1. Module 8: Lyophilization Design Introduction

2. Module 8 Purpose and Objectives
Design considerations will be discussed. Commercial lyophilizers are custom built even by the major vendors and within their model names.
Module Objectives:
After this module, you will be able to
Ask questions of the manufacturers related to design.

3. Major Elements Refrigeration Vacuum Process Air/Nitrogen
Shelf mechanics
Chambers
CIP
Steam Sterilization
Isolation Valve
PLC/HMI Control System

4. Lyo Refrigeration The refrigeration skid has 2 tasks.
Keep the lyo-condenser (evaporator) cold &
Use coolant as needed for the shelfs.
This is a typical (simple) redundant system.
Each compressor cools its own lyo-condenser coil (evaporator) by direct expansion.
Each compressor cools a inline (in series) heat exchanger for the shelf system.
Piece identification:
Compressor – 2 stage, compresses the gases, sending hot gas to the aqueous cooled condenser.
Condenser – chills the hot compressed gas using either chilled water (best) or city water and makes it a liquid.
Dryer – The one depicted is a liquid line combination filter and activated charcoal desiccant. Refrigerants have as break down products, acids that can be adsorbed out of the system. Polyolester lubricants (POE) refrigerants are also aggressive solvents, quite hygroscopic, and they tend to pick up particles, so filtration is desireable. Moisture in the system promotes hydrolysis and acid formation. The three most common desiccants are molecular sieve, activated alumina, and silica gel.
Molecular sieves are crystalline sodium aluminosilicates (synthetic zeolites) having cubic crystals, which selectively adsorb molecules based on molecular size and polarity. The crystal structure is honeycombed with regularly spaced cavities or pores. Each of these cavities or pores are uniform in size. This uniformity eliminates the co-adsorption of molecules varying in size. This permits molecules, such as water, to be adsorbed, while allowing other larger molecules, such as the refrigerant, lubricant and acids, to pass by. The surface of this desiccant is charged positively with cations, which act as a magnet and will therefore adsorb polarized molecules, such as water, first and hold them tightly. The water molecules are physically separated from the lubricant, minimizing the potential for POE hydrolysis.
Activated alumina is formed from aluminum oxide (Al2O3) and is not a highly crystalline material. Both alumina and silica gel show a wide range of pore sizes and neither exhibit any selectivity based on molecular size. Due to the varying pore sizes, they can co-adsorb the much larger refrigerant, lubricant and acid molecules, eliminating the surface area available to adsorb water. Alumina can also aid in the hydrolysis of the POE lubricants creating organic acids since both water and lubricant are adsorbed into the pore openings of
the alumina.
Silica gel is a non-crystalline material with a molecular structure formed by bundles of polymerized silica (SiO2). Gel-type desiccants are indicative of the weaker bond formed between water and the desiccant. Silica gel is the old type of desiccant and is not widely used in today’s filter dryers.

5. Compressor
The Mechanical compression of the gaseous refrigerant is pressurized to move or “pump” the refrigerant through the system.

6. Dual Refrigerant System
Another application for Clausius-Clapeyron
Liquid
Liquid
Gas
Gas

7. Cascade Compressor
This is how compressors can achieve temperatures of -100C in the lyo condenser.

8. 2-Stage Compressor
Two Stage Compressors usually use just one refrigerant.
Compression is done in two stages separated by a mixing chamber.
After the first expansion, a liquid-vapor mix is present.
Since the system is under pressure, the gas portion of the flash chamber goes to the high side compressor.
And the liquid continues to a second expansion valve.
Other solutions to this problem exist.

9. Two Stage Compressor
Flash Chamber would be internal to the compressor.

10. Compressor Condenser
Purpose is to make liquid out of the hot compressed gas that comes from the compressor.
The condenser is a simple heat exchanger.
The heat is removed by tap water or chilled water.

11. Filter Dryer
Desiccant:
Molecular Sieve
Activated Alumina
Silica Gel

12. Expansion Valve When bulb pressure expands, the valve will open.
B/C. Evaporation Pressure (Temp) and Spring Pressure will close the valve.

13. Evaporator Lyo Condensers
Internal vs External
Coil vs Plate
Baffles: Must cause vapor to pass over condensers.

14. Vacuum

15. ‘Roots Pump’ [Rotary Lobe]
Courtesy of Mr. Philander Roots (ca1868).
Pump is very efficient high volume low P and runs with close tolerance, and no oil.
May be used as an isolator between the condenser and the oil diffusion pump to control backstreaming.

16. Rotary Vane Vacuum Pump
We pump by volumetric flow in units of L/s or cfm.
Ultimate pressure (or vacuum) is the pressure achieved by the pump when its inlet is capped.

17. Rotary Vane
Requires Lubrication of the contact between vane and housing.

18. Pipe Conductance
Conductance is the transmission of gas through a pipe in unit time. While having the same units as pump speed, it isn’t the same.
Conductance is 1/resistance (of course).
Conductance for circular pipe with elbows is usually looked up in “Dushman” tables. Scientific Foundations of Vacuum Technique by Saul Dushman 2nd edition (J.J. Laffery - ed) John Wiley & Sons. 1962
Conductance is important because it limits the speed that we can evacuate the system.
Although conductance can be theoretically calculated, it usually isn’t. It is analogous to an electrical engineer trying to calculate the resistance of an insulator prior to putting it into a circuit. Look it up in a table.
Conductance Limits Pump Speed.
There are two places that conductance matters and we are only going to focus on one of them – the foreline.
The other one is the isolation valve. Bigger is better – without end – amen.

