Selection, Scale-up, Operation and Control of

Bioreactors

ChE 3BK3October 22, 2004

Chapter 10, Shuler & Kargi

MidtermWorth 25% of the final markHeld in class (MDCL 1010), Friday, October 29th, 9:30-10:20amCovers Chapters 1,2,3,6,7,9 (lectures 1-16)Open textbook, open notesFormat: 3 questions, total of 40 marks• Budget 1 minute per mark (so you should finish a 15

mark question in 15 minutes)• Questions are problems similar to those you have seen

on the assignments• Know the algorithm used to solve problems on each of

the topics we have covered to date

Outline

Scale upSample calculations

Scale UpRecall that fermenters growing microbial cultures typically have a height-to-diameter ratio of 2-3:1; 1:1 for animal cell culture• However, if the H:D ratio remains constant, then the

surface-to-volume ratio decrease dramatically during scale-up

• This decreases the relative contribution of surface aeration vs sparging to oxygen supply

• For traditional bacterial fermentations, surface aeration is unimportant, but for shear-sensitive cultures, it can be critical because of restrictions on sparging and stirring

Scale UpA more important consideration in bacterial and fungal fermentations is wall growth• If cells adhere to surfaces, it can be difficult to predict

performance in a large fermenter from data at the small scale

Even more critical is the fact that the physical conditions in a large fermenter can never exactly duplicate those in a smaller fermenterif geometric similarity is maintained• Depending on the sensitivity of a given organism

to changes in its environment, this can result in dramatic differences in physiology, metabolism and performance on scale-up

Scale UpScale up rules can be used to establish which parameters will be varied and howRules:• Constant power input (P0/V)

• Implies constant oxygen transfer rate (OTR)• Constant impeller rotation number (N)

• Gives constant mixing times• Constant speeds at the impeller tip (N·Di)

• Gives constant shear • Constant Reynold’s number (Re)

• Gives geometrically similar flow patterns

Interdependence of Scale-Up Parameters

Scale UpIn practice, scale up is highly empirical, meaning that the operating parameters for the larger scale are often determined experimentally (i.e. trial and error)Common to design for a constant kLa value, or constant substrate (e.g. DO) or product level on scale-up• For example, if DO is a constant, then the setpoint

value for DO is maintained at the larger scale, and other parameters (agitation speed, aeration rate, gas mixture) are varied to ensure the setpoint is achieved

Scale Up Problems

Predictable• Mixing times• Oxygen transfer• Heat transfer• Power input• Aeration rates

Difficult to predict• Product quality (e.g. protein degradation)• Foaming• By-product formation

Economic Considerations on Scale Up

Relative cost of changes at various stages of scale up:• Pre-design phase 1• Design phase 10• Construction phase 100• Plant in operation 1000

Reactor types (CSTRs, bubble columns, loop bioreactors)Changes in medium composition (serum-free)

Practical Operating Boundaries for Aerated, Agitated Fermenters

Example 10.2

Example 10.2 - Solution

Example 10.3

Example 10.3 - Solution

Example 10.3 - Solution