_2$), and Carbon Dioxide ($CO_2$).

• Water Systems: Water for Injection (WFI) and Purified Water.

• Cleaning Systems: Clean-in-Place (CIP) and Steam-in-Place (SIP) systems.

• Impact: Utilities determine process feasibility, energy/water costs in TEA, and the environmental footprint in LCA.

Step-by-Step Methodology for Building a PFD

1. Understand the Product: Clarify the final form (e.g., bulk drug substance vs. filled syringes). Recall the User Requirement Specifications (URS) and Critical Quality Attributes (CQAs) such as potency, purity limits, stability, and sterility.

2. Identify Major Sections (BFD Level): Define the high-level flow (e.g., Upstream to Formulation).

3. List Unit Operations: Break down each major section into specific equipment steps.

4. Connect with Streams: Draw flows and define material movement.

5. Check Completeness and Consistency: Ensure all feeds and wastes are accounted for. For "Level 2" PFDs, add details like holding tanks or recycle loops.

Case Study: Limonene Recovery Process

An example PFD for Limonene recovery illustrates the integration of fermentation and purification:

• Overall Limonene Recovery: $84.05\%$.

• Inputs:

  • Feed (Molasses): $436.27\,kg/h$.

  • Air: $562.5\,m^3/h$.

• Unit Operations in Series:

  • Air Compressor $\rightarrow$ Fermenter (venting Limonene $12.65\,kg/h$, Air $715.82\,kg/h$, Water $17.64\,kg/h$).

  • LLE (Liquid-Liquid Extraction) Unit: Receives broth/limonene mixture (Limonene $67.35\,kg/h$; Broth/Water $52073.00\,kg/h$).

  • Decanter and Centrifuge: Used for phase separation.

  • Distillation Column: Separates organic mixture (Limonene $67.35\,kg/h$; Dodecane $3835.30\,kg/h$).

• Distillation Results:

  • Light key (Purified Limonene at $96\%$): Limonene $66.67\,kg/h$, Dodecane $2.78\,kg/h$.

  • Heavy key (Regenerated Dodecane): Limonene $0.67\,kg/h$, Dodecane $3832.52\,kg/h$.

Tools for PFD Construction

• Microsoft Visio: A standard industry tool for diagramming.

• draw.io (diagrams.net): A free online alternative providing various shapes for process engineering, vessels, and pumps.

• Key Software Features: Use "Proc. Eng." shapes, grids for alignment, and consistent connection points to maintain professional clarity.

Best Practices Summary

• Clarity: Use simple boxes or pictograms.

• Logic: Maintain a left-to-right flow direction.

• Consistency: Use uniform labels and logical stream numbering.

• Transparency: Explicitly show boundaries and external feeds/products.

• Criticality: Highlight operations like viral inactivation or steps with major yield loss.

• Iteration: Revise the PFD as URS, CQAs, and process understanding evolve.