19. Effective Pump Speed
The pipe section with the smallest conductance will determine the maximum conductance.
A pipe is a resistor in a linear circuit.
Effective Pump Speed = S
In this example, Rated Pump Speed = Pump Capacity = Sm.
As you can see, calculating effective pump speed is similar to calculating conductance in an electrical circuit.
Indeed, a pipe is a resistor in a linear circuit.
Since pipe resistance matters – use short fat straight pipes.
In this example, the rated pump speed is 200 cfm but the forline conductance is barely ½ of that. Consequently, gas is removed from the chamber as if the pump speed were 31.3 L/s = 66 cfm. Even using a very much larger and more expensive pump would not matter.

20. Pump Down Time
Estimate the time to pump a chamber (8400 L) from atmospheric to 13 Pa (98 mmHg = 98 mTorr = 98 microns). S = 31.3 L/s
The effective pump speed can be used to find the time to go from atmospheric pressure to any new pressure.
I am not going through this math. There is plenty later.

21. Work Together Exercise
A new lyophilizer will be installed as a split skid, with the vacuum and refrigeration separate from the chamber and condenser. Management has decided that due to real estate, the R/V skid will be put into an adjacent room. You have determined that the minimum pipe run from lyo condenser to the vacuum pump is 30 feet. Chamber+Cond volume is 8500 L, and the vacuum system is rated for 450 m3/hr. What pipe diameter will be needed to pump down the system in 30 minutes from atm to 100 mTorr.

22. Answer Part 1
Find the overall Throughput (Effective Pump Speed) needed to meet the conditions of the problem.
This number won’t change. It doesn’t involve the pump or the pipe.

23. Answer Part 2
Find the Pipe Conductance needed to meet the Effective Pump Speed.
This value doesn’t involve distance. You could get there by moving the pump closer.

24. Answer Part 3
Knowing the pipe conductance and the necessary run length, estimate the pipe diameter. (note: bends & valves decrease the conductance value – this is an estimate.)
This cubic equation relates pipe diameter to pipe conductance and pipe length. It isn’t fun to solve with algebra.

25. Answer Part 4
Always use a consistent set of units throughout.

26. Answer Part 5
Procurement got a deal on 4” pipe. How long will it take to pump down?

27. Process Air & Nitrogen
Valve these together and input to the sterile filter.

28. Shelf Mechanics
Set up the RAM to be both Manual and PLC/HMI controlled.

29. Chambers Round vs Rectangular External Condenser behind, under, above?
If rectangular, then slope to drain.
External Condenser behind, under, above?
Number and size of penetrations
Door opening mechanism
Door might deserve its own design.

30. Lyo Condenser
Condenser surface area should be large enough to keep the ice thickness less than 0.5 cc. It will still be thicker in some spots and thinner in others.
Common request is for condenser capacity to equal the total shelf area by 1 inch deep.

31. Clean In Place
Use a dye such as riboflavin to commission. Expect to need to move or reposition nozzles.

32. Steam in Place
Steam needs to go to every path that will be open at any time during the lyophilization.

33. Liquid Ring Pump

34. Isolation Valve Determine the type of open/close mechanism.
The rate of closing could become an issue in the future. Although MTM is not currently used on commercial units, it would provide a “no thermocouple” (think PAT) method for measuring ice surface temperature. It requires a rapid (<0.5 sec) valve closure.

35. Isolation Valve
Size the valve large enough to permit adequate sublimation without choked flow.

36. PLC/HMI Control Choose an HMI that is convenient.
For example: Intellution / Wonderware
Assure 21 CFR Part 11 Compliance
The vendor will pick the PLC, but you will pick the vendor. Ergo, there is some choice of PLCs.

37. Module 8 Quiz Question 1 of 2
During primary drying, it was noted that the condenser pressure was much higher (150mT) than the chamber pressure (75 mT). Why?
The gas molecules are limited to the speed of sound, but need to go faster for pressure equilibrium.
The cycle called for 2 different pressures in chamber and condenser.
Too much ice on the condensers is causing them to warm up.
Pressures are higher when you measure closer to the vacuum source.

38. Module 8 Quiz Question 2 of 2
B. The first programmed step in primary dry was a temperature hold at -50C (the shelf freezing temperature) for 30 minutes. Purpose was to let the vacuum ‘settle in’ before starting a ramp. In fact, the primary ramp never started. Why?
A. System vacuum was undersized to overcome the water vapor pressure when the system is at -50C. Consequently, the vacuum set point could not be attained until the shelf ramp started and thus the hold segment couldn’t start.
B. Product vapor pressure at the chosen vacuum level caused the product temperature to be approximately -36C. That high temperature in contact with the shelves kept the shelf temperature high and prevented the -50C set point from being obtained. Therefore, the system couldn’t complete the segment.
C. In most systems, the condensers cool down when the vacuum starts (start of primary). Compressor power was insufficient to cool condensers and shelves to -50C, so the shelf set point for the segment wasn’t obtained. Ergo, the segment to hold at -50.

39. Module 8 What to Remember
Understand the system refrigeration well enough to relate anomalies back to the refrigeration. At least ½ of all cycle problems trace to temperature control.
No pump can overcome small diameter pipe. If the vacuum pumps are too far away or have small diameter pipe (3” is small), then they will evacuate the system very slowly. Putting on a bigger pump (e.g. Roots pump) can’t help.
Manual valves (not PLC controlled) contribute to human error. For example, manual air/N2 valves require an operator to select the correct cycle and to open the correct valves. Reduce errors through automation.
Steam must go through every input line to achieve sterility.
Find out if choked flow can be attained for the system. If so, then that limits how aggressive a cycle can get